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Sample records for opioid peptides

  1. Chimeric opioid peptides: tools for identifying opioid receptor types.

    OpenAIRE

    Xie, G X; Miyajima, A; Yokota, T; Arai, K; Goldstein, A

    1990-01-01

    We synthesized several chimeric peptides in which the N-terminal nine residues of dynorphin-32, a peptide selective for the kappa opioid receptor, were replaced by opioid peptides selective for other opioid receptor types. Each chimeric peptide retained the high affinity and type selectivity characteristic of its N-terminal sequence. The common C-terminal two-thirds of the chimeric peptides served as an epitope recognized by the same monoclonal antibody. When bound to receptors on a cell surf...

  2. Chimeric opioid peptides: Tools for identifying opioid receptor types

    International Nuclear Information System (INIS)

    Xie, G.; Miyajima, A.; Yokota, T.; Arai, K.; Goldstein, A.

    1990-01-01

    The authors synthesized several chimeric [125J-labelled] peptides in which the N-terminal nine residues of dynorphin-32, a peptide selective for the κ opioid receptor, were replaced by opioid peptides selective for other opioid receptor types. Each chimeric peptide retained the high affinity and type selectivity characteristic of its N-terminal sequence. The common C-terminal two-thirds of the chimeric peptides served as an epitope recognized by the same monoclonal antibody. When bound to receptors on a cell surface or membrane preparation, these peptides could still bind specifically to the monoclonal antibody. These chimeric peptides should be useful for isolating μ, δ, and κ opioid receptors and for identifying opioid receptors on transfected cells in expression cloning procedures. The general approach using chimeric peptides should be applicable to other peptide receptors

  3. Distinct roles of exogenous opioid agonists and endogenous opioid peptides in the peripheral control of neuropathy-triggered heat pain.

    Science.gov (United States)

    Labuz, Dominika; Celik, Melih Ö; Zimmer, Andreas; Machelska, Halina

    2016-09-08

    Neuropathic pain often results from peripheral nerve damage, which can involve immune response. Local leukocyte-derived opioid peptides or exogenous opioid agonists inhibit neuropathy-induced mechanical hypersensitivity in animal models. Since neuropathic pain can also be augmented by heat, in this study we investigated the role of opioids in the modulation of neuropathy-evoked heat hypersensitivity. We used a chronic constriction injury of the sciatic nerve in wild-type and opioid peptide-knockout mice, and tested opioid effects in heat and mechanical hypersensitivity using Hargreaves and von Frey tests, respectively. We found that although perineural exogenous opioid agonists, including peptidergic ligands, were effective, the endogenous opioid peptides β-endorphin, Met-enkephalin and dynorphin A did not alleviate heat hypersensitivity. Specifically, corticotropin-releasing factor, an agent triggering opioid peptide secretion from leukocytes, applied perineurally did not attenuate heat hypersensitivity in wild-type mice. Exogenous opioids, also shown to release opioid peptides via activation of leukocyte opioid receptors, were equally analgesic in wild-type and opioid peptide-knockout mice, indicating that endogenous opioids do not contribute to exogenous opioid analgesia in heat hypersensitivity. Furthermore, exogenously applied opioid peptides were ineffective as well. Conversely, opioid peptides relieved mechanical hypersensitivity. Thus, both opioid type and sensory modality may determine the outcome of neuropathic pain treatment.

  4. Mycobacteria attenuate nociceptive responses by formyl peptide receptor triggered opioid peptide release from neutrophils.

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    Heike L Rittner

    2009-04-01

    Full Text Available In inflammation, pain is regulated by a balance of pro- and analgesic mediators. Analgesic mediators include opioid peptides which are secreted by neutrophils at the site of inflammation, leading to activation of opioid receptors on peripheral sensory neurons. In humans, local opioids and opioid peptides significantly downregulate postoperative as well as arthritic pain. In rats, inflammatory pain is induced by intraplantar injection of heat inactivated Mycobacterium butyricum, a component of complete Freund's adjuvant. We hypothesized that mycobacterially derived formyl peptide receptor (FPR and/or toll like receptor (TLR agonists could activate neutrophils, leading to opioid peptide release and inhibition of inflammatory pain. In complete Freund's adjuvant-induced inflammation, thermal and mechanical nociceptive thresholds of the paw were quantified (Hargreaves and Randall-Selitto methods, respectively. Withdrawal time to heat was decreased following systemic neutrophil depletion as well as local injection of opioid receptor antagonists or anti-opioid peptide (i.e. Met-enkephalin, beta-endorphin antibodies indicating an increase in pain. In vitro, opioid peptide release from human and rat neutrophils was measured by radioimmunoassay. Met-enkephalin release was triggered by Mycobacterium butyricum and formyl peptides but not by TLR-2 or TLR-4 agonists. Mycobacterium butyricum induced a rise in intracellular calcium as determined by FURA loading and calcium imaging. Opioid peptide release was blocked by intracellular calcium chelation as well as phosphoinositol-3-kinase inhibition. The FPR antagonists Boc-FLFLF and cyclosporine H reduced opioid peptide release in vitro and increased inflammatory pain in vivo while TLR 2/4 did not appear to be involved. In summary, mycobacteria activate FPR on neutrophils, resulting in tonic secretion of opioid peptides from neutrophils and in a decrease in inflammatory pain. Future therapeutic strategies may aim

  5. Endogenous opioid peptides as neurotransmitters in the rat hippocampus

    International Nuclear Information System (INIS)

    Neumaier, J.F.

    1989-01-01

    The role of endogenous opioid peptides as neurotransmitters in the rat hippocampus was investigated by using extracellular recording and radioligand binding techniques in the hippocampal slice preparation. Synaptic conductances from endogenously released opioid peptides have been difficult to detect. This problem was approach by designing a novel assay of opioid peptide release, in which release was detected by measuring binding competition between endogenous opioids and added radioligand. Membrane depolarization displaced [ 3 H]-diprenorphine binding in a transient, calcium-dependent, and peptidase-sensitive manner. Autoradiographic localization of the sites of [ 3 H]-diprenorphine binding displacement showed that significant opioid peptide release and receptor occupancy occurred in each major subregion of the hippocampal slices. This assay method can not be used to define optimal electrical stimulation conditions for releasing endogenous opioids. The binding displacement method was extended to the study of the sigma receptor. Depolarization of hippocampal slices was found to reduce the binding of the sigma-selective radioligand [ 3 H]-ditolylguanidine in a transient and calcium-dependent manner with no apparent direct effects on sigma receptor affinity

  6. Biased Agonism of Endogenous Opioid Peptides at the μ-Opioid Receptor.

    Science.gov (United States)

    Thompson, Georgina L; Lane, J Robert; Coudrat, Thomas; Sexton, Patrick M; Christopoulos, Arthur; Canals, Meritxell

    2015-08-01

    Biased agonism is having a major impact on modern drug discovery, and describes the ability of distinct G protein-coupled receptor (GPCR) ligands to activate different cell signaling pathways, and to result in different physiologic outcomes. To date, most studies of biased agonism have focused on synthetic molecules targeting various GPCRs; however, many of these receptors have multiple endogenous ligands, suggesting that "natural" bias may be an unappreciated feature of these GPCRs. The μ-opioid receptor (MOP) is activated by numerous endogenous opioid peptides, remains an attractive therapeutic target for the treatment of pain, and exhibits biased agonism in response to synthetic opiates. The aim of this study was to rigorously assess the potential for biased agonism in the actions of endogenous opioids at the MOP in a common cellular background, and compare these to the effects of the agonist d-Ala2-N-MePhe4-Gly-ol enkephalin (DAMGO). We investigated activation of G proteins, inhibition of cAMP production, extracellular signal-regulated kinase 1 and 2 phosphorylation, β-arrestin 1/2 recruitment, and MOP trafficking, and applied a novel analytical method to quantify biased agonism. Although many endogenous opioids displayed signaling profiles similar to that of DAMGO, α-neoendorphin, Met-enkephalin-Arg-Phe, and the putatively endogenous peptide endomorphin-1 displayed particularly distinct bias profiles. These may represent examples of natural bias if it can be shown that they have different signaling properties and physiologic effects in vivo compared with other endogenous opioids. Understanding how endogenous opioids control physiologic processes through biased agonism can reveal vital information required to enable the design of biased opioids with improved pharmacological profiles and treat diseases involving dysfunction of the endogenous opioid system. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  7. Combined autoradiographic-immunocytochemical analysis of opioid receptors and opioid peptide neuronal systems in brain

    Energy Technology Data Exchange (ETDEWEB)

    Lewis, M.E.; Khachaturian, H.; Watson, S.J.

    1985-01-01

    Using adjacent section autoradiography-immunocytochemistry, the distribution of (TH)naloxone binding sites was studied in relation to neuronal systems containing (Leu)enkephalin, dynorphin A, or beta-endorphin immunoreactivity in rat brain. Brain sections from formaldehyde-perfused rats show robust specific binding of (TH)naloxone, the pharmacological (mu-like) properties of which appear unaltered. In contrast, specific binding of the delta ligand (TH)D-Ala2,D-Leu5-enkephalin was virtually totally eliminated as a result of formaldehyde perfusion. Using adjacent section analysis, the authors have noted associations between (TH)naloxone binding sites and one, two, or all three opioid systems in different brain regions; however, in some areas, no apparent relationship could be observed. Within regions, the relationship was complex. The complexity of the association between (TH)naloxone binding sites and the multiple opioid systems, and previous reports of co-localization of mu and kappa receptors in rat brain, are inconsistent with a simple-one-to-one relationship between a given opioid precursor and opioid receptor subtype. Instead, since differential processing of the three precursors gives rise to peptides of varying receptor subtype potencies and selectivities, the multiple peptide-receptor relationships may point to a key role of post-translational processing in determining the physiological consequences of opioid neurotransmission.

  8. Radioreceptor assay of opioid peptides in selected canine brain regions

    Energy Technology Data Exchange (ETDEWEB)

    Desiderio, D.M.; Takeshita, H.

    1985-09-01

    A radioreceptor assay using the opioid delta receptor-preferring ligand D-/sup 2/ala, D-/sup 5/leu leucine enkephalin (/sup 3/H-DADL) and the broader-specificity ligand /sup 3/H-etorphine was used to measure five HPLC-purified neuropeptide fractions derived from the peptide-rich fraction of tissue homogenates of nine anatomical regions of the canine brain. The receptoractive peptides studied were methionine enkephalin, alpha-neo-endorphin, dynorphin 1-8, methionine enkephalin-Arg-Phe, and leucine enkephalin. These peptides derive from two larger precursors: proenkephalin A, which contains methionine enkephalin, leucine enkephalin, methionine enkephalin-Arg-Phe; and proenkephalin B, which contains alpha-neo-endorphin and dynorphin 1-8. Receptoractive peptides were measured in the peptide-rich fraction derived from homogenates of canine hypothalamus, pituitary, caudate nucleus, amygdala, hippocampus, mid-brain, thalamus, pons-medulla, and cortex.

  9. Radioreceptor assay of opioid peptides in selected canine brain regions

    International Nuclear Information System (INIS)

    Desiderio, D.M.; Takeshita, H.

    1985-01-01

    A radioreceptor assay using the opioid delta receptor-preferring ligand D- 2 ala, D- 5 leu leucine enkephalin ( 3 H-DADL) and the broader-specificity ligand 3 H-etorphine was used to measure five HPLC-purified neuropeptide fractions derived from the peptide-rich fraction of tissue homogenates of nine anatomical regions of the canine brain. The receptoractive peptides studied were methionine enkephalin, alpha-neo-endorphin, dynorphin 1-8, methionine enkephalin-Arg-Phe, and leucine enkephalin. These peptides derive from two larger precursors: proenkephalin A, which contains methionine enkephalin, leucine enkephalin, methionine enkephalin-Arg-Phe; and proenkephalin B, which contains alpha-neo-endorphin and dynorphin 1-8. Receptoractive peptides were measured in the peptide-rich fraction derived from homogenates of canine hypothalamus, pituitary, caudate nucleus, amygdala, hippocampus, mid-brain, thalamus, pons-medulla, and cortex

  10. CXCL10 Controls Inflammatory Pain via Opioid Peptide-Containing Macrophages in Electroacupuncture

    Science.gov (United States)

    Wang, Ying; Gehringer, Rebekka; Mousa, Shaaban A.; Hackel, Dagmar; Brack, Alexander; Rittner, Heike L.

    2014-01-01

    Acupuncture is widely used for pain treatment in patients with osteoarthritis or low back pain, but molecular mechanisms remain largely enigmatic. In the early phase of inflammation neutrophilic chemokines direct opioid-containing neutrophils in the inflamed tissue and stimulate opioid peptide release and antinociception. In this study the molecular pathway and neuroimmune connections in complete Freund's adjuvant (CFA)-induced hind paw inflammation and electroacupuncture for peripheral pain control were analyzed. Free moving Wistar rats with hind paw inflammation were treated twice with electroacupuncture at GB30 (Huan Tiao - gall bladder meridian) (day 0 and 1) and analyzed for mechanical and thermal nociceptive thresholds. The cytokine profiles as well as the expression of opioid peptides were quantified in the inflamed paw. Electroacupuncture elicited long-term antinociception blocked by local injection of anti-opioid peptide antibodies (beta-endorphin, met-enkephalin, dynorphin A). The treatment altered the cytokine profile towards an anti-inflammatory pattern but augmented interferon (IFN)-gamma and the chemokine CXCL10 (IP-10: interferon gamma-inducible protein) protein and mRNA expression with concomitant increased numbers of opioid peptide-containing CXCR3+ macrophages. In rats with CFA hind paw inflammation without acupuncture repeated injection of CXCL10 triggered opioid-mediated antinociception and increase opioid-containing macrophages. Conversely, neutralization of CXCL10 time-dependently decreased electroacupuncture-induced antinociception and the number of infiltrating opioid peptide-expressing CXCR3+ macrophages. In summary, we describe a novel function of the chemokine CXCL10 - as a regulator for an increase of opioid-containing macrophages and antinociceptive mediator in inflammatory pain and as a key chemokine regulated by electroacupuncture. PMID:24732949

  11. Hyperthermic responses to central injections of some peptide and non-peptide opioids in the guinea-pig

    Science.gov (United States)

    Kandasamy, S. B.; Williams, B. A.

    1983-01-01

    The intracerebroventricular administration of prototype nonpeptide opioid receptor (mu, kappa, and sigma) agonists, morphine, ketocyclazocine, and N-allyl normetazocine and an agonist at both kappa and sigma receptors, pentazocine, was found to induce hyperthermia in guinea pigs. The similar administration of peptide opioids like beta endorphin, methionine endkephalin, leucine endkephaline, and several of their synthetic analogues was also found to cause hyperthermia. Only the liver-like transport system of the three anion transport systems (iodide, hippurate, and liver-like) present in the choroid plexus was determined to be important to the central inactivation of beta-endorphin and two synthetic analogues. Prostaglandins and norepinephrine (NE) as well as cAMP were not involved in peptide and nonpeptide opioid-induced hyperthermia. Naloxone-sensitive receptors were found to be involved in the induction of hyperthermia by morphine and beta-endorphin, while hyperthermic responses to ketocyclazocine, N-allyl normetazocine, pentazocine, Met-enkephalin, Leu-enkephalin, and two of the synthetic analogues were not antagonized by nalozone. The lack of antagonism of naloxone on pyrogen, arachidonic acid, PGE2, dibutyryl cAMP, and NE-induced hyperthermia shows that endogenous opioid peptides are not likely to be central mediators of the hyperthermia induced by these agents.

  12. Stereochemical Basis for a Unified Structure Activity Theory of Aromatic and Heterocyclic Rings in Selected Opioids and Opioid Peptides

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    Joel S. Goldberg

    2010-02-01

    Full Text Available This paper presents a novel unified theory of the structure activity relationship of opioids and opioid peptides. It is hypothesized that a virtual or known heterocyclic ring exists in all opioids which have activity in humans, and this ring occupies relative to the aromatic ring of the drug, approximately the same plane in space as the piperidine ring of morphine. Since the rings of morphine are rigid, and the aromatic and piperidine rings are critical structural components for morphine’s analgesic properties, the rigid morphine molecule allows for approximations of the aromatic and heterocyclic relationships in subsequent drug models where bond rotations are common. This hypothesis and five propositions are supported by stereochemistry and experimental observations. Proposition #1 The structure of morphine provides a template. Proposition #2 Steric hindrance of some centric portion of the piperidine ring explains antagonist properties of naloxone, naltrexone and alvimopam. Proposition #3 Methadone has an active conformation which contains a virtual heterocyclic ring which explains its analgesic activity and racemic properties. Proposition #4 The piperidine ring of fentanyl can assume the morphine position under conditions of nitrogen inversion. Proposition #5 The first 3 amino acid sequences of beta endorphin (l-try-gly-gly and the active opioid dipeptide, l-tyr-pro, (as a result of a peptide turn and zwitterion bonding form a virtual piperazine-like ring which is similar in size, shape and location to the heterocyclic rings of morphine, meperidine, and methadone. Potential flaws in this theory are discussed. This theory could be important for future analgesic drug design.

  13. Concomitant duplications of opioid peptide and receptor genes before the origin of jawed vertebrates.

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    Görel Sundström

    Full Text Available BACKGROUND: The opioid system is involved in reward and pain mechanisms and consists in mammals of four receptors and several peptides. The peptides are derived from four prepropeptide genes, PENK, PDYN, PNOC and POMC, encoding enkephalins, dynorphins, orphanin/nociceptin and beta-endorphin, respectively. Previously we have described how two rounds of genome doubling (2R before the origin of jawed vertebrates formed the receptor family. METHODOLOGY/PRINCIPAL FINDINGS: Opioid peptide gene family members were investigated using a combination of sequence-based phylogeny and chromosomal locations of the peptide genes in various vertebrates. Several adjacent gene families were investigated similarly. The results show that the ancestral peptide gene gave rise to two additional copies in the genome doublings. The fourth member was generated by a local gene duplication, as the genes encoding POMC and PNOC are located on the same chromosome in the chicken genome and all three teleost genomes that we have studied. A translocation has disrupted this synteny in mammals. The PDYN gene seems to have been lost in chicken, but not in zebra finch. Duplicates of some peptide genes have arisen in the teleost fishes. Within the prepropeptide precursors, peptides have been lost or gained in different lineages. CONCLUSIONS/SIGNIFICANCE: The ancestral peptide and receptor genes were located on the same chromosome and were thus duplicated concomitantly. However, subsequently genetic linkage has been lost. In conclusion, the system of opioid peptides and receptors was largely formed by the genome doublings that took place early in vertebrate evolution.

  14. Role of endogenous opioid peptides in the pathogenesis of motion sickness

    International Nuclear Information System (INIS)

    Yasnetsov, V.V.; Il'ina, S.L.; Karsanova, S.K.; Medvedev, O.S.; Mokrousova, A.V.; Sabaev, V.V.; Shashkov, V.A.; Tigranyan, R.A.; Vakulina, O.P

    1986-01-01

    This paper examines the pathogenesis of motion sickness and the role of the various neurochemical systems of the body in the genesis of the condition. It has been shown that the endogenous opioid system participates in the genesis of several pathological processes; this was the motivation for the study. The plasma beta-endorphin level was determined in samples from 19 clinically healthy males. Considering the positive prophylactic and therapeutic effect of naloxone against motion sickness it can be postulated that endogenous opioid peptides participate in the genesis of the vestibulo-autonomic disorders in motion sickness

  15. Role of endogenous opioid peptides in the pathogenesis of motion sickness

    Energy Technology Data Exchange (ETDEWEB)

    Yasnetsov, V.V.; Il' ina, S.L.; Karsanova, S.K.; Medvedev, O.S.; Mokrousova, A.V.; Sabaev, V.V.; Shashkov, V.A.; Tigranyan, R.A.; Vakulina, O.P

    1986-01-01

    This paper examines the pathogenesis of motion sickness and the role of the various neurochemical systems of the body in the genesis of the condition. It has been shown that the endogenous opioid system participates in the genesis of several pathological processes; this was the motivation for the study. The plasma beta-endorphin level was determined in samples from 19 clinically healthy males. Considering the positive prophylactic and therapeutic effect of naloxone against motion sickness it can be postulated that endogenous opioid peptides participate in the genesis of the vestibulo-autonomic disorders in motion sickness.

  16. Electroacupuncture-Induced Dynamic Processes of Gene Expression Levels of Endogenous Opioid Peptide Precursors and Opioid Receptors in the CNS of Goats

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    Li-Li Cheng

    2013-01-01

    Full Text Available In order to investigate the dynamic processes of mRNA levels of proenkephalin, proopiomelanocortin, prodynorphin, and opioid receptors (δ-, μ-, and κ-receptor induced by electroacupuncture (EA in the central nerve system, goats were stimulated by EA of 60 Hz for 0.5 h at a set of Baihui, Santai, Ergen, and Sanyangluo points. The pain threshold was measured using the method of potassium iontophoresis. The mRNA levels of the three opioid peptide precursors and three opioid receptors were determined with quantitative real-time PCR and the levels of Met-enkephalin with SABC immunohistochemistry at 0.5 h before and at 0, 2, 4, 6, 8, 12, and 24 h after EA. The results showed that the pain threshold correlated (P<0.01 with Met-enkephalin immunoactivities in the measured nuclei and areas of goats. The analgesic aftereffect lasted for 12 h at least. The mRNA levels of the three opioid peptide precursors and three opioid receptors began to increase at 0 h, reached the peak during the time from 4 h to 6 h or at 12 h, and remained higher at 24 h after EA was discontinued. These results suggested that the initiation of gene expression of opioid peptides and the three receptors may be associated with EA-induced analgesic aftereffect.

  17. Opioid peptides and gastrointestinal symptoms in autism spectrum disorders

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    Cristiane P. Lázaro

    2016-01-01

    Full Text Available Autism spectrum disorders (ASDs are characterized by deficits in the individual’s ability to socialize, communicate, and use the imagination, in addition to stereotyped behaviors. These disorders have a heterogenous phenotype, both in relation to symptoms and regarding severity. Organic problems related to the gastrointestinal tract are often associated with ASD, including dysbiosis, inflammatory bowel disease, exocrine pancreatic insufficiency, celiac disease, indigestion, malabsorption, food intolerance, and food allergies, leading to vitamin deficiencies and malnutrition. In an attempt to explain the pathophysiology involved in autism, a theory founded on opioid excess has been the focus of various investigations, since it partially explains the symptomatology of the disorder. Another hypothesis has been put forward whereby the probable triggers of ASDs would be related to the presence of bacteria in the bowel, oxidative stress, and intestinal permeability. The present update reviews these hypotheses.

  18. New insights on mu/delta selectivity of opioid peptides: conformational analysis of deltorphin analogues.

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    Tancredi, T; Temussi, P A; Picone, D; Amodeo, P; Tomatis, R; Salvadori, S; Marastoni, M; Santagada, V; Balboni, G

    1991-05-01

    The message domain of dermorphin (Tyr-D-Ala-Phe), a natural mu-opioid heptapeptide, has long been considered the main cause of the high mu selectivity of this peptide and of its analogues. The recent discovery, in the skin of Phyllomedusa sauvagei (i.e., the same natural source of dermorphin) and of Phyllomedusa bicolor of deltorphins, challenges this belief. Deltorphins, in fact, are three heptapeptides characterized by a message domain typical of mu-selective peptides, but endowed of an extremely high delta selectivity, the highest of all natural opioid peptides. A conformational analysis of dermorphin and deltorphins, based on nmr studies in DMSO and cryoprotective mixtures and internal energy calculations, showed that the enormous differences in receptor selectivity can be interpreted on the basis of receptor models for mu and delta opioids that recognize the same beta-turn in the N-terminal part, but discriminate for the conformation and polarity of the C-terminal part. Here we present the synthesis, biological activity, and conformational analysis in solution of three deltorphin analogues with very similar constitution, but with different net charge, different location of negative residues, or even without negative residues, which confirm these hypotheses and show that His4 can play a specific structural role.

  19. MDR1 P-glycoprotein transports endogenous opioid peptides

    NARCIS (Netherlands)

    Oude Elferink, R. P.; Zadina, J.

    2001-01-01

    MDR1 P-glycoprotein is generally regarded as an efflux pump for amphipathic toxic compounds. The question remains, however, whether certain endogenous compounds are also substrates for this transporter. Certain peptides have been shown to interact with MDR1 Pgp as well and we have therefore

  20. Endogenous Opioid Peptides and Epilepsy: Quieting the Seizing Brain?

    Science.gov (United States)

    1988-08-01

    circuitry and highly sen- upon EEG findings could be tor, acid systems, remains sitive to epileptogenesis (see Refs misleading. to be l iated. The...Langwinski, R. (1986) Drug Alchoho! Depend. 18. 361-367: " Meldrum . B. S. et a. (1979) Brain Res. 170, 333-348; ’Sajorek, J. G. and Lomax, P. (1982... Acids . Peptides and Trophic Factors Engel, J., Jr, eds), pp. 263-274, Raven the outcome of which depends (Ferrendelli. J., Collins, R. and Johnson

  1. Endogenous opioid peptide-mediated neurotransmission in central and pericentral nuclei of the inferior colliculus recruits μ1-opioid receptor to modulate post-ictal antinociception.

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    Felippotti, Tatiana Tocchini; de Freitas, Renato Leonardo; Coimbra, Norberto Cysne

    2012-02-01

    The aim of the present work was to investigate the involvement of the μ1-endogenous opioid peptide receptor-mediated system in post-ictal antinociception. Antinociceptive responses were determined by the tail-flick test after pre-treatment with the selective μ1-opioid receptor antagonist naloxonazine, peripherally or centrally administered at different doses. Peripheral subchronic (24 h) pre-treatment with naloxonazine antagonised the antinociception elicited by tonic-clonic seizures. Acute (10 min) pre-treatment, however, did not have the same effect. In addition, microinjections of naloxonazine into the central, dorsal cortical and external cortical nuclei of the inferior colliculus antagonised tonic-clonic seizure-induced antinociception. Neither acute (10-min) peripheral pre-treatment with naloxonazine nor subchronic intramesencephalic blockade of μ1-opioid receptors resulted in consistent statistically significant differences in the severity of tonic-clonic seizures shown by Racine's index (1972), although the intracollicular specific antagonism of μ1-opioid receptor decreased the duration of seizures. μ1-Opioid receptors and the inferior colliculus have been implicated in several endogenous opioid peptide-mediated responses such as antinociception and convulsion. The present findings suggest the involvement of μ1-opiate receptors of central and pericentral nuclei of the inferior colliculus in the modulation of tonic-clonic seizures and in the organisation of post-ictal antinociception. Copyright © 2011 Elsevier Ltd. All rights reserved.

  2. Enhanced efficacy (intrinsic activity) of cyclic opioid peptide analogs at the μ-receptor

    International Nuclear Information System (INIS)

    Schiller, P.W.; Lemieux, C.; Nguyen, T.M.D.; Maziak, L.A.

    1986-01-01

    Side-chain to end group cyclized enkephalin analogs (e.g. H-Tyr-cyclo[-D-Lys-Gly-Phe-Leu-] and cyclic opioid peptide analogs obtained through covalent linkage of two side-chains (e.g. H-Tyr-D-Cys-Gly-Phe-Cys-NH 2 or H-Tyr-D-Lys-Gly-Phe-Glu-NH 3 ) were tested in the μ-receptor-representative guinea pig ileum (GPI) bioassay and in a binding assay based on displacement of the μ-ligand [ 3 H]DAGO from rat brain membranes. The cyclic analogs were 5 to 70 times more potent in the GPI assay than in the binding assay, whereas linear analogs showed equal potency in the two assays. These results suggest that the efficacy (intrinsic activity) of cyclic opioid peptide analogs at the μ-receptor is increased as a consequence of the conformation constraint imposed through ring closure. This effect was most pronounced in analogs containing a long hydrophobic sidechain as part of the ring structure in the 2-position of the peptide sequence. Further experimental evidence ruled out the possibilities that these potency discrepancies may be due to differences in enzymatic degradation, dissimilar exposure of the receptors in their lipid environment or interaction with different receptor types in the two assay systems. It can be hypothesized that the semi-rigid cyclic analogs may induce a more productive conformational change in the receptor protein than the linear peptides

  3. Adoptive transfer of M2 macrophages reduces neuropathic pain via opioid peptides.

    Science.gov (United States)

    Pannell, Maria; Labuz, Dominika; Celik, Melih Ö; Keye, Jacqueline; Batra, Arvind; Siegmund, Britta; Machelska, Halina

    2016-10-07

    During the inflammation which occurs following nerve damage, macrophages are recruited to the site of injury. Phenotypic diversity is a hallmark of the macrophage lineage and includes pro-inflammatory M1 and anti-inflammatory M2 populations. Our aim in this study was to investigate the ability of polarized M0, M1, and M2 macrophages to secrete opioid peptides and to examine their relative contribution to the modulation of neuropathic pain. Mouse bone marrow-derived cells were cultured as unstimulated M0 macrophages or were stimulated into an M1 phenotype using lipopolysaccharide and interferon-γ or into an M2 phenotype using interleukin-4. The macrophage phenotypes were verified using flow cytometry for surface marker analysis and cytokine bead array for cytokine profile assessment. Opioid peptide levels were measured by radioimmunoassay and enzyme immunoassay. As a model of neuropathic pain, a chronic constriction injury (CCI) of the sciatic nerve was employed. Polarized M0, M1, and M2 macrophages (5 × 10 5 cells) were injected perineurally twice, on days 14 and 15 following CCI or sham surgery. Mechanical and heat sensitivity were measured using the von Frey and Hargreaves tests, respectively. To track the injected macrophages, we also transferred fluorescently stained polarized cells and analyzed the surface marker profile of endogenous and injected cells in the nerves ex vivo. Compared to M0 and M1 cells, M2 macrophages contained and released higher amounts of opioid peptides, including Met-enkephalin, dynorphin A (1-17), and β-endorphin. M2 cells transferred perineurally at the nerve injury site reduced mechanical, but not heat hypersensitivity following the second injection. The analgesic effect was reversed by the perineurally applied opioid receptor antagonist naloxone methiodide. M2 cells did not affect sensitivity following sham surgery. Neither M0 nor M1 cells altered mechanical and heat sensitivity in CCI or sham-operated animals. Tracing the

  4. Synthesis and Pharmacology of Halogenated δ-Opioid-Selective [D-Ala2]Deltorphin II Peptide Analogues

    Science.gov (United States)

    Pescatore, Robyn; Marrone, Gina F.; Sedberry, Seth; Vinton, Daniel; Finkelstein, Netanel; Katlowitz, Yitzchak E.; Pasternak, Gavril W.; Wilson, Krista R.; Majumdar, Susruta

    2015-01-01

    Deltorphins are naturally occurring peptides produced by the skin of the giant monkey frog (Phyllomedusa bicolor). They are δ-opioid receptor-selective agonists. Herein, we report the design and synthesis of a peptide, Tyr-D-Ala-(pI)Phe-Glu-Ile-Ile-Gly-NH2 3 (GATE3-8), based on the [D-Ala2]deltorphin II template, which is δ-selective in in vitro radioligand binding assays over the μ- and κ-opioid receptors. It is a full agonist in [35S]GTPγS functional assays and analgesic when administered supraspinally to mice. Analgesia of 3 (GATE3-8) is blocked by the selective δ receptor antagonist naltrindole, indicating that the analgesic action of 3 is mediated by the δ-opioid receptor. We have established a radioligand in which 125I isincorporated into 3 (GATE3-8). The radioligand has a KD of 0.1 nM in Chinese hamster ovary (CHO) cells expressing the δ receptor. Additionally, a series of peptides based on 3 (GATE3-8) was synthesized by incorporating various halogens in the para position on the aromatic ring of Phe3. The peptides were characterized for binding affinity at the μ-, δ-, and κ-opioid receptors, which showed a linear correlation between binding affinity and the size of the halogen substituent. These peptides may be interesting tools for probing δ-opioid receptor pharmacology. PMID:25844930

  5. Synthesis and pharmacology of halogenated δ-opioid-selective [d-Ala(2)]deltorphin II peptide analogues.

    Science.gov (United States)

    Pescatore, Robyn; Marrone, Gina F; Sedberry, Seth; Vinton, Daniel; Finkelstein, Netanel; Katlowitz, Yitzchak E; Pasternak, Gavril W; Wilson, Krista R; Majumdar, Susruta

    2015-06-17

    Deltorphins are naturally occurring peptides produced by the skin of the giant monkey frog (Phyllomedusa bicolor). They are δ-opioid receptor-selective agonists. Herein, we report the design and synthesis of a peptide, Tyr-d-Ala-(pI)Phe-Glu-Ile-Ile-Gly-NH2 3 (GATE3-8), based on the [d-Ala(2)]deltorphin II template, which is δ-selective in in vitro radioligand binding assays over the μ- and κ-opioid receptors. It is a full agonist in [(35)S]GTPγS functional assays and analgesic when administered supraspinally to mice. Analgesia of 3 (GATE3-8) is blocked by the selective δ receptor antagonist naltrindole, indicating that the analgesic action of 3 is mediated by the δ-opioid receptor. We have established a radioligand in which (125)I is incorporated into 3 (GATE3-8). The radioligand has a KD of 0.1 nM in Chinese hamster ovary (CHO) cells expressing the δ receptor. Additionally, a series of peptides based on 3 (GATE3-8) was synthesized by incorporating various halogens in the para position on the aromatic ring of Phe(3). The peptides were characterized for binding affinity at the μ-, δ-, and κ-opioid receptors, which showed a linear correlation between binding affinity and the size of the halogen substituent. These peptides may be interesting tools for probing δ-opioid receptor pharmacology.

  6. The cardiovascular effects of a chimeric opioid peptide based on morphiceptin and PFRTic-NH2.

    Science.gov (United States)

    Li, Meixing; Zhou, Lanxia; Ma, Guoning; Cao, Shuo; Dong, Shouliang

    2013-01-01

    MCRT (YPFPFRTic-NH(2)) is a chimeric opioid peptide based on morphiceptin and PFRTic-NH(2). In order to assess the cardiovascular effect of MCRT, it was administered by intravenous (i.v.) injection targeting at the peripheral nervous system and by intracerebroventricular (i.c.v.) injection targeting at the central nervous system. Naloxone and L-NAME were injected before MCRT to investigate possible interactions with MCRT. Results show that administration of MCRT by i.v. or i.c.v. injection could induce bradycardia and decrease in mean arterial pressure (MAP) at a greater degree than that with morphiceptin and PFRTic-NH(2). When MCRT and NPFF were coinjected, we observed a dose-dependent weakening of these cardiovascular effects by MCRT. Because naloxone completely abolished the cardiovascular effects of MCRT, we conclude that opioid receptors are involved in regulating the MAP of MCRT regardless of modes of injection. The effect of MCRT on heart rate is completely dependent on opioid receptors when MCRT was administered by i.c.v. instead of i.v. The central nitric oxide (NO) pathway is involved in regulating blood pressure by MCRT under both modes of injection, but the peripheral NO pathway had no effect on lowering blood pressure mediated by MCRT when it was administered by i.c.v. Based on the results from different modes of injection, the regulation of heart rate by MCRT mainly involves in the central NO pathway. Lastly, we observed that the cardiovascular effects of MCRT such as bradycardia and decrease of blood pressure, were stronger than that of its parent peptides. Opioid receptors and the NO pathway are involved in the cardiovascular regulation by MCRT, and their degree of involvement differs between intravenous and intracerebroventricular injection. Copyright © 2012 Elsevier Inc. All rights reserved.

  7. Sympathoadrenal, cardiovascular and blood gas responses to highly selective mu and delta opioid peptides.

    Science.gov (United States)

    Kiritsy-Roy, J A; Marson, L; Van Loon, G R

    1989-12-01

    The relative importance of mu and delta opioid receptors in brain regulation of sympathoadrenal, cardiovascular and respiratory function was investigated using highly selective mu and delta opioid peptide analogs. Groups of conscious rats received i.c.v. injections of either the mu-selective agonist, [D-Ala2, MePhe4, Gly-ol5]enkephalin (DAMGO) or the delta-selective agonist, [D-Pen2, D-Pen5]enkephalin (DPDPE). Blood pressure and heart rate were recorded continuously via a chronic catheter in the carotid artery, and arterial blood samples were taken at intervals through the same catheter for determination of blood pH, pCO2, pO2 and plasma catecholamine concentrations. Both DAMGO and DPDPE increased plasma catecholamine levels and blood pressure in a dose-related manner. The slopes of the dose-response lines were parallel, but the delta compound was about 250 times less potent than DAMGO. Only the highest dose of 5 nmol of DAMGO caused a significant bradycardia, mediated by parasympathetic (vagal) activation. DAMGO and DPDPE also induced dose-dependent acidosis, with DAMGO again being much more potent than DPDPE. The effects of both DAMGO and DPDPE on plasma catecholamines, blood pressure and blood gases were antagonized by a mu-selective dose of naloxone (0.4 mg/kg i.a.). Intracerebroventricular administration of the delta-selective antagonist, ICI 174,864, only partially attenuated sympathoadrenal and blood gas responses to DAMGO or DPDPE. The pressor responses to DAMGO or DPDPE were resistant to antagonism by ICI 174,864. These results indicate that brain opioid receptors regulating autonomic outflow, cardiovascular and respiratory function are mainly of the mu type, although a delta opioid system may contribute to sympathoadrenal and respiratory effects of opioids.

  8. Stereospecific effects of morphine on plasma opioid peptide levels and nociception in dogs

    Energy Technology Data Exchange (ETDEWEB)

    Adams, M.L.; Morris, D.L.; Dewey, W.L.

    1986-03-05

    ..beta..-endorphin, (met)enkephalin, and (leu)enkephalin were quantitated in canine plasma by radioimmunoassay (RIA) after extraction of the peptides on Sep Pak C18 cartridges. Plasma samples were taken one hour after a 10 mg/kg s.c. injection of (-)-morphine SO/sub 4/ or (+)-morphine HBr. Antinociception, measured by a dog tail-flick test, and morphine-induced emesis, salivation, diarrhea, and ataxia were quantitated before sampling. Control levels for each dog were taken one week earlier at the same time of day after saline injections. Antinociception, morphine signs, and opioid peptide levels in plasma were significantly increased by (-)-morphine. Antinociception increased from zero to 83.54 +/- 11.0%. The number of morphine signs increased from zero to 2.9 +/- 0.28 per dog. ..beta..-endorphin levels increased from 44.52 +/- 4.25 to 90.6 +/- 7.38 pg/ml; (met)enkephalin levels increased from 253.56 +/- 22.04 to 497.1 +/- 58.12 pg/ml; (leu)-enkephalin increased from 141.65 +/- 12.9 to 313.24 +/- 35.95 pg/ml. None of these effects were observed in the dogs that received (+)-morphine. The conclude that morphine stereospecifically inhibits nociception, induces observable signs, and increases plasma opioid peptide levels in dogs.

  9. Stereospecific effects of morphine on plasma opioid peptide levels and nociception in dogs

    International Nuclear Information System (INIS)

    Adams, M.L.; Morris, D.L.; Dewey, W.L.

    1986-01-01

    β-endorphin, [met]enkephalin, and [leu]enkephalin were quantitated in canine plasma by radioimmunoassay (RIA) after extraction of the peptides on Sep Pak C18 cartridges. Plasma samples were taken one hour after a 10 mg/kg s.c. injection of (-)-morphine SO 4 or (+)-morphine HBr. Antinociception, measured by a dog tail-flick test, and morphine-induced emesis, salivation, diarrhea, and ataxia were quantitated before sampling. Control levels for each dog were taken one week earlier at the same time of day after saline injections. Antinociception, morphine signs, and opioid peptide levels in plasma were significantly increased by (-)-morphine. Antinociception increased from zero to 83.54 +/- 11.0%. The number of morphine signs increased from zero to 2.9 +/- 0.28 per dog. β-endorphin levels increased from 44.52 +/- 4.25 to 90.6 +/- 7.38 pg/ml; [met]enkephalin levels increased from 253.56 +/- 22.04 to 497.1 +/- 58.12 pg/ml; [leu]-enkephalin increased from 141.65 +/- 12.9 to 313.24 +/- 35.95 pg/ml. None of these effects were observed in the dogs that received (+)-morphine. The conclude that morphine stereospecifically inhibits nociception, induces observable signs, and increases plasma opioid peptide levels in dogs

  10. Central effects of some peptide and non-peptide opioids and naloxone on thermoregulation in the rabbit

    Science.gov (United States)

    Kandasamy, S. B.; Williams, B. A.

    1983-01-01

    The effects of several peptide and non-peptide opiods and naloxone on induced hyperthermia is studied in rabbits. The effect of tyical mu, kappa, and sigma receptor antagonists (morphine, ketocyclazcine and SKF 10,0 10, 047) and some opioid peptides (Beta-endorphin /BE/, methionine-enkaphalin /ME/, and D-Ala2-methionine-enkaphalin-amide /DAME/ are determined. The role of prostaglandins (PG), cAMP, and norepinephrine (NE) in morphine, BE, and DAME induced hyperthermia is investigated. In addition, the effect of naloxone on pyrogen, arachidonic acid, PGE2, prostacyclin, dibutyryl cAMP, and NE induced hyperthermia is determined. Among other results, it is found that the three receptor antagonists induced hyperthermia in rabbits. BE, ME, and DAME were also found to cause hyperthermia, and it is suggested that they act on the same type of receptor. It is also determined that neither NE nor cAMP is involved in the hyperthermia due to morphine, BE, and DAME. It is suggested that an action of endogenous peptides on naloxone sensitive receptors plays little role in normal thermoregulation or in hyperthermia.

  11. Evaluation of CART peptide level in rat plasma and CSF: Possible role as a biomarker in opioid addiction.

    Science.gov (United States)

    Bakhtazad, Atefeh; Vousooghi, Nasim; Garmabi, Behzad; Zarrindast, Mohammad Reza

    2016-10-01

    It has been shown previously that cocaine- and amphetamine-regulated transcript (CART) peptide has a modulatory role and homeostatic regulatory effect in motivation to and reward of the drugs of abuse specially psychostimulants. Recent data also showed that in addition to psychostimulants, CART is critically involved in the different stages of opioid addiction. Here we have evaluated the fluctuations in the level of CART peptide in plasma and CSF in different phases of opioid addiction to find out whether CART can serve as a suitable marker in opioid addiction studies. Male rats were randomly distributed in groups of control, acute low-dose (10mg/kg) morphine, acute high-dose morphine (80mg/kg), chronic escalating doses of morphine, withdrawal syndrome precipitated by administration of naloxone (1mg/kg), and abstinent after long-term drug-free maintenance of addicted animals. The level of CART peptide in CSF and plasma samples was measured by enzyme immunoassay. CART peptide concentration in the CSF and plasma was significantly elevated in acute high-dose morphine and withdrawal state animals and down-regulated in addicted rats. In abstinent group, CART peptide level was up-regulated in plasma but not in CSF samples. As the observed results are in agreement with data regarding the CART mRNA and protein expression in the brain reward pathway in opioid addiction phases, it may be suggested that evaluation of CART peptide level in CSF or plasma could be a suitable marker which reflects the rises and falls of the peptide concentration in brain in the development of opioid addiction. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Deltorphins: a family of naturally occurring peptides with high affinity and selectivity for delta opioid binding sites.

    Science.gov (United States)

    Erspamer, V; Melchiorri, P; Falconieri-Erspamer, G; Negri, L; Corsi, R; Severini, C; Barra, D; Simmaco, M; Kreil, G

    1989-07-01

    Deltorphins are endogenous linear heptapeptides, isolated from skin extracts of frogs belonging to the genus Phyllomedusa, that have a higher affinity and selectivity for delta opioid binding sites than any other natural compound known. Two deltorphins with the sequence Tyr-Ala-Phe-Asp(or Glu)-Val-Val-Gly-NH2 have been isolated from skin extracts of Phyllomedusa bicolor. The alanine in position 2 is in the D configuration. These peptides, [D-Ala2]deltorphins I and II, show an even higher affinity for delta receptors than the previously characterized deltorphin, which contains D-methionine as the second amino acid. These peptides show some similarity to another constituent of Phyllomedusa skin, dermorphin, which is highly selective for mu-opioid receptors. These peptides all have the N-terminal sequence Tyr-D-Xaa-Phe, where D-Xaa is either D-alanine or D-methionine. While this structure seems to be capable of activating both mu and delta opioid receptors, differences in the C-terminal regions of these peptides are probably responsible for the observed high receptor selectivity of dermorphin and deltorphin.

  13. Dermorphin-related peptides from the skin of Phyllomedusa bicolor and their amidated analogs activate two mu opioid receptor subtypes that modulate antinociception and catalepsy in the rat.

    OpenAIRE

    Negri, L; Erspamer, G F; Severini, C; Potenza, R L; Melchiorri, P; Erspamer, V

    1992-01-01

    Three naturally occurring dermorphin-like peptides from the skin of the frog Phyllomedusa bicolor, the related carboxyl-terminal amides, and some substituted analogs were synthesized, their binding profiles to opioid receptors were determined, and their biological activities were studied in isolated organ preparations and intact animals. The opioid binding profile revealed a very high selectivity of these peptides for mu sites and suggested the existence of two receptor subtypes, of high and ...

  14. Receptor binding properties and antinociceptive effects of chimeric peptides consisting of a micro-opioid receptor agonist and an ORL1 receptor antagonist.

    Science.gov (United States)

    Kawano, Susumu; Ito, Risa; Nishiyama, Miharu; Kubo, Mai; Matsushima, Tomoko; Minamisawa, Motoko; Ambo, Akihiro; Sasaki, Yusuke

    2007-07-01

    Receptor binding properties and antinociceptive activities of chimeric peptides linked by spacers were investigated. The peptides consisted of the micro-opioid receptor ligand dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH(2)) or its analog YRFB (Tyr-D-Arg-Phe-betaAla-NH(2)) linked to the ORL1 receptor ligand Ac-Arg-Tyr-Tyr-Arg-Ile-Lys-NH(2) (Ac-RYYRIK-NH(2)). All chimeric peptides were found to possess high receptor binding affinities for both micro-opioid and ORL1 receptors in mouse brain membranes although their binding affinities for both receptors in spinal membranes were significantly lower. Among them, chimeric peptide 2, which consists of dermorphin and Ac-RYYRIK-NH(2) connected by a long spacer, had the highest binding affinity towards both receptors. In the tail-flick test following intrathecal (i.t.) administration to mice, all chimeric peptides showed potent and dose-dependent antinociceptive activities with an ED(50) of 1.34-4.51 (pmol/mouse), nearly comparable to dermorphin alone (ED(50); 1.08 pmol/mouse). In contrast to their micro-opioid receptor binding profiles, intracerebroventricular (i.c.v.) administration of the chimeric peptides resulted in much less potent antinociceptive activity (ED(50) 5.55-100peptides, and the regulation of mu-opioid receptor-mediated antinociception in brain. The present chimeric peptides may be useful as pharmacological tools for studies on micro-opioid receptor/ORL1 receptor heterodimers.

  15. Delta opioid peptide (D-Ala 2, D-Leu 5) enkephalin: linking hibernation and neuroprotection.

    Science.gov (United States)

    Borlongan, Cesario V; Wang, Yun; Su, Tsung-Ping

    2004-09-01

    Hibernation is a potential protective strategy for the peripheral, as well as for the central nervous system. A protein factor termed hibernation induction trigger (HIT) was found to induce hibernation in summer-active ground squirrels. Purification of HIT yielded an 88-kD peptide that is enriched in winter hibernators. Partial sequence of the 88-kD protein indicates that it may be related to the inhibitor of metalloproteinase. Using opioid receptor antagonists to elucidate the mechanisms of HIT, it was found that HIT targeted the delta opioid receptors. Indeed, delta opioid (D-Ala 2, D-Leu 5) enkephalin (DADLE) was shown to induce hibernation. Specifically, HIT and DADLE were found to prolong survival of peripheral organs, such as the lung, the heart, liver, and kidney preserved en bloc or as a single preparation. In addition, DADLE has been recently demonstrated to promote survival of neurons in the central nervous system. Exposure to DADLE dose-dependently enhanced cell viability of cultured primary rat fetal dopaminergic cells. Subsequent transplantation of these DADLE-treated dopaminergic cells into the Parkinsonian rat brain resulted in a two-fold increase in surviving grafted cells. Interestingly, delivery of DADLE alone protected against dopaminergic depletion in a rodent model of Parkinson s disease. Similarly, DADLE blocked and reversed the dopaminergic terminal damage induced by methamphetamine (METH). Such neuroprotective effects of DADLE against METH neurotoxicity was accompanied by attenuation of mRNA expressions of a tumor necrosis factor p53 and an immediate early gene c-fos. In parallel to these beneficial effects of DADLE on the dopaminergic system, DADLE also ameliorated the neuronal damage induced by ischemia-reperfusion following a transient middle cerebral artery occlusion. In vitro replication of this ischemia cell death by serum-deprivation of PC12 cells revealed that DADLE exerted neuroprotection in a naltrexone-sensitive manner. These

  16. Regulation of nonsmall-cell lung cancer stem cell like cells by neurotransmitters and opioid peptides.

    Science.gov (United States)

    Banerjee, Jheelam; Papu John, Arokya M S; Schuller, Hildegard M

    2015-12-15

    Nonsmall-cell lung cancer (NSCLC) is the leading type of lung cancer and has a poor prognosis. We have shown that chronic stress promoted NSCLC xenografts in mice via stress neurotransmitter-activated cAMP signaling downstream of beta-adrenergic receptors and incidental beta-blocker therapy was reported to improve clinical outcomes in NSCLC patients. These findings suggest that psychological stress promotes NSCLC whereas pharmacologically or psychologically induced decreases in cAMP may inhibit NSCLC. Cancer stem cells are thought to drive the development, progression and resistance to therapy of NSCLC. However, their potential regulation by stress neurotransmitters has not been investigated. In the current study, epinephrine increased the number of cancer stem cell like cells (CSCs) from three NSCLC cell lines in spheroid formation assays while enhancing intracellular cAMP and the stem cell markers sonic hedgehog (SHH), aldehyde dehydrogenase-1 (ALDH-1) and Gli1, effects reversed by GABA or dynorphin B via Gαi -mediated inhibition of cAMP formation. The growth of NSCLC xenografts in a mouse model of stress reduction was significantly reduced as compared with mice maintained under standard conditions. Stress reduction reduced serum levels of corticosterone, norepinephrine and epinephrine while the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and opioid peptides increased. Stress reduction significantly reduced cAMP, VEGF, p-ERK, p-AKT, p-CREB, p-SRc, SHH, ALDH-1 and Gli1 in xenograft tissues whereas cleaved caspase-3 and p53 were induced. We conclude that stress neurotransmitters activate CSCs in NSCLC via multiple cAMP-mediated pathways and that pharmacologically or psychologically induced decreases in cAMP signaling may improve clinical outcomes in NSCLC patients. © 2015 UICC.

  17. Plasma levels of cortisol and opioid peptide beta-endorphin during spontaneous vaginal delivery

    Directory of Open Access Journals (Sweden)

    Arsenijević Ljubica

    2006-01-01

    Full Text Available INTRODUCTION Labor pain is very frequent in clinical practice, but the underlying mechanisms as well as numerous neuroendocrine responses activated by such pain have not been fully explained yet. OBJECTIVE The objective of the study was to determine the influence of labor pain on plasma levels of cortisol and opioid peptide ß-endorphin. METHOD Cortisol and ß-endorphin levels were measured in blood plasma of: health, non-pregnant women (group 1, n=8, health pregnant women (group 2, n=8 and in parturitions, through fourth ages (group 3, n=8, Plasma level of cortisol was measured by radioimmunoassay, and ß-endorphin by enzyme immunoassay. Data were expressed as mean ± standard error of mean and were analyzed by Student's t test and Mann Whitney test. RESULTS Plasma level of cortisol in group 2 was significantly increased compared to the group 1. During labor progression, plasma level of cortisol was rising till the third labor age. Plasma level of cortisol in fourth labor age was not significantly different from the ag.e one and group 1. Plasma level of ß-endorphin was (n.g/L: in group 1:64±20, group 2:70±22, group 3:the first labor age: 75±15, the second labor age: 193±54, the third labor age: 346+97 and the fourth labor age: 114±31. CONCLUSION These results indicate that both ß-endorphin and cortisol are involved in regulation and modulation of labor pain and stress.

  18. PK20, a new opioid-neurotensin hybrid peptide that exhibits central and peripheral antinociceptive effects

    Directory of Open Access Journals (Sweden)

    Tsuda Yuko

    2010-12-01

    Full Text Available Abstract Background The clinical treatment of various types of pain relies upon the use of opioid analgesics. However most of them produce, in addition to the analgesic effect, several side effects such as the development of dependence and addiction as well as sedation, dysphoria, and constipation. One solution to these problems are chimeric compounds in which the opioid pharmacophore is hybridized with another type of compound to incease antinociceptive effects. Neurotensin-induced antinociception is not mediated through the opioid system. Therefore, hybridizing neurotensin with opioid elements may result in a potent synergistic antinociceptor. Results Using the known structure-activity relationships of neurotensin we have synthesized a new chimeric opioid-neurotensin compound PK20 which is characterized by a very strong antinociceptive potency. The observation that the opioid antagonist naltrexone did not completely reverse the antinociceptive effect, indicates the partial involvement of the nonopioid component in PK20 in the produced analgesia. Conclusions The opioid-neurotensin hybrid analogue PK20, in which opioid and neurotensin pharmacophores overlap partially, expresses high antinociceptive tail-flick effects after central as well as peripheral applications.

  19. Deltorphins: a family of naturally occurring peptides with high affinity and selectivity for delta opioid binding sites.

    OpenAIRE

    Erspamer, V; Melchiorri, P; Falconieri-Erspamer, G; Negri, L; Corsi, R; Severini, C; Barra, D; Simmaco, M; Kreil, G

    1989-01-01

    Deltorphins are endogenous linear heptapeptides, isolated from skin extracts of frogs belonging to the genus Phyllomedusa, that have a higher affinity and selectivity for delta opioid binding sites than any other natural compound known. Two deltorphins with the sequence Tyr-Ala-Phe-Asp(or Glu)-Val-Val-Gly-NH2 have been isolated from skin extracts of Phyllomedusa bicolor. The alanine in position 2 is in the D configuration. These peptides, [D-Ala2]deltorphins I and II, show an even higher affi...

  20. Dermorphin-related peptides from the skin of Phyllomedusa bicolor and their amidated analogs activate two mu opioid receptor subtypes that modulate antinociception and catalepsy in the rat.

    Science.gov (United States)

    Negri, L; Erspamer, G F; Severini, C; Potenza, R L; Melchiorri, P; Erspamer, V

    1992-08-01

    Three naturally occurring dermorphin-like peptides from the skin of the frog Phyllomedusa bicolor, the related carboxyl-terminal amides, and some substituted analogs were synthesized, their binding profiles to opioid receptors were determined, and their biological activities were studied in isolated organ preparations and intact animals. The opioid binding profile revealed a very high selectivity of these peptides for mu sites and suggested the existence of two receptor subtypes, of high and low affinity. The peptides tested acted as potent mu opioid agonists on isolated organ preparations. They were several times more active in inhibiting electrically evoked contractions in guinea pig ileum than in mouse vas deferens. When injected into the lateral brain ventricle or peritoneum of rats, the high-affinity-site-preferring ligand, [Lys7-NH2]dermorphin, behaved as a potent analgesic agent. By contrast, the low-affinity-site-preferring ligand, [Trp4,Asn7-NH2]dermorphin, produced a weak antinociception but an intense catalepsy.

  1. Measurement of opioid peptides with combinations of reversed phase high performance liquid chromatography, radioimmunoassay, radioreceptorassay, and mass spectrometry

    International Nuclear Information System (INIS)

    Fridland, G.H.; Desiderio, D.M.

    1987-01-01

    As the first step, RP-HPLC gradient elution is performed of a Sep-Pak treated peptide-rich fraction from a tissue extract, and the eluent is monitored by a variety of post-HPLC detectors. In an effort to maximize the structural information that can be obtained from the analysis, UV provides the analog absorption trace; receptorassay analysis (RRA) data of all fractions that are collected are used to construct the profile of opioid-receptoractive peptides; radioimmunoassay (RIA) of selected HPLC fractions at retention times corresponding to the retention time of standards, or in some special cases of all 90-fractions, provides immunoreactivity information; and fast atom bombardment mass spectrometry (FAB-MS) in two modes - corroboration of the (M + H) + of the expected peptide, or MS/MS to monitor an amino acid sequence-determining fragment ion unique to that peptide in the selected ion monitoring (SIM) mode - provides structural information. As a demonstration of the level of quantification sensitivity that can be attained by these novel MS methods, FAB-MS-MS-SIM of solutions of synthetic leucine enkephalin was sensitive to the 70 femtomole level. This paper discusses RIA versus RRA data, and recent MS measurements of peptides in human tissues. 4 references, 1 figure

  2. Respiratory depression after intravenous administration of delta-selective opioid peptide analogs.

    Science.gov (United States)

    Szeto, H H; Soong, Y; Wu, D; Olariu, N; Kett, A; Kim, H; Clapp, J F

    1999-01-01

    We compared the effects of three micro-(DAMGO, DALDA, TNPO) and three delta-(DPDPE, DELT, SNC-80) opioid agonists on arterial blood gas after IV administration in awake sheep. None of the mu agonists altered pO2, pCO2 or pH. All three mu agonists decreased pO2 increased pCO2 and decreased pO2, and this effect was not sensitive to naloxone or TIPPpsi, a delta-antagonist, suggesting that it is not mediated by beta-opioid receptors. When administered to pregnant animals, there were significant changes in fetal pCO2 and pH. It may be possible to develop delta-selective opioid agonists which do not produce respiratory depression.

  3. Role of neurotensin and opioid receptors in the cardiorespiratory effects of [Ile⁹]PK20, a novel antinociceptive chimeric peptide.

    Science.gov (United States)

    Kaczyńska, Katarzyna; Szereda-Przestaszewska, Małgorzata; Kleczkowska, Patrycja; Lipkowski, Andrzej W

    2014-10-15

    Ile(9)PK20 is a novel hybrid of opioid-neurotensin peptides synthesized from the C-terminal hexapeptide of neurotensin and endomorphin-2 pharmacophore. This chimeric compound shows potent central and peripheral antinociceptive activity in experimental animals, however nothing is known about its influence on the respiratory and cardiovascular parameters. The present study was designed to determine the cardiorespiratory effects exerted by an intravenous injection (i.v.) of [Ile(9)]PK20. Share of the vagal afferentation and the contribution of NTS1 neurotensin and opioid receptors were tested. Intravenous injection of the hybrid at a dose of 100 μg/kg in the intact, anaesthetized rats provoked an increase in tidal volume preceded by a prompt short-lived decrease. Immediately after the end of injection brief acceleration of the respiratory rhythm appeared, and was ensued by the slowing down of breathing. Changes in respiration were concomitant with a bi-phasic response of the blood pressure: an immediate increase was followed by a sustained hypotension. Midcervical vagotomy eliminated the increase in tidal volume and respiratory rate responses. Antagonist of opioid receptors - naloxone hydrochloride eliminated only [Ile(9)]PK20-evoked decline in tidal volume response. Blockade of NTS1 receptors with an intravenous dose of SR 142,948, lessened the remaining cardiorespiratory effects. This study depicts that [Ile(9)]PK20 acting through neurotensin NTS1 receptors augments the tidal component of the breathing pattern and activates respiratory timing response through the vagal pathway. Blood pressure effects occur outside vagal afferentation and might result from activation of the central and peripheral vascular NTS1 receptors. In summary the respiratory effects of the hybrid appeared not to be profound, but they were accompanied with unfavourable prolonged hypotension. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Potent μ-Opioid Receptor Agonists from Cyclic Peptides Tyr-c[D-Lys-Xxx-Tyr-Gly]: Synthesis, Biological, and Structural Evaluation.

    Science.gov (United States)

    Li, Yangmei; Cazares, Margret; Wu, Jinhua; Houghten, Richard A; Toll, Laurence; Dooley, Colette

    2016-02-11

    To optimize the structure of a μ-opioid receptor ligand, analogs H-Tyr-c[D-Lys-Xxx-Tyr-Gly] were synthesized and their biological activity was tested. The analog containing a Phe(3) was identified as not only exhibiting binding affinity 14-fold higher than the original hit but also producing agonist activity 3-fold more potent than morphine. NMR study suggested that a trans conformation at D-Lys(2)-Xxx(3) is crucial for these cyclic peptides to maintain high affinity, selectivity, and functional activity toward the μ-opioid receptor.

  5. Precursors of vertebrate peptide antibiotics dermaseptin b and adenoregulin have extensive sequence identities with precursors of opioid peptides dermorphin, dermenkephalin, and deltorphins.

    Science.gov (United States)

    Amiche, M; Ducancel, F; Mor, A; Boulain, J C; Menez, A; Nicolas, P

    1994-07-08

    The dermaseptins are a family of broad spectrum antimicrobial peptides, 27-34 amino acids long, involved in the defense of the naked skin of frogs against microbial invasion. They are the first vertebrate peptides to show lethal effects against the filamentous fungi responsible for severe opportunistic infections accompanying immunodeficiency syndrome and the use of immunosuppressive agents. A cDNA library was constructed from skin poly(A+) RNA of the arboreal frog Phyllomedusa bicolor and screened with an oligonucleotide probe complementary to the COOH terminus of dermaseptin b. Several clones contained a full-length DNA copy of a 443-nucleotide mRNA that encoded a 78-residue dermaseptin b precursor protein. The deduced precursor contained a putative signal sequence at the NH2 terminus, a 20-residue spacer sequence extremely rich (60%) in glutamic and aspartic acids, and a single copy of a dermaseptin b progenitor sequence at the COOH terminus. One clone contained a complete copy of adenoregulin, a 33-residue peptide reported to enhance the binding of agonists to the A1 adenosine receptor. The mRNAs encoding adenoregulin and dermaseptin b were very similar: 70 and 75% nucleotide identities between the 5'- and 3'-untranslated regions, respectively; 91% amino acid identity between the signal peptides; 82% identity between the acidic spacer sequences; and 38% identity between adenoregulin and dermaseptin b. Because adenoregulin and dermaseptin b have similar precursor designs and antimicrobial spectra, adenoregulin should be considered as a new member of the dermaseptin family and alternatively named dermaseptin b II. Preprodermaseptin b and preproadenoregulin have considerable sequence identities to the precursors encoding the opioid heptapeptides dermorphin, dermenkephalin, and deltorphins. This similarity extended into the 5'-untranslated regions of the mRNAs. These findings suggest that the genes encoding the four preproproteins are all members of the same family

  6. Hydrogen sulfide inhibits opioid withdrawal-induced pain sensitization in rats by down-regulation of spinal calcitonin gene-related peptide expression in the spine.

    Science.gov (United States)

    Yang, Hai-Yu; Wu, Zhi-Yuan; Bian, Jin-Song

    2014-09-01

    Hyperalgesia often occurs in opioid-induced withdrawal syndrome. In the present study, we found that three hourly injections of DAMGO (a μ-opioid receptor agonist) followed by naloxone administration at the fourth hour significantly decreased rat paw nociceptive threshold, indicating the induction of withdrawal hyperalgesia. Application of NaHS (a hydrogen sulfide donor) together with each injection of DAMGO attenuated naloxone-precipitated withdrawal hyperalgesia. RT-PCR and Western blot analysis showed that NaHS significantly reversed the gene and protein expression of up-regulated spinal calcitonin gene-related peptide (CGRP) in naloxone-treated animals. NaHS also inhibited naloxone-induced cAMP rebound and cAMP response element-binding protein (CREB) phosphorylation in rat spinal cord. In SH-SY5Y neuronal cells, NaHS inhibited forskolin-stimulated cAMP production and adenylate cyclase (AC) activity. Moreover, NaHS pre-treatment suppressed naloxone-stimulated activation of protein kinase C (PKC) α, Raf-1, and extracellular signal-regulated kinase (ERK) 1/2 in rat spinal cord. Our data suggest that H2S prevents the development of opioid withdrawal-induced hyperalgesia via suppression of synthesis of CGRP in spine through inhibition of AC/cAMP and PKC/Raf-1/ERK pathways.

  7. cDNAs encoding [D-Ala2]deltorphin precursors from skin of Phyllomedusa bicolor also contain genetic information for three dermorphin-related opioid peptides.

    Science.gov (United States)

    Richter, K; Egger, R; Negri, L; Corsi, R; Severini, C; Kreil, G

    1990-06-01

    We present the structure of four precursors for [D-Ala2]deltorphins I and II as deduced from cDNAs cloned from skin of the frog Phyllomedusa bicolor. These contain the genetic information for one copy of [D-Ala2]deltorphin II and zero, one, or three copies of [D-Ala2]deltorphin I. In each case, the D-alanine of the end product is encoded by a normal GCG codon for L-alanine. In addition, the existence of three peptides related to dermorphin was predicted from the amino acid sequence of the precursors. These peptides were synthesized with a D-alanine in position 2 and their pharmacological properties were tested. Two of them, [Lys7]dermorphin-OH and [Trp4,Asn7]dermorphin-OH, were found to have roughly the same affinity and selectivity for mu-type opioid receptors as dermorphin.

  8. Rationally designed chimeric peptide of met-enkephalin and FMRFa-[D-Ala2,p-Cl-Phe4]YFa induce multiple opioid receptors mediated antinociception and up-regulate their expression.

    Science.gov (United States)

    Vats, Ishwar Dutt; Chaudhary, Snehlata; Sharma, Ahuti; Nath, Mahendra; Pasha, Santosh

    2010-07-25

    The physiological role of NPFF/FMRFa family of peptides appears to be complex and exact mechanism of action of these peptides is not yet completely understood. In same line of scrutiny, another analog of YGGFMKKKFMRFamide (YFa), a chimeric peptide of met-enkephalin and FMRFamide, was rationally designed and synthesized which contain D-alanine and p-Cl-phenylalanine residues at 2nd and 4th positions, respectively i.e., Y-(D-Ala)-G-(p-Cl-Phe)-MKKKFMRFamide ([D-Ala(2), p-Cl-Phe(4)]YFa) in order to achieve improved bioavailability and blood brain barrier penetration. Therefore, present study investigates the possible antinociceptive effect of [D-Ala(2), p-Cl-Phe(4)]YFa on intra-peritoneal (i.p.) administration using tail-flick test in rats followed by its opioid receptor(s) specificity using mu, delta and kappa receptor antagonists. Further, its antinociceptive effect was examined during 6 days of chronic i.p. treatment and assessed effect of this treatment on differential expression of opioid receptors. [D-Ala(2), p-Cl-Phe(4)]YFa in comparison to parent peptide YFa, induce significantly higher dose dependent antinociception in rats which was mediated by all three opioid receptors (mu, delta and kappa). Importantly, it induced comparable antinociception in rats throughout the chronic i.p. treatment and significantly up-regulated the overall expression (mRNA and protein) of mu, delta and kappa opioid receptors. Therefore, pharmacological and molecular behavior of [D-Ala(2), p-Cl-Phe(4)]YFa demonstrate that incorporation of D-alanine and p-Cl-phenylalanine residues at appropriate positions in chimeric peptide leads to altered opioid receptor selectivity and enhanced antinociceptive potency, relative to parent peptide. (c) 2010 Elsevier B.V. All rights reserved.

  9. Discrete mapping of brain Mu and delta opioid receptors using selective peptides: Quantitative autoradiography, species differences and comparison with kappa receptors

    Energy Technology Data Exchange (ETDEWEB)

    Sharif, N.A.; Hughes, J. (Addenbrookes Hospital Site, Cambridge (England))

    1989-05-01

    The opioid peptides, (3H)DAGO and (3H)DPDPE, bound to rat and guinea pig brain homogenates with a high, nanomolar affinity and to a high density of mu and delta receptors, respectively. (3H)DAGO binding to mu receptors was competitively inhibited by unlabelled opioids with the following rank order of potency: DAGO greater than morphine greater than DADLE greater than naloxone greater than etorphine much greater than U50488 much greater than DPDPE. In contrast, (3H)DPDPE binding to delta receptors was inhibited by compounds with the following rank order of potency: DPDPE greater than DADLE greater than etorphine greater than dynorphin(1-8) greater than naloxone much greater than U50488 much greater than DAGO. These profiles were consistent with specific labelling of the mu and delta opioid receptors, respectively. In vitro autoradiographic techniques coupled with computer-assisted image analyses revealed a discrete but differential anatomical localization of mu and delta receptors in the rat and guinea pig brain. In general, mu and delta receptor density in the rat exceeded that in the guinea pig brain and differed markedly from that of kappa receptors in these species. However, while mu receptors were distributed throughout the brain with hotspots in the fore-, mid- and hindbrain of the two rodents, the delta sites were relatively diffusely distributed, and were mainly concentrated in the forebrain with particularly high levels within the olfactory bulb (OB), n. accumbens and striatum. Notable regions of high density of mu receptors in the rat and guinea pig brain were the accessory olfactory bulb, striatal patches and streaks, amygdaloid nuclei, ventral hippocampal subiculum and dentate gyrus, numerous thalamic nuclei, geniculate bodies, central grey, superior and inferior colliculi, solitary and pontine nuclei and s. nigra.

  10. Evidence that morphine and opioid peptides do not share a common pathway with adenosine in inhibiting acetylcholine release from isolated intestine.

    Science.gov (United States)

    Vizi, E S; Somogyi, G T; Magyar, K

    1981-12-01

    1 The release of acetylcholine from guinea-pig ileal isolated longitudinal muscle strip with intact Auerbach's plexus was measured by bioassay and by a radioisotope technique. 2 Normorphine (5 x 10(-7)M) and D-Met2, Pro5-enkephalinamide (D-Met, Pro-EA) reduced the release of acetylcholine. Theophylline, an adenosine antagonist, failed to prevent the inhibitory effect of normorphine or D-Met, Pro-EA. 3 Theophylline (1.7 x 10(-4)M) by itself enhanced the twitch responses to field stimulation (0.1 Hz) but did not prevent the inhibitory effect of normorphine and D-Met, Pro-EA. 4 From the results it can be concluded that morphine and opioid peptides do not share a common pathway with adenosine in inhibiting acetylcholine release from axon terminals of Auerbach's plexus.

  11. Interleukin-1 interaction with neuroregulatory systems: selective enhancement by recombinant human and mouse interleukin-1 of in vitro opioid peptide receptor binding in rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Wiedermann, C.J.

    1989-02-01

    Interleukin-1 (IL-1) exerts a wide variety of biological effects on various cell types and may be regarded as a pleiotropic peptide hormone. Biological evidence suggests that IL-1 participates in the modulation of central nervous system physiology and behavior in a fashion characteristic of neuroendocrine hormones. In this investigation, recombinant (r) human (h) IL-1 and r mouse (m) IL-1 were examined for their modulation of opioid peptide receptor binding in vitro. Experiments were performed on frozen sections of rat brain. Receptor binding of radiolabeled substance P and of radiolabeled neurotensin were not significantly affected by the presence of rIL-1s. Recombinant IL-1s, however, significantly enhanced specific binding of 125I-beta-endorphin (125I-beta-END) and of D-ala2-(tyrosyl-3,5-3H)enkephalin-(5-D-leucine) (3H-D-ALA), equipotently and in a concentration-dependent manner with maximal activity occurring at a concentration of 10 LAF units/ml. The increased binding of 125I-beta-END and 3H-D-ALA was blocked steroselectively by (-)-naloxone and by etorphine, suggesting detection of opiate receptors. In addition, brain distribution patterns of receptors labeled in the presence of rIL-1s corresponded to patterns previously published for opiate receptors. Autoradiographic visualization of receptors revealed that rIL-1s in the different areas of the brain exert their effect on opioid binding with comparable potencies. The data suggest that certain central nervous system effects of IL-1s may be mediated by their selective interaction with opiatergic systems at the receptor level.

  12. Opioid intoxication

    Science.gov (United States)

    ... easily result in intoxication. The provider prescribes a sleep medicine (sedative) in addition to the opioid. The provider ... an opioid with certain other drugs, such as sleep medicines or alcohol Taking the opioid in ways not ...

  13. [The endogenous opioid system and drug addiction].

    Science.gov (United States)

    Maldonado, R

    2010-01-01

    Drug addiction is a chronic brain disorder leading to complex adaptive changes within the brain reward circuits. Several neurotransmitters, including the endogenous opioid system are involved in these changes. The opioid system plays a pivotal role in different aspects of addiction. Thus, opioid receptors and endogenous opioid peptides are largely distributed in the mesolimbic system and modulate dopaminergic activity within the reward circuits. Opioid receptors and peptides are selectively involved in several components of the addictive processes induced by opioids, cannabinoids, psychostimulants, alcohol and nicotine. This review is focused on the contribution of each component of the endogenous opioid system in the addictive properties of the different drugs of abuse. Copyright 2010 Elsevier Masson SAS. All rights reserved.

  14. β-lipotropin is the major opioid-like peptide of human pituitary and rat pars distalis: lack of significant β-endorphin

    International Nuclear Information System (INIS)

    Liotta, A.S.; Suda, T.; Krieger, D.T.

    1978-01-01

    β-Lipotropin is the predominant opioid peptide of the human pituitary and rat pars distalis and is present in concentrations essentially equimolar with corticotropin. When freshly obtained nonfrozen rat anterior pituitaries were homogenized with 0.2 M HCl, approximately 98% of the immunoreactivity detected utilizing an antiserum that crossreacts equally with β-lipotropin and β-endorphin coeluted with 125 I-labeled human β-lipotropin upon molecular sieve chromatography. The remainder of the activity eluted with synthetic human β-endorphin. Similar results were obtained for human pituitary. HCl homogenization of thawed tissue or homogenization of fresh tissue with acetic acid yielded substantially greater concentrations of β-endorphin and decreased concentrations of β-lipotropin. In human subjects, acute anterior pituitary stimulation using either insulin-induced hypoglycemia or vasopressin administration was associated with increased plasma β-lipotropin and corticotropin levels. At the time of peak concentrations, no significant levels of β-endorphin were detectable. These data indicate the lack of significant amounts of β-endorphin in human pituitary. Additionally, there appears to be no specific intrapituitary conversion of β-lipotropin to β-endorphin

  15. Systemic morphine blocks the seizures induced by intracerebroventricular (i.c.v.) injections of opiates and opioid peptides.

