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Sample records for opioid tolerance development

  1. Opioid and non-opioid mechanisms of stress analgesia: lack of cross-tolerance between stressors.

    PubMed

    Terman, G W; Lewis, J W; Liebeskind, J C

    1983-01-31

    Qualitatively different analgesic responses can be evoked in rats by exposure to prolonged, intermittent or brief, continuous footshock stress. These two forms of stress analgesia appear to be mediated by opioid and nonopioid pain-inhibitory substrates, respectively. The present study confirms our previous observation that tolerance develops to only the opioid form of stress analgesia and shows that cross-tolerance does not occur between the opioid and nonopioid forms. These data provide further evidence that independent mechanisms underlie opioid and nonopioid stress analgesia. PMID:6297681

  2. Upregulation of the opioid receptor complex by the chronic administration of morphine: a biochemical marker related to the development of tolerance and dependence.

    PubMed

    Rothman, R B; Long, J B; Bykov, V; Xu, H; Jacobson, A E; Rice, K C; Holaday, J W

    1991-01-01

    Studies conducted after the development of the rapid filtration assay for opiate receptors, and before the recognition of multiple opioid receptors, failed to detect changes in opioid receptors induced by chronic morphine. Recent experiments conducted in our laboratories were designed to examine the hypothesis that only one of several opioid receptor types might be altered by chronic morphine. Using binding surface analysis and irreversible ligands to increase the "resolving power" of the ligand binding assay, the results indicated that chronic morphine increased both the Bmax and Kd of the opioid receptor complex, labeled with either [3H][D-Ala2,D-Leu5]enkephalin, [3H][D-Ala2-MePhe4,Gly-ol5]enkephalin or [3H]6-desoxy-6 beta-fluoronaltreone. In the present study rats were pretreated with drugs known to attenuate the development of tolerance and dependence [the irreversible mu-receptor antagonist, beta-funaltrexamine (beta-FNA), and the inhibitor of tryptophan hydroxylase, para-chlorophenylalanine], prior to subcutaneous implantation of morphine pellets. The results demonstrated that 1) unlike chronic naltrexone, beta-FNA failed to upregulate opioid receptors and 2) both beta-funaltrexamine and PCPA pretreatment attenuated the chronic morphine-induced increase in the Bmax, but not the Kd, of the opioid receptor complex. These results provide evidence that naltrex-one-induced upregulation of the opioid receptor complex might occur indirectly as a consequence of interactions at beta-funaltrexamine-insensitive opioid receptors and that morphine-induced upregulation (increased Bmax) of the opioid receptor complex is a relevant in vitro marker related to the development of tolerance and dependence. These data collectively support the hypothesis that endogenous antiopiate peptides play an important role in the development of tolerance and dependence to morphine. PMID:1646998

  3. Comparative effects of cyclo-oxygenase and nitric oxide synthase inhibition on the development and reversal of spinal opioid tolerance.

    PubMed

    Powell, K J; Hosokawa, A; Bell, A; Sutak, M; Milne, B; Quirion, R; Jhamandas, K

    1999-06-01

    1. This study examined the effects of the COX inhibitors, ketorolac and ibuprofen, and the NOS inhibitor L-NAME for their potential to both inhibit the development and reverse tolerance to the antinociceptive action of morphine. 2. Repeated administration of intrathecal morphine (15 micrograms), once daily, resulted in a progressive decline of antinociceptive effect and an increase in the ED50 value in the tailflick and paw pressure tests. Co-administration of ketorolac (30 and 45 micrograms) or S(+) ibuprofen (10 micrograms) with morphine (15 micrograms) prevented the decline of antinociceptive effect and increase in ED50 value. Similar treatment with L-NAME (100 micrograms) exerted weaker effects. Administration of S(+) but not R(-) ibuprofen (10 mg kg-1) had similar effects on systemic administration of morphine (15 mg kg-1). 3. Intrathecal or systemic administration of the COX or NOS inhibitors did not alter the baseline responses in either tests. Acute keterolac or S(+) ibuprofen also did not potentiate the acute actions of spinal or systemic morphine, but chronic intrathecal administration of these agents increased the potency of acute morphine. 4. In animals already tolerant to intrathecal morphine, subsequent administration of ketorolac (30 micrograms) with morphine (15 micrograms) partially restored the antinociceptive effect and ED50 value of acute morphine, reflecting the reversal of tolerance. Intrathecal L-NAME (100 micrograms) exerted a weaker effect. 5. These data suggest that spinal COX activity, and to a lesser extent NOS activity, contributes to the development and expression of opioid tolerance. Inhibition of COX may represent a useful approach for the prevention as well as reversal of opioid tolerance. PMID:10401553