    Science.gov (United States)

    Urca, G; Frenk, H

    1982-08-19

    Intracerebroventricular (i.c.v.) injections of the endorphins and of morphine in rats produce highly characteristic, naloxone sensitive, electrographic seizures. In contrast, systemic injections of morphine have been shown to exert a marked anticonvulsant effect. The present study demonstrates that systemic morphine pretreatment can prevent the occurrence of electrographic seizures injected by i.c.v. morphine, Leu-enkephalin and beta-endorphin and that the anti-epileptic effect of morphine can be reversed by naloxone. Male albino rats, previously prepared for chronic i.c.v. injections and EEG recordings, were pretreated with 0--100 mg/kg of intraperitoneal (i.p.) morphine. Thirty five minutes later morphine (520 nmol), Leu-enkephalin (80 nmol) or beta-endorphin (5 nmol) were injected i.c.v. Pretreatment with i.p. morphine blocked the occurrence of seizures induced by morphine and both endogenous opioids. Lower doses of systemic morphine (50 mg/kg) were necessary to block i.c.v. morphine seizures than the dose (100 mg/kg) necessary to block seizures induced by i.c.v. Leu-enkephalin and beta-endorphin. Naloxone (1 mg/kg) administered 25 min following 50 mg/kg of i.p. morphine and preceding the injections of i.c.v. morphine reversed the antiepileptic effect of systemic morphine. These results demonstrate the possible existence of two opiate sensitive systems, one with excitatory-epileptogenic effects and the other possessing inhibitory-antiepileptic properties. The possible relationship between these findings and the known heterogeneity of opiate receptors and opiate actions is discussed.

  16. Emerging Roles for MAS-Related G Protein-Coupled Receptor-X2 in Host Defense Peptide, Opioid, and Neuropeptide-Mediated Inflammatory Reactions.

    Science.gov (United States)

    Ali, Hydar

    2017-01-01

    Mast cells (MCs) are tissue-resident immune cells that contribute to host defense but are best known for their roles in allergic and inflammatory diseases. In humans, MCs are divided into two subtypes based on the protease content of their secretory granules. Thus, human lung MCs contain only tryptase and are known as MC T , whereas skin MCs contain both tryptase and chymase and are known as MC TC . Patients with severe asthma display elevated MCs in the lung, which undergo phenotypic change from MC T to MC TC . Although the human genome contains four Mas related G protein coupled receptor X (MRGPRX) genes, an important feature of MC TC is that they selectively express MRGPRX2. It is activated by antimicrobial host defense peptides such as human β-defensins and the cathelicidin LL-37 and likely contributes to host defense. MRGPRX2 is also a receptor for the neuropeptide substance P, major basic protein, eosinophil peroxidase, opioids, and many FDA-approved cationic drugs. Increased expression of MRGPRX2 or enhanced downstream signaling likely contributes to chronic inflammatory diseases such as rosacea, atopic dermatitis, chronic urticaria, and severe asthma. In this chapter, I will discuss the expression profile and function of MRGPRX1-4 and review the emerging roles of MRGPRX2 on host defense, chronic inflammatory diseases, and drug-induced pseudoallergic reactions. I will also examine the novel aspects of MRGPRX2 signaling in MCs as it related to degranulation and review the mechanisms of its regulation. © 2017 Elsevier Inc. All rights reserved.

  17. Prescription Opioids

    Science.gov (United States)

    ... therapy in a primary care setting struggles with opioid addiction. 4,5,6 Once addicted, it can be ... of drug overdose deaths involving methadone and other opioid analgesics in West Virginia. Addiction 2009;104(9):1541-8. Dunn KM, Saunders ...

  18. /sup 3/H)-(H-D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2) ((/sup 3/H)CTOP), a potent and highly selective peptide for mu opioid receptors in rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Hawkins, K.N.; Knapp, R.J.; Lui, G.K.; Gulya, K.; Kazmierski, W.; Wan, Y.P.; Pelton, J.T.; Hruby, V.J.; Yamamura, H.I.

    1989-01-01

    The cyclic, conformationally restricted octapeptide (3H)-(H-D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2) ((3H)CTOP) was synthesized and its binding to mu opioid receptors was characterized in rat brain membrane preparations. Association rates (k+1) of 1.25 x 10(8) M-1 min-1 and 2.49 x 10(8) M-1 min-1 at 25 and 37 degrees C, respectively, were obtained, whereas dissociation rates (k-1) at the same temperatures were 1.93 x 10(-2) min-1 and 1.03 x 10(-1) min-1 at 25 and 37 degrees C, respectively. Saturation isotherms of (3H)CTOP binding to rat brain membranes gave apparent Kd values of 0.16 and 0.41 nM at 25 and 37 degrees C, respectively. Maximal number of binding sites in rat brain membranes were found to be 94 and 81 fmol/mg of protein at 25 and 37 degrees C, respectively. (3H)CTOP binding over a concentration range of 0.1 to 10 nM was best fit by a one site model consistent with binding to a single site. The general effect of different metal ions and guanyl-5'-yl-imidodiphosphate on (3H)CTOP binding was to reduce its affinity. High concentrations (100 mM) of sodium also produced a reduction of the apparent mu receptor density. Utilizing the delta opioid receptor specific peptide (3H)-(D-Pen2,D-Pen5)enkephalin, CTOP appeared to be about 2000-fold more specific for mu vs. delta opioid receptor than naloxone. Specific (3H)CTOP binding was inhibited by a large number of opioid or opiate ligands.

  19. Opioid Addiction

    Science.gov (United States)

    ... breathing rate nausea, vomiting constipation physical agitation poor decision making abandoning responsibilities slurred speech sleeping more or less than normal mood swings euphoria (feeling high) irritability depression lowered motivation anxiety attacks. Symptoms of opioid overdose An overdose ...

  20. Opioid Overdose

    Science.gov (United States)

    ... Updated: 03/10/2016 Medications to Treat OPIOID ADDICTION Methadone Naltrexone Buprenorphine Related SAMHSA Resources Behavioral Health ... Systems Integration Health Disparities Health Financing Health Information Technology HIV, AIDS, and Viral Hepatitis Homelessness and Housing ...

  1. Molecular characterization of opioid receptors

    Energy Technology Data Exchange (ETDEWEB)

    Howard, A.D.

    1986-01-01

    The aim of this research was to purify and characterize active opioid receptors and elucidate molecular aspects of opioid receptor heterogeneity. Purification to apparent homogeneity of an opioid binding protein from bovine caudate was achieved by solubilization in the non-ionic detergent, digitonin, followed by sequential chromatography on the opiate affinity matrix, ..beta..-naltrexylethylenediamine-CH-Sepharose 4B, and on the lectine affinity matrix, wheat germ agglutinin-agarose. Polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate (SDS-PAGE) followed by autoradiography revealed that radioiodinated purified receptor gave a single band. Purified receptor preparations showed a specific activity of 12,000-15,000 fmol of opiate bound per mg of protein. Radioiodinated human beta-endorphin (/sup 125/I-beta-end/sub H/) was used as a probe to investigate the ligand binding subunits of mu and delta opioid receptors. /sup 125/I-beta-end/sub H/ was shown to bind to a variety of opioid receptor-containing tissues with high affinity and specificity with preference for mu and delta sites, and with little, if any, binding to kappa sites. Affinity crosslinking techniques were employed to covalently link /sup 125/I-beta-end/sub H/ to opioid receptors, utilizing derivatives of bis-succinimidyl esters that are bifunctional crosslinkers with specificities for amino and sulfhydryl groups. This, and competition experiments with high type-selective ligands, permitted the assignment of two labeled peptides to their receptor types, namely a peptide of M/sub r/ = 65,000 for mu receptors and one of M/sub r/ = 53,000 for delta receptors.

  2. Chronic ethanol consumption in rats produces opioid antinociceptive tolerance through inhibition of mu opioid receptor endocytosis.

    Directory of Open Access Journals (Sweden)

    Li He

    Full Text Available It is well known that the mu-opioid receptor (MOR plays an important role in the rewarding properties of ethanol. However, it is less clear how chronic ethanol consumption affects MOR signaling. Here, we demonstrate that rats with prolonged voluntary ethanol consumption develop antinociceptive tolerance to opioids. Signaling through the MOR is controlled at many levels, including via the process of endocytosis. Importantly, agonists at the MOR that promote receptor endocytosis, such as the endogenous peptides enkephalin and β-endorphin, show a reduced propensity to promote antinociceptive tolerance than do agonists, like morphine, which do not promote receptor endocytosis. These observations led us to examine whether chronic ethanol consumption produced opioid tolerance by interfering with MOR endocytosis. Indeed, here we show that chronic ethanol consumption inhibits the endocytosis of MOR in response to opioid peptide. This loss of endocytosis was accompanied by a dramatic decrease in G protein coupled receptor kinase 2 (GRK2 protein levels after chronic drinking, suggesting that loss of this component of the trafficking machinery could be a mechanism by which endocytosis is lost. We also found that MOR coupling to G-protein was decreased in ethanol-drinking rats, providing a functional explanation for loss of opioid antinociception. Together, these results suggest that chronic ethanol drinking alters the ability of MOR to endocytose in response to opioid peptides, and consequently, promotes tolerance to the effects of opioids.

  3. γ-endorphin and Nα-acetyl-γ-endorphin interfere with distinct dopaminergic systems in the nucleus accumbens via opioid and non-opioid mechanisms

    NARCIS (Netherlands)

    Ree, J.M. van; Gaffori, O.; Kiraly, I.

    1984-01-01

    Low doses (10 ng) of the dopamine agonist apomorphine induced hypolocomotion when injected into the nucleus accumbens of rats. This behavioral response was antagonized by local treatment with either the opioid peptide γ-endorphin (γE) or the non-opioid peptide Nα-acetyl-γ-endorphin (AcγE) in a dose

  4. Molecular and cellular mechanisms of the age-dependency of opioid analgesia and tolerance

    Directory of Open Access Journals (Sweden)

    Zhao Jing

    2012-05-01

    Full Text Available Abstract The age-dependency of opioid analgesia and tolerance has been noticed in both clinical observation and laboratory studies. Evidence shows that many molecular and cellular events that play essential roles in opioid analgesia and tolerance are actually age-dependent. For example, the expression and functions of endogenous opioid peptides, multiple types of opioid receptors, G protein subunits that couple to opioid receptors, and regulators of G protein signaling (RGS proteins change with development and age. Other signaling systems that are critical to opioid tolerance development, such as N-methyl-D-aspartic acid (NMDA receptors, also undergo age-related changes. It is plausible that the age-dependent expression and functions of molecules within and related to the opioid signaling pathways, as well as age-dependent cellular activity such as agonist-induced opioid receptor internalization and desensitization, eventually lead to significant age-dependent changes in opioid analgesia and tolerance development.

  5. Healthy Adult Male Facial Skin Surface Lipid Pheromone p.o. to Treat Opioid Addiction

    Science.gov (United States)

    2018-03-20

    Opioid Addiction; Opioid Abuse, Continuous Use; Opioid Use; Opioid-Related Disorders; Paternal Pheromone Deficiency; Opioid Dependence; Opioid Abuse; Opioid-use Disorder; Opioid Intoxication; Opioid Abuse, Episodic

  6. cDNAs encoding [D-Ala2]deltorphin precursors from skin of Phyllomedusa bicolor also contain genetic information for three dermorphin-related opioid peptides.

    OpenAIRE

    Richter, K; Egger, R; Negri, L; Corsi, R; Severini, C; Kreil, G

    1990-01-01

    We present the structure of four precursors for [D-Ala2]deltorphins I and II as deduced from cDNAs cloned from skin of the frog Phyllomedusa bicolor. These contain the genetic information for one copy of [D-Ala2]deltorphin II and zero, one, or three copies of [D-Ala2]deltorphin I. In each case, the D-alanine of the end product is encoded by a normal GCG codon for L-alanine. In addition, the existence of three peptides related to dermorphin was predicted from the amino acid sequence of the pre...

  7. Opioid adjuvant strategy: improving opioid effectiveness.

    Science.gov (United States)

    Bihel, Frédéric

    2016-01-01

    Opioid analgesics continue to be the mainstay of pharmacologic treatment of moderate to severe pain. Many patients, particularly those suffering from chronic pain, require chronic high-dose analgesic therapy. Achieving clinical efficacy and tolerability of such treatment regimens is hampered by the appearance of opioid-induced side effects such as tolerance, hyperalgesia and withdrawal syndrome. Among the therapeutic options to improve the opioid effectiveness, this current review focuses on strategies combining opioids to other drugs that can modulate opioid-mediated effects. We will discuss about experimental evidences reported for several potential opioid adjuvants, including N-methyl-D-aspartate receptor antagonists, 5-HT7 agonists, sigma-1 antagonists, I2-R ligands, cholecystokinin antagonists, neuropeptide FF-R antagonists and toll-like receptor 4 antagonists.

  8. Neonatal opioid withdrawal syndrome.

    Science.gov (United States)

    Sutter, Mary Beth; Leeman, Lawrence; Hsi, Andrew

    2014-06-01

    Neonatal opioid withdrawal syndrome is common due to the current opioid addiction epidemic. Infants born to women covertly abusing prescription opioids may not be identified as at risk until withdrawal signs present. Buprenorphine is a newer treatment for maternal opioid addiction and appears to result in a milder withdrawal syndrome than methadone. Initial treatment is with nonpharmacological measures including decreasing stimuli, however pharmacological treatment is commonly required. Opioid monotherapy is preferred, with phenobarbital or clonidine uncommonly needed as adjunctive therapy. Rooming-in and breastfeeding may decease the severity of withdrawal. Limited evidence is available regarding long-term effects of perinatal opioid exposure. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Radioreceptor opioid assay

    International Nuclear Information System (INIS)

    Miller, R.J.; Chang, K.-J.

    1981-01-01

    A radioreceptor assay is described for assaying opioid drugs in biological fluids. The method enables the assay of total opioid activity, being specific for opioids as a class but lacking specificity within the class. A radio-iodinated opioid and the liquid test sample are incubated with an opiate receptor material. The percentage inhibition of the binding of the radio-iodinated compound to the opiate receptor is calculated and the opioid activity of the test liquid determined from a standard curve. Examples of preparing radio-iodinated opioids and assaying opioid activity are given. A test kit for the assay is described. Compared to other methods, this assay is cheap, easy and rapid. (U.K.)

  10. Genetics Home Reference: opioid addiction

    Science.gov (United States)

    ... Facebook Twitter Home Health Conditions Opioid addiction Opioid addiction Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Opioid addiction is a long-lasting (chronic) disease that can ...

  11. Opioid-induced preconditioning: recent advances and future perspectives.

    Science.gov (United States)

    Peart, Jason N; Gross, Eric R; Gross, Garrett J

    2005-01-01

    Opioids, named by Acheson for compounds with morphine-like actions despite chemically distinct structures, have received much research interest, particularly for their central nervous system (CNS) actions involved in pain management, resulting in thousands of scientific papers focusing on their effects on the CNS and other organ systems. A more recent area which may have great clinical importance concerns the role of opioids, either endogenous or exogenous compounds, in limiting the pathogenesis of ischemia-reperfusion injury in heart and brain. The role of endogenous opioids in hibernation provides tantalizing evidence for the protective potential of opioids against ischemia or hypoxia. Mammalian hibernation, a distinct energy-conserving state, is associated with depletion of energy stores, intracellular acidosis and hypoxia, similar to those which occur during ischemia. However, despite the potentially detrimental cellular state induced with hibernation, the myocardium remains resilient for many months. What accounts for the hypoxia-tolerant state is of great interest. During hibernation, circulating levels of opioid peptides are increased dramatically, and indeed, are considered a "trigger" of hibernation. Furthermore, administration of opioid antagonists can effectively reverse hibernation in mammals. Therefore, it is not surprising that activation of opioid receptors has been demonstrated to preserve cellular status following a hypoxic insult, such as ischemia-reperfusion in many model systems including the intestine [Zhang, Y., Wu, Y.X., Hao, Y.B., Dun, Y. Yang, S.P., 2001. Role of endogenous opioid peptides in protection of ischemic preconditioning in rat small intestine. Life Sci. 68, 1013-1019], skeletal muscle [Addison, P.D., Neligan, P.C., Ashrafpour, H., Khan, A., Zhong, A., Moses, M., Forrest, C.R., Pang, C.Y., 2003. Noninvasive remote ischemic preconditioning for global protection of skeletal muscle against infarction. Am. J. Physiol. Heart Circ

  12. Differences between opioids

    DEFF Research Database (Denmark)

    Drewes, Asbjørn; Jensen, Rasmus D.; Nielsen, Lecia M.

    2013-01-01

    to morphine. Although this approach is recognized as cost-effective in most cases there is solid evidence that, on an individual patient basis, opioids are not all equal. Therefore it is important to have an armamentarium of strong analgesics in clinical practice to ensure a personalized approach in patients...... who do not respond to standard treatment. In this review we highlight differences between opioids in human studies from a pharmacological, experimental, clinical and health economics point of view. We provide evidence that individuals respond differently to opioids, and that general differences......Clinical studies comparing the response and side effects of various opioids have not been able to show robust differences between drugs. Hence, recommendations of the regulatory authorities have been driven by costs with a general tendency in many countries to restrict physician's use of opioids...

  13. Is this ?complicated? opioid withdrawal?

    OpenAIRE

    Parkar, S.R.; Seethalakshmi, R; Adarkar, S; Kharawala, S

    2006-01-01

    Seven patients with opioid dependence admitted in the de-addiction centre for detoxification developed convulsions and delirium during the withdrawal phase. After ruling out all other possible causes of these complications, opioid withdrawal seemed to emerge as the most likely explanation. The unpredictability of the course of opioid dependence and withdrawal needs to be considered when treating patients with opioid dependence.

  14. The endogenous opioid system: a common substrate in drug addiction.

    Science.gov (United States)

    Trigo, José Manuel; Martin-García, Elena; Berrendero, Fernando; Robledo, Patricia; Maldonado, Rafael

    2010-05-01

    Drug addiction is a chronic brain disorder leading to complex adaptive changes within the brain reward circuits that involve several neurotransmitters. One of the neurochemical systems that plays a pivotal role in different aspects of addiction is the endogenous opioid system (EOS). Opioid receptors and endogenous opioid peptides are largely distributed in the mesolimbic system and modulate dopaminergic activity within these reward circuits. Chronic exposure to the different prototypical drugs of abuse, including opioids, alcohol, nicotine, psychostimulants and cannabinoids has been reported to produce significant alterations within the EOS, which seem to play an important role in the development of the addictive process. In this review, we will describe the adaptive changes produced by different drugs of abuse on the EOS, and the current knowledge about the contribution of each component of this neurobiological system to their addictive properties.

  15. Opioid withdrawal syndrome: emerging concepts and novel therapeutic targets.

    Science.gov (United States)

    Rehni, Ashish K; Jaggi, Amteshwar S; Singh, Nirmal

    2013-02-01

    Opioid withdrawal syndrome is a debilitating manifestation of opioid dependence and responds poorly to the available clinical therapies. Studies from various in vivo and in vitro animal models of opioid withdrawal syndrome have led to understanding of its pathobiology which includes complex interrelated pathways leading to adenylyl cyclase superactivation based central excitation. Advancements in the elucidation of opioid withdrawal syndrome mechanisms have revealed a number of key targets that have been hypothesized to modulate clinical status. The present review discusses the neurobiology of opioid withdrawal syndrome and its therapeutic target recptors like calcitonin gene related peptide receptors (CGRP), N-methyl-D-aspartate (NMDA) receptors, gamma aminobutyric acid receptors (GABA), G-proteingated inwardly rectifying potassium (GIRK) channels and calcium channels. The present review further details the potential role of second messengers like calcium (Ca2+) / calmodulin-dependent protein kinase (CaMKII), nitric oxide synthase, cytokines, arachidonic acid metabolites, corticotropin releasing factor, fos and src kinases in causing opioid withdrawal syndrome. The exploitation of these targets may provide effective therapeutic agents for the management of opioid dependence-induced abstinence syndrome.

  16. Medications Development for Opioid Abuse

    Science.gov (United States)

    Negus, S. Stevens; Banks, Matthew L.

    2013-01-01

    Here we describe methods for preclinical evaluation of candidate medications to treat opioid abuse and dependence. Our perspective is founded on the propositions that (1) drug self-administration procedures provide the most direct method for assessment of medication effects, (2) procedures that assess choice between opioid and nondrug reinforcers are especially useful, and (3) the states of opioid dependence and withdrawal profoundly influence both opioid reinforcement and the effects of candidate medications. Effects of opioid medications on opioid choice in nondependent and opioid-dependent subjects are reviewed. Various nonopioid medications have also been examined, but none yet have been identified that safely and reliably reduce opioid choice. Future research will focus on (1) strategies for increasing safety and/or effectiveness of opioid medications, and (2) continued development of nonopioids such as inhibitors of endocannabinoid catabolic enzymes or inhibitors of opioid-induced glial activation. PMID:23125072

  17. Sleep-waking states and the endogenous opioid system

    NARCIS (Netherlands)

    O.E. Ukponmwan (Otas)

    1986-01-01

    textabstractIn the general introductory part of this thesis (Chapters and 2) a review of some pertinent literature related to sleep-waking states and opioid peptides is offered. A global view of the neurochemical mechanisms and theories of functions of sleep, as well as the physiological and

  18. Hiperalgesia Inducida por Opioides

    OpenAIRE

    Jiménez Salazar, Andrés

    2013-01-01

    Los opioides producen analgesia a través de un efecto inhibitorio sobre el sistema nociceptivo principalmente. Hasta la fecha, los opioides siguen siendo los analgésicos más potentes para el manejo de dolor moderado a severo. La Asociación Internacional del Estudio del Dolor (IASP, en inglés) define hiperalgesia como "un aumento de la respuesta a un estímulo que normalmente es doloroso". En contraste, está bien establecido que la terapia crónica con opioides se asocia con el desarrollo de ...

  19. Are peripheral opioid antagonists the solution to opioid side effects?

    LENUS (Irish Health Repository)

    Bates, John J

    2012-02-03

    Opioid medication is the mainstay of therapy for severe acute and chronic pain. Unfortunately, the side effects of these medications can affect patient comfort and safety, thus limiting their proven therapeutic potential. Whereas the main analgesic effects of opioids are centrally mediated, many of the common side effects are mediated via peripheral receptors. Novel peripheral opioid antagonists have been recently introduced that can block the peripheral actions of opioids without affecting centrally mediated analgesia. We review the clinical and experimental evidence of their efficacy in ameliorating opioid side effects and consider what further information might be useful in defining their role. IMPLICATIONS: The major analgesic effects of opioid medication are mediated within the brain and spinal cord. Many of the side effects of opioids are caused by activation of receptors outside these areas. Recently developed peripherally restricted opioid antagonists have the ability to block many opioid side effects without affecting analgesia.

  20. Benzodiazepines and Opioid

    Science.gov (United States)

    ... Alcohol Club Drugs Cocaine Fentanyl Hallucinogens Inhalants Heroin Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Over-the-Counter Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/ ...

  1. Opioid Summaries by State

    Science.gov (United States)

    ... Alcohol Club Drugs Cocaine Fentanyl Hallucinogens Inhalants Heroin Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Over-the-Counter Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/ ...

  2. Opioid Overdose Crisis

    Science.gov (United States)

    ... Alcohol Club Drugs Cocaine Fentanyl Hallucinogens Inhalants Heroin Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Over-the-Counter Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/ ...

  3. Opioid Prescribing PSA (:60)

    Centers for Disease Control (CDC) Podcasts

    This 60 second public service announcement is based on the July 2017 CDC Vital Signs report. Higher opioid prescribing puts patients at risk for addiction and overdose. Learn what can be done about this serious problem.

  4. Are Prescription Opioids Driving the Opioid Crisis? Assumptions vs Facts.

    Science.gov (United States)

    Rose, Mark Edmund

    2018-04-01

    Sharp increases in opioid prescriptions, and associated increases in overdose deaths in the 2000s, evoked widespread calls to change perceptions of opioid analgesics. Medical literature discussions of opioid analgesics began emphasizing patient and public health hazards. Repetitive exposure to this information may influence physician assumptions. While highly consequential to patients with pain whose function and quality of life may benefit from opioid analgesics, current assumptions about prescription opioid analgesics, including their role in the ongoing opioid overdose epidemic, have not been scrutinized. Information was obtained by searching PubMed, governmental agency websites, and conference proceedings. Opioid analgesic prescribing and associated overdose deaths both peaked around 2011 and are in long-term decline; the sharp overdose increase recorded in 2014 was driven by illicit fentanyl and heroin. Nonmethadone prescription opioid analgesic deaths, in the absence of co-ingested benzodiazepines, alcohol, or other central nervous system/respiratory depressants, are infrequent. Within five years of initial prescription opioid misuse, 3.6% initiate heroin use. The United States consumes 80% of the world opioid supply, but opioid access is nonexistent for 80% and severely restricted for 4.1% of the global population. Many current assumptions about opioid analgesics are ill-founded. Illicit fentanyl and heroin, not opioid prescribing, now fuel the current opioid overdose epidemic. National discussion has often neglected the potentially devastating effects of uncontrolled chronic pain. Opioid analgesic prescribing and related overdoses are in decline, at great cost to patients with pain who have benefited or may benefit from, but cannot access, opioid analgesic therapy.

  5. Adrenergic Agonists Bind to Adrenergic-Receptor-Like Regions of the Mu Opioid Receptor, Enhancing Morphine and Methionine-Enkephalin Binding: A New Approach to "Biased Opioids"?

    Science.gov (United States)

    Root-Bernstein, Robert; Turke, Miah; Subhramanyam, Udaya K Tiruttani; Churchill, Beth; Labahn, Joerg

    2018-01-17

    Extensive evidence demonstrates functional interactions between the adrenergic and opioid systems in a diversity of tissues and organs. While some effects are due to receptor and second messenger cross-talk, recent research has revealed an extracellular, allosteric opioid binding site on adrenergic receptors that enhances adrenergic activity and its duration. The present research addresses whether opioid receptors may have an equivalent extracellular, allosteric adrenergic binding site that has similar enhancing effects on opioid binding. Comparison of adrenergic and opioid receptor sequences revealed that these receptors share very significant regions of similarity, particularly in some of the extracellular and transmembrane regions associated with adrenergic binding in the adrenergic receptors. Five of these shared regions from the mu opioid receptor (muOPR) were synthesized as peptides and tested for binding to adrenergic, opioid and control compounds using ultraviolet spectroscopy. Adrenergic compounds bound to several of these muOPR peptides with low micromolar affinity while acetylcholine, histamine and various adrenergic antagonists did not. Similar studies were then conducted with purified, intact muOPR with similar results. Combinations of epinephrine with methionine enkephalin or morphine increased the binding of both by about half a log unit. These results suggest that muOPR may be allosterically enhanced by adrenergic agonists.

  6. Structure of the [delta]-opioid receptor bound to naltrindole

    Energy Technology Data Exchange (ETDEWEB)

    Granier, Sébastien; Manglik, Aashish; Kruse, Andrew C.; Kobilka, Tong Sun; Thian, Foon Sun; Weis, William I.; Kobilka, Brian K. (Stanford-MED)

    2012-07-11

    The opioid receptor family comprises three members, the {mu}-, {delta}- and {kappa}-opioid receptors, which respond to classical opioid alkaloids such as morphine and heroin as well as to endogenous peptide ligands like endorphins. They belong to the G-protein-coupled receptor (GPCR) superfamily, and are excellent therapeutic targets for pain control. The {delta}-opioid receptor ({delta}-OR) has a role in analgesia, as well as in other neurological functions that remain poorly understood. The structures of the {mu}-OR and {kappa}-OR have recently been solved. Here we report the crystal structure of the mouse {delta}-OR, bound to the subtype-selective antagonist naltrindole. Together with the structures of the {mu}-OR and {kappa}-OR, the {delta}-OR structure provides insights into conserved elements of opioid ligand recognition while also revealing structural features associated with ligand-subtype selectivity. The binding pocket of opioid receptors can be divided into two distinct regions. Whereas the lower part of this pocket is highly conserved among opioid receptors, the upper part contains divergent residues that confer subtype selectivity. This provides a structural explanation and validation for the 'message-address' model of opioid receptor pharmacology, in which distinct 'message' (efficacy) and 'address' (selectivity) determinants are contained within a single ligand. Comparison of the address region of the {delta}-OR with other GPCRs reveals that this structural organization may be a more general phenomenon, extending to other GPCR families as well.

  7. Exercise induced asthma and endogenous opioids.

    Science.gov (United States)

    Gaillard, R C; Bachman, M; Rochat, T; Egger, D; de Haller, R; Junod, A F

    1986-01-01

    Concentrations of endogenous opioid peptides in the plasma are increased during exercise and these substances have been implicated in the pathogenesis of asthma induced by chloropropramide and alcohol in diabetic patients. This work was undertaken to determine whether exercise induced asthma might be mediated by endogenous opioids. Plasma beta endorphin, met-enkephalin, and adrenocorticotrophic hormone (ACTH) concentrations were measured in five asthmatic patients and five normal volunteers breathing cold air during exercise. In four of the patients the effect of an infusion of naloxone on FEV1 was also measured during exercise induced asthma. Exercise produced acute bronchoconstriction in all asthmatics, characterised by a fall in FEV1; whereas no change occurred in normal subjects. There was no difference in plasma met-enkephalin, beta endorphin, and ACTH concentration between the two groups. Infusion of naloxone neither prevented nor worsened exercise induced asthma. These data suggest that endogenous opioids probably do not play a part in the development of exercise induced asthma. PMID:2944240

  8. Neurobiological mechanisms involved in nicotine dependence and reward: participation of the endogenous opioid system

    Science.gov (United States)

    Berrendero, Fernando; Robledo, Patricia; Trigo, José Manuel; Martín-García, Elena; Maldonado, Rafael

    2010-01-01

    Nicotine is the primary component of tobacco that maintains the smoking habit and develops addiction. The adaptive changes of nicotinic acetylcholine receptors produced by repeated exposure to nicotine play a crucial role in the establishment of dependence. However, other neurochemical systems also participate in the addictive effects of nicotine including glutamate, cannabinoids, GABA and opioids. This review will cover the involvement of these neurotransmitters in nicotine addictive properties, with a special emphasis on the endogenous opioid system. Thus, endogenous enkephalins and beta-endorphins acting on mu-opioid receptors are involved in nicotine rewarding effects, whereas opioid peptides derived from prodynorphin participate in nicotine aversive responses. An upregulation of mu-opioid receptors has been reported after chronic nicotine treatment that could counteract the development of nicotine tolerance, whereas the downregulation induced on kappa-opioid receptors seems to facilitate nicotine tolerance. Endogenous enkephalins acting on mu-opioid receptors also play a role in the development of physical dependence to nicotine. In agreement with these actions of the endogenous opioid system, the opioid antagonist naltrexone has shown to be effective for smoking cessation in certain subpopulations of smokers. PMID:20170672

  9. Opioid system and human emotions.

    Science.gov (United States)

    Nummenmaa, Lauri; Tuominen, Lauri

    2017-04-10

    Emotions are states of vigilant readiness that guide human and animal behaviour during survival-salient situations. Categorical models of emotions posit neurally and physiologically distinct basic human emotions (anger, fear, disgust, happiness, sadness and surprise) that govern different survival functions. Opioid receptors are expressed abundantly in the mammalian emotion circuit, and the opioid system modulates a variety of functions related to arousal and motivation. Yet, its specific contribution to different basic emotions has remained poorly understood. Here, we review how the endogenous opioid system and particularly the μ receptor contribute to emotional processing in humans. Activation of the endogenous opioid system is consistently associated with both pleasant and unpleasant emotions. In general, exogenous opioid agonists facilitate approach-oriented emotions (anger, pleasure) and inhibit avoidance-oriented emotions (fear, sadness). Opioids also modulate social bonding and affiliative behaviour, and prolonged opioid abuse may render both social bonding and emotion recognition circuits dysfunctional. However, there is no clear evidence that the opioid system is able to affect the emotions associated with surprise and disgust. Taken together, the opioid systems contribute to a wide array of positive and negative emotions through their general ability to modulate the approach versus avoidance motivation associated with specific emotions. Because of the protective effects of opioid system-mediated prosociality and positive mood, the opioid system may constitute an important factor contributing to psychological and psychosomatic resilience. © 2017 The British Pharmacological Society.

  10. Opioid Prescribing PSA (:60)

    Centers for Disease Control (CDC) Podcasts

    2017-07-06

    This 60 second public service announcement is based on the July 2017 CDC Vital Signs report. Higher opioid prescribing puts patients at risk for addiction and overdose. Learn what can be done about this serious problem.  Created: 7/6/2017 by Centers for Disease Control and Prevention (CDC).   Date Released: 7/6/2017.

  11. Opioid dependence - management in general practice.

    Science.gov (United States)

    Frei, Matthew

    2010-08-01

    Addiction to opioids, or opioid dependence, encompasses the biopsychosocial dysfunction seen in illicit heroin injectors, as well as aberrant behaviours in patients prescribed opioids for chronic nonmalignant pain. To outline the management of opioid dependence using opioid pharmacotherapy as part of a comprehensive chronic illness management strategy. The same principles and skills general practitioners employ in chronic illness management underpin the care of patients with opioid dependence. Opioid pharmacotherapy, with the substitution medications methadone and buprenorphine, is an effective management of opioid dependence. Training and regulatory requirements for prescribing opioid pharmacotherapies vary between jurisdictions, but this treatment should be within the scope of most Australian GPs.

  12. Opioid Abuse and Addiction - Multiple Languages

    Science.gov (United States)

    ... Spanish) PDF The basics - Opioids, part 1 - English MP3 The basics - Opioids, part 1 - español (Spanish) MP3 The basics - Opioids, part 1 - English MP4 The ... español (Spanish) PDF Pain - Opioids, part 2 - English MP3 Pain - Opioids, part 2 - español (Spanish) MP3 Pain - ...

  13. New features of the delta opioid receptor: conformational properties of deltorphin I analogues.

    Science.gov (United States)

    Balboni, G; Marastoni, M; Picone, D; Salvadori, S; Tancredi, T; Temussi, P A; Tomatis, R

    1990-06-15

    Deltorphin I is an opioid peptide of sequence H-Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2, recently isolated from the skin of Phyllomedusa bicolor. Its enormous selectivity towards the delta opioid receptor and the similarity of the conformation of the N-terminal part of the sequence with that of dermorphin (H-Tyr-D-Ala-he-Gly-Tyr-Pro-Ser-NH2), a mu selective peptide, prompted the synthesis, biological evaluation and comparative conformational study of four analogs. A 1H-NMR study showed that the conformational preferences of the N-terminal sequences of all peptides are similar. The different selectivities towards opioid receptors have been interpreted in terms of charge effects in the interaction with the membrane and at the receptor site and of hydrophobicity of the C-terminal part, when structured in a folded conformation.

  14. Nicotine and endogenous opioids: neurochemical and pharmacological evidence.

    Science.gov (United States)

    Hadjiconstantinou, Maria; Neff, Norton H

    2011-06-01

    Although the mesolimbic dopamine hypothesis is the most influential theory of nicotine reward and reinforcement, there has been a consensus that other neurotransmitter systems contribute to the addictive properties of nicotine as well. In this regard, the brain opioidergic system is of interest. Striatum is rich in opioid peptides and opioid receptors, and striatal opioidergic neurons are engaged in a bidirectional communication with midbrain dopaminergic neurons, closely regulating each other's activity. Enkephalins and dynorphins exert opposing actions on dopaminergic neurons, increasing and decreasing dopamine release respectively, and are components of circuits promoting positive or negative motivational and affective states. Moreover, dopamine controls the synthesis of striatal enkephalins and dynorphins. Evidence suggests that opioidergic function is altered after nicotine and endogenous opioids are involved in nicotine's behavioral effects. 1) The synthesis and release of β-endorphin, met-enkephalin and dynorphin in brain, especially nucleus accumbens (NAc), are altered after acute or chronic nicotine treatment and during nicotine withdrawal. 2) Although opioid receptor binding and mRNA do not appear to change in the striatum during nicotine withdrawal, the activity of κ-opioid (KOPr) and δ-opioid (DOPr) receptors is attenuated in NAc. 3) The nicotine withdrawal syndrome reminisces that of opiates, and naloxone precipitates some of its somatic, motivational, and affective signs. 4) Genetic and pharmacological studies indicate that μ-opioid (MOPr) receptors are mainly involved in nicotine reward, while DOPrs contribute to the emotional and KOPrs to the aversive responses of nicotine. 5) Finally, MOPrs and enkephalin, but not β-endorphin or dynorphin, are necessary for the physical manifestations of nicotine withdrawal. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. Copyright © 2010 Elsevier

  15. The opioid receptors of the rat periaqueductal gray

    Energy Technology Data Exchange (ETDEWEB)

    Fedynyshyn, J.P.

    1989-01-01

    The opioid binding characteristics of the rat (PAG) and the signal transduction mechanisms of the opioid receptors were examined with in vitro radioligand binding, GTPase, adenylyl cyclase, and inositol phosphate assays. The nonselective ligand {sup 3}H-ethylketocyclazocine (EKC), the {mu} and {delta} selective ligand {sup 3}H-(D-Ala{sup 2}, D-Leu{sup 5}) enkephalin (DADLE), the {mu} selective ligand {sup 3}H-(D-Ala{sup 2}, N-methyl Phe{sup 4}, Glyol{sup 5}) enkephalin (DAGO), and the {delta} selective ligand {sup 3}H-(D-Pen{sup 2}, D-Pen{sup 5}) enkephalin (DPDPE) were separately used as tracer ligands to label opioid binding sites in rat PAG enriched P{sub 2} membrane in competition with unlabeled DADLE, DAGO, DPDPE, or the {kappa} selective ligand trans-3,4-dichloro-N-(2-(1-pyrrolidinyl)cyclohexyl)benzeneacetamide, methane sulfonate, hydrate (U50, 488H). Only {mu} selective high affinity opioid binding was observed. No high affinity {delta} or {kappa} selective binding was detected. {sup 3}H-DAGO was used as a tracer ligand to label {mu} selective high affinity opioid binding sites in PAG enriched P{sub 2} membrane in competition with unlabeled {beta}-endorphin, dynorphin A (1-17), BAM-18, methionine enkephalin, dynorphin A (1-8), and leucine enkephalin. Of these endogenous opioid peptides only those with previously reported high affinity {mu} type opioid binding activity competed with {sup 3}H-DAGO for binding sites in rat PAG enriched P{sub 2} membrane with affinities similar to that of unlabeled DAGO.

  16. Opioid and nicotine receptors affect growth regulation of human lung cancer cell lines

    International Nuclear Information System (INIS)

    Maneckjee, R.; Minna, J.D.

    1990-01-01

    Using specific radioactively-labeled ligands, the authors find that lung cancer cell lines of diverse histologic types express multiple, high-affinity membrane receptors for μ, δ, and κ opioid agonists and for nicotine and α-bungarotoxin. These receptors are biologically active because cAMP levels decreased in lung cancer cells after opioid and nicotine application. Nicotine at concentrations found in the blood of smokers had no effect on in vitro lung cancer cell growth, whereas μ, δ, and κ opioid agonists at low concentrations inhibited lung cancer growth in vitro. They also found that lung cancer cells expressed various combinations of immunoreactive opioid peptides (β-endorphin, enkephalin, or dynorphin), suggesting the participation of opioids in a negative autocrine loop or tumor-suppressing system. Due to the almost universal exposure of patients with lung cancer to nicotine, they tested whether nicotine affected the response of lung cancer cell growth to opioids and found that nicotine at concentrations of 100-200 nM partially or totally reversed opioid-induced growth inhibition in 9/14 lung cancer cell lines. These in vitro results for lung cancer cells suggest that opioids could function as part of a tumor suppressor system and that nicotine can function to circumvent this system in the pathogenesis of lung cancer

  17. Opioid and nicotine receptors affect growth regulation of human lung cancer cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Maneckjee, R.; Minna, J.D. (National Cancer Institute-Navy Medical Oncology Branch, Bethesda, MD (USA) Uniformed Services Univ. of the Health Sciences, Bethesda, MD (USA))

    1990-05-01

    Using specific radioactively-labeled ligands, the authors find that lung cancer cell lines of diverse histologic types express multiple, high-affinity membrane receptors for {mu}, {delta}, and {kappa} opioid agonists and for nicotine and {alpha}-bungarotoxin. These receptors are biologically active because cAMP levels decreased in lung cancer cells after opioid and nicotine application. Nicotine at concentrations found in the blood of smokers had no effect on in vitro lung cancer cell growth, whereas {mu}, {delta}, and {kappa} opioid agonists at low concentrations inhibited lung cancer growth in vitro. They also found that lung cancer cells expressed various combinations of immunoreactive opioid peptides ({beta}-endorphin, enkephalin, or dynorphin), suggesting the participation of opioids in a negative autocrine loop or tumor-suppressing system. Due to the almost universal exposure of patients with lung cancer to nicotine, they tested whether nicotine affected the response of lung cancer cell growth to opioids and found that nicotine at concentrations of 100-200 nM partially or totally reversed opioid-induced growth inhibition in 9/14 lung cancer cell lines. These in vitro results for lung cancer cells suggest that opioids could function as part of a tumor suppressor system and that nicotine can function to circumvent this system in the pathogenesis of lung cancer.

  18. CDC Vital Signs: Opioid Painkiller Prescribing

    Science.gov (United States)

    ... Mental Health Services Administration Medication-Assisted Treatment for Opioid Addiction: Facts for Families and Friends Opioid Overdose Prevention ... Abuse Drugs, Brains, and Behavior: The Science of Addiction Opioid and Pain Management CMEs/CEs Prescription Drugs U.S. ...

  19. [Effects of chronic experimental stress and endogenous opioids on histophysiological parameters of the thyroid gland].

    Science.gov (United States)

    Krasnoperov, R A; Glumova, V A; Riashchikov, S N; Proshutina, N E

    1992-01-01

    In adult rabbits stress was modelled by electrostimulation of the hypothalamus ventromedial nucleus (15-hour-long session during 30 days) and medulla's raphe big nucleus which is one of the central places of the opioid peptides synthesis was irritated. It is revealed, that under stress thyroid gland responds by serum T3 increase in comparison with control animals with statistically significant variability of the T4 profile. Chronicity of the emotional agitation involves destructive changes in the thyroid parenchyma the hurting effect of the negative emotional factor is expressed less during opioid peptides complex activation. It is suggested that there are its own stress-limiting mechanisms in thyroid gland.

  20. Changing patterns in opioid addiction

    Science.gov (United States)

    Sproule, Beth; Brands, Bruna; Li, Selina; Catz-Biro, Laura

    2009-01-01

    ABSTRACT OBJECTIVE To evaluate the clinical observation that the number of individuals seeking opioid detoxification from oxycodone was increasing at the Centre for Addiction and Mental Health (CAMH) in Toronto, Ont; and to identify the characteristics of individuals seeking opioid detoxification at CAMH. DESIGN Retrospective analysis of patient health records. SETTING Medical Withdrawal Management Service at CAMH. PARTICIPANTS All patients admitted for opioid detoxification between January 2000 and December 2004. MAIN OUTCOME MEASURES Number of opioid detoxification admissions each year; type, dose, and source of opioids; comorbid problems and symptoms. RESULTS There were 571 opioid detoxification admissions during the 5-year study period. The number of admissions increased steadily over the 5 years; in particular, the number of admissions related to controlled-release oxycodone increased substantially (3.8%, 8.3%, 20.8%, 30.6%, and 55.4% of the total opioid admissions in 2000 to 2004, respectively; χ42= 105.5, P < .001). The rates of admissions involving heroin remained low and stable. Use of controlled-release oxycodone was associated with considerably higher doses than use of other prescription opioids was. Physician prescriptions were the source of the prescription opioids for a large percentage of patients, particularly for older patients. Prescription opioid users reported considerable comorbid substance use problems, pain, and psychiatric symptoms. CONCLUSION This study has demonstrated a significant rise in the number of individuals seeking treatment at CAMH for controlled-release oxycodone addiction. The substantial comorbid pain, psychiatric symptoms, and other psychoactive substance use problems in these patients, coupled with the finding that prescriptions were an important source of opioids, highlight the clinical complexities encountered in the treatment of these individuals. Further research examining these complexities and the many possible

  1. PET imaging of human cardiac opioid receptors

    Energy Technology Data Exchange (ETDEWEB)

    Villemagne, Patricia S.R.; Dannals, Robert F. [Department of Radiology, The Johns Hopkins University School of Medicine, 605 N Caroline St., Baltimore, Maryland (United States); Department of Environmental Health Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Ravert, Hayden T. [Department of Radiology, The Johns Hopkins University School of Medicine, 605 N Caroline St., Baltimore, Maryland (United States); Frost, James J. [Department of Radiology, The Johns Hopkins University School of Medicine, 605 N Caroline St., Baltimore, Maryland (United States); Department of Environmental Health Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States)

    2002-10-01

    The presence of opioid peptides and receptors and their role in the regulation of cardiovascular function has been previously demonstrated in the mammalian heart. The aim of this study was to image {mu} and {delta} opioid receptors in the human heart using positron emission tomography (PET). Five subjects (three females, two males, 65{+-}8 years old) underwent PET scanning of the chest with [{sup 11}C]carfentanil ([{sup 11}C]CFN) and [{sup 11}C]-N-methyl-naltrindole ([{sup 11}C]MeNTI) and the images were analyzed for evidence of opioid receptor binding in the heart. Either [{sup 11}C]CFN or [{sup 11}C]MeNTI (20 mCi) was injected i.v. with subsequent dynamic acquisitions over 90 min. For the blocking studies, either 0.2 mg/kg or 1 mg/kg of naloxone was injected i.v. 5 min prior to the injection of [{sup 11}C]CFN and [{sup 11}C]MeNTI, respectively. Regions of interest were placed over the left ventricle, left ventricular chamber, lung and skeletal muscle. Graphical analysis demonstrated average baseline myocardial binding potentials (BP) of 4.37{+-}0.91 with [{sup 11}C]CFN and 3.86{+-}0.60 with [{sup 11}C]MeNTI. Administration of 0.2 mg/kg naloxone prior to [{sup 11}C]CFN produced a 25% reduction in BP in one subject in comparison with baseline values, and a 19% decrease in myocardial distribution volume (DV). Administration of 1 mg/kg of naloxone before [{sup 11}C]MeNTI in another subject produced a 14% decrease in BP and a 21% decrease in the myocardial DV. These results demonstrate the ability to image these receptors in vivo by PET. PET imaging of cardiac opioid receptors may help to better understand their role in cardiovascular pathophysiology and the effect of abuse of opioids and drugs on heart function. (orig.)

  2. Mu Opioid Receptor Gene: New Point Mutations in Opioid Addicts

    Directory of Open Access Journals (Sweden)

    Amin Dinarvand

    2014-02-01

    Full Text Available Introduction: Association between single-nucleotide polymorphisms (SNPs in mu opioid receptor gene and drug addiction has been shown in various studies. Here, we have evaluated the existence of polymorphisms in exon 3 of this gene in Iranian population and investigated the possible association between these mutations and opioid addiction.  Methods: 79 opioid-dependent subjects (55 males, 24 females and 134 non-addict or control individuals (74 males, 60 females participated in the study. Genomic DNA was extracted from volunteers’ peripheral blood and exon 3 of the mu opioid receptor gene was amplified by polymerase chain reaction (PCR whose products were then sequenced.  Results: Three different heterozygote polymorphisms were observed in 3 male individuals: 759T>C and 877G>A mutations were found in 2 control volunteers and 1043G>C substitution was observed in an opioid-addicted subject. Association between genotype and opioid addiction for each mutation was not statistically significant.  Discussion: It seems that the sample size used in our study is not enough to confirm or reject any association between 759T>C, 877G>A and 1043G>C substitutions in exon 3 of the mu opioid receptor gene and opioid addiction susceptibility in Iranian population.

  3. Opioid modulation of immunocompetence: Receptor characterization and second messenger involvement

    International Nuclear Information System (INIS)

    Hemmick, L.M.

    1989-01-01

    The purpose of this thesis was to examine the effects of opioids on several indices of immunocompetence, determined the receptor specificity of these effects, and ascertain whether the actions of opioids on lymphocytes could be correlated with activation of second messenger systems. By measuring 45 Ca 2+ uptake into lymphocytes, it was demonstrated that β-endorphin 1-31 (β-END 1-31) enhanced rat thymocyte Ca 2+ uptake in response to concanavalin A (Con A) but not phytohemagglutinin (PHA). Related opioid peptides and alkaloids were unable to mimic the effect, and naloxone did not block it, suggesting that β-END 1-31 acted by binding to specific, non-opioid receptors on the thymocytes. Rat splenocyte Con A-stimulated Ca 2+ uptake was not affected by β-END 1-31. β-END 1-31 did not affect basal Ca 2+ uptake by either cell type. Using [ 3 H]thymidine uptake as an index of lymphocyte proliferation, β-END 1-31 and several related opioid peptides reversed prostaglandin E 1 (PGE 1 ) suppression of rat lymph node cell Con A- and PHA-stimulated proliferation. Naloxone did not block the reversal. β-END 1-31 was unable to reverse forskolin and cholera toxin suppression of proliferation, indicating that the lowering of cyclic AMP levels was not the mechanism involved. Verapamil inhibition of proliferation was also not reversed by β-END 1-31, suggesting that promotion of Ca 2+ influx was not a major mechanism involved

  4. Opioid modulation of immunocompetence: Receptor characterization and second messenger involvement

    Energy Technology Data Exchange (ETDEWEB)

    Hemmick, L.M.

    1989-01-01

    The purpose of this thesis was to examine the effects of opioids on several indices of immunocompetence, determined the receptor specificity of these effects, and ascertain whether the actions of opioids on lymphocytes could be correlated with activation of second messenger systems. By measuring {sup 45}Ca{sup 2+} uptake into lymphocytes, it was demonstrated that {beta}-endorphin 1-31 ({beta}-END 1-31) enhanced rat thymocyte Ca{sup 2+} uptake in response to concanavalin A (Con A) but not phytohemagglutinin (PHA). Related opioid peptides and alkaloids were unable to mimic the effect, and naloxone did not block it, suggesting that {beta}-END 1-31 acted by binding to specific, non-opioid receptors on the thymocytes. Rat splenocyte Con A-stimulated Ca{sup 2+} uptake was not affected by {beta}-END 1-31. {beta}-END 1-31 did not affect basal Ca{sup 2+} uptake by either cell type. Using ({sup 3}H)thymidine uptake as an index of lymphocyte proliferation, {beta}-END 1-31 and several related opioid peptides reversed prostaglandin E{sub 1} (PGE{sub 1}) suppression of rat lymph node cell Con A- and PHA-stimulated proliferation. Naloxone did not block the reversal. {beta}-END 1-31 was unable to reverse forskolin and cholera toxin suppression of proliferation, indicating that the lowering of cyclic AMP levels was not the mechanism involved. Verapamil inhibition of proliferation was also not reversed by {beta}-END 1-31, suggesting that promotion of Ca{sup 2+} influx was not a major mechanism involved.

  5. Reward systems and food intake: role of opioids.

    Science.gov (United States)

    Gosnell, B A; Levine, A S

    2009-06-01

    Humans eat for many reasons, including the rewarding qualities of foods. A host of neurotransmitters have been shown to influence eating behavior and some of these appear to be involved in reward-induced eating. Endogenous opioid peptides and their receptors were first reported more than 30 years ago, and studies suggesting a role of opioids in the regulation of food intake date back nearly as far. Opioid agonists and antagonists have corresponding stimulatory and inhibitory effects on feeding. In addition to studies aimed at identifying the relevant receptor subtypes and sites of action within the brain, there has been a continuing interest in the role of opioids on diet/taste preferences, food reward, and the overlap of food reward with others types of reward. Data exist that suggest a role for opioids in the control of appetite for specific macronutrients, but there is also evidence for their role in the stimulation of intake based on already-existing diet or taste preferences and in controlling intake motivated by hedonics rather than by energy needs. Finally, various types of studies indicate an overlap between mechanisms mediating drug reward and palatable food reward. Preference or consumption of sweet substances often parallels the self-administration of several drugs of abuse, and under certain conditions, the termination of intermittent access to sweet substances produces symptoms that resemble those observed during opiate withdrawal. The overconsumption of readily available and highly palatable foods likely contributes to the growing rates of obesity worldwide. An understanding of the role of opioids in mediating food reward and promoting the overconsumption of palatable foods may provide insights into new approaches for preventing obesity.

  6. Macroeconomic conditions and opioid abuse.

    Science.gov (United States)

    Hollingsworth, Alex; Ruhm, Christopher J; Simon, Kosali

    2017-12-01

    We examine how deaths and emergency department (ED) visits related to use of opioid analgesics (opioids) and other drugs vary with macroeconomic conditions. As the county unemployment rate increases by one percentage point, the opioid death rate per 100,000 rises by 0.19 (3.6%) and the opioid overdose ED visit rate per 100,000 increases by 0.95 (7.0%). Macroeconomic shocks also increase the overall drug death rate, but this increase is driven by rising opioid deaths. Our findings hold when performing a state-level analysis, rather than county-level; are primarily driven by adverse events among whites; and are stable across time periods. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Opioids and breast cancer recurrence

    DEFF Research Database (Denmark)

    Cronin-Fenton, Deirdre P; Heide-Jørgensen, Uffe; Ahern, Thomas P

    2015-01-01

    BACKGROUND: Opioids may alter immune function, thereby potentially affecting cancer recurrence. The authors investigated the association between postdiagnosis opioid use and breast cancer recurrence. METHODS: Patients with incident, early stage breast cancer who were diagnosed during 1996 through...... 2008 in Denmark were identified from the Danish Breast Cancer Cooperative Group Registry. Opioid prescriptions were ascertained from the Danish National Prescription Registry. Follow-up began on the date of primary surgery for breast cancer and continued until breast cancer recurrence, death......, emigration, 10 years, or July 31, 2013, whichever occurred first. Cox regression models were used to compute hazard ratios and 95% confidence intervals associating breast cancer recurrence with opioid prescription use overall and by opioid type and strength, immunosuppressive effect, chronic use (≥6 months...

  8. What peptides these deltorphins be.

    Science.gov (United States)

    Lazarus, L H; Bryant, S D; Cooper, P S; Salvadori, S

    1999-02-01

    The deltorphins are a class of highly selective delta-opioid heptapeptides from the skin of the Amazonian frogs Phyllomedusa sauvagei and P. bicolor. The first of these fascinating peptides came to light in 1987 by cloning of the cDNA of from frog skins, while the other members of this family were identified either by cDNA or isolation of the peptides. The distinctive feature of deltorphins is the presence of a naturally occurring D-enantiomer at the second position in their common N-terminal sequence, Tyr-D-Xaa-Phe, comparable to dermorphin, which is the prototype of a group of mu-selective opioids from the same source. The D-amino acid and the anionic residues, either Glu or Asp, as well as their unique amino acid compositions are responsible for the remarkable biostability, high delta-receptor affinity, bioactivity and peptide conformation. This review summarizes a decade of research from many laboratories that defined which residues and substituents in the deltorphins interact with the delta-receptor and characterized pharmacological and physiological activities in vitro and in vivo. It begins with a historical description of the topic and presents general schema for the synthesis of peptide analogues of deltorphins A, B and C as a means to document the methods employed in producing a myriad of analogues. Structure activity studies of the peptides and their pharmacological activities in vitro are detailed in abundantly tabulated data. A brief compendium of the current level of knowledge of the delta-receptor assists the reader to appreciate the rationale for the design of these analogues. Discussion of the conformation of these peptides addresses how structure leads to further hypotheses regarding ligand receptor interaction. The review ends with a broad discussion of the potential applications of these peptides in clinical and therapeutic settings.

  9. Medication-assisted therapy for opioid addiction

    OpenAIRE

    Tai, Betty; Saxon, Andrew J.; Ling, Walter

    2013-01-01

    The “Medication-Assisted Therapy for Opioid Addiction” session was chaired by Dr. Betty Tai and had three presenters. The presenters (and their topics) were: Dr. Andrew J. Saxon (Methadone and Buprenorphine for Treatment of Opioid Addiction and HIV Risk Reduction), Dr. Walter Ling (Opioid Antagonist Treatment for Opioid Addiction), and Dr. Betty Tai (Chronic Care Model for Substance Use Disorder).

  10. The role of opioid antagonist efficacy and constitutive opioid receptor activity in the opioid withdrawal syndrome in mice

    OpenAIRE

    Navani, Dipesh M.; Sirohi, Sunil; Madia, Priyanka A.; Yoburn, Byron C.

    2011-01-01

    On the basis of efficacy, opioid antagonists are classified as inverse opioid agonists (e.g. naltrexone) or neutral opioid antagonists (e.g. 6β-naltrexol). This study examined the interaction between naltrexone and 6β-naltrexol in the precipitated opioid withdrawal syndrome in morphine dependent mice. Furthermore, the possible contribution of constitutive opioid receptor activity to precipitated withdrawal was evaluated using increasing levels of morphine dependence. In the first experiment, ...

  11. Acute stimulation of brain mu opioid receptors inhibits glucose-stimulated insulin secretion via sympathetic innervation.

    Science.gov (United States)

    Tudurí, Eva; Beiroa, Daniel; Stegbauer, Johannes; Fernø, Johan; López, Miguel; Diéguez, Carlos; Nogueiras, Rubén

    2016-11-01

    Pancreatic insulin-secreting β-cells express opioid receptors, whose activation by opioid peptides modulates hormone secretion. Opioid receptors are also expressed in multiple brain regions including the hypothalamus, where they play a role in feeding behavior and energy homeostasis, but their potential role in central regulation of glucose metabolism is unknown. Here, we investigate whether central opioid receptors participate in the regulation of insulin secretion and glucose homeostasis in vivo. C57BL/6J mice were acutely treated by intracerebroventricular (i.c.v.) injection with specific agonists for the three main opioid receptors, kappa (KOR), delta (DOR) and mu (MOR) opioid receptors: activation of KOR and DOR did not alter glucose tolerance, whereas activation of brain MOR with the specific agonist DAMGO blunted glucose-stimulated insulin secretion (GSIS), reduced insulin sensitivity, increased the expression of gluconeogenic genes in the liver and, consequently, impaired glucose tolerance. Pharmacological blockade of α2A-adrenergic receptors prevented DAMGO-induced glucose intolerance and gluconeogenesis. Accordingly, DAMGO failed to inhibit GSIS and to impair glucose tolerance in α2A-adrenoceptor knockout mice, indicating that the effects of central MOR activation on β-cells are mediated via sympathetic innervation. Our results show for the first time a new role of the central opioid system, specifically the MOR, in the regulation of insulin secretion and glucose metabolism. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Frog secretions and hunting magic in the upper Amazon: identification of a peptide that interacts with an adenosine receptor.

    Science.gov (United States)

    Daly, J W; Caceres, J; Moni, R W; Gusovsky, F; Moos, M; Seamon, K B; Milton, K; Myers, C W

    1992-11-15

    A frog used for "hunting magic" by several groups of Panoan-speaking Indians in the borderline between Brazil and Peru is identified as Phyllomedusa bicolor. This frog's skin secretion, which the Indians introduce into the body through fresh burns, is rich in peptides. These include vasoactive peptides, opioid peptides, and a peptide that we have named adenoregulin, with the sequence GLWSKIKEVGKEAAKAAAKAAGKAALGAVSEAV as determined from mass spectrometry and Edman degradation. The natural peptide may contain a D amino acid residue, since it is not identical in chromatographic properties to the synthetic peptide. Adenoregulin enhances binding of agonists to A1 adenosine receptors; it is accompanied in the skin secretion by peptides that inhibit binding. The vasoactive peptide sauvagine, the opioid peptides, and adenoregulin and related peptides affect behavior in mice and presumably contribute to the behavioral sequelae observed in humans.

  13. Creating opioid dependence in the emergency department.

    Science.gov (United States)

    Upadhye, Suneel

    2018-01-01

    Clinical question What is the risk of creating opioid dependence from an ED opioid prescription? Article chosen Barnett ML, Olenski AR, Jena AB. Opioid-prescribing patterns of emergency physicians and risk of long-term use. N Engl J Med 2017;376:663-73, doi:10.1056/NEJMsa1610524. This study examined the risk of creating long-term opioid dependence from a prescription written in an opioid-naive patient in the ED.

  14. The role of the opioid system in binge eating disorder.

    Science.gov (United States)

    Giuliano, Chiara; Cottone, Pietro

    2015-12-01

    Binge eating disorder is characterized by excessive, uncontrollable consumption of palatable food within brief periods of time. Excessive intake of palatable food is thought to be driven by hedonic, rather than energy homeostatic, mechanisms. However, reward processing does not only comprise consummatory actions; a key component is represented by the anticipatory phase directed at procuring the reward. This phase is highly influenced by environmental food-associated stimuli, which can robustly enhance the desire to eat even in the absence of physiological needs. The opioid system (endogenous peptides and their receptors) has been strongly linked to the rewarding aspects of palatable food intake, and perhaps represents the key system involved in hedonic overeating. Here we review evidence suggesting that the opioid system can also be regarded as one of the systems that regulates the anticipatory incentive processes preceding binge eating hedonic episodes.

  15. Newer approaches to opioid detoxification

    Directory of Open Access Journals (Sweden)

    Siddharth Sarkar

    2012-01-01

    Full Text Available Opioid use disorders present with distressing withdrawal symptoms at the time of detoxification. The pharmacological agents and methods currently in use for detoxification mainly include buprenorphine, methadone, and clonidine. Many other pharmacological agents have been tried for opioid detoxification. This review takes a look at the newer pharmacological options, both opioid agonists and non-agonist medications that have been utilized for detoxification. Peer reviewed articles were identified using PubMed and PsychInfo databases. The keywords included for the search were a combination of ′opioid′ and ′detoxification′ and their synonyms. All the articles published in the last 10 years were screened for. Relevant data was extracted from identified studies. Many newer pharmacological agents have been tried in detoxification of opioids. However, the quest for a safe, efficacious, cost-effective pharmacological option which requires minimal monitoring still continues. The role of non-pharmacological measures and alternative medicine needs further evaluation.

  16. Towards safer use of opioids.

    LENUS (Irish Health Repository)

    Carson, R W R

    2009-09-01

    The main aim of our work was to improve the safety of opioid use in our institution, an acute generalhospital with 620 beds. Initially, all reported opioid errors from 2001 - 2006 were audited. The findings directed a range of multidisciplinary staff educational inputs to improve opioid prescribing and administration practice, and encourage drug error reporting. 448 drug errors were reported, of which 54 (12%) involved opioids; of these, 43 (79%) involved codeine, morphine or oxycodone. 31 of the errors (57%) were associated with administration, followed by 12 (22%) with dispensing and 11 (20%) with prescribing. There were 2 reports of definite patient harm. A subsequent audit examined a 17-month period following the introduction of the above teaching: 17 errors were noted, of which 14 (83%) involved codeine, morphine or oxycodone. Again, drug administration was most error-prone, comprising 11 (65%) of reports. However, just 2 (12%) of the reported errors now involved prescribing, which was a reduction.

  17. Gene Variants Reduce Opioid Risks

    Science.gov (United States)

    ... Alcohol Club Drugs Cocaine Fentanyl Hallucinogens Inhalants Heroin Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Over-the-Counter Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/ ...

  18. Positron Emission Tomography (PET) Imaging of Opioid Receptors

    NARCIS (Netherlands)

    van Waarde, Aren; Absalom, Anthony; Visser, Anniek; Dierckx, Rudi; Dierckx, Rudi AJO; Otte, Andreas; De Vries, Erik FJ; Van Waarde, Aren; Luiten, Paul GM

    2014-01-01

    The opioid system consists of opioid receptors (which mediate the actions of opium), their endogenous ligands (the enkephalins, endorphins, endomorphins, dynorphin, and nociceptin), and the proteins involved in opioid production, transport, and degradation. PET tracers for the various opioid

  19. Involvement of the endogenous opioid system in the psychopharmacological actions of ethanol: the role of acetaldehyde

    Directory of Open Access Journals (Sweden)

    Laura eFont

    2013-07-01

    Full Text Available Significant evidence implicates the endogenous opioid system (opioid peptides and receptors in the mechanisms underlying the psychopharmacological effects of ethanol. Ethanol modulates opioidergic signaling and function at different levels, including biosynthesis, release, and degradation of opioid peptides, as well as binding of endogenous ligands to opioid receptors. The role of β-endorphin and µ-opioid receptors (OR have been suggested to be of particular importance in mediating some of the behavioral effects of ethanol, including psychomotor stimulation and sensitization, consumption and conditioned place preference. Ethanol increases the release of β-endorphin from the hypothalamic arcuate nucleus (NArc, which can modulate activity of other neurotransmitter systems such as mesolimbic dopamine. The precise mechanism by which ethanol induces a release of β-endorphin, thereby inducing behavioral responses, remains to be elucidated. The present review summarizes accumulative data suggesting that the first metabolite of ethanol, the psychoactive compound acetaldehyde, could participate in such mechanism. Two lines of research involving acetaldehyde are reviewed: 1 implications of the formation of acetaldehyde in brain areas such as the NArc, with high expression of ethanol metabolizing enzymes and presence of cell bodies of endorphinic neurons and 2 the formation of condensation products between DA and acetaldehyde such as salsolinol, which exerts its actions via OR.

  20. Illicit Opioid Intoxication: Diagnosis and Treatment

    Directory of Open Access Journals (Sweden)

    A. Fareed

    2011-01-01

    Full Text Available Opioid intoxications and overdose are associated with high rates of morbidity and mortality. Opioid overdose may occur in the setting of intravenous or intranasal heroin use, illicit use of diverted opioid medications, intentional or accidental misuse of prescription pain medications, or iatrogenic overdose. In this review, we focused on the epidemiology of illict opioid use in the United States and on the mechanism of action of opioid drugs. We also described the signs and symptoms, and diagnoses of intoxication and overdose. Lastly, we updated the reader about the most recent recommendations for treatment and prevention of opioid intoxications and overdose.

  1. Targinact--opioid pain relief without constipation?

    Science.gov (United States)

    2010-12-01

    Targinact (Napp Pharmaceuticals Ltd) is a modified-release combination product containing the strong opioid oxycodone plus the opioid antagonist naloxone. It is licensed for "severe pain, which can be adequately managed only with opioid analgesics".1 The summary of product characteristics (SPC) states that "naloxone is added to counteract opioid-induced constipation by blocking the action of oxycodone at opioid receptors locally in the gut". Advertising for the product claims "better pain relief", "superior GI [gastrointestinal] tolerability" and "improved quality of life" "compared to previous treatment in a clinical practice study (n=7836)". Here we consider whether Targinact offers advantages over using strong opioids plus laxatives where required.

  2. Low efficacy of non-opioid drugs in opioid withdrawal symptoms.

    Science.gov (United States)

    Hermann, Derik; Klages, Eckard; Welzel, Helga; Mann, Karl; Croissant, Bernhard

    2005-06-01

    Opioid withdrawal, stress or cues associated with opioid consumption can induce opioid craving. If opioids are not available, opioid-dependent patients usually search for alternative drugs. Because several non-opioid drugs stimulate the endogenous opioidergic system, this concept may explain their frequent use by opioid-dependent patients. We hypothesized that non-opioid drugs alleviate opioid withdrawal symptoms and are therefore consumed by opioid addicts. We asked 89 opioid-dependent patients participating in an out-patient opioid maintenance program to estimate the potential of several non-opioid drugs in being able to alleviate opioid withdrawal. We applied a five-point Lickert scale (1 = very good reduction of opioid withdrawal; 5 = no reduction of opioid withdrawal). Patients could also indicate a worsening of opioid withdrawal. Values (mean +/- SD) were: for benzodiazepines, 3.2 +/- 1.1; tricyclic antidepressants, 3.6 +/- 1.1; cannabis, 3.6 +/- 1.0; alcohol, 4.1 +/- 1.1; cocaine, 4.2 +/- 1.1; amphetamine, 4.4 +/- 0.9; nicotine, 4.7 +/- 0.7; and caffeine, 4.9 +/- 0.5. A worsening of opioid withdrawal was reported by 62% of the patients for cocaine, 62% for amphetamine, 50% for caffeine, 37.5% for cannabis, 27% for nicotine, 26% for alcohol, 8% for tricyclic antidepressants and 3% for benzodiazepines. Our study shows a low efficacy of non-opioid drugs in alleviating opioid withdrawal symptoms. The data basis of this study was good and the sample was suitable to be asked for estimations of drug-drug interactions. Of the patients, 26 - 62% even reported a worsening of opioid withdrawal for cannabis, alcohol, cocaine and amphetamine. Only benzodiazepines and tricyclic antidepressants were reported to have a moderate positive effect on opioid withdrawal.

  3. 42 CFR 8.11 - Opioid treatment program certification.

    Science.gov (United States)

    2010-10-01

    ... Substances Act (21 U.S.C. 823(g)(1)) to dispense opioid drugs in the treatment of opioid addiction. An OTP... opioid addiction. (2) To obtain certification from SAMHSA, an OTP must meet the Federal opioid treatment... governmental entities to regulate the use of opioid drugs in the treatment of opioid addiction. The provisions...

  4. Peptide dendrimers

    Czech Academy of Sciences Publication Activity Database

    Niederhafner, Petr; Šebestík, Jaroslav; Ježek, Jan

    2005-01-01

    Roč. 11, - (2005), 757-788 ISSN 1075-2617 R&D Projects: GA ČR(CZ) GA203/03/1362 Institutional research plan: CEZ:AV0Z40550506 Keywords : multiple antigen peptides * peptide dendrimers * synthetic vaccine * multipleantigenic peptides Subject RIV: CC - Organic Chemistry Impact factor: 1.803, year: 2005

  5. Co-morbid pain and opioid addiction: long term effect of opioid maintenance on acute pain.

    Science.gov (United States)

    Wachholtz, Amy; Gonzalez, Gerardo

    2014-12-01

    Medication assisted treatment for opioid dependence alters the pain experience. This study will evaluate changes pain sensitivity and tolerance with opioid treatments; and duration of this effect after treatment cessation. 120 Individuals with chronic pain were recruited in 4 groups (N = 30): 1-methadone for opioid addiction; 2-buprenorphine for opioid addiction; 3-history of opioid maintenance treatment for opioid addiction but with prolonged abstinence (M = 121 weeks; SD = 23.3); and 4-opioid naïve controls. Participants completed a psychological assessment and a cold water task including, time to first pain (sensitivity) and time to stopping the pain task (tolerance). Data analysis used survival analyses. A Kaplan-Meier-Cox survival analysis showed group differences for both pain sensitivity (log rank = 15.50; p opioid maintenance resulted in differing pain sensitivity compared to opioid naïve (p's opioid maintenance compared to active methadone patients (p opioid naïve control group participants (p's opioid abstinence increased (R = .37; p opioid maintenance, there appears to be long-term differences in pain sensitivity that do not resolve with discontinuation of opioid maintenance. Although pain sensitivity does not change, pain tolerance does improve after opioid maintenance cessation. Implications for treating co-morbid opioid addiction and pain (acute and chronic) are discussed. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  6. Opioid tapering in patients with prescription opioid use disorder : A retrospective study

    NARCIS (Netherlands)

    Zhou, Kehua; Jia, Peng; Bhargava, Swati; Zhang, Yong; Reza, Taslima; Peng, Yuan Bo; Wang, Gary G.

    2017-01-01

    Background and aims: Opioid use disorder (OUD) refers to a maladaptive pattern of opioid use leading to clinically significant impairment or distress. OUD causes, and vice versa, misuses and abuse of opioid medications. Clinicians face daily challenges to treat patients with prescription opioid use

  7. Help, Resources and Information: National Opioids Crisis

    Science.gov (United States)

    ... Search Search Help, Resources and Information National Opioids Crisis Search Search Need Help? Call the National Helpline ... HHS 5-POINT STRATEGY TO COMBAT THE OPIOIDS CRISIS BETTER ADDICTION PREVENTION, TREATMENT, AND RECOVERY SERVICES BETTER ...

  8. Role and psychological dependenci arrangement of opioid by type of reseptor opioid

    OpenAIRE

    Arif Nurrochmad, Arif Nurrochmad

    2015-01-01

    Opioid receptor can be classified as p., 8, and K-opioid receptor that widely expressed in the CNS. The development of selective receptor agonist and cloning of each receptor have contributed greatly to our increasing knowledge of the neuropharmacological profile of each opioid receptor type. This review focuses on the functional interaction among these opioid receptor types that contribute to opioid dependence especially in psychological dependence. Several lines of evidence provide argument...

  9. TRV0109101, a G Protein-Biased Agonist of the µ-Opioid Receptor, Does Not Promote Opioid-Induced Mechanical Allodynia following Chronic Administration.

    Science.gov (United States)

    Koblish, Michael; Carr, Richard; Siuda, Edward R; Rominger, David H; Gowen-MacDonald, William; Cowan, Conrad L; Crombie, Aimee L; Violin, Jonathan D; Lark, Michael W

    2017-08-01

    Prescription opioids are a mainstay in the treatment of acute moderate to severe pain. However, chronic use leads to a host of adverse consequences including tolerance and opioid-induced hyperalgesia (OIH), leading to more complex treatment regimens and diminished patient compliance. Patients with OIH paradoxically experience exaggerated nociceptive responses instead of pain reduction after chronic opioid usage. The development of OIH and tolerance tend to occur simultaneously and, thus, present a challenge when studying the molecular mechanisms driving each phenomenon. We tested the hypothesis that a G protein-biased µ -opioid peptide receptor (MOPR) agonist would not induce symptoms of OIH, such as mechanical allodynia, following chronic administration. We observed that the development of opioid-induced mechanical allodynia (OIMA), a model of OIH, was absent in β -arrestin1 -/- and β -arrestin2 -/- mice in response to chronic administration of conventional opioids such as morphine, oxycodone and fentanyl, whereas tolerance developed independent of OIMA. In agreement with the β -arrestin knockout mouse studies, chronic administration of TRV0109101, a G protein-biased MOPR ligand and structural analog of oliceridine, did not promote the development of OIMA but did result in drug tolerance. Interestingly, following induction of OIMA by morphine or fentanyl, TRV0109101 was able to rapidly reverse allodynia. These observations establish a role for β -arrestins in the development of OIH, independent of tolerance, and suggest that the use of G protein-biased MOPR ligands, such as oliceridine and TRV0109101, may be an effective therapeutic avenue for managing chronic pain with reduced propensity for opioid-induced hyperalgesia. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  10. Does the kappa opioid receptor system contribute to pain aversion?