  4. Opioid receptor desensitization: mechanisms and its link to tolerance

    PubMed Central

    Allouche, Stéphane; Noble, Florence; Marie, Nicolas

    2014-01-01

    Opioid receptors (OR) 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. PMID:25566076

  5. Direct association of Mu-opioid and NMDA glutamate receptors supports their cross-regulation: molecular implications for opioid tolerance.

    PubMed

    Garzón, Javier; Rodríguez-Muñoz, María; Sánchez-Blázquez, Pilar

    2012-09-01

    In the nervous system, the interaction of opioids like morphine and its derivatives, with the G protein-coupled Mu-opioid receptor (MOR) provokes the development of analgesic tolerance, as well as physical dependence. Tolerance implies that increasing doses of the drug are required to achieve the same effect, a phenomenon that contributes significantly to the social problems surrounding recreational opioid abuse. In recent years, our understanding of the mechanisms that control MOR function in the nervous system, and that eventually produce opioid tolerance, has increased greatly. Pharmacological studies have identified a number of signaling proteins involved in morphine-induced tolerance, including the N-methyl-D-aspartate acid glutamate receptor (NMDAR), nitric oxide synthase (NOS), protein kinase C (PKC), protein kinase A (PKA), calcium (Ca²⁺)/calmodulin (CaM)-dependent kinase II (CaMKII), delta-opioid receptor (DOR) and the regulators of G-protein signaling (RGS) proteins. There is general agreement on the critical role of the NMDAR/nNOS/CaMKII pathway in this process, which is supported by the recent demonstration of a physical association between MORs and NMDARs in post-synaptic structures. Indeed, it is feasible that treatments that diminish morphine tolerance may target distinct elements within the same regulatory MOR-NMDAR pathway. Accordingly, we propose a model that incorporates the most relevant signaling components implicated in opioid tolerance in which, certain signals originating from the activated MOR are perceived by the associated NMDAR, which in turn exerts a negative feedback effect on MOR signaling. MOR- and NMDAR-mediated signals work together in a sequential and interconnected manner to ultimately induce MOR desensitization. Future studies of these phenomena should focus on adding further components to this signaling pathway in order to better define the mechanism underlying MOR desensitization in neural cells. PMID:22920535

  6. Acute pain management in opioid-tolerant patients: a growing challenge.

    PubMed

    Huxtable, C A; Roberts, L J; Somogyi, A A; MacIntyre, P E

    2011-09-01

    In Australia and New Zealand, in parallel with other developed countries, the number of patients prescribed opioids on a long-term basis has grown rapidly over the last decade. The burden of chronic pain is more widely recognised and there has been an increase in the use of opioids for both cancer and non-cancer indications. While the prevalence of illicit opioid use has remained relatively stable, the diversion and abuse of prescription opioids has escalated, as has the number of individuals receiving methadone or buprenorphine pharmacotherapy for opioid addiction. As a result, the proportion of opioid-tolerant patients requiring acute pain management has increased, often presenting clinicians with greater challenges than those faced when treating the opioid-naïve. Treatment aims include effective relief of acute pain, prevention of drug withdrawal, assistance with any related social, psychiatric and behavioural issues, and ensuring continuity of long-term care. Pharmacological approaches incorporate the continuation of usual medications (or equivalent), short-term use of sometimes much higher than average doses of additional opioid, and prescription of non-opioid and adjuvant drugs, aiming to improve pain relief and attenuate opioid tolerance and/or opioid-induced hyperalgesia. Discharge planning should commence at an early stage and may involve the use of a 'Reverse Pain Ladder' aiming to limit duration of additional opioid use. Legislative requirements may restrict which drugs can be prescribed at the time of hospital discharge. At all stages, there should be appropriate and regular consultation and liaison with the patient, other treating teams and specialist services. PMID:21970125

  7. Regulation of µ-Opioid Receptors: Desensitization, Phosphorylation, Internalization, and Tolerance

    PubMed Central

    Williams, John T.; Ingram, Susan L.; Henderson, Graeme; Chavkin, Charles; von Zastrow, Mark; Schulz, Stefan; Koch, Thomas; Evans, Christopher J.