    Directory of Open Access Journals (Sweden)

    Catherine M Cahill

    2014-11-01

    Full Text Available The kappa opioid receptor (KOR and the endogenous peptide-ligand dynorphin have received significant attention due the involvement in mediating a variety of behavioral and neurophysiological responses, including opposing the rewarding properties of drugs of abuse including opioids. Accumulating evidence indicates this system is involved in regulating states of motivation and emotion. Acute activation of the KOR produces an increase in motivational behavior to escape a threat, however, KOR activation associated with chronic stress leads to the expression of symptoms indicative of mood disorders. It is well accepted that KOR can produce analgesia and is engaged in chronic pain states including neuropathic pain. Spinal studies have revealed KOR-induced analgesia in reversing pain hypersensitivities associated with peripheral nerve injury. While systemic administration of KOR agonists attenuates nociceptive sensory transmission, this effect appears to be a stress-induced effect as anxiolytic agents, including delta opioid receptor agonists, mitigate KOR agonist-induced analgesia. Additionally, while the role of KOR and dynorphin in driving the dysphoric and aversive components of stress and drug withdrawal has been well characterized, how this system mediates the negative emotional states associated with chronic pain is relatively unexplored. This review provides evidence that dynorphin and the KOR system contribute to the negative affective component of pain and that this receptor system likely contributes to the high comorbidity of mood disorders associated with chronic neuropathic pain.

  11. Opiate Drugs with Abuse Liability Hijack the Endogenous Opioid System to Disrupt Neuronal and Glial Maturation in the Central Nervous System.

    Science.gov (United States)

    Hauser, Kurt F; Knapp, Pamela E

    2017-01-01

    The endogenous opioid system, comprised of multiple opioid neuropeptide and receptor gene families, is highly expressed by developing neural cells and can significantly influence neuronal and glial maturation. In many central nervous system (CNS) regions, the expression of opioid peptides and receptors occurs only transiently during development, effectively disappearing with subsequent maturation only to reemerge under pathologic conditions, such as with inflammation or injury. Opiate drugs with abuse liability act to modify growth and development by mimicking the actions of endogenous opioids. Although typically mediated by μ-opioid receptors, opiate drugs can also act through δ- and κ-opioid receptors to modulate growth in a cell-type, region-specific, and developmentally regulated manner. Opioids act as biological response modifiers and their actions are highly contextual, plastic, modifiable, and influenced by other physiological processes or pathophysiological conditions, such as neuro-acquired immunodeficiency syndrome. To date, most studies have considered the acute effects of opiates on cellular maturation. For example, activating opioid receptors typically results in acute growth inhibition in both neurons and glia. However, with sustained opioid exposure, compensatory factors become operative, a concept that has been largely overlooked during CNS maturation. Accordingly, this article surveys prior studies on the effects of opiates on CNS maturation, and also suggests new directions for future research in this area. Identifying the cellular and molecular mechanisms underlying the adaptive responses to chronic opiate exposure (e.g., tolerance) during maturation is crucial toward understanding the consequences of perinatal opiate exposure on the CNS.

  12. Opioid antagonists with minimal sedation for opioid withdrawal.

    Science.gov (United States)

    Gowing, Linda; Ali, Robert; White, Jason M

    2017-05-29

    Managed withdrawal is a necessary step prior to drug-free treatment or as the endpoint of long-term substitution treatment. To assess the effects of opioid antagonists plus minimal sedation for opioid withdrawal. Comparators were placebo as well as more established approaches to detoxification, such as tapered doses of methadone, adrenergic agonists, buprenorphine and symptomatic medications. We updated our searches of the following databases to December 2016: CENTRAL, MEDLINE, Embase, PsycINFO and Web of Science. We also searched two trials registers and checked the reference lists of included studies for further references to relevant studies. We included randomised and quasi-randomised controlled clinical trials along with prospective controlled cohort studies comparing opioid antagonists plus minimal sedation versus other approaches or different opioid antagonist regimens for withdrawal in opioid-dependent participants. We used standard methodological procedures expected by Cochrane. Ten studies (6 randomised controlled trials and 4 prospective cohort studies, involving 955 participants) met the inclusion criteria for the review. We considered 7 of the 10 studies to be at high risk of bias in at least one of the domains we assessed.Nine studies compared an opioid antagonist-adrenergic agonist combination versus a treatment regimen based primarily on an alpha 2 -adrenergic agonist (clonidine or lofexidine). Other comparisons (placebo, tapered doses of methadone, buprenorphine) made by included studies were too diverse for any meaningful analysis. This review therefore focuses on the nine studies comparing an opioid antagonist (naltrexone or naloxone) plus clonidine or lofexidine versus treatment primarily based on clonidine or lofexidine.Five studies took place in an inpatient setting, two studies were in outpatients with day care, two used day care only for the first day of opioid antagonist administration, and one study described the setting as outpatient

  13. Behavioral and electrographic effects of opioids on kindled seizures in rats.

    Science.gov (United States)

    Caldecott-Hazard, S; Shavit, Y; Ackermann, R F; Engel, J; Frederickson, R C; Liebeskind, J C

    1982-11-18

    Our laboratory previously suggested that opioid peptides are released by an amygdaloid kindled seizure and may affect the elicitation of a subsequent seizure. The present study examined the effects of morphine, naloxone, enkephalin analogues, and conditions of morphine tolerance and withdrawal on the severity and duration of a series of amygdaloid kindled seizures. The results suggest two distinct opiate/opioid actions on seizures. The first is an anticonvulsant effect on the behavioral manifestations of seizures. This effect is seen following a high dose (50 mg/kg) of morphine or a low dose (6 mg/kg) of enkephalin analogue (LY146104), and is reversed by naloxone. The second is a naloxone-reversible prolonging effect of the high dose of morphine on the electrographic components of the seizures. Receptor affinities of these various opiate/opioid drugs suggest that these two actions are mediated by different receptors which appear not to include high affinity mu receptors.

  14. Dependence and addiction during chronic opioid therapy.

    Science.gov (United States)

    Juurlink, David N; Dhalla, Irfan A

    2012-12-01

    The use of opioids for chronic noncancer pain has increased dramatically over the past 25 years in North America and has been accompanied by a major increase in opioid addiction and overdose deaths. The increase in opioid prescribing is multifactorial and partly reflects concerns about the effectiveness and safety of alternative medications, particularly the nonsteroidal anti-inflammatory drugs. However, much of the rise in opioid prescribing reflects the assertion, widely communicated to physicians in the 1990s, that the risks of dependence and addiction during chronic opioid therapy were low, predictable, and could be minimized by the use of controlled-release opioid formulations. In this narrative review, we offer a critical appraisal of the publications most frequently cited as evidence that the risk of addiction during chronic opioid therapy is low. We conclude that very few well-designed studies support the notion that opioid addiction is rare during chronic opioid therapy and that none can be readily generalized to present-day practice. Despite serious methodological limitations, these studies have been repeatedly mischaracterized as showing that the risk of addiction during chronic opioid therapy is rare. These studies are countered by a larger, more rigorous and contemporary body of evidence demonstrating that dependence and addiction are relatively common consequences of chronic opioid therapy, occurring in up to one-third of patients in some series.

  15. Opioid-free anaesthesia in three dogs

    Directory of Open Access Journals (Sweden)

    Donna M. White

    2017-05-01

    Full Text Available Opioid-free anaesthesia (OFA is a relatively new and growing field in human medicine. There are multiple motivations behind this emerging practice with the recognition of several serious potential opioid-related adverse effects including opioid induced hyperalgesia, opioid tolerance and immunomodulatory effects of opioids. Opioids have long been the mainstay of veterinary anaesthesia and pain management practice. The feasibility of OFA in veterinary patients is presented here. A case series of three dogs that underwent OFA for canine ovariohysterectomy is reported. The authors conclude OFA is possible in veterinary medicine; however the move away from the familiar effects of opioids perioperatively is challenging. Gaining experience with these types of protocols for standard procedures in healthy animals, such as neutering, will provide the anaesthetist with the building blocks for more invasive surgeries.

  16. Non-analgesic effects of opioids: opioids and the endocrine system.

    Science.gov (United States)

    Elliott, Jennifer A; Opper, Susan E; Agarwal, Sonali; Fibuch, Eugene E

    2012-01-01

    Opioids are among the oldest known and most widely used analgesics. The application of opioids has expanded over the last few decades, especially in the treatment of chronic non-malignant pain. This upsurge in opioid use has been accompanied by the increasingly recognized occurrence of opioid-associated endocrinopathy. This may arise after exposure to enteral, parenteral, or neuraxial opioids. Opioid-associated endocrinopathy consists primarily of hypothalamic-pituitary-gonadal axis or hypothalamic-pituitary-adrenal axis dysfunction and may manifest with symptoms of hypogonadism, adrenal dysfunction, and other hormonal disturbances. Additionally, opioid related endocrine dysfunction may be coupled with such disorders as osteoporosis and mood disturbances including depression. Undesirable changes in pain sensitivity such as opioid-induced hyperalgesia, and reduced potency of opioid analgesia may also be potential consequences of chronic opioid consumption. Few studies to date have been able to establish what degree of opioid exposure, in terms of dose or duration of therapy, may predispose patients to opioid-associated endocrinopathy. This article will review the currently available literature concerning opioid-associated endocrinopathy and will provide recommendations for the evaluation, monitoring, and management of opioid-associated endocrinopathy and its other accompanying undesired effects.

  17. Opioid rotation with extended-release opioids: where should we begin?

    Directory of Open Access Journals (Sweden)

    Nalamachu S

    2011-12-01

    Full Text Available Srinivas NalamachuInternational Clinical Research Institute and Pain Management Institute, Overland Park, KS, USAAbstract: Opioid rotation is a common and necessary clinical practice in the management of chronic non-cancer pain to improve therapeutic efficacy with the lowest opioid dose. When dose escalations fail to achieve adequate analgesia or are associated with intolerable side effects, a trial of a new opioid should be considered. Much of the scientific rationale of opioid rotation is based on the wide interindividual variability in sensitivity to opioid analgesics and the novel patient response observed when introducing an opioid-tolerant patient to a new opioid. This article discusses patient indicators for opioid rotation, the conversion process between opioid medications, and additional practical considerations for increasing the effectiveness of opioid therapy during a trial of a new opioid. A Patient vignette that demonstrates a step-wise approach to opioid rotation is also presented.Keywords: extended-release opioids, chronic pain, opioid rotation

  18. Opioid use in palliative care

    African Journals Online (AJOL)

    Repro

    care. The confident and safe use of opioids in palliative care is an essential skill required by all. d o c t o r s . ... patient for ongoing clinical review. Start the elderly and frail .... (24 hour subcutaneous infusion ... (nursing or medical), pain special-.

  19. Feeding Releases Endogenous Opioids in Humans.

    Science.gov (United States)

    Tuulari, Jetro J; Tuominen, Lauri; de Boer, Femke E; Hirvonen, Jussi; Helin, Semi; Nuutila, Pirjo; Nummenmaa, Lauri

    2017-08-23

    The endogenous opioid system supports a multitude of functions related to appetitive behavior in humans and animals, and it has been proposed to govern hedonic aspects of feeding thus contributing to the development of obesity. Here we used positron emission tomography to investigate whether feeding results in hedonia-dependent endogenous opioid release in humans. Ten healthy males were recruited for the study. They were scanned with the μ-opioid-specific ligand [ 11 C]carfentanil three times, as follows: after a palatable meal, a nonpalatable meal, and after an overnight fast. Subjective mood, satiety, and circulating hormone levels were measured. Feeding induced significant endogenous opioid release throughout the brain. This response was more pronounced following a nonpalatable meal versus a palatable meal, and independent of the subjective hedonic responses to feeding. We conclude that feeding consistently triggers cerebral opioid release even in the absence of subjective pleasure associated with feeding, suggesting that metabolic and homeostatic rather than exclusively hedonic responses play a role in the feeding-triggered cerebral opioid release. SIGNIFICANCE STATEMENT The endogenous opioid system supports both hedonic and homeostatic functions. It has been proposed that overeating and concomitant opioid release could downregulate opioid receptors and promote the development of obesity. However, it remains unresolved whether feeding leads to endogenous opioid release in humans. We used in vivo positron emission tomography to test whether feeding triggers cerebral opioid release and whether this response is associated with pleasurable sensations. We scanned volunteers using the μ-opioid receptor-specific radioligand [ 11 C]carfentanil three times, as follows: after an overnight fast, after consuming a palatable meal, and after consuming a nonpalatable meal. Feeding led to significant endogenous opioid release, and this occurred also in the absence of feeding

  20. Using behavioral economics to predict opioid use during prescription opioid dependence treatment.

    Science.gov (United States)

    Worley, Matthew J; Shoptaw, Steven J; Bickel, Warren K; Ling, Walter

    2015-03-01

    Research grounded in behavioral economics has previously linked addictive behavior to disrupted decision-making and reward-processing, but these principles have not been examined in prescription opioid addiction, which is currently a major public health problem. This study examined whether pre-treatment drug reinforcement value predicted opioid use during outpatient treatment of prescription opioid addiction. Secondary analyses examined participants with prescription opioid dependence who received 12 weeks of buprenorphine-naloxone and counseling in a multi-site clinical trial (N=353). Baseline measures assessed opioid source and indices of drug reinforcement value, including the total amount and proportion of income spent on drugs. Weekly urine drug screens measured opioid use. Obtaining opioids from doctors was associated with lower pre-treatment drug spending, while obtaining opioids from dealers/patients was associated with greater spending. Controlling for demographics, opioid use history, and opioid source frequency, patients who spent a greater total amount (OR=1.30, peconomic resources to drugs, reflects propensity for continued opioid use during treatment among individuals with prescription opioid addiction. Future studies should examine disrupted decision-making and reward-processing in prescription opioid users more directly and test whether reinforcer pathology can be remediated in this population. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  1. FMRFamide: low affinity inhibition of opioid binding to rabbit brain membranes

    International Nuclear Information System (INIS)

    Zhu, X.Z.; Raffa, R.B.

    1986-01-01

    FMRFamide (Phe-Met-Arg-Phe-NH 2 ) was first isolated from the ganglia of molluscs by Price and Greenberg in 1977. The peptide was subsequently shown to have diverse actions on various types of molluscan and mammalian tissues. The presence of immunoreactive FMRFamide-like material (irFMRF) in multiple areas of rat brain, spinal cord, and gastrointestinal tract suggests that irFMRF may have a physiological role in mammals. Tang, Yang and Costa recently demonstrated that FMRFamide attenuates morphine antinociception in rats and postulated, based on this and several other lines of evidence, that irFMRF might be an endogenous opioid antagonist. In the present study, they tested the ability of FMRFamide to inhibit the binding of opioid receptor ligands to rabbit membrane preparations. FMRFamide inhibited the specific binding of both 3 [H]-dihydromorphine and 3 [H]-ethylketocyclazocine (IC 50 = 14 μM and 320 μM, respectively) in a dose-related manner, suggesting that FMRFamide may affect binding to at least two types of opioid receptors (mu and kappa). These data are consistent with the concept that irFMRF might act as an endogenous opioid antagonist. However, the low affinity of FMRFamide leaves open the possibility of another mechanism of opioid antagonism, such as neuromodulation

  2. FMRFamide: low affinity inhibition of opioid binding to rabbit brain membranes

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, X.Z.; Raffa, R.B.

    1986-03-05

    FMRFamide (Phe-Met-Arg-Phe-NH/sub 2/) was first isolated from the ganglia of molluscs by Price and Greenberg in 1977. The peptide was subsequently shown to have diverse actions on various types of molluscan and mammalian tissues. The presence of immunoreactive FMRFamide-like material (irFMRF) in multiple areas of rat brain, spinal cord, and gastrointestinal tract suggests that irFMRF may have a physiological role in mammals. Tang, Yang and Costa recently demonstrated that FMRFamide attenuates morphine antinociception in rats and postulated, based on this and several other lines of evidence, that irFMRF might be an endogenous opioid antagonist. In the present study, they tested the ability of FMRFamide to inhibit the binding of opioid receptor ligands to rabbit membrane preparations. FMRFamide inhibited the specific binding of both /sup 3/(H)-dihydromorphine and /sup 3/(H)-ethylketocyclazocine (IC/sub 50/ = 14 ..mu..M and 320 ..mu..M, respectively) in a dose-related manner, suggesting that FMRFamide may affect binding to at least two types of opioid receptors (mu and kappa). These data are consistent with the concept that irFMRF might act as an endogenous opioid antagonist. However, the low affinity of FMRFamide leaves open the possibility of another mechanism of opioid antagonism, such as neuromodulation.

  3. Stress-evoked opioid release inhibits pain in major depressive disorder.

    Science.gov (United States)

    Frew, Ashley K; Drummond, Peter D

    2008-10-15

    To determine whether stress-evoked release of endogenous opioids might account for hypoalgesia in major depressive disorder (MDD), the mu-opioid antagonist naltrexone (50mg) or placebo was administered double-blind to 24 participants with MDD and to 31 non-depressed controls. Eighty minutes later participants completed a painful foot cold pressor test and, after a 5-min interval, began a 25-min arithmetic task interspersed with painful electric shocks. Ten minutes later participants completed a second cold pressor test. Negative affect was greater in participants with MDD than in non-depressed controls throughout the experiment, and increased significantly in both groups during mental arithmetic. Before the math task, naltrexone unmasked direct linear relationships between severity of depression, negative affect while resting quietly, and cold-induced pain in participants with MDD. In contrast, facilitatory effects of naltrexone on cold- and shock-induced pain were greatest in controls with the lowest depression scores. Naltrexone strengthened the relationship between negative affect and shock-induced pain during the math task, particularly in the depressed group, and heightened anxiety in both groups toward the end of the task. Thus, mu-opioid activity apparently masked a positive association between negative affect and pain in the most distressed participants. These findings suggest that psychological distress inhibits pain via stress-evoked release of opioid peptides in severe cases of MDD. In addition, tonic endogenous opioid neurotransmission could inhibit depressive symptoms and pain in people with low depression scores.

  4. Reasons for opioid use among patients with dependence on prescription opioids: the role of chronic pain.

    Science.gov (United States)

    Weiss, Roger D; Potter, Jennifer Sharpe; Griffin, Margaret L; McHugh, R Kathryn; Haller, Deborah; Jacobs, Petra; Gardin, John; Fischer, Dan; Rosen, Kristen D

    2014-08-01

    The number of individuals seeking treatment for prescription opioid dependence has increased dramatically, fostering a need for research on this population. The aim of this study was to examine reasons for prescription opioid use among 653 participants with and without chronic pain, enrolled in the Prescription Opioid Addiction Treatment Study, a randomized controlled trial of treatment for prescription opioid dependence. Participants identified initial and current reasons for opioid use. Participants with chronic pain were more likely to report pain as their primary initial reason for use; avoiding withdrawal was rated as the most important reason for current use in both groups. Participants with chronic pain rated using opioids to cope with physical pain as more important, and using opioids in response to social interactions and craving as less important, than those without chronic pain. Results highlight the importance of physical pain as a reason for opioid use among patients with chronic pain. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Peripherally applied opioids for postoperative pain

    DEFF Research Database (Denmark)

    Nielsen, B N; Henneberg, S W; Schmiegelow, K

    2015-01-01

    BACKGROUND: Opioids applied peripherally at the site of surgery may produce postoperative analgesia with few side effects. We performed this systematic review to evaluate the analgesic effect of peripherally applied opioids for acute postoperative pain. METHODS: We searched PubMed (1966 to June...... 2013), Embase (1980 to June 2013), and the Cochrane Central Register of Controlled Trials (The Cochrane Library 2013, Issue 6). Randomized controlled trials investigating the postoperative analgesic effect of peripherally applied opioids vs. systemic opioids or placebo, measured by pain intensity...... difference -5 mm, 95% CI: -7 to -3) for peripherally applied opioids vs. placebo and statistically significant increased time to first analgesic (mean difference 153 min, 95% CI: 41-265). When preoperative inflammation was reported (five studies), peripherally applied opioids significantly improved...

  6. NPYFa, A Chimeric Peptide of Met-Enkephalin, and NPFF Induces Tolerance-Free Analgesia.

    Science.gov (United States)

    Mudgal, Annu; Kumar, Krishan; Mollereau, Catherine; Pasha, Santosh

    2016-06-01

    Methionine-enkephalin-Arg-Phe is an endogenous amphiactive analgesic peptide. Neuropeptide FF, on the other hand, is reported for its role in opioid modulation and tolerance development. Based on these reports, in the present study we designed a chimeric peptide NPYFa (YGGFMKKKPQRFamide), having the Met-enkephalin (opioid) and PQRFamide sequence of neuropeptide FF, which can then target both the opioid and neuropeptide FF receptors. We hypothesized that the chimeric peptide so designed would have both analgesic properties and further aid in understanding of the role of neuropeptide FF in the development of opiate tolerance. Our studies indicated that NPYFa induced an early onset, potent, dose-dependent and prolonged antinociception. Additionally, antagonists (MOR, KOR, and DOR) pretreatment studies determined a KOR-mediated antinociception activity of the ligand. Further, in vitro binding studies using the Eu-GTP-γS binding assay on cell lines expressing opioid and NPFF receptors showed binding to both the opioid and neuropeptide FF receptors suggesting a multiple receptor binding character of NPYFa. Moreover, chronic (6 days) treatment with NPYFa exhibited an absence of tolerance development subsequent to its analgesia. The current study proposes NPYFa as a potent, long-acting antinociceptor lacking tolerance development as well as a probe to study opioid analgesia and the associated complex mechanisms of tolerance development. © 2016 John Wiley & Sons A/S.

  7. Functional μ-Opioid-Galanin Receptor Heteromers in the Ventral Tegmental Area.

    Science.gov (United States)

    Moreno, Estefanía; Quiroz, César; Rea, William; Cai, Ning-Sheng; Mallol, Josefa; Cortés, Antoni; Lluís, Carme; Canela, Enric I; Casadó, Vicent; Ferré, Sergi

    2017-02-01

    The neuropeptide galanin has been shown to interact with the opioid system. More specifically, galanin counteracts the behavioral effects of the systemic administration of μ-opioid receptor (MOR) agonists. Yet the mechanism responsible for this galanin-opioid interaction has remained elusive. Using biophysical techniques in mammalian transfected cells, we found evidence for selective heteromerization of MOR and the galanin receptor subtype Gal1 (Gal1R). Also in transfected cells, a synthetic peptide selectively disrupted MOR-Gal1R heteromerization as well as specific interactions between MOR and Gal1R ligands: a negative cross talk, by which galanin counteracted MAPK activation induced by the endogenous MOR agonist endomorphin-1, and a cross-antagonism, by which a MOR antagonist counteracted MAPK activation induced by galanin. These specific interactions, which represented biochemical properties of the MOR-Gal1R heteromer, could then be identified in situ in slices of rat ventral tegmental area (VTA) with MAPK activation and two additional cell signaling pathways, AKT and CREB phosphorylation. Furthermore, in vivo microdialysis experiments showed that the disruptive peptide selectively counteracted the ability of galanin to block the dendritic dopamine release in the rat VTA induced by local infusion of endomorphin-1, demonstrating a key role of MOR-Gal1R heteromers localized in the VTA in the direct control of dopamine cell function and their ability to mediate antagonistic interactions between MOR and Gal1R ligands. The results also indicate that MOR-Gal1R heteromers should be viewed as targets for the treatment of opioid use disorders. The μ-opioid receptor (MOR) localized in the ventral tegmental area (VTA) plays a key role in the reinforcing and addictive properties of opioids. With parallel in vitro experiments in mammalian transfected cells and in situ and in vivo experiments in rat VTA, we demonstrate that a significant population of these MORs form

  8. Opioid Therapy for Chronic Nonmalignant Pain

    Directory of Open Access Journals (Sweden)

    Russell K Portenoy

    1996-01-01

    Full Text Available Long term administration of an opioid drug for chronic nonmalignant pain continues to be controversial, but is no longer uniformly rejected by pain specialists. This is true despite concerns that the regulatory agencies that oversee physician prescribing of opioid drugs continue to stigmatize the practice. The changing clinical perspective has been driven, in part, by widespread acknowledgement of the remarkably favourable outcomes achieved during opioid treatment of cancer pain. These outcomes contrast starkly with popular teaching about chronic opioid therapy and affirm the potential for prolonged efficacy, tolerable side effects, enhanced function associated with improved comfort and minimal risk of aberrant drug-related behaviours consistent with addiction. A large anecdotal experience in populations with nonmalignant pain suggests that these patients are more heterogeneous and that opioid therapy will greatly benefit some and will contribute to negative outcomes for others. The few controlled clinical trials that have been performed support the safety and efficacy of opioid therapy, but have been too limited to ensure generalization to the clinical setting. A critical review of the medical literature pertaining to chronic pain, opioid pharmacology and addiction medicine can clarify misconceptions about opioid therapy and provide a foundation for patient selection and drug administration. The available data support the view that opioids are no panacea for chronic pain, but should be considered in carefully selected patients using clinically derived guidelines that stress a structured approach and ongoing monitoring of efficacy, adverse effects, functional outcomes and the occurrence of aberrant drug-related behaviours.

  9. America's Opioid Epidemic: Supply and Demand Considerations.

    Science.gov (United States)

    Clark, David J; Schumacher, Mark A

    2017-11-01

    America is in the midst of an opioid epidemic characterized by aggressive prescribing practices, highly prevalent opioid misuse, and rising rates of prescription and illicit opioid overdose-related deaths. Medical and lay public sentiment have become more cautious with respect to prescription opioid use in the past few years, but a comprehensive strategy to reduce our reliance on prescription opioids is lacking. Addressing this epidemic through reductions in unnecessary access to these drugs while implementing measures to reduce demand will be important components of any comprehensive solution. Key supply-side measures include avoiding overprescribing, reducing diversion, and discouraging misuse through changes in drug formulations. Important demand-side measures center around educating patients and clinicians regarding the pitfalls of opioid overuse and methods to avoid unnecessary exposure to these drugs. Anesthesiologists, by virtue of their expertise in the use of these drugs and their position in guiding opioid use around the time of surgery, have important roles to play in reducing patient exposure to opioids and providing education about appropriate use. Aside from the many immediate steps that can be taken, clinical and basic research directed at understanding the interaction between pain and opioid misuse is critical to identifying the optimal use of these powerful pain relievers in clinical practice.

  10. Psychiatric disorders in opioid dependants.

    Science.gov (United States)

    Ahmadi, Jamshid; Toobaee, Shahin; Kharras, Mohammad; Radmehr, Mohammad

    2003-09-01

    Psychiatric disorders are common among substance dependants. The objectives of this study were to assess the rate of neurotic disorders among opioid addicts, and reassess the rate of those neurotic disorders two weeks after complete detoxification of the patients. Data were gathered from 500 (496 men and 4 women) opioid dependants, using DSM-IV criteria. The Middlesex Hospital Questionnaire (MHQ) was used to measure free-floating anxiety, depression, phobia, obsession, hysteria and somatization. Four hundred and ninety-six (99.2%) of the subjects were men of whom the majority (65.2%) were married, 26.4% single and the others were divorced or separated. Three hundred and thirty-four (66.8%) were in age range of 20 to 39 years. Of the subjects 154 (30.8) were self-employed, 116 (23.2%) were factory workers, 100 (20%) unemployed, 64 (12.8%) employees and 32 (6.4%) retailers. The majority, 322 (64.4%), reported elementary and high school as their level of education and only 20 (4%) were illiterate. The means for neurotic disorders (using the MHQ) before and two weeks after detoxification were 10.12 and 9.98 for anxiety, 7.54 and 7.41 for phobia, 10.10 and 9.76 for depression, 11.11 and 11.05 for obsession, 8.47 and 8.49 for hysteria and 9.82 and 9.46 for somatization, respectively. The mean difference was significant only for depression. Present findings indicated that the rate of neurotic disorders in opioid dependants is high and (except for depression) was not significantly different before detoxification and two weeks after detoxification. Opium was found to be the most prevalent form of opioid used. Also it can be concluded that during the last years some demographic characteristics of Iranian opioid addicts in this sample have changed. Cultural attitudes toward substance use quite likely affect the pattern of substance use. These findings can be considered when planning preventive and therapeutic programs.

  11. Craving and subsequent opioid use among opioid dependent patients who initiate treatment with buprenorphine

    Science.gov (United States)

    Tsui, Judith I.; Anderson, Bradley J.; Strong, David R.; Stein, Michael D.

    2016-01-01

    Background Few studies have directly assessed associations between craving and subsequent opioid use among treated patients. Our objective was to prospectively evaluate the relative utility of two craving questionnaires to predict opioid use among opioid dependent patients in treatment. Method Opioid dependent patients (n=147) initiating buprenorphine treatment were assessed for three months. Craving was measured using: 1) the Desires for Drug Questionnaire (DDQ) and 2) the Penn Alcohol-Craving Scale adapted for opioid craving (PCS) for this study. Multi-level logistic regression models estimated the effects of craving on the likelihood of opioid use after adjusting for gender, age, ethnicity, education, opioid of choice, frequency of use, pain and depression. In these analyses craving assessed at time t was entered as a time-varying predictor of opioid use at time t+1. Results In adjusted regression models, a 1-point increase in PCS scores (on a 7-point scale) was associated with a significant increase in the odds of opioid use at the subsequent assessment (OR = 1.27, 95% CI 1.08; 1.49, p .05) or DDQ control (OR = 0.97, 95%CI 0.85; 1.11, p > .05) scores. Conclusion Self-reported craving for opioids was associated with subsequent lapse to opioid use among a cohort of patients treated with buprenorphine. PMID:24521036

  12. Sex differences in opioid analgesia and addiction: interactions among opioid receptors and estrogen receptors

    Science.gov (United States)

    2013-01-01

    Opioids are widely used as the pain reliever and also notorious for being addictive drugs. Sex differences in the opioid analgesia and addiction have been reported and investigated in human subjects and animal models. Yet, the molecular mechanism underlying the differences between males and females is still unclear. Here, we reviewed the literature describing the sex differences in analgesic responses and addiction liabilities to clinically relevant opioids. The reported interactions among opioids, estrogens, opioid receptors, and estrogen receptors are also evaluated. We postulate that the sex differences partly originated from the crosstalk among the estrogen and opioid receptors when stimulated by the exogenous opioids, possibly through common secondary messengers and the downstream gene transcriptional regulators. PMID:24010861

  13. [3H]naloxone as an opioid receptor label: Analysis of binding site heterogeneity and use for determination of opioid affinities of casomorphin analogues

    International Nuclear Information System (INIS)

    Schnittler, M.; Repke, H.; Liebmann, C.; Schrader, U.; Schulze, H.P.; Neubert, K.

    1990-01-01

    The nonselective antagonist [ 3 H]naloxone was used to identify opioid receptors in rat brain membranes. The multiple naloxone binding sites were related to different opioid receptors by means of selective opiod ligands as well as various β-casomorphin analogues. Analysis of binding site heterogeneity was performed using several computer curve fitting methods. The results indicate that structurally modified casomorphin peptides are able to discriminate between μ 1 and μ 2 binding sites. The affinities to the μ sites obtained with [ 3 H]naloxone as label are in a good agreement with those from experiments with the μ selective radioligand [ 3 H]DAGO. The μ 1 site affinities of these casomorphin derivatives are well correlated with their antinociceptive potencies. This finding suggests the mediation of the analgesic activity via the high-affinity μ 1 subtype. (author)

  14. The opioid overdose epidemic: opportunities for pharmacists

    Directory of Open Access Journals (Sweden)

    Wu LT

    2017-07-01

    Full Text Available Li-Tzy Wu,1–4 Udi E Ghitza,5 Anne L Burns,6 Paolo Mannelli,1 1Department of Psychiatry and Behavioral Sciences, 2Department of Medicine, 3Duke Clinical Research Institute, Duke University School of Medicine, 4Center for Child and Family Policy, Sanford School of Public Policy, Duke University, Durham, NC, 5Center for Clinical Trials Network, National Institute on Drug Abuse, Bethesda, MD, 6American Pharmacists Association, Washington, DC, USA The USA is experiencing an opioid overdose epidemic. It has been driven largely by prescription opioids and intensified by a surge of illicit opioids (e.g., heroin and fentanyl.1,2 Drug-involved overdose, mainly opioids (e.g., prescription opioids and heroin, is a leading cause of accidental death in the USA. The opioid overdose epidemic has been escalating consistently for over a decade.2 Every day, an estimated 91 Americans die from opioid-related overdose.3 Opioid overdose appears to have disproportionally affected men, adults aged 25–64 years, and non-Hispanic whites.2

  15. Role of Endogenous Opioid System in Ischemic-Induced Late Preconditioning.

    Directory of Open Access Journals (Sweden)

    Jan Fraessdorf

    Full Text Available Opioid receptors (OR are involved in myocardial late preconditioning (LPC induced by morphine and δ1-opioid receptor (δ1-OR agonists. The role of OR in ischemic-induced LPC is unknown. We investigated whether 1 OR are involved in the trigger and/or mediation phase of LPC and 2 a time course effect on the expression of different opioid receptors and their endogenous ligands exists.Male Wistar rats were randomly allocated to four groups (each group n = 8. Awake animals were ischemic preconditioned by a 5 minutes coronary occlusion. 24 hours later, anesthetized animals underwent 25 minutes coronary occlusion followed by 2 hours of reperfusion. The role of OR was investigated by treatment with intraperitoneal naloxone (Nal 10 minutes prior to LPC (Nal-LPC; trigger phase or 10 min prior to sustained ischemia (LPC-Nal; mediation phase.LPC reduced infarct size from 61±10% in controls to 25±9% (P<0.001. Naloxone during trigger or mediation phase completely abolished LPC-induced cardioprotection (59±9% and 62±9%; P<0.001 vs. LPC. 8, 12 and 24 hours after the ischemic stimulus, expression of δ-OR in the heart was increased, whereas μ-opioid receptor (μ-OR and κ-opioid receptor (κ-OR were not. Plasma concentrations of β-endorphin and leu-enkephalin but not dynorphin were increased by LPC.Ischemic LPC is triggererd and mediated by OR. Expression of δ-OR and plasma levels of endogenous opioid peptides are increased after ischemic LPC.

  16. Opioid modulation of GABA release in the rat inferior colliculus

    Directory of Open Access Journals (Sweden)

    Forge Andrew

    2004-09-01

    Full Text Available Abstract Background The inferior colliculus, which receives almost all ascending and descending auditory signals, plays a crucial role in the processing of auditory information. While the majority of the recorded activities in the inferior colliculus are attributed to GABAergic and glutamatergic signalling, other neurotransmitter systems are expressed in this brain area including opiate peptides and their receptors which may play a modulatory role in neuronal communication. Results Using a perfusion protocol we demonstrate that morphine can inhibit KCl-induced release of [3H]GABA from rat inferior colliculus slices. DAMGO ([D-Ala(2, N-Me-Phe(4, Gly(5-ol]-enkephalin but not DADLE ([D-Ala2, D-Leu5]-enkephalin or U69593 has the same effect as morphine indicating that μ rather than δ or κ opioid receptors mediate this action. [3H]GABA release was diminished by 16%, and this was not altered by the protein kinase C inhibitor bisindolylmaleimide I. Immunostaining of inferior colliculus cryosections shows extensive staining for glutamic acid decarboxylase, more limited staining for μ opiate receptors and relatively few neurons co-stained for both proteins. Conclusion The results suggest that μ-opioid receptor ligands can modify neurotransmitter release in a sub population of GABAergic neurons of the inferior colliculus. This could have important physiological implications in the processing of hearing information and/or other functions attributed to the inferior colliculus such as audiogenic seizures and aversive behaviour.

  17. Opioid modulation of GABA release in the rat inferior colliculus

    Science.gov (United States)

    Tongjaroenbungam, Walaiporn; Jongkamonwiwat, Nopporn; Cunningham, Joanna; Phansuwan-Pujito, Pansiri; Dodson, Hilary C; Forge, Andrew; Govitrapong, Piyarat; Casalotti, Stefano O

    2004-01-01

    Background The inferior colliculus, which receives almost all ascending and descending auditory signals, plays a crucial role in the processing of auditory information. While the majority of the recorded activities in the inferior colliculus are attributed to GABAergic and glutamatergic signalling, other neurotransmitter systems are expressed in this brain area including opiate peptides and their receptors which may play a modulatory role in neuronal communication. Results Using a perfusion protocol we demonstrate that morphine can inhibit KCl-induced release of [3H]GABA from rat inferior colliculus slices. DAMGO ([D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin) but not DADLE ([D-Ala2, D-Leu5]-enkephalin or U69593 has the same effect as morphine indicating that μ rather than δ or κ opioid receptors mediate this action. [3H]GABA release was diminished by 16%, and this was not altered by the protein kinase C inhibitor bisindolylmaleimide I. Immunostaining of inferior colliculus cryosections shows extensive staining for glutamic acid decarboxylase, more limited staining for μ opiate receptors and relatively few neurons co-stained for both proteins. Conclusion The results suggest that μ-opioid receptor ligands can modify neurotransmitter release in a sub population of GABAergic neurons of the inferior colliculus. This could have important physiological implications in the processing of hearing information and/or other functions attributed to the inferior colliculus such as audiogenic seizures and aversive behaviour. PMID:15353008

  18. Gut Homeostasis, Microbial Dysbiosis, and Opioids.

    Science.gov (United States)

    Wang, Fuyuan; Roy, Sabita

    2017-01-01

    Gut homeostasis plays an important role in maintaining animal and human health. The disruption of gut homeostasis has been shown to be associated with multiple diseases. The mutually beneficial relationship between the gut microbiota and the host has been demonstrated to maintain homeostasis of the mucosal immunity and preserve the integrity of the gut epithelial barrier. Currently, rapid progress in the understanding of the host-microbial interaction has redefined toxicological pathology of opioids and their pharmacokinetics. However, it is unclear how opioids modulate the gut microbiome and metabolome. Our study, showing opioid modulation of gut homeostasis in mice, suggests that medical interventions to ameliorate the consequences of drug use/abuse will provide potential therapeutic and diagnostic strategies for opioid-modulated intestinal infections. The study of morphine's modulation of the gut microbiome and metabolome will shed light on the toxicological pathology of opioids and its role in the susceptibility to infectious diseases.

  19. Chronic Opioid Use After Surgery: Implications for Perioperative Management in the Face of the Opioid Epidemic.

    Science.gov (United States)

    Hah, Jennifer M; Bateman, Brian T; Ratliff, John; Curtin, Catherine; Sun, Eric

    2017-11-01

    Physicians, policymakers, and researchers are increasingly focused on finding ways to decrease opioid use and overdose in the United States both of which have sharply increased over the past decade. While many efforts are focused on the management of chronic pain, the use of opioids in surgical patients presents a particularly challenging problem requiring clinicians to balance 2 competing interests: managing acute pain in the immediate postoperative period and minimizing the risks of persistent opioid use after the surgery. Finding ways to minimize this risk is particularly salient in light of a growing literature suggesting that postsurgical patients are at increased risk for chronic opioid use. The perioperative care team, including surgeons and anesthesiologists, is poised to develop clinical- and systems-based interventions aimed at providing pain relief in the immediate postoperative period while also reducing the risks of opioid use longer term. In this paper, we discuss the consequences of chronic opioid use after surgery and present an analysis of the extent to which surgery has been associated with chronic opioid use. We follow with a discussion of the risk factors that are associated with chronic opioid use after surgery and proceed with an analysis of the extent to which opioid-sparing perioperative interventions (eg, nerve blockade) have been shown to reduce the risk of chronic opioid use after surgery. We then conclude with a discussion of future research directions.

  20. Physician Introduction to Opioids for Pain Among Patients with Opioid Dependence and Depressive Symptoms

    Science.gov (United States)

    Tsui, Judith I.; Herman, Debra S.; Kettavong, Malyna; Alford, Daniel; Anderson, Bradley J.; Stein, Michael D.

    2011-01-01

    This study determined the frequency of reporting being introduced to opioids by a physician among opioid dependent patients. Cross-sectional analyses were performed using baseline data from a cohort of opioid addicts seeking treatment with buprenorphine. The primary outcome was response to the question: “Who introduced you to opiates?” Covariates included sociodemographics, depression, pain, current and prior substance use. Of 140 participants, 29% reported that they had been introduced to opioids by a physician. Of those who were introduced to opioids by a physician, all indicated that they had initially used opioids for pain, versus only 11% of those who did not report being introduced to opioids by a physician (p<0.01). There was no difference in current pain (78% vs. 85%, p=0.29), however participants who were introduced to opioids by a physician were more likely to have chronic pain (63% vs. 43%, p=0.04). A substantial proportion of individuals with opioid dependence seeking treatment may have been introduced to opioids by a physician. PMID:20727704

  1. Distance traveled and frequency of interstate opioid dispensing in opioid shoppers and nonshoppers.

    Science.gov (United States)

    Cepeda, M Soledad; Fife, Daniel; Yuan, Yingli; Mastrogiovanni, Greg

    2013-10-01

    Little is known about how far opioid shoppers travel or how often they cross state lines to fill their opioid prescriptions. This retrospective cohort study evaluated these measures for opioid shoppers and nonshoppers using a large U.S. prescription database. Patients with ≥3 opioid dispensings were followed for 18 months. A subject was considered a shopper when he or she filled overlapping opioid prescriptions written by >1 prescriber at ≥3 pharmacies. A heavy shopper had ≥5 shopping episodes. Outcomes assessed were distance traveled among pharmacies and number of states visited to fill opioid prescriptions. A total of 10,910,451 subjects were included; .7% developed any shopping behavior and their prescriptions accounted for 8.6% of all opioid dispensings. Shoppers and heavy shoppers were younger than the nonshoppers. Shoppers traveled a median of 83.8 miles, heavy shoppers 199.5 miles, and nonshoppers 0 miles. Almost 20% of shoppers or heavy shoppers, but only 4% of nonshoppers, visited >1 state. Shoppers traveled greater distances and more often crossed state borders to fill opioid prescriptions than nonshoppers, and their dispensings accounted for a disproportionate number of opioid dispensings. Sharing of data among prescription-monitoring programs will likely strengthen those programs and may decrease shopping behavior. This study shows that opioid shoppers travel greater distances and more often cross state borders to fill opioid prescriptions than nonshoppers, and their dispensings accounted for a disproportionate number of opioid dispensings. The findings support the need for data sharing among prescription-monitoring programs to deter opioid shopping behavior. Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.

  2. Neurogenesis in the olfactory bulb induced by paced mating in the female rat is opioid dependent.

    Directory of Open Access Journals (Sweden)

    Marianela Santoyo-Zedillo

    Full Text Available The possibility to control the rate of sexual stimulation that the female rat receives during a mating encounter (pacing increases the number of newborn neurons that reach the granular layer of the accessory olfactory bulb (AOB. If females mate repeatedly, the increase in the number of neurons is observed in other regions of the AOB and in the main olfactory bulb (MOB. It has also been shown that paced mating induces a reward state mediated by opioids. There is also evidence that opioids modulate neurogenesis. In the present study, we evaluated whether the opioid receptor antagonist naloxone (NX could reduce the increase in neurogenesis in the AOB induced by paced mating. Ovariectomized female rats were randomly divided in 5 different groups: 1 Control (not mated treated with saline, 2 control (not mated treated with naloxone, 3 females that mated without controlling the sexual interaction (no-pacing, 4 females injected with saline before pacing the sexual interaction and 5 females injected with NX before a paced mating session. We found, as previously described, that paced mating induced a higher number of new cells in the granular layer of the AOB. The administration of NX before paced mating, blocked the increase in the number of newborn cells and prevented these cells from differentiating into neurons. These data suggest that opioid peptides play a fundamental role in the neurogenesis induced by paced mating in female rats.

  3. Interactions of the opioid and cannabinoid systems in reward: Insights from knockout studies

    Directory of Open Access Journals (Sweden)

    Katia eBefort

    2015-02-01

    Full Text Available The opioid system consists of three receptors, mu, delta, and kappa, which are activated by endogenous opioid peptides (enkephalins, endorphins and dynorphins. The endogenous cannabinoid system comprises lipid neuromodulators (endocannabinoids, enzymes for their synthesis and their degradation and two well-characterized receptors, cannabinoid receptors CB1 and CB2. These systems play a major role in the control of pain as well as in mood regulation, reward processing and the development of addiction. Both opioid and cannabinoid receptors are coupled to G proteins and are expressed throughout the brain reinforcement circuitry. Extending classical pharmacology, research using genetically modified mice has provided important progress in the identification of the specific contribution of each component of these endogenous systems in vivo on reward process. This review will summarize available genetic tools and our present knowledge on the consequences of gene knockout on reinforced behaviors in both systems, with a focus on their potential interactions. A better understanding of opioid-cannabinoid interactions may provide novel strategies for therapies in addicted individuals.

  4. High-Dose Opioid Prescribing and Opioid-Related Hospitalization: A Population-Based Study.

    Directory of Open Access Journals (Sweden)

    Kimberly Fernandes

    Full Text Available To examine the impact of national clinical practice guidelines and provincial drug policy interventions on prevalence of high-dose opioid prescribing and rates of hospitalization for opioid toxicity.Interventional time-series analysis.Ontario, Canada, from 2003 to 2014.Ontario Drug Benefit (ODB beneficiaries aged 15 to 64 years from 2003 to 2014.Publication of Canadian clinical practice guidelines for use of opioids in chronic non-cancer pain (May 2010 and implementation of Ontario's Narcotics Safety and Awareness Act (NSAA; November 2011.Three outcomes were explored: the rate of opioid use among ODB beneficiaries, the prevalence of opioid prescriptions exceeding 200 mg and 400 mg morphine equivalents per day, and rates of opioid-related emergency department visits and hospital admissions.Over the 12 year study period, the rate of opioid use declined 15.2%, from 2764 to 2342 users per 10,000 ODB eligible persons. The rate of opioid use was significantly impacted by the Canadian clinical practice guidelines (p-value = .03 which led to a decline in use, but no impact was observed by the enactment of the NSAA (p-value = .43. Among opioid users, the prevalence of high-dose prescribing doubled (from 4.2% to 8.7% over the study period. By 2014, 40.9% of recipients of long-acting opioids exceeded daily doses of 200 mg morphine or equivalent, including 55.8% of long-acting oxycodone users and 76.3% of transdermal fentanyl users. Moreover, in the last period, 18.7% of long-acting opioid users exceeded daily doses of 400 mg morphine or equivalent. Rates of opioid-related emergency department visits and hospital admissions increased 55.0% over the study period from 9.0 to 14.0 per 10,000 ODB beneficiaries from 2003 to 2013. This rate was not significantly impacted by the Canadian clinical practice guidelines (p-value = .68 or enactment of the NSAA (p-value = .59.Although the Canadian clinical practice guidelines for use of opioids in chronic non

  5. Functional role of peripheral opioid receptors in the regulation of cardiac spinal afferent nerve activity during myocardial ischemia

    Science.gov (United States)

    Longhurst, John C.

    2013-01-01

    Thinly myelinated Aδ-fiber and unmyelinated C-fiber cardiac sympathetic (spinal) sensory nerve fibers are activated during myocardial ischemia to transmit the sensation of angina pectoris. Although recent observations showed that myocardial ischemia increases the concentrations of opioid peptides and that the stimulation of peripheral opioid receptors inhibits chemically induced visceral and somatic nociception, the role of opioids in cardiac spinal afferent signaling during myocardial ischemia has not been studied. The present study tested the hypothesis that peripheral opioid receptors modulate cardiac spinal afferent nerve activity during myocardial ischemia by suppressing the responses of cardiac afferent nerve to ischemic mediators like bradykinin and extracellular ATP. The nerve activity of single unit cardiac afferents was recorded from the left sympathetic chain (T2–T5) in anesthetized cats. Forty-three ischemically sensitive afferent nerves (conduction velocity: 0.32–3.90 m/s) with receptive fields in the left and right ventricles were identified. The responses of these afferent nerves to repeat ischemia or ischemic mediators were further studied in the following protocols. First, epicardial administration of naloxone (8 μmol), a nonselective opioid receptor antagonist, enhanced the responses of eight cardiac afferent nerves to recurrent myocardial ischemia by 62%, whereas epicardial application of vehicle (PBS) did not alter the responses of seven other cardiac afferent nerves to ischemia. Second, naloxone applied to the epicardial surface facilitated the responses of seven cardiac afferent nerves to epicardial ATP by 76%. Third, administration of naloxone enhanced the responses of seven other afferent nerves to bradykinin by 85%. In contrast, in the absence of naloxone, cardiac afferent nerves consistently responded to repeated application of ATP (n = 7) or bradykinin (n = 7). These data suggest that peripheral opioid peptides suppress the

  6. Long-term course of opioid addiction.

    Science.gov (United States)

    Hser, Yih-Ing; Evans, Elizabeth; Grella, Christine; Ling, Walter; Anglin, Douglas

    2015-01-01

    Opioid addiction is associated with excess mortality, morbidities, and other adverse conditions. Guided by a life-course framework, we review the literature on the long-term course of opioid addiction in terms of use trajectories, transitions, and turning points, as well as other factors that facilitate recovery from addiction. Most long-term follow-up studies are based on heroin addicts recruited from treatment settings (mostly methadone maintenance treatment), many of whom are referred by the criminal justice system. Cumulative evidence indicates that opioid addiction is a chronic disorder with frequent relapses. Longer treatment retention is associated with a greater likelihood of abstinence, whereas incarceration is negatively related to subsequent abstinence. Over the long term, the mortality rate of opioid addicts (overdose being the most common cause) is about 6 to 20 times greater than that of the general population; among those who remain alive, the prevalence of stable abstinence from opioid use is low (less than 30% after 10-30 years of observation), and many continue to use alcohol and other drugs after ceasing to use opioids. Histories of sexual or physical abuse and comorbid mental disorders are associated with the persistence of opioid use, whereas family and social support, as well as employment, facilitates recovery. Maintaining opioid abstinence for at least five years substantially increases the likelihood of future stable abstinence. Recent advances in pharmacological treatment options (buprenorphine and naltrexone) include depot formulations offering longer duration of medication; their impact on the long-term course of opioid addiction remains to be assessed.

  7. Dextromethorphan differentially affects opioid antinociception in rats

    Science.gov (United States)

    Chen, Shiou-Lan; Huang, Eagle Yi-Kung; Chow, Lok-Hi; Tao, Pao-Luh

    2005-01-01

    Opioid drugs such as morphine and meperidine are widely used in clinical pain management, although they can cause some adverse effects. A number of studies indicate that N-methyl-D-aspartate (NMDA) receptors may play a role in the mechanism of morphine analgesia, tolerance and dependence. Being an antitussive with NMDA antagonist properties, dextromethorphan (DM) may have some therapeutic benefits when coadministered with morphine. In the present study, we investigated the effects of DM on the antinociceptive effects of different opioids. We also investigated the possible pharmacokinetic mechanisms involved. The antinociceptive effects of the μ-opioid receptor agonists morphine (5 mg kg−1, s.c.), meperidine (25 mg kg−1, s.c.) and codeine (25 mg kg−1, s.c.), and the κ-opioid agonists nalbuphine (8 mg kg−1, s.c.) and U-50,488H (20 mg kg−1, s.c.) were studied using the tail-flick test in male Sprague–Dawley rats. Coadministration of DM (20 mg kg−1, i.p.) with these opioids was also performed and investigated. The pharmacokinetic effects of DM on morphine and codeine were examined, and the free concentration of morphine or codeine in serum was determined by HPLC. It was found that DM potentiated the antinociceptive effects of some μ-opioid agonists but not codeine or κ-opioid agonists in rats. DM potentiated morphine's antinociceptive effect, and acutely increased the serum concentration of morphine. In contrast, DM attenuated the antinociceptive effect of codeine and decreased the serum concentration of its active metabolite (morphine). The pharmacokinetic interactions between DM and opioids may partially explain the differential effects of DM on the antinociception caused by opioids. PMID:15655510

  8. Hiperalgesia asociada al tratamiento con opioides

    OpenAIRE

    A. Gil Martín; M. Moreno García; J. Sánchez-Rubio Ferrández; T. Molina García

    2014-01-01

    La hiperalgesia inducida por opioides es una reacción paradójica caracterizada por una percepción intensificada de dolor relacionada con el uso de estos medicamentos en ausencia de progresión de la enfermedad o de síndrome de retirada. A diferencia de los casos de tolerancia, definida como pérdida de potencia analgésica durante el uso prolongado de opioides, no se produce mejoría con el escalado de dosis. La hiperalgesia inducida por opioides se ha manifestado en pacientes con dosis de manten...

  9. Neuraxial opioid-induced pruritus: a review.

    LENUS (Irish Health Repository)

    Szarvas, Szilvia

    2012-02-03

    When intrathecal and epidural opioids are administered, pruritus occurs as an unwanted and troublesome side effect. The reported incidence varies between 30% and 100%. The exact mechanisms of neuraxial opioid-induced pruritus remain unclear. Postulated mechanisms include the presence of an "itch center" in the central nervous system, medullary dorsal horn activation, and antagonism of inhibitory transmitters. The treatment of intrathecal opioid-induced pruritus remains a challenge. Many pharmacological therapies, including antihistamines, 5-HT(3)-receptor antagonists, opiate-antagonists, propofol, nonsteroid antiinflammatory drugs, and droperidol, have been studied. In this review, we will summarize pathophysiological and pharmacological advances that will improve understanding and ultimately the management of this troublesome problem.

  10. Opioid tapering in patients with prescription opioid use disorder: A retrospective study.

    Science.gov (United States)

    Zhou, Kehua; Jia, Peng; Bhargava, Swati; Zhang, Yong; Reza, Taslima; Peng, Yuan Bo; Wang, Gary G

    2017-10-01

    Opioid use disorder (OUD) refers to a maladaptive pattern of opioid use leading to clinically significant impairment or distress. OUD causes, and vice versa, misuses and abuse of opioid medications. Clinicians face daily challenges to treat patients with prescription opioid use disorder. An evidence-based management for people who are already addicted to opioids has been identified as the national priority in the US; however, options are limited in clinical practices. In this study, we aimed to explore the success rate and important adjuvant medications in the medication assisted treatment with temporary use of methadone for opioid discontinuation in patients with prescription OUD. This is a retrospective chart review performed at a private physician office for physical medicine and rehabilitation. We reviewed all medical records dated between December 1st, 2011 and August 30th, 2016. The initial evaluation of the included patients (N=140) was completed between December 1st, 2011 and December 31st, 2014. They all have concumittant prescription OUD and chronic non-cancer pain. The patients (87 female and 53 male) were 46.7±12.7 years old, and had a history of opioid use of 7.7±6.1 years. All patients received the comprehensive opioid taper treatments (including interventional pain management techniques, psychotherapy, acupuncture, physical modalities and exercises, and adjuvant medications) on top of the medication assisted treatment using methadone (transient use). Opioid tapering was considered successful when no opioid medication was used in the last patient visit. The 140 patients had pain of 9.6±8.4 years with 8/10 intensity before treatment which decreased after treatment in all comparisons (pOUD. For patients with OUD, indefinite opioid maintenance treatment may not be necessary. Considering the ethical values of autonomy, nonmaleficence, and beneficence, clinicians should provide patients with OUD the option of opioid tapering. Copyright © 2017

  11. Adrenergic Agonists Bind to Adrenergic-Receptor-Like Regions of the Mu Opioid Receptor, Enhancing Morphine and Methionine-Enkephalin Binding: A New Approach to “Biased Opioids”?

    Science.gov (United States)

    Turke, Miah; Subhramanyam, Udaya K. Tiruttani; Churchill, Beth; Labahn, Joerg

    2018-01-01

    Extensive evidence demonstrates functional interactions between the adrenergic and opioid systems in a diversity of tissues and organs. While some effects are due to receptor and second messenger cross-talk, recent research has revealed an extracellular, allosteric opioid binding site on adrenergic receptors that enhances adrenergic activity and its duration. The present research addresses whether opioid receptors may have an equivalent extracellular, allosteric adrenergic binding site that has similar enhancing effects on opioid binding. Comparison of adrenergic and opioid receptor sequences revealed that these receptors share very significant regions of similarity, particularly in some of the extracellular and transmembrane regions associated with adrenergic binding in the adrenergic receptors. Five of these shared regions from the mu opioid receptor (muOPR) were synthesized as peptides and tested for binding to adrenergic, opioid and control compounds using ultraviolet spectroscopy. Adrenergic compounds bound to several of these muOPR peptides with low micromolar affinity while acetylcholine, histamine and various adrenergic antagonists did not. Similar studies were then conducted with purified, intact muOPR with similar results. Combinations of epinephrine with methionine enkephalin or morphine increased the binding of both by about half a log unit. These results suggest that muOPR may be allosterically enhanced by adrenergic agonists. PMID:29342106

  12. Adrenergic Agonists Bind to Adrenergic-Receptor-Like Regions of the Mu Opioid Receptor, Enhancing Morphine and Methionine-Enkephalin Binding: A New Approach to “Biased Opioids”?

    Directory of Open Access Journals (Sweden)

    Robert Root-Bernstein

    2018-01-01

    Full Text Available Extensive evidence demonstrates functional interactions between the adrenergic and opioid systems in a diversity of tissues and organs. While some effects are due to receptor and second messenger cross-talk, recent research has revealed an extracellular, allosteric opioid binding site on adrenergic receptors that enhances adrenergic activity and its duration. The present research addresses whether opioid receptors may have an equivalent extracellular, allosteric adrenergic binding site that has similar enhancing effects on opioid binding. Comparison of adrenergic and opioid receptor sequences revealed that these receptors share very significant regions of similarity, particularly in some of the extracellular and transmembrane regions associated with adrenergic binding in the adrenergic receptors. Five of these shared regions from the mu opioid receptor (muOPR were synthesized as peptides and tested for binding to adrenergic, opioid and control compounds using ultraviolet spectroscopy. Adrenergic compounds bound to several of these muOPR peptides with low micromolar affinity while acetylcholine, histamine and various adrenergic antagonists did not. Similar studies were then conducted with purified, intact muOPR with similar results. Combinations of epinephrine with methionine enkephalin or morphine increased the binding of both by about half a log unit. These results suggest that muOPR may be allosterically enhanced by adrenergic agonists.

  13. Opioid-Induced Glial Activation: Mechanisms of Activation and Implications for Opioid Analgesia, Dependence, and Reward

    Directory of Open Access Journals (Sweden)

    Mark R. Hutchinson

    2007-01-01

    Full Text Available This review will introduce the concept of toll-like receptor (TLR–mediated glial activation as central to all of the following: neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects (tolerance, dependence, and reward. Attenuation of glial activation has previously been demonstrated both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. Here we demonstrate that selective acute antagonism of TLR4 results in reversal of neuropathic pain as well as potentiation of opioid analgesia. Attenuating central nervous system glial activation was also found to reduce the development of opioid dependence, and opioid reward at a behavioral (conditioned place preference and neurochemical (nucleus accumbens microdialysis of morphine-induced elevations in dopamine level of analysis. Moreover, a novel antagonism of TLR4 by (+- and (˗-isomer opioid antagonists has now been characterized, and both antiallodynic and morphine analgesia potentiating activity shown. Opioid agonists were found to also possess TLR4 agonistic activity, predictive of glial activation. Targeting glial activation is a novel and as yet clinically unexploited method for treatment of neuropathic pain. Moreover, these data indicate that attenuation of glial activation, by general or selective TLR antagonistic mechanisms, may also be a clinical method for separating the beneficial (analgesia and unwanted (tolerance, dependence, and reward actions of opioids, thereby improving the safety and efficacy of their use.

  14. Opioids, pain, the brain, and hyperkatifeia: a framework for the rational use of opioids for pain.

    Science.gov (United States)

    Shurman, Joseph; Koob, George F; Gutstein, Howard B

    2010-07-01

    Opioids have relieved more human suffering than any other medication, but their use is still fraught with significant concerns of misuse, abuse, and addiction. This theoretical article explores the hypothesis that opioid misuse in the context of pain management produces a hypersensitivity to emotional distress, termed hyperkatifeia. In the misuse of opioids, neural substrates that mediate positive emotional states (brain reward systems) are compromised, and substrates mediating negative emotional states (brain stress systems) are enhanced. A reflection and early marker of such a nonhomeostatic state may be the development of opioid-induced hyperkatifeia, defined as the increased intensity of the constellation of negative emotional/motivational symptoms and signs observed during withdrawal from drugs of abuse (derived from the Greek "katifeia" for dejection or negative emotional state) and is most likely to occur in subjects in whom the opioid produces a break with homeostasis and less likely to occur when the opioid is restoring homeostasis, such as in effective pain treatment. When the opioid appropriately relieves pain, opponent processes are not engaged. However, if the opioid is administered in excess of need because of overdose, pharmacokinetic variables, or treating an individual without pain, then the body will react to that perturbation by engaging opponent processes in the domains of both pain (hyperalgesia) and negative emotional states (hyperkatifeia). Repeated engagement of opponent processes without time for the brain's emotional systems to reestablish homeostasis will further drive changes in emotional processes that may produce opioid abuse or addiction, particularly in individuals with genetic or environmental vulnerability.

  15. Peptide chemistry toolbox - Transforming natural peptides into peptide therapeutics.

    Science.gov (United States)

    Erak, Miloš; Bellmann-Sickert, Kathrin; Els-Heindl, Sylvia; Beck-Sickinger, Annette G

    2018-06-01

    The development of solid phase peptide synthesis has released tremendous opportunities for using synthetic peptides in medicinal applications. In the last decades, peptide therapeutics became an emerging market in pharmaceutical industry. The need for synthetic strategies in order to improve peptidic properties, such as longer half-life, higher bioavailability, increased potency and efficiency is accordingly rising. In this mini-review, we present a toolbox of modifications in peptide chemistry for overcoming the main drawbacks during the transition from natural peptides to peptide therapeutics. Modifications at the level of the peptide backbone, amino acid side chains and higher orders of structures are described. Furthermore, we are discussing the future of peptide therapeutics development and their impact on the pharmaceutical market. Copyright © 2018 Elsevier Ltd. All rights reserved.

  16. Opiate Drugs with Abuse Liability Hijack the Endogenous Opioid System to Disrupt Neuronal and Glial Maturation in the Central Nervous System

    Directory of Open Access Journals (Sweden)

    Kurt F. Hauser

    2018-01-01

    Full Text Available The endogenous opioid system, comprised of multiple opioid neuropeptide and receptor gene families, is highly expressed by developing neural cells and can significantly influence neuronal and glial maturation. In many central nervous system (CNS regions, the expression of opioid peptides and receptors occurs only transiently during development, effectively disappearing with subsequent maturation only to reemerge under pathologic conditions, such as with inflammation or injury. Opiate drugs with abuse liability act to modify growth and development by mimicking the actions of endogenous opioids. Although typically mediated by μ-opioid receptors, opiate drugs can also act through δ- and κ-opioid receptors to modulate growth in a cell-type, region-specific, and developmentally regulated manner. Opioids act as biological response modifiers and their actions are highly contextual, plastic, modifiable, and influenced by other physiological processes or pathophysiological conditions, such as neuro-acquired immunodeficiency syndrome. To date, most studies have considered the acute effects of opiates on cellular maturation. For example, activating opioid receptors typically results in acute growth inhibition in both neurons and glia. However, with sustained opioid exposure, compensatory factors become operative, a concept that has been largely overlooked during CNS maturation. Accordingly, this article surveys prior studies on the effects of opiates on CNS maturation, and also suggests new directions for future research in this area. Identifying the cellular and molecular mechanisms underlying the adaptive responses to chronic opiate exposure (e.g., tolerance during maturation is crucial toward understanding the consequences of perinatal opiate exposure on the CNS.

  17. Opioid Overdose Reversal with Naloxone (Narcan, Evzio)

    Science.gov (United States)

    ... Alcohol Club Drugs Cocaine Fentanyl Hallucinogens Inhalants Heroin Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Over-the-Counter Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/ ...

  18. Teens Mix Prescription Opioids with Other Substances

    Science.gov (United States)

    ... Alcohol Club Drugs Cocaine Fentanyl Hallucinogens Inhalants Heroin Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Over-the-Counter Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/ ...

  19. Endogenous opioids encode relative taste preference.

    Science.gov (United States)

    Taha, Sharif A; Norsted, Ebba; Lee, Lillian S; Lang, Penelope D; Lee, Brian S; Woolley, Joshua D; Fields, Howard L

    2006-08-01

    Endogenous opioid signaling contributes to the neural control of food intake. Opioid signaling is thought to regulate palatability, the reward value of a food item as determined by orosensory cues such as taste and texture. The reward value of a food reflects not only these sensory properties but also the relative value of competing food choices. In the present experiment, we used a consummatory contrast paradigm to manipulate the relative value of a sucrose solution for two groups of rats. Systemic injection of the nonspecific opioid antagonist naltrexone suppressed sucrose intake; for both groups, however, this suppression was selective, occurring only for the relatively more valuable sucrose solution. Our results indicate that endogenous opioid signaling contributes to the encoding of relative reward value.

  20. Medicare Part D Opioid Drug Mapping Tool

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Medicare Part D opioid prescribing mapping tool is an interactive tool that shows geographic comparisons, at the state, county, and ZIP code levels, of...

  1. Role of the brain dopaminergic and opioid system in the regulation of "child's" (maternal bonding) behavior of newborn albino rats.

    Science.gov (United States)

    Stovolosov, I S; Dubynin, V A; Kamensky, A A

    2011-01-01

    Administration of D(2) receptor antagonist clebopride in a dose not affecting locomotor activity was followed by a decrease in maternal bonding behavior of 10-day-old and 15-day-old albino rat pups. D(1) receptor antagonist SCH23390 had a stimulatory effect only on the behavior of 10-day-old newborns. Opioid peptide β-casomorphin-7 abolished the effect of clebopride in rat pups of the older age group.

  2. Opioid withdrawal signs and symptoms in children: frequency and determinants.

    Science.gov (United States)

    Fisher, Deborah; Grap, Mary Jo; Younger, Janet B; Ameringer, Suzanne; Elswick, R K

    2013-01-01

    The purpose of this study was to, in a pediatric population, describe the frequency of opioid withdrawal signs and symptoms and to identify factors associated with these opioid withdrawal signs and symptoms. Opioids are used routinely in the pediatric intensive care population for analgesia, sedation, blunting of physiologic responses to stress, and safety. In children, physical dependence may occur in as little as 2-3 days of continuous opioid therapy. Once the child no longer needs the opioid, the medications are reduced over time. A prospective, descriptive study was conducted. The sample of 26 was drawn from all patients, ages 2 weeks to 21 years admitted to the Children's Hospital of Richmond pediatric intensive care unit (PICU) and who have received continuous infusion or scheduled opioids for at least 5 days. Data collected included: opioid withdrawal score (WAT-1), opioid taper rate (total dose of opioid per day in morphine equivalents per kilogram [MEK]), pretaper peak MEK, pretaper cumulative MEK, number of days of opioid exposure prior to taper, and age. Out of 26 enrolled participants, only 9 (45%) had opioid withdrawal on any given day. In addition, there was limited variability in WAT-1 scores. The most common symptoms notes were diarrhea, vomit, sweat, and fever. For optimal opioid withdrawal assessments, clinicians should use a validated instrument such as the WAT-1 to measure for signs and symptoms of opioid withdrawal. Further research is indicated to examine risk factors for opioid withdrawal in children. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. State Emergency Department Opioid Guidelines: Current Status.

    Science.gov (United States)

    Broida, Robert I; Gronowski, Tanner; Kalnow, Andrew F; Little, Andrew G; Lloyd, Christopher M

    2017-04-01

    The purpose of this study was to evaluate and categorize current state-sponsored opioid guidelines for the practice of emergency medicine (EM). We conducted a comprehensive search of EM-specific opioid prescribing guidelines and/or policies in each state to determine current state involvement in EM opioid prescribing, as well as to evaluate some of the specifics of each guideline or policy. The search was conducted using an online query and a follow-up email request to each state chapter of ACEP. We found that 17 states had emergency department-specific guidelines. We further organized the guidelines into four categories: limiting prescriptions for opioids with 67 total recommendations; preventing/diverting abuse with 56 total recommendations; addiction-related guidelines with 29 total recommendations; and a community resources section with 24 total recommendations. Our results showed that current state guidelines focus on providers limiting opioid pain prescriptions and vetting patients for possible abuse/diversion. This study highlights the 17 states that have addressed opioid prescribing guidelines and categorizes their efforts to date. It is hoped that this study will provide the basis for similar efforts in other states.

  4. PSYCHIATRIC COMORBIDITY IN PATIENTS WITH OPIOID DEPENDENCE

    Directory of Open Access Journals (Sweden)

    Shihab Kattukulathil

    2018-02-01

    Full Text Available BACKGROUND Opioid dependence is a major public health problem in Kerala. Presence of psychiatric disorder among opioid dependent patients worsens the scenario. To date no attempts have been made to analyse the magnitude and pattern of comorbid psychiatric disorders in the state. MATERIALS AND METHODS We assessed 30 patients with ICD-10 diagnosis of opioid dependence syndrome for the presence of comorbid psychiatric disorders using structured clinical interview for DSM IV Axis 1 disorder (SCID-1. Patients with opioid withdrawal state, delirium and acute medical emergencies were excluded. RESULTS 56.7% of our subjects had a comorbid psychiatric disorder. Major depressive disorder was the most common one (n=7, 23.3%. Prevalence of other disorders were generalised anxiety disorder (n=6, 20%, bipolar affective disorder (n=3, 10% and schizophrenia (n=1, 3.3%. CONCLUSION Comorbid Psychiatric disorders are highly prevalent in opioid dependence. There is a need for further large sample studies in the areas of comorbidities and in the integrated strategies for the identification and management of both opioid dependence and comorbid psychiatric disorders.

  5. Drug interactions: volatile anesthetics and opioids.

    Science.gov (United States)

    Glass, P S; Gan, T J; Howell, S; Ginsberg, B

    1997-09-01

    Multiple drugs are used to provide anesthesia. Volatile anesthetics are commonly combined with opioids. Several studies have demonstrated that small doses of opioid (i.e., within the analgesic range) result in a marked reduction in minimum alveolar concentration (MAC) of the volatile anesthetic that will prevent purposeful movement in 50% of patients at skin incision). Further increases in opioid dose provide only a further small reduction in MAC. Thus, a ceiling effect of the opioid is observed at a MAC value of the volatile anesthetic equal to its MAC awake. Recovery from anesthesia when an opioid is combined with a volatile anesthetic is dependent on the rate of decrease of both drugs to their respective concentrations that are associated with adequate spontaneous ventilation and awakening. Through an understanding of the pharmacodynamic interaction of volatile anesthetics with opioids and the pharmacokinetic processes responsible for the recovery from drug effect, optimal dosing schemes can thus be developed. A review of these pharmacodynamic and pharmacokinetic principles that will allow clinicians to administer drugs to provide a more optimal anesthetic is provided.

  6. Activation of endogenous opioid gene expression in human keratinocytes and fibroblasts by pulsed radiofrequency energy fields

    Directory of Open Access Journals (Sweden)

    Moffett J

    2012-09-01

    Full Text Available John Moffett,1 Linley M Fray,1 Nicole J Kubat21Life Science Department, 2Independent Consultant, Regenesis Biomedical Inc, Scottsdale, AZ, USABackground: Pulsed radiofrequency energy (PRFE fields are being used increasingly for the treatment of pain arising from dermal trauma. However, despite their increased use, little is known about the biological and molecular mechanism(s responsible for PRFE-mediated analgesia. In general, current therapeutics used for analgesia target either endogenous factors involved in inflammation, or act on endogenous opioid pathways.Methods and Results: Using cultured human dermal fibroblasts (HDF and human epidermal keratinocytes (HEK, we investigated the effect of PRFE treatment on factors, which are involved in modulating peripheral analgesia in vivo. We found that PRFE treatment did not inhibit cyclooxygenase enzyme activity, but instead had a positive effect on levels of endogenous opioid precursor mRNA (proenkephalin, pro-opiomelanocortin, prodynorphin and corresponding opioid peptide. In HEK cells, increases in opioid mRNA were dependent, at least in part, on endothelin-1. In HDF cells, additional pathways also appear to be involved. PRFE treatment was also followed by changes in endogenous expression of several cytokines, including increased levels of interleukin-10 mRNA and decreased levels of interleukin-1β mRNA in both cell types.Conclusion: These findings provide a new insight into the molecular mechanism underlying PRFE-mediated analgesia reported in the clinical setting.Keywords: peripheral analgesia, endogenous opioids, endothelin-1, endothelin receptor A, endothelin receptor B, pulsed radiofrequency energy field, cyclooxygenase

  7. Interacting cannabinoid and opioid receptors in the nucleus accumbens core control adolescent social play

    Directory of Open Access Journals (Sweden)

    Antonia Manduca

    2016-11-01

    Full Text Available Social play behavior is a highly rewarding, developmentally important form of social interaction in young mammals. However, its neurobiological underpinnings remain incompletely understood. Previous work has suggested that opioid and endocannabinoid neurotransmission interact in the modulation of social play. Therefore, we combined behavioral, pharmacological, electrophysiological and genetic approaches to elucidate the role of the endocannabinoid 2-arachidonoylglycerol (2-AG in social play, and how cannabinoid and opioid neurotransmission interact to control social behavior in adolescent rodents. Systemic administration of the 2-AG hydrolysis inhibitor JZL184 or the opioid receptor agonist morphine increased social play behavior in adolescent rats. These effects were blocked by systemic pretreatment with either CB1 cannabinoid receptor (CB1R or mu-opioid receptor (MOR antagonists. The social play-enhancing effects of systemic morphine or JZL184 treatment were also prevented by direct infusion of the CB1R antagonist SR141716 and the MOR antagonist naloxone into the nucleus accumbens core (NAcC. Searching for synaptic correlates of these effects in adolescent NAcC excitatory synapses, we observed that CB1R antagonism blocked the effect of the MOR agonist DAMGO and, conversely, that naloxone reduced the effect of a cannabinoid agonist. These results were recapitulated in mice, and completely abolished in CB1R and MOR knockout mice, suggesting that the functional interaction between CB1R and MOR in the NAcC in the modulation of mediates social behavior is widespread in rodents. The data shed new light on the mechanism by which endocannabinoid lipids and opioid peptides interact to orchestrate rodent socioemotional behaviors.

  8. Ghrelin interacts with neuropeptide Y Y1 and opioid receptors to increase food reward.

    Science.gov (United States)

    Skibicka, Karolina P; Shirazi, Rozita H; Hansson, Caroline; Dickson, Suzanne L

    2012-03-01

    Ghrelin, a stomach-derived hormone, is an orexigenic peptide that was recently shown to potently increase food reward behavior. The neurochemical circuitry that links ghrelin to the mesolimbic system and food reward behavior remains unclear. Here we examined the contribution of neuropeptide Y (NPY) and opioids to ghrelin's effects on food motivation and intake. Both systems have well-established links to the mesolimbic ventral tegmental area (VTA) and reward/motivation control. NPY mediates the effect of ghrelin on food intake via activation of NPY-Y1 receptor (NPY-Y1R); their connection with respect to motivated behavior is unexplored. The role of opioids in any aspect of ghrelin's action on food-oriented behaviors is unknown. Rats were trained in a progressive ratio sucrose-induced operant schedule to measure food reward/motivation behavior. Chow intake was measured immediately after the operant test. In separate experiments, we explored the suppressive effects of a selective NPY-Y1R antagonist or opioid receptor antagonist naltrexone, injected either intracerebroventricularly or intra-VTA, on ghrelin-induced food reward behavior. The ventricular ghrelin-induced increase in sucrose-motivated behavior and chow intake were completely blocked by intracerebroventricular pretreatment with either an NPY-Y1R antagonist or naltrexone. The intra-VTA ghrelin-induced sucrose-motivated behavior was blocked only by intra-VTA naltrexone. In contrast, the intra-VTA ghrelin-stimulated chow intake was attenuated only by intra-VTA NPY-Y1 blockade. Finally, ghrelin infusion was associated with an elevated VTA μ-opioid receptor expression. Thus, we identify central NPY and opioid signaling as the necessary mediators of food intake and reward effects of ghrelin and localize these interactions to the mesolimbic VTA.

  9. The opioid manager: a point-of-care tool to facilitate the use of the Canadian Opioid Guideline.

    Science.gov (United States)

    Furlan, Andrea D; Reardon, Rhoda; Salach, Lena

    2012-01-01

    The Opioid Manager is designed to be used as a point-of-care tool for providers prescribing opioids for chronic noncancer pain. It condenses the key elements from the Canadian Opioid Guideline and can be used as a chart insert. The Opioid Manager has been validated and is available for download from the Guideline's Web site http://nationalpaincentre.mcmaster.ca/opioidmanager/. The Opioid Manager is divided into the following four parts: A) before you write the first script, B) initiation trial, C) maintenance and monitoring, and D) when is it time to decrease the dose or stop the opioid completely? The Opioid Manager has been downloaded by 1,432 users: 47 percent family physicians, 18 percent pharmacists, 13 percent other physicians, and 22 percent miscellaneous. To show how to use the Opioid Manager, the authors created a 10-minute video that is available on the Internet. The Opioid Manager is being translated to French, Spanish, Portuguese, and Farsi.

  10. Non-analgesic effects of opioids: management of opioid-induced constipation by peripheral opioid receptor antagonists: prevention or withdrawal?

    Science.gov (United States)

    Holzer, Peter

    2012-01-01

    The therapeutic action of opioid analgesics is compromised by peripheral adverse effects among which opioid-induced constipation (OIC) is the most disabling, with a prevalence reported to vary between 15 and 90 %. Although OIC is usually treated with laxatives, there is insufficient clinical evidence that laxatives are efficacious in this indication. In contrast, there is ample evidence from double- blind, randomized and placebo-controlled trials that peripheral opioid receptor antagonists (PORAs) counteract OIC. This specific treatment modality is currently based on subcutaneous methylnaltrexone for the interruption of OIC in patients with advanced illness, and a fixed combination of oral prolonged-release naloxone with prolonged-release oxycodone for the prevention of OIC in the treatment of non-cancer and cancer pain. Both drugs counteract OIC while the analgesic effect of opioids remains unabated. The clinical studies show that more than 50 % of the patients with constipation under opioid therapy may benefit from the use of PORAs, while PORA-resistant patients are likely to suffer from non-opioid-induced constipation, the prevalence of which increases with age. While the addition of naloxone to oxycodone seems to act by preventing OIC, the intermittent dosing of methylnaltrexone every other day seems to stimulate defaecation by provoking an intestinal withdrawal response. The availability of PORAs provides a novel opportunity to specifically control OIC and other peripheral adverse effects of opioid analgesics (e.g., urinary retention and pruritus). The continuous dosing of a PORA has the advantage of few adverse effects, while intermittent dosing of a PORA can be associated with abdominal cramp-like pain.

  11. Variants of opioid system genes are associated with non-dependent opioid use and heroin dependence

    NARCIS (Netherlands)

    Randesi, Matthew; van den Brink, Wim; Levran, Orna; Blanken, Peter; Butelman, Eduardo R; Yuferov, Vadim; da Rosa, Joel Correa; Ott, Jurg; van Ree, Jan M; Kreek, Mary Jeanne

    2016-01-01

    BACKGROUND: Heroin addiction is a chronic, relapsing brain disease. Genetic factors are involved in the development of drug addiction. The aim of this study was to determine whether specific variants in genes of the opioid system are associated with non-dependent opioid use and heroin dependence.

  12. Variants of opioid system genes are associated with non-dependent opioid use and heroin dependence

    NARCIS (Netherlands)

    Randesi, Matthew; van den Brink, Wim; Levran, Orna; Blanken, Peter; Butelman, Eduardo R.; Yuferov, Vadim; da Rosa, Joel Correa; Ott, Jurg; van Ree, Jan M.; Kreek, Mary Jeanne

    2016-01-01

    Heroin addiction is a chronic, relapsing brain disease. Genetic factors are involved in the development of drug addiction. The aim of this study was to determine whether specific variants in genes of the opioid system are associated with non-dependent opioid use and heroin dependence. Genetic

  13. Peptide profiling of bovine kefir reveals 236 unique peptides released from caseins during its production by starter culture or kefir grains.

    Science.gov (United States)

    Ebner, Jennifer; Aşçı Arslan, Ayşe; Fedorova, Maria; Hoffmann, Ralf; Küçükçetin, Ahmet; Pischetsrieder, Monika

    2015-03-18

    Kefir has a long tradition in human nutrition due to its presupposed health promoting effects. To investigate the potential contribution of bioactive peptides to the physiological effects of kefir, comprehensive analysis of the peptide profile was performed by nano-ESI-LTQ-Orbitrap MS coupled to nano-ultrahigh-performance liquid chromatography. Thus, 257 peptides were identified, mainly released from β-casein, followed by αS1-, κ-, and αS2-casein. Most (236) peptides were uniquely detected in kefir, but not in raw milk indicating that the fermentation step does not only increase the proteolytic activity 1.7- to 2.4-fold compared to unfermented milk, but also alters the composition of the peptide fraction. The influence of the microflora was determined by analyzing kefir produced from traditional kefir grains or commercial starter culture. Kefir from starter culture featured 230 peptide sequences and showed a significantly, 1.4-fold higher proteolytic activity than kefir from kefir grains with 127 peptides. A match of 97 peptides in both varieties indicates the presence of a typical kefir peptide profile that is not influenced by the individual composition of the microflora. Sixteen of the newly identified peptides were previously described as bioactive, including angiotensin-converting enzyme (ACE)-inhibitory, antimicrobial, immunomodulating, opioid, mineral binding, antioxidant, and antithrombotic effects. The present study describes a comprehensive peptide profile of kefir comprising 257 sequences. The peptide list was used to identify 16 bioactive peptides with ACE-inhibitory, antioxidant, antithrombotic, mineral binding, antimicrobial, immunomodulating and opioid activity in kefir. Furthermore, it was shown that a majority of the kefir peptides were not endogenously present in the raw material milk, but were released from milk caseins by proteases of the microbiota and are therefore specific for the product. Consequently, the proteolytic activity and the

  14. The prescription opioid epidemic: an overview for anesthesiologists.

    Science.gov (United States)

    Alam, Asim; Juurlink, David N

    2016-01-01

    The objectives for preparing this article were to review the historical context and epidemiology surrounding the North American prescription opioid crisis, to summarize the evidence regarding the benefits and harms of long-term opioid therapy for non-cancer pain, and to outline ways in which anesthesiologists may help ameliorate the problem. We searched PubMed, Google Scholar, and EMBASE™ for relevant articles using various search terms, including pain, opioid epidemic, history of opioid use, perioperative care, and addiction. Related citations were further explored and searched depending on the specific subtopic of interest. In the 1980s and early 1990s, opioids were infrequently used for the treatment of chronic pain. Thereafter, however, physicians were gradually inculcated with the message that long-term opioid therapy was a safe and effective treatment option for patients with chronic non-cancer pain. Pharmaceutical companies supported this growing movement and employed aggressive and sometimes misleading marketing strategies for new opioid formulations. As a result, the practice of prescribing opioids flourished in the late 1990s. The surge in prescribing opioids was accompanied by a marked increase in opioid-related morbidity and mortality. This change in practice transpired despite the absence of randomized trials showing clinically significant benefit from the long-term use of opioids. Subsequently, however, a large and growing body of evidence has emerged quantifying the harms associated with long-term opioid therapy. Anesthesiologists widely prescribe opioids for acute and chronic pain; yet, as a group, they may be largely unaware of the current state of this growing epidemic and what role they can play to rectify this problem. Anesthesiologists are well positioned to take a leadership role in the management of postoperative discharge opioid therapy in an effort to curb the overutilization of opioids. Furthermore, anesthesiologists who regularly

  15. The impact of opioids on the endocrine system.

    Science.gov (United States)

    Katz, Nathaniel; Mazer, Norman A

    2009-02-01

    Opioids have been used for medicinal and analgesic purposes for centuries. However, their negative effects on the endocrine system, which have been known for some times, are barely discussed in modern medicine. Therefore, we conducted a systematic review of the impact of opioids on the endocrine system. A review of the English language literature on preclinical and clinical studies of any type on the influence of opioids on the endocrine system was conducted. Preliminary recommendations for monitoring and managing these problems were provided. Long-term opioid therapy for either addiction or chronic pain often induces hypogonadism owing to central suppression of hypothalamic secretion of gonadotropin-releasing hormone. Symptoms of opioid-induced hypogonadism include loss of libido, infertility, fatigue, depression, anxiety, loss of muscle strength and mass, osteoporosis, and compression fractures in both men and women; impotence in men; and menstrual irregularities and galactorrhea in women. In view of the increased use of opioids for chronic pain, it has become increasingly important to monitor patients taking opioids and manage endocrine complications. Therefore, patients on opioid therapy should be routinely screened for such symptoms and for laboratory abnormalities in sex hormones. Opioid-induced hypogonadism seems to be a common complication of therapeutic or illicit opioid use. Patients on long-term opioid therapy should be prospectively monitored, and in cases of opioid-induced hypogonadism, we recommend nonopioid pain management, opioid rotation, or sex hormone supplementation after careful consideration of the risks and benefits.

  16. Possible Opioid Shopping and its Correlates.

    Science.gov (United States)

    Walker, Alexander M; Weatherby, Lisa B; Cepeda, M Soledad; Bradford, Daniel; Yuan, Yingli

    2017-11-01

    We created an operational definition of possible opioid shopping in US commercial health insurance data and examined its correlates. The population consisted of 264,204 treatment courses in persons with a fill for an opioid or diuretic prescription in 2012 and a second within 18 months. We examined counts of prescribers and pharmacies and the numbers of fills and overlaps for ability to discriminate courses of opioids from diuretics, which were a negative control. The most discriminatory measure, indicating possible shopping behavior, was cross-tabulated against other prescriptions filled and diagnoses as found in insurance claims. The associations between claims characteristics and shopping behavior were assessed in a logistic regression. A definition that classified possible "moderate" or "extensive" shopping when a person obtained drug through at least 3 practices and at least 3 pharmacies over 18 months was highly discriminatory between opioid and diuretic treatment. Overlaps between fills and number of fills did not improve the discrimination. Data from insurance claims strongly predicted moderate-to-extensive levels of possible shopping (c=0.82). Prominent among 20 significant predictors were: state of residence; amount of opioid dispensed; self-payment; use of nonspecialist prescribers; high use of anxiolytics, hypnotics, psychostimulants, and antipsychotics; and use of both immediate release and extended-release or long-acting opioids. The use of ≥3 prescribing practices and ≥3 dispensing pharmacies over 18 months sharply discriminated courses of opioid treatment from courses of diuretics. This pattern of fills was additionally associated with the numbers of nonspecialist and self-paid fills, the total morphine milligram equivalents dispensed, and heavier use of drugs for anxiety, sleep, attention, and psychosis.

  17. Milk bioactive peptides and beta-casomorphins induce mucus release in rat jejunum.

    Science.gov (United States)

    Trompette, Aurélien; Claustre, Jean; Caillon, Fabienne; Jourdan, Gérard; Chayvialle, Jean Alain; Plaisancié, Pascale

    2003-11-01

    Intestinal mucus is critically involved in the protection of the mucosa. An enzymatic casein hydrolysate and beta-casomorphin-7, a mu-opioid peptide generated in the intestine during bovine casein digestion, markedly induce mucus discharge. Because shorter mu-opioid peptides have been described, the effects of the opioid peptides in casein, beta-casomorphin-7, -6, -4, -4NH2 and -3, and of opioid neuropeptides met-enkephalin, dynorphin A and (D-Ala2,N-Me-Phe4,glycinol5)enkephalin (DAMGO) on intestinal mucus secretion were investigated. The experiments were conducted with isolated perfused rat jejunum. Mucus secretion under the influence of beta-casomorphins and opioid neuropeptides administered intraluminally or intra-arterially was evaluated using an ELISA for rat intestinal mucus. Luminal administration of beta-casomorphin-7 (1.2 x 10(-4) mol/L) provoked a mucus discharge (500% of controls) that was inhibited by naloxone, a specific opiate receptor antagonist. Luminal beta-casomorphin-6, -4 and -4NH2 did not modify basal mucus secretion, whereas intra-arterial administration of beta-casomorphin-4 (1.2 x 10(-6) mol/L) induced a mucus discharge. In contrast, intra-arterial administration of the nonopioid peptide beta-casomorphin-3 did not release mucus. Among the opioid neuropeptides, intra-arterial infusion of Met-enkephalin or dynorphin-A did not provoke mucus secretion. In contrast, beta-endorphin (1.2 x 10(-8) to 1.2 x 10(-6) mol/L) induced a dose-dependent release of mucus (maximal response at 500% of controls). DAMGO (1.2 x 10(-6) mol/L), a mu-receptor agonist, also evoked a potent mucus discharge. Our findings suggest that mu-opioid neuropeptides, as well as beta-casomorphins after absorption, modulate intestinal mucus discharge. Milk opioid-derived peptides may thus be involved in defense against noxious agents and could have dietary and health applications.

  18. Buprenorphine for managing opioid withdrawal.

    Science.gov (United States)

    Gowing, Linda; Ali, Robert; White, Jason M; Mbewe, Dalitso

    2017-02-21

    Managed withdrawal is a necessary step prior to drug-free treatment or as the endpoint of substitution treatment. To assess the effects of buprenorphine versus tapered doses of methadone, alpha 2 -adrenergic agonists, symptomatic medications or placebo, or different buprenorphine regimens for managing opioid withdrawal, in terms of the intensity of the withdrawal syndrome experienced, duration and completion of treatment, and adverse effects. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 11, 2016), MEDLINE (1946 to December week 1, 2016), Embase (to 22 December 2016), PsycINFO (1806 to December week 3, 2016), and the Web of Science (to 22 December 2016) and handsearched the reference lists of articles. Randomised controlled trials of interventions using buprenorphine to modify the signs and symptoms of withdrawal in participants who were primarily opioid dependent. Comparison interventions involved reducing doses of methadone, alpha 2 -adrenergic agonists (clonidine or lofexidine), symptomatic medications or placebo, and different buprenorphine-based regimens. We used standard methodological procedures expected by Cochrane. We included 27 studies involving 3048 participants. The main comparators were clonidine or lofexidine (14 studies). Six studies compared buprenorphine versus methadone, and seven compared different rates of buprenorphine dose reduction. We assessed 12 studies as being at high risk of bias in at least one of seven domains of methodological quality. Six of these studies compared buprenorphine with clonidine or lofexidine and two with methadone; the other four studies compared different rates of buprenorphine dose reduction.For the comparison of buprenorphine and methadone in tapered doses, meta-analysis was not possible for the outcomes of intensity of withdrawal or adverse effects. However, information reported by the individual studies was suggestive of buprenorphine and methadone having similar capacity to

  19. Bioactive peptides from meat muscle and by-products: generation, functionality and application as functional ingredients.

    Science.gov (United States)

    Lafarga, Tomas; Hayes, Maria

    2014-10-01

    Bioactive peptides are sequences of between 2-30 amino acids in length that impart a positive health effect to the consumer when ingested. They have been identified from a range of foods, including milk and muscle sources including beef, chicken, pork and marine muscles. The myriad of peptides identified from these sources have known antihypertensive, opioid, antioxidant, antithrombotic and other bioactivities. Indeed, bioactive peptides could play a role in the prevention of diseases associated with the development of metabolic syndrome and mental health diseases. The aim of this work is to present an overview of the bioactive peptides identified in muscle proteins and by-products generated during the processing of meat. The paper looks at the isolation, enrichment and characterisation strategies that have been employed to date to generate bioactive peptides and the potential future applications of these peptides in functional foods for the prevention of heart and mental health problems and obesity. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. The opioid epidemic and national guidelines for opioid therapy for chronic noncancer pain: a perspective from different continents.

    Science.gov (United States)

    Häuser, Winfried; Schug, Stephan; Furlan, Andrea D

    2017-05-01

    A marked rise in opioid prescriptions for patients with chronic noncancer pain (CNCP) with a parallel increase in opioid abuse/misuse, and resulting deaths was noted in the Unites states in the past decade (opioid epidemic). In response, the US Center of Diseases Control (CDC) developed a guideline for prescribing of opioids for patients with CNCP. To assess (1) if there is an opioid epidemic in Australia, Canada, and Germany (2) to compare Australian, Canadian, German, and Center of Diseases Control guidelines recommendations for long-term opioid therapy for CNCP. National evidence-based guidelines and PubMed were searched for recommendations for opioid prescriptions for CNCP. There are signs of an opioid epidemic in Australia and Canada, but not in Germany. Guidelines in all 4 countries provide similar recommendations: opioids are not the first-line therapy for patients with CNCP; regular clinical assessments of benefits and harms are necessary; excessive doses should be avoided (recommended morphine equivalent daily doses range from 50 to 200 mg/d); stopping rules should be followed. All guidelines do not recommend the use of opioids in chronic pain conditions without an established nociceptive or neuropathic cause such as fibromyalgia and primary headache. Implementation of opioid prescribing guidelines should ensure that physicians prescribe opioids only for appropriate indications in limited doses for selected patients and advice patients on their safe use. These measures could contribute to reduce prescription opioid misuse/abuse and deaths.

  1. Opioid Overdoses Treated in Emergency Departments PSA (:60)

    Centers for Disease Control (CDC) Podcasts

    This 60 second public service announcement is based on the March 2018 CDC Vital Signs report. Opioid overdoses continue to increase in the United States. Learn what can be done to help prevent opioid overdose and death.

  2. Opioids and Chronic Pain | NIH MedlinePlus the Magazine

    Science.gov (United States)

    ... Long-term daily use of opioids leads to physical dependence, which is not to be confused with addiction ... be screened and closely monitored. When people have physical dependence and the opioid use is stopped, withdrawal symptoms ...

  3. Pain Management in the Opioid-Dependent Pregnant Woman.

    Science.gov (United States)

    Safley, Rebecca R; Swietlikowski, Jamie

    Opioid dependence is an epidemic in the United States, and the percentage of pregnant women who are opioid dependent has increased dramatically in the last decade. Pain management, already a concern for intrapartum and postpartum care, is complicated in the context of opioid dependence. This clinical review surveys the literature on pain management in opioid-dependent pregnant women to summarize current consensus and evidence to guide clinical practice. Points of consensus for pain management in opioid-dependent pregnant women include continual opioid maintenance therapy throughout the pregnancy and the postpartum period; adequate management of acute pain; the contraindication of opioid agonist-antagonists for pain management; and the need for interdisciplinary teams using a multimodal approach to provide optimal care to opioid-dependent pregnant women.

  4. Recovering from Opioid Overdose: Resources for Overdose Survivors & Family Members

    Science.gov (United States)

    ... and gratitude, all accompanied by the discomfort of opioid withdrawal. Most need the support of family and friends to take the next steps toward recovery. While many factors can contribute to opioid overdose, it is al most always an accident. ...

  5. Past-year Prescription Drug Monitoring Program Opioid Prescriptions and Self-reported Opioid Use in an Emergency Department Population With Opioid Use Disorder.

    Science.gov (United States)

    Hawk, Kathryn; D'Onofrio, Gail; Fiellin, David A; Chawarski, Marek C; O'Connor, Patrick G; Owens, Patricia H; Pantalon, Michael V; Bernstein, Steven L

    2017-11-22

    Despite increasing reliance on prescription drug monitoring programs (PDMPs) as a response to the opioid epidemic, the relationship between aberrant drug-related behaviors captured by the PDMP and opioid use disorder is incompletely understood. How PDMP data should guide emergency department (ED) assessment has not been studied. The objective was to evaluate a relationship between PDMP opioid prescription records and self-reported nonmedical opioid use of prescription opioids in a cohort of opioid-dependent ED patients enrolled in a treatment trial. PDMP opioid prescription records during 1 year prior to study enrollment on 329 adults meeting Diagnostic and Statistical Manual IV criteria for opioid dependence entering a randomized clinical trial in a large, urban ED were cross-tabulated with data on 30-day nonmedical prescription opioid use self-report. The association among these two types of data was assessed by the Goodman and Kruskal's gamma; a logistic regression was used to explore characteristics of participants who had PDMP record of opioid prescriptions. During 1 year prior to study enrollment, 118 of 329 (36%) patients had at least one opioid prescription (range = 1-51) in our states' PDMP. Patients who reported ≥15 of 30 days of nonmedical prescription opioid use were more likely to have at least four PDMP opioid prescriptions (20/38; 53%) than patients reporting 1 to 14 days (14/38, 37%) or zero days of nonmedical prescription opioid use (4/38, 11%; p = 0.002). Female sex and having health insurance were significantly more represented in the PDMP (p Medicine.

  6. BIOACTIVE PEPTIDES OF THE COW MILK WHEY PROTEINS (Bos taurus

    Directory of Open Access Journals (Sweden)

    A. V. Iukalo

    2013-10-01

    Full Text Available Data on the biological functions of milk whey proteins, which are implemented at the level of their proteolytic degradation products — bioactive peptides have been reviewed. The main functions of these proteins is to provide the amino acid nutrition of mammals in the early stages of development, as well as the transport of fatty acids, retinol, involved in the synthesis of lactose, ions of calcium and iron, immune protection, antimicrobial action, etc. However, in recent years, it has been found that milk proteins like casein are precursors of biologically active peptides. Аngiotensin — converting enzyme, opioid peptides which are opiate receptor agonists, anti–microbial peptides, peptides with immunomodulatory and hypocholesterolemic action, and peptides affecting motility have been found among the products of proteolytic degradation of ?-lactoglobulin, ?-laktoalbumin, lactoferrin and milk whey albumin. Also data on the possible participation of peptides from milk whey proteins in the implementation of the biological functions of both the assimilation of calcium, antioxidant effect, the regulation of appetite, anticarcinogenic are provided. The authors assume that the phenomenon of bioactive peptides formation could be considered as an additional function of natural food proteins, which gives advantages to the mammals and has a positive effect on their development in the postnatal period. Ways of bioactive peptides formation, their resistance to action of proteolytic enzymes, the ability to cross into the bloodstream and have biological effects have been also discussed. Up to date, only a few products with bioactive peptides from milk whey proteins are obtained. Further studies of their structure, mechanism of action, ways of formation and methods of isolation are required for their wider use. Formation of functional products based on bioactive peptides from milk whey proteins will allow efficient use of milk whey, which is often a

  7. The evolution of chronic opioid therapy and recognizing addiction.

    Science.gov (United States)

    Daum, Akiva M; Berkowitz, Oren; Renner, John A

    2015-05-01

    Chronic pain is one of the most common complaints in the United States. Opioids have become a frequently prescribed treatment for patients with chronic nonmalignant pain. Concurrently, opioid use disorders have risen to epidemic levels. Studies investigating iatrogenic opioid addiction have been of limited quality. Aberrant drug-related behaviors may be warning signs of impending addiction. Proper screening and close monitoring are essential for managing patients on opioids for chronic nonmalignant pain.

  8. Growth inhibition of thyroid follicular cell-derived cancers by the opioid growth factor (OGF) - opioid growth factor receptor (OGFr) axis

    International Nuclear Information System (INIS)

    McLaughlin, Patricia J; Zagon, Ian S; Park, Sunny S; Conway, Andrea; Donahue, Renee N; Goldenberg, David

    2009-01-01

    Carcinoma of the thyroid gland is an uncommon cancer, but the most frequent malignancy of the endocrine system. Most thyroid cancers are derived from the follicular cell. Follicular carcinoma (FTC) is considered more malignant than papillary thyroid carcinoma (PTC), and anaplastic thyroid cancer (ATC) is one of the most lethal human cancers. Opioid Growth Factor (OGF; chemical term - [Met 5 ]-enkephalin) and its receptor, OGFr, form an inhibitory axis regulating cell proliferation. Both the peptide and receptor have been detected in a wide variety of cancers, and OGF is currently used clinically as a biotherapy for some non-thyroid neoplasias. This study addressed the question of whether the OGF-OGFr axis is present and functional in human thyroid follicular cell - derived cancer. Utilizing human ATC (KAT-18), PTC (KTC-1), and FTC (WRO 82-1) cell lines, immunohistochemistry was employed to ascertain the presence and location of OGF and OGFr. The growth characteristics in the presence of OGF or the opioid antagonist naltrexone (NTX), and the specificity of opioid peptides for proliferation of ATC, were established in KAT-18 cells. Dependence on peptide and receptor were investigated using neutralization studies with antibodies and siRNA experiments, respectively. The mechanism of peptide action on DNA synthesis and cell survival was ascertained. The ubiquity of the OGF-OGFr axis in thyroid follicular cell-derived cancer was assessed in KTC-1 (PTC) and WRO 82-1 (FTC) tumor cells. OGF and OGFr were present in KAT-18 cells. Concentrations of 10 -6 M OGF inhibited cell replication up to 30%, whereas NTX increased cell growth up to 35% relative to cultures treated with sterile water. OGF treatment reduced cell number by as much as 38% in KAT-18 ATC in a dose-dependent and receptor-mediated manner. OGF antibodies neutralized the inhibitory effects of OGF, and siRNA knockdown of OGFr negated growth inhibition by OGF. Cell survival was not altered by OGF, but DNA synthesis

  9. Opioid withdrawal suppression efficacy of oral dronabinol in opioid dependent humans.

    Science.gov (United States)

    Lofwall, Michelle R; Babalonis, Shanna; Nuzzo, Paul A; Elayi, Samy Claude; Walsh, Sharon L

    2016-07-01

    The cannabinoid (CB) system is a rational novel target for treating opioid dependence, a significant public health problem around the world. This proof-of-concept study examined the potential efficacy of a CB1 receptor partial agonist, dronabinol, in relieving signs and symptoms of opioid withdrawal. Twelve opioid dependent adults participated in this 5-week, inpatient, double-blind, randomized, placebo-controlled study. Volunteers were maintained on double-blind oxycodone (30mg oral, four times/day) and participated in a training session followed by 7 experimental sessions, each testing a single oral test dose (placebo, oxycodone 30 and 60mg, dronabinol 5, 10, 20, and 30mg [decreased from 40mg]). Placebo was substituted for oxycodone maintenance doses for 21h before each session in order to produce measurable opioid withdrawal. Outcomes included observer- and participant-ratings of opioid agonist, opioid withdrawal and psychomotor/cognitive performance. Oxycodone produced prototypic opioid agonist effects (i.e. suppressing withdrawal and increasing subjective effects indicative of abuse liability). Dronabinol 5 and 10mg produced effects most similar to placebo, while the 20 and 30mg doses produced modest signals of withdrawal suppression that were accompanied by dose-related increases in high, sedation, bad effects, feelings of heart racing, and tachycardia. Dronabinol was not liked more than placebo, showed some impairment in cognitive performance, and was identified as marijuana with increasing dose. CB1 receptor activation is a reasonable strategy to pursue for the treatment of opioid withdrawal; however, dronabinol is not a likely candidate given its modest withdrawal suppression effects of limited duration and previously reported tachycardia during opioid withdrawal. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  10. Access to opioids: a global pain management crisis.

    Science.gov (United States)

    Buitrago, Rosa

    2013-03-01

    The lack of availability of opioids in many countries has created a pain management crisis. Because the Single Convention on Narcotic Drugs requires governments to report annual opioid statistics, there is a need for methods to calculate individual nations' opioid needs. Ways to address this need are discussed.

  11. Global Supply and Demand of Opioids for Pain Management.

    Science.gov (United States)

    Kunnumpurath, Sreekumar; Julien, Natasha; Kodumudi, Gopal; Kunnumpurath, Anamika; Kodumudi, Vijay; Vadivelu, Nalini

    2018-04-04

    The goal of this review is to evaluate the global supply and demand of opioids used for pain management and discuss how it relates to the utilization of opioids around the world. The purpose of the review is also to determine the factors that contribute to inappropriate pain management. The total global production of opium for opioid manufacturing is enough to supply the growing global demands. However, licit opioids are only consumed by 20% of the world population. Most people throughout the world had no access to opioid analgesics for pain relief in case of need. Opioid misuse and abuse is not only a phenomena plague by the USA but globally across many countries. Many countries have a lack of availability of opioids, contributing factors being strict government regulations limiting access, lack of knowledge of the efficacy of opioid analgesics in treating acute and chronic pain and palliative care, and the stigma that opioids are highly addictive. For the countries in which opioids are readily available and prescribed heavily, diversion, misuse, abuse, and the resurgence of heroin have become problems leading to morbidity and mortality. It is pertinent to find a balance between having opioids accessible to patients in need, with ensuring that opioids are regulated along with other illicit drugs to decrease abuse potential.

  12. Opioid Analgesics and Nicotine: More Than Blowing Smoke.

    Science.gov (United States)

    Yoon, Jin H; Lane, Scott D; Weaver, Michael F

    2015-09-01

    Practitioners are highly likely to encounter patients with concurrent use of nicotine products and opioid analgesics. Smokers present with more severe and extended chronic pain outcomes and have a higher frequency of prescription opioid use. Current tobacco smoking is a strong predictor of risk for nonmedical use of prescription opioids. Opioid and nicotinic-cholinergic neurotransmitter systems interact in important ways to modulate opioid and nicotine effects: dopamine release induced by nicotine is dependent on facilitation by the opioid system, and the nicotinic-acetylcholine system modulates self-administration of several classes of abused drugs-including opioids. Nicotine can serve as a prime for the use of other drugs, which in the case of the opioid system may be bidirectional. Opioids and compounds in tobacco, including nicotine, are metabolized by the cytochrome P450 enzyme system, but the metabolism of opioids and tobacco products can be complicated. Accordingly, drug interactions are possible but not always clear. Because of these issues, asking about nicotine use in patients taking opioids for pain is recommended. When assessing patient tobacco use, practitioners should also obtain information on products other than cigarettes, such as cigars, pipes, smokeless tobacco, and electronic nicotine delivery systems (ENDS, or e-cigarettes). There are multiple forms of behavioral therapy and pharmacotherapy available to assist patients with smoking cessation, and opioid agonist maintenance and pain clinics represent underutilized opportunities for nicotine intervention programs.

  13. The opioid ketobemidone has a NMDA blocking effect

    DEFF Research Database (Denmark)

    Andersen, S; Dickenson, A H; Kohn, M

    1996-01-01

    There are clinical observations that neurogenic pain can respond well to the opioid ketobemidone, in contrast to pethidine and morphine. This has led us to the hypothesis that the analgesic effect of ketobemidone in neurogenic pain may be due to both opioid as well as additional non-opioid effect...

  14. Postoperative opioid analgesia: time for a reconsideration?

    DEFF Research Database (Denmark)

    Kehlet, H; Rung, G W; Callesen, T

    1996-01-01

    Postoperative pain relief has improved in recent years with the development of new analgesics, additional routes of administration and the appearance of the hypothesis of preemptive as well as balanced analgesia (Kehlet H; Postoperative pain relief-what is the issue? Br J Anaesth 1994;72:375-8). ......Postoperative pain relief has improved in recent years with the development of new analgesics, additional routes of administration and the appearance of the hypothesis of preemptive as well as balanced analgesia (Kehlet H; Postoperative pain relief-what is the issue? Br J Anaesth 1994......;72:375-8). Many initial improvements simply involved the administration of opioid analgesics in new ways, such as continuous or on demand intravenous (i.v.) or epidural infusion. These methods allow lower total opioid dosages, provide a more stable concentration of opioid at the receptor and correspondingly...

  15. Extensive changes in the expression of the opioid genes between humans and chimpanzees.

    Science.gov (United States)

    Cruz-Gordillo, Peter; Fedrigo, Olivier; Wray, Gregory A; Babbitt, Courtney C

    2010-01-01

    The various means by which the body perceives, transmits, and resolves the experiences of pain and nociception are mediated by a host of molecules, including neuropeptides within the opioid gene signaling pathway. The peptide ligands and receptors encoded by this group of genes have been linked to behavioral disorders as well as a number of psychiatric affective disorders. Our aim was to explore the recent evolutionary history of these two gene families by taking a comparative genomics approach, specifically through a comparison between humans and chimpanzees. Our analyses indicate differential expression of these genes between the two species, more than expected based on genome-wide comparisons, indicating that differential expression is pervasive among the opioid genes. Of the 8 family members, three genes showed significant expression differences (PENK, PNOC, and OPRL1), with two others marginally significant (OPRM1 and OPRD1). Accelerated substitution rates along human and chimpanzee lineages within the putative regulatory regions of OPRM1, POMC, and PDYN between the human and chimpanzee branches are consistent with positive selection. Collectively, these results suggest that there may have been a selective advantage to modulating the expression of the opioid genes in humans compared with our closest living relatives. Information about the cognitive roles mediated by these genes in humans may help to elucidate the trait consequences of these putatively adaptive expression changes. Copyright © 2010 S. Karger AG, Basel.

  16. Sensory Neuropeptides and Endogenous Opioids Expression in Human Dental Pulp with Asymptomatic Inflammation: In Vivo Study

    Directory of Open Access Journals (Sweden)

    Daniel Chavarria-Bolaños

    2015-01-01

    Full Text Available Purpose. This study quantified the expression of substance P (SP, calcitonin gene-related peptide (CGRP, β-endorphins (β-End, and methionine-enkephalin (Met-Enk in human dental pulp following orthodontic intrusion. Methods. Eight patients were selected according to preestablished inclusion criteria. From each patient, two premolars (indicated for extraction due to orthodontic reasons were randomly assigned to two different groups: the asymptomatic inflammation group (EXPg, which would undergo controlled intrusive force for seven days, and the control group (CTRg, which was used to determine the basal levels of each substance. Once extracted, dental pulp tissue was prepared to determine the expression levels of both neuropeptides and endogenous opioids by radioimmunoassay (RIA. Results. All samples from the CTRg exhibited basal levels of both neuropeptides and endogenous opioids. By day seven, all patients were asymptomatic, even when all orthodontic-intrusive devices were still active. In the EXPg, the SP and CGRP exhibited statistically significant different levels. Although none of the endogenous opioids showed statistically significant differences, they all expressed increasing trends in the EXPg. Conclusions. SP and CGRP were identified in dental pulp after seven days of controlled orthodontic intrusion movement, even in the absence of pain.

  17. Cholecystokinin octapeptide induces endogenous opioid-dependent anxiolytic effects in morphine-withdrawal rats.

    Science.gov (United States)

    Wen, D; Sun, D; Zang, G; Hao, L; Liu, X; Yu, F; Ma, C; Cong, B

    2014-09-26

    Cholecystokinin octapeptide (CCK-8), a brain-gut peptide, plays an important role in several opioid addictive behaviors. We previously reported that CCK-8 attenuated the expression and reinstatement of morphine-induced conditioned place preference. The possible effects of CCK-8 on the negative affective components of drug abstinence are not clear. There are no studies evaluating the effect of CCK-8 on emotional symptoms, such as anxiety, in morphine-withdrawal animals. We investigated the effects of CCK-8 on the anxiety-like behavior in morphine-withdrawal rats using an elevated plus-maze. Morphine withdrawal elicited time-dependent anxiety-like behaviors with peak effects on day 10 (5 days after induction of morphine dependence). Treatment with CCK-8 (0.1 and 1 μg, i.c.v.) blocked this anxiety in a dose-dependent fashion. A CCK1 receptor antagonist (L-364,718, 10 μg, i.c.v.) blocked the effect of CCK-8. Mu-opioid receptor antagonism with CTAP (10 μg, i.c.v.) decreased the 'anxiolytic' effect. CCK-8 inhibited anxiety-like behaviors in morphine-withdrawal rats by up-regulating endogenous opioids via the CCK1 receptor in rats. This study clearly identifies a distinct function of CCK-8 and a potential medication target of central CCK1 receptors for drugs aimed at ameliorating drug addiction. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  18. Satiety and the role of μ-opioid receptors in the portal vein.

    Science.gov (United States)

    De Vadder, Filipe; Gautier-Stein, Amandine; Mithieux, Gilles

    2013-12-01

    Mu-opioid receptors (MORs) are known to influence food intake at the brain level, through their involvement in the food reward system. MOR agonists stimulate food intake. On the other hand, MOR antagonists suppress food intake. MORs are also active in peripheral organs, especially in the small intestine where they control the gut motility. Recently, an indirect role in the control of food intake was ascribed to MORs in the extrinsic gastrointestinal neural system. MORs present in the neurons of the portal vein walls sense blood peptides released from the digestion of dietary protein. These peptides behave as MOR antagonists. Their MOR antagonist action initiates a gut-brain circuitry resulting in the induction of intestinal gluconeogenesis, a function controlling food intake. Thus, periportal MORs are a key mechanistic link in the satiety effect of protein-enriched diets. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Primary care for opioid use disorder

    Directory of Open Access Journals (Sweden)

    Mannelli P

    2016-08-01

    Full Text Available Paolo Mannelli,1 Li-Tzy Wu1–41Department of Psychiatry and Behavioral Sciences, 2Department of Medicine, 3Duke Clinical Research Institute, Duke University Medical Center, 4Center for Child and Family Policy, Sanford School of Public Policy, Duke University, Durham, NC, USARecent reports on prescription opioid misuse and abuse have described unprecedented peaks of a national crisis and the only answer is to expand prevention and treatment, including different levels of care.1 Nonetheless, concerns remain about the ability of busy primary care settings to manage problem opioid users along with other patients. In particular, proposed extensions of buprenorphine treatment, a critically effective intervention for opioid use disorder (OUD, are cautiously considered due to the potential risk of misuse or abuse.2 General practitioners are already facing this burden daily in the treatment of chronic pain, and expert supervision and treatment model adjustment are needed to help improve outcomes. Approximately 20% of patients in primary care have noncancer pain symptoms, with most of them receiving opioid prescriptions by their physicians, and their number is increasing.3 Pain diagnoses are comparable in severity to those of tertiary centers and are complicated by significant psychiatric comorbidity, with a measurable lifetime risk of developing OUD.4,5 Some primary care physicians report frustration about opioid abuse and diversion by their patients; support from pain specialists would improve their competence, the quality f their performance, and the ability to identify patients at risk of opioid misuse.6 Thus, buprenorphine treatment should not be adding to a complex clinical scenario. To this end, the promising models of care emphasize the integration of medical with psychological and pharmacological expertise for the management of OUD. 

  20. Opioid receptor mediated anticonvulsant effect of pentazocine.

    Science.gov (United States)

    Khanna, N; Khosla, R; Kohli, J

    1998-01-01

    Intraperitoneal (i.p.) administration of (+/-) pentazocine (10, 30 & 50 mg/kg), a Sigma opioid agonist, resulted in a dose dependent anticonvulsant action against maximal electroshock seizures in mice. This anticonvulsant effect of pentazocine was not antagonized by both the doses of naloxone (1 and 10 mg/kg) suggesting thereby that its anticonvulsant action is probably mediated by Sigma opiate binding sites. Its anticonvulsant effect was potentiated by both the anticonvulsant drugs viz. diazepam and diphenylhydantoin. Morphine, mu opioid agonist, on the other hand, failed to protect the animals against maximal electroshock seizures when it was given in doses of 10-40 mg/kg body wt.

  1. Non-analgesic effects of opioids

    DEFF Research Database (Denmark)

    Højsted, Jette; Kurita, Geana Paula; Kendall, Sally

    2012-01-01

    Opioids constitute the basis for pharmacological treatment of moderate to severe pain in cancer pain and non-cancer pain patients. Their action is mediated by the activation of opioid receptors, which integrates the pain modulation system with other effects in the central nervous system including...... groups: no effects or worsening of cognitive function in cancer pain patients and no effect or improvements in the chronic non-cancer pain patients, however, due to methodological limitations and a huge variety of designs definite conclusions are difficult to draw from the studies. In studies of higher...

  2. Opioids in Cancer Pain: Right or Privilege?

    Science.gov (United States)

    Jackson, Leanne K; Imam, Syed N; Braun, Ursula K

    2017-09-01

    Opioid analgesia is a mainstay of the treatment of cancer pain. Treatment of pain in patients with cancer with an ongoing substance abuse disorder can be difficult. We report the ethical challenges of treating a patient with cancer with a concomitant substance abuse disorder in an outpatient palliative care setting. We present an analysis of ethical considerations for the palliative care physician and strategies to aid in the successful treatment of such patients. We argue that there are select patients with cancer for whom exclusion from treatment with opioid therapy is warranted if their health is endangered by prescription of these medications.

  3. The opioid epidemic and national guidelines for opioid therapy for chronic noncancer pain: a perspective from different continents

    Directory of Open Access Journals (Sweden)

    Winfried Häuser

    2017-06-01

    Conclusion:. Implementation of opioid prescribing guidelines should ensure that physicians prescribe opioids only for appropriate indications in limited doses for selected patients and advice patients on their safe use. These measures could contribute to reduce prescription opioid misuse/abuse and deaths.

  4. Risk factors for opioid overdose and awareness of overdose risk among veterans prescribed chronic opioids for addiction or pain.

    Science.gov (United States)

    Wilder, Christine M; Miller, Shannon C; Tiffany, Elizabeth; Winhusen, Theresa; Winstanley, Erin L; Stein, Michael D

    2016-01-01

    Rising overdose fatalities among U.S. veterans suggest veterans taking prescription opioids may be at risk for overdose. However, it is unclear whether veterans prescribed chronic opioids are aware of this risk. The objective of this study was to identify risk factors and determine awareness of risk for opioid overdose in veterans treated with opioids for chronic pain, using veterans treated with methadone or buprenorphine for opioid use disorder as a high-risk comparator group. In the current study, 90 veterans on chronic opioid medication, for either opioid use disorder or pain management, completed a questionnaire assessing risk factors, knowledge, and self-estimate of risk for overdose. Nearly all veterans in both groups had multiple overdose risk factors, although individuals in the pain management group had on average a significantly lower total number of risk factors than did individuals in the opioid use disorder group (5.9 versus 8.5, p opioid overdose risk factors (12.1 versus 13.5, p opioid overdose risk factors. Our results suggest that veterans in both groups underestimated their risk for opioid overdose. Expansion of overdose education to include individuals on chronic opioids for pain management and a shift in educational approaches to overdose prevention may be indicated.

  5. Prescription opioid abuse, pain and addiction: clinical issues and implications.

    Science.gov (United States)

    Ling, Walter; Mooney, Larissa; Hillhouse, Maureen

    2011-05-01

    Prescription opioid misuse in the USA has increased over threefold since 1990 to epidemic proportions, with substantial increases in prescription opioid use also reported in other countries, such as Australia and New Zealand. The broad availability of prescription pain medications, coupled with public misconceptions about their safety and addictive potential, have contributed to the recent surge in non-medical use of prescription opioids and corresponding increases in treatment admissions for problems related to opioid misuse. Given competing pressures faced by physicians to both diagnose and treat pain syndromes and identify individuals at risk for addictive disorders, the use of opioids in the treatment of pain poses a significant clinical challenge. This paper reviews the interaction between pain and opioid addiction with a focus on clinical management issues, including risk factors for opioid dependence in patients with chronic pain and the use of assessment tools to identify and monitor at-risk individuals. Treatment options for opioid dependence and pain are reviewed, including the use of the partial µ agonist buprenorphine in the management of concurrent pain and opioid addiction. Physicians should strive to find a reasonable balance between minimising potential adverse effects of opioid medications without diminishing legitimate access to opioids for analgesia. The article discusses the need to identify methods for minimising risks and negative consequences associated with opioid analgesics and poses research directions, including the development of abuse-deterrent opioid formulations, genetic risk factors for opioid dependence and opioid-induced hyperalgesia as a potential target for medication therapy. © 2011 Australasian Professional Society on Alcohol and other Drugs.

  6. Structural and pharmacological characteristics of chimeric peptides derived from peptide E and beta-endorphin reveal the crucial role of the C-terminal YGGFL and YKKGE motifs in their analgesic properties.

    Science.gov (United States)

    Condamine, Eric; Courchay, Karine; Rego, Jean-Claude Do; Leprince, Jérôme; Mayer, Catherine; Davoust, Daniel; Costentin, Jean; Vaudry, Hubert

    2010-05-01

    Peptide E (a 25-amino acid peptide derived from proenkephalin A) and beta-endorphin (a 31-amino acid peptide derived from proopiomelanocortin) bind with high affinity to opioid receptors and share structural similarities but induce analgesic effects of very different intensity. Indeed, whereas they possess the same N-terminus Met-enkephalin message sequence linked to a helix by a flexible spacer and a C-terminal part in random coil conformation, in contrast with peptide E, beta-endorphin produces a profound analgesia. To determine the key structural elements explaining this very divergent opioid activity, we have compared the structural and pharmacological characteristics of several chimeric peptides derived from peptide E and beta-endorphin. Structures were obtained under the same experimental conditions using circular dichroism, computational estimation of helical content and/or nuclear magnetic resonance spectroscopy (NMR) and NMR-restrained molecular modeling. The hot-plate and writhing tests were used in mice to evaluate the antinociceptive effects of the peptides. Our results indicate that neither the length nor the physicochemical profile of the spacer plays a fundamental role in analgesia. On the other hand, while the functional importance of the helix cannot be excluded, the last 5 residues in the C-terminal part seem to be crucial for the expression or absence of the analgesic activity of these peptides. These data raise the question of the true function of peptides E in opioidergic systems. Copyright (c) 2010 Elsevier Inc. All rights reserved.

  7. Human peptide transporters

    DEFF Research Database (Denmark)

    Nielsen, Carsten Uhd; Brodin, Birger; Jørgensen, Flemming Steen

    2002-01-01

    Peptide transporters are epithelial solute carriers. Their functional role has been characterised in the small intestine and proximal tubules, where they are involved in absorption of dietary peptides and peptide reabsorption, respectively. Currently, two peptide transporters, PepT1 and PepT2, wh...

  8. Development and preliminary validation of the Opioid Abuse Risk Screener

    Directory of Open Access Journals (Sweden)

    Patricia Henrie-Barrus

    2016-05-01

    Full Text Available Prescription opioid drug abuse has reached epidemic proportions. Individuals with chronic pain represent a large population at considerable risk of abusing opioids. The Opioid Abuse Risk Screener was developed as a comprehensive self-administered measure of potential risk that includes a wide range of critical elements noted in the literature to be relevant to opioid risk. The creation, refinement, and preliminary modeling of the item pool, establishment of preliminary concurrent validity, and the determination of the factor structure are presented. The initial development and validation of the Opioid Abuse Risk Screener shows promise for effective risk stratification.

  9. δ-opioid receptor and somatostatin receptor-4 heterodimerization: possible implications in modulation of pain associated signaling.

    Directory of Open Access Journals (Sweden)

    Rishi K Somvanshi

    Full Text Available Pain relief is the principal action of opioids. Somatostatin (SST, a growth hormone inhibitory peptide is also known to alleviate pain even in cases when opioids fail. Recent studies have shown that mice are prone to sustained pain and devoid of analgesic effect in the absence of somatostatin receptor 4 (SSTR4. In the present study, using brain slices, cultured neurons and HEK-293 cells, we showed that SSTR4 and δ-Opioid receptor (δOR exist in a heteromeric complex and function in synergistic manner. SSTR4 and δOR co-expressed in cortical/striatal brain regions and spinal cord. Using cultured neuronal cells, we describe the heterogeneous complex formation of SSTR4 and δOR at neuronal cell body and processes. Cotransfected cells display inhibition of cAMP/PKA and co-activation of SSTR4 and δOR oppose receptor trafficking induced by individual receptor activation. Furthermore, downstream signaling pathways either associated with withdrawal or pain relief are modulated synergistically with a predominant role of SSTR4. Inhibition of cAMP/PKA and activation of ERK1/2 are the possible cellular adaptations to prevent withdrawal induced by chronic morphine use. Our results reveal direct intra-membrane interaction between SSTR4 and δOR and provide insights for the molecular mechanism for the anti-nociceptive property of SST in combination with opioids as a potential therapeutic approach to avoid undesirable withdrawal symptoms.

  10. The Relative Potency of Inverse Opioid Agonists and a Neutral Opioid Antagonist in Precipitated Withdrawal and Antagonism of Analgesia and Toxicity

    OpenAIRE

    Sirohi, Sunil; Dighe, Shveta V.; Madia, Priyanka A.; Yoburn, Byron C.

    2009-01-01

    Opioid antagonists can be classified as inverse agonists and neutral antagonists. In the opioid-dependent state, neutral antagonists are significantly less potent in precipitating withdrawal than inverse agonists. Consequently, neutral opioid antagonists may offer advantages over inverse agonists in the management of opioid overdose. In this study, the relative potency of three opioid antagonists to block opioid analgesia and toxicity and precipitate withdrawal was exa...

  11. Non-canonical Opioid Signaling Inhibits Itch Transmission in the Spinal Cord of Mice

    Directory of Open Access Journals (Sweden)

    Admire Munanairi

    2018-04-01

    Full Text Available Summary: Chronic itch or pruritus is a debilitating disorder that is refractory to conventional anti-histamine treatment. Kappa opioid receptor (KOR agonists have been used to treat chronic itch, but the underlying mechanism remains elusive. Here, we find that KOR and gastrin-releasing peptide receptor (GRPR overlap in the spinal cord, and KOR activation attenuated GRPR-mediated histamine-independent acute and chronic itch in mice. Notably, canonical KOR-mediated Gαi signaling is not required for desensitizing GRPR function. In vivo and in vitro studies suggest that KOR activation results in the translocation of Ca2+-independent protein kinase C (PKCδ from the cytosol to the plasma membrane, which in turn phosphorylates and inhibits GRPR activity. A blockade of phospholipase C (PLC in HEK293 cells prevented KOR-agonist-induced PKCδ translocation and GRPR phosphorylation, suggesting a role of PLC signaling in KOR-mediated GRPR desensitization. These data suggest that a KOR-PLC-PKCδ-GRPR signaling pathway in the spinal cord may underlie KOR-agonists-induced anti-pruritus therapies. : Munanairi et al. show that the kappa opioid receptor (KOR agonists inhibit nonhistaminergic itch transmission by attenuating the function of the gastrin-releasing peptide receptor (GRPR, an itch receptor in the spinal cord. KOR activation causes the translocation of PKCδ from plasma to membrane, which phosphorylates GRPR to dampen itch transmission. Keywords: KOR, GRPR, itch, PKC, phosphorylation, GPCR cross-signaling, spinal cord, mouse

  12. Sucrose ingestion causes opioid analgesia

    Directory of Open Access Journals (Sweden)

    F.N. Segato

    1997-08-01

    Full Text Available The intake of saccharin solutions for relatively long periods of time causes analgesia in rats, as measured in the hot-plate test, an experimental procedure involving supraspinal components. In order to investigate the effects of sweet substance intake on pain modulation using a different model, male albino Wistar rats weighing 180-200 g received either tap water or sucrose solutions (250 g/l for 1 day or 14 days as their only source of liquid. Each rat consumed an average of 15.6 g sucrose/day. Their tail withdrawal latencies in the tail-flick test (probably a spinal reflex were measured immediately before and after this treatment. An analgesia index was calculated from the withdrawal latencies before and after treatment. The indexes (mean ± SEM, N = 12 for the groups receiving tap water for 1 day or 14 days, and sucrose solution for 1 day or 14 days were 0.09 ± 0.04, 0.10 ± 0.05, 0.15 ± 0.08 and 0.49 ± 0.07, respectively. One-way ANOVA indicated a significant difference (F(3,47 = 9.521, P<0.001 and the Tukey multiple comparison test (P<0.05 showed that the analgesia index of the 14-day sucrose-treated animals differed from all other groups. Naloxone-treated rats (N = 7 receiving sucrose exhibited an analgesia index of 0.20 ± 0.10 while rats receiving only sucrose (N = 7 had an index of 0.68 ± 0.11 (t = 0.254, 10 degrees of freedom, P<0.03. This result indicates that the analgesic effect of sucrose depends on the time during which the solution is consumed and extends the analgesic effects of sweet substance intake, such as saccharin, to a model other than the hot-plate test, with similar results. Endogenous opioids may be involved in the central regulation of the sweet substance-produced analgesia.

  13. Computational opioid prescribing: a novel application of clinical pharmacokinetics.

    Science.gov (United States)

    Linares, Oscar A; Linares, Annemarie L

    2011-01-01

    We implemented a pharmacokinetics-based mathematical modeling technique using algebra to assist prescribers with point-of-care opioid dosing. We call this technique computational opioid prescribing (COP). Because population pharmacokinetic parameter values are needed to estimate drug dosing regimen designs for individual patients using COP, and those values are not readily available to prescribers because they exist scattered in the vast pharmacology literature, we estimated the population pharmacokinetic parameter values for 12 commonly prescribed opioids from various sources using the bootstrap resampling technique. Our results show that opioid dosing regimen design, evaluation, and modification is feasible using COP. We conclude that COP is a new technique for the quantitative assessment of opioid dosing regimen design evaluation and adjustment, which may help prescribers to manage acute and chronic pain at the point-of-care. Potential benefits include opioid dose optimization and minimization of adverse opioid drug events, leading to potential improvement in patient treatment outcomes and safety.

  14. Comparison of craving for opioid in opioid-dependent individuals and people under methadone maintenance treatment

    Directory of Open Access Journals (Sweden)

    Azita Chehri

    2014-02-01

    Full Text Available Background: Methadone Maintenance Therapy (MMT is the most important treatment for opioid -dependency recurrence. The aim of this study was to compare the craving level in opioid-dependent individuals and people under methadone maintenance therapy. Methods: In this case – control study, 120 men with opioid dependency were selected through cluster sampling method. They were divided into two groups, 60 people in opioid-dependent group and 60 people in MMT group. Both groups were matched for age, sex, marital status, education, duration of opioid dependency and method of consumption. Then, they completed INCAS Substance Abuse Profile (ISAP, opiate withdrawal symptoms checklist, self–report of craving, Desire for Drug Questionnaire (DDQ, Obsessive Compulsive Drug Use Scale (OCDUS and visual cue-induced craving questionnaire. Data were analyzed by SPSS 15 using t-test and ANOVA. Results: Mean craving for drug significantly was lower in MMT group comparing opioid-dependent group (P<0.01. Conclusion: Methadone Maintenance Therapy decreased the craving for drugs and substances This can have an important role in relapse prevention.

  15. Who Benefits from Chronic Opioid Therapy? Rethinking the Question of Opioid Misuse Risk

    Directory of Open Access Journals (Sweden)

    Elizabeth Huber

    2016-05-01

    Full Text Available Beginning in the late 1990s, a movement began within the pain management field focused upon the underutilization of opioids, thought to be a potentially safe and effective class of pain medication. Concern for addiction and misuse were present at the start of this shift within pain medicine, and an emphasis was placed on developing reliable and valid methods and measures of identifying those at risk for opioid misuse. Since that time, the evidence for the safety and effectiveness of chronic opioid therapy (COT has not been established. Rather, the harmful, dose-dependent deleterious effects have become clearer, including addiction, increased risk of injuries, respiratory depression, opioid induced hyperalgesia, and death. Still, many individuals on low doses of opioids for long periods of time appear to have good pain control and retain social and occupational functioning. Therefore, we propose that the question, “Who is at risk of opioid misuse?” should evolve to, “Who may benefit from COT?” in light of the current evidence.

  16. Prescription opioid abuse: pharmacists’ perspective and response

    Directory of Open Access Journals (Sweden)

    Cochran G

    2016-08-01

    Full Text Available Gerald Cochran,1,2 Valerie Hruschak,2 Brooke DeFosse,3 Kenneth C Hohmeier3 1Department of Psychiatry, School of Medicine, 2School of Social Work, University of Pittsburgh, Pittsburgh, PA, 3Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee, Memphis, TN, USA Abstract: Opioid medication abuse and overdose are major concerns for public health, and a number of responses to address these issues have taken place across the US. Pharmacists and the pharmacy profession have made important contributions as a part of the response to this national crisis. This article provides a brief review of the antecedents, driving forces, and health status of patients involved in the opioid medication and overdose epidemic. This review further discusses pharmacy-based actions that have been undertaken to address this issue, including prescription drug monitoring, take-back, and naloxone training/distribution programs. This review likewise examines current efforts underway in the field to educate practitioners and needed future steps that must be taken by pharmacists in order to continue the profession’s pivotal role in working toward resolving this national public health problem. In particular, evidence and arguments are presented for proactively identifying and intervening with patients who abuse and/or are at risk for overdose. Continued and active engagement by pharmacists in these efforts has the potential to result in important reductions in opioid medication abuse and overdose and improvements for patient’s health. Keywords: opioid pain medication, addiction, pharmacy practice

  17. Prediction of withdrawal symptoms during opioid detoxification

    NARCIS (Netherlands)

    Dijkstra, Boukje A G; Krabbe, Paul F M; De Jong, Cor A J; van der Staak, Cees P F

    2008-01-01

    OBJECTIVE: The severity of self-reported withdrawal symptoms varies during detoxification of opioid-dependent patients. The aim of this study is to identify subgroups of withdrawal symptoms within the detoxification trajectory and to predict the severity of withdrawal symptoms on the basis of

  18. The Prescription Opioid Pain Medication Overdose Epidemic

    Centers for Disease Control (CDC) Podcasts

    2016-04-19

    Overdose related to prescription opioids has become an epidemic. This podcast discusses the risks of this type of drug sometimes used to treat pain, and how to protect yourself. .  Created: 4/19/2016 by National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP).   Date Released: 4/19/2016.

  19. Most drug overdose deaths from nonprescription opioids

    Directory of Open Access Journals (Sweden)

    Robbins RA

    2016-12-01

    Full Text Available No abstract available. Article truncated at 150 words. The Centers for Disease Control (CDC is reporting in Morbidity and Mortality Weekly that the number of people dying from an opioid overdose rose 15.5% from 2014 to 2015, but the increase had little to do with prescription painkillers such as oxycodone or hydrocodone (1. Roughly 52,000 people died from drug overdoses in 2015 and of those deaths 33,091 involved an opioid. The increases in “death rates were driven by synthetic opioids other than methadone (72.2%, most likely illicitly-manufactured fentanyl, and heroin (20.6%”. Deaths from methadone, which is usually prescribed by physicians, decreased 9.1%. The largest increase in deaths occurred in the South and Northeast with 3% and 24% increases in deaths from synthetic opioids from 2014 to 2015. In the Midwest and West, there were more modest 17% and 9% increases during the same period. States in the Southwest with “good” to “excellent” reporting included Colorado, Nevada, and New …

  20. Endogenous Opioid-Masked Latent Pain Sensitization

    DEFF Research Database (Denmark)

    Pereira, Manuel P; Donahue, Renee R; Dahl, Jørgen B

    2015-01-01

    UNLABELLED: Following the resolution of a severe inflammatory injury in rodents, administration of mu-opioid receptor inverse agonists leads to reinstatement of pain hypersensitivity. The mechanisms underlying this form of latent pain sensitization (LS) likely contribute to the development of chr...

  1. Prediction of withdrawal symptoms during opioid detoxification

    NARCIS (Netherlands)

    Dijkstra, B.A.G.; Krabbe, P.F.M.; Jong, C.A.J. de; Staak, C.P.F. van der

    2008-01-01

    Objective: The severity of self-reported withdrawal symptoms varies during detoxification of opioid-dependent patients. The aim of this study is to identify subgroups of withdrawal symptoms within the detoxification trajectory and to predict the severity of withdrawal symptoms on the basis of

  2. Increased opioid dependence in a mouse model of panic disorder

    Directory of Open Access Journals (Sweden)

    Xavier Gallego

    2010-02-01

    Full Text Available Panic disorder is a highly prevalent neuropsychiatric disorder that shows co-occurrence with substance abuse. Here, we demonstrate that TrkC, the high affinity receptor for neurotrophin-3, is a key molecule involved in panic disorder and opiate dependence, using a transgenic mouse model (TgNTRK3. Constitutive TrkC overexpression in TgNTRK3 mice dramatically alters spontaneous firing rates of locus coeruleus neurons and the response of the noradrenergic system to chronic opiate exposure, possibly related to the altered regulation of neurotrophic peptides observed. Notably, TgNTRK3 locus coeruleus neurons showed an increased firing rate in saline-treated conditions and profound abnormalities in their response to met5-enkephalin. Behaviorally, chronic morphine administration induced a significantly increased withdrawal syndrome in TgNTRK3 mice. In conclusion, we show here that the NT-3/TrkC system is an important regulator of neuronal firing in locus coeruleus and could contribute to the adaptations of the noradrenergic system in response to chronic opiate exposure. Moreover, our results indicate that TrkC is involved in the molecular and cellular changes in noradrenergic neurons underlying both panic attacks and opiate dependence and support a functional endogenous opioid deficit in panic disorder patients.

  3. Women who abuse prescription opioids: findings from the Addiction Severity Index-Multimedia Version Connect prescription opioid database.

    Science.gov (United States)

    Green, Traci C; Grimes Serrano, Jill M; Licari, Andrea; Budman, Simon H; Butler, Stephen F

    2009-07-01

    Evidence suggests gender differences in abuse of prescription opioids. This study aimed to describe characteristics of women who abuse prescription opioids in a treatment-seeking sample and to contrast gender differences among prescription opioid abusers. Data collected November 2005 to April 2008 derived from the Addiction Severity Index Multimedia Version Connect (ASI-MV Connect) database. Bivariate and multivariable logistic regression examined correlates of prescription opioid abuse stratified by gender. 29,906 assessments from 220 treatment centers were included, of which 12.8% (N=3821) reported past month prescription opioid abuse. Women were more likely than men to report use of any prescription opioid (29.8% females vs. 21.1% males, phistory of drug overdose. Men-specific correlates were age screen and identify those at highest risk of prescription opioid abuse. Prevention and intervention efforts with a gender-specific approach are warranted.

  4. Thallium exists in opioid poisoned patients.

    Science.gov (United States)

    Ghaderi, Amir; Vahdati-Mashhadian, Naser; Oghabian, Zohreh; Moradi, Valiallah; Afshari, Reza; Mehrpour, Omid

    2015-08-01

    Thallium (Tl) is a toxic heavy metal that exists in nature. Tl poisoning (thallotoxicosis) may occur in opioid addicts. This study was designed to evaluate the frequency and level of urinary Tl in opioid abusers. In addition, clinical findings were evaluated. A total of 150 subjects were examined. Cases with a history of at least 3 years of abuse were admitted in the Imam Reza Hospital as the case group; 50 non-opioid abusers from the target population were included as the control group. Twenty-four hour urinary qualitative and quantitative Tl analyses were performed on both groups. Out of the 150 subjects, 128 (85 %) were negative for qualitative urinary Tl, followed by 5 % (trace), 7 % (1+), 2 % (2+), and 1 % (3+). Mean (standard error (SE), Min-Max) quantitative urinary Tl level was 14 μg/L (3.5 μg/L, 0-346 μg/L). Mean urinary Tl level in the case group was 21 μg/L (5 μg/L, 0-346 μg/L) and that in the controls was 1 μg/L (0.14 μg/L, 0-26 μg/L), which were significantly different (P = 0.001). The most frequent clinical findings were ataxia (86 %), sweating (81 %), and constipation (54 %). In all cases (n = 150), the mean (SE) value for cases with positive qualitative urinary Tl was 26.8 μg/L (0.9 μg/L) and that in the negative cases was 2.3 μg/L (0.2 μg/L), which were significantly different (P = 0.002). This study showed that long-term opioid abuse may lead to Tl exposure. In opioid abusers with the clinical manifestation of thallotoxicosis, urinary Tl should be determined.

  5. Nonopioid substance use disorders and opioid dose predict therapeutic opioid addiction.

    Science.gov (United States)

    Huffman, Kelly L; Shella, Elizabeth R; Sweis, Giries; Griffith, Sandra D; Scheman, Judith; Covington, Edward C

    2015-02-01

    Limited research examines the risk of therapeutic opioid addiction (TOA) in patients with chronic noncancer pain. This study examined TOA among 199 patients undergoing long-term opioid therapy at the time of admission to a pain rehabilitation program. It was hypothesized that nonopioid substance use disorders and opioid dosage would predict TOA. Daily mean opioid dose was 132.85 mg ± 175.39. Patients with nonopioid substance use disorders had 28 times the odds (odds ratio [OR] = 28.58; 95% confidence interval [CI] = 10.86, 75.27) of having TOA. Each 50-mg increase in opioid dose nearly doubled the odds of TOA (OR = 1.73; 95% CI = 1.29, 2.32). A 100-mg increase was associated with a 3-fold increase in odds (OR = 3.00; 95% CI = 1.67, 5.41). Receiver operating characteristic analysis revealed that opioid dose was a moderately accurate predictor (area under the curve = .75; 95% CI = .68, .82) of TOA. The sensitivity (.70) and specificity (.68) of opioid dose in predicting TOA was maximized at 76.10 mg; in addition, 46.00 mg yielded 80% sensitivity in identifying TOA. These results underscore the importance of obtaining a substance use history prior to prescribing and suggest a low screening threshold for TOA in patients who use opioids in the absence of improvement in pain or functional impairment. This article examines TOA in patients with chronic noncancer pain undergoing long-term opioid therapy. Results suggest that patients should be screened for nonopioid substance use disorders prior to prescribing. In the absence of improvement in pain or function, there is a low threshold (∼50 mg daily opioid dose) for addiction screening. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

  6. Bioactive peptides released from in vitro digestion of human milk with or without pasteurization.

    Science.gov (United States)

    Wada, Yasuaki; Lönnerdal, Bo

    2015-04-01

    Pasteurized donor human milk (HM) serves as the best alternative for breast-feeding when availability of mother's milk is limited. Pasteurization is also applied to mother's own milk for very low birth weight infants, who are vulnerable to microbial infection. Whether pasteurization affects protein digestibility and therefore modulates the profile of bioactive peptides released from HM proteins by gastrointestinal digestion, has not been examined to date. HM with and without pasteurization (62.5 °C for 30 min) were subjected to in vitro gastrointestinal digestion, followed by peptidomic analysis to compare the formation of bioactive peptides. Some of the bioactive peptides, such as caseinophosphopeptide homologues, a possible opioid peptide (or propeptide), and an antibacterial peptide, were present in undigested HM and showed resistance to in vitro digestion, suggesting that these peptides are likely to exert their bioactivities in the gastrointestinal lumen, or be stably transported to target organs. In vitro digestion of HM released a large variety of bioactive peptides such as angiotensin I-converting enzyme-inhibitory, antioxidative, and immunomodulatory peptides. Bioactive peptides were released largely in the same manner with and without pasteurization. Provision of pasteurized HM may be as beneficial as breast-feeding in terms of milk protein-derived bioactive peptides.

  7. Affinity crosslinking of /sup 125/I-human beta-endorphin to cell lines possessing either mu or delta type opioid binding sites

    Energy Technology Data Exchange (ETDEWEB)

    Keren, O.; Gioannini, T.L.; Hiller, J.M.; Simon, E.J.

    1986-01-01

    Affinity crosslinking of human /sup 125/I-beta-Endorphin to cell lines possessing either mu or delta binding sites was carried out. Autoradiography of SDS-PAGE gels from these crosslinked cell lines revealed that these two sites contain major peptide subunits that differ in molecular size. This confirms our earlier finding in mammalian brain which demonstrated separate and distinct subunits for mu and delta opioid receptors.

  8. Pain, opioids, and sleep: implications for restless legs syndrome treatment.

    Science.gov (United States)

    Trenkwalder, Claudia; Zieglgänsberger, Walter; Ahmedzai, Sam H; Högl, Birgit

    2017-03-01

    Opioid receptor agonists are known to relieve restless legs syndrome (RLS) symptoms, including both sensory and motor events, as well as improving sleep. The mechanisms of action of opioids in RLS are still a matter of speculation. The mechanisms by which endogenous opioids contribute to the pathophysiology of this polygenetic disorder, in which there are a number of variants, including developmental factors, remains unknown. A summary of the cellular mode of action of morphine and its (partial) antagonist naloxone via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and the involvement of dendritic spine activation is described. By targeting pain and its consequences, opioids are the first-line treatment in many diseases and conditions with both acute and chronic pain and have thus been used in both acute and chronic pain conditions over the last 40 years. Addiction, dependence, and tolerability of opioids show a wide variability interindividually, as the response to opioids is influenced by a complex combination of genetic, molecular, and phenotypic factors. Although several trials have now addressed opioid treatment in RLS, hyperalgesia as a complication of long-term opioid treatment, or opioid-opioid interaction have not received much attention so far. Therapeutic opioids may act not only on opioid receptors but also via histamine or N-methyl-d-aspartate (NMDA) receptors. In patients with RLS, one of the few studies investigating opioid bindings found that possible brain regions involved in the severity of RLS symptoms are similar to those known to be involved in chronic pain, such as the medial pain system (medial thalamus, amygdala, caudate nucleus, anterior cingulate gyrus, insular cortex, and orbitofrontal cortex). The results of this diprenorphine positron emission tomography study suggested that the more severe the RLS, the greater the release of endogenous opioids. Since 1993, when the first small controlled study was performed with

  9. Tolerance to non-opioid analgesics is opioid-sensitive in nucleus raphe magnus

    Directory of Open Access Journals (Sweden)

    Merab G Tsagareli

    2011-07-01

    Full Text Available Repeated injection of opioid analgesics can lead to a progressive loss of its effect. This phenomenon is known as tolerance. Several lines of investigations have shown that systemic, intraperitoneal administration or the microinjection of non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs in the midbrain periaqueductal gray matter induces antinociception with some effects of tolerance. Our recent study has revealed that microinjection of three drugs analgin, ketorolac and xefocam into the central nucleus of amygdala produce tolerance to them and cross-tolerance to morphine. Here we report that repeated administrations of these NSAIDs into the nucleus raphe magnus (NRM in the following four days result in progressively less antinociception, i.e. produce the development of tolerance to these drugs in mail rats. Special control experiments showed that post-treatment with μ-opioid antagonist naloxone in NRM significantly decreased antinociceptive effects of NSAIDs at the first day in behavioral tail flick reflex (TF and hot plate (HP latencies. At the second day, naloxone generally had trend effects in both TF and HP tests impeded the development of tolerance to the antinociceptive effect of non-opioid analgesics. These findings strongly support the suggestion on endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain control system. Moreover, repeated injections of NSAIDs progressively lead to tolerance to them, cross-tolerance to morphine and the risk of a withdrawal syndrome. Therefore, these results are important for human medicine too.

  10. PeptideAtlas

    Data.gov (United States)

    U.S. Department of Health & Human Services — PeptideAtlas is a multi-organism, publicly accessible compendium of peptides identified in a large set of tandem mass spectrometry proteomics experiments. Mass...

  11. The gut-brain interaction in opioid tolerance.

    Science.gov (United States)

    Akbarali, Hamid I; Dewey, William L

    2017-12-01

    The prevailing opioid crisis has necessitated the need to understand mechanisms leading to addiction and tolerance, the major contributors to overdose and death and to develop strategies for developing drugs for pain treatment that lack abuse liability and side-effects. Opioids are commonly used for treatment of pain and symptoms of inflammatory bowel disease. The significant effect of opioids in the gut, both acute and chronic, includes persistent constipation and paradoxically may also worsen pain symptoms. Recent work has suggested a significant role of the gastrointestinal microbiome in behavioral responses to opioids, including the development of tolerance to its pain-relieving effects. In this review, we present current concepts of gut-brain interaction in analgesic tolerance to opioids and suggest that peripheral mechanisms emanating from the gut can profoundly affect central control of opioid function. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Neurobiology of opioid withdrawal: Role of the endothelin system.