    2013-01-01

    Morphine and related µ-opioid receptor (MOR) agonists remain among the most effective drugs known for acute relief of severe pain. A major problem in treating painful conditions is that tolerance limits the long-term utility of opioid agonists. Considerable effort has been expended on developing an understanding of the molecular and cellular processes that underlie acute MOR signaling, short-term receptor regulation, and the progression of events that lead to tolerance for different MOR agonists. Although great progress has been made in the past decade, many points of contention and controversy cloud the realization of this progress. This review attempts to clarify some confusion by clearly defining terms, such as desensitization and tolerance, and addressing optimal pharmacological analyses for discerning relative importance of these cellular mechanisms. Cellular and molecular mechanisms regulating MOR function by phosphorylation relative to receptor desensitization and endocytosis are comprehensively reviewed, with an emphasis on agonist-biased regulation and areas where knowledge is lacking or controversial. The implications of these mechanisms for understanding the substantial contribution of MOR signaling to opioid tolerance are then considered in detail. While some functional MOR regulatory mechanisms contributing to tolerance are clearly understood, there are large gaps in understanding the molecular processes responsible for loss of MOR function after chronic exposure to opioids. Further elucidation of the cellular mechanisms that are regulated by opioids will be necessary for the successful development of MOR-based approaches to new pain therapeutics that limit the development of tolerance. PMID:23321159

  8. Managing Opioid-Tolerant Patients in the Perioperative Surgical Home.

    PubMed

    Wenzel, John T; Schwenk, Eric S; Baratta, Jaime L; Viscusi, Eugene R

    2016-06-01

    Management of acute postoperative pain is important to decrease perioperative morbidity and improve patient satisfaction. Opioids are associated with potential adverse events that may lead to significant risk. Uncontrolled pain is a risk factor in the transformation of acute pain to chronic pain. Balancing these issues can be especially challenging in opioid-tolerant patients undergoing surgery, for whom rapidly escalating opioid doses in an effort to control pain can be associated with increased complications. In the perioperative surgical home model, anesthesiologists are positioned to coordinate a comprehensive perioperative analgesic plan that begins with the preoperative assessment and continues through discharge. PMID:27208711

  9. Two opioid forms of stress analgesia: studies of tolerance and cross-tolerance.

    PubMed

    Terman, G W; Lewis, J W; Liebeskind, J C

    1986-03-12

    We have previously reported that stress analgesia sensitive to and insensitive to opiate antagonists can be differentially produced in rats by varying the severity or temporal pattern of inescapable footshock. In these studies, we give further evidence for the opioid and non-opioid bases of these paradigms of stress analgesia. We find that naloxone-sensitive analgesia demonstrates tolerance with repeated stress and cross-tolerance with morphine, whereas naloxone-insensitive analgesia demonstrates neither of these characteristics. Moreover, different forms of opioid, but not non-opioid, stress analgesia manifest cross-tolerance with each other. These data are discussed in terms of the similarities and differences between two forms of opioid stress analgesia. PMID:3955348