    Science.gov (United States)

    Bhalla, Shaifali; Andurkar, Shridhar V; Gulati, Anil

    2016-08-15

    Morphine and oxycodone are potent opioid analgesics most commonly used for the management of moderate to severe acute and chronic pain. Their clinical utility is limited by undesired side effects like analgesic tolerance, dependence, and withdrawal. We have previously demonstrated that endothelin-A (ETA) receptor antagonists potentiate opioid analgesia and eliminate analgesic tolerance. Mechanistically, G proteins and regulatory proteins such as β-arrestins have shown to play an important role in mediating opioid tolerance, dependence, and withdrawal. Recently, the involvement of central ET mechanisms in opioid withdrawal was investigated. ETA receptor antagonist was shown to block majority of the signs and symptoms associated with opioid withdrawal. This review focuses on ET as one of the potential novel strategies to manage the challenge of opioid withdrawal. An overview of additional players in this process (G proteins and β-arrestin2), and the possible therapeutic implications of these findings are presented. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Induction of synaptic long-term potentiation after opioid withdrawal.

    Science.gov (United States)

    Drdla, Ruth; Gassner, Matthias; Gingl, Ewald; Sandkühler, Jürgen

    2009-07-10

    mu-Opioid receptor (MOR) agonists represent the gold standard for the treatment of severe pain but may paradoxically also enhance pain sensitivity, that is, lead to opioid-induced hyperalgesia (OIH). We show that abrupt withdrawal from MOR agonists induces long-term potentiation (LTP) at the first synapse in pain pathways. Induction of opioid withdrawal LTP requires postsynaptic activation of heterotrimeric guanine nucleotide-binding proteins and N-methyl-d-aspartate receptors and a rise of postsynaptic calcium concentrations. In contrast, the acute depression by opioids is induced presynaptically at these synapses. Withdrawal LTP can be prevented by tapered withdrawal and shares pharmacology and signal transduction pathways with OIH. These findings provide a previously unrecognized target to selectively combat pro-nociceptive effects of opioids without compromising opioid analgesia.

  14. General anaesthesia does not improve outcome in opioid antagonist detoxification treatment: a randomised controlled trial

    NARCIS (Netherlands)

    Jong, C.A.J. de; Laheij, R.J.F.; Krabbe, P.F.M.

    2005-01-01

    Aim  Opioid detoxification by administering opioid-antagonists under general anaesthesia has caused considerable controversy. This study is conducted to determine whether rapid detoxification under general anaesthesia results in higher levels of opioid abstinence than rapid detoxification without

  15. General anaesthesia does not improve outcome in opioid antagonist detoxification treatment : a randomized controlled trial

    NARCIS (Netherlands)

    De Jong, Cor A J; Laheij, Robert J F; Krabbe, Paul F M

    AIM: Opioid detoxification by administering opioid-antagonists under general anaesthesia has caused considerable controversy. This study is conducted to determine whether rapid detoxification under general anaesthesia results in higher levels of opioid abstinence than rapid detoxification without

  16. General anaesthesia does not improve outcome in opioid antagonist detoxification treatment: a randomized controlled trial.

    NARCIS (Netherlands)

    Jong, C.A.J. de; Laheij, R.J.F.; Krabbe, P.F.M.

    2005-01-01

    AIM: Opioid detoxification by administering opioid-antagonists under general anaesthesia has caused considerable controversy. This study is conducted to determine whether rapid detoxification under general anaesthesia results in higher levels of opioid abstinence than rapid detoxification without

  17. Heterogeneity of Opioid Binding Sites in Guinea Pig Spinal Cord

    Science.gov (United States)

    1984-11-30

    MEDICAL CENTER WILFORD HALL AIR FORCE MEDICAL CENTER Title of Thesis: "Heterogeneity of Opioid Binding Sites in Guinea Pig Spinal Cord" Name of...that the use of any copyrighted material in the dissertation manuscript entitled: "Heterogeneity of Opioid Binding Sites in Guinea Pig Spinal Cord...University of the Health Sciences 11 Abstract Title of Thesis: Heterogenity of Opioid Binding Sites In Guinea Pig Spinal Cord Gary Dean Zarr MAJ/ANC

  18. Peptide-Carrier Conjugation

    DEFF Research Database (Denmark)

    Hansen, Paul Robert

    2015-01-01

    To produce antibodies against synthetic peptides it is necessary to couple them to a protein carrier. This chapter provides a nonspecialist overview of peptide-carrier conjugation. Furthermore, a protocol for coupling cysteine-containing peptides to bovine serum albumin is outlined....

  19. PH dependent adhesive peptides

    Science.gov (United States)

    Tomich, John; Iwamoto, Takeo; Shen, Xinchun; Sun, Xiuzhi Susan

    2010-06-29

    A novel peptide adhesive motif is described that requires no receptor or cross-links to achieve maximal adhesive strength. Several peptides with different degrees of adhesive strength have been designed and synthesized using solid phase chemistries. All peptides contain a common hydrophobic core sequence flanked by positively or negatively charged amino acids sequences.

  20. Peptide Nucleic Acids

    DEFF Research Database (Denmark)

    2003-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary ssDNA and RNA strands more strongly than a corresponding DNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  1. Peptide Nucleic Acids

    DEFF Research Database (Denmark)

    1998-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary ssDNA and RNA strands more strongly than a corresponding DNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  2. Peptide Nucleic Acids (PNA)

    DEFF Research Database (Denmark)

    2002-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary ssDNA and RNA strands more strongly than a corresponding DNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  3. Peptide Nucleic Acid Synthons

    DEFF Research Database (Denmark)

    2004-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary ssDNA and RNA strands more strongly than a corresponding DNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  4. Antimicrobial Peptides in 2014

    Directory of Open Access Journals (Sweden)

    Guangshun Wang

    2015-03-01

    Full Text Available This article highlights new members, novel mechanisms of action, new functions, and interesting applications of antimicrobial peptides reported in 2014. As of December 2014, over 100 new peptides were registered into the Antimicrobial Peptide Database, increasing the total number of entries to 2493. Unique antimicrobial peptides have been identified from marine bacteria, fungi, and plants. Environmental conditions clearly influence peptide activity or function. Human α-defensin HD-6 is only antimicrobial under reduced conditions. The pH-dependent oligomerization of human cathelicidin LL-37 is linked to double-stranded RNA delivery to endosomes, where the acidic pH triggers the dissociation of the peptide aggregate to release its cargo. Proline-rich peptides, previously known to bind to heat shock proteins, are shown to inhibit protein synthesis. A model antimicrobial peptide is demonstrated to have multiple hits on bacteria, including surface protein delocalization. While cell surface modification to decrease cationic peptide binding is a recognized resistance mechanism for pathogenic bacteria, it is also used as a survival strategy for commensal bacteria. The year 2014 also witnessed continued efforts in exploiting potential applications of antimicrobial peptides. We highlight 3D structure-based design of peptide antimicrobials and vaccines, surface coating, delivery systems, and microbial detection devices involving antimicrobial peptides. The 2014 results also support that combination therapy is preferred over monotherapy in treating biofilms.

  5. Computer Modeling of Human Delta Opioid Receptor

    Directory of Open Access Journals (Sweden)

    Tatyana Dzimbova

    2013-04-01

    Full Text Available The development of selective agonists of δ-opioid receptor as well as the model of interaction of ligands with this receptor is the subjects of increased interest. In the absence of crystal structures of opioid receptors, 3D homology models with different templates have been reported in the literature. The problem is that these models are not available for widespread use. The aims of our study are: (1 to choose within recently published crystallographic structures templates for homology modeling of the human δ-opioid receptor (DOR; (2 to evaluate the models with different computational tools; and (3 to precise the most reliable model basing on correlation between docking data and in vitro bioassay results. The enkephalin analogues, as ligands used in this study, were previously synthesized by our group and their biological activity was evaluated. Several models of DOR were generated using different templates. All these models were evaluated by PROCHECK and MolProbity and relationship between docking data and in vitro results was determined. The best correlations received for the tested models of DOR were found between efficacy (erel of the compounds, calculated from in vitro experiments and Fitness scoring function from docking studies. New model of DOR was generated and evaluated by different approaches. This model has good GA341 value (0.99 from MODELLER, good values from PROCHECK (92.6% of most favored regions and MolProbity (99.5% of favored regions. Scoring function correlates (Pearson r = -0.7368, p-value = 0.0097 with erel of a series of enkephalin analogues, calculated from in vitro experiments. So, this investigation allows suggesting a reliable model of DOR. Newly generated model of DOR receptor could be used further for in silico experiments and it will give possibility for faster and more correct design of selective and effective ligands for δ-opioid receptor.

  6. Tobacco withdrawal among opioid-dependent smokers.

    Science.gov (United States)

    Streck, Joanna M; Heil, Sarah H; Higgins, Stephen T; Bunn, Janice Y; Sigmon, Stacey C

    2018-04-01

    Prevalence of cigarette smoking among opioid-dependent individuals is 6-fold that of the general U.S. adult population and their quit rates are notoriously poor. One possible reason for the modest cessation outcomes in opioid-dependent smokers may be that they experience more severe tobacco withdrawal upon quitting. In this secondary analysis, we evaluated tobacco withdrawal in opioid-dependent (OD) smokers versus smokers without co-occurring substance use disorders (SUDs). Participants were 47 methadone- or buprenorphine-maintained smokers and 25 non-SUD smokers who completed 1 of several 2-week studies involving daily visits for biochemical monitoring, delivery of financial incentives contingent on smoking abstinence, and assessment of withdrawal via the Minnesota Nicotine Withdrawal Scale (MNWS). Prior to quitting smoking, OD smokers presented with higher baseline withdrawal scores than non-SUD smokers (1.7 ± 0.2 vs. 0.7 ± 0.2, respectively; F [1, 63] = 7.31, p non-SUD smokers, suggesting that elevated withdrawal severity following quitting may not be a major factor contributing to the poor cessation outcomes consistently observed among OD smokers. Further scientific efforts are needed to improve our understanding of the high smoking rates and modest cessation outcomes in this challenging population. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

  7. BmK-YA, an enkephalin-like peptide in scorpion venom.

    Directory of Open Access Journals (Sweden)

    Yan Zhang

    Full Text Available By screening extracts of venom from the Asian scorpion Buthus martensii Karsch (BmK for their abilities to activate opioid receptors, we have identified BmK-YA, an amidated peptide containing an enkephalin-like sequence. BmK-YA is encoded by a precursor that displays a signal sequence and contains four copies of BmK-YA sequences and four of His(4-BmK-YA, all flanked by single amino acid residues. BmK-YA and His(4-BmK-YA are amidated and thus fulfill the characteristics expected of bioactive peptides. BmK-YA can activate mammalian opioid receptors with selectivity for the δ subtype while His(4-BmK-YA is inactive at opioid receptors. The discovery of BmK-YA suggests that scorpion venom may represent a novel source of bioactive molecules targeting G protein-coupled receptors (GPCRs and reveal additional insights on the evolution of the opioid precursors.

  8. Chronic Pain, Chronic Opioid Addiction: a Complex Nexus.

    Science.gov (United States)

    Salsitz, Edwin A

    2016-03-01

    Over the past two decades, there has been a significant increase in the prescribing of opioids, with associated increases in opioid addiction and overdose deaths. This article reviews the evidence for the effectiveness and risk of developing an opioid use disorder (OUD) in those patients treated with chronic opioid therapy (COT) for chronic non-cancer pain (CNCP). Rates of development of OUD range from 0-50 %, and aberrant drug related behaviors (ADRBs) are reported to be 20 %. Health care providers must properly assess, screen, and carefully monitor patients on COT utilizing evidence-based tools.

  9. Pain management and opioid risk mitigation in the military.

    Science.gov (United States)

    Sharpe Potter, Jennifer; Bebarta, Vikhyat S; Marino, Elise N; Ramos, Rosemarie G; Turner, Barbara J

    2014-05-01

    Opioid analgesics misuse is a significant military health concern recognized as a priority issue by military leadership. Opioids are among those most commonly prescribed medications in the military for pain management. The military has implemented opioid risk mitigation strategies, including the Sole Provider Program and the Controlled Drug Management Analysis and Reporting Tool, which are used to identify and monitor for risk and misuse. However, there are substantial opportunities to build on these existing systems to better ensure safer opioid prescribing and monitor for misuse. Opioid risk mitigation strategies implemented by the civilian sector include establishing clinical guidelines for opioid prescribing and prescription monitoring programs. These strategies may help to inform opioid risk mitigation in the military health system. Reducing the risk of opioid misuse and improving quality of care for our Warfighters is necessary. This must be done through evidence-based approaches with an investment in research to improve patient care and prevent opioid misuse as well as its sequelae. Reprint & Copyright © 2014 Association of Military Surgeons of the U.S.

  10. A case of rhabdomyolysis associated with severe opioid withdrawal.

    Science.gov (United States)

    Gangahar, Deepali

    2015-08-01

    While the risk of opioid overdose is widely accepted, the dangers of opioid withdrawal are far less clearly defined. The purpose of this publication is to provide evidence against the erroneous clinical dictum that opioid withdrawal is never life-threatening. This case report (N = 1) illustrates an unfortunate, common scenario of a man abusing prescription opioids and heroin. His attempt at self-detoxification with buprenorphine-naloxone resulted in life-threatening opioid withdrawal. A detailed account of each day of his withdrawal period was documented by patient and family report and review of all medical records. The patient was contacted three months after hospitalization to verify information and determine progress in treatment and abstinence from drugs and alcohol. A review of the literature was completed on severe cases of precipitated and spontaneous opioid withdrawal followed by a discussion of the significance as it relates to this case. Given the widespread use of prescription opioids and opioid maintenance treatment, physicians should be aware of the complications of acute opioid withdrawal and should be equipped to treat these complications. © American Academy of Addiction Psychiatry.

  11. Provider confidence in opioid prescribing and chronic pain management: results of the Opioid Therapy Provider Survey

    Science.gov (United States)

    Pearson, Amy CS; Moman, Rajat N; Moeschler, Susan M; Eldrige, Jason S; Hooten, W Michael

    2017-01-01

    Introduction Many providers report lack of confidence in managing patients with chronic pain. Thus, the primary aim of this study was to investigate the associations of provider confidence in managing chronic pain with their practice behaviors and demographics. Materials and methods The primary outcome measure was the results of the Opioid Therapy Provider Survey, which was administered to clinicians attending a pain-focused continuing medical education conference. Nonparametric correlations were assessed using Spearman’s rho. Results Of the respondents, 55.0% were women, 92.8% were white, and 56.5% were physicians. Primary care providers accounted for 56.5% of the total respondents. The majority of respondents (60.8%) did not feel confident managing patients with chronic pain. Provider confidence in managing chronic pain was positively correlated with 1) following an opioid therapy protocol (P=0.001), 2) the perceived ability to identify patients at risk for opioid misuse (P=0.006), and 3) using a consistent practice-based approach to improve their comfort level with prescribing opioids (Pcorrelated with the perception that treating pain patients was a “problem in my practice” (P=0.005). Conclusion In this study, the majority of providers did not feel confident managing chronic pain. However, provider confidence was associated with a protocolized and consistent practice-based approach toward managing opioids and the perceived ability to identify patients at risk for opioid misuse. Future studies should investigate whether provider confidence is associated with measurable competence in managing chronic pain and explore approaches to enhance appropriate levels of confidence in caring for patients with chronic pain. PMID:28652805

  12. Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast).

    Science.gov (United States)

    Hutchinson, Mark R; Lewis, Susannah S; Coats, Benjamen D; Skyba, David A; Crysdale, Nicole Y; Berkelhammer, Debra L; Brzeski, Anita; Northcutt, Alexis; Vietz, Christine M; Judd, Charles M; Maier, Steven F; Watkins, Linda R; Johnson, Kirk W

    2009-02-01

    Morphine-induced glial proinflammatory responses have been documented to contribute to tolerance to opioid analgesia. Here, we examined whether drugs previously shown to suppress glial proinflammatory responses can alter other clinically relevant opioid effects; namely, withdrawal or acute analgesia. AV411 (ibudilast) and minocycline, drugs with distinct mechanisms of action that result in attenuation of glial proinflammatory responses, each reduced naloxone-precipitated withdrawal. Analysis of brain nuclei associated with opioid withdrawal revealed that morphine altered expression of glial activation markers, cytokines, chemokines, and a neurotrophic factor. AV411 attenuated many of these morphine-induced effects. AV411 also protected against spontaneous withdrawal-induced hyperactivity and weight loss recorded across a 12-day timecourse. Notably, in the spontaneous withdrawal study, AV411 treatment was delayed relative to the start of the morphine regimen so to also test whether AV411 could still be effective in the face of established morphine dependence, which it was. AV411 did not simply attenuate all opioid effects, as co-administering AV411 with morphine or oxycodone caused three-to-five-fold increases in acute analgesic potency, as revealed by leftward shifts in the analgesic dose response curves. Timecourse analyses revealed that plasma morphine levels were not altered by AV411, suggestive that potentiated analgesia was not simply due to prolongation of morphine exposure or increased plasma concentrations. These data support and extend similar potentiation of acute opioid analgesia by minocycline, again providing converging lines of evidence of glial involvement. Hence, suppression of glial proinflammatory responses can significantly reduce opioid withdrawal, while improving analgesia.

  13. Intentional intrathecal opioid detoxification in 3 patients: characterization of the intrathecal opioid withdrawal syndrome.

    Science.gov (United States)

    Jackson, Tracy P; Lonergan, Daniel F; Todd, R David; Martin, Peter R

    2013-04-01

    Intrathecal (IT) drug delivery systems for patients with chronic non-malignant pain are intended to improve pain and quality of life and reduce side effects of systemic use. A subset of patients may have escalating pain, functional decline, and/or intolerable side effects even as IT opioid doses are increased. Discontinuation of IT medications may represent a viable treatment option but strategies to accomplish this are needed. Three patients with intrathecal drug delivery systems (IDDS), inadequate pain control, and declining functionality underwent abrupt IT opioid cessation. This was accomplished through a standardized protocol with symptom-triggered administration of clonidine and buprenorphine, monitored using the clinical opiate withdrawal scale. Symptoms of IT withdrawal were similar in all patients and included diuresis, agitation, hyperalgesia, mild diarrhea, yawning, and taste and smell aversion. Hypertension and tachycardia were effectively controlled by clonidine administration. Classic symptoms of withdrawal, such as piloerection, chills, severe diarrhea, nausea, vomiting, diaphoresis, myoclonus, and mydriasis, were not noted. At 2 to 3 months follow-up, patients reported decreased, but ongoing pain, with improvements in functional capacity and quality of life. This preliminary work demonstrates the safety of abrupt IT opioid cessation utilizing standardized inpatient withdrawal protocols. To our knowledge, these are among the first reported cases of intentional, controlled IT opioid cessation without initiation of an opioid bridge: self-reported pain scores, functional capacity, and quality of life improved. The IT opioid withdrawal syndrome is characterized based upon our observations and a review of the literature. © 2012 The Authors. Pain Practice © 2012 World Institute of Pain.

  14. Observational study to calculate addictive risk to opioids: a validation study of a predictive algorithm to evaluate opioid use disorder

    Directory of Open Access Journals (Sweden)

    Brenton A

    2017-05-01

    Full Text Available Ashley Brenton,1 Steven Richeimer,2,3 Maneesh Sharma,4 Chee Lee,1 Svetlana Kantorovich,1 John Blanchard,1 Brian Meshkin1 1Proove Biosciences, Irvine, CA, 2Keck school of Medicine, University of Southern California, Los Angeles, CA, 3Departments of Anesthesiology and Psychiatry, University of Southern California, Los Angeles, CA, 4Interventional Pain Institute, Baltimore, MD, USA Background: Opioid abuse in chronic pain patients is a major public health issue, with rapidly increasing addiction rates and deaths from unintentional overdose more than quadrupling since 1999. Purpose: This study seeks to determine the predictability of aberrant behavior to opioids using a comprehensive scoring algorithm incorporating phenotypic risk factors and neuroscience-associated single-nucleotide polymorphisms (SNPs. Patients and methods: The Proove Opioid Risk (POR algorithm determines the predictability of aberrant behavior to opioids using a comprehensive scoring algorithm incorporating phenotypic risk factors and neuroscience-associated SNPs. In a validation study with 258 subjects with diagnosed opioid use disorder (OUD and 650 controls who reported using opioids, the POR successfully categorized patients at high and moderate risks of opioid misuse or abuse with 95.7% sensitivity. Regardless of changes in the prevalence of opioid misuse or abuse, the sensitivity of POR remained >95%. Conclusion: The POR correctly stratifies patients into low-, moderate-, and high-risk categories to appropriately identify patients at need for additional guidance, monitoring, or treatment changes. Keywords: opioid use disorder, addiction, personalized medicine, pharmacogenetics, genetic testing, predictive algorithm

  15. Bilateral Breast Reduction Without Opioid Analgesics: A Comparative Study.

    Science.gov (United States)

    Parsa, Fereydoun Don; Cheng, Justin; Stephan, Brad; Castel, Nikki; Kim, Leslie; Murariu, Daniel; Parsa, Alan A

    2017-09-01

    Breast reduction has traditionally been performed under general anesthesia with adjunct opioid use. However, opioids are associated with a wide variety of adverse effects, including nausea, vomiting, constipation, postoperative sedation, dizziness, and addiction. This study compares bilateral breast reduction using a multimodal opioid-free pain management regimen vs traditional general anesthesia with adjunct opioids. A total of 83 female patients were enrolled in this study. Group 1 includes a retrospective series of 39 patients that underwent breast reduction via general anesthesia with adjunct opioid use. This series was compared to 2 prospective groups of patients who did not receive opioids either preoperatively or intraoperatively. In group 2, twenty-six patients underwent surgery under intravenous sedation and local anesthesia. In group 3, eighteen patients underwent surgery with general anesthesia. All patients in groups 2 and 3 received preoperative gabapentin and celecoxib along with infiltration of local anesthetics during the operation and prior to discharge to the Post-Anesthesia Care Unit (PACU). Primary outcome measures included the duration of surgery, time from end of operation to discharge home, postoperative opioid and antiemetic use, and unplanned postoperative hospitalizations. When compared to group 1, groups 2 and 3 experienced a shorter time from end of operation to discharge home (P opioid use (P opioid-free bilateral breast reduction either under local or general anesthesia as an outpatient. This method resulted in significantly less morbidity, use of opioids postoperatively, as well as unplanned hospital admissions compared to "traditional" breast reduction under general anesthesia with the use of opioids. 3. © 2017 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com

  16. [Plant signaling peptides. Cysteine-rich peptides].

    Science.gov (United States)

    Ostrowski, Maciej; Kowalczyk, Stanisław

    2015-01-01

    Recent bioinformatic and genetic analyses of several model plant genomes have revealed the existence of a highly abundant group of signaling peptides that are defined as cysteine-rich peptides (CRPs). CRPs are usually in size between 50 and 90 amino acid residues, they are positively charged, and they contain 4-16 cysteine residues that are important for the correct conformational folding. Despite the structural differences among CRP classes, members from each class have striking similarities in their molecular properties and function. The present review presents the recent progress in research on signaling peptides from several families including: EPF/EPFL, SP11/SCR, PrsS, RALF, LURE, and some other peptides belonging to CRP group. There is convincing evidence indicating multiple roles for these CRPs as signaling molecules during the plant life cycle, ranging from stomata development and patterning, self-incompatibility, pollen tube growth and guidance, reproductive processes, and nodule formation.

  17. Bioactive peptides: production, health effects and application as natural supplements for functional foods production

    Directory of Open Access Journals (Sweden)

    S. Mirdamadi

    2017-05-01

    Full Text Available Bioactive peptides, are inactive components within the structure of the protein and when they are released by enzymatic hydrolysis, show different physiological functions. Recently, the identification and characterization of bioactive peptides derived from plant and animal sources and different microorganisms is highly regarded. They are produced during enzymatic hydrolysis by gastrointestinal enzymes or enzymes extracted from microorganisms and plants or by proteolytic starter cultures during fermentation process and exhibit different activities including: opioid, mineral binding, immunomodulatory, antioxidant, antimicrobial, anti-inflammatory, chlosterol lowering and so on. Take advantage of bioactive peptides as components of health is related to bio stability assurance, bioavailability and safety of them. The use of computer-based techniques and the use of various databases completed in laboratory studies,  have provided the possibility of studying the mechanisms of action of different peptides.

  18. Tolerance and withdrawal from prolonged opioid use in critically ill children.

    Science.gov (United States)

    Anand, Kanwaljeet J S; Willson, Douglas F; Berger, John; Harrison, Rick; Meert, Kathleen L; Zimmerman, Jerry; Carcillo, Joseph; Newth, Christopher J L; Prodhan, Parthak; Dean, J Michael; Nicholson, Carol

    2010-05-01

    After prolonged opioid exposure, children develop opioid-induced hyperalgesia, tolerance, and withdrawal. Strategies for prevention and management should be based on the mechanisms of opioid tolerance and withdrawal. Relevant manuscripts published in the English language were searched in Medline by using search terms "opioid," "opiate," "sedation," "analgesia," "child," "infant-newborn," "tolerance," "dependency," "withdrawal," "analgesic," "receptor," and "individual opioid drugs." Clinical and preclinical studies were reviewed for data synthesis. Mechanisms of opioid-induced hyperalgesia and tolerance suggest important drug- and patient-related risk factors that lead to tolerance and withdrawal. Opioid tolerance occurs earlier in the younger age groups, develops commonly during critical illness, and results more frequently from prolonged intravenous infusions of short-acting opioids. Treatment options include slowly tapering opioid doses, switching to longer-acting opioids, or specifically treating the symptoms of opioid withdrawal. Novel therapies may also include blocking the mechanisms of opioid tolerance, which would enhance the safety and effectiveness of opioid analgesia. Opioid tolerance and withdrawal occur frequently in critically ill children. Novel insights into opioid receptor physiology and cellular biochemical changes will inform scientific approaches for the use of opioid analgesia and the prevention of opioid tolerance and withdrawal.

  19. Opioid Overdoses Treated in Emergency Departments PSA (:60)

    Centers for Disease Control (CDC) Podcasts

    2018-03-06

    This 60 second public service announcement is based on the March 2018 CDC Vital Signs report. Opioid overdoses continue to increase in the United States. Learn what can be done to help prevent opioid overdose and death.  Created: 3/6/2018 by Centers for Disease Control and Prevention (CDC).   Date Released: 3/6/2018.

  20. Secular trends in opioid prescribing in the USA

    Directory of Open Access Journals (Sweden)

    Pezalla EJ

    2017-02-01

    Full Text Available Edmund J Pezalla,1 David Rosen,2 Jennifer G Erensen,2 J David Haddox,2,3 Tracy J Mayne2 1Bioconsult, LLC, Wethersfield, 2Purdue Pharma L.P., Stamford, CT, 3Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA Abstract: Opioid abuse and misuse in the USA is a public health crisis. The use of prescription opioid analgesics increased substantially from 2002 through 2010, then plateaued and began to decrease in 2011. This study examined prescriptions of branded and generic immediate- and extended-release opioid analgesics from 1992 to 2016. This was juxtaposed against state and federal policies designed to decrease overutilization and abuse, as well as the launch of new opioid products, including opioids with abuse-deterrent properties (OADPs. The data indicate that these health policies, including the utilization and reimbursement of OADPs, have coincided with decreased opioid utilization. The hypothesis that OADPs will paradoxically increase opioid prescribing is not supported. Keywords: OADP, prescription, utilization trends, legislation, opioids

  1. Critical issues on opioids in chronic non-cancer pain

    DEFF Research Database (Denmark)

    Eriksen, Jørgen; Sjøgren, Per; Bruera, Eduardo

    2006-01-01

    -related quality of life (SF-36), use of the health care system, functional capabilities, satisfaction with medical pain treatment and regular or continuous use of medications. Participants reporting pain were divided into opioid and non-opioid users. The analyses were adjusted for age, gender, concomitant use...

  2. Treating opioid dependence. Growing implications for primary care.

    Science.gov (United States)

    Krantz, Mori J; Mehler, Philip S

    2004-02-09

    Almost 3 million Americans have abused heroin. The most effective treatment for this concerning epidemic is opioid replacement therapy. Although, from a historical perspective, acceptance of this therapy has been slow, growing evidence supports its efficacy. There are 3 approved medications for opioid maintenance therapy: methadone hydrochloride, levomethadyl acetate, and buprenorphine hydrochloride. Each has unique characteristics that determine its suitability for an individual patient. Cardiac arrhythmias have been reported with methadone and levomethadyl, but not with buprenorphine. Due to concerns about cardiac risk, levomethadyl use has declined and the product may ultimately be discontinued. These recent safety concerns, specifics about opioid detoxification and maintenance, and new federal initiatives were studied. Opioid detoxification has a role in both preventing acute withdrawal and maintaining long-term abstinence. Although only a minority of eligible patients are engaged in treatment, opioid maintenance therapy appears to offer the greatest public health benefits. There is growing interest in expanding treatment into primary care, allowing opioid addiction to be managed like other chronic illnesses. This model has gained wide acceptance in Europe and is now being implemented in the United States. The recent Drug Addiction Treatment Act enables qualified physicians to treat opioid-dependent patients with buprenorphine in an office-based setting. Mainstreaming opioid addiction treatment has many advantages; its success will depend on resolution of ethical and delivery system issues as well as improved and expanded training of physicians in addiction medicine.

  3. Endogene opioider og deres terapeutiske anvendelse i smertebehandling

    DEFF Research Database (Denmark)

    Juul, A; Pedersen, A T

    1990-01-01

    Cancer patients with chronic pain and obstetric patients have participated in clinical trials of the analgesic effects of endogenous opioids. It is possible to achieve adequate relief of pain in these patients following epidural or intrathecal administration of endogenous opioids. Further investi...

  4. Delta opioid receptor on equine sperm cells: subcellular localization and involvement in sperm motility analyzed by computer assisted sperm analyzer (CASA

    Directory of Open Access Journals (Sweden)

    Lacalandra Giovanni M

    2010-06-01

    Full Text Available Abstract Background Opioid receptors and endogenous opioid peptides act not only in the control of nociceptive pathways, indeed several reports demonstrate the effects of opiates on sperm cell motility and morphology suggesting the importance of these receptors in the modulation of reproduction in mammals. In this study we investigated the expression of delta opioid receptors on equine spermatozoa by western blot/indirect immunofluorescence and its relationship with sperm cell physiology. Methods We analyzed viability, motility, capacitation, acrosome reaction and mitochondrial activity in the presence of naltrindole and DPDPE by means of a computer assisted sperm analyzer and a fluorescent confocal microscope. The evaluation of viability, capacitation and acrosome reaction was carried out by the double CTC/Hoechst staining, whereas mitochondrial activity was assessed by means of MitoTracker Orange dye. Results We showed that in equine sperm cells, delta opioid receptor is expressed as a doublet of 65 and 50 kDa molecular mass and is localized in the mid piece of tail; we also demonstrated that naltrindole, a delta opioid receptor antagonist, could be utilized in modulating several physiological parameters of the equine spermatozoon in a dose-dependent way. We also found that low concentrations of the antagonist increase sperm motility whereas high concentrations show the opposite effect. Moreover low concentrations hamper capacitation, acrosome reaction and viability even if the percentage of cells with active mitochondria seems to be increased; the opposite effect is exerted at high concentrations. We have also observed that the delta opioid receptor agonist DPDPE is scarcely involved in affecting the same parameters at the employed concentrations. Conclusions The results described in this paper add new important details in the comprehension of the mammalian sperm physiology and suggest new insights for improving reproduction and for

  5. Tolerance to Non-Opioid Analgesics is Opioid Sensitive in the Nucleus Raphe Magnus.

    Science.gov (United States)

    Tsagareli, Merab G; Nozadze, Ivliane; Tsiklauri, Nana; Gurtskaia, Gulnaz

    2011-01-01

    Repeated injection of opioid analgesics can lead to a progressive loss of effect. This phenomenon is known as tolerance. Several lines of investigations have shown that systemic, intraperitoneal administration or the microinjection of non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) into the midbrain periaqueductal gray matter induces antinociception with some effects of tolerance. Our recent study has revealed that microinjection of three drugs analgin, ketorolac, and xefocam into the central nucleus of amygdala produce tolerance to them and cross-tolerance to morphine. Here we report that repeated administrations of these NSAIDs into the nucleus raphe magnus (NRM) in the following 4 days result in progressively less antinociception compare to the saline control, i.e., tolerance develops to these drugs in male rats. Special control experiments showed that post-treatment with the μ-opioid antagonist naloxone into the NRM significantly decreased antinociceptive effects of NSAIDs on the first day of testing in the tail-flick (TF) reflex and hot plate (HP) latency tests. On the second day, naloxone generally had trend effects in both TF and HP tests and impeded the development of tolerance to the antinociceptive effect of non-opioid analgesics. These findings strongly support the suggestion of endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain-control system. Moreover, repeated injections of NSAIDs progressively lead to tolerance to them, cross-tolerance to morphine, and the risk of a withdrawal syndrome. Therefore, these results are important for human medicine too.

  6. Addiction to opioids in chronic pain patients: a literature review

    DEFF Research Database (Denmark)

    Højsted, Jette; Sjøgren, Per

    2007-01-01

    , incidence and prevalence of addiction in opioid treated pain patients, screening tools for assessing opioid addiction in chronic pain patients and recommendations regarding addiction problems in national and international guidelines for opioid treatment in cancer patients and chronic non-malignant pain...... patients. The review indicates that the prevalence of addiction varied from 0% up to 50% in chronic non-malignant pain patients, and from 0% to 7.7% in cancer patients depending of the subpopulation studied and the criteria used. The risk of addiction has to be considered when initiating long-term opioid...... long-term opioid treatment, and specialised treatment facilities for pain management or addiction medicine should be consulted in these cases....

  7. Disruption of gut homeostasis by opioids accelerates HIV disease progression

    Directory of Open Access Journals (Sweden)

    Jingjing eMeng

    2015-06-01

    Full Text Available Cumulative studies during the past 30 years have established the correlation between opioid abuse and human immunodeficiency virus (HIV infection. Further studies also demonstrate that opioid addiction is associated with faster progression to AIDS in patients. Recently, it was revealed that disruption of gut homeostasis and subsequent microbial translocation play important roles in pathological activation of the immune system during HIV infection and contributes to accelerated disease progression. Similarly, opioids have been shown to modulate gut immunity and induce gut bacterial translocation. This review will explore the mechanisms by which opioids accelerate HIV disease progression by disrupting gut homeostasis. Better understanding of these mechanisms will facilitate the search for new therapeutic interventions to treat HIV infection especially in opioid abusing population.

  8. Opioid prescriptions before and after high-energy trauma

    DEFF Research Database (Denmark)

    Zwisler, Stine T; Hallas, Jesper; Larsen, Morten S

    2015-01-01

    OBJECTIVE: To describe the legal use of opioids in adult patients before and after high-energy trauma. DESIGN: The study was a retrospective database study. SETTING: Clinical care outside hospitals. PATIENTS: All patients who suffered high-energy trauma and were brought to Odense University...... Hospital (OUH), Denmark, in 2007 and 2008 were retrieved from the trauma database. These patients were linked with data on opioid use from the regional prescription database. In all, 938 patients were included. MAIN OUTCOME MEASURE: Redemption of opioid prescription during the 6 months prior...... to a multitrauma or redemption of two or more prescriptions for opioids 6 months or later after a multitrauma. RESULTS: Of the 938 patients brought to OUH with severe trauma within the study period, 61 patients died (7 percent) and six of these had redeemed prescriptions for opioids within 6 months prior...

  9. The role of the opioid system in alcohol dependence.

    Science.gov (United States)

    Nutt, David J

    2014-01-01

    The role of the brain opioid system in alcohol dependence has been the subject of much research for over 25 years. This review explores the evidence: firstly describing the opioid receptors in terms of their individual subtypes, neuroanatomy, neurophysiology and ligands; secondly, summarising emerging data from specific neurochemical, behavioural and neuroimaging studies, explaining the characteristics of addiction with a focus on alcohol dependence and connecting the opioid system with alcohol dependence; and finally reviewing the known literature regarding opioid antagonists in clinical use for alcohol dependence. Further interrogation of how modulation of the opioid system, via use of MOP (mu), DOP (delta) and KOP (kappa) agents, restores the balance of a dysregulated system in alcohol dependence should increase our insight into this disease process and therefore guide better methods for understanding and treating alcohol dependence in the future.

  10. Long-term evaluation of opioid treatment in fibromyalgia.

    Science.gov (United States)

    Peng, Xiaomei; Robinson, Rebecca L; Mease, Philip; Kroenke, Kurt; Williams, David A; Chen, Yi; Faries, Douglas; Wohlreich, Madelaine; McCarberg, Bill; Hann, Danette

    2015-01-01

    In a 12-month observational study, we evaluated the effect of opioid use on the outcomes in 1700 adult patients with fibromyalgia. Data were evaluated using propensity score matching after patients were divided into cohorts based on their baseline medication use: (1) taking an opioid (concurrent use of tramadol was permitted); (2) taking tramadol (but no opioids); and (3) not taking opioids or tramadol. Changes in outcomes were assessed using the Brief Pain Inventory for severity and pain-related interference (BPI-S, BPI-I), Fibromyalgia Impact Questionnaire (FIQ), Patient Health Questionnaire for depression (PHQ-8), Insomnia Severity Index (ISI), Sheehan Disability Scale (SDS), 7-item Generalized Anxiety Disorder Scale (GAD-7), and economic factors. Time-to-opioid or tramadol discontinuation was analyzed using Kaplan-Meier survival analyses. Compared with the opioid cohort, the nonopioid cohort demonstrated significantly greater reductions (PFIQ, PHQ-8, SDS, and ISI; the tramadol cohort compared with the opioid group showed greater reductions on FIQ and ISI. Reductions in BPI-S and GAD-7 did not differ significantly among cohorts. Compared with the opioid cohort, patients in the tramadol cohort had fewer outpatient visits to health care providers. Few significant differences were found between the tramadol and nonopioid cohorts across outcomes. Although pain severity was reduced over time in all cohorts, opioid users showed less improvement in pain-related interference with daily living, functioning, depression, and insomnia. Overall, the findings show little support for the long-term use of opioid medications in patients with fibromyalgia given the poorer outcomes across multiple assessment domains associated with this cohort.

  11. Opioid Prescriptions by Specialty in Ohio, 2010-2014.

    Science.gov (United States)

    Weiner, Scott G; Baker, Olesya; Rodgers, Ann F; Garner, Chad; Nelson, Lewis S; Kreiner, Peter W; Schuur, Jeremiah D

    2018-05-01

    The current US opioid epidemic is attributed to the large volume of prescribed opioids. This study analyzed the contribution of different medical specialties to overall opioids by evaluating the pill counts and morphine milligram equivalents (MMEs) of opioid prescriptions, stratified by provider specialty, and determined temporal trends. This was an analysis of the Ohio prescription drug monitoring program database, which captures scheduled medication prescriptions filled in the state as well as prescriber specialty. We extracted prescriptions for pill versions of opioids written in the calendar years 2010 to 2014. The main outcomes were the number of filled prescriptions, pill counts, MMEs, and extended-released opioids written by physicians in each specialty, and annual prescribing trends. There were 56,873,719 prescriptions for the studied opioids dispensed, for which 41,959,581 (73.8%) had prescriber specialty type available. Mean number of pills per prescription and MMEs were highest for physical medicine/rehabilitation (PM&R; 91.2 pills, 1,532 mg, N = 1,680,579), anesthesiology/pain (89.3 pills, 1,484 mg, N = 3,261,449), hematology/oncology (88.2 pills, 1,534 mg, N = 516,596), and neurology (84.4 pills, 1,230 mg, N = 573,389). Family medicine (21.8%) and internal medicine (17.6%) wrote the most opioid prescriptions overall. Time trends in the average number of pills and MMEs per prescription also varied depending on specialty. The numbers of pills and MMEs per opioid prescription vary markedly by prescriber specialty, as do trends in prescribing characteristics. Pill count and MME values define each specialty's contribution to overall opioid prescribing more accurately than the number of prescriptions alone.

  12. Medication-Assisted Treatment For Opioid Addiction in Opioid Treatment Programs. Treatment Improvement Protocol (TIP) Series 43

    Science.gov (United States)

    Tinkler, Emily; Vallejos Bartlett, Catalina; Brooks, Margaret; Gilbert, Johnatnan Max; Henderson, Randi; Shuman, Deborah, J.

    2005-01-01

    TIP 43 provides best-practice guidelines for medication-assisted treatment of opioid addiction in opioid treatment programs (OTPs). The primary intended audience for this volume is substance abuse treatment providers and administrators who work in OTPs. Recommendations in the TIP are based on both an analysis of current research and determinations…

  13. Peptides in melanoma therapy.

    Science.gov (United States)

    Mocellin, Simone

    2012-01-01

    Peptides derived from tumor associated antigens can be utilized to elicit a therapeutically effective immune response against melanoma in experimental models. However, patient vaccination with peptides - although it is often followed by the induction of melanoma- specific T lymphocytes - is rarely associated with tumor response of clinical relevance. In this review I summarize the principles of peptide design as well as the results so far obtained in the clinical setting while treating cutaneous melanoma by means of this active immunotherapy strategy. I also discuss some immunological and methodological issues that might be helpful for the successful development of peptide-based vaccines.

  14. Antimicrobial Peptides in Reptiles

    Science.gov (United States)

    van Hoek, Monique L.

    2014-01-01

    Reptiles are among the oldest known amniotes and are highly diverse in their morphology and ecological niches. These animals have an evolutionarily ancient innate-immune system that is of great interest to scientists trying to identify new and useful antimicrobial peptides. Significant work in the last decade in the fields of biochemistry, proteomics and genomics has begun to reveal the complexity of reptilian antimicrobial peptides. Here, the current knowledge about antimicrobial peptides in reptiles is reviewed, with specific examples in each of the four orders: Testudines (turtles and tortosises), Sphenodontia (tuataras), Squamata (snakes and lizards), and Crocodilia (crocodilans). Examples are presented of the major classes of antimicrobial peptides expressed by reptiles including defensins, cathelicidins, liver-expressed peptides (hepcidin and LEAP-2), lysozyme, crotamine, and others. Some of these peptides have been identified and tested for their antibacterial or antiviral activity; others are only predicted as possible genes from genomic sequencing. Bioinformatic analysis of the reptile genomes is presented, revealing many predicted candidate antimicrobial peptides genes across this diverse class. The study of how these ancient creatures use antimicrobial peptides within their innate immune systems may reveal new understandings of our mammalian innate immune system and may also provide new and powerful antimicrobial peptides as scaffolds for potential therapeutic development. PMID:24918867

  15. DYNAMICS OF OPIOID SUBSTITUTION TREATMENTIN DIFFERENT INITIAL SUBSTANCE USER OPIOID DEPENDENT PATIENTS.

    Science.gov (United States)

    Todadze, Kh; Mosia, S

    2016-05-01

    Injecting drug user size estimation studies carried out in 2009, 2012 and 2015 revealed growing trends of drug abuse in Georgia:estimated number of people who inject drugs (PWID) have been increased from 40000 and 45000 to 50000. Since Soviet period the most popular injective narcotics have been opioids: home-made opium, heroine, buprenorphine and home-made desomorphine ("Krokodile") replacing each other on the black market. Self-made desomorphine typically contains big amounts of different toxic substances and causes significant somatic disorders, especially skin, bone, blood infections, liver and kidney failure; is highly addictive, associates with frequent injections that enhance injecting-related harm, including the risk of HIV transmission, in comparison with typical opioids. The aim of the study was to determine the effectiveness of opioid substitution treatment (OST) on depression and anxiety in opioid dependent clients with history of different opioid substance use. 104 opioid drug users undergoing OST with intensive psychological counseling have been divided in 5 groups according to the principal opioid drug that was abused during past 6 months before starting treatment: heroine, desomorphine, illicit methadone injectors, illicit buprenorphine injectors, and multiple drug abusers consuming opioids as primary drugs. Level of depression (Beck Depression Inventory), anxiety (Spielberger Anxiety Inventory) as well as clinical symptoms, risky behavior, quality of life (WHO), and other data were measured before starting and after 3, 9, 15, 21 months of treatment. The illegal use of psychotropic-narcotics was checked through random urine-testing 1-2 times per patient per month. In all five groups remarkable decrease of depression and anxiety was observed in comparison with the starting data. Before inclusion desomorphine and poly-drug users had the highest scores of depression and anxiety while buprenorphine users manifested the lowest rate. Improvement of

  16. Effectiveness of ketamine as an adjuvant to opioid-based therapy in decreasing pain associated with opioid tolerance in adults undergoing orthopedic surgery: a systematic review protocol.

    Science.gov (United States)

    Bennett, Marsha; Bonanno, Laura; Kuhn, William

    2016-10-01

    The objective of this systematic review is to examine the best available evidence on the clinical effectiveness of ketamine as an adjuvant to opioid-based therapy versus opioid-based therapy alone in decreasing perioperative pain associated with opioid tolerance in adult patients, aged 18-70 years, undergoing orthopedic surgical procedures.The following question guides the systematic review: does the administration of ketamine as an adjuvant to opioid-based therapy, compared to opioid-based therapy alone, improve perioperative pain relief in opioid-tolerant adult patients undergoing orthopedic surgical procedures?

  17. Opioid system of the brain and ethanol.

    Science.gov (United States)

    Gogichadze, M; Mgaloblishvili-Nemsadze, M; Oniani, N; Emukhvary, N; Basishvili, T

    2009-04-01

    Influence of blocking of opioid receptors with concomitant intraperitoneal injections of Naloxone (20 mg/kg) (non-selective antagonist of opioid system) on the outcomes of anesthetic dose of ethanol (4,25 ml /kg 25% solution) was investigated in the rats. The sleep-wakefulness cycle (SWC) was used as a model for identification of the effects. Alterations of the SWC structure adequately reflect the neuro-chemical changes, which may develop during pharmacological and non-pharmacological impact. Administration of anesthetic dose of ethanol evoked considerable modification of spontaneous EEG activity of the neocortex. The EEG activity was depressed and full inhibition of spinal reflexes and somatic muscular relaxation did occur. During EEG depression regular SWC did not develop. All phases of SWC were reduced. The disturbances of SWC, such as decrease of slow wave sleep and paradoxical sleep duration and increase of wakefulness, remained for several days. At concomitant administration of Naloxone and ethanol, duration of EEG depression decreased significantly. Generation of normal SWC was observed on the same experimental day. However, it should be noted that complete abolishment of ethanol effects by Naloxone was not observed. The results obtained suggest that Naloxone partially blocks ethanol depressogenic effects and duration of this effect is mediated by GABA-ergic system of the brain.

  18. A Motion Videogame for Opioid Relapse Prevention.

    Science.gov (United States)

    Abroms, Lorien C; Leavitt, Leah E; Van Alstyne, Judy M; Schindler-Ruwisch, Jennifer M; Fishman, Marc J; Greenberg, Daniel

    2015-12-01

    This study examined the feasibility and acceptability of a body motion-activated videogame, targeting the prevention of opioid relapse among youth in the context of outpatient treatment. Participants attended four weekly gameplay sessions. Surveys were conducted at baseline and following each week's gameplay and assessed satisfaction with gameplay, craving intensity, and self-efficacy to refuse opioids. Participants expressed a high level of satisfaction with the videogame throughout the 4 weeks and agreed with the statement that they would be more likely to attend treatment sessions if the game was present (mean=4.6; standard deviation [SD]=0.7) and would recommend the videogame to other people in treatment (mean=4.2; SD=0.8). All participants recommended playing the videogame as part of treatment at least weekly, with a third recommending playing daily. Self-reported cravings declined over the 4-week period from baseline (mean=12.7; SD=8.4) to Week 4 (mean=9.8; SD=8.3), although the decline was not significant. Although participants stated that they liked the game, one-third of participants had dropped out of the study by the fourth session of gameplay. Preliminary evidence indicates that a motion videogame for addiction recovery may be feasible and acceptable within the context of outpatient treatment, although additional efforts are needed to keep youth in treatment. Future studies are needed to assess the impact of the game on long-term abstinence, treatment adherence, and engagement.

  19. β-Endorphin via the Delta Opioid Receptor is a Major Factor in the Incubation of Cocaine Craving

    Science.gov (United States)

    Dikshtein, Yahav; Barnea, Royi; Kronfeld, Noam; Lax, Elad; Roth-Deri, Ilana; Friedman, Alexander; Gispan, Iris; Elharrar, Einat; Levy, Sarit; Ben-Tzion, Moshe; Yadid, Gal

    2013-01-01

    Cue-induced cocaine craving intensifies, or ‘incubates', during the first few weeks of abstinence and persists over extended periods of time. One important factor implicated in cocaine addiction is the endogenous opioid β-endorphin. In the present study, we examined the possible involvement of β-endorphin in the incubation of cocaine craving. Rats were trained to self-administer cocaine (0.75 mg/kg, 10 days, 6 h/day), followed by either a 1-day or a 30-day period of forced abstinence. Subsequent testing for cue-induced cocaine-seeking behavior (without cocaine reinforcement) was performed. Rats exposed to the drug-associated cue on day 1 of forced abstinence demonstrated minimal cue-induced cocaine-seeking behavior concurrently with a significant increase in β-endorphin release in the nucleus accumbens (NAc). Conversely, exposure to the cue on day 30 increased cocaine seeking, while β-endorphin levels remained unchanged. Intra-NAc infusion of an anti-β-endorphin antibody (4 μg) on day 1 increased cue-induced cocaine seeking, whereas infusion of a synthetic β-endorphin peptide (100 ng) on day 30 significantly decreased cue response. Both intra-NAc infusions of the δ opioid receptor antagonist naltrindole (1 μg) on day 1 and naltrindole together with β-endorphin on day 30 increased cue-induced cocaine-seeking behavior. Intra-NAc infusion of the μ opioid receptor antagonist CTAP (30 ng and 3 μg) had no behavioral effect. Altogether, these results demonstrate a novel role for β-endorphin and the δ opioid receptor in the development of the incubation of cocaine craving. PMID:23800967

  20. Insulin C-peptide test

    Science.gov (United States)

    C-peptide ... the test depends on the reason for the C-peptide measurement. Ask your health care provider if ... C-peptide is measured to tell the difference between insulin the body produces and insulin someone injects ...

  1. Comorbid Post-Traumatic Stress Disorder and Opioid Dependence.

    Science.gov (United States)

    Patel, Rikinkumar S; Elmaadawi, Ahmed; Nasr, Suhayl; Haskin, John

    2017-09-03

    Post-traumatic stress disorder (PTSD) is predominant amongst individuals addicted to opioids and obscures the course of illness and the treatment outcome. We report the case of a patient with major depressive disorder and opioid dependence, who experienced post-traumatic stress disorder symptoms during a recent visit to the inpatient unit. The similarity of symptoms between post-traumatic stress disorder and opioid dependence is so high that, sometimes, it is a challenge to differentiate between these conditions. Since opioid withdrawal symptoms mimic hyper vigilance, this results in an exaggeration of the response of patients with post-traumatic stress disorder. This comorbidity is associated with worse health outcomes, as its pathophysiology involves a common neurobiological circuit. Opioid substitution therapy and psychotherapeutic medications in combination with evidence-based cognitive behavioral therapy devised for individuals with comorbid post-traumatic stress disorder and opioid dependence may improve treatment outcomes in this population. Therefore, we conclude that the screening for post-traumatic stress disorder in the opioid-abusing population is crucial. To understand the underlying mechanisms for this comorbidity and to improve the treatment response, further research should be encouraged.

  2. Pain in the management of opioid use disorder

    Directory of Open Access Journals (Sweden)

    Sirohi S

    2016-11-01

    Full Text Available Sunil Sirohi,1 Amit K Tiwari21Laboratory of Endocrine and Neuropsychiatric Disorders, Division of Basic Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans, LA, 2Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, USAOpioids remain the drug of choice for the clinical management of moderate to severe pain. However, in addition to their most effective analgesic actions, opioids also produce a sense of well-being and euphoria, which may trigger significant concerns associated with their use.1 In fact, there has been an alarming increase in prescription opioid use, abuse and illicit use; and according to the National Center for Health Statistics, the total number of deaths related to opioid overdose has more than tripled from 2011 to 2014.2–5 Although representing 5.0 % of the global population, studies report that Americans consume 80% of the global opioid supply,3 and the United States is experiencing an opioid abuse epidemic.6 Considering this unprecedented rise in opioid consumption, the United States Centers for Disease Control and Prevention has listed prescription opioid overdose among one of the 10 most important public health problems in all the 50 states.7

  3. Risk Factors for Opioid-Use Disorder and Overdose.

    Science.gov (United States)

    Webster, Lynn R

    2017-11-01

    Opioid analgesics are recognized as a legitimate medical therapy for selected patients with severe chronic pain that does not respond to other therapies. However, opioids are associated with risks for patients and society that include misuse, abuse, diversion, addiction, and overdose deaths. Therapeutic success depends on proper candidate selection, assessment before administering opioid therapy, and close monitoring throughout the course of treatment. Risk assessment and prevention include knowledge of patient factors that may contribute to misuse, abuse, addiction, suicide, and respiratory depression. Risk factors for opioid misuse or addiction include past or current substance abuse, untreated psychiatric disorders, younger age, and social or family environments that encourage misuse. Opioid mortality prevalence is higher in people who are middle aged and have substance abuse and psychiatric comorbidities. Suicides are probably undercounted or frequently misclassified in reports of opioid-related poisoning deaths. Greater understanding and better assessment are needed of the risk associated with suicide risk in patients with pain. Clinical tools and an evolving evidence base are available to assist clinicians with identifying patients whose risk factors put them at risk for adverse outcomes with opioids.

  4. Comparison of periodontal manifestations in amphetamine and opioids' consumers

    Directory of Open Access Journals (Sweden)

    Masoome Eivazi

    2016-03-01

    Full Text Available Background: Drug abuse is one of the most important etiologic and deteriorating factors in periodontal disease. Amphetamines and opioids, the most commonly used drugs worldwide, play an important role in this regard. The aim of this study was to compare the periodontal status of amphetamines and opioids consumers in Kermanshah city, Iran in 1393. Methods: Three drug rehabilitation clinics were selected randomly in Kermanshah. According to inclusion and exclusion criteria, 20 amphetamine consumers and 20 opioid consumers were selected randomly and participated in this study. A questionnaire for drug use and periodontal variables was designed. The collected data were entered into SPSS-18 software and Mann-Whitney and t-test were used for statistical analysis. Results: Pocket depth, gingival index and gingival bleeding in amphetamines users were more than those in opioids consumers (P<0.021. Plaque index and gingival recession in opioids users were more than those of amphetamines consumers (P<0.001. The number of periodontal disease cases in amphetamines group were 13 persons (65% and in opioids group 8 persons (40%. Conclusion: Our study showed that periodontal hygine in amphetamine consumers was worse than opioid consumers.

  5. Methylnaltrexone in the treatment of opioid-induced constipation

    Directory of Open Access Journals (Sweden)

    Beverley Greenwood-Van Meerveld

    2008-12-01

    Full Text Available Beverley Greenwood-Van Meerveld1, Kelly M Standifer21Veterans Affairs Medical Center, Oklahoma Center for Neuroscience, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; 2Department of Pharmaceutical Sciences, Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USAAbstract: Constipation is a significant problem related to opioid medications used to manage pain. This review attempts to outline the latest findings related to the therapeutic usefulness of a μ opioid receptor antagonist, methylnaltrexone in the treatment of opioid-induced constipation. The review highlights methylnaltrexone bromide (RelistorTM; Progenics/Wyeth a quaternary derivative of naltrexone, which was recently approved in the United States, Europe and Canada. The Food and Drug Administration in the United States approved a subcutaneous injection for the treatment of opioid bowel dysfunction in patients with advanced illness who are receiving palliative care and when laxative therapy has been insufficient. Methylnaltrexone is a peripherally restricted, μ opioid receptor antagonist that accelerates oral–cecal transit in patients with opioidinduced constipation without reversing the analgesic effects of morphine or inducing symptoms of opioid withdrawal. An analysis of the mechanism of action and the potential benefits of using methylnaltrexone is based on data from published basic research and recent clinical studies.Keywords: methylnaltrexone, constipation, opioid

  6. Peptide Vaccines for Leishmaniasis

    Directory of Open Access Journals (Sweden)

    Rory C. F. De Brito

    2018-05-01

    Full Text Available Due to an increase in the incidence of leishmaniases worldwide, the development of new strategies such as prophylactic vaccines to prevent infection and decrease the disease have become a high priority. Classic vaccines against leishmaniases were based on live or attenuated parasites or their subunits. Nevertheless, the use of whole parasite or their subunits for vaccine production has numerous disadvantages. Therefore, the use of Leishmania peptides to design more specific vaccines against leishmaniases seems promising. Moreover, peptides have several benefits in comparison with other kinds of antigens, for instance, good stability, absence of potentially damaging materials, antigen low complexity, and low-cost to scale up. By contrast, peptides are poor immunogenic alone, and they need to be delivered correctly. In this context, several approaches described in this review are useful to solve these drawbacks. Approaches, such as, peptides in combination with potent adjuvants, cellular vaccinations, adenovirus, polyepitopes, or DNA vaccines have been used to develop peptide-based vaccines. Recent advancements in peptide vaccine design, chimeric, or polypeptide vaccines and nanovaccines based on particles attached or formulated with antigenic components or peptides have been increasingly employed to drive a specific immune response. In this review, we briefly summarize the old, current, and future stands on peptide-based vaccines, describing the disadvantages and benefits associated with them. We also propose possible approaches to overcome the related weaknesses of synthetic vaccines and suggest future guidelines for their development.

  7. Peptide Vaccines for Leishmaniasis.

    Science.gov (United States)

    De Brito, Rory C F; Cardoso, Jamille M De O; Reis, Levi E S; Vieira, Joao F; Mathias, Fernando A S; Roatt, Bruno M; Aguiar-Soares, Rodrigo Dian D O; Ruiz, Jeronimo C; Resende, Daniela de M; Reis, Alexandre B

    2018-01-01

    Due to an increase in the incidence of leishmaniases worldwide, the development of new strategies such as prophylactic vaccines to prevent infection and decrease the disease have become a high priority. Classic vaccines against leishmaniases were based on live or attenuated parasites or their subunits. Nevertheless, the use of whole parasite or their subunits for vaccine production has numerous disadvantages. Therefore, the use of Leishmania peptides to design more specific vaccines against leishmaniases seems promising. Moreover, peptides have several benefits in comparison with other kinds of antigens, for instance, good stability, absence of potentially damaging materials, antigen low complexity, and low-cost to scale up. By contrast, peptides are poor immunogenic alone, and they need to be delivered correctly. In this context, several approaches described in this review are useful to solve these drawbacks. Approaches, such as, peptides in combination with potent adjuvants, cellular vaccinations, adenovirus, polyepitopes, or DNA vaccines have been used to develop peptide-based vaccines. Recent advancements in peptide vaccine design, chimeric, or polypeptide vaccines and nanovaccines based on particles attached or formulated with antigenic components or peptides have been increasingly employed to drive a specific immune response. In this review, we briefly summarize the old, current, and future stands on peptide-based vaccines, describing the disadvantages and benefits associated with them. We also propose possible approaches to overcome the related weaknesses of synthetic vaccines and suggest future guidelines for their development.

  8. Peptide Nucleic Acids

    DEFF Research Database (Denmark)

    2004-01-01

    A novel class of compounds known as peptide nucleic acids, bind complementary DNA and RNA strands, and generally do so more strongly than the corresponding DNA or RNA strands while exhibiting increased sequence specificity and solubility. The peptide nucleic acids comprise ligands selected from...

  9. The influence of propoxyphene withdrawal on opioid use in veterans.

    Science.gov (United States)

    Hayes, Corey J; Hudson, Teresa J; Phillips, Martha M; Bursac, Zoran; Williams, James S; Austin, Mark A; Edlund, Mark J; Martin, Bradley C

    2015-11-01

    Our aim is to determine if propoxyphene withdrawal from the US market was associated with opioid continuation, continued chronic opioid use, and secondary propoxyphene-related adverse events (emergency department visits, opioid-related events, and acetaminophen toxicity). Medical service use and pharmacy data from 19/11/08 to 19/11/11 were collected from the national Veterans Healthcare Administration healthcare databases. A quasi-experimental pre-post retrospective cohort design utilizing a historical comparison group provided the study framework. Logistic regression controlling for baseline covariates was used to estimate the effect of propoxyphene withdrawal. There were 24,328 subjects (policy affected n = 10,747; comparison n = 13,581) meeting inclusion criteria. In the policy-affected cohort, 10.6% of users ceased using opioids, and 26.6% stopped chronic opioid use compared with 3.8% and 13.5% in the historical comparison cohort, respectively. Those in the policy-affected cohort were 2.7 (95%CI: 2.5-2.8) and 3.2 (95%CI: 2.9-3.6) times more likely than those in the historical comparison cohort to discontinue chronic opioid and any opioid use, respectively. Changes in adverse events and Emergency Department (ED) visits were not different between policy-affected and historical comparison cohorts (p > 0.05). The withdrawal of propoxyphene-containing products resulted in rapid and virtually complete elimination in propoxyphene prescribing in the veterans population; however, nearly 90% of regular users of propoxyphene switched to an alternate opioid, and three quarters continued to use opioids chronically. Copyright © 2015 John Wiley & Sons, Ltd.

  10. Isobolographic analysis of the opioid-opioid interactions in a tonic and a phasic mouse model of induced nociceptive pain.

    Science.gov (United States)

    Miranda, Hugo F; Noriega, Viviana; Zanetta, Pilar; Prieto, Juan Carlos; Prieto-Rayo, Juan Carlos; Aranda, Nicolás; Sierralta, Fernando

    2014-07-15

    Opioids have been used for the management of pain and coadministration of two opioids may induce synergism. In a model of tonic pain, the acetic acid writhing test and in a phasic model, the hot plate, the antinociceptive interaction between fentanyl, methadone, morphine, and tramadol was evaluated. The potency of opioids in the writhing test compared to the hot plate assay was from 2.5 (fentanyl) to 15.5 (morphine) times, respectively. The ED50 was used in a fixed ratio for each of the six pairs of opioid combinations, which, resulted in a synergistic antinociception except for methadone/tramadol and fentanyl/tramadol which were additive, in the hot plate. The opioid antagonists naltrexone, naltrindole and nor-binaltorphimine, suggests that the synergism of morphine combinations are due to the activation of MOR subtypes with partially contribution of DOR and KOR, however fentanyl and methadone combinations are partially due to the activation of MOR and DOR subtypes and KOR lack of participation. The antinociceptive effects of tramadol combinations, are partially due to the activation of MOR, DOR and KOR opioid subtypes. These results suggets that effectiveness and magnitude of the interactions between opioids are dependent on pain stimulus intensity.

  11. Health-Related Quality of Life among Chronic Opioid Users, Nonchronic Opioid Users, and Nonopioid Users with Chronic Noncancer Pain.

    Science.gov (United States)

    Hayes, Corey J; Li, Xiaocong; Li, Chenghui; Shah, Anuj; Kathe, Niranjan; Bhandari, Naleen Raj; Payakachat, Nalin

    2018-02-25

    Evaluate the association between opioid therapy and health-related quality of life (HRQoL) in participants with chronic, noncancer pain (CNCP). Medical Expenditure Panel Survey Longitudinal, Medical Conditions, and Prescription Files. Using a retrospective cohort study design, the Mental Health Component (MCS12) and Physical Health Component (PCS12) scores of the Short Form-12 Version 2 were assessed to measure mental and physical HRQoL. Chronic, noncancer pain participants were classified as chronic, nonchronic, and nonopioid users. One-to-one propensity score matching was employed to match chronic opioid users to nonchronic opioid users plus nonchronic opioid users and chronic opioid users to nonopioid users. A total of 5,876 participants were identified. After matching, PCS12 was not significantly different between nonchronic versus nonopioid users (LSM Diff = -0.98, 95% CI: -2.07, 0.10), chronic versus nonopioid users (LSM Diff = -2.24, 95% CI: -4.58, 0.10), or chronic versus nonchronic opioid users (LSM Diff = -2.23, 95% CI: -4.53, 0.05). Similarly, MCS12 was not significantly different between nonchronic versus nonopioid users (LSM Diff = 0.76, 95% CI: -0.46, 1.98), chronic versus nonopioid users (LSM Diff = 1.08, 95% CI: -1.26, 3.42), or chronic versus nonchronic opioid users (LSM Diff = -0.57, 95% CI: -2.90, 1.77). Clinicians should evaluate opioid use in participants with CNCP as opioid use is not correlated with better HRQoL. © Health Research and Educational Trust.

  12. Inhibition of Snake Venom Metalloproteinase by β-Lactoglobulin Peptide from Buffalo (Bubalus bubalis) Colostrum.

    Science.gov (United States)

    Arpitha, Ashok; Sebastin Santhosh, M; Rohit, A C; Girish, K S; Vinod, D; Aparna, H S

    2017-08-01

    Bioactive peptide research has experienced considerable therapeutic interest owing to varied physiological functions, efficacy in excretion, and tolerability of peptides. Colostrum is a rich natural source of bioactive peptides with many properties elucidated such as anti-thrombotic, anti-hypertensive, opioid, immunomodulatory, etc. In this study, a variant peptide derived from β-lactoglobulin from buffalo colostrum was evaluated for the anti-ophidian property by targeting snake venom metalloproteinases. These are responsible for rapid local tissue damages that develop after snakebite such as edema, hemorrhage, myonecrosis, and extracellular matrix degradation. The peptide identified by LC-MS/MS effectively neutralized hemorrhagic activity of the Echis carinatus venom in a dose-dependent manner. Histological examinations revealed that the peptide mitigated basement membrane degradation and accumulation of inflammatory leucocytes at the venom-injected site. Inhibition of proteolytic activity was evidenced in both casein and gelatin zymograms. Also, inhibition of fibrinolytic and fibrinogenolytic activities was seen. The UV-visible spectral study implicated Zn 2+ chelation, which was further confirmed by molecular docking and dynamic studies by assessing molecular interactions, thus implicating the probable mechanism for inhibition of venom-induced proteolytic and hemorrhagic activities. The present investigation establishes newer vista for the BLG-col peptide with anti-ophidian efficacy as a promising candidate for therapeutic interventions.

  13. Long-term opioid therapy in Denmark

    DEFF Research Database (Denmark)

    Birke, H; Ekholm, Ola; Sjøgren, P

    2017-01-01

    significantly associated with initiation of L-TOT in individuals with CNCP at baseline. During follow-up, L-TOT in CNCP patients increased the likelihood of negative changes in pain interference with work (OR 9.2; 95% CI 1.9-43.6) and in moderate activities (OR 3.7; 95% CI 1.1-12.6). The analysis of all......,145). A nationally representative subsample of individuals (n = 2015) completed the self-administered questionnaire in both 2000 and 2013. Collected information included chronic pain (≥6 months), health behaviour, self-rated health, pain interference with work activities and physical activities. Long-term users were...... individuals indicated a dose-response relationship between longer treatment duration and the risk of experiencing negative changes. CONCLUSIONS: Individuals on L-TOT seemed not to achieve the key goals of opioid therapy: pain relief, improved quality of life and functional capacity. SIGNIFICANCE: Long...

  14. Opioids and immunosupression in oncological postoperative patients

    Directory of Open Access Journals (Sweden)

    José Luis Bonilla-García

    Full Text Available Summary Introduction: Recent animal studies demonstrated immunosuppressive effects of opioid withdrawal resulting in a higher risk of infection. The aim of this study was to determine the impact of remifentanil discontinuation on Post-Anesthesia Care Unit (PACU-acquired infection after a schedule of sedoanalgesia of at least 6 days. Method: All patients over 18 years of age with a unit admission of more than 4 days were consecutively selected. The study population was the one affected by surgical pathology of any origin where sedation was based on any hypnotic and the opioid remifentanil was used as analgesic for at least 96 hours in continuous perfusion. Patients who died during admission to the unit and those with combined analgesia (peripheral or neuroaxial blocks were excluded. Bivariate analysis was performed to determine risk factors for infection acquired in the unit. A comparative study between periods of 6 days before and after the cessation of remifentanil was performed. Paired samples test and McNemar test was used for quantitative and categorical variables, respectively. Results: There were 1,789 patients admitted to the PACU during the study and the population eligible was constituted for 102 patients. The incidence rate of PACU-acquired infection was 38 per 1,000 PACU days. Ventilator-associated pneumonia was the most frequently diagnosed PACU-acquired infection. Pseudomona aeruginosa was the most frequently isolated microorganism. Hospital mortality was 36.27%. No statistically significant differences were seen in the incidence of HAI in cancer patients in relation to discontinuation of remifentanil (p=0.068. Conclusion: The baseline state of immunosuppression of cancer patients does not imply a higher incidence of HAI in relation to the interruption of remifentanil. It would be of interest to carry out a multicenter PACU study that included immunological patterns.

  15. Opioid Epidemic: Cellular & Molecular Anesthesia as a Key Solution

    Directory of Open Access Journals (Sweden)

    Ali Dabbagh

    2017-12-01

    Full Text Available Opioids are one of the most important arsenals armamentarium of physicians for fighting against pain. During the decades, opioids have been used in a wide range of indications; both for treatment of acute and chronic pain; as natural and synthetic compounds and in a variety of delivery forms from intravenous infusion to intrathecal adjuvants of local anesthetics or as transdermal patches. There is no doubt that we are in an opioid misuse epidemic status; whether in the US or other countries; but if we want to resolve this miserable multilateral complication, there is no doubt that Cellular and Molecular aspects of Anesthesia has a key role in resolving the problem; through creating an opioid free pain management era.

  16. Opioid interruptions, pain, and withdrawal symptoms in nursing home residents.

    Science.gov (United States)

    Redding, Sarah E; Liu, Sophia; Hung, William W; Boockvar, Kenneth S

    2014-11-01

    Interruptions in opioid use have the potential to cause pain relapse and withdrawal symptoms. The objectives of this study were to observe patterns of opioid interruption during acute illness in nursing home residents and examine associations between interruptions and pain and withdrawal symptoms. Patients from 3 nursing homes in a metropolitan area who were prescribed opioids were assessed for symptoms of pain and withdrawal by researchers blinded to opioid dosage received, using the Brief Pain Inventory Scale and the Clinical Opioid Withdrawal Scale, respectively, during prespecified time periods. The prespecified time periods were 2 weeks after onset of acute illness (eg, urinary tract infection), and 2 weeks after hospital admission and nursing home readmission, if they occurred. Opioid dosing was recorded and a significant interruption was defined as a complete discontinuation or a reduction in dose of >50% for ≥1 day. The covariates age, sex, race, comorbid conditions, initial opioid dose, and initial pain level were recorded. Symptoms pre- and post-opioid interruptions were compared and contrasted with those in a group without opioid interruptions. Sixty-six patients receiving opioids were followed for a mean of 10.9 months and experienced a total of 104 acute illnesses. During 64 (62%) illnesses, patients experienced any reduction in opioid dosing, with a mean (SD) dose reduction of 63.9% (29.9%). During 39 (38%) illnesses, patients experienced a significant opioid interruption. In a multivariable model, residence at 1 of the 3 nursing homes was associated with a lower risk of interruption (odds ratio = 0.073; 95% CI, 0.009 to 0.597; P pain score (difference -0.50 [2.66]; 95% CI, -3.16 to 2.16) and withdrawal score (difference -0.91 [3.12]; 95% CI, -4.03 to 2.21) after the interruption as compared with before interruption. However, when compared with patients without interruptions, patients with interruptions experienced larger increases in pain scores

  17. Opioid Overdose Prevention: Safety Advice for Patients & Family Members

    Science.gov (United States)

    ... the effects of opioids. Naloxone works by blocking opiate receptor sites. It is not effective in treating ... agitation, anxiety, confusion, or ringing in your ears.  Seizures (convulsions).  Feeling that you might pass out.  Slow ...

  18. Dramatic Increases in Maternal Opioid Use and Neonatal Abstinence Syndrome

    Science.gov (United States)

    ... Alcohol Club Drugs Cocaine Fentanyl Hallucinogens Inhalants Heroin Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Over-the-Counter Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/ ...

  19. Although Relatively Few, "Doctor Shoppers" Skew Opioid Prescribing

    Science.gov (United States)

    ... Alcohol Club Drugs Cocaine Fentanyl Hallucinogens Inhalants Heroin Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Over-the-Counter Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/ ...

  20. Fentanyl and Other Synthetic Opioids Drug Overdose Deaths

    Science.gov (United States)

    ... Alcohol Club Drugs Cocaine Fentanyl Hallucinogens Inhalants Heroin Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Over-the-Counter Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/ ...

  1. Polyglycerol-opioid conjugate produces analgesia devoid of side effects.

    Science.gov (United States)

    González-Rodríguez, Sara; Quadir, Mohiuddin A; Gupta, Shilpi; Walker, Karolina A; Zhang, Xuejiao; Spahn, Viola; Labuz, Dominika; Rodriguez-Gaztelumendi, Antonio; Schmelz, Martin; Joseph, Jan; Parr, Maria K; Machelska, Halina; Haag, Rainer; Stein, Christoph

    2017-07-04

    Novel painkillers are urgently needed. The activation of opioid receptors in peripheral inflamed tissue can reduce pain without central adverse effects such as sedation, apnoea, or addiction. Here, we use an unprecedented strategy and report the synthesis and analgesic efficacy of the standard opioid morphine covalently attached to hyperbranched polyglycerol (PG-M) by a cleavable linker. With its high-molecular weight and hydrophilicity, this conjugate is designed to selectively release morphine in injured tissue and to prevent blood-brain barrier permeation. In contrast to conventional morphine, intravenous PG-M exclusively activated peripheral opioid receptors to produce analgesia in inflamed rat paws without major side effects such as sedation or constipation. Concentrations of morphine in the brain, blood, paw tissue, and in vitro confirmed the selective release of morphine in the inflamed milieu. Thus, PG-M may serve as prototype of a peripherally restricted opioid formulation designed to forego central and intestinal side effects.