  10. Perspectives on opioid tolerance from basic research: behavioural studies after spinal administration in rodents.

    PubMed

    Stevens, C W

    1994-01-01

    For tolerance development studies, computer modelling and statistical tests suggested that the equation which best described the decrement of analgesic effect was best served by an exponential decay function. Further analysis of the time course data led to the tentative conclusion that all groups of animals became tolerant at the same rate, regardless of drug or dose. A literature search revealed then, as it does now, that although there are many statements regarding the rate of opioid tolerance, there has been little systematic investigation of this. The Holy Grail of obtaining the rates of tolerance for a number of opioid agents in a systematic study is well within grasp. This information will be needed in clinical practice for the rational choice of opioid with regard to rate of the development of tolerance. The working hypothesis that emerges for the magnitude of opioid tolerance is that more potent agonists produce less tolerance. Further confirmation of this hypothesis has been forthcoming. This suggests that clinical use of more potent opioids, such as fentanyl, should be considered as a substitute for morphine in long term treatment regimens. The working hypothesis for cross-tolerance is that agents acting on the same receptors will show cross-tolerance. Cross-tolerance will also be observed among agents acting on different receptors, but only those that exhibit pharmacological synergy after short term administration. Asymmetry of cross-tolerance can occur, as the magnitude of this cross-tolerance is determined by the relative potency of the toleragen with regard to that of the probe agent. Given the additional factor of receptor selectivity with agents of different receptor classes, types and subtypes, new studies need to be designed combining the toleragen with a selective antagonist to determine the precise receptor mediation of the magnitude of tolerance, and thus cross-tolerance. For example, the delta opioid DADLE infused with a mu selective opioid

  11. IRAS Modulates Opioid Tolerance and Dependence by Regulating μ Opioid Receptor Trafficking.

    PubMed

    Li, Fei; Ma, Hao; Wu, Ning; Li, Jin

    2016-09-01

    Imidazoline receptor antisera-selected (IRAS) protein, the mouse homologue named Nischarin, was found to target to early endosomes with properties of sorting nexins in vitro. Recently, we generated IRAS knockout mice and found IRAS deficiency exacerbated the analgesic tolerance and physical dependence caused by opioids, suggesting that IRAS plays a role in regulating μ opioid receptor (MOR) functions. In the present study, we found that IRAS interacts with MOR and regulates MOR trafficking in vitro. In the CHO or HEK293 cells co-expressing MOR and IRAS, IRAS, through its PX domain, interacted with MOR. The interaction facilitated the recycling of internalized MOR and prevented MOR downregulation induced by DAMGO, the MOR agonist. Functionally, IRAS accelerated MOR resensitization and attenuated DAMGO-induced MOR desensitization, which is believed as one of mechanisms mediating opioid tolerance and dependence. Taken together, we propose that IRAS is a new MOR interacting protein and regulates agonist-induced trafficking of MOR via sorting internalized MOR to the recycling pathway, which may be a molecular mechanism underlying IRAS modulating opioid tolerance and dependence. PMID:26363797

  12. Development of peripheral opioid antagonists' new insights into opioid effects.

    PubMed

    Moss, Jonathan; Rosow, Carl E

    2008-10-01

    The recent approval by the US Food and Drug Administration of 2 medications--methylnaltrexone and alvimopan--introduces a new class of therapeutic entities to clinicians. These peripherally acting mu-opioid receptor antagonists selectively reverse opioid actions mediated by receptors outside the central nervous system, while preserving centrally mediated analgesia. Methylnaltrexone, administered subcutaneously, has been approved in the United States, Europe, and Canada. In the United States, it is indicated for the treatment of opioid-induced constipation in patients with advanced illness (eg, cancer, AIDS) who are receiving palliative care, when response to laxative therapy has not been sufficient. Alvimopan, an orally administered medication, has been approved in the United States to facilitate recovery of gastrointestinal function after bowel resection and primary anastomosis. Clinical and laboratory studies performed during the development of these drugs have indicated that peripheral receptors mediate other opioid effects, including decreased gastric emptying, nausea and vomiting, pruritus, and urinary retention. Laboratory investigations with these compounds suggest that opioids affect fundamental cellular processes through mechanisms that were previously unknown. These mechanisms include modifications of human immunodeficiency virus penetration, tumor angiogenesis, vascular permeability, and bacterial virulence. PMID:18828971

  13. Curcumin Attenuates Opioid Tolerance and Dependence by Inhibiting Ca2+/Calmodulin-Dependent Protein Kinase II α Activity