  2. Addiction to opioids in chronic pain patients: a literature review

    DEFF Research Database (Denmark)

    Højsted, Jette; Sjøgren, Per

    2007-01-01

    , incidence and prevalence of addiction in opioid treated pain patients, screening tools for assessing opioid addiction in chronic pain patients and recommendations regarding addiction problems in national and international guidelines for opioid treatment in cancer patients and chronic non-malignant pain...... patients. The review indicates that the prevalence of addiction varied from 0% up to 50% in chronic non-malignant pain patients, and from 0% to 7.7% in cancer patients depending of the subpopulation studied and the criteria used. The risk of addiction has to be considered when initiating long-term opioid...... treatment as addiction may result in poor pain control. Several screening tools were identified, but only a few were thoroughly validated with respect to validity and reliability. Most of the identified guidelines mention addiction as a potential problem. The guidelines in cancer pain management...

  3. Blocking opioid receptors alters short-term feed intake and oro-sensorial preferences in weaned calves.

    Science.gov (United States)

    Montoro, C; Ipharraguerre, I R; Bach, A

    2012-05-01

    Opioid peptides may participate in the control of feed intake through mechanisms involving pleasure reward linked to consumption of palatable feed. The objective of this study was to determine whether blocking opioid receptors might void oro-sensorial preferences of calves, and affect circulating glucose, insulin, and anorexigenic hormones in fasted and fed calves. Two experiments involved 32 Holstein calves [body weight (BW)=86.5±1.73 kg, age=72±0.6 d]. In experiment 1, all calves received an ad libitum choice of the same feed either unflavored or flavored with a sweetener (Luctarom SFS-R, Lucta, Montornès del Vallès, Spain). Feed consumption was recorded every 2 h from 0800 to 1400 h for 3 consecutive days to verify the establishment of an oro-sensorial preference for sweet feed (SF). The SF was preferred over the control feed (CF) at all recorded times. In experiment 2, calves were subjected to a 2 × 2 factorial design to study the interaction between opioid activity and metabolic state. Half of the calves were fasted for 14 h (FAS), whereas the other half remained well fed (FED). Within each of these groups, at feeding time (0800 h), half of the calves received an i.v. injection of naloxone (NAL, an opioid receptor antagonist; 1 mg/kg of BW) and the other half was injected with saline solution (SAL; 0.9% NaCl). Therefore, treatments were FED-NAL, FED-SAL, FAS-NAL, and FAS-SAL. Blood samples were taken at -10, 20, 180, and 240 min relative to NAL or SAL injections. As expected, cumulative consumption of starter feed was greater in FAS than in FED calves. Total feed consumption 2 h after feeding was lower in NAL than in SAL calves. Calves in the FAS group did not discern between CF and SF during the first 4 h after feed offer. Preference for SF was greater in SAL than in NAL calves. Calves in the FED-SAL treatment preferred SF at 2 and 6 h after feed offer and tended to prefer SF at 4 h after feeding. However, FED-NAL calves did not discern between SF and CF

  4. Orexin Receptor Multimerization versus Functional Interactions: Neuropharmacological Implications for Opioid and Cannabinoid Signalling and Pharmacogenetics

    Directory of Open Access Journals (Sweden)

    Miles D. Thompson

    2017-10-01

    Full Text Available Orexins/hypocretins are neuropeptides formed by proteolytic cleavage of a precursor peptide, which are produced by neurons found in the lateral hypothalamus. The G protein-coupled receptors (GPCRs for these ligands, the OX1 and OX2 orexin receptors, are more widely expressed throughout the central nervous system. The orexin/hypocretin system has been implicated in many pathways, and its dysregulation is under investigation in a number of diseases. Disorders in which orexinergic mechanisms are being investigated include narcolepsy, idiopathic sleep disorders, cluster headache and migraine. Human narcolepsy has been associated with orexin deficiency; however, it has only rarely been attributed to mutations in the gene encoding the precursor peptide. While gene variations within the canine OX2 gene hcrtr2 have been directly linked with narcolepsy, the majority of human orexin receptor variants are weakly associated with diseases (the idiopathic sleep disorders, cluster headache and polydipsia-hyponatremia in schizophrenia or are of potential pharmacogenetic significance. Evidence for functional and/or heterodimerization between wild-type variant orexin receptors and opioid and cannabinoid receptors is discussed in the context of its relevance to depression and epilepsy.

  5. Influence of intravenous opioid dose on postoperative ileus.

    Science.gov (United States)

    Barletta, Jeffrey F; Asgeirsson, Theodor; Senagore, Anthony J

    2011-07-01

    Intravenous opioids represent a major component in the pathophysiology of postoperative ileus (POI). However, the most appropriate measure and threshold to quantify the association between opioid dose (eg, average daily, cumulative, maximum daily) and POI remains unknown. To evaluate the relationship between opioid dose, POI, and length of stay (LOS) and identify the opioid measure that was most strongly associated with POI. Consecutive patients admitted to a community teaching hospital who underwent elective colorectal surgery by any technique with an enhanced-recovery protocol postoperatively were retrospectively identified. Patients were excluded if they received epidural analgesia, developed a major intraabdominal complication or medical complication, or had a prolonged workup prior to surgery. Intravenous opioid doses were quantified and converted to hydromorphone equivalents. Classification and regression tree (CART) analysis was used to determine the dosing threshold for the opioid measure most associated with POI and define high versus low use of opioids. Risk factors for POI and prolonged LOS were determined through multivariate analysis. The incidence of POI in 279 patients was 8.6%. CART analysis identified a maximum daily intravenous hydromorphone dose of 2 mg or more as the opioid measure most associated with POI. Multivariate analysis revealed maximum daily hydromorphone dose of 2 mg or more (p = 0.034), open surgical technique (p = 0.045), and days of intravenous narcotic therapy (p = 0.003) as significant risk factors for POI. Variables associated with increased LOS were POI (p POI and prolonged LOS, particularly when the maximum hydromorphone dose per day exceeds 2 mg. Clinicians should consider alternative, nonopioid-based pain management options when this occurs.

  6. The Neuroanatomy of Sexual Dimorphism in Opioid Analgesia

    Science.gov (United States)

    2014-04-13

    2012 for review). Studies utilizing orofacial , somatosensory or visceral pain assays typically report that morphine produces a significantly greater...Review The neuroanatomy of sexual dimorphism in opioid analgesia Dayna R. Loyd a, Anne Z. Murphy b,⁎ a Pain Management Research Area, United States...online 13 April 2014 Keywords: Pain Periaqueductal gray Morphine Mu opioid receptor The influence of sex has been neglected in clinical studies on pain

  7. Safety of oral dronabinol during opioid withdrawal in humans.

    Science.gov (United States)

    Jicha, Crystal J; Lofwall, Michelle R; Nuzzo, Paul A; Babalonis, Shanna; Elayi, Samy Claude; Walsh, Sharon L

    2015-12-01

    Opioid dependence remains a significant public health problem worldwide with only three FDA-approved treatments, all targeting the mu-opioid receptor. Dronabinol, a cannabinoid (CB) 1 receptor agonist, is currently under investigation as a novel opioid withdrawal treatment. This study reports on safety outcomes of dronabinol among adults in opioid withdrawal. Twelve adults physically dependent on short-acting opioids participated in this 5-week within-subject, randomized, double blind, placebo-controlled inpatient study. Volunteers were maintained on oral oxycodone 30 mg qid. Double-blind placebo substitutions occurred for 21 h before each of 7 experimental sessions in order to produce opioid withdrawal. A single oral test dose was administered each session (placebo, oxycodone 30 and 60 mg, dronabinol 5, 10, 20, and 30 mg [decreased from 40 mg]). Heart rate, blood pressure, respiratory outcomes and pupil diameter were assessed repeatedly. Dronabinol 40 mg produced sustained sinus tachycardia accompanied by anxiety and panic necessitating dose reduction to 30 mg. Sinus tachycardia and anxiety also occurred in one volunteer after dronabinol 20mg. Compared to placebo, dronabinol 20 and 30 mg produced significant increases in heart rate beginning 1h after drug administration that lasted approximately 2h (popioid agonist effects (e.g., miosis). Dronabinol 20mg and higher increased heart rate among healthy adults at rest who were in a state of opioid withdrawal, raising concern about its safety. These results have important implications for future dosing strategies and may limit the utility of dronabinol as a treatment for opioid withdrawal. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  8. Is there a role for opioids in the treatment of fibromyalgia?

    Science.gov (United States)

    Littlejohn, Geoffrey O; Guymer, Emma K; Ngian, Gene-Siew

    2016-05-01

    The use of opioids for chronic pain has increased significantly due to a combination of the high patient burden of pain and the more widespread availability of a range of long-acting opioid preparations. This increased opioid use has translated into the care of many patients with fibromyalgia. The pain mechanism in fibromyalgia is complex but does not seem to involve disturbance of opioid analgesic functions. Hence, there is general concern about the harms in the absence of benefits of opioids in this setting. There is no evidence that pure opioids are effective in fibromyalgia but there is some evidence that opioids with additional actions on the norepinephrine-related pain modulatory pathways, such as tramadol, can be clinically useful in some patients. Novel actions of low-dose opioid antagonists may lead to better understanding of the role of opioid function in fibromyalgia.

  9. Diversity-oriented peptide stapling

    DEFF Research Database (Denmark)

    Tran, Thu Phuong; Larsen, Christian Ørnbøl; Røndbjerg, Tobias

    2017-01-01

    as a powerful method for peptide stapling. However, to date CuAAC stapling has not provided a simple method for obtaining peptides that are easily diversified further. In the present study, we report a new diversity-oriented peptide stapling (DOPS) methodology based on CuAAC chemistry. Stapling of peptides...

  10. A nationwide pharmacy chain responds to the opioid epidemic.

    Science.gov (United States)

    Shafer, Emily; Bergeron, Nyahne; Smith-Ray, Renae; Robson, Chester; O'Koren, Rachel

    To describe the 3-pronged approach taken by a large national retail pharmacy chain to address the opioid epidemic and associated overdoses. Large national retail pharmacy chain with more than 8200 stores in 50 states. Eight million customer interactions daily through in-store and digital settings. This is a company with a long history of responding to public health crises. Initiated 3 programs to respond to the opioid crisis: 1) provide safe medication disposal kiosks; 2) expand national access to naloxone; and 3) provide education on the risk and avoidance of opioid overdose. Used the RE-AIM framework to evaluate and enhance the quality, speed, and public health impact of the interventions. Not applicable. Early results are safe medication disposal kiosks in more than 43 states, naloxone-dispensing program in 33 states, and patient and support system education using the Opioid Overdose Toolkit from the Substance Abuse and Mental Health Services Administration. The availability of safe drug-disposal kiosks, naloxone dispensing at pharmacies, and patient education are key prevention initiatives to address the opioid epidemic and reduce the increasing national burden of opioid overdose. Early results are quantitatively and qualitatively promising. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  11. Preventing Opioid Use Disorders among Fishing Industry Workers

    Directory of Open Access Journals (Sweden)

    Angela Wangari Walter

    2018-03-01

    Full Text Available Fishing industry workers are at high risk for work-related musculoskeletal disorders (MSDs and injuries. Prescription opioids used to treat pain injuries may put these workers at increased risk for developing substance disorders. Using a Community-Based Participatory Research approach, formative research was conducted to inform the eventual development of relevant interventions to prevent and reduce opioid use disorders among fishing industry workers. Qualitative interviews (n = 21 were conducted to assess: knowledge and attitudes about opioid use disorders; features of fishing work that might affect use and/or access to treatment; and community and organizational capacity for prevention and treatment. Participants reported numerous pathways connecting commercial fishing with opioid use. The combination of high stress and physically tasking job duties requires comprehensive workplace interventions to prevent chronic pain and MSDs, in addition to tailored and culturally responsive treatment options to address opioid use disorders in this population. Public health programs must integrate workplace health and safety protection along with evidence-based primary, secondary, and tertiary interventions in order to address opioid use disorders, particularly among workers in strenuous jobs.

  12. Clinical implications of patient-provider agreements in opioid prescribing.

    Science.gov (United States)

    Kraus, Carl N; Baldwin, Alan T; Curro, Frederick A; McAllister, R G

    2015-01-01

    In June, 2012 the United States Food and Drug Administration (FDA) developed a "blueprint" for prescriber education as a means of directing Certified Medical Education (CME) activities that included content which would meet the regulatory requirements of the class-wide, longacting/ extended-release (LA-ER) opioid Risk Evaluation Mitigation Strategies (REMS). Within the blueprint is the suggested adoption of Patient-Provider Agreements (PPAs) to be used in association with opioid prescribing, but, to our knowledge, there have been no reported evaluations of the role played by opioid-agent PPAs in clinical practice, or of the perceptions of this regulatory mandate by clinicians. Therefore, we conducted a survey regarding PPA perceptions by opioid prescribers that was posted for five weeks on a well-trafficked online CME service provider (Medscape). Of the 1,232 respondents (reflecting a 99.5% completion rate), 52.4% treat acute or chronic pain with opioids. The survey identified an improvement of opioid safe-use education (21% of respondents) as the most frequently selected beneficial element of PPAs. Conversely, the challenges to adoption included time constraints (21% of physicians) as well as lack of evidence that PPAs will reduce drug misuse, and the lack of a uniform, patient-friendly PPA. Based on our survey, clinicians consider the PPA of potential value, but data regarding the utility of such an instrument are lacking.

  13. Reviewing opioid use, monitoring, and legislature: Nursing perspectives

    Directory of Open Access Journals (Sweden)

    Deniece A. Jukiewicz

    2017-10-01

    Full Text Available The phenomena of prescription opioid misuse and abuse have a complicated history of contributing factors including policies, practices, and prescribing leading to contemporary phenomena. Some factors implicated in the opioid drug abuse problem include inefficient prescribing and improper use, lack of knowledge related to interpretation and assessment of pain levels, and decreased oversight and regulation from government and policy agents. Nurses, often frontline providers, need to be knowledgeable and embrace the guidelines, and necessary implications associated with both prescribing and administration of opioids. Additionally, all providers including physicians, physician assistants, nurse practitioners, and bedside nurses must have a firm understanding of the improper use and abuse of opioids. The examination and review of opioid policies at the state and federal level has revealed inconsistency with regulations, policies, and guidelines that have lead to the current situation. The use of an interdisciplinary team with nurses and various other practitioners is a good strategy to help reduce this problem. Keywords: Abuse, Administration, Legislature, Nursing, Opioid, Overdose, Policy, Prescribing

  14. Preference or fat? Revisiting opioid effects on food intake.

    Science.gov (United States)

    Taha, Sharif A

    2010-07-14

    It is well established that opioid signaling in the central nervous system constitutes a powerful stimulus for food intake. The role of opioids in determining food preference, however, is less well defined. Opioids have been proposed to promote intake of preferred foods, or, alternatively, to preferentially increase consumption of fat. In the present manuscript, I comprehensively review results from previous studies investigating this issue. Data from these studies suggests a mechanism for opioid action that may reconcile the previously proposed hypotheses: opioid effects on food intake do appear to be largely specific for fat consumption, but individual animals' sensitivity to this effect may be dependent on baseline food preferences. In addition, I highlight the possibility that the selectivity of endogenous opioid effects may importantly differ from that of exogenous agonists in the degree to which baseline preferences, rather than macronutrient intake, are altered. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009. 2010 Elsevier Inc. All rights reserved.

  15. Yiguanjian cataplasm attenuates opioid dependence in a mouse

    Science.gov (United States)

    Gao, Shuai; Gao, Hong; Fan, Yuchen; Zhang, Guanghua; Sun, Fengkai; Zhao, Jing; Li, Feng; Yang, Yang; Wang, Kai

    2016-08-01

    To investigate the effect of Yiguanjian (YGJ) cataplasm on the development of opioid dependence in a mouse model of naloxone-induced opioid withdrawal syndrome. One hundred Swiss albino mice, of equal male to female ratio, were randomly and equally divided into 10 groups. A portion (3 cm2) of the backside hair of the mice was removed 1 day prior to the experiment. Morphine (5 mg/kg) was intraperitoneally administered twice daily for 5 days. YGJ cataplasm was prepared and pasted on the bare region of the mice immediately before morphine administration on day 3 and subsequently removed at the end day 5. On day 6, naloxone (8 mg/kg) was intraperitoneally injected to precipitate opioid withdrawal syndrome. Behavioral observation was performed in two 30-min phases immediately after naloxone injection. The YGJ cataplasm significantly and dose-dependently attenuated morphine-naloxone- induced experimental opioid withdrawal, in terms of withdrawal severity score and the frequencies of jumping, rearing, forepaw licking, and circling behaviors. However, YGJ cataplasm treatment did not alter the acute analgesic effect of morphine. YGJ cataplasm could attenuate opioid dependence and its associated withdrawal symptoms. Therefore, YGJ cataplasm could serve as a potential therapy for opioid addiction in the future.

  16. Pavlovian conditioning of multiple opioid-like responses in mice.

    Science.gov (United States)

    Bryant, Camron D; Roberts, Kristofer W; Culbertson, Christopher S; Le, Alan; Evans, Christopher J; Fanselow, Michael S

    2009-07-01

    Conditional responses in rodents such as locomotion have been reported for drugs of abuse and similar to the placebo response in humans, may be associated with the expectation of reward. We examined several conditional opioid-like responses and the influence of drug expectation on conditioned place preference and concomitant conditional locomotion. Male C57BL/6J mice were conditioned with the selective mu opioid receptor agonist fentanyl (0.2mg/kg, i.p.) in a novel context and subsequently given a vehicle injection. In separate experiments, locomotor activity, Straub tail, hot plate sensitivity, and conditioned place preference (CPP) were measured. Mice exhibited multiple conditional opioid-like responses including conditional hyperlocomotion, a conditional pattern of opioid-like locomotion, Straub tail, analgesia, and place preference. Modulating drug expectation via administration of fentanyl to "demonstrator" mice in the home cage did not affect the expression of conditioned place preference or the concomitant locomotor activity in "observer" mice. In summary, Pavlovian conditioning of an opioid in a novel context induced multiple conditional opioid-like behaviors and provides a model for studying the neurobiological mechanisms of the placebo response in mice.

  17. Peptide secretion in the cutaneous glands of South American tree frog Phyllomedusa bicolor: an ultrastructural study.

    Science.gov (United States)

    Lacombe, C; Cifuentes-Diaz, C; Dunia, I; Auber-Thomay, M; Nicolas, P; Amiche, M

    2000-09-01

    The development of the dermal glands of the arboreal frog Phyllomedusa bicolor was investigated by immunocytochemistry and electron microscopy. The 3 types of glands (mucous, lipid and serous) differed in size and secretory activity. The mucous and serous glands were apparent in the tadpole skin, whereas the lipid glands developed later in ontogenesis. The peptide antibiotics dermaseptins and the D-amino acid-containing peptide opioids dermorphins and deltorphins are abundant in the skin secretions of P. bicolor. Although these peptides differ in their structure and activity they are derived from precursors that have very similar preproregions. We used an antibody to the common preproregion of preprodermaseptins and preprodeltorphins and immunofluorescence analysis to show that only the serous glands are specifically involved in the biosynthesis and secretion of dermaseptins and deltorphins. Scanning and transmission electron microscopy revealed that the serous glands of P bicolor have morphological features, especially the secretory granules, which differ from those of the glands in Xenopus laevis skin.

  18. Healthcare resource use and costs of opioid-induced constipation among non-cancer and cancer patients on opioid therapy

    DEFF Research Database (Denmark)

    Søndergaard, Jens; Christensen, Helene Nordahl; Ibsen, Rikke

    2017-01-01

    -based cohort study including patients ≥18 years of age initiating ≥4 weeks opioid therapy (1998–2012) in Denmark. A measure of OIC was constructed based on data from Danish national health registries, and defined as ≥1 diagnosis of constipation, diverticulitis, mega colon, ileus/subileus, abdominal pain....../acute abdomen or haemorrhoids and/or ≥2 subsequent prescription issues of laxatives. Total healthcare resource utilization and costs (including pharmacy dispense, inpatient-, outpatient-, emergency room- and primary care) were estimated according to OIC status, opioid treatment dosage and length, gender, age...... characteristics of non-cancer OIC patients showed a higher frequency of strong opioid treatment (69% versus 41%), long-term opioid treatment (1189 days versus 584 days), advanced age (73 years versus 61 years), and cardiovascular disease (31% versus 19%) compared to those without OIC (P 

  19. Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study.

    Directory of Open Access Journals (Sweden)

    Tara Gomes

    2017-10-01

    Full Text Available Prescription opioid use is highly associated with risk of opioid-related death, with 1 of every 550 chronic opioid users dying within approximately 2.5 years of their first opioid prescription. Although gabapentin is widely perceived as safe, drug-induced respiratory depression has been described when gabapentin is used alone or in combination with other medications. Because gabapentin and opioids are both commonly prescribed for pain, the likelihood of co-prescription is high. However, no published studies have examined whether concomitant gabapentin therapy is associated with an increased risk of accidental opioid-related death in patients receiving opioids. The objective of this study was to investigate whether co-prescription of opioids and gabapentin is associated with an increased risk of accidental opioid-related mortality.We conducted a population-based nested case-control study among opioid users who were residents of Ontario, Canada, between August 1, 1997, and December 31, 2013, using administrative databases. Cases, defined as opioid users who died of an opioid-related cause, were matched with up to 4 controls who also used opioids on age, sex, year of index date, history of chronic kidney disease, and a disease risk index. After matching, we included 1,256 cases and 4,619 controls. The primary exposure was concomitant gabapentin use in the 120 days preceding the index date. A secondary analysis characterized gabapentin dose as low (<900 mg daily, moderate (900 to 1,799 mg daily, or high (≥1,800 mg daily. A sensitivity analysis examined the effect of concomitant nonsteroidal anti-inflammatory drug (NSAID use in the preceding 120 days. Overall, 12.3% of cases (155 of 1,256 and 6.8% of controls (313 of 4,619 were prescribed gabapentin in the prior 120 days. After multivariable adjustment, co-prescription of opioids and gabapentin was associated with a significantly increased odds of opioid-related death (odds ratio [OR] 1.99, 95% CI

  20. PNA Peptide chimerae

    DEFF Research Database (Denmark)

    Koch, T.; Næsby, M.; Wittung, P.

    1995-01-01

    Radioactive labelling of PNA has been performed try linking a peptide segment to the PNA which is substrate for protein kinase A. The enzymatic phosphorylation proceeds in almost quantitative yields....

  1. Tumor penetrating peptides

    Directory of Open Access Journals (Sweden)

    Tambet eTeesalu

    2013-08-01

    Full Text Available Tumor-homing peptides can be used to deliver drugs into tumors. Phage library screening in live mice has recently identified homing peptides that specifically recognize the endothelium of tumor vessels, extravasate, and penetrate deep into the extravascular tumor tissue. The prototypic peptide of this class, iRGD (CRGDKGPDC, contains the integrin-binding RGD motif. RGD mediates tumor homing through binding to αv integrins, which are selectively expressed on various cells in tumors, including tumor endothelial cells. The tumor-penetrating properties of iRGD are mediated by a second sequence motif, R/KXXR/K. This C-end Rule (or CendR motif is active only when the second basic residue is exposed at the C-terminus of the peptide. Proteolytic processing of iRGD in tumors activates the cryptic CendR motif, which then binds to neuropilin-1 activating an endocytic bulk transport pathway through tumor tissue. Phage screening has also yielded tumor-penetrating peptides that function like iRGD in activating the CendR pathway, but bind to a different primary receptor. Moreover, novel tumor-homing peptides can be constructed from tumor-homing motifs, CendR elements and protease cleavage sites. Pathologies other than tumors can be targeted with tissue-penetrating peptides, and the primary receptor can also be a vascular zip code of a normal tissue. The CendR technology provides a solution to a major problem in tumor therapy, poor penetration of drugs into tumors. The tumor-penetrating peptides are capable of taking a payload deep into tumor tissue in mice, and they also penetrate into human tumors ex vivo. Targeting with these peptides specifically increases the accumulation in tumors of a variety of drugs and contrast agents, such as doxorubicin, antibodies and nanoparticle-based compounds. Remarkably the drug to be targeted does not have to be coupled to the peptide; the bulk transport system activated by the peptide sweeps along any compound that is

  2. Characteristics of opioid-users whose death was related to opioid-toxicity: a population-based study in Ontario, Canada.

    Directory of Open Access Journals (Sweden)

    Parvaz Madadi

    Full Text Available The impact of the prescription opioid public health crisis has been illustrated by the dramatic increase in opioid-related deaths in North America. We aimed to identify patterns and characteristics amongst opioid-users whose cause of death was related to opioid toxicity.This was a population-based study of Ontarians between the years 2006 and 2008. All drug-related deaths which occurred during this time frame were reviewed at the Office of the Chief Coroner of Ontario, and opioid-related deaths were identified. Medical, toxicology, pathology, and police reports were comprehensively reviewed. Narratives, semi-quantitative, and quantitative variables were extracted, tabulated, and analyzed.Out of 2330 drug-related deaths in Ontario, 58% were attributed either in whole or in part, to opioids (n = 1359. Oxycodone was involved in approximately one-third of all opioid-related deaths. At least 7% of the entire cohort used opioids that were prescribed for friends and/or family, 19% inappropriately self-administered opioids (injection, inhalation, chewed patch, 3% were recently released from jail, and 5% had been switched from one opioid to another near the time of death. Accidental deaths were significantly associated with personal history of substance abuse, enrollment in methadone maintenance programs, cirrhosis, hepatitis, and cocaine use. Suicides were significantly associated with mental illness, previous suicide attempts, chronic pain, and a history of cancer.These results identify novel, susceptible groups of opioid-users whose cause of death was related to opioids in Ontario and provide the first evidence to assist in quantifying the contribution of opioid misuse and diversion amongst opioid-related mortality in Canada. Multifaceted prevention strategies need to be developed based on subpopulations of opioid users.

  3. Nurses and opioids: results of a bi-national survey on mental models regarding opioid administration in hospitals.

    Science.gov (United States)

    Guest, Charlotte; Sobotka, Fabian; Karavasopoulou, Athina; Ward, Stephen; Bantel, Carsten

    2017-01-01

    Pain remains insufficiently treated in hospitals. Increasing evidence suggests human factors contribute to this, due to nurses failing to administer opioids. This behavior might be the consequence of nurses' mental models about opioids. As personal experience and conceptions shape these models, the aim of this prospective survey was to identify model-influencing factors. A questionnaire was developed comprising of 14 statements concerning ideations about opioids and seven questions concerning demographics, indicators of adult learning, and strength of religious beliefs. Latent variables that may underlie nurses' mental models were identified using undirected graphical dependence models. Representative items of latent variables were employed for ordinal regression analysis. Questionnaires were distributed to 1,379 nurses in two London, UK, hospitals (n=580) and one German (n=799) hospital between September 2014 and February 2015. A total of 511 (37.1%) questionnaires were returned. Mean (standard deviation) age of participants were 37 (11) years; 83.5% participants were female; 45.2% worked in critical care; and 51.5% had more than 10 years experience. Of the nurses, 84% were not scared of opioids, 87% did not regard opioids as drugs to help patients die, and 72% did not view them as drugs of abuse. More English (41%) than German (28%) nurses were afraid of criminal investigations and were constantly aware of side effects (UK, 94%; Germany, 38%) when using opioids. Four latent variables were identified which likely influence nurses' mental models: "conscious decision-making"; "medication-related fears"; "practice-based observations"; and "risk assessment". They were predicted by strength of religious beliefs and indicators of informal learning such as experience but not by indicators of formal learning such as conference attendance. Nurses in both countries employ analytical and affective mental models when administering the opioids and seem to learn from experience

  4. Pleiotropic opioid regulation of spinal endomorphin 2 release and its adaptations to opioid withdrawal are sexually dimorphic.

    Science.gov (United States)

    Chakrabarti, Sumita; Liu, Nai-Jiang; Zadina, James E; Sharma, Tarak; Gintzler, Alan R

    2012-01-01

    We studied adaptations to acute precipitated opioid withdrawal of spinal μ-opioid receptor (MOR)-coupled regulation of the release of endomorphin 2 (EM2). The release of this highly MOR-selective endogenous opioid from opioid-naive spinal tissue of male rats is subjected to MOR-coupled positive as well as negative modulation via cholera toxin-sensitive G(s) and pertussis toxin-sensitive G(i)/G(o), respectively. The net effect of this concomitant bidirectional modulation is inhibitory. MOR-coupled pleiotropic regulation of EM2 release is retained in opioid-withdrawn spinal tissue of male rats, but the balance of MOR-coupled inhibitory and facilitatory regulation shifted such that facilitatory regulation predominates. Augmented coupling of MOR to G(s) is causally associated with this change. Strikingly, pleiotropic characteristics of MOR-coupled regulation of spinal EM2 release and adaptations thereof to opioid withdrawal are male-specific. In females, MOR-coupled regulation of EM2 release from opioid-naive and -withdrawn spinal tissue does not have a significant G(s)-coupled facilitatory component, and MOR-coupled inhibition of EM2 release persists unabated in withdrawn preparations. The male-specific adaptations to chronic morphine that shift the relative predominance of opposing dual G protein-coupled MOR pathways provides a mechanism for mitigating inhibitory MOR signaling without losing MOR-coupled feedback regulation. These adaptations enable using endogenous EM2 as a substitute for morphine that had been precipitously removed. The sexually dimorphic functionality and regulation of spinal EM2/MOR-coupled signaling suggest the clinical utility of using sex-specific treatments for addiction that harness the activity of endogenous opioids.

  5. beta. -Endorphin and related peptides suppress phorbol myristate acetate-induced respiratory burst in human polymorphonuclear leukocytes

    Energy Technology Data Exchange (ETDEWEB)

    Diamant, M.; Henricks, P.A.J.; Nijkamp, F.P.; de Wied, D. (Univ. of Utrecht (Netherlands))

    1989-01-01

    In the present study, the immunomodulatory effect of {beta}-endorphin ({beta}-E) and shorter pro-opiomelancortin (POMC) fragments was evaluated by assessing their influence on respiratory burst in human polymorphonuclear leukocytes (PMN). The effect of the peptides on phorbol myristate acetate (PMA)-stimulated production of reactive oxygen metabolites was measured in a lucigenin-enhanced chemiluminescence (CL) assay. Both POMC peptides with opiate-like activity and their non-opioid derivatives were tested. With the exception of {alpha}-E, PMA-stimulated respiratory burst was suppressed by all POMC fragments tested. A U-shaped dose-response relation was observed. Doses lower than 10{sup {minus}17}M and higher than 10{sup {minus}8}M were without effect. {beta}-E and dT{beta}E both suppressed PMA-induced oxidative burst in human PMN at physiological concentrations. {gamma}-E and dT{gamma}E proved to be less potent inhibitors, reaching maximal effect at higher concentrations. DE{gamma}E exerted an even less pronounced but still significant suppressive effect at the concentration of 10{sup {minus}10}M. None of the endorphins tested was shown to affect resting oxidative metabolism in the PMN. The modulatory effects of the opioid peptides could not be blocked by the opioid antagonist naloxone.

  6. Undertreatment of pain and low use of opioids in Latin America.

    Science.gov (United States)

    García, César Amescua; Santos Garcia, Joao Batista; Rosario Berenguel Cook, María Del; Colimon, Frantz; Flores Cantisani, José Alberto; Guerrero, Carlos; Rocío Guillén Núnez, María Del; Hernández Castro, John Jairo; Kraychete, Durval Campos; Lara-Solares, Argelia; Lech, Osvandré; Rico Pazos, María Antonieta; Gallegos, Manuel Sempértegui; Marcondes, Lizandra Pattaro

    2018-05-01

    Pain is highly prevalent among the adult Latin American population. However, many patients with moderate to severe pain do not have access to effective pain management with opioids due to limited access to healthcare, overuse of nonopioid analgesics, regulatory barriers and lack of appropriate information about opioids. There is scarce training on use of opioids among physicians and other healthcare providers, which leads to misconceptions, mainly related to a fear of prescribing opioids. Although opioids are safe and effective drugs for the treatment of moderate to severe chronic pain, the use of opioids in Latin American nations is clearly below standards compared with developed countries.

  7. Peptide aldehyde inhibitors of bacterial peptide deformylases.

    Science.gov (United States)

    Durand, D J; Gordon Green, B; O'Connell, J F; Grant, S K

    1999-07-15

    Bacterial peptide deformylases (PDF, EC 3.5.1.27) are metalloenzymes that cleave the N-formyl groups from N-blocked methionine polypeptides. Peptide aldehydes containing a methional or norleucinal inhibited recombinant peptide deformylase from gram-negative Escherichia coli and gram-positive Bacillus subtilis. The most potent inhibitor was calpeptin, N-CBZ-Leu-norleucinal, which was a competitive inhibitor of the zinc-containing metalloenzymes, E. coli and B. subtilis PDF with Ki values of 26.0 and 55.6 microM, respectively. Cobalt-substituted E. coli and B. subtilis deformylases were also inhibited by these aldehydes with Ki values for calpeptin of 9.5 and 12.4 microM, respectively. Distinct spectral changes were observed upon binding of calpeptin to the Co(II)-deformylases, consistent with the noncovalent binding of the inhibitor rather than the formation of a covalent complex. In contrast, the chelator 1,10-phenanthroline caused the time-dependent inhibition of B. subtilis Co(II)-PDF activity with the loss of the active site metal. The fact that calpeptin was nearly equipotent against deformylases from both gram-negative and gram-positive bacterial sources lends further support to the idea that a single deformylase inhibitor might have broad-spectrum antibacterial activity. Copyright 1999 Academic Press.

  8. Opioid mediated activity and expression of mu and delta opioid receptors in isolated human term non-labouring myometrium.

    LENUS (Irish Health Repository)

    Fanning, Rebecca A

    2013-01-05

    The existence of opioid receptors in mammalian myometrial tissue is now widely accepted. Previously enkephalin degrading enzymes have been shown to be elevated in pregnant rat uterus and a met-enkephalin analogue has been shown to alter spontaneous contractility of rat myometrium. Here we have undertaken studies to determine the effects of met-enkephalin on in vitro human myometrial contractility and investigate the expression of opioid receptors in pregnant myometrium. Myometrial biopsies were taken from women undergoing elective caesarean delivery at term. Organ bath experiments were used to investigate the effect of the met-enkephalin analogue [d-Ala 2, d-met 5] enkephalin (DAMEA) on spontaneous contractility. A confocal immunofluorescent technique and real time PCR were used to determine the expression of protein and mRNA, respectively for two opioid receptor subtypes, mu and delta. DAMEA had a concentration dependent inhibitory effect on contractile activity (1 × 10(-7)M-1 × 10(-4)M; 54% reduction in contractile activity, P<0.001 at 1 × 10(-4)M concentration). Mu and delta opioid receptor protein sub-types and their respective mRNA were identified in all tissues sampled. This is the first report of opioid receptor expression and of an opioid mediated uterorelaxant action in term human non-labouring myometrium in vitro.

  9. Experience of the use of Ketamine to manage opioid withdrawal in an addicted woman: a case report

    OpenAIRE

    Lalanne, Laurence; Nicot, Chloe; Lang, Jean-Philippe; Bertschy, Gilles; Salvat, Eric

    2016-01-01

    Background Opioids are good painkillers, but many patients treated with opioids as painkillers developed a secondary addiction. These patients need to stop misusing opioids, but the mild-to-severe clinical symptoms associated with opioid withdrawal risk increasing their existing pain. In such cases, ketamine, which is used by anaesthetists and pain physicians to reduce opioid medication, may be an effective agent for managing opioid withdrawal. Case presentation We describe the case of a woma...

  10. Melanocortin and Opioid Peptide Interactions in the Modulation of Binge Alcohol Drinking

    Science.gov (United States)

    2013-04-01

    Spain (June, 2010). Talk titled A Role for Central Neuropeptides in Binge Alcohol Drinking. 4. Departamento de Neurociencia y Ciencias de la Salud...Hill, Chapel Hill, North Carolina; Department of Neurociencia y Ciencias de la Salud (JML-C, FC, IC), University of Almerı́a, Almerı́a, Spain. Received...Low, 2008). From the Department of Neurociencia y Ciencias de la Salud (IC, FC, JML-C), University of Almerı́a, Almerı́a, Spain; and Department of

  11. Characteristics of prescribers whose patients shop for opioids: results from a cohort study.

    Science.gov (United States)

    Cepeda, M Soledad; Fife, Daniel; Berlin, Jesse A; Mastrogiovanni, Gregory; Yuan, Yingli

    2012-01-01

    Little is known about the prevalence of opioid shoppers in clinical practices and the relation between prescriber characteristics and the risk of having opioid shoppers. Describe the prevalence of opioid shoppers in prescribers' practices. Assess the relation between prescribers' characteristics and patient opioid shopping behavior. Retrospective cohort study using a large US retail prescription database. Patients with ≥1 opioid dispensing were followed 18 months. These patients' prescribers are the focus of the study. A patient was a "shopper" if he or she had opioid prescriptions written by ≥1 prescriber with ≥1 day of overlap filled at ≥3 pharmacies and a "heavy shopper" if he or she had ≥5 shopping episodes. The proportions of shoppers by prescriber and the proportion of prescribers with ≥1 shopper or heavy shopper were calculated. Among 858,290 opioid prescribers, most (87 percent) had no shoppers and 98 percent had no heavy shoppers. Prescribers who were aged 70-79 years, male, or who prescribed schedule II opioids had an increased likelihood of having shoppers. As the number of patients for whom a prescriber prescribed opioids increased, the proportion of shoppers also increased. Prescribers with 66 or more patients receiving opioids, who represented 25 percent of prescribers, prescribed for 82 percent of all shoppers. The great majority of opioid prescribers appear to have no shoppers in their practice. Any educational program will be more cost effective if targeted to prescribers of schedule II opioids with a large volume of patients requiring opioids.

  12. Advances in the delivery of buprenorphine for opioid dependence

    Directory of Open Access Journals (Sweden)

    Rosenthal RN

    2017-08-01

    Full Text Available Richard N Rosenthal,1 Viral V Goradia2 1Department of Psychiatry, Addiction Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, 2Department of Psychiatry, Upstate Medical University, Syracuse, NY, USA Abstract: Opioid use disorders (OUDs have long been a global problem, but the prevalence rates have increased over 20 years to epidemic proportions in the US, with concomitant increases in morbidity and all-cause mortality, but especially opioid overdose. These increases are in part attributable to a several-fold expansion in the prescription of opioid pain medications over the same time period. Opioid detoxification and psychosocial treatments alone have each not yielded sufficient efficacy for OUD, but μ-opioid receptor agonist, partial agonist, and antagonist medications have demonstrated the greatest overall benefit in OUD treatment. Buprenorphine, a μ-opioid receptor partial agonist, has been used successfully on an international basis for several decades in sublingual tablet and film preparations for the treatment of OUD, but the nature of formulation, which is typically self-administered, renders it susceptible to nonadherence, diversion, and accidental exposure. This article reviews the clinical trial data for novel buprenorphine delivery systems in the form of subcutaneous depot injections, transdermal patches, and subdermal implants for the treatment of OUD and discusses both the clinical efficacy of longer-acting formulations through increasing consistent medication exposure and their potential utility in reducing diversion. These new delivery systems also offer new dosing opportunities for buprenorphine and strategies for dosing intervals in the treatment of OUD. Keywords: opioid use disorder, buprenorphine, drug diversion, drug implants, depot medications, maintenance therapy, treatment adherence

  13. Review of Opioid Pharmacogenetics and Considerations for Pain Management.

    Science.gov (United States)

    Owusu Obeng, Aniwaa; Hamadeh, Issam; Smith, Michael

    2017-09-01

    Opioid analgesics are the standards of care for the treatment of moderate to severe nociceptive pain, particularly in the setting of cancer and surgery. Their analgesic properties mainly emanate from stimulation of the μ receptors, which are encoded by the OPRM1 gene. Hepatic metabolism represents the major route of elimination, which, for some opioids, namely codeine and tramadol, is necessary for their bioactivation into more potent analgesics. The highly polymorphic nature of the genes coding for phase I and phase II enzymes (pharmacokinetics genes) that are involved in the metabolism and bioactivation of opioids suggests a potential interindividual variation in their disposition and, most likely, response. In fact, such an association has been substantiated in several pharmacokinetic studies described in this review, in which drug exposure and/or metabolism differed significantly based on the presence of polymorphisms in these pharmacokinetics genes. Furthermore, in some studies, the observed variability in drug exposure translated into differences in the incidence of opioid-related adverse effects, particularly nausea, vomiting, constipation, and respiratory depression. Although the influence of polymorphisms in pharmacokinetics genes, as well as pharmacodynamics genes (OPRM1 and COMT) on response to opioids has been a subject of intense research, the results have been somehow conflicting, with some evidence insinuating for a potential role for OPRM1. The Clinical Pharmacogenetics Implementation Consortium guidelines provide CYP2D6-guided therapeutic recommendations to individualize treatment with tramadol and codeine. However, implementation guidelines for other opioids, which are more commonly used in real-world settings for pain management, are currently lacking. Hence, further studies are warranted to bridge this gap in our knowledge base and ultimately ascertain the role of pharmacogenetic markers as predictors of response to opioid analgesics. © 2017

  14. Impact of opioid therapy on gonadal hormones: focus on buprenorphine.

    Science.gov (United States)

    Varma, Anjali; Sapra, Mamta; Iranmanesh, Ali

    2018-02-17

    Objective The USA is in the midst of an opioid crisis. Understanding the impact of opioids and commonly used treatments for opioid dependence is essential for clinicians and researchers in order to educate and treat the nation's growing population with opioid use disorders. As a relatively new treatment for opioid dependence, buprenorphine is gaining popularity to the extent of becoming not only a preferred approach to the maintenance of opiate addiction, but also an option for chronic pain management. The purpose of this report is to review the available evidence on the endocrine effects of buprenorphine, particularly as it relates to the hypothalamic-pituitary-gonadal (HPG) axis, which is controversial and not fully defined. Method We conducted a Pubmed search (2000-2017) for human studies in the English language for articles that were available as full length regarding buprenorphine, endocrinopathy, hypogonadism, bone density, opioids. Case reports were also reviewed, although prospective studies and randomized controlled trials received more weight. Results Opioid induced hypogonadism is well established. Most studies report that buprenorphine being a partial agonist/antagonist may not be impacting the pituitary trophic hormones as much. There are reports of sexual dysfunction in subjects maintained on buprenorphine, some without hormonal correlation. Thus with the understanding that pertinent clinical studies are limited in number, varied in methodology, mostly cross sectional, predominantly in men and small number of participants, more research in this area is warranted. Conclusion Based on a comprehensive review of the available literature, we conclude that despite its increasing popularity, buprenorphine has not been adequately studied in respect to its long-term effects on the hypothalamic-pituitary-adrenal (HPA) axis. There is a great need for longitudinal systematic trials to define the potential buprenorphine-induced endocrine consequences.

  15. A Conceptual Framework for Understanding Unintended Prolonged Opioid Use.

    Science.gov (United States)

    Hooten, W Michael; Brummett, Chad M; Sullivan, Mark D; Goesling, Jenna; Tilburt, Jon C; Merlin, Jessica S; St Sauver, Jennifer L; Wasan, Ajay D; Clauw, Daniel J; Warner, David O

    2017-12-01

    An urgent need exists to better understand the transition from short-term opioid use to unintended prolonged opioid use (UPOU). The purpose of this work is to propose a conceptual framework for understanding UPOU that posits the influence of 3 principal domains that include the characteristics of (1) individual patients, (2) the practice environment, and (3) opioid prescribers. Although no standardized method exists for developing a conceptual framework, the process often involves identifying corroborative evidence, leveraging expert opinion to identify factors for inclusion in the framework, and developing a graphic depiction of the relationships between the various factors and the clinical problem of interest. Key patient characteristics potentially associated with UPOU include (1) medical and mental health conditions; (2) pain etiology; (3) individual affective, behavioral, and neurophysiologic reactions to pain and opioids; and (4) sociodemographic factors. Also, UPOU could be influenced by structural and health care policy factors: (1) the practice environment, including the roles of prescribing clinicians, adoption of relevant practice guidelines, and clinician incentives or disincentives, and (2) the regulatory environment. Finally, characteristics inherent to clinicians that could influence prescribing practices include (1) training in pain management and opioid use; (2) personal attitudes, knowledge, and beliefs regarding the risks and benefits of opioids; and (3) professionalism. As the gatekeeper to opioid access, the behavior of prescribing clinicians directly mediates UPOU, with the 3 domains interacting to determine this behavior. This proposed conceptual framework could guide future research on the topic and allow plausible hypothesis-based interventions to reduce UPOU. Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

  16. Variability in prescription opioid intake and reinforcement amongst 129 substrains.

    Science.gov (United States)

    Jimenez, S M; Healy, A F; Coelho, M A; Brown, C N; Kippin, T E; Szumlinski, K K

    2017-09-01

    Opioid abuse in the United States has reached epidemic proportions, with treatment admissions and deaths associated with prescription opioid abuse quadrupling over the past 10 years. Although genetics are theorized to contribute substantially to inter-individual variability in the development, severity and treatment outcomes of opioid abuse/addiction, little direct preclinical study has focused on the behavioral genetics of prescription opioid reinforcement and drug-taking. Herein, we employed different 129 substrains of mice currently available from The Jackson Laboratory (129S1/SvlmJ, 129X1/SvJ, 129S4/SvJaeJ and 129P3/J) as a model system of genetic variation and assayed mice for oral opioid intake and reinforcement, as well as behavioral and somatic signs of dependence. All substrains exhibited a dose-dependent increase in oral oxycodone and heroin preference and intake under limited-access procedures and all, but 129S1/SvlmJ mice, exhibited oxycodone reinforcement. Relative to the other substrains, 129P3/J mice exhibited higher heroin and oxycodone intake. While 129X1/SvJ exhibited the highest anxiety-like behavior during natural opioid withdrawal, somatic and behavior signs of precipitated withdrawal were most robust in 129P3/J mice. These results demonstrate the feasibility and relative sensitivity of our oral opioid self-administration procedures for detecting substrain differences in drug reinforcement/intake among 129 mice, of relevance to the identification of genetic variants contributing to high vs. low oxycodone reinforcement and intake. © 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  17. Growth hormone-releasing peptides.

    Science.gov (United States)

    Ghigo, E; Arvat, E; Muccioli, G; Camanni, F

    1997-05-01

    Growth hormone-releasing peptides (GHRPs) are synthetic, non-natural peptides endowed with potent stimulatory effects on somatotrope secretion in animals and humans. They have no structural homology with GHRH and act via specific receptors present either at the pituitary or the hypothalamic level both in animals and in humans. The GHRP receptor has recently been cloned and, interestingly, it does not show sequence homology with other G-protein-coupled receptors known so far. This evidence strongly suggests the existence of a natural GHRP-like ligand which, however, has not yet been found. The mechanisms underlying the GHRP effect are still unclear. At present, several data favor the hypothesis that GHRPs could act by counteracting somatostatinergic activity both at the pituitary and the hypothalamic level and/or, at least partially, via a GHRH-mediated mechanism. However, the possibility that GHRPs act via an unknown hypothalamic factor (U factor) is still open. GHRP-6 was the first hexapeptide to be extensively studied in humans. More recently, a heptapeptide, GHRP-1, and two other hexapeptides, GHRP-2 and Hexarelin, have been synthesized and are now available for human studies. Moreover, non-peptidyl GHRP mimetics have been developed which act via GHRP receptors and their effects have been clearly demonstrated in animals and in humans in vivo. Among non-peptidyl GHRPs, MK-0677 seems the most interesting molecule. The GH-releasing activity of GHRPs is marked and dose-related after intravenous, subcutaneous, intranasal and even oral administration. The effect of GHRPs is reproducible and undergoes partial desensitization, more during continuous infusion, less during intermittent administration: in fact, prolonged administration of GHRPs increases IGF-1 levels both in animals and in humans. The GH-releasing effect of GHRPs does not depend on sex but undergoes age-related variations. It increases from birth to puberty, persists at a similar level in adulthood and

  18. Responses of proenkephalin Peptide F to aerobic exercise stress in the plasma and white blood cell biocompartments.

    Science.gov (United States)

    Kraemer, William J; Fragala, Maren S; van Henegouwen, Wendy R H Beijersbergen; Gordon, Scott E; Bush, Jill A; Volek, Jeff S; Triplett, N Travis; Dunn-Lewis, Courtenay; Comstock, Brett A; Szivak, Tunde K; Flanagan, Shawn D; Hooper, David R; Luk, Hui-Ying; Mastro, Andrea M

    2013-04-01

    Proenkephalin Peptide F [107-140] is an enkephalin-containing peptide found predominantly within the adrenal medulla, co-packaged with epinephrine within the chromaffin granules. In vivo studies indicate that Peptide F has classic opioid analgesia effects; in vitro studies suggest potential immune cell interactions. In this investigation we examined patterns of Peptide F concentrations in different bio-compartments of the blood at rest and following sub-maximal cycle exercise to determine if Peptide F interacts with the white blood cell (WBC) bio-compartment during aerobic exercise. Eight physically active men (n=8) performed sub-maximal (80-85% V˙O2peak) cycle ergometer exercise for 30 min. Plasma Peptide F and WBC Peptide F immunoreactivity were examined pre-exercise, mid-exercise and immediately post-, 5-min post-, 15-min post-, 30-min post- and 60-min post-exercise and at similar time-points during a control condition (30 min rest). Peptide F concentrations significantly (pexercise, compared to pre-exercise concentrations. No significant increases in Peptide F concentrations in the WBC fraction were observed during or after exercise. However, a significant decrease was observed at 30 min post-exercise. An ultradian pattern of Peptide F distribution was apparent during rest. Furthermore, concentrations of T cells, B cells, NK cells, and total WBCs demonstrated significant changes in response to aerobic exercise. Data indicated that Peptide F was bound in significant molar concentrations in the WBC fraction and that this biocompartment may be one of the tissue targets for binding interactions. These data indicate that Peptide F is involved with immune cell modulation in the white blood circulatory biocompartment of blood. Copyright © 2013. Published by Elsevier Inc.

  19. Resisting Prescribed Opioids: A Qualitative Study of Decision Making in Patients Taking Opioids for Chronic Noncancer Pain.

    Science.gov (United States)

    Paterson, Charlotte; Ledgerwood, Kay; Arnold, Carolyn; Hogg, Malcolm; Xue, Charlie; Zheng, Zhen

    2016-04-01

    Opioids are increasingly prescribed for chronic noncancer pain across the developed world. Clinical guidelines for management of these patients focus on over-use. However, research into other types of long-term medication indicates that many patients minimize drug use whenever possible. To identify the varying influences on patients' decisions about their use of prescribed opioids and explore whether concepts of resistance and minimization of intake apply to these patients. A multiprofessional team performed a qualitative interview study using the constant-comparative method. Patient's decision making was explored in depth and with a thematic analysis utilizing a published "Model of medicine-taking." A purposive sample of 20 participants drawn from two pain clinics in Melbourne, Australia. The sample was biased toward patients interested in nonmedication pain management options. Patients' needs to obtain relief from severe pain, maintain function, and minimize side effects could lead to under-use as well as over-use of prescribed opioids. In keeping with the published Model of medicine-taking, resistance to taking opioids was a common and important influence on behavior. In the face of severe chronic pain, many participants used a variety of strategies to evaluate, avoid, reduce, self-regulate, and replace opioids. Furthermore, participants perceived a resistance to opioids within the system and among some healthcare professionals. This sometimes adversely affected their adherence. Both patients and doctors exhibit aspects of resistance to the use of prescribed opioids for chronic noncancer pain, suggesting that this shared concern could be the basis of a productive therapeutic alliance to improve communication and shared decision making. Clinical guidelines for opioids use for chronic noncancer pain focus on over-use. Our qualitative interview study found that many patients resisted and minimized the use of opioids. Using a published "Model of medicine-taking," we

  20. Kappa-Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials.

    Science.gov (United States)

    Carlezon, William A; Krystal, Andrew D

    2016-10-01

    Kappa-opioid receptor (KOR) antagonists are currently being considered for the treatment of a variety of neuropsychiatric conditions, including depressive, anxiety, and substance abuse disorders. A general ability to mitigate the effects of stress, which can trigger or exacerbate these conditions, may explain their putative efficacy across such a broad array of conditions. The discovery of their potentially therapeutic effects evolved from preclinical research designed to characterize the molecular mechanisms by which experience causes neuroadaptations in the nucleus accumbens (NAc), a key element of brain reward circuitry. This research established that exposure to drugs of abuse or stress increases the activity of the transcription factor CREB (cAMP response element binding protein) in the NAc, which leads to elevated expression of the opioid peptide dynorphin that in turn causes core signs of depressive- and anxiety-related disorders. Disruption of KORs-the endogenous receptors for dynorphin-produces antidepressant- and anxiolytic-like actions in screening procedures that identify standard drugs of these classes, and reduces stress effects in tests used to study addiction and stress-related disorders. Although interest in this target is high, prototypical KOR antagonists have extraordinarily persistent pharmacodynamic effects that complicate clinical trials. The development of shorter acting KOR antagonists together with more rapid designs for clinical trials may soon provide insight on whether these drugs are efficacious as would be predicted by preclinical work. If successful, KOR antagonists would represent a unique example in psychiatry where the therapeutic mechanism of a drug class is understood before it is shown to be efficacious in humans. © 2016 Wiley Periodicals, Inc.

  1. Orexin/hypocretin role in reward: implications for opioid and other addictions.

    Science.gov (United States)

    Baimel, Corey; Bartlett, Selena E; Chiou, Lih-Chu; Lawrence, Andrew J; Muschamp, John W; Patkar, Omkar; Tung, Li-Wei; Borgland, Stephanie L

    2015-01-01

    Addiction is a devastating disorder that affects 15.3 million people worldwide. While prevalent, few effective treatments exist. Orexin receptors have been proposed as a potential target for anti-craving medications. Orexins, also known as hypocretins, are neuropeptides produced in neurons of the lateral and dorsomedial hypothalamus and perifornical area, which project widely throughout the brain. The absence of orexins in rodents and humans leads to narcolepsy. However, orexins also have an established role in reward seeking. This review will discuss some of the original studies describing the roles of the orexins in reward seeking as well as specific works that were presented at the 2013 International Narcotics Research Conference. Orexin signalling can promote drug-induced plasticity of glutamatergic synapses onto dopamine neurons of the ventral tegmental area (VTA), a brain region implicated in motivated behaviour. Additional evidence suggests that orexin signalling can also promote drug seeking by initiating an endocannabinoid-mediated synaptic depression of GABAergic inputs to the VTA, and thereby disinhibiting dopaminergic neurons. Orexin neurons co-express the inhibitory opioid peptide dynorphin. It has been proposed that orexin in the VTA may not mediate reward per se, but rather occludes the 'anti-reward' effects of dynorphin. Finally, orexin signalling in the prefrontal cortex and the central amygdala is implicated in reinstatement of reward seeking. This review will highlight recent work describing the role of orexin signalling in cellular processes underlying addiction-related behaviours and propose novel hypotheses for the mechanisms by which orexin signalling may impart drug seeking. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. © 2014 The British Pharmacological Society.

  2. Irradiation exposure modulates central opioid functions

    International Nuclear Information System (INIS)

    Dougherty, P.M.; Dafny, N.

    1987-01-01

    Exposure to low doses of gamma irradiation results in the modification of both the antinociceptive properties of morphine and the severity of naloxone-precipitated withdrawal in morphine-dependent rats. To better define the interactions between gamma irradiation and these opiate-mediated phenomena, dose-response studies were undertaken of the effect of irradiation on morphine-induced antinociception, and on the naloxone-precipitated withdrawal syndrome of morphine-dependent rats. In addition, electrophysiologic studies were conducted in rats after irradiation exposure and morphine treatment correlating with the behavioral studies. The observations obtained demonstrated that the antinociceptive effects of morphine as well as naloxone-precipitated withdrawal were modified in a dose-dependent manner by irradiation exposure. In addition, irradiation-induced changes in the evoked responses obtained from four different brain regions demonstrated transient alterations in both baseline and morphine-treated responses that may reflect the alterations observed in the behavioral paradigms. These results suggest that the effects of irradiation on opiate activities resulted from physiologic alterations of central endogenous opioid systems due to alterations manifested within peripheral targets

  3. Irradiation exposure modulates central opioid functions

    Energy Technology Data Exchange (ETDEWEB)

    Dougherty, P.M.; Dafny, N.

    1987-11-01

    Exposure to low doses of gamma irradiation results in the modification of both the antinociceptive properties of morphine and the severity of naloxone-precipitated withdrawal in morphine-dependent rats. To better define the interactions between gamma irradiation and these opiate-mediated phenomena, dose-response studies were undertaken of the effect of irradiation on morphine-induced antinociception, and on the naloxone-precipitated withdrawal syndrome of morphine-dependent rats. In addition, electrophysiologic studies were conducted in rats after irradiation exposure and morphine treatment correlating with the behavioral studies. The observations obtained demonstrated that the antinociceptive effects of morphine as well as naloxone-precipitated withdrawal were modified in a dose-dependent manner by irradiation exposure. In addition, irradiation-induced changes in the evoked responses obtained from four different brain regions demonstrated transient alterations in both baseline and morphine-treated responses that may reflect the alterations observed in the behavioral paradigms. These results suggest that the effects of irradiation on opiate activities resulted from physiologic alterations of central endogenous opioid systems due to alterations manifested within peripheral targets.

  4. Peptide Integrated Optics.

    Science.gov (United States)

    Handelman, Amir; Lapshina, Nadezda; Apter, Boris; Rosenman, Gil

    2018-02-01

    Bio-nanophotonics is a wide field in which advanced optical materials, biomedicine, fundamental optics, and nanotechnology are combined and result in the development of biomedical optical chips. Silk fibers or synthetic bioabsorbable polymers are the main light-guiding components. In this work, an advanced concept of integrated bio-optics is proposed, which is based on bioinspired peptide optical materials exhibiting wide optical transparency, nonlinear and electrooptical properties, and effective passive and active waveguiding. Developed new technology combining bottom-up controlled deposition of peptide planar wafers of a large area and top-down focus ion beam lithography provides direct fabrication of peptide optical integrated circuits. Finding a deep modification of peptide optical properties by reconformation of biological secondary structure from native phase to β-sheet architecture is followed by the appearance of visible fluorescence and unexpected transition from a native passive optical waveguiding to an active one. Original biocompatibility, switchable regimes of waveguiding, and multifunctional nonlinear optical properties make these new peptide planar optical materials attractive for application in emerging technology of lab-on-biochips, combining biomedical photonic and electronic circuits toward medical diagnosis, light-activated therapy, and health monitoring. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Antimicrobial Peptides from Plants

    Directory of Open Access Journals (Sweden)

    James P. Tam

    2015-11-01

    Full Text Available Plant antimicrobial peptides (AMPs have evolved differently from AMPs from other life forms. They are generally rich in cysteine residues which form multiple disulfides. In turn, the disulfides cross-braced plant AMPs as cystine-rich peptides to confer them with extraordinary high chemical, thermal and proteolytic stability. The cystine-rich or commonly known as cysteine-rich peptides (CRPs of plant AMPs are classified into families based on their sequence similarity, cysteine motifs that determine their distinctive disulfide bond patterns and tertiary structure fold. Cystine-rich plant AMP families include thionins, defensins, hevein-like peptides, knottin-type peptides (linear and cyclic, lipid transfer proteins, α-hairpinin and snakins family. In addition, there are AMPs which are rich in other amino acids. The ability of plant AMPs to organize into specific families with conserved structural folds that enable sequence variation of non-Cys residues encased in the same scaffold within a particular family to play multiple functions. Furthermore, the ability of plant AMPs to tolerate hypervariable sequences using a conserved scaffold provides diversity to recognize different targets by varying the sequence of the non-cysteine residues. These properties bode well for developing plant AMPs as potential therapeutics and for protection of crops through transgenic methods. This review provides an overview of the major families of plant AMPs, including their structures, functions, and putative mechanisms.

  6. Managing Opioid Addiction Risk in Plastic Surgery during the Perioperative Period.

    Science.gov (United States)

    Demsey, Daniel; Carr, Nicholas J; Clarke, Hance; Vipler, Sharon

    2017-10-01

    Opioid addiction is a public health crisis that affects all areas of medicine. Large numbers of the population across all racial and economic demographics misuse prescription opioids and use illicit opioids. The current understanding is that opioid misuse is a disease that requires treatment, and is not an issue of choice or character. Use of opioid medication is a necessary part of postoperative analgesia, but many physicians are unsure of how to do this safely given the risk of patients developing an opioid misuse disorder. This review gives an update of the current state of the opioid crisis, explains how current surgeons' prescribing practices are contributing to it, and gives recommendations on how to use opioid medication safely in the perioperative period.

  7. Endogenous opioids regulate moment-to-moment neuronal communication and excitability

    Science.gov (United States)

    Winters, Bryony L.; Gregoriou, Gabrielle C.; Kissiwaa, Sarah A.; Wells, Oliver A.; Medagoda, Danashi I.; Hermes, Sam M.; Burford, Neil T.; Alt, Andrew; Aicher, Sue A.; Bagley, Elena E.

    2017-01-01

    Fear and emotional learning are modulated by endogenous opioids but the cellular basis for this is unknown. The intercalated cells (ITCs) gate amygdala output and thus regulate the fear response. Here we find endogenous opioids are released by synaptic stimulation to act via two distinct mechanisms within the main ITC cluster. Endogenously released opioids inhibit glutamate release through the δ-opioid receptor (DOR), an effect potentiated by a DOR-positive allosteric modulator. Postsynaptically, the opioids activate a potassium conductance through the μ-opioid receptor (MOR), suggesting for the first time that endogenously released opioids directly regulate neuronal excitability. Ultrastructural localization of endogenous ligands support these functional findings. This study demonstrates a new role for endogenously released opioids as neuromodulators engaged by synaptic activity to regulate moment-to-moment neuronal communication and excitability. These distinct actions through MOR and DOR may underlie the opposing effect of these receptor systems on anxiety and fear. PMID:28327612

  8. Effect of Intravenous Acetaminophen on Postoperative Opioid Use in Bariatric Surgery Patients

    OpenAIRE

    Wang, Shan; Saha, Ronik; Shah, Neal; Hanna, Adel; DeMuro, Jonas; Calixte, Rose; Brathwaite, Collin

    2015-01-01

    Opioids are often used to relieve pain after surgery, but they are associated with serious adverse effects. In this retrospective chart-review analysis, the use of intravenous acetaminophen did not reduce opioid use following bariatric surgery.

  9. South African guideline for the use of chronic opioid therapy for ...

    African Journals Online (AJOL)

    pain and chronic pain associated with cancer and at the end of life. Although .... Opioid drugs are agonists that bind to endogenous opioid receptors and mimic ..... interstitial cystitis/painful bladder syndrome, chronic prostate pain, and irritable ...

  10. The challenge of perioperative pain management in opioid-tolerant patients

    Science.gov (United States)

    Coluzzi, Flaminia; Bifulco, Francesca; Cuomo, Arturo; Dauri, Mario; Leonardi, Claudio; Melotti, Rita Maria; Natoli, Silvia; Romualdi, Patrizia; Savoia, Gennaro; Corcione, Antonio

    2017-01-01

    The increasing number of opioid users among chronic pain patients, and opioid abusers among the general population, makes perioperative pain management challenging for health care professionals. Anesthesiologists, surgeons, and nurses should be familiar with some pharmacological phenomena which are typical of opioid users and abusers, such as tolerance, physical dependence, hyperalgesia, and addiction. Inadequate pain management is very common in these patients, due to common prejudices and fears. The target of preoperative evaluation is to identify comorbidities and risk factors and recognize signs and symptoms of opioid abuse and opioid withdrawal. Clinicians are encouraged to plan perioperative pain medications and to refer these patients to psychiatrists and addiction specialists for their evaluation. The aim of this review was to give practical suggestions for perioperative management of surgical opioid-tolerant patients, together with schemes of opioid conversion for chronic pain patients assuming oral or transdermal opioids, and patients under maintenance programs with methadone, buprenorphine, or naltrexone. PMID:28919771

  11. 77 FR 44695 - Revised Meeting Notice: Leadership Meeting on Maternal, Fetal, and Infant Opioid Exposure and...

    Science.gov (United States)

    2012-07-30

    ... maternal prescription drug abuse and dependence and resulting increases in opioid exposed babies with NAS and possibly other consequences. Misuse and abuse of, and dependence upon, prescription opioid drugs... access treatment through family medicine and gynecological practitioners, and specialty treatment...

  12. Dexmedetomidine infusion to facilitate opioid detoxification and withdrawal in a patient with chronic opioid abuse

    Directory of Open Access Journals (Sweden)

    Surjya Prasad Upadhyay

    2011-01-01

    Full Text Available Many patients are admitted to the intensive care unit (ICU for acute intoxication, serious complication of overdose, or withdrawal symptoms of illicit drugs. An acute withdrawal of drugs with addiction potential is associated with a sympathetic overactivity leading to marked psychomimetic disturbances. Acute intoxication or withdrawal of such drugs is often associated with life-threatening complications which require ICU admission and necessitate prolonged sedative analgesic medications, weaning from which is often complicated by withdrawal and other psychomimetic symptoms. Dexmedetomidine, an alpha-2 (α2 agonist, has been used successfully to facilitate withdrawal and detoxification of various drugs and also to control delirium in ICU patients. Herein, we report a case of a chronic opioid abuse (heroin patient admitted with acute overdose complications leading to a prolonged ICU course requiring sedative-analgesic medication; the drug withdrawal-related symptoms further complicated the weaning process. Dexmedetomidine infusion was successfully used as a sedative-analgesic to control the withdrawal-related psychomimetic symptoms and to facilitate smooth detoxification and weaning from opioid and other sedatives.

  13. Age differences in heroin and prescription opioid abuse among enrolees into opioid treatment programs

    Directory of Open Access Journals (Sweden)

    Fong Chunki

    2011-06-01

    Full Text Available Abstract Background In the United States, among those entering opioid treatment programs (OTPs, prescription opioid (PO abusers tend to be younger than heroin users. Admissions of older persons to OTPs have been increasing, and it is important to understand typical patterns of use among those older enrolees. Methods To disentangle the effect of age on recent heroin and PO abuse 29,114 enrolees into 85 OTPs were surveyed across 34 states from 2005-2009. OTPs where PO use was prevalent were oversampled. Results Mean age was 34; 28% used heroin only. Younger enrolees had increased odds of using POs relative to using heroin only but mixed model analysis showed that much of the total variability in type of use was attributed to variation in age between OTPs rather than within OTPs. Conclusions Organizational and cultural phenomena (e.g., OTP characteristics must be examined to better understand the context of individual characteristics (e.g., age. If nesting of enrolees within OTPs is ignored, then associations that primarily operate at the OTP level may be misinterpreted as exclusively dependent on individuals.

  14. Opioid receptors in midbrain dopaminergic regions of the rat. 1. Mu receptor autoradiography

    International Nuclear Information System (INIS)

    German, D.C.; Speciale, S.G.; Manaye, K.F.; Sadeq, M.

    1993-01-01

    Several lines of evidence indicate that an interaction exists between opioid peptides and midbrain dopaminergic neurons. The purpose of this study was to map and quantify the density of the mu opioid receptor subtype relative to the location of the dopaminergic (DA) neurons in the retrorubral field (nucleus A8), substantia nigra (nucleus A9), and ventral tegmental area and related nuclei (nucleus A10) in the rat. Sections through the rostral-caudal extent of the midbrain were stained with an antibody against tyrosine hydroxylase, as a DA cell marker, and comparable sections were processed for in vitro receptor autoradiography using the mu-selective ligand, 3 H-Tyr-D-Ala-N-MePhe-Gyl-ol enkephalin. In the nucleus A8 region, there were low levels of mu binding. In the rostral portion of nucleus A9, there was prominent mu binding both in the ventral pars compacta, which contains numerous DA neurons, and in regions that correspond to the location of the DA dendrites which project ventrally into the underlying substantia nigra pars reticulata. In the caudal portion of nucleus A9, mu binding was greatest in the substantia nigra pars reticulata, but also in the same region that contains DA neurons. In nucleus A10, mu receptor densities differed depending upon the nucleus A10 subdivision, and the rostral-caudal position in the nucleus. Low receptor densities were observed in rostral portions of the ventral tegmental area and interfascicular nucleus, and there was negligible binding in the parabrachial pigmented nucleus and paranigral nucleus at the level of the interpeduncular nucleus; all regions where there are high densities of DA somata. Mu binding was relatively high in the central linear nucleus, and in the dorsal and medial divisions of the medial terminal nucleus of the accessory optic system, which has been shown to contain DA dendrites. These data indicate that mu opioid receptors are located in certain regions occupied by all three midbrain DA nuclei, but in a

  15. Using [11C]diprenorphine to image opioid receptor occupancy by methadone in opioid addiction: clinical and preclinical studies.

    Science.gov (United States)

    Melichar, Jan K; Hume, Susan P; Williams, Tim M; Daglish, Mark R C; Taylor, Lindsay G; Ahmad, Rabia; Malizia, Andrea L; Brooks, David J; Myles, Judith S; Lingford-Hughes, Anne; Nutt, David J

    2005-01-01

    Substitute methadone prescribing is one of the main modes of treatment for opioid dependence with established evidence for improved health and social outcomes. However, the pharmacology underpinning the effects of methadone is little studied despite controversies about dosing in relation to outcome. We therefore examined the relationship between methadone dose and occupation of opioid receptors in brain using the positron emission tomography (PET) radioligand [(11)C]diprenorphine in humans and rats. Eight opioid-dependent subjects stable on their substitute methadone (18-90 mg daily) had an [(11)C]diprenorphine PET scan at predicted peak plasma levels of methadone. These were compared with eight healthy controls. No difference in [(11)C]diprenorphine binding was found between the groups, with no relationship between methadone dose and occupancy. Adult male Sprague-Dawley rats that had been given an acute i.v. injection of methadone hydrochloride (0.35, 0.5, 0.7, or 1.0 mg kg(-1)) before [(11)C]diprenorphine showed a dose-dependent increase in biodistribution but no reduction in [(11)C]diprenorphine binding. We suggest that the lack of a dose-dependent relationship between methadone dose, either given chronically in human or acutely in rat, and occupancy of opioid receptor measured with [(11)C]diprenorphine PET is related to efficacy of this opioid agonist at very low levels of opioid receptor occupancy. This has implications for understanding the actions of methadone in comparison with other opioid drugs such as partial agonists and antagonists.

  16. Buprenorphine implants in medical treatment of opioid addiction.

    Science.gov (United States)

    Chavoustie, Steven; Frost, Michael; Snyder, Ole; Owen, Joel; Darwish, Mona; Dammerman, Ryan; Sanjurjo, Victoria

    2017-08-01

    Opioid use disorder is a chronic, relapsing disease that encompasses use of both prescription opioids and heroin and is associated with a high annual rate of overdose deaths. Medical treatment has proven more successful than placebo treatment or psychosocial intervention, and the partial µ-opioid receptor agonist and κ-opioid receptor antagonist buprenorphine is similar in efficacy to methadone while offering lower risk of respiratory depression. However, frequent dosing requirements and potential for misuse and drug diversion contribute to significant complications with treatment adherence for available formulations. Areas covered: This review describes the development of and preliminary data from clinical trials of an implantable buprenorphine formulation. Efficacy and safety data from comparative studies with other administrations of buprenorphine, including tablets and sublingual film, will be described. Key premises of the Risk Evaluation and Mitigation Strategy program for safely administering buprenorphine implants, which all prescribing physicians must complete, are also discussed. Expert commentary: Long-acting implantable drug formulations that offer consistent drug delivery and lower risk of misuse, diversion, or accidental pediatric exposure over traditional formulations represent a promising development for the effective treatment of opioid use disorder.

  17. Reducing the health consequences of opioid addiction in primary care.

    Science.gov (United States)

    Bowman, Sarah; Eiserman, Julie; Beletsky, Leo; Stancliff, Sharon; Bruce, R Douglas

    2013-07-01

    Addiction to prescription opioids is prevalent in primary care settings. Increasing prescription opioid use is largely responsible for a parallel increase in overdose nationally. Many patients most at risk for addiction and overdose come into regular contact with primary care providers. Lack of routine addiction screening results in missed treatment opportunities in this setting. We reviewed the literature on screening and brief interventions for addictive disorders in primary care settings, focusing on opioid addiction. Screening and brief interventions can improve health outcomes for chronic illnesses including diabetes, hypertension, and asthma. Similarly, through the use of screening and brief interventions, patients with addiction can achieve improved health outcome. A spectrum of low-threshold care options can reduce the negative health consequences among individuals with opioid addiction. Screening in primary care coupled with short interventions, including motivational interviewing, syringe distribution, naloxone prescription for overdose prevention, and buprenorphine treatment are effective ways to manage addiction and its associated risks and improve health outcomes for individuals with opioid addiction. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. [Management of opioid maintenance treatments when analgesic treatments are required].

    Science.gov (United States)

    Laprevote, Vincent; Geoffroy, Pierre A; Rolland, Benjamin; Leheup, Benoît F; Di Patrizio, Paolo; Cottencin, Olivier; Schwan, Raymund

    2013-01-01

    Opioid maintenance treatments (OMT) reduce illicit opiate use and its associated risks. They are often prescribed on a long-term basis. Physiological changes induced by long-term OMT may cause hyperalgesia and cross-tolerance to opioid agonists, which suggests that the dosage of analgesic treatment should be modified in cases of acute pain, especially when an opioid-based analgesia is required. When treatment with analgesics is necessary, OMT must be maintained, except in exceptional cases. If a split-dosing schedule is temporarily employed during OMT, the daily dosage should not be increased for analgesic purposes. Analgesic treatment must be managed differently in case of treatment with buprenorphine or methadone. With buprenorphine, non-opioid analgesics should be introduced first, if possible. If this strategy is inefficient or contraindicated, a temporary or definitive switch to methadone should be considered. In the case of methadone-based OMT, opioid analgesics should be added directly and the dosage should be adapted according to the level of pain reported by the patient. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  19. GRK2 Constitutively Governs Peripheral Delta Opioid Receptor Activity

    Directory of Open Access Journals (Sweden)

    Allison Doyle Brackley

    2016-09-01

    Full Text Available Opioids remain the standard for analgesic care; however, adverse effects of systemic treatments contraindicate long-term administration. While most clinical opioids target mu opioid receptors (MOR, those that target the delta class (DOR also demonstrate analgesic efficacy. Furthermore, peripherally restrictive opioids represent an attractive direction for analgesia. However, opioid receptors including DOR are analgesically incompetent in the absence of inflammation. Here, we report that G protein-coupled receptor kinase 2 (GRK2 naively associates with plasma membrane DOR in peripheral sensory neurons to inhibit analgesic agonist efficacy. This interaction prevents optimal Gβ subunit association with the receptor, thereby reducing DOR activity. Importantly, bradykinin stimulates GRK2 movement away from DOR and onto Raf kinase inhibitory protein (RKIP. protein kinase C (PKC-dependent RKIP phosphorylation induces GRK2 sequestration, restoring DOR functionality in sensory neurons. Together, these results expand the known function of GRK2, identifying a non-internalizing role to maintain peripheral DOR in an analgesically incompetent state.

  20. Haloperidol Disrupts Opioid-Antinociceptive Tolerance and Physical Dependence

    Science.gov (United States)

    Yang, Cheng; Chen, Yan; Tang, Lei

    2011-01-01

    Previous studies from our laboratory and others have implicated a critical role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in opioid tolerance and dependence. Translational research targeting the CaMKII pathway is challenging, if not impossible, because of a lack of selective inhibitors. We discovered in a preliminary study that haloperidol, a butyrophenone antipsychotic drug, inhibited CaMKII, which led us to hypothesize that haloperidol can attenuate opioid tolerance and dependence by inhibiting CaMKII. The hypothesis was tested in two rodent models of opioid tolerance and dependence. Pretreatment with haloperidol (0.2–1.0 mg/kg i.p.) prevented the development of morphine tolerance and dependence in a dose-dependent manner. Short-term treatment with haloperidol (0.06–0.60 mg/kg i.p.) dose-dependently reversed the established morphine-antinociceptive tolerance and physical dependence. Correlating with behavioral effects, pretreatment or short-term treatment with haloperidol dose-dependently inhibited morphine-induced up-regulation of supraspinal and spinal CaMKIIα activity. Moreover, haloperidol given orally was also effective in attenuating morphine-induced CaMKIIα activity, antinociceptive tolerance, and physical dependence. Taken together, these data suggest that haloperidol attenuates opioid tolerance and dependence by suppressing CaMKII activity. Because haloperidol is a clinically used drug that can be taken orally, we propose that the drug may be of use in attenuating opioid tolerance and dependence. PMID:21436292

  1. Pennsylvania State Core Competencies for Education on Opioids and Addiction.

    Science.gov (United States)

    Ashburn, Michael A; Levine, Rachel L

    2017-10-01

    The objective of this project was to develop core competencies for education on opioids and addiction to be used in all Pennsylvania medical schools. The Pennsylvania Physician General created a task force that was responsible for the creation of the core competencies. A literature review was completed, and a survey of graduating medical students was conducted. The task force then developed, reviewed, and approved the core competencies. The competencies were grouped into nine domains: understanding core aspects of addiction; patient screening for substance use disorder; proper referral for specialty evaluation and treatment of substance use disorder; proper patient assessment when treating pain; proper use of multimodal treatment options when treating acute pain; proper use of opioids for the treatment of acute pain (after consideration of alternatives); the role of opioids in the treatment of chronic noncancer pain; patient risk assessment related to the use of opioids to treat chronic noncancer pain, including the assessment for substance use disorder or increased risk for aberrant drug-related behavior; and the process for patient education, initiation of treatment, careful patient monitoring, and discontinuation of therapy when using opioids to treat chronic noncancer pain. Specific competencies were developed for each domain. These competencies will be incorporated into the educational process at all Pennsylvania medical schools. It is hoped that these curriculum changes will improve student knowledge and attitudes in these areas, thus improving patient outcomes. © 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  2. Benzodiazepines, opioids and driving: an overview of the experimental research.

    Science.gov (United States)

    Leung, Stefanie Y

    2011-05-01

    Road crashes contribute significantly to the total burden of injury in Australia, with the risk of injury being associated with the presence of drugs and/or alcohol in the driver's blood. Increasingly, some of the most commonly detected drugs include prescription medicines, the most notable of these being benzodiazepines and opioids. However, there is a paucity of experimental research into the effects of prescribed psychoactive drugs on driving behaviours. This paper provides an overview of experimental studies investigating the effects of prescribed doses of benzodiazepines and opioids on driving ability, and points to future directions for research. There is growing epidemiological evidence linking the therapeutic use of benzodiazepines and opioids to an increased crash risk. However, the current experimental literature remains unclear. Limitations to study methodologies have resulted in inconsistent findings. Limited experimental evidence exists to inform policy and guidelines regarding fitness-to-drive for patients taking prescribed benzodiazepines and opioids. Further experimental research is required to elucidate the effects of these medications on driving, under varying conditions and in different medical contexts. This will ensure that doctors prescribing benzodiazepines and opioids are well informed, and can appropriately advise patients of the risks associated with driving whilst taking these medications. © 2011 Australasian Professional Society on Alcohol and other Drugs.

  3. Atypical Opioid Mechanisms of Control of Injury-Induced Cutaneous Pain by Delta Receptors

    Science.gov (United States)

    2016-07-01

    treat, and current opioids (i.e. mu opioid receptor agonists such as morphine) cause unacceptable side effects including addiction . Injuries suffered...treat, and current opioids that act on mu opioid receptors such as morphine generate significant side effects including addiction . War-related...al., J Neurosci Methods, 1994), starting with 0.1 g and ending with 2.0 g filament as cutoff value. As shown in Figure 2, our preliminary experiments

  4. Evaluation of the Tolerability of Switching Patients on Chronic Full ?-Opioid Agonist Therapy to Buccal Buprenorphine

    OpenAIRE

    Webster, Lynn; Gruener, Daniel; Kirby, Todd; Xiang, Qinfang; Tzanis, Evan; Finn, Andrew

    2016-01-01

    Objective?Assess whether patients with chronic pain receiving 80 to 220?mg oral morphine sulfate equivalent of a full ?-opioid agonist could be transitioned to buccal buprenorphine at approximately 50% of their full dose without inducing opioid withdrawal or sacrificing analgesic efficacy. Methods.?A randomized, double-blind, double-dummy, active-controlled, two-period crossover study in adult patients receiving around-the-clock full opioid agonist therapy and confirmed to be opioid dependent...

  5. Changing Trends in Opioid Use Among Patients With Rheumatoid Arthritis in the United States.

    Science.gov (United States)

    Curtis, Jeffrey R; Xie, Fenglong; Smith, Christian; Saag, Kenneth G; Chen, Lang; Beukelman, Timothy; Mannion, Melissa; Yun, Huifeng; Kertesz, Stefan

    2017-09-01

    Opioid prescribing recently has come under intense scrutiny. However, longitudinal patterns of prescription opioid receipt in a population-based cohort of patients with chronic pain, such as those with rheumatoid arthritis (RA), have not been well characterized. The aim of this study was to examine both trends over time and variability in individual physician prescribing of short-term and long-term use of opioids. We identified a cohort of RA patients based on 2006-2014 Medicare data and evaluated longitudinal time trends in "regular" use of opioids. A separate analysis conducted in 2014 assessed rheumatologist-specific variability in regular use of opioid prescriptions in patients with RA. We identified 97,859 RA patients meeting the eligibility criteria. The mean age of the patients was 67 years, 80% were female, 82% were white, and 12% were African American. The most commonly used opioids were those that combined acetaminophen with hydrocodone or propoxyphene. Regular opioid prescribing increased slowly but peaked in 2010 before propoxyphene was withdrawn from the market. Following the withdrawal of propoxyphene, receipt of hydrocodone and tramadol increased commensurately, and overall opioid use declined only slightly. Factors associated with regular use of opioids included younger age, female sex, African American race, back pain, fibromyalgia, anxiety, and depression. Variability between US rheumatologists (n = 4,024) in prescribing the regular use of opioids for their RA patients was high; in the average rheumatologist's practice, 40% of RA patients used prescription opioids regularly. In almost half of the patients, at least some opioid prescriptions were written by a rheumatologist, and 14% received opioids that were co-prescribed concurrently by more than 1 physician. In the US, opioid use in older patients with RA peaked in 2010 and is now declining slightly. Withdrawal of propoxyphene from the US market in 2010 had minimal effect on overall opioid

  6. Novel pharmacotherapeutic strategies for treatment of opioid-induced neonatal abstinence syndrome

    OpenAIRE

    McLemore, Gabrielle L.; Lewis, Tamorah; Jones, Catherine H.; Gauda, Estelle B.

    2012-01-01

    The non-medical use of prescription drugs, in general, and opioids, in particular, is a national epidemic, resulting in enormous addiction rates, healthcare expenditures, and overdose deaths. Prescription opioids are overly prescribed, illegally trafficked, and frequently abused, all of which have created a new opioid addiction pathway, adding to the number of opioid-dependent newborns requiring treatment for neonatal abstinence syndrome (NAS), and contributing to challenges in effective care...

  7. Acylation of Therapeutic Peptides

    DEFF Research Database (Denmark)

    Trier, Sofie; Henriksen, Jonas Rosager; Jensen, Simon Bjerregaard

    ) , which promotes intestinal growth and is used to treat bowel disorders such as inflammatory bowel diseases and short bowel syndrome, and the 32 amino acid salmon calcitonin (sCT), which lowers blood calcium and is employed in the treatment of post-menopausal osteoporosis and hypercalcemia. The two...... peptides are similar in size and structure, but oppositely charged at physiological pH. Both peptides were acylated with linear acyl chains of systematically increasing length, where sCT was furthermore acylated at two different positions on the peptide backbone. For GLP-2, we found that increasing acyl...... remained optimal overall. The results indicate that rational acylation of GLP-2 can increase its in vitro intestinal absorption, alone or in combination with permeation enhancers, and are consistent with the initial project hypothesis. For sCT, an unpredicted effect of acylation largely superseded...

  8. The changing landscape of opioid prescribing: long-acting and extended-release opioid class-wide Risk Evaluation and Mitigation Strategy

    Directory of Open Access Journals (Sweden)

    Gudin JA

    2012-05-01

    Full Text Available Jeffrey A GudinEnglewood Hospital and Medical Center, Englewood, NJ, USAAbstract: Prescriptions for opioid analgesics to manage moderate-to-severe chronic noncancer pain have increased markedly over the last decade, as have postmarketing reports of adverse events associated with opioids. As an unintentional consequence of greater prescription opioid utilization, there has been the parallel increase in misuse, abuse, and overdose, which are serious risks associated with all opioid analgesics. In response to these concerns, the Food and Drug Administration announced the requirement for a class-wide Risk Evaluation and Mitigation Strategy (REMS for long-acting and extended-release (ER opioid analgesics in April 2011. An understanding of the details of this REMS will be of particular importance to primary care providers. The class-wide REMS is focused on educating health care providers and patients on appropriate prescribing and safe use of ER opioids. Support from primary care will be necessary for the success of this REMS, as these clinicians are the predominant providers of care and the main prescribers of opioid analgesics for patients with chronic pain. Although currently voluntary, future policy will likely dictate that providers undergo mandatory training to continue prescribing medications within this class. This article outlines the elements of the class-wide REMS for ER opioids and clarifies the impact on primary care providers with regard to training, patient education, and clinical practice.Keywords: long-acting opioid, extended-release opioid, risk, REMS, FDA, primary care

  9. Therapeutic HIV Peptide Vaccine

    DEFF Research Database (Denmark)

    Fomsgaard, Anders

    2015-01-01

    Therapeutic vaccines aim to control chronic HIV infection and eliminate the need for lifelong antiretroviral therapy (ART). Therapeutic HIV vaccine is being pursued as part of a functional cure for HIV/AIDS. We have outlined a basic protocol for inducing new T cell immunity during chronic HIV-1...... infection directed to subdominant conserved HIV-1 epitopes restricted to frequent HLA supertypes. The rationale for selecting HIV peptides and adjuvants are provided. Peptide subunit vaccines are regarded as safe due to the simplicity, quality, purity, and low toxicity. The caveat is reduced immunogenicity...

  10. Descriptors for antimicrobial peptides

    DEFF Research Database (Denmark)

    Jenssen, Håvard

    2011-01-01

    of these are currently being used in quantitative structure--activity relationship (QSAR) studies for AMP optimization. Additionally, some key commercial computational tools are discussed, and both successful and less successful studies are referenced, illustrating some of the challenges facing AMP scientists. Through...... examples of different peptide QSAR studies, this review highlights some of the missing links and illuminates some of the questions that would be interesting to challenge in a more systematic fashion. Expert opinion: Computer-aided peptide QSAR using molecular descriptors may provide the necessary edge...

  11. Behavioral intervention to reduce opioid overdose among high-risk persons with opioid use disorder: A pilot randomized controlled trial.

    Directory of Open Access Journals (Sweden)

    Phillip Oliver Coffin

    Full Text Available The United States is amidst an opioid epidemic, including synthetic opioids that may result in rapid death, leaving minimal opportunity for bystander rescue. We pilot tested a behavioral intervention to reduce the occurrence of opioid overdose among opioid dependent persons at high-risk for subsequent overdose.We conducted a single-blinded randomized-controlled trial of a repeated dose motivational interviewing intervention (REBOOT to reduce overdose versus treatment as usual, defined as information and referrals, over 16 months at the San Francisco Department of Public Health from 2014-2016. Participants were 18-65 years of age, had opioid use disorder by Structured Clinical Interview, active opioid use, opioid overdose within 5 years, and prior receipt of naloxone kits. The intervention was administered at months 0, 4, 8, and 12, preceded by the assessment which was also administered at month 16. Dual primary outcomes were any overdose event and number of events, collected by computer-assisted personal interview, as well as any fatal overdose events per vital records.A total of 78 persons were screened and 63 enrolled. Mean age was 43 years, 67% were born male, 65% White, 17% African-American, and 14% Latino. Ninety-two percent of visits and 93% of counseling sessions were completed. At baseline, 33.3% of participants had experienced an overdose in the past four months, with a similar mean number of overdoses in both arms (p = 0.95; 29% overdosed during follow-up. By intention-to-treat, participants assigned to REBOOT were less likely to experience any overdose (incidence rate ratio [IRR] 0.62 [95%CI 0.41-0.92, p = 0.019 and experienced fewer overdose events (IRR 0.46, 95%CI 0.24-0.90, p = 0.023, findings that were robust to sensitivity analyses. There were no differences between arms in days of opioid use, substance use treatment, or naloxone carriage.REBOOT reduced the occurrence of any opioid overdose and the number of overdoses

  12. Effect Of A “No Superuser Opioid Prescription” Policy On ED Visits And Statewide Opioid Prescription

    Directory of Open Access Journals (Sweden)

    Zachary P. Kahler

    2017-07-01

    Full Text Available Introduction: The U.S. opioid epidemic has highlighted the need to identify patients at risk of opioid abuse and overdose. We initiated a novel emergency department- (ED based interventional protocol to transition our superuser patients from the ED to an outpatient chronic pain program. The objective was to evaluate the protocol’s effect on superusers’ annual ED visits. Secondary outcomes included a quantitative evaluation of statewide opioid prescriptions for these patients, unique prescribers of controlled substances, and ancillary testing. Methods: Patients were referred to the program with the following inclusion criteria: ≥ 6 visits per year to the ED; at least one visit identified by the attending physician as primarily driven by opioid-seeking behavior; and a review by a committee comprising ED administration and case management. Patients were referred to a pain management clinic and informed that they would no longer receive opioid prescriptions from visits to the ED for chronic pain complaints. Electronic medical record (EMR alerts notified ED providers of the patient’s referral at subsequent visits. We analyzed one year of data pre- and post-referral. Results: A total of 243 patients had one year of data post-referral for analysis. Median annual ED visits decreased from 14 to 4 (58% decrease, 95% CI [50 to 66]. We also found statistically significant decreases for these patients’ state prescription drug monitoring program (PDMP opioid prescriptions (21 to 13, total unique controlled-substance prescribers (11 to 7, computed tomography imaging (2 to 0, radiographs (5 to 1, electrocardiograms (12 to 4, and labs run (47 to 13. Conclusion: This program and the EMR-based alerts were successful at decreasing local ED visits, annual opioid prescriptions, and hospital resource allocation for this population of patients. There is no evidence that these patients diverted their visits to neighboring EDs after being informed that they

  13. Nurses and opioids: results of a bi-national survey on mental models regarding opioid administration in hospitals

    Directory of Open Access Journals (Sweden)

    Guest C

    2017-03-01

    Full Text Available Charlotte Guest,1 Fabian Sobotka,2 Athina Karavasopoulou,3 Stephen Ward,3 Carsten Bantel4,5 1Pain Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK; 2Division of Epidemiology and Biometry, Department of Health Services Research, Faculty 6, Medicine and Health Sciences, Carl von Ossietzky Universität Oldenburg, Oldenburg, Germany; 3Pain Service, Barts Health, St Bartholomew’s Hospital, London, UK; 4Department of Anaesthesiology, Intensive Care, Emergency Medicine and Pain Therapy, Oldenburg University, Klinikum Oldenburg Campus, Oldenburg, Germany; 5Department of Surgery and Cancer, Anaesthetics Section, Imperial College London, Chelsea and Westminster Hospital Campus, London, UK Objective: Pain remains insufficiently treated in hospitals. Increasing evidence suggests human factors contribute to this, due to nurses failing to administer opioids. This behavior might be the consequence of nurses’ mental models about opioids. As personal experience and conceptions shape these models, the aim of this prospective survey was to identify model-influencing factors. Material and methods: A questionnaire was developed comprising of 14 statements concerning ideations about opioids and seven questions concerning demographics, indicators of adult learning, and strength of religious beliefs. Latent variables that may underlie nurses’ mental models were identified using undirected graphical dependence models. Representative items of latent variables were employed for ordinal regression analysis. Questionnaires were distributed to 1,379 nurses in two London, UK, hospitals (n=580 and one German (n=799 hospital between September 2014 and February 2015. Results: A total of 511 (37.1% questionnaires were returned. Mean (standard deviation age of participants were 37 (11 years; 83.5% participants were female; 45.2% worked in critical care; and 51.5% had more than 10 years experience. Of the nurses, 84% were not scared of opioids, 87

  14. European Pain Federation position paper on appropriate opioid use in chronic pain management

    DEFF Research Database (Denmark)

    O'Brien, T; Christrup, L L; Drewes, A M

    2017-01-01

    rests with the primary care physician and other non-specialist opioid prescribers. There is much confusing and conflicting information available to non-specialist prescribers regarding opioid therapy and a great deal of unjustified fear is generated. Opioid therapy should only be initiated by competent...

  15. Information on risk of constipation for Danish users of opioids, and their laxative use

    DEFF Research Database (Denmark)

    Pottegård, Anton; Knudsen, Thomas Bøllingtoft; van Heesch, Kim

    2014-01-01

    of opioids by the time of the first prescription regarding the risk of constipation. Method Interviews with patients filling an opioid at a community pharmacy were performed by the dispensing pharmacist or pharmaconomist at the pharmacy. Information collected concerned the patient, the opioid, information...

  16. Detecting aberrant opioid behavior in the emergency department: a prospective study using the screener and Opioid Assessment for Patients with Pain-Revised (SOAPP®-R), Current Opioid Misuse Measure (COMM)™, and provider gestalt.

    Science.gov (United States)

    Varney, Shawn M; Perez, Crystal A; Araña, Allyson A; Carey, Katherine R; Ganem, Victoria J; Zarzabal, Lee A; Ramos, Rosemarie G; Bebarta, Vikhyat S

    2018-03-03

    Emergency department (ED) providers have limited time to evaluate patients at risk for opioid misuse. A validated tool to assess the risk for aberrant opioid behavior may mitigate adverse sequelae associated with prescription opioid misuse. We sought to determine if SOAPP-R, COMM, and provider gestalt were able to identify patients at risk for prescription opioid misuse as determined by pharmacy records at 12 months. We conducted a prospective observational study of adult patients in a high volume US ED. Patients completed the SOAPP-R and COMM, and treating EM providers evaluated patients' opioid misuse risk. We performed variable-centered, person-centered, and hierarchical cluster analyses to determine whether provider gestalt, SOAPP-R, or COMM, or a combination, predicted higher misuse risk. The primary outcome was the number of opioid prescriptions at 12 months according to pharmacy records. For 169 patients (mean age 43 years, 51% female, 73% white), correlation analysis showed a strong relationship between SOAPP-R and COMM with predicting the number of opioid prescriptions dispensed at 12 months. Provider scores estimating opioid misuse were not related to SOAPP-R and only weakly associated with COMM. In our adjusted regression models, provider gestalt and SOAPP-R uniquely predicted opioid prescriptions at 6 and 12 months. Using designated cutoff scores, only SOAPP-R detected a difference in the number of opioid prescriptions. Cluster analysis revealed that provider gestalt, SOAPP-R, and COMM scores jointly predicted opioid prescriptions. Provider gestalt and self-report instruments uniquely predicted the number of opioid prescriptions in ED patients. A combination of gestalt and self-assessment scores can be used to identify at-risk patients who otherwise miss the cutoff scores for SOAPP-R and COMM.

  17. A Trigger for Opioid Misuse: Chronic Pain and Stress Dysregulate the Mesolimbic Pathway and Kappa Opioid System.

    Science.gov (United States)

    Massaly, Nicolas; Morón, Jose A; Al-Hasani, Ream

    2016-01-01

    Pain and stress are protective mechanisms essential in avoiding harmful or threatening stimuli and ensuring survival. Despite these beneficial roles, chronic exposure to either pain or stress can lead to maladaptive hormonal and neuronal modulations that can result in chronic pain and a wide spectrum of stress-related disorders including anxiety and depression. By inducing allostatic changes in the mesolimbic dopaminergic pathway, both chronic pain and stress disorders affect the rewarding values of both natural reinforcers, such as food or social interaction, and drugs of abuse. Despite opioids representing the best therapeutic strategy in pain conditions, they are often misused as a result of these allostatic changes induced by chronic pain and stress. The kappa opioid receptor (KOR) system is critically involved in these neuronal adaptations in part through its control of dopamine release in the nucleus accumbens. Therefore, it is likely that changes in the kappa opioid system following chronic exposure to pain and stress play a key role in increasing the misuse liability observed in pain patients treated with opioids. In this review, we will discuss how chronic pain and stress-induced pathologies can affect mesolimbic dopaminergic transmission, leading to increased abuse liability. We will also assess how the kappa opioid system may underlie these pathological changes.

  18. A trigger for opioid misuse: Chronic pain and stress dysregulate the mesolimbic pathway and kappa opioid system

    Directory of Open Access Journals (Sweden)

    Nicolas Massaly

    2016-11-01

    Full Text Available Pain and stress are protective mechanisms essential in avoiding harmful or threatening stimuli and ensuring survival. Despite these beneficial roles, chronic exposure to either pain or stress can lead to maladaptive hormonal and neuronal modulations that can result in chronic pain and a wide spectrum of stress-related disorders including anxiety and depression. By inducing allostatic changes in the mesolimbic dopaminergic pathway, both chronic pain and stress disorders affect the rewarding values of both natural reinforcers, such as food or social interaction, and drugs of abuse. Despite opioids representing the best therapeutic strategy in acute pain conditions, they are often misused as a result of these allostatic changes induced by chronic pain and stress. The kappa opioid receptor system is critically involved in these neuronal adaptations in part through its control of dopamine release in the nucleus accumbens. Therefore, it is likely that changes in the kappa opioid system following chronic exposure to pain and stress play a key role in increasing the misuse liability observed in pain patients treated with opioids. In this review, we will discuss how chronic pain and stress-induced pathologies can affect mesolimbic dopaminergic transmission, leading to increased abuse liability. We will also assess how the kappa opioid system may underlie these pathological changes.

  19. Novel approaches for the treatment of psychostimulant and opioid abuse - focus on opioid receptor-based therapies.

    Science.gov (United States)

    Bailey, Chris P; Husbands, Stephen M

    2014-11-01

    Psychostimulant and opioid addiction are poorly treated. The majority of abstinent users relapse back to drug-taking within a year of abstinence, making 'anti-relapse' therapies the focus of much current research. There are two fundamental challenges to developing novel treatments for drug addiction. First, there are three key stimuli that precipitate relapse back to drug-taking: stress, presentation of drug-conditioned cue, taking a small dose of drug. The most successful novel treatment would be effective against all three stimuli. Second, a large number of drug users are poly-drug users: taking more than one drug of abuse at a time. The ideal anti-addiction treatment would, therefore, be effective against all classes of drugs of abuse. In this review, the authors discuss the clinical need and animal models used to uncover potential novel treatments. There is a very broad range of potential treatment approaches and targets currently being examined as potential anti-relapse therapies. These broadly fit into two categories: 'memory-based' and 'receptor-based' and the authors discuss the key targets here within. Opioid receptors and ligands have been widely studied, and research into how different opioid subtypes affect behaviours related to addiction (reward, dysphoria, motivation) suggests that they are tractable targets as anti-relapse treatments. Regarding opioid ligands as novel 'anti-relapse' medication targets, research suggests that a 'non-selective' approach to targeting opioid receptors will be the most effective.

  20. Pharmacist's role in dispensing opioids for acute and chronic pain.

    Science.gov (United States)

    Marlowe, Karen F; Geiler, Richard

    2012-10-01

    Pain continues to be a serious health care concern in the United States. Patients with chronic pain experience the impact of the disease throughout their lives including their social interactions, family relationships, and in many cases economic productivity. Multiple surveys have found that many pharmacists hold misconceptions regarding opioids, pain disease states, and their understandings of current regulations. Multiple barriers affect the ability of pharmacists to deliver care to patients' prescribed opioid therapy. Inadequate communication between health care professionals and patients is one of the hurdles, which prevents quality care. Increased communication between health care providers including access to health information is one step, which is crucial to improving provision of pharmacotherapy. Finally, the quality of educational opportunities relative to opioids and pain management specifically for pharmacists needs to be increased, and consideration needs to be given for making appropriate pain management education mandatory.

  1. Endogenous opioid antagonism in physiological experimental pain models

    DEFF Research Database (Denmark)

    Werner, Mads U; Pereira, Manuel P; Andersen, Lars Peter H

    2015-01-01

    hyperalgesia models (6 studies), 'pain' models (25 studies), summation models (2 studies), nociceptive reflex models (3 studies) and miscellaneous models (2 studies). A consistent reversal of analgesia by a MOR-antagonist was demonstrated in 10 of the 25 ITP-studies, including stress-induced analgesia and r...... ratings, threshold assessments and somatosensory evoked potentials (SSEP), did not appear consistent in 28 out of 32 'pain' model studies. In conclusion, only in 2 experimental human pain models, i.e., stress-induced analgesia and rTMS, administration of MOR-antagonist demonstrated a consistent effect......Opioid antagonists are pharmacological tools applied as an indirect measure to detect activation of the endogenous opioid system (EOS) in experimental pain models. The objective of this systematic review was to examine the effect of mu-opioid-receptor (MOR) antagonists in placebo-controlled, double...

  2. Substitution treatment for opioid addicts in Germany

    Directory of Open Access Journals (Sweden)

    Gerlach Ralf

    2007-02-01

    Full Text Available Abstract Background After a long and controversial debate methadone maintenance treatment (MMT was first introduced in Germany in 1987. The number of patients in MMT – first low because of strict admission criteria – increased considerably since the 1990s up to some 65,000 at the end of 2006. In Germany each general practitioner (GP, who has completed an additional training in addiction medicine, is allowed to prescribe substitution drugs to opioid dependent patients. Currently 2,700 GPs prescribe substitution drugs. Psychosocial care should be made available to all MMT patients. Results The results of research studies and practical experiences clearly indicate that patients benefit substantially from MMT with improvements in physical and psychological health. MMT proves successful in attaining high retention rates (65 % to 85 % in the first years, up to 50 % after more than seven years and plays a major role in accessing and maintaining ongoing medical treatment for HIV and hepatitis. MMT is also seen as a vital factor in the process of social re-integration and it contributes to the reduction of drug related harms such as mortality and morbidity and to the prevention of infectious diseases. Some 10 % of MMT patients become drug-free in the long run. Methadone is the most commonly prescribed substitution medication in Germany, although buprenorphine is attaining rising importance. Access to MMT in rural areas is very patchy and still constitutes a problem. There are only few employment opportunities for patients participating in MMT, although regular employment is considered unanimously as a positive factor of treatment success. Substitution treatment in German prisons is heterogeneous in access and treatment modalities. Access is very patchy and the number of inmates in treatment is limited. Nevertheless, substitution treatment plays a substantial part in the health care system provided to drug users in Germany. Conclusion In Germany, a

  3. Substitution treatment for opioid addicts in Germany.

    Science.gov (United States)

    Michels, Ingo Ilja; Stöver, Heino; Gerlach, Ralf

    2007-02-02

    After a long and controversial debate methadone maintenance treatment (MMT) was first introduced in Germany in 1987. The number of patients in MMT--first low because of strict admission criteria--increased considerably since the 1990s up to some 65,000 at the end of 2006. In Germany each general practitioner (GP), who has completed an additional training in addiction medicine, is allowed to prescribe substitution drugs to opioid dependent patients. Currently 2,700 GPs prescribe substitution drugs. Psychosocial care should be made available to all MMT patients. The results of research studies and practical experiences clearly indicate that patients benefit substantially from MMT with improvements in physical and psychological health. MMT proves successful in attaining high retention rates (65% to 85% in the first years, up to 50% after more than seven years) and plays a major role in accessing and maintaining ongoing medical treatment for HIV and hepatitis. MMT is also seen as a vital factor in the process of social re-integration and it contributes to the reduction of drug related harms such as mortality and morbidity and to the prevention of infectious diseases. Some 10% of MMT patients become drug-free in the long run. Methadone is the most commonly prescribed substitution medication in Germany, although buprenorphine is attaining rising importance. Access to MMT in rural areas is very patchy and still constitutes a problem. There are only few employment opportunities for patients participating in MMT, although regular employment is considered unanimously as a positive factor of treatment success. Substitution treatment in German prisons is heterogeneous in access and treatment modalities. Access is very patchy and the number of inmates in treatment is limited. Nevertheless, substitution treatment plays a substantial part in the health care system provided to drug users in Germany. In Germany, a history of substitution treatment spanning 20 years has meanwhile

  4. Spinal antinociceptive effects of [D-Ala2]deltorphin II, a novel and highly selective delta-opioid receptor agonist.

    Science.gov (United States)

    Improta, G; Broccardo, M

    1992-01-01

    Pharmacological assays in isolated tissues and binding tests have recently shown that two peptides, with the sequence Tyr-D-Ala-Phe-Asp-(or Glu)- Val-Val-Gly-NH2, isolated from skin extracts of Phyllomedusa bicolor and named [D-Ala2]deltorphin I and II, respectively, possess a higher affinity and selectivity for delta-opioid receptors than any other known natural compound. Since much evidence supports the role of spinal delta-opioid sites in producing antinociceptive effects, we investigated whether analgesia might be detected by direct spinal cord administration of [D-Ala2]deltorphin II (DADELT II) in the rat. The thermal antinociceptive effects of intrathecal DADELT II and dermorphin, a potent mu-selective agonist, were compared at different postinjection times by means of the tail-flick test. The DADELT II produced a dose-related inhibition of the tail-flick response, which lasted 10-60 min depending on the dose and appeared to be of shorter duration than the analgesia produced in rats after intrathecal injection of dermorphin (20-120 min). The analgesic effect of infused or injected DADELT II was completely abolished by naltrindole, the highly selective delta antagonist. These results confirm the involvement of delta receptors in spinal analgesic activity in the rat.

  5. Evidence for opioid involvement in the motivation to sing

    Science.gov (United States)

    Riters, Lauren V.

    2009-01-01

    Songbirds produce high rates of song within multiple social contexts, suggesting that they are highly motivated to sing and that song production itself may be rewarding. Progress has been made in understanding the neural basis of song learning and sensorimotor processing, however little is known about neurobiological mechanisms regulating the motivation to sing. Neural systems involved in motivation and reward have been conserved across species and in songbirds are neuroanatomically well-positioned to influence the song control system. Opioid neuropeptides within these systems play a primary role in hedonic reward, at least in mammals. In songbirds, opioid neuropeptides and receptors are found throughout the song control system and within several brain regions implicated in both motivation and reward, including the medial preoptic nucleus (POM) and ventral tegmental area (VTA). Growing research shows these regions to play a role in birdsong that differs depending upon whether song is sexually-motivated in response to a female, used for territorial defense or sung as part of a flock but not directed towards an individual (undirected song). Opioid pharmacological manipulations and immunocytochemical data demonstrate a role for opioid activity possibly within VTA and POM in the regulation of song production. Although future research is needed, data suggest that opioids may be most critically involved in reinforcing song that does not result in any obvious form of immediate externally-mediated reinforcement, such as undirected song produced in large flocks or during song learning. Data are reviewed supporting the idea that dopamine activity underlies the motivation or drive to sing, but that opioid release is what makes song production rewarding. PMID:19995531

  6. Prescription History of Emergency Department Patients Prescribed Opioids

    Directory of Open Access Journals (Sweden)

    Jason A Hoppe

    2013-05-01

    Full Text Available Introduction: To use Colorado’s prescription drug monitoring program (PDMP to describe the recent opioid prescription history of patients discharged from our emergency department (ED with a prescription for opioid pain medications.Methods: Retrospective cohort study of 300 adult ED patients who received an opioid prescription. We abstracted prescription histories for the six months prior to the ED visit from the PDMP, and abstracted clinical and demographic variables from the chart.Results: There were 5,379 ED visits during the study month, 3,732 of which were discharged. Providers wrote 1,165 prescriptions for opioid analgesics to 1,124/3,732 (30% of the patients. Median age was 36 years. Thirty-nine percent were male. Patients were 46% Caucasian, 26% African American, 22% Hispanic, 2% Asian and 4% other. These were similar to our overall ED population. There was substantial variability in the number of prescriptions, prescribers and total number of pills. A majority (205/296 of patients had zero or one prescription. The 90th percentile for number of prescriptions was seven, while the 10th percentile was zero. Patients in the highest decile tended to be older, with a higher proportion of Caucasians and females. Patients in the lowest decile resembled the general ED population. The most common diagnoses associated with opioid prescriptions were abdominal pain (11.5%, cold/flu symptoms (9.5%, back pain (5.4%, flank pain (5.0% and motor vehicle crash (4.7%.Conclusion: Substantial variability exists in the opioid prescription histories of ED patients, but a majority received zero or one prescription in the preceding six months. The top decile of patients averaged more than two prescriptions per month over the six months prior to ED visit, written by more than 6 different prescribers. There was a trend toward these patients being older, Caucasian and female. [West J Emerg Med. 2013;14(3:247–252.

  7. Analgesic synergy between opioid and α2 -adrenoceptors.

    Science.gov (United States)

    Chabot-Doré, A-J; Schuster, D J; Stone, L S; Wilcox, G L

    2015-01-01

    Opioid and α2 -adrenoceptor agonists are potent analgesic drugs and their analgesic effects can synergize when co-administered. These supra-additive interactions are potentially beneficial clinically; by increasing efficacy and/or reducing the total drug required to produce sufficient pain relief, undesired side effects can be minimized. However, combination therapies of opioids and α2 -adrenoceptor agonists remain underutilized clinically, in spite of a large body of preclinical evidence describing their synergistic interaction. One possible obstacle to the translation of preclinical findings to clinical applications is a lack of understanding of the mechanisms underlying the synergistic interactions between these two drug classes. In this review, we provide a detailed overview of the interactions between different opioid and α2 -adrenoceptor agonist combinations in preclinical studies. These studies have identified the spinal cord as an important site of action of synergistic interactions, provided insights into which receptors mediate these interactions and explored downstream signalling events enabling synergy. It is now well documented that the activation of both μ and δ opioid receptors can produce synergy with α2 -adrenoceptor agonists and that α2 -adrenoceptor agonists can mediate synergy through either the α2A or the α2C adrenoceptor subtypes. Current hypotheses surrounding the cellular mechanisms mediating opioid-adrenoceptor synergy, including PKC signalling and receptor oligomerization, and the evidence supporting them are presented. Finally, the implications of these findings for clinical applications and drug discovery are discussed. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. © 2014 The British Pharmacological Society.

  8. Evidence for opioid involvement in the motivation to sing.

    Science.gov (United States)

    Riters, Lauren V

    2010-03-01

    Songbirds produce high rates of song within multiple social contexts, suggesting that they are highly motivated to sing and that song production itself may be rewarding. Progress has been made in understanding the neural basis of song learning and sensorimotor processing, however little is known about neurobiological mechanisms regulating the motivation to sing. Neural systems involved in motivation and reward have been conserved across species and in songbirds are neuroanatomically well-positioned to influence the song control system. Opioid neuropeptides within these systems play a primary role in hedonic reward, at least in mammals. In songbirds, opioid neuropeptides and receptors are found throughout the song control system and within several brain regions implicated in both motivation and reward, including the medial preoptic nucleus (POM) and ventral tegmental area (VTA). Growing research shows these regions to play a role in birdsong that differs depending upon whether song is sexually motivated in response to a female, used for territorial defense or sung as part of a flock but not directed towards an individual (undirected song). Opioid pharmacological manipulations and immunocytochemical data demonstrate a role for opioid activity possibly within VTA and POM in the regulation of song production. Although future research is needed, data suggest that opioids may be most critically involved in reinforcing song that does not result in any obvious form of immediate externally mediated reinforcement, such as undirected song produced in large flocks or during song learning. Data are reviewed supporting the idea that dopamine activity underlies the motivation or drive to sing, but that opioid release is what makes song production rewarding. Copyright 2009 Elsevier B.V. All rights reserved.

  9. Opioid use following gynecologic and pelvic reconstructive surgery.

    Science.gov (United States)

    Hota, Lekha S; Warda, Hussein A; Haviland, Miriam J; Searle, Frances M; Hacker, Michele R

    2017-09-09

    Opioid use, addiction, and overdose are a growing epidemic in the USA. Our objective was to determine whether the amount of opioid medication prescribed following gynecologic and pelvic reconstructive surgery is insufficient, adequate, or in excess. We hypothesized that we were overprescribing postoperative opioids. Participants who were at least 18 years old and underwent gynecologic and/or pelvic reconstructive surgery from April through August 2016 were eligible to participate. Routine practice for pain management is to prescribe 30 tablets of opioids for major procedures and ten to 15 tablets for minor procedures. At the 2-week postoperative visit, participants completed a questionnaire regarding the number of tablets prescribed and used, postoperative pain control, and relevant medical history. Fisher's exact test was used to compare data. Sixty-five participants completed questionnaires. Half (49.1%) reported being prescribed more opioids than needed, while two (3.5%) felt the amount was less than needed. Though not significant, participants who underwent major surgeries were more likely to report being prescribed more than needed (53.5%) compared with participants who underwent minor surgeries (35.7%; p = 0.47). Though not significant, participants with anxiety were less likely to report being prescribed more tablets than needed compared with participants without anxiety (44.4% vs. 57.1%; p = 0.38). This was also true of participants with depression compared with those without (37.5% vs. 58.3%; p = 0.17), and those with chronic pain compared with those without (33.3% vs. 60.0%; p = 0.10). Our current opioid prescription practice for postoperative pain management may exceed what patients need.

  10. Peripheral δ-opioid receptors attenuate the exercise pressor reflex.

    Science.gov (United States)

    Leal, Anna K; Yamauchi, Katsuya; Kim, Joyce; Ruiz-Velasco, Victor; Kaufman, Marc P

    2013-10-15

    In rats with ligated femoral arteries, the exercise pressor reflex is exaggerated, an effect that is attenuated by stimulation of peripheral μ-opioid receptors on group IV metabosensitive afferents. In contrast, δ-opioid receptors are expressed mostly on group III mechanosensitive afferents, a finding that prompted us to determine whether stimulation of these opioid receptors could also attenuate the exaggerated exercise pressor reflex in "ligated" rats. We found femoral arterial injection of [D-Pen2,D-Pen5]enkephalin (DPDPE; 1.0 μg), a δ-opioid agonist, significantly attenuated the pressor and cardioaccelerator components of the exercise pressor reflex evoked by hindlimb muscle contraction in both rats with ligated and patent femoral arteries. DPDPE significantly decreased the pressor responses to muscle mechanoreflex activation, evoked by tendon stretch, in ligated rats only. DPDPE (1.0 μg) had no effect in either group on the pressor and cardioaccelerator responses to capsaicin (0.2 μg), which primarily stimulates group IV afferents. DPDPE (1.0 μg) had no effect on the pressor and cardioaccelerator responses to lactic acid (24 mM), which stimulates group III and IV afferents, in rats with patent femoral arteries but significantly decreased the pressor response in ligated rats. Western blots revealed the amount of protein comprising the δ-opioid receptor was greater in dorsal root ganglia innervating hindlimbs with ligated femoral arteries than in dorsal root ganglia innervating hindlimbs with patent femoral arteries. Our findings support the hypothesis that stimulation of δ-opioid receptors on group III afferents attenuated the exercise pressor reflex.

  11. In-hospital resuscitation: opioids and other factors influencing survival

    Directory of Open Access Journals (Sweden)

    Karamarie Fecho

    2009-12-01

    Full Text Available Karamarie Fecho1, Freeman Jackson1, Frances Smith1, Frank J Overdyk21Department of Anesthesiology, University of North Carolina, Chapel Hill, North Carolina, USA; 2Department of Anesthesia and Perioperative Medicine, Medical University of South Carolina, Charleston, South Carolina, USAPurpose: “Code Blue” is a standard term used to alertt hospital staff that a patient requires resuscitation. This study determined rates of survival from Code Blue events and the role of opioids and other factors on survival.Methods: Data derived from medical records and the Code Blue and Pharmacy databases were analyzed for factors affecting survival.Results: During 2006, rates of survival from the code only and to discharge were 25.9% and 26.4%, respectively, for Code Blue events involving cardiopulmonary resuscitation (CPR; N = 216. Survival rates for events not ultimately requiring CPR (N = 77 were higher, with 32.5% surviving the code only and 62.3% surviving to discharge. For CPR events, rates of survival to discharge correlated inversely with time to chest compressions and defibrillation, precipitating event, need for airway management, location and age. Time of week, witnessing, postoperative status, gender and opioid use did not influence survival rates. For non-CPR events, opioid use was associated with decreased survival. Survival rates were lowest for patients receiving continuous infusions (P < 0.01 or iv boluses of opioids (P < 0.05.Conclusions: One-quarter of patients survive to discharge after a CPR Code Blue event and two-thirds survive to discharge after a non-CPR event. Opioids may influence survival from non-CPR events.Keywords: code blue, survival, opioids, cardiopulmonary resuscitation, cardiac arrest, patient safety

  12. Impact of Prior Therapeutic Opioid Use by Emergency Department Providers on Opioid Prescribing Decisions

    Directory of Open Access Journals (Sweden)

    Adam C Pomerleau

    2016-11-01

    Full Text Available INTRODUCTION: Our study sought to examine the opioid analgesic (OA prescribing decisions of emergency department (ED providers who have themselves used OA therapeutically and those who have not. A second objective was to determine if OA prescribing decisions would differ based on the patient's relationship to the provider. METHODS: We distributed an electronic survey to a random sample of ED providers at participating centers in a nationwide research consortium. Question topics included provider attitudes about OA prescribing, prior personal therapeutic use of OAs (indications, dosing, and disposal of leftover medication, and hypothetical analgesic-prescribing decisions for their patients, family members, and themselves for different painful conditions. RESULTS: The total survey population was 957 individuals; 515 responded to the survey, a 54% response rate. Prior personal therapeutic OA use was reported in 63% (95% CI = [58-68]. A majority of these providers (82%; 95% CI = [77-87] took fewer than half the number of pills prescribed. Regarding provider attitudes towards OA prescribing, 66% (95% CI = [61-71] agreed that OA could lead to addiction even with short-term use. When providers were asked if they would prescribe OA to a patient with 10/10 pain from an ankle sprain, 21% (95% CI = [17-25] would for an adult patient, 13% (95% CI = [10-16] would for an adult family member, and 6% (95% CI = [4-8] indicated they themselves would take an opioid for the same pain. When the scenario involved an ankle fracture, 86% (95% CI = [83-89] would prescribe OA for an adult patient, 75% (95% CI = [71-79] for an adult family member, and 52% (95% CI = [47-57] would themselves take OA. Providers who have personally used OA to treat their pain were found to make similar prescribing decisions compared to those who had not. CONCLUSION: No consistent differences in prescribing decisions were found between ED providers based on their prior therapeutic use of OA

  13. Willingness to pay for opioid agonist treatment among opioid dependent people who inject drugs in Ukraine.

    Science.gov (United States)

    Makarenko, Iuliia; Mazhnaya, Alyona; Marcus, Ruthanne; Bojko, Martha J; Madden, Lynn; Filippovich, Sergii; Dvoriak, Sergii; Altice, Frederick L

    2017-07-01

    In the context of decreasing external and limited Ukrainian governmental funding for opioid agonist treatments (OAT) for opioid dependent people who inject drugs in Ukraine, information on sustainable financial models is needed. Data on 855 opioid dependent people who inject drugs (PWID) were drawn from a cross-sectional nationwide survey of 1613 PWID. They comprised 434 participants who were receiving OAT and 421 who were on OAT in the past or have never been on OAT and were interested in receiving the treatment. Multivariate logistic regression was used to examine factors associated with willingness-to-pay (WTP) for OAT, stratified by OAT experience. Variation in the price which respondents were willing to pay for OAT and its effect on their monthly income among PWID with different OAT experience were assessed as a continuous variable using one-way ANOVA and Kruskal-Wallis test. Overall, 378 (44%) expressed WTP for OAT. Factors independently associated with WTP differed by OAT experience. Among those using OAT, independent predictors of WTP included: city (Dnipro - aOR=1.9; 95%CI=1.1-4.8 and Lviv - (aOR=2.2; 95%CI=1.1-4.8) compared to those elsewhere in Ukraine), higher income (aOR=1.8; 95%CI=1.2-2.7) and receiving psychosocial counseling (aOR=1.8; 95%CI=1.2-2.7). Among those who had previously been on OAT, positive attitude towards OAT (aOR=1.3; 95%CI=1.1-1.6) and family support of OAT (aOR=2.5; 95%CI=1.1-5.7) were independently associated with WTP. Among PWID who had never been on OAT, being male (aOR=2.2; 95%CI=1.1-4.2), younger age (aOR=1.9; 95%CI=1.2-3.2), higher income (aOR=2.0; 95%CI=1.2-3.4) and previous unsuccessful attempts to enter OAT (aOR=2.3; 95%CI=1.1-4.7) were independently associated with WTP. PWID were willing to commit a large percentage of their monthly income for OAT, which, however, varied significantly based on OAT experience: current OAT: 37% of monthly income, previous OAT: 53%, and never OAT: 60% (p-value=0.0009). WTP for OAT was

  14. Prescription opioid use: Patient characteristics and misuse in community pharmacy.

    Science.gov (United States)

    Cochran, Gerald; Bacci, Jennifer L; Ylioja, Thomas; Hruschak, Valerie; Miller, Sharon; Seybert, Amy L; Tarter, Ralph

    2016-01-01

    Opioid pain medication misuse is a major concern for US public health. The purpose of this article is to: 1) describe the demographic and physical, behavioral, and mental health characteristics of patients who fill opioid medications in community pharmacy settings; and 2) describe the extent of opioid medication misuse behaviors among these patients. We recruited and screened a convenience sample of patients with the use of a tablet computer-based assessment protocol that examined behavioral, mental, and physical health. Descriptive and inferential statistics were calculated to describe respondents and their opioid medication misuse and health characteristics. Patients were screened in 2 urban and 2 rural community pharmacies in southwestern Pennsylvania. Survey participants were adult patients filling opioid pain medications who were not currently receiving treatment for a cancer diagnosis. None. Validated screening measures included the Prescription Opioid Misuse Index, Alcohol Use Disorders Identification Test C, Short Form 12, Drug Abuse Screening Test 10, Primary Care Post-traumatic Stress Disorder (PTSD) screen, and the Patient Health Questionnaire 2. A total of 333 patients were screened (71.2% response rate). Nearly the entire population reported pain above and general health below national norms. Hydrocodone (19.2%) and morphine (20.8%) were found to be the medications with the highest rates of misuse-with hydrocodone having more than 4 times higher odds of misuse compared with other medications (adjusted odds ratio [AOR] 4.48, 95% confidence interval [CI] 1.1-17.4). Patients with positive screens for illicit drug use (AOR 8.07, 95% CI 2.7-24.0), PTSD (AOR 5.88, 95% CI 2.3-14.7), and depression (AOR 2.44, 95% CI 1.0-5.9) also had significantly higher odds for misuse compared with those with negative screening results. These findings provide important foundational data that suggest implementation of regular opioid misuse screening protocols within

  15. The US Opioid Crisis: Current Federal and State Legal Issues.

    Science.gov (United States)

    Soelberg, Cobin D; Brown, Raeford E; Du Vivier, Derick; Meyer, John E; Ramachandran, Banu K

    2017-11-01

    The United States is in the midst of a devastating opioid misuse epidemic leading to over 33,000 deaths per year from both prescription and illegal opioids. Roughly half of these deaths are attributable to prescription opioids. Federal and state governments have only recently begun to grasp the magnitude of this public health crisis. In 2016, the Centers for Disease Control and Prevention released their Guidelines for Prescribing Opioids for Chronic Pain. While not comprehensive in scope, these guidelines attempt to control and regulate opioid prescribing. Other federal agencies involved with the federal regulatory effort include the Food and Drug Administration (FDA), the Drug Enforcement Agency (DEA), and the Department of Justice. Each federal agency has a unique role in helping to stem the burgeoning opioid misuse epidemic. The DEA, working with the Department of Justice, has enforcement power to prosecute pill mills and physicians for illegal prescribing. The DEA could also implement use of prescription drug monitoring programs (PDMPs), currently administered at the state level, and use of electronic prescribing for schedule II and III medications. The FDA has authority to approve new and safer formulations of immediate- and long-acting opioid medications. More importantly, the FDA can also ask pharmaceutical companies to cease manufacturing a drug. Additionally, state agencies play a critical role in reducing overdose deaths, protecting the public safety, and promoting the medically appropriate treatment of pain. One of the states' primary roles is the regulation of practice of medicine and the insurance industry within their borders. Utilizing this authority, states can both educate physicians about the dangers of opioids and make physician licensure dependent on registering and using PDMPs when prescribing controlled substances. Almost every state has implemented a PDMP to some degree; however, in addition to mandating their use, increased interstate

  16. Pain relief and clinical outcome: from opioids to balanced analgesia

    DEFF Research Database (Denmark)

    Kehlet, H

    1996-01-01

    If it is generally accepted that adequate postoperative pain relief will improve outcome from surgery, several controlled trials demonstrated this only for lower body surgical procedures with epidural and spinal anesthetics. Important effects on outcome were not shown when postoperative opioids...... were administered with patient controlled (PCA) or epidural techniques. However, the most optimal pain relief seems to be best achieved with balanced analgesia techniques using combinations of epidural opioids and local anesthetics and systemic non-steroidal antiinflammatory drugs. Future efforts...... should aim at including physical rehabilitation programs in the pain treatment regimen....

  17. Predictors of opioid efficacy in patients with chronic pain

    DEFF Research Database (Denmark)

    Grosen, Kasper; Olesen, Anne E; Gram, Mikkel

    2017-01-01

    of life after 14 days of opioid treatment. Secondary outcomes included patient's global impression of clinical change and side effects. Logistic regression models adjusted for age and sex were used to identify biomarkers predictive for successful treatment, defined as at least a 30% reduction in average.......03), relative delta (OR: 0.76; P = 0.03) and beta EEG activity (OR: 1.18; P = 0.04) induced by experimental cold pain. None of the study variables were related to improvement in quality of life. For the first time, individual pain processing characteristics have been linked to opioid response in a mixed chronic...

  18. Mu opioid receptor binding sites in human brain

    International Nuclear Information System (INIS)

    Pilapil, C.; Welner, S.; Magnan, J.; Zamir, N.; Quirion, R.

    1986-01-01

    Our experiments focused on the examination of the distribution of mu opioid receptor binding sites in normal human brain using the highly selective ligand [ 3 H]DAGO, in both membrane binding assay and in vitro receptor autoradiography. Mu opioid binding sites are very discretely distributed in human brain with high densities of sites found in the posterior amygdala, caudate, putamen, hypothalamus and certain cortical areas. Moreover the autoradiographic distribution of [ 3 H]DAGO binding sites clearly reveals the discrete lamination (layers I and III-IV) of mu sites in cortical areas

  19. Opioid receptor desensitization: mechanisms and its link to tolerance

    Directory of Open Access Journals (Sweden)

    Stéphane eAllouche

    2014-12-01

    Full Text Available Opioid receptors are part of the class A of G-protein coupled receptors and the target of the opiates, the most powerful analgesic molecules used in clinic. During a protracted use, a tolerance to analgesic effect develops resulting in a reduction of the effectiveness. So understanding mechanisms of tolerance is a great challenge and may help to find new strategies to tackle this side effect. This review will summarize receptor-related mechanisms that could underlie tolerance especially receptor desensitization. We will focus on the latest data obtained on molecular mechanisms involved in opioid receptor desensitization: phosphorylation, receptor uncoupling, internalization and post-endocytic fate of the receptor.

  20. Pavlovian conditioning of multiple opioid-like responses in mice

    OpenAIRE

    Bryant, Camron D.; Roberts, Kristofer W.; Culbertson, Christopher S.; Le, Alan; Evans, Christopher J.; Fanselow, Michael S.

    2009-01-01

    Conditional responses in rodents such as locomotion have been reported for drugs of abuse and similar to the placebo response in humans, may be associated with the expectation of reward. We examined several conditional opioid-like responses and the influence of drug expectation on conditioned place preference and concomitant conditional locomotion. Male C57BL/6J mice were conditioned with the selective mu opioid receptor agonist fentanyl (0.2 mg/kg, i.p.) in a novel context and subsequently g...

  1. Antimicrobial Peptides: An Introduction.

    Science.gov (United States)

    Haney, Evan F; Mansour, Sarah C; Hancock, Robert E W

    2017-01-01

    The "golden era" of antibiotic discovery has long passed, but the need for new antibiotics has never been greater due to the emerging threat of antibiotic resistance. This urgency to develop new antibiotics has motivated researchers to find new methods to combat pathogenic microorganisms resulting in a surge of research focused around antimicrobial peptides (AMPs; also termed host defense peptides) and their potential as therapeutics. During the past few decades, more than 2000 AMPs have been identified from a diverse range of organisms (animals, fungi, plants, and bacteria). While these AMPs share a number of common features and a limited number of structural motifs; their sequences, activities, and targets differ considerably. In addition to their antimicrobial effects, AMPs can also exhibit immunomodulatory, anti-biofilm, and anticancer activities. These diverse functions have spurred tremendous interest in research aimed at understanding the activity of AMPs, and various protocols have been described to assess different aspects of AMP function including screening and evaluating the activities of natural and synthetic AMPs, measuring interactions with membranes, optimizing peptide function, and scaling up peptide production. Here, we provide a general overview of AMPs and introduce some of the methodologies that have been used to advance AMP research.

  2. Pain Therapy Guided by Purpose and Perspective in Light of the Opioid Epidemic

    Directory of Open Access Journals (Sweden)

    Amie L. Severino

    2018-04-01

    Full Text Available Prescription opioid misuse is an ongoing and escalating epidemic. Although these pharmacological agents are highly effective analgesics prescribed for different types of pain, opioids also induce euphoria, leading to increasing diversion and misuse. Opioid use and related mortalities have developed in spite of initial claims that OxyContin, one of the first opioids prescribed in the USA, was not addictive in the presence of pain. These claims allayed the fears of clinicians and contributed to an increase in the number of prescriptions, quantity of drugs manufactured, and the unforeseen diversion of these drugs for non-medical uses. Understanding the history of opioid drug development, the widespread marketing campaign for opioids, the immense financial incentive behind the treatment of pain, and vulnerable socioeconomic and physical demographics for opioid misuse give perspective on the current epidemic as an American-born problem that has expanded to global significance. In light of the current worldwide opioid epidemic, it is imperative that novel opioids are developed to treat pain without inducing the euphoria that fosters physical dependence and addiction. We describe insights from preclinical findings on the properties of opioid drugs that offer insights into improving abuse-deterrent formulations. One finding is that the ability of some agonists to activate one pathway over another, or agonist bias, can predict whether several novel opioid compounds bear promise in treating pain without causing reward among other off-target effects. In addition, we outline how the pharmacokinetic profile of each opioid contributes to their potential for misuse and discuss the emergence of mixed agonists as a promising pipeline of opioid-based analgesics. These insights from preclinical findings can be used to more effectively identify opioids that treat pain without causing physical dependence and subsequent opioid abuse.

  3. Pain Therapy Guided by Purpose and Perspective in Light of the Opioid Epidemic

    Science.gov (United States)

    Severino, Amie L.; Shadfar, Arash; Hakimian, Joshua K.; Crane, Oliver; Singh, Ganeev; Heinzerling, Keith; Walwyn, Wendy M.

    2018-01-01

    Prescription opioid misuse is an ongoing and escalating epidemic. Although these pharmacological agents are highly effective analgesics prescribed for different types of pain, opioids also induce euphoria, leading to increasing diversion and misuse. Opioid use and related mortalities have developed in spite of initial claims that OxyContin, one of the first opioids prescribed in the USA, was not addictive in the presence of pain. These claims allayed the fears of clinicians and contributed to an increase in the number of prescriptions, quantity of drugs manufactured, and the unforeseen diversion of these drugs for non-medical uses. Understanding the history of opioid drug development, the widespread marketing campaign for opioids, the immense financial incentive behind the treatment of pain, and vulnerable socioeconomic and physical demographics for opioid misuse give perspective on the current epidemic as an American-born problem that has expanded to global significance. In light of the current worldwide opioid epidemic, it is imperative that novel opioids are developed to treat pain without inducing the euphoria that fosters physical dependence and addiction. We describe insights from preclinical findings on the properties of opioid drugs that offer insights into improving abuse-deterrent formulations. One finding is that the ability of some agonists to activate one pathway over another, or agonist bias, can predict whether several novel opioid compounds bear promise in treating pain without causing reward among other off-target effects. In addition, we outline how the pharmacokinetic profile of each opioid contributes to their potential for misuse and discuss the emergence of mixed agonists as a promising pipeline of opioid-based analgesics. These insights from preclinical findings can be used to more effectively identify opioids that treat pain without causing physical dependence and subsequent opioid abuse. PMID:29740351

  4. Intraoperative ketamine reduces immediate postoperative opioid consumption after spinal fusion surgery in chronic pain patients with opioid dependency

    DEFF Research Database (Denmark)

    Nielsen, Rikke Vibeke; Fomsgaard, Jonna Storm; Siegel, Hanna

    2017-01-01

    Perioperative handling of surgical patients with opioid dependency represents an important clinical problem. Animal studies suggest that ketamine attenuates central sensitization and hyperalgesia and thereby reduces postoperative opioid tolerance. We hypothesized that intraoperative ketamine would...... to 24 hours postoperatively (visual analogue scale), adverse events, and persistent pain 6 months postoperatively. One hundred fifty patients were randomly assigned to intraoperative S-ketamine bolus 0.5 mg/kg and infusion 0.25 mg·kg·h or placebo. Postoperatively, patients received their usual opioids......, paracetamol and IV patient-controlled analgesia with morphine. In the final analyses, 147 patients were included. Patient-controlled analgesia IV morphine consumption 0 to 24 hours postoperatively was significantly reduced in the ketamine group compared with the placebo group: 79 (47) vs 121 (53) mg IV, mean...

  5. Opioid abusers’ ability to differentiate an opioid from placebo in laboratory challenge testing*

    Science.gov (United States)

    Antoine, Denis G.; Strain, Eric C.; Tompkins, D. Andrew; Bigelow, George E.

    2013-01-01

    Background Abuse liability assessments influence drug development, federal regulation, and clinical care. One suggested procedure to reduce variability of assessments is a qualification phase, which assesses whether study applicants adequately distinguish active drug from placebo; applicants failing to make this distinction are disqualified. The present analyses assessed differences between qualification phase qualifiers and non-qualifiers. Methods Data were collected from 23 completers of the qualification phase of an abuse liability study. Opioid abusing participants received 30 mg oxycodone and placebo orally on separate days, and were characterized as qualifiers (vs. non-qualifiers) if their peak visual analog scale liking rating for oxycodone was at least 20 points higher than placebo’s peak rating. Groups were compared on demographic characteristics, drug history, and physiologic, subject and observer ratings. Results 61% of participants were qualifiers and 39% were non-qualifiers. Groups had similar demographic characteristics, drug use histories, and pupillary constriction responses. However, unlike qualifiers, non-qualifiers had an exaggerated placebo response for the liking score (p=0.03) and an attenuated oxycodone response for the liking score (p<.0001). Non-qualifiers’ failure to differentiate oxycodone versus placebo was evident for subject and observer ratings. Conclusion Different subjective responses to identical stimuli support the use of a qualification phase in abuse liability assessments. Further research should explore objective measures that may better account for these differences, determine optimal qualification criteria, and explore the developmental course of drug use. This study also documents certain opioid abusers fail to differentiate 30 mg of oxycodone from placebo, a phenomenon deserving further study. PMID:23369645

  6. Comparative Analysis of Inpatient Costs for Obstetrics and Gynecology Surgery Patients Treated With IV Acetaminophen and IV Opioids Versus IV Opioid-only Analgesia for Postoperative Pain.

    Science.gov (United States)

    Hansen, Ryan N; Pham, An T; Lovelace, Belinda; Balaban, Stela; Wan, George J

    2017-10-01

    Recovery from obstetrics and gynecology (OB/GYN) surgery, including hysterectomy and cesarean section delivery, aims to restore function while minimizing hospital length of stay (LOS) and medical expenditures. Our analyses compare OB/GYN surgery patients who received combination intravenous (IV) acetaminophen and IV opioid analgesia with those who received IV opioid-only analgesia and estimate differences in LOS, hospitalization costs, and opioid consumption. We performed a retrospective analysis of the Premier Database between January 2009 and June 2015, comparing OB/GYN surgery patients who received postoperative pain management with combination IV acetaminophen and IV opioids with those who received only IV opioids starting on the day of surgery and continuing up to the second postoperative day. We performed instrumental variable 2-stage least-squares regressions controlling for patient and hospital covariates to compare the LOS, hospitalization costs, and daily opioid doses (morphine equivalent dose) of IV acetaminophen recipients with that of opioid-only analgesia patients. We identified 225 142 OB/GYN surgery patients who were eligible for our study of whom 89 568 (40%) had been managed with IV acetaminophen and opioids. Participants averaged 36 years of age and were predominantly non-Hispanic Caucasians (60%). Multivariable regression models estimated statistically significant differences in hospitalization cost and opioid use with IV acetaminophen associated with $484.4 lower total hospitalization costs (95% CI = -$760.4 to -$208.4; P = 0.0006) and 8.2 mg lower daily opioid use (95% CI = -10.0 to -6.4), whereas the difference in LOS was not significant, at -0.09 days (95% CI = -0.19 to 0.01; P = 0.07). Compared with IV opioid-only analgesia, managing post-OB/GYN surgery pain with the addition of IV acetaminophen is associated with decreased hospitalization costs and reduced opioid use.

  7. Comparison of the risks of shopping behavior and opioid abuse between tapentadol and oxycodone and association of shopping behavior and opioid abuse.

    Science.gov (United States)

    Cepeda, M Soledad; Fife, Daniel; Kihm, Mary A; Mastrogiovanni, Greg; Yuan, Yingli

    2014-12-01

    This study compared the risks of opioid shopping behavior and opioid abuse between tapentadol immediate release and oxycodone immediate release and, to validate the definition of shopping, examined the association between opioid shopping and opioid abuse further. This retrospective cohort study using linked dispensing and diagnosis databases followed opioid-naive patients for development of shopping behavior and/or opioid abuse during 1 year after initial exposure to tapentadol or oxycodone. Shopping was defined by having overlapping opioid prescriptions from >1 prescriber filled at ≥3 pharmacies; abuse by having International Classification of Diseases, 9th revision diagnoses reflecting opioid abuse, addiction, or dependence. To determine their association, we cross-tabulated shopping and opioid abuse and calculated odds ratios. Risks of developing each outcome were estimated using logistic regression. Among 277,401 participants initiating opioid use with tapentadol (39,524) or oxycodone (237,877), 0.6% developed shopping behavior, 0.75% developed abuse. Higher proportions of patients in the oxycodone group developed shopping behavior and abuse than in the tapentadol group (shopping: adjusted odds ratio [95% confidence interval], 0.45 [0.36-0.55]; abuse: 0.44 [0.37-0.54]). Shopping behavior and abuse were associated; of those with shopping behavior, 6.5% had abuse. Age (18 to 64 y), sex (male), prior benzodiazepine use, paying cash, and history (mood disorders, abuse of nonopioid medications, and back pain) were risk factors for developing either outcome. Shopping behavior and abuse measure complementary, but associated, constructs, which further validates the current definition of shopping. The risk of developing either is lower among patients who initiate opioid use with tapentadol than those who initiate opioid use with oxycodone.

  8. Parenteral opioids for maternal pain management in labour.

    Science.gov (United States)

    Smith, Lesley A; Burns, Ethel; Cuthbert, Anna

    2018-06-05

    Parenteral opioids (intramuscular and intravenous drugs including patient-controlled analgesia) are used for pain relief in labour in many countries throughout the world. This review is an update of a review first published in 2010. To assess the effectiveness, safety and acceptability to women of different types, doses and modes of administration of parenteral opioid analgesia in labour. A second objective is to assess the effects of opioids in labour on the baby in terms of safety, condition at birth and early feeding. We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (11 May 2017) and reference lists of retrieved studies. We included randomised controlled trials examining the use of intramuscular or intravenous opioids (including patient-controlled analgesia) for women in labour. Cluster-randomised trials were also eligible for inclusion, although none were identified. We did not include quasi-randomised trials. We looked at studies comparing an opioid with another opioid, placebo, no treatment, other non-pharmacological interventions (transcutaneous electrical nerve stimulation (TENS)) or inhaled analgesia. Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the quality of each evidence synthesis using the GRADE approach. We included 70 studies that compared an opioid with placebo or no treatment, another opioid administered intramuscularly or intravenously or compared with TENS applied to the back. Sixty-one studies involving more than 8000 women contributed data to the review and these studies reported on 34 different comparisons; for many comparisons and outcomes only one study contributed data. All of the studies were conducted in hospital settings, on healthy women with uncomplicated pregnancies at 37 to 42 weeks' gestation. We excluded studies focusing on women with pre

  9. [Distiller Yeasts Producing Antibacterial Peptides].

    Science.gov (United States)

    Klyachko, E V; Morozkina, E V; Zaitchik, B Ts; Benevolensky, S V

    2015-01-01

    A new method of controlling lactic acid bacteria contamination was developed with the use of recombinant Saccharomyces cerevisiae strains producing antibacterial peptides. Genes encoding the antibacterial peptides pediocin and plantaricin with codons preferable for S. cerevisiae were synthesized, and a system was constructed for their secretory expression. Recombinant S. cerevisiae strains producing antibacterial peptides effectively inhibit the growth of Lactobacillus sakei, Pediacoccus pentasaceus, Pediacoccus acidilactici, etc. The application of distiller yeasts producing antibacterial peptides enhances the ethanol yield in cases of bacterial contamination. Recombinant yeasts producing the antibacterial peptides pediocin and plantaricin can successfully substitute the available industrial yeast strains upon ethanol production.

  10. Pharmacological characterization of EN-9, a novel chimeric peptide of endomorphin-2 and neuropeptide FF that produces potent antinociceptive activity and limited tolerance.

    Science.gov (United States)

    Wang, Zi-Long; Li, Ning; Wang, Pei; Tang, Hong-Hai; Han, Zheng-Lan; Song, Jing-Jing; Li, Xu-Hui; Yu, Hong-Ping; Zhang, Ting; Zhang, Run; Xu, Biao; Zhang, Meng-Na; Fang, Quan; Wang, Rui

    2016-09-01

    Mounting evidences indicate the functional interactions between neuropeptide FF (NPFF) and opioids, including the endogenous opioids. In the present work, EN-9, a chimeric peptide containing the functional domains of the endogenous opioid endomorphin-2 (EM-2) and NPFF, was synthesized and pharmacologically characterized. In vitro cAMP assay demonstrated that EN-9 was a multifunctional agonist of κ-opioid, NPFF1 and NPFF2 receptors. In the mouse tail-flick test, intracerebroventricularly (i.c.v.) administration of EN-9 produced significant antinociception with an ED50 value of 13.44 nmol, which lasted longer than that of EM-2. In addition, EN-9 induced potent antinociception after both intravenous (i.v.) and subcutaneous (s.c.) injection. Furthermore, the experiments using the antagonists of opioid and NPFF receptors indicated that the central antinociception of EN-9 was mainly mediated by κ-opioid receptor, independently on NPFF receptors. Notably, the central antinociception of EN-9 was not reduced over a period of 6 days repeated i.c.v. injection. Repeated i.c.v. administration of EN-9 with the NPFF1 and NPFF2 receptors antagonist RF9 resulted in a progressive loss of analgesic potency, consistent with the development of tolerance. Moreover, central administration of EN-9 induced the place conditioning aversion only at a high dose of 60 nmol, but not at low doses. At supraspinal level, only high dose of EN-9 (60 nmol, i.c.v.) inhibited gastrointestinal transit via NPFF receptors. Similarly, systemic administration of EN-9 also inhibited gastrointestinal transit at high doses (10 and 30 mg/kg, i.v.). Taken together, the multifunctional agonist of κ-opioid and NPFF receptors EN-9 produced a potent, non-tolerance forming antinociception with limited side effects. Copyright © 2016. Published by Elsevier Ltd.

  11. Opioid shopping behavior: how often, how soon, which drugs, and what payment method.

    Science.gov (United States)

    Cepeda, M Soledad; Fife, Daniel; Chow, Wing; Mastrogiovanni, Gregory; Henderson, Scott C

    2013-01-01

    Doctor shopping (obtaining opioid prescriptions from multiple prescribers) is one example of opioid abuse and diversion. The authors assessed how soon shopping behavior was observed after opioid exposure, number of events per shopper, preferred opioids, and method of payment. This was a cohort study. Individuals with ≤1 dispensing for any opioid in 2008 were followed for 18 months. Shopping behavior was defined as ≤2 prescriptions by different prescribers with ≤1 day of overlap and filled at ≤3 pharmacies. Of 25,161,024 subjects, 0.30% exhibited shopping behavior. Opioid-experienced subjects were 13.7 times more likely to exhibit shopping behavior and had more shopping episodes than opioid-naive subjects. Time to first shopping event was 246.90 ± 163.61 days. Number of episodes was 2.74 ± 4.66. Most subjects with shopping behavior (55.27%) had 1 shopping episode, whereas 9.52% had ≤6 episodes; 88.99% had ≤4 prescribers. Subjects with shopping behavior filled schedule II opioids more often than subjects without shopping behavior (19.51% vs 10.89%) and more often paid in cash (44.85% vs 18.54%). Three of 1000 people exposed to opioids exhibit shopping behavior, on average, 8 months after exposure. Opioid shoppers seek strong opioids, avoid combination products, often pay cash, and obtain prescriptions from few prescribers. © 2012 The Author(s).

  12. Autism and urinary exogenous neuropeptides: development of an on-line SPE-HPLC-tandem mass spectrometry method to test the opioid excess theory.

    Science.gov (United States)

    Dettmer, K; Hanna, D; Whetstone, P; Hansen, R; Hammock, B D

    2007-08-01

    Autism is a complex neurodevelopmental disorder with unknown etiology. One hypothesis regarding etiology in autism is the "opioid peptide excess" theory that postulates that excessive amounts of exogenous opioid-like peptides derived from dietary proteins are detectable in urine and that these compounds may be pathophysiologically important in autism. A selective LC-MS/MS method was developed to analyze gliadinomorphin, beta-casomorphin, deltorphin 1, and deltorphin 2 in urine. The method is based on on-line SPE extraction of the neuropeptides from urine, column switching, and subsequent HPLC analysis. A limit of detection of 0.25 ng/mL was achieved for all analytes. Analyte recovery rates from urine ranged between 78% and 94%, with relative standard deviations of 0.2-6.8%. The method was used to screen 69 urine samples from children with and without autism spectrum disorders for the occurrence of neuropeptides. The target neuropeptides were not detected above the detection limit in either sample set.

  13. Disruption of δ-opioid receptor phosphorylation at threonine 161 attenuates morphine tolerance in rats with CFA-induced inflammatory hypersensitivity.