    PubMed Central

    Hu, Xiaoyu; Huang, Fang; Szymusiak, Magdalena

    2015-01-01

    Chronic use of opioid analgesics has been hindered by the development of opioid addiction and tolerance. We have reported that curcumin, a natural flavonoid from the rhizome of Curcuma longa, attenuated opioid tolerance, although the underlying mechanism remains unclear. In this study, we tested the hypothesis that curcumin may inhibit Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα), a protein kinase that has been previously proposed to be critical for opioid tolerance and dependence. In this study, we used state-of-the-art polymeric formulation technology to produce poly(lactic-co-glycolic acid) (PLGA)-curcumin nanoparticles (nanocurcumin) to overcome the drug’s poor solubility and bioavailability, which has made it extremely difficult for studying in vivo pharmacological actions of curcumin. We found that PLGA-curcumin nanoparticles reduced the dose requirement by 11- to 33-fold. Pretreatment with PLGA-curcumin (by mouth) prevented the development of opioid tolerance and dependence in a dose-dependent manner, with ED50 values of 3.9 and 3.2 mg/kg, respectively. PLGA-curcumin dose-dependently attenuated already-established opioid tolerance (ED50 = 12.6 mg/kg p.o.) and dependence (ED50 = 3.1 mg/kg p.o.). Curcumin or PLGA-curcumin did not produce antinociception by itself or affect morphine (1–10 mg/kg) antinociception. Moreover, we found that the behavioral effects of curcumin on opioid tolerance and dependence correlated with its inhibition of morphine-induced CaMKIIα activation in the brain. These results suggest that curcumin may attenuate opioid tolerance and dependence by suppressing CaMKIIα activity. PMID:25515789

  14. Epigenetic regulation of spinal cord gene expression contributes to enhanced postoperative pain and analgesic tolerance subsequent to continuous opioid exposure

    PubMed Central

    Liang, De-Yong; Shi, Xiao-You; Sun, Yuan; Clark, J David

    2016-01-01

    Background Opioids have become the mainstay for treatment of moderate to severe pain and are commonly used to treat surgical pain. While opioid administration has been shown to cause opioid-induced hyperalgesia and tolerance, interactions between opioid administration and surgery with respect to these problematic adaptations have scarcely been addressed. Accumulating evidence suggests opioids and nociceptive signaling may converge on epigenetic mechanisms in spinal cord to enhance or prolong neuroplastic changes. Epigenetic regulation of Bdnf (brain-derived neurotrophic factor) and Pdyn (prodynorphin) genes may be involved. Results Four days of ascending doses of morphine treatment caused opioid-induced hyperalgesia and reduced opioid analgesic efficacy in mice. Both opioid-induced hyperalgesia and the reduced opioid analgesic efficacy were enhanced in mice that received hindpaw incisions. The expression of Bdnf and Pdyn (qPCR) was increased after morphine treatment and incision. Chromatin immunoprecipitation assays demonstrated that the Pdyn and Bdnf promoters were more strongly associated with acetylated H3K9 after morphine plus incision than in the morphine or incision alone groups. Selective tropomyosin-related kinase B (ANA-12) and κ-opioid receptor (nor-binaltorphimine) antagonists were administered intrathecally, both reduced hyperalgesia one or three days after surgery. Administration of ANA-12 or nor-binaltorphimine attenuated the decreased morphine analgesic efficacy on day 1, but only nor-binaltorphimine was effective on day 3 after incision in opioid-exposed group. Coadministration of histone acetyltransferase inhibitor anacardic acid daily with morphine blocked the development of opioid-induced hyperalgesia and attenuated incision-enhanced hyperalgesia in morphine-treated mice. Anacardic acid had similar effects on analgesic tolerance, showing the involvement of histone acetylation in the interactions detected. Conclusions Spinal epigenetic changes

  15. Acute cross-tolerance to opioids in heroin delta-opioid-responding Swiss Webster mice.

    PubMed

    Rady, J J; Fujimoto, J M

    2000-01-01

    It is generally thought that the mu receptor actions of metabolites, 6-monoacetylmorphine (6MAM) and morphine, account for the pharmacological actions of heroin. However, upon intracerebroventricular (i.c.v.) administration in Swiss Webster mice, heroin and 6MAM act on delta receptors while morphine acts on mu receptors. Swiss Webster mice made tolerant to subcutaneous (s.c.) morphine by morphine pellet were not cross-tolerant to s.c. heroin (at 20 min in the tail flick test). Now, opioids were given in combination, s.c. (6.5 h) and i.c.v. (3 h) preceding testing the challenging agonist i.c.v. (at 10 min in the tail flick test). The combination (s.c. + i.c.v.) morphine pretreatment induced tolerance to the mu action of morphine but no cross-tolerance to the delta action of heroin, 6MAM and DPDPE and explained why morphine pelleting did not produce cross-tolerance to s.c. heroin above. Heroin plus heroin produced tolerance to delta agonists but not to mu agonists. Surprisingly, all combinations of morphine with the delta agonists produced tolerance to morphine which now acted through delta receptors (inhibited by i.c.v. naltrindole), an unusual change in receptor selectivity for morphine. PMID:10810246