    Science.gov (United States)

    Chen, Hai-Jing; Xie, Wei-Yan; Hu, Fang; Zhang, Ying; Wang, Jun; Wang, Yun

    2012-04-01

    Our previous study identified Threonine 161 (Thr-161), located in the second intracellular loop of the δ-opioid receptor (DOR), as the only consensus phosphorylation site for cyclin-dependent kinase 5 (Cdk5). The aim of this study was to assess the function of DOR phosphorylation by Cdk5 in complete Freund's adjuvant (CFA)-induced inflammatory pain and morphine tolerance. Dorsal root ganglion (DRG) neurons of rats with CFA-induced inflammatory pain were acutely dissociated and the biotinylation method was used to explore the membrane localization of phosphorylated DOR at Thr-161 (pThr-161-DOR), and paw withdrawal latency was measured after intrathecal delivery of drugs or Tat-peptide, using a radiant heat stimulator in rats with CFA-induced inflammatory pain. Both the total amount and the surface localization of pThr-161-DOR were significantly enhanced in the ipsilateral DRG following CFA injection. Intrathecal delivery of the engineered Tat fusion-interefering peptide corresponding to the second intracellular loop of DOR (Tat-DOR-2L) increased inflammatory hypersensitivity, and inhibited DOR- but not µ-opioid receptor-mediated spinal analgesia in CFA-treated rats. However, intrathecal delivery of Tat-DOR-2L postponed morphine antinociceptive tolerance in rats with CFA-induced inflammatory pain. Phosphorylation of DOR at Thr-161 by Cdk5 attenuates hypersensitivity and potentiates morphine tolerance in rats with CFA-induced inflammatory pain, while disruption of the phosphorylation of DOR at Thr-161 attenuates morphine tolerance.

  14. Successful Treatment of Opioid-Refractory Cancer Pain with Short-Course, Low-Dose Ketamine.

    Science.gov (United States)

    Waldfogel, Julie M; Nesbit, Suzanne; Cohen, Steven P; Dy, Sydney M

    2016-12-01

    Opioids remain the mainstay of treatment for severe cancer pain, but up to 20% of patients have persistent or refractory pain despite rapid and aggressive opioid titration, or develop refractory pain after long-term opioid use. In these scenarios, alternative agents and mechanisms for analgesia should be considered. This case report describes a 28-year-old man with metastatic pancreatic neuroendocrine cancer with severe, intractable pain despite high-dose opioids including methadone and a hydromorphone patient-controlled analgesia (PCA). After treatment with short-course, low-dose ketamine, his opioid requirements decreased by 99% and pain ratings by 50%, with the majority of this decrease occurring in the first 48 hours. As this patient's pain and opioid regimen escalated, he likely experienced some component of central sensitization and hyperalgesia. Administration of ketamine reduced opioid consumption by 99% and potentially "reset" neuronal hyperexcitability and reduced pain signaling, allowing for improved pain control.

  15. A new and novel treatment of opioid dependence: nigella sativa 500 mg

    International Nuclear Information System (INIS)

    Sangi, S.; Ahmed, S.P.; Channa, M.A.

    2008-01-01

    Opioid dependence is one of the major social and psychiatric problem of society. Unfortunately there is no non opiate treatment available. For centuries man has used plants for their healing proprieties. These plants play a fundamental part in all treatment modalities, both ancient and modern. This study was conducted to find non opiate treatment for opiate withdrawal. Total 35 known addicts of opiates were included in the study. This study was based on DSM IV criteria for opioid dependence. This study demonstrates that non opioid treatment for opioid addiction decreases the withdrawal effects significantly. It further demonstrates that there are no changes in physiological parameters of subjects during treatment (BP, Pulse rate etc.). There is increased appetite but no significant weight gain in the subjects. Non opioid drug Nigella sativa is effective in long term treatment of opioid dependence. It not merely cures the opioid dependence but also cures the infections and weakness from which majority of addicts suffer. (author)

  16. Striatal μ-opioid receptor availability predicts cold pressor pain threshold in healthy human subjects

    DEFF Research Database (Denmark)

    Hagelberg, Nora; Aalto, Sargo; Tuominen, Lauri

    2012-01-01

    the potential associations between μ-opioid receptor BP(ND) and psychophysical measures. The results show that striatal μ-opioid receptor BP(ND) predicts cold pressor pain threshold, but not cold pressor pain tolerance or tactile sensitivity. This finding suggests that striatal μ-opioid receptor density......Previous PET studies in healthy humans have shown that brain μ-opioid receptor activation during experimental pain is associated with reductions in the sensory and affective ratings of the individual pain experience. The aim of this study was to find out whether brain μ-opioid receptor binding...... at the resting state, in absence of painful stimulation, can be a long-term predictor of experimental pain sensitivity. We measured μ-opioid receptor binding potential (BP(ND)) with μ-opioid receptor selective radiotracer [(11)C]carfentanil and positron emission tomography (PET) in 12 healthy male subjects...

  17. Predictors of long-term opioid use among chronic nonmalignant pain patients

    DEFF Research Database (Denmark)

    Hansen, Carrinna; Abrahamsen, Bo

    2016-01-01

    , socioeconomic and demographic characteristics. Data analysis is ongoing. Conclusions: It is expected that this study will serve as a significant supplement of existing knowledge in the area of opioid consumption among CNP patients in Denmark. In a future perspective of prevention and health promotion......Aims: 1) To determine the distribution and determinants of opioid use among chronic nonmalignant pain(CNP) patients. 2) To identify the patient, treatment and socioeconomic characteristics as determinants for potential risk groups. We hypothesized that CNP patient who use opioids for more than 1...... product using the ATC codes N02AA01-N02AX06. Patients were then classified as either opioid use for more than 1 year(group A), as opioid use for more than 6 months but less than 1 year(group B) and opioid use equal to or less than 6 months(group C). Results: The quantity of sold opioids has been...

  18. Clinical utility of naloxegol in the treatment of opioid-induced constipation.

    Science.gov (United States)

    Bruner, Heather C; Atayee, Rabia S; Edmonds, Kyle P; Buckholz, Gary T

    2015-01-01

    Opioids are a class of medications frequently used for the treatment of acute and chronic pain, exerting their desired effects at central opioid receptors. Agonism at peripherally located opioid receptors, however, leads to opioid-induced constipation (OIC), one of the most frequent and debilitating side effects of prolonged opioid use. Insufficient relief of OIC with lifestyle modification and traditional laxative treatments may lead to decreased compliance with opioid regimens and undertreated pain. Peripherally acting mu-opioid receptor antagonists (PAMORAs) offer the reversal of OIC without loss of central pain relief. Until recently, PAMORAs were restricted to subcutaneous route or to narrow patient populations. Naloxegol is the first orally dosed PAMORA indicated for the treatment of OIC in noncancer patients. Studies have suggested its efficacy in patients failing traditional constipation treatments; however, insufficient evidence exists to establish its role in primary prevention of OIC at this time.

  19. Structure, synthesis, and molecular cloning of dermaseptins B, a family of skin peptide antibiotics.

    Science.gov (United States)

    Charpentier, S; Amiche, M; Mester, J; Vouille, V; Le Caer, J P; Nicolas, P; Delfour, A

    1998-06-12

    Analysis of antimicrobial activities that are present in the skin secretions of the South American frog Phyllomedusa bicolor revealed six polycationic (lysine-rich) and amphipathic alpha-helical peptides, 24-33 residues long, termed dermaseptins B1 to B6, respectively. Prepro-dermaseptins B all contain an almost identical signal peptide, which is followed by a conserved acidic propiece, a processing signal Lys-Arg, and a dermaseptin progenitor sequence. The 22-residue signal peptide plus the first 3 residues of the acidic propiece are encoded by conserved nucleotides encompassed by the first coding exon of the dermaseptin genes. The 25-residue amino-terminal region of prepro-dermaseptins B shares 50% identity with the corresponding region of precursors for D-amino acid containing opioid peptides or for antimicrobial peptides originating from the skin of distantly related frog species. The remarkable similarity found between prepro-proteins that encode end products with strikingly different sequences, conformations, biological activities and modes of action suggests that the corresponding genes have evolved through dissemination of a conserved "secretory cassette" exon.

  20. Ligand-regulated peptide aptamers.

    Science.gov (United States)

    Miller, Russell A

    2009-01-01

    The peptide aptamer approach employs high-throughput selection to identify members of a randomized peptide library displayed from a scaffold protein by virtue of their interaction with a target molecule. Extending this approach, we have developed a peptide aptamer scaffold protein that can impart small-molecule control over the aptamer-target interaction. This ligand-regulated peptide (LiRP) scaffold, consisting of the protein domains FKBP12, FRB, and GST, binds to the cell-permeable small-molecule rapamycin and the binding of this molecule can prevent the interaction of the randomizable linker region connecting FKBP12 with FRB. Here we present a detailed protocol for the creation of a peptide aptamer plasmid library, selection of peptide aptamers using the LiRP scaffold in a yeast two-hybrid system, and the screening of those peptide aptamers for a ligand-regulated interaction.

  1. Biosynthesis of cardiac natriuretic peptides

    DEFF Research Database (Denmark)

    Goetze, Jens Peter

    2010-01-01

    Cardiac-derived peptide hormones were identified more than 25 years ago. An astonishing amount of clinical studies have established cardiac natriuretic peptides and their molecular precursors as useful markers of heart disease. In contrast to the clinical applications, the biogenesis of cardiac...... peptides has only been elucidated during the last decade. The cellular synthesis including amino acid modifications and proteolytic cleavages has proven considerably more complex than initially perceived. Consequently, the elimination phase of the peptide products in circulation is not yet well....... An inefficient post-translational prohormone maturation will also affect the biology of the cardiac natriuretic peptide system. This review aims at summarizing the myocardial synthesis of natriuretic peptides focusing on B-type natriuretic peptide, where new data has disclosed cardiac myocytes as highly...

  2. Radiolabelled peptides for oncological diagnosis

    Energy Technology Data Exchange (ETDEWEB)

    Laverman, Peter; Boerman, Otto C.; Oyen, Wim J.G. [Radboud University Nijmegen Medical Centre, Department of Nuclear Medicine, Nijmegen (Netherlands); Sosabowski, Jane K. [Queen Mary University of London, Centre for Molecular Oncology, Barts Cancer Institute, London (United Kingdom)

    2012-02-15

    Radiolabelled receptor-binding peptides targeting receptors (over)expressed on tumour cells are widely under investigation for tumour diagnosis and therapy. The concept of using radiolabelled receptor-binding peptides to target receptor-expressing tissues in vivo has stimulated a large body of research in nuclear medicine. The {sup 111}In-labelled somatostatin analogue octreotide (OctreoScan trademark) is the most successful radiopeptide for tumour imaging, and was the first to be approved for diagnostic use. Based on the success of these studies, other receptor-targeting peptides such as cholecystokinin/gastrin analogues, glucagon-like peptide-1, bombesin (BN), chemokine receptor CXCR4 targeting peptides, and RGD peptides are currently under development or undergoing clinical trials. In this review, we discuss some of these peptides and their analogues, with regard to their potential for radionuclide imaging of tumours. (orig.)

  3. Upregulation of gene expression in reward-modulatory striatal opioid systems by sleep loss.

    Science.gov (United States)

    Baldo, Brian A; Hanlon, Erin C; Obermeyer, William; Bremer, Quentin; Paletz, Elliott; Benca, Ruth M

    2013-12-01

    Epidemiological studies have shown a link between sleep loss and the obesity 'epidemic,' and several observations indicate that sleep curtailment engenders positive energy balance via increased palatable-food 'snacking.' These effects suggest alterations in reward-modulatory brain systems. We explored the effects of 10 days of sleep deprivation in rats on the expression of striatal opioid peptide (OP) genes that subserve food motivation and hedonic reward, and compared effects with those seen in hypothalamic energy balance-regulatory systems. Sleep-deprived (Sleep-Dep) rats were compared with yoked forced-locomotion apparatus controls (App-Controls), food-restricted rats (Food-Restrict), and unmanipulated controls (Home-Cage). Detection of mRNA levels with in situ hybridization revealed a subregion-specific upregulation of striatal preproenkephalin and prodynorhin gene expression in the Sleep-Dep group relative to all other groups. Neuropeptide Y (NPY) gene expression in the hippocampal dentate gyrus and throughout neocortex was also robustly upregulated selectively in the Sleep-Dep group. In contrast, parallel gene expression changes were observed in the Sleep-Dep and Food-Restrict groups in hypothalamic energy-sensing systems (arcuate nucleus NPY was upregulated, and cocaine- and amphetamine-regulated transcript was downregulated), in alignment with leptin suppression in both groups. Together, these results reveal a novel set of sleep deprivation-induced transcriptional changes in reward-modulatory peptide systems, which are dissociable from the energy-balance perturbations of sleep loss or the potentially stressful effects of the forced-locomotion procedure. The recruitment of telencephalic food-reward systems may provide a feeding drive highly resistant to feedback control, which could engender obesity through the enhancement of palatable feeding.

  4. Effects of Rearing Conditions on Behaviour and Endogenous Opioids in Rats with Alcohol Access during Adolescence

    Science.gov (United States)

    Roman, Erika; Nylander, Ingrid

    2013-01-01

    Causal links between early-life stress, genes and later psychiatric diagnoses are not possible to fully address in human studies. Animal models therefore provide an important complement in which conditions can be well controlled and are here used to study and distinguish effects of early-life stress and alcohol exposure. The objective of this study was to investigate the impact of rearing conditions on behaviour in young rats and if these changes could be followed over time and to examine interaction effects between early-life environment and adolescent alcohol drinking on behaviour and immunoreactive levels of the opioid peptides dynorphin B, met-enkephalin-Arg6Phe7 and beta-endorphin. We employed a rodent model, maternal separation, to study the impact of rearing conditions on behaviour, voluntary alcohol consumption and alcohol-induced effects. The consequences of short, 15 min (MS 15), and long, 360 min (MS 360), maternal separation in combination with adolescent voluntary alcohol consumption on behaviour and peptides were examined. A difference in the development of risk taking behaviour was found between the MS15 and MS360 while the development of general activity was found to differ between intake groups. Beta-endorphin levels in the pituitary and the periaqueductal gray area was found to be higher in the MS15 than the MS360. Adolescent drinking resulted in higher dynorphin B levels in the hippocampus and higher met-enkephalin-Arg6Phe7 levels in the amygdala. Amygdala and hippocampus are involved in addiction processes and changes in these brain areas after adolescent alcohol drinking may have consequences for cognitive function and drug consumption behaviour in adulthood. The study shows that individual behavioural profiling over time in combination with neurobiological investigations provides means for studies of causality between early-life stress, behaviour and vulnerability to psychiatric disorders. PMID:24098535

  5. Availability and utilization of opioids for pain management: global issues.

    Science.gov (United States)

    Manjiani, Deepak; Paul, D Baby; Kunnumpurath, Sreekumar; Kaye, Alan David; Vadivelu, Nalini

    2014-01-01

    Pain can significantly influence an individual's health status and can have serious negative consequences: poor nutrition, decreased appetite, abnormal sleep patterns, fatigue, and impairment of daily living activities. Pain can cause psychological impairment and decrease healing and recovery from injuries and illness. A hallmark of many chronic conditions, pain affects more patients' lives than diabetes mellitus, heart disease, and cancer combined. However, many chronic sufferers do not have access to effective pain management for a variety of reasons, including limited access, restrictions, and personal and cultural biases. This review summarizes issues of access, distribution, and cultural bias with regard to opioid agents and seeks to clarify the challenges related to opioid delivery. The considerable negative physical and mental consequences of chronic pain are discussed for the general and palliative care population. Opioids are an effective treatment for various intractable painful conditions, but problems in global opioid access for safe and rational use in pain management contribute to unnecessary suffering. These problems persist despite increased understanding in recent years of the pathophysiology of pain. Comprehensive guidelines for goal-directed and patient-friendly chronic opiate therapy will potentially enhance the outlook for future chronic pain management. The improvement of pain education in undergraduate and postgraduate training will benefit patients and clinicians. The promise of new medications, along with the utilization of multimodal approaches, has the potential to provide effective pain relief to future generations of sufferers.

  6. The Misuse of Prescription Opioids: A Threat for Europe?

    NARCIS (Netherlands)

    van Amsterdam, Jan; van den Brink, Wim

    2015-01-01

    In the the past two decades the medical use of prescription opioids (POs), in particular oxycodone, increased up to 14-fold in the U.S. and Canada. The high consumption of these pain relievers also led to non-medical use and abuse of these substances which in turn resulted in a dramatic increase in

  7. Does naltrexone affect craving in abstinent opioid-dependent patients?

    NARCIS (Netherlands)

    Dijkstra, B.A.G.; Jong, C.A.J. de; Bluschke, S.M.; Krabbe, P.F.M.; Staak, C.P.F. van der

    2007-01-01

    Naltrexone blocks the opioid receptors that modulate the release of dopamine in the brain reward system and therefore blocks the rewarding effects of heroin and alcohol. It is generally assumed that naltrexone leads to reduction of craving, but few studies have been performed to prove this. The

  8. Personality Disorders Classification and Symptoms in Cocaine and Opioid Addicts.

    Science.gov (United States)

    Malow, Robert M.; And Others

    1989-01-01

    Examined extent to which personality disorders and associated symptom criteria were found among 117 cocaine- and opioid-dependent men in drug dependence treatment unit. Drug groups were distinguished by higher rates of antisocial and borderline symptomatology rather than by features associated with other personality disorders. Different…

  9. Identification of Unique Metabolites of the Designer Opioid Furanyl Fentanyl.

    Science.gov (United States)

    Goggin, Melissa M; Nguyen, An; Janis, Gregory C

    2017-06-01

    The illicit drug market has seen an increase in designer opioids, including fentanyl and methadone analogs, and other structurally unrelated opioid agonists. The designer opioid, furanyl fentanyl, is one of many fentanyl analogs clandestinely synthesized for recreational use and contributing to the fentanyl and opioid crisis. A method has been developed and validated for the analysis of furanyl fentanyl and furanyl norfentanyl in urine specimens from pain management programs. Approximately 10% of samples from a set of 500 presumptive heroin-positive urine specimens were found to contain furanyl fentanyl, with an average concentration of 33.8 ng/mL, and ranging from 0.26 to 390 ng/mL. Little to no furanyl norfentanyl was observed; therefore, the furanyl fentanyl specimens were further analyzed by untargeted high-resolution mass spectrometry to identify other metabolites. Multiple metabolites, including a dihydrodiol metabolite, 4-anilino-N-phenethyl-piperidine (4-ANPP) and a sulfate metabolite were identified. The aim of the presented study was to identify the major metabolite(s) of furanyl fentanyl and estimate their concentrations for the purpose of toxicological monitoring. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  10. Addictive behaviors related to opioid use for chronic pain

    DEFF Research Database (Denmark)

    Højsted, Jette; Ekholm, Kim Ola Michael; Kurita, Geana Paula

    2013-01-01

    ,281 individuals were analyzed through multiple logistic regression analyses to assess the association between chronic pain (lasting ⩾6 months), opioid use, health behavior, and body mass index. Six potential addictive behaviors were identified: daily smoking; high alcohol intake; illicit drug use in the past year...

  11. Cognitive function in patients with chronic pain treated with opioids

    DEFF Research Database (Denmark)

    Kurita, G P; de Mattos Pimenta, C A; Braga, P E

    2012-01-01

    The paucity of studies regarding cognitive function in patients with chronic pain, and growing evidence regarding the cognitive effects of pain and opioids on cognitive function prompted us to assess cognition via neuropsychological measurement in patients with chronic non-cancer pain treated...

  12. CDC Vital Signs–Opioid Prescribing

    Centers for Disease Control (CDC) Podcasts

    2017-07-06

    This podcast is based on the July 2017 CDC Vital Signs report. Higher opioid prescribing puts patients at risk for addiction and overdose. Learn what can be done about this serious problem.  Created: 7/6/2017 by Centers for Disease Control and Prevention (CDC).   Date Released: 7/6/2017.

  13. 42 CFR 8.12 - Federal opioid treatment standards.

    Science.gov (United States)

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Federal opioid treatment standards. 8.12 Section 8.12 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS... and administration decisions shall be made by a program physician familiar with the most up-to-date...

  14. Opioid-free anaesthesia in three dogs | White | Open Veterinary ...

    African Journals Online (AJOL)

    A case series of three dogs that underwent OFA for canine ovariohysterectomy is reported. The authors conclude OFA is possible in veterinary medicine; however the move away from the familiar effects of opioids perioperatively is challenging. Gaining experience with these types of protocols for standard procedures in ...

  15. Implementing opioid substitution in Lebanon: Inception and challenges.

    Science.gov (United States)

    El-Khoury, Joseph; Abbas, Zeinab; Nakhle, Pascale E; Matar, Marie-Therese

    2016-05-01

    Opioid Substitution Treatment (OST) is a firmly established method of treating and managing dependence to opioids in Europe, the US and rest of the developed world. It has a solid evidence base and a positive safety track record. Dissemination of its practice, in parallel to the acceptance of harm reduction as an effective approach, is still timid in low and middle Income countries. After years of advocacy on the parts of clinicians and the voluntary sector, the government of Lebanon launched a national opioid substitution program in 2011 using buprenorphine as the substance of substitution. Lebanon is one of the first countries in the MENA region to establish such a program despite a difficult socio-political context. This paper provides the background of harm reduction efforts in the region and presents the outline of the program from inception to present date. Challenges and recommendations for the future are also discussed. The Lebanese experience with opioid substitution is encouraging so far and can be used as a template for others in the region who might be contemplating broadening the range of services available to tackle addiction to heroin and related substances. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Law enforcement attitudes towards naloxone following opioid overdose training.

    Science.gov (United States)

    Purviance, Donna; Ray, Bradley; Tracy, Abigail; Southard, Erik

    2017-01-01

    Opioid intoxication and overdoses are life-threatening emergencies requiring rapid treatment. One response to this has been to train law enforcement to detect the signs of an opioid overdose and train them to administer naloxone to reverse the effects. Although not a new concept, few studies have attempted to examine this policy. At 4 different locations in Indiana, law enforcement personnel were trained to detect the signs of an opioid-related overdose and how to administer naloxone to reverse the effects of the overdose. Pre and post surveys were administered at each location (N = 97). To examine changes in attitudes following training, the authors included items from the Opioid Overdose Attitudes Scale (OOAS), which measures respondents' competency, concerns, and readiness to administer naloxone. Among the full sample, naloxone training resulted in significant increases in competency, concerns, and readiness. Examining changes in attitudes by each location revealed that the training had the greatest effect on competency to administer naloxone and in easing concerns that law enforcement personal might have in administering naloxone. This study adds to others in showing that law enforcement personnel are receptive to naloxone training and that the OOAS is able to capture these attitudes. This study advances this literature by examining pre-post changes across multiple locations. As the distribution of naloxone continues to proliferate, this study and the OOAS may be valuable towards the development of an evidence-based training model for law enforcement.

  17. Opioid use in palliative care | Hosking | Continuing Medical Education

    African Journals Online (AJOL)

    Continuing Medical Education. Journal Home · ABOUT THIS JOURNAL · Advanced Search · Current Issue · Archives · Journal Home > Vol 21, No 5 (2003) >. Log in or Register to get access to full text downloads. Username, Password, Remember me, or Register. Opioid use in palliative care. M Hosking. Abstract.

  18. Opioid prescribing habits of physicians in Kwara State, Nigeria ...

    African Journals Online (AJOL)

    Participants: These were physicians at the monthly workshops organized by the Pain and Palliative Care Unit of the hospital between August 2011 and July, 2012. Interventions: Pre-tested semi-structured questionnaires were used to obtain responses to questions on pain management including opioids utilization in the ...

  19. Borderline Personality Disorder: A Dysregulation of the Endogenous Opioid System?

    Science.gov (United States)

    Bandelow, Borwin; Schmahl, Christian; Falkai, Peter; Wedekind, Dirk

    2010-01-01

    The neurobiology of borderline personality disorder (BPD) remains unclear. Dysfunctions of several neurobiological systems, including serotoninergic, dopaminergic, and other neurotransmitter systems, have been discussed. Here we present a theory that alterations in the sensitivity of opioid receptors or the availability of endogenous opioids…

  20. The cognitive effects of opioids in cancer: a systematic review

    DEFF Research Database (Denmark)

    Kurita, Geana Paula; Lundorff, Lena; Pimenta, Cibele Andrucioli de Mattos

    2008-01-01

    OBJECTIVE AND METHODS: In order to better understand the effects of opioids on the cognitive function in cancer pain patients, a literature search was performed in PubMed, EMBASE, PsycInfo, CINAHL and Lilacs databases. Ten controlled trials were selected and classified according to the study design...

  1. Opioids Switching with Transdermal Systems in Chronic Cancer Pain

    Directory of Open Access Journals (Sweden)

    Barbarisi M

    2009-05-01

    Full Text Available Abstract Background Due to tolerance development and adverse side effects, chronic pain patients frequently need to be switched to alternative opioid therapy Objective To assess the efficacy and tolerability of an alternative transdermally applied (TDS opioid in patients with chronic cancer pain receiving insufficient analgesia using their present treatment. Methods A total of 32 patients received alternative opioid therapy, 16 were switched from buprenorphine to fentanyl and 16 were switched from fentanyl to buprenorphine. The dosage used was 50% of that indicated in equipotency conversion tables. Pain relief was assessed at weekly intervals for the next 3 weeks Results Pain relief as assessed by VAS, PPI, and PRI significantly improved (p Conclusion Opioid switching at 50% of the calculated equianalgesic dose produced a significant reduction in pain levels and rescue medication. The incidence of side effects decreased and no new side effects were noted. Further studies are required to provide individualized treatment for patients according to their different types of cancer.

  2. Premenstrual Syndrome and Self-Medication With Opioids

    NARCIS (Netherlands)

    Qurishi, R.; Sonneborn, C.; Jong, M. de; Jong, C.A.J. de

    2013-01-01

    We have described a patient in opioid substitution treatment using heroin to treat her premenstrual complaints. After a short review of the diagnosis and etiology of premenstrual syndrome or premenstrual dysphoric disorder, the relation between premenstrual syndrome/premenstrual dysphoric disorder

  3. The Impact of Opioid Treatment on Regional Gastrointestinal Transit

    DEFF Research Database (Denmark)

    Poulsen, Jakob Lykke; Nilsson, Matias; Brock, Christina

    2016-01-01

    BACKGROUND/AIMS: To employ an experimental model of opioid-induced bowel dysfunction in healthy human volunteers, and evaluate the impact ofopioid treatment compared to placebo on gastrointestinal (GI) symptoms and motility assessed by questionnaires and regional GItransit times using the 3...

  4. Identifying Primary Care Skills and Competencies in Opioid Risk Management

    Science.gov (United States)

    Chiauzzi, Emil; Trudeau, Kimberlee J.; Zacharoff, Kevin; Bond, Kathleen

    2011-01-01

    Introduction: Primary care physicians (PCPs) treat a high proportion of chronic pain patients but often lack training about how to assess and address issues associated with prescribing opioids when they are an appropriate component of therapy. The result may be that they may avoid treating these patients, which can lead to an undertreatment of…

  5. Criminal justice continuum for opioid users at risk of overdose.

    Science.gov (United States)

    Brinkley-Rubinstein, Lauren; Zaller, Nickolas; Martino, Sarah; Cloud, David H; McCauley, Erin; Heise, Andrew; Seal, David

    2018-02-24

    The United States (US) is in the midst of an epidemic of opioid use; however, overdose mortality disproportionately affects certain subgroups. For example, more than half of state prisoners and approximately two-thirds of county jail detainees report issues with substance use. Overdose is one of the leading causes of mortality among individuals released from correctional settings. Even though the criminal justice (CJ) system interacts with a disproportionately high number of individuals at risk of opioid use and overdose, few CJ agencies screen for opioid use disorder (OUD). Even less provide access to medication assisted treatment (e.g. methadone, buprenorphine, and depot naltrexone), which is one of the most effective tools to combat addiction and lower overdose risk. However, there is an opportunity to implement programs across the CJ continuum in collaboration with law enforcement, courts, correctional facilities, community service providers, and probation and parole. In the current paper, we introduce the concept of a "CJ Continuum of Care for Opioid Users at Risk of Overdose", grounded by the Sequential Intercept Model. We present each step on the CJ Continuum and include a general overview and highlight opportunities for: 1) screening for OUD and overdose risk, 2) treatment and/or diversion, and 3) overdose prevention and naloxone provision. Copyright © 2018 Elsevier Ltd. All rights reserved.

  6. Classification and identification of opioid addiction in chronic pain patients

    DEFF Research Database (Denmark)

    Højsted, Jette; Nielsen, Per Rotbøll; Guldstrand, Sally Kendall

    2010-01-01

    Addiction is a feared consequence of long-term opioid treatment of chronic pain patients. The ICD-10 and DSM-IV diagnostic addiction criteria may not be appropriate in these patients. Therefore Portenoy's criteria (PC) were launched. The aim was to estimate the prevalence of addiction, to investi......Addiction is a feared consequence of long-term opioid treatment of chronic pain patients. The ICD-10 and DSM-IV diagnostic addiction criteria may not be appropriate in these patients. Therefore Portenoy's criteria (PC) were launched. The aim was to estimate the prevalence of addiction......, to investigate whether PC were applicable and to compare these criteria with the ICD-10 criteria. The study was cross-sectional and included 253 patients with chronic pain at a tertiary pain centre. Patients were screened for addiction by a physician and a nurse. The addiction prevalence was 14.4% according...... as addicted were treated with significantly higher opioid doses, drank more alcohol, smoked more tobacco, used benzodiazepines and had higher levels of depression. According to ICD-10 patients classified as addicted used higher doses of opioids, drank more alcohol and had higher scores of anxiety...

  7. Social Laughter Triggers Endogenous Opioid Release in Humans.

    Science.gov (United States)

    Manninen, Sandra; Tuominen, Lauri; Dunbar, Robin I; Karjalainen, Tomi; Hirvonen, Jussi; Arponen, Eveliina; Hari, Riitta; Jääskeläinen, Iiro P; Sams, Mikko; Nummenmaa, Lauri

    2017-06-21

    The size of human social networks significantly exceeds the network that can be maintained by social grooming or touching in other primates. It has been proposed that endogenous opioid release after social laughter would provide a neurochemical pathway supporting long-term relationships in humans (Dunbar, 2012), yet this hypothesis currently lacks direct neurophysiological support. We used PET and the μ-opioid-receptor (MOR)-specific ligand [ 11 C]carfentanil to quantify laughter-induced endogenous opioid release in 12 healthy males. Before the social laughter scan, the subjects watched laughter-inducing comedy clips with their close friends for 30 min. Before the baseline scan, subjects spent 30 min alone in the testing room. Social laughter increased pleasurable sensations and triggered endogenous opioid release in thalamus, caudate nucleus, and anterior insula. In addition, baseline MOR availability in the cingulate and orbitofrontal cortices was associated with the rate of social laughter. In a behavioral control experiment, pain threshold-a proxy of endogenous opioidergic activation-was elevated significantly more in both male and female volunteers after watching laughter-inducing comedy versus non-laughter-inducing drama in groups. Modulation of the opioidergic activity by social laughter may be an important neurochemical pathway that supports the formation, reinforcement, and maintenance of human social bonds. SIGNIFICANCE STATEMENT Social contacts are vital to humans. The size of human social networks significantly exceeds the network that can be maintained by social grooming in other primates. Here, we used PET to show that endogenous opioid release after social laughter may provide a neurochemical mechanism supporting long-term relationships in humans. Participants were scanned twice: after a 30 min social laughter session and after spending 30 min alone in the testing room (baseline). Endogenous opioid release was stronger after laughter versus the

  8. Antimicrobial Peptides (AMPs

    Directory of Open Access Journals (Sweden)

    Mehrzad Sadredinamin

    2016-04-01

    Full Text Available Antimicrobial peptides (AMPs are extensive group of molecules that produced by variety tissues of invertebrate, plants, and animal species which play an important role in their immunity response. AMPs have different classifications such as; biosynthetic machines, biological sources, biological functions, molecular properties, covalent bonding patterns, three dimensional structures, and molecular targets.These molecules have multidimensional properties including antimicrobial activity, antiviral activity, antifungal activity, anti-parasite activity, biofilm control, antitumor activity, mitogens activity and linking innate to adaptive immunity that making them promising agents for therapeutic drugs. In spite of this advantage of AMPs, their clinical developments have some limitation for commercial development. But some of AMPs are under clinical trials for the therapeutic purpose such as diabetic foot ulcers, different bacterial infections and tissue damage. In this review, we emphasized on the source, structure, multidimensional properties, limitation and therapeutic applications of various antimicrobial peptides.

  9. A Genetic Polymorphism of the Endogenous Opioid Dynorphin Modulates Monetary Reward Anticipation in the Corticostriatal Loop

    Science.gov (United States)

    Votinov, Mikhail; Pripfl, Juergen; Windischberger, Christian; Kalcher, Klaudius; Zimprich, Alexander; Zimprich, Fritz; Moser, Ewald

    2014-01-01

    The dynorphin/κ-opioid receptor (KOP-R) system has been shown to play a role in different types of behavior regulation, including reward-related behavior and drug craving. It has been shown that alleles with 3 or 4 repeats (HH genotype) of the variable nucleotide tandem repeat (68-bp VNTR) functional polymorphism of the prodynorphin (PDYN) gene are associated with higher levels of dynorphin peptides than alleles with 1 or 2 repeats (LL genotype). We used fMRI on N = 71 prescreened healthy participants to investigate the effect of this polymorphism on cerebral activation in the limbic-corticostriatal loop during reward anticipation. Individuals with the HH genotype showed higher activation than those with the LL genotype in the medial orbitofrontal cortex (mOFC) when anticipating a possible monetary reward. In addition, the HH genotype showed stronger functional coupling (as assessed by effective connectivity analyses) of mOFC with VMPFC, subgenual anterior cingulate cortex, and ventral striatum during reward anticipation. This hints at a larger sensitivity for upcoming rewards in individuals with the HH genotype, resulting in a higher motivation to attain these rewards. These findings provide first evidence in humans that the PDYN polymorphism modulates neural processes associated with the anticipation of rewards, which ultimately may help to explain differences between genotypes with respect to addiction and drug abuse. PMID:24587148

  10. A genetic polymorphism of the endogenous opioid dynorphin modulates monetary reward anticipation in the corticostriatal loop.

    Directory of Open Access Journals (Sweden)

    Mikhail Votinov

    Full Text Available The dynorphin/κ-opioid receptor (KOP-R system has been shown to play a role in different types of behavior regulation, including reward-related behavior and drug craving. It has been shown that alleles with 3 or 4 repeats (HH genotype of the variable nucleotide tandem repeat (68-bp VNTR functional polymorphism of the prodynorphin (PDYN gene are associated with higher levels of dynorphin peptides than alleles with 1 or 2 repeats (LL genotype. We used fMRI on N = 71 prescreened healthy participants to investigate the effect of this polymorphism on cerebral activation in the limbic-corticostriatal loop during reward anticipation. Individuals with the HH genotype showed higher activation than those with the LL genotype in the medial orbitofrontal cortex (mOFC when anticipating a possible monetary reward. In addition, the HH genotype showed stronger functional coupling (as assessed by effective connectivity analyses of mOFC with VMPFC, subgenual anterior cingulate cortex, and ventral striatum during reward anticipation. This hints at a larger sensitivity for upcoming rewards in individuals with the HH genotype, resulting in a higher motivation to attain these rewards. These findings provide first evidence in humans that the PDYN polymorphism modulates neural processes associated with the anticipation of rewards, which ultimately may help to explain differences between genotypes with respect to addiction and drug abuse.

  11. A genetic polymorphism of the endogenous opioid dynorphin modulates monetary reward anticipation in the corticostriatal loop.

    Science.gov (United States)

    Votinov, Mikhail; Pripfl, Juergen; Windischberger, Christian; Kalcher, Klaudius; Zimprich, Alexander; Zimprich, Fritz; Moser, Ewald; Lamm, Claus; Sailer, Uta

    2014-01-01

    The dynorphin/κ-opioid receptor (KOP-R) system has been shown to play a role in different types of behavior regulation, including reward-related behavior and drug craving. It has been shown that alleles with 3 or 4 repeats (HH genotype) of the variable nucleotide tandem repeat (68-bp VNTR) functional polymorphism of the prodynorphin (PDYN) gene are associated with higher levels of dynorphin peptides than alleles with 1 or 2 repeats (LL genotype). We used fMRI on N = 71 prescreened healthy participants to investigate the effect of this polymorphism on cerebral activation in the limbic-corticostriatal loop during reward anticipation. Individuals with the HH genotype showed higher activation than those with the LL genotype in the medial orbitofrontal cortex (mOFC) when anticipating a possible monetary reward. In addition, the HH genotype showed stronger functional coupling (as assessed by effective connectivity analyses) of mOFC with VMPFC, subgenual anterior cingulate cortex, and ventral striatum during reward anticipation. This hints at a larger sensitivity for upcoming rewards in individuals with the HH genotype, resulting in a higher motivation to attain these rewards. These findings provide first evidence in humans that the PDYN polymorphism modulates neural processes associated with the anticipation of rewards, which ultimately may help to explain differences between genotypes with respect to addiction and drug abuse.

  12. The Prescription Opioid Addiction Treatment Study: What have we learned.

    Science.gov (United States)

    Weiss, Roger D; Rao, Vinod

    2017-04-01

    The multi-site Prescription Opioid Addiction Treatment Study (POATS), conducted by the National Drug Abuse Treatment Clinical Trials Network, was the largest clinical trial yet conducted with patients dependent upon prescription opioids (N=653). In addition to main trial results, the study yielded numerous secondary analyses, and included a 3.5-year follow-up study, the first of its kind with this population. This paper reviews key findings from POATS and its follow-up study. The paper summarizes the POATS design, main outcomes, predictors of outcome, subgroup analyses, the predictive power of early treatment response, and the long-term follow-up study. POATS examined combinations of buprenorphine-naloxone of varying duration and counseling of varying intensity. The primary outcome analysis showed no overall benefit to adding drug counseling to buprenorphine-naloxone and weekly medical management. Only 7% of patients achieved a successful outcome (abstinence or near-abstinence from opioids) during a 4-week taper and 8-week follow-up; by comparison, 49% of patients achieved success while subsequently stabilized on buprenorphine-naloxone. Long-term follow-up results were more encouraging, with higher abstinence rates than in the main trial. Patients receiving opioid agonist treatment at the time of follow-up were more likely to have better outcomes, though a sizeable number of patients succeeded without agonist treatment. Some patients initiated risky use patterns, including heroin use and drug injection. A limitation of the long-term follow-up study was the low follow-up rate. POATS was the first large-scale study of the treatment of prescription opioid dependence; its findings can influence both treatment guidelines and future studies. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

  13. Misuse of Novel Synthetic Opioids: A Deadly New Trend

    Science.gov (United States)

    Prekupec, Matthew P.; Mansky, Peter A.; Baumann, Michael H.

    2017-01-01

    Novel synthetic opioids (NSOs) include various analogs of fentanyl and newly emerging non-fentanyl compounds. Together with illicitly manufactured fentanyl (IMF), these drugs have caused a recent spike in overdose deaths, whereas deaths from prescription opioids have stabilized. NSOs are used as stand-alone products, as adulterants in heroin, or as constituents of counterfeit prescription medications. During 2015 alone, there were 9580 deaths from synthetic opioids other than methadone. Most of these fatalities were associated with IMF rather than diverted pharmaceutical fentanyl. In opioid overdose cases, where the presence of fentanyl analogs was examined, analogs were implicated in 17% of fatalities. Recent data from law enforcement sources show increasing confiscation of acetylfentanyl, butyrylfentanyl, and furanylfentanyl, in addition to non-fentanyl compounds such as U-47700. Since 2013, deaths from NSOs in the United States were 52 for acetylfentanyl, 40 for butyrylfentanyl, 128 for furanylfentanyl, and 46 for U-47700. All of these substances induce a classic opioid toxidrome, which can be reversed with the competitive antagonist naloxone. However, due to the putative high potency of NSOs and their growing prevalence, it is recommended to forgo the 0.4 mg initial dose of naloxone and start with 2 mg. Because NSOs offer enormous profit potential, and there is strong demand for their use, these drugs are being trafficked by organized crime. NSOs present major challenges for medical professionals, law enforcement agencies, and policymakers. Resources must be distributed equitably to enhance harm reduction though public education, medication-assisted therapies, and improved access to naloxone. PMID:28590391

  14. Opioid use in knee arthroplasty after receiving intravenous acetaminophen.

    Science.gov (United States)

    Kelly, Jennifer S; Opsha, Yekaterina; Costello, Jennifer; Schiller, Daryl; Hola, Eric T

    2014-12-01

    Intravenous (IV) acetaminophen may be an effective component of multimodal postoperative pain management. The primary objective of this study was to evaluate the impact of IV acetaminophen on total opioid use in postoperative patients. The secondary objective was to evaluate the effect of IV acetaminophen on hospital length of stay. This retrospective, case-control study evaluated the impact of IV acetaminophen on total opioid use in surgical patients. Patients were included if they received at least one perioperative dose of IV acetaminophen and underwent a surgical knee procedure. Controls were matched and randomly selected based on procedure type, age, and severity of illness. Postoperative opioids were converted into oral morphine equivalents, and overall use was compared between groups. One hundred patients were enrolled, with 25 patients receiving IV acetaminophen and 75 matched controls. A total of 135 mg versus 112.5 mg oral morphine equivalents were used in the IV acetaminophen group and control group, respectively (p=0.987). There were 45 mg/day oral morphine equivalents used in the IV acetaminophen group versus 37.5 mg in the control group (p=0.845). The median hospital length of stay in both groups was 3 days (p=0.799). IV acetaminophen did not significantly decrease postoperative opioid use in patients who underwent surgical knee procedures. In addition, there was a nonsignificant trend toward increased opioid use in the IV acetaminophen group. There was no significant difference in hospital length of stay between the IV acetaminophen group and the control group. These findings require further study in larger patient populations and in other orthopedic procedures that typically require longer hospital stays. © 2014 Pharmacotherapy Publications, Inc.

  15. A practical and ethical solution to the opioid scheduling conundrum

    Directory of Open Access Journals (Sweden)

    Schatman ME

    2013-12-01

    Full Text Available Michael E Schatman,1 Beth D Darnall21Foundation for Ethics in Pain Care, Bellevue, WA, USA; 2Stanford University School of Medicine, Division of Pain Medicine, Palo Alto, CA, USAAbuse-deterrent formulations (ADFs of opioids have been in existence since the 1970s,1 with abuse-deterrent mechanisms including physical barriers (eg, barriers to crushing, chemical additives such as opioid antagonists or irritants, and prodrugs that require conversion of the medication into their active forms in the gastrointestinal tract.2 A recent systematic review and meta-analysis3 found no difference between ADFs and non-ADFs in terms of efficacy or adverse events including nausea, vomiting, dizziness, headache, somnolence, constipation, and pruritus. Notably, the efficacy of ADFs in preventing abuse is not yet established, and therefore the authors could only comment on their "potential … to deter or resist some of the common forms of tampering associated with opioid misuse and abuse". While Turk et al2 have elucidated the complexity of producing high-quality research on the efficacy of ADFs to reduce opioid abuse, recent data are encouraging. For example, since Purdue Pharma’s (Stamford, CT, USA voluntary reformulation of OxyContin® to an ADF in 2010, abuse of the medication has decreased significantly.4–6 As a specific example, National Poison Data System statistics indicated a 36% reduction in abuse exposure for OxyContin following ADF reformulation. Meanwhile, researchers for Purdue Pharma found an increase in abuse exposure for other single-entity oxycodone products and a 42% increase in abuse exposure for heroin during the same time frame.7 Although OxyContin has been the most investigated abuse deterrent formulation, ADFs of other opioids have demonstrated promise in preliminary investigations.8,9

  16. Use of opioids and sedatives at End-of-Life

    Directory of Open Access Journals (Sweden)

    Shin Wei Sim

    2014-01-01

    Full Text Available Despite their proven efficacy and safety, opioid and sedative use for palliation in patients afflicted with cancer in Singapore have been shown to be a fraction of that in other countries. This paper explores the various psychosocial and system-related factors that appear to propagate this conservative approach to care in what is largely a western-influenced care practice. A search for publications relating to sedative and opioid usage in Asia was performed on PubMed, Google, Google Scholar, World Health Organization, and Singapore′s government agency websites using search terms such as "opioids," "sedatives," "palliation," "end-of-life-care," "pain management," "palliative care," "cancer pain," "Asia," "Singapore," and "morphine." Findings were classified into three broad groups - system-related, physician-related, and patient-related factors. A cautious medico-legal climate, shortage of physicians trained in palliative care, and lack of instruments for symptom assessment of patients at the end of life contribute to system-related barriers. Physician-related barriers include delayed access to palliative care due to late referrals, knowledge deficits in non-palliative medicine physicians, and sub-optimal care provided by palliative physicians. Patients′ under-reporting of symptoms and fear of addiction, tolerance, and side effects of opioids and sedatives may lead to conservative opioid use in palliative care as well. System-related, physician-related, and patient-related factors play crucial roles in steering the management of palliative patients. Addressing and increasing the awareness of these factors may help ensure patients receive adequate relief and control of distressing symptoms.

  17. Experience of the use of Ketamine to manage opioid withdrawal in an addicted woman: a case report.

    Science.gov (United States)

    Lalanne, Laurence; Nicot, Chloe; Lang, Jean-Philippe; Bertschy, Gilles; Salvat, Eric

    2016-11-10

    Opioids are good painkillers, but many patients treated with opioids as painkillers developed a secondary addiction. These patients need to stop misusing opioids, but the mild-to-severe clinical symptoms associated with opioid withdrawal risk increasing their existing pain. In such cases, ketamine, which is used by anaesthetists and pain physicians to reduce opioid medication, may be an effective agent for managing opioid withdrawal. We describe the case of a woman who developed a severe secondary addiction to opioids in the context of lombo-sciatic pain. She presented a severe opioid addiction, and her physicians refused to prescribe such high doses of opioid treatment (oxycontin® extended-release 120 mg daily, oxycodone 60 mg daily, and acetaminophen/codeine 300 mg/25 mg 6 times per day). To assist her with her opioid withdrawal which risked increasing her existing pain, she received 1 mg/kg ketamine oral solution, and two days after ketamine initiation her opioid treatment was gradually reduced. The patient dramatically reduced the dosage of opioid painkillers and ketamine was withdrawn without any withdrawal symptoms. Ketamine displays many interesting qualities for dealing with all symptoms relating to opioid withdrawal. Accordingly, it could be used instead of many psychotropic treatments, which interact with each other, to help with opioid withdrawal. However, the literature describes addiction to ketamine. All in all, although potentially addictive, ketamine could be a good candidate for the pharmacological management of opioid withdrawal.

  18. Effects of peptides derived from dietary proteins on mucus secretion in rat jejunum.

    Science.gov (United States)

    Claustre, Jean; Toumi, Férial; Trompette, Aurélien; Jourdan, Gérard; Guignard, Henri; Chayvialle, Jean Alain; Plaisancié, Pascale

    2002-09-01

    The hypothesis that dietary proteins or their hydrolysates may regulate intestinal mucin discharge was investigated in the isolated vascularly perfused rat jejunum using an enzyme-linked immunosorbent assay for rat intestinal mucins. On luminal administration, casein hydrolysate [0.05-5% (wt/vol)] stimulated mucin secretion in rat jejunum (maximal response at 417% of controls). Lactalbumin hydrolysate (5%) also evoked mucin discharge. In contrast, casein, and a mixture of amino acids was without effect. Chicken egg albumin and its hydrolysate or meat hydrolysate also did not modify mucin release. Interestingly, casein hydrolysate-induced mucin secretion was abolished by intra-arterial TTX or naloxone (an opioid antagonist). beta-Casomorphin-7, an opioid peptide released from beta-casein on milk ingestion, induced a strong mucin secretion (response at 563% of controls) that was inhibited by naloxone. Intra-arterial beta-casomorphin-7 also markedly increased mucin secretion (410% of controls). In conclusion, two enzymatic milk protein hydrolysates (casein and lactalbumin hydrolysates) and beta-casomorphin-7, specifically, induced mucin release in rat jejunum. The casein hydrolysate-induced mucin secretion is triggered by a neural pathway and mediated by opioid receptor activation.

  19. Prescription Opioid Abuse, Prescription Opioid Addiction, and Heroin Abuse among Adolescents in a Recovery High School: A Pilot Study

    Science.gov (United States)

    Vosburg, Suzanne K.; Eaton, Thomas A.; Sokolowska, Marta; Osgood, Eric D.; Ashworth, Judy B.; Trudeau, Jeremiah J.; Muffett-Lipinski, Michelle; Katz, Nathaniel P.

    2016-01-01

    The progression from prescription opioid (RXO) abuse to RXO addiction is not well understood in adolescents, nor is the progression from RXO addiction to heroin abuse. The purpose of this pilot study was to characterize the development of RXO drug abuse, RXO drug addiction, and heroin abuse in a small cohort of adolescents recovering from opioid…

  20. Incidence of iatrogenic opioid dependence or abuse in patients with pain who were exposed to opioid analgesic therapy: a systematic review and meta-analysis.

    Science.gov (United States)

    Higgins, C; Smith, B H; Matthews, K

    2018-06-01

    The prevalence and incidence of chronic conditions, such as pain and opioid dependence, have implications for policy development, resource allocation, and healthcare delivery. The primary objective of the current review was to estimate the incidence of iatrogenic opioid dependence or abuse after treatment with opioid analgesics. Systematic electronic searches utilised six research databases (Embase, Medline, PubMed, Cinahl Plus, Web of Science, OpenGrey). A 'grey' literature search and a reference search of included articles were also undertaken. The PICOS framework was used to develop search strategies and the findings are reported in accordance with the PRISMA Statement. After eligibility reviews of 6164 articles, 12 studies (involving 310 408 participants) were retained for inclusion in the meta-analyses. A random effects model (DerSimonian-Laird method) generated a pooled incidence of opioid dependence or abuse of 4.7%. There was little within-study risk of bias and no significant publication bias; however, substantial heterogeneity was found among study effects (99.78%). Sensitivity analyses indicated that the diagnostic criteria selected for identifying opioid dependence or abuse (Diagnostic Statistical Manual (DSM-IV) vs International Classification of Diseases (ICD-9)) accounted for 20% and duration of exposure to opioid analgesics accounted for 18% of variance in study effects. Longer-term opioid analgesic exposure, and prescription of strong rather than weak opioids, were associated with a significantly lower incidence of opioid dependence or abuse. The incidence of iatrogenic opioid dependence or abuse was 4.7% of those prescribed opioids for pain. Further research is required to confirm the potential for our findings to inform prevention of this serious adverse event. Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

  1. Patient-reported opioid analgesic requirements after elective inguinal hernia repair: A call for procedure-specific opioid-administration strategies.

    Science.gov (United States)

    Mylonas, Konstantinos S; Reinhorn, Michael; Ott, Lauren R; Westfal, Maggie L; Masiakos, Peter T

    2017-11-01

    A better understanding of the analgesia needs of patients who undergo common operative procedures is necessary as we address the growing opioid public health crisis in the United States. The aim of this study was to evaluate patient experience with our opioid prescribing practice after elective inguinal hernia repairs. A prospective, observational study was conducted between October 1, 2015, and September 30, 2016, in a single-surgeon, high-volume, practice of inguinal hernia operation. Adult patients undergoing elective inguinal herniorrhaphy under local anesthesia with intravenous sedation were invited to participate. All patients were prescribed 10 opioid analgesic tablets postoperatively and were counseled to reserve opioids for pain not controlled by nonopioid analgesics. Their experience was captured by completing a questionnaire 2 to 3 weeks postoperatively during their postoperative visit. A total of 185 patients were surveyed. The majority of the participants were males (177, 95.7%) and ≥60 years old (96, 51.9%). Of the 185 patients, 159 (85.9%) reported using ≤4 opioid tablets; 110 patients (59.5%) reported that they used no opioid analgesics postoperatively. None of the patients was taking opioids within 7 days of their postoperative appointment. Of the 147 patients who were employed, 111 (75.5%) reported missing ≤3 work days, 57 of whom (51.4%) missed no work at all. Patients who were employed were more likely to take opioid analgesics postoperatively (P = .049). Patients who took no opioid analgesics experienced less maximum (P require any opioid analgesics, and nearly all of those who thought that they did need opioids used reserved.

  2. Low pain intensity after opioid withdrawal as a first step of a comprehensive pain rehabilitation program predicts long-term nonuse of opioids in chronic noncancer pain.

    Science.gov (United States)

    Krumova, Elena K; Bennemann, Philipp; Kindler, Doris; Schwarzer, Andreas; Zenz, Michael; Maier, Christoph

    2013-09-01

    In specialized pain clinics there is an increasing number of patients with severe chronic noncancer pain (CNCP) despite long-term opioid medication. Few clinical studies show short-term pain relief after opioid withdrawal (OW). We have evaluated the relation between pain intensity after OW and long-term opioid nonuse. One hundred two consecutive patients with severe CNCP despite opioid medication (mean treatment duration, 43 mo) reported pain intensity (numerical rating scale, 0 to 10), Pain Disability Index, mood (CES-D), and quality of life (Short Form 36) before, shortly, and 12 to 24 months after inpatient OW. Total opioid withdrawal (n = 78) or significant dose reduction (DR; n = 24, mean reduction, 82%) was performed after individual decision. Opioid intake 12 to 24 months later, respectively dose increase ≥ 100% (DR group), was considered relapse. T tests, multivariable analysis of variance, logistic regression. After OW current pain intensity significantly decreased on an average by 41% (6.4 ± 2.4 vs. 3.8 ± 2.5), maximal and average pain by 18% and 24%, respectively. Twelve to 24 months later 42 patients (41%) relapsed (31 of the total opioid withdrawal group, 6 of the DR group, 5 lost). Patients without later relapse showed significantly lower pain scores than the later relapsed patients already shortly after OW (5.0 ± 2.2 vs. 5.9 ± 2.1) and 12 to 24 months later (5.5 ± 2.4 vs. 6.5 ± 2.0). There was a significant relation between relapse probability and pain intensity immediately after OW. In many patients with severe CNCP, despite opioid medication, sustainable pain relief can be achieved if OW is included in the rehabilitation program. Consequently, we recommend OW for opioid-resistant CNCP before any opioid escalation. Lower pain intensity shortly after OW may predict the long-term opioid nonuse probability.

  3. The relative potency of inverse opioid agonists and a neutral opioid antagonist in precipitated withdrawal and antagonism of analgesia and toxicity.

    Science.gov (United States)

    Sirohi, Sunil; Dighe, Shveta V; Madia, Priyanka A; Yoburn, Byron C

    2009-08-01

    Opioid antagonists can be classified as inverse agonists and neutral antagonists. In the opioid-dependent state, neutral antagonists are significantly less potent in precipitating withdrawal than inverse agonists. Consequently, neutral opioid antagonists may offer advantages over inverse agonists in the management of opioid overdose. In this study, the relative potency of three opioid antagonists to block opioid analgesia and toxicity and precipitate withdrawal was examined. First, the potency of two opioid inverse agonists (naltrexone and naloxone) and a neutral antagonist (6beta-naltrexol) to antagonize fentanyl-induced analgesia and lethality was determined. The order of potency to block analgesia was naltrexone > naloxone > 6beta-naltrexol (17, 4, 1), which was similar to that to block lethality (13, 2, 1). Next, the antagonists were compared using withdrawal jumping in fentanyl-dependent mice. The order of potency to precipitate withdrawal jumping was naltrexone > naloxone 6beta-naltrexol (1107, 415, 1). The relative potencies to precipitate withdrawal for the inverse agonists compared with the neutral antagonist were dramatically different from that for antagonism of analgesia and lethality. Finally, the effect of 6beta-naltrexol pretreatment on naloxone-precipitated jumping was determined in morphine and fentanyl-dependent mice. 6beta-Naltrexol pretreatment decreased naloxone precipitated withdrawal, indicating that 6beta-naltrexol is a neutral antagonist. These data demonstrate that inverse agonists and neutral antagonists have generally comparable potencies to block opioid analgesia and lethality, whereas the neutral opioid antagonist is substantially less potent in precipitating opioid withdrawal. These results support suggestions that neutral antagonists may have advantages over inverse agonists in the management of opioid overdose.

  4. Comparison of (/sup 125/I)beta-endorphin binding to rat brain and NG108-15 cells using a monoclonal antibody directed against the opioid receptor

    Energy Technology Data Exchange (ETDEWEB)

    Bidlack, J.M.; O' Malley, W.E.; Schulz, R.

    1988-02-01

    The properties of (/sup 125/I)beta h-endorphin-binding sites from rat brain membranes and membranes from the NG108-15 cell line were compared using a monoclonal antibody directed against the opioid receptor and opioid peptides as probes. The binding of (/sup 125/I)beta h-endorphin to both rat brain and NG108-15 membranes yielded linear Scatchard plots with Kd values of 1.2 nM and 1.5 nM, respectively, and Bmax values of 865 fmol/mg rat brain membrane protein and 1077 fmol/mg NG108-15 membrane protein. A monoclonal antibody, OR-689.2.4, capable of inhibiting mu and delta binding but not kappa binding to rat brain membranes, noncompetitively inhibited the binding of 1 nM (/sup 125/I)beta h-endorphin to rat brain and NG108-15 membranes with an IC50 value of 405 nM for rat brain membranes and 543 nM for NG108-15 membranes. The monoclonal antibody also inhibited the binding of 3 nM (/sup 3/H) (D-penicillamine2, D-penicillamine5) enkephalin to NG108-15 membranes with an IC50 value of 370 nM. In addition to blocking the binding of (/sup 125/I)beta h-endorphin to brain membranes, the antibody also displaced (/sup 125/I)beta h-endorphin from membranes. Site-specific opioid peptides had large variations in their IC50 values depending on whether they were inhibiting (/sup 125/I)beta h-endorphin binding to rat brain or the NG108-15 membranes. When the peptides were tested with the monoclonal antibody for their combined ability to inhibit (/sup 125/I)beta h-endorphin binding to both membrane preparations, the peptides and antibody blocked binding as though they were acting at allosterically coupled sites, not two totally independent sites. These studies suggest that mu-, delta-, and beta-endorphin-binding sites share some sequence homology with the 35,000-dalton protein that the antibody is directed against.

  5. Inhibition of GABAergic Neurotransmission by HIV-1 Tat and Opioid Treatment in the Striatum Involves μ-opioid Receptors

    Directory of Open Access Journals (Sweden)

    Changqing Xu

    2016-11-01

    Full Text Available Due to combined antiretroviral therapy (cART, human immunodeficiency virus type 1 (HIV-1 is considered a chronic disease with high prevalence of mild forms of neurocognitive impairments, also referred to as HIV-associated neurocognitive disorders (HAND. Although opiate drug use can exacerbate HIV-1 Tat-induced neuronal damage, it remains unknown how and to what extent opioids interact with Tat on the GABAergic system. We conducted whole-cell recordings in mouse striatal slices and examined the effects of HIV-1 Tat in the presence and absence of morphine (1 μM and damgo (1 μM on GABAergic neurotransmission. Results indicated a decrease in the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs and miniature IPSCs (mIPSCs by Tat (5 – 50 nM in a concentration-dependent manner. The significant Tat-induced decrease in IPSCs was abolished when removing extracellular and/or intracellular calcium. Treatment with morphine or damgo alone significantly decreased the frequency, but not amplitude of IPSCs. Interestingly, morphine but not damgo indicated an additional downregulation of the mean frequency of mIPSCs in combination with Tat. Pretreatment with naloxone (1 μM and CTAP (1 μM prevented the Tat-induced decrease in sIPSCs frequency but only naloxone prevented the combined Tat and morphine effect on mIPSCs frequency. Results indicate a Tat- or opioid-induced decrease in GABAergic neurotransmission via µ-opioid receptors with combined Tat and morphine effects involving additional opioid receptor-related mechanisms. Exploring the interactions between Tat and opioids on the GABAergic system may help to guide future research on HAND in the context of opiate drug use.

  6. Opioid pharmaceuticals and addiction: the issues, and research directions seeking solutions.

    Science.gov (United States)

    Walwyn, Wendy M; Miotto, Karen A; Evans, Christopher J

    2010-05-01

    There are few pharmaceuticals superior to opiates for the treatment of pain. However, with concerns of addiction, withdrawal and questionable efficacy for all types of pain, these compounds are far from a magical panacea for pain-relief. As it is unlikely that other classes of compounds will supersede the opioids in the very near future, it is important to both optimize current opioid therapies and curb the astounding diversion of opioids from their intended analgesic use to non-medical abuse. In optimizing opioid therapeutics it is necessary to enhance the clinical awareness of the benefits of treating pain and combine this with aggressive strategies to reduce diversion for non-medical use. At the heart of the issue of opioid misuse is the role of opioid systems in the reward circuitry, and the adaptive processes associated with repetitive opioid use that manifest during withdrawal. Emerging pharmacological insights of opioid receptors will be reviewed that provide future hope for developing opioid-based analgesics with reduced addictive properties and perhaps, reduced opponent processes. In addition, with the increased understanding of nociceptive circuitry and the molecules involved in transmitting pain, new therapeutic targets have become evident that may result in effective analgesics either alone or in combination with current opioid therapies.

  7. Effects of opioid drugs on dopamine mediated locomotor activity in rats

    Energy Technology Data Exchange (ETDEWEB)

    Leathern, L L

    1986-01-01

    Opioid drugs influence various behavioural parameters including locomotor activity in experimental animals. The interaction between the opioid and dopaminergic systems is one possible explanation for the effect of opioid drugs on locomotor activity. In this study behavioural and biochemical assays were done to investigate the interaction between the opioid and dopaminergic systems. Behavioural studies were done by measurement of locomotor activity (LA) of rats after acute or chronic pretreatment with opioid andor dopaminergic drugs. Biochemical studies were in the form of radioligand binding assays, the effect on the number (Bmax) and affinity (K/sub D/) of receptors was measured after chronic pretreatment with opioid andor dopaminergic drugs. The opioid drugs used are morphine, nalbuphine and naloxone. Dopaminergic drugs used included: agonists-apomorphine and piribedil; antagonists-pimozide, haloperidol, chlorpromazine. In the acute situation increased LA was obtained with morphine and the DA agonists. A correlation between the behavioural and biochemical assays was found. Chronic pretreatment with morphine enhanced apomorphine induced LA, this supersensitivity was also measured as an increased receptor density (Bmax) of D2 receptors in the striatum. Chronic morphine pretreatment caused a decrease in morphine induced LA, while this subsensitivity was not apparent in the ligand binding assays - where no change in receptor number was observed. Chronic naloxone pretreatment enhanced morphine induced LA, as well as increased the Bmax of opioid receptors in the whole brain. It is concluded that an interaction between the opioid and dopaminergic systems does exist, and may account for the mechanism of action of the opioids.

  8. Endogenous Opioid Function and Responses to Morphine: The Moderating Effects of Anger Expressiveness.

    Science.gov (United States)

    Burns, John W; Bruehl, Stephen; France, Christopher R; Schuster, Erik; Orlowska, Daria; Chont, Melissa; Gupta, Rajnish K; Buvanendran, Asokumar

    2017-08-01

    Long-term use of opioid analgesics may be ineffective or associated with significant negative side effects for some people. At present, there is no sound method of identifying optimal opioid candidates. Individuals with chronic low back pain (n = 89) and healthy control individuals (n = 102) underwent ischemic pain induction with placebo, opioid blockade (naloxone), and morphine in counterbalanced order. They completed the Spielberger Anger-Out subscale. Endogenous opioid function × Anger-out × Pain status (chronic pain, healthy control) interactions were tested for morphine responses to ischemic threshold, tolerance, and pain intensity (McGill Sensory and Affective subscales) and side effects. For individuals with chronic pain and healthy control participants, those with low endogenous opioid function and low anger-out scores exhibited the largest morphine analgesic responses, whereas those with high anger-out and low endogenous opioid function showed relatively weaker morphine analgesic responses. Further, individuals with chronic pain with low endogenous opioid function and low anger-out scores also reported the fewest negative effects to morphine, whereas those with low endogenous opioid function and high anger-out reported the most. Findings point toward individuals with chronic pain who may strike a favorable balance of good analgesia with few side effects, as well as those who have an unfavorable balance of poor analgesia and many side effects. We sought to identify optimal candidates for opioid pain management. Low back pain patients who express anger and also have deficient endogenous opioid function may be poor candidates for opioid therapy. In contrast, low back patients who tend not to express anger and who also have deficient endogenous opioid function may make optimal candidates for opioid therapy. Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.

  9. Therapeutic peptides for cancer therapy. Part II - cell cycle inhibitory peptides and apoptosis-inducing peptides.

    Science.gov (United States)

    Raucher, Drazen; Moktan, Shama; Massodi, Iqbal; Bidwell, Gene L

    2009-10-01

    Therapeutic peptides have great potential as anticancer agents owing to their ease of rational design and target specificity. However, their utility in vivo is limited by low stability and poor tumor penetration. The authors review the development of peptide inhibitors with potential for cancer therapy. Peptides that arrest the cell cycle by mimicking CDK inhibitors or induce apoptosis directly are discussed. The authors searched Medline for articles concerning the development of therapeutic peptides and their delivery. Inhibition of cancer cell proliferation directly using peptides that arrest the cell cycle or induce apoptosis is a promising strategy. Peptides can be designed that interact very specifically with cyclins and/or cyclin-dependent kinases and with members of apoptotic cascades. Use of these peptides is not limited by their design, as a rational approach to peptide design is much less challenging than the design of small molecule inhibitors of specific protein-protein interactions. However, the limitations of peptide therapy lie in the poor pharmacokinetic properties of these large, often charged molecules. Therefore, overcoming the drug delivery hurdles could open the door for effective peptide therapy, thus making an entirely new class of molecules useful as anticancer drugs.

  10. Changes in misuse and abuse of prescription opioids following implementation of Extended-Release and Long-Acting Opioid Analgesic Risk Evaluation and Mitigation Strategy.

    Science.gov (United States)

    Bucher Bartelson, Becki; Le Lait, M Claire; Green, Jody L; Cepeda, M Soledad; Coplan, Paul M; Maziere, Jean-Yves; Wedin, Gregory P; Dart, Richard C

    2017-09-01

    An unintended consequence of extended-release (ER) and long-acting (LA) prescription opioids is that these formulations can be more attractive to abusers than immediate-release (IR) formulations. The US Food and Drug Administration recognized these risks and approved the ER/LA Opioid Analgesic Risk Evaluation and Mitigation Strategy (ER/LA REMS), which has a goal of reducing opioid misuse and abuse and their associated consequences. The primary objective of this analysis is to determine whether ER/LA REMS implementation was associated with decreased reports of misuse and abuse. Data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS(R)) System Poison Center Program were utilized. Poison center cases are assigned a reason for exposure, a medical outcome, and a level of health care received. Rates adjusted for population and drug utilization were analyzed over time. RADARS System Poison Center Program data indicate a notable decrease in ER/LA opioid rates of intentional abuse and misuse as well as major medical outcomes or hospitalizations following implementation of the ER/LA REMS. While similar decreases were observed for the IR prescription opioid group, the decreasing rate for the ER/LA opioids exceeded the decreasing rates for the IR prescription opioids and was distinctly different than that for the prescription stimulants, indicating that the ER/LA REMS program may have had an additional effect on decreases in opioid abuse and intentional misuse beyond secular trends. Copyright © 2017 John Wiley & Sons, Ltd.

  11. Beta-lipotropin is the major component of the plasma opioid response to surgical stress in humans

    Energy Technology Data Exchange (ETDEWEB)

    Porro, C.A.; Facchinetti, F.; Bertellini, E.; Petraglia, F.; Stacca, R.; Barbieri, G.C.; Genazzani, A.R.

    1987-12-07

    There is growing experimental evidence that beta-endorphin immunoreactivity is raised by surgical stress in patients undergoing general anesthesia. As the assay methods employed to date did not allow to fully discriminate between beta-endorphin and its immediate precursor, beta-lipotropin, the authors have investigated in the present study plasma levels of these two peptides by separating them by chromatography on plasma extracts prior to radioimmunoassay. Beta-lipotropin, but not beta-endorphin, plasma levels were found to be significantly elevated during surgery in the general anesthesia group, while no change was found in either peptide concentration in the spinal one. Cortisol plasma levels also increased significantly 90 minutes after the beginning of surgery. Although the sampling time they adopted may have prevented them from detecting an early peak of beta-endorphin during the first 30 minutes of surgery, the major component of the pituitary opioid response to surgical stress appears to be related to beta-lipotropin. This is in agreement with results of experimental work on various kinds of stress in animals and humans and seems to rule out a role for plasma beta-endorphin in post-operative analgesia. 38 references, 1 figure, 1 table.

  12. Stereotype threat and social function in opioid substitution therapy patients.

    Science.gov (United States)

    von Hippel, Courtney; Henry, Julie D; Terrett, Gill; Mercuri, Kimberly; McAlear, Karen; Rendell, Peter G

    2017-06-01

    People with a history of substance abuse are subject to widespread stigmatization. It seems likely that this societal disapproval will result in feelings of stereotype threat, or the belief that one is the target of demeaning stereotypes. If so, stereotype threat has the potential to contribute to functional difficulties including poor social outcomes. Eighty drug users on opioid substitution therapy and 84 demographically matched controls completed measures of mental health and social function. The opioid substitution therapy group were additionally asked to complete a measure that focused on their feelings of stereotype threat in relation to their drug use history. Bivariate correlations and hierarchical regression analyses were conducted to establish the magnitude and specificity of the relationship between stereotype threat and social functioning. Relative to controls, the opioid substitution therapy group reported higher levels of negative affect and schizotypy, and poorer social functioning, with all three of these indices significantly correlated with their feelings of stereotype threat. The results also showed that stereotype threat contributed significant unique variance to social functioning in the opioid substitution therapy group, even after taking into account other background, clinical, and mental health variables. Social functioning is an important aspect of recovery, yet these data indicate that people with a history of drug abuse who believe they are the target of stereotypical attitudes have poorer social functioning. This relationship holds after controlling for the impact of other variables on social functioning, including mental health. The theoretical and practical implications of these findings are discussed. Concerns about being stereotyped can shape the social experiences of opioid substitution therapy patients. Opioid substitution therapy patients who feel negatively stereotyped experience greater social function deficits, and this

  13. Quantitative immunolocalization of {mu} opioid receptors: regulation by naltrexone

    Energy Technology Data Exchange (ETDEWEB)

    Evans, C.J.; Lam, H.; To, T.; Anton, B. [Department of Psychiatry and Biobehavioral Sciences, Neuropsychiatric Institute, University of California, Los Angeles, CA (United States); Unterwald, E.M. [Department of Psychiatry, New York University Medical Center, New York, NY (United States)

    1998-04-24

    The present study utilized a newly developed quantitative immunohistochemical assay to measure changes in {mu} opioid receptor abundance following chronic administration of the opioid receptor antagonist naltrexone. These data were compared with those obtained from {mu} receptor radioligand binding on adjacent tissue sections, in order to determine whether the characteristic antagonist-induced increase in radioligand binding is due to an increase in the total number of {mu} receptors and/or to an increase in the proportion of receptors that are in an active binding conformation in the absence of a change in the total number of receptors. Adult male Sprague-Dawley rats were administered naltrexone, 7-8 mg/kg per day, or saline continuously for seven days by osmotic minipumps, after which time their brains were processed for immunohistochemistry and receptor autoradiography on adjacent fresh frozen tissue sections. Semiquantitative immunohistochemistry was performed using a radiolabelled secondary antibody for autoradiographic determination and a set of radioactive standards. Results demonstrate an overall concordance between the distribution of {mu} opioid receptors as measured by the two different methods with a few exceptions. Following naltrexone administration, {mu} receptor immunoreactivity was significantly higher in the amygdala, thalamus, hippocampus, and interpeduncular nucleus as compared with the saline-treated control animals. [{sup 3}H]D-Ala{sup 2},N-Me-Phe{sup 4},Gly-ol{sup 5}-enkephalin binding to {mu} opioid receptors was significantly higher in the globus pallidus, amygdala, thalamus, hypothalamus, hippocampus, substantia nigra, ventral tegmental area, central gray, and interpeduncular nucleus of the naltrexone-treated rats.These findings indicate that in some brain regions chronic naltrexone exposure increases the total number of {mu} opioid receptors, while in other regions there is an increase in the percent of active receptors without an

  14. Quantitative immunolocalization of μ opioid receptors: regulation by naltrexone

    International Nuclear Information System (INIS)

    Evans, C.J.; Lam, H.; To, T.; Anton, B.; Unterwald, E.M.

    1998-01-01

    The present study utilized a newly developed quantitative immunohistochemical assay to measure changes in μ opioid receptor abundance following chronic administration of the opioid receptor antagonist naltrexone. These data were compared with those obtained from μ receptor radioligand binding on adjacent tissue sections, in order to determine whether the characteristic antagonist-induced increase in radioligand binding is due to an increase in the total number of μ receptors and/or to an increase in the proportion of receptors that are in an active binding conformation in the absence of a change in the total number of receptors. Adult male Sprague-Dawley rats were administered naltrexone, 7-8 mg/kg per day, or saline continuously for seven days by osmotic minipumps, after which time their brains were processed for immunohistochemistry and receptor autoradiography on adjacent fresh frozen tissue sections. Semiquantitative immunohistochemistry was performed using a radiolabelled secondary antibody for autoradiographic determination and a set of radioactive standards. Results demonstrate an overall concordance between the distribution of μ opioid receptors as measured by the two different methods with a few exceptions. Following naltrexone administration, μ receptor immunoreactivity was significantly higher in the amygdala, thalamus, hippocampus, and interpeduncular nucleus as compared with the saline-treated control animals. [ 3 H]D-Ala 2 ,N-Me-Phe 4 ,Gly-ol 5 -enkephalin binding to μ opioid receptors was significantly higher in the globus pallidus, amygdala, thalamus, hypothalamus, hippocampus, substantia nigra, ventral tegmental area, central gray, and interpeduncular nucleus of the naltrexone-treated rats.These findings indicate that in some brain regions chronic naltrexone exposure increases the total number of μ opioid receptors, while in other regions there is an increase in the percent of active receptors without an observable change in the total number

  15. Empirical and bioinformatic characterization of buffalo (Bubalus bubalis) colostrum whey peptides & their angiotensin I-converting enzyme inhibition.

    Science.gov (United States)

    Ashok, N R; Aparna, H S

    2017-08-01

    Whey based peptides