  16. Mesenchymal Stem Cells Reversed Morphine Tolerance and Opioid-induced Hyperalgesia.

    PubMed

    Hua, Zhen; Liu, LiPing; Shen, Jun; Cheng, Katherine; Liu, Aijun; Yang, Jing; Wang, Lina; Qu, Tingyu; Yang, HongNa; Li, Yan; Wu, Haiyan; Narouze, John; Yin, Yan; Cheng, Jianguo

    2016-01-01

    More than 240 million opioid prescriptions are dispensed annually to treat pain in the US. The use of opioids is commonly associated with opioid tolerance (OT) and opioid-induced hyperalgesia (OIH), which limit efficacy and compromise safety. The dearth of effective way to prevent or treat OT and OIH is a major medical challenge. We hypothesized that mesenchymal stem cells (MSCs) attenuate OT and OIH in rats and mice based on the understanding that MSCs possess remarkable anti-inflammatory properties and that both OT and chronic pain are associated with neuroinflammation in the spinal cord. We found that the development of OT and OIH was effectively prevented by either intravenous or intrathecal MSC transplantation (MSC-TP), which was performed before morphine treatment. Remarkably, established OT and OIH were significantly reversed by either intravenous or intrathecal MSCs when cells were transplanted after repeated morphine injections. The animals did not show any abnormality in vital organs or functions. Immunohistochemistry revealed that the treatments significantly reduced activation level of microglia and astrocytes in the spinal cord. We have thus demonstrated that MSC-TP promises to be a potentially safe and effective way to prevent and reverse two of the major problems of opioid therapy. PMID:27554341

  17. Mesenchymal Stem Cells Reversed Morphine Tolerance and Opioid-induced Hyperalgesia

    PubMed Central

    Hua, Zhen; Liu, LiPing; Shen, Jun; Cheng, Katherine; Liu, Aijun; Yang, Jing; Wang, Lina; Qu, Tingyu; Yang, HongNa; Li, Yan; Wu, Haiyan; Narouze, John; Yin, Yan; Cheng, Jianguo

    2016-01-01

    More than 240 million opioid prescriptions are dispensed annually to treat pain in the US. The use of opioids is commonly associated with opioid tolerance (OT) and opioid-induced hyperalgesia (OIH), which limit efficacy and compromise safety. The dearth of effective way to prevent or treat OT and OIH is a major medical challenge. We hypothesized that mesenchymal stem cells (MSCs) attenuate OT and OIH in rats and mice based on the understanding that MSCs possess remarkable anti-inflammatory properties and that both OT and chronic pain are associated with neuroinflammation in the spinal cord. We found that the development of OT and OIH was effectively prevented by either intravenous or intrathecal MSC transplantation (MSC-TP), which was performed before morphine treatment. Remarkably, established OT and OIH were significantly reversed by either intravenous or intrathecal MSCs when cells were transplanted after repeated morphine injections. The animals did not show any abnormality in vital organs or functions. Immunohistochemistry revealed that the treatments significantly reduced activation level of microglia and astrocytes in the spinal cord. We have thus demonstrated that MSC-TP promises to be a potentially safe and effective way to prevent and reverse two of the major problems of opioid therapy. PMID:27554341

  18. Analgesic tolerance of opioid agonists in mutant mu-opioid receptors expressed in sensory neurons following intrathecal plasmid gene delivery

    PubMed Central

    2013-01-01

    Background Phosphorylation sites in the C-terminus of mu-opioid receptors (MORs) are known to play critical roles in the receptor functions. Our understanding of their participation in opioid analgesia is mostly based on studies of opioid effects on mutant receptors expressed in in vitro preparations, including cell lines, isolated neurons and brain slices. The behavioral consequences of the mutation have not been fully explored due to the complexity in studies of mutant receptors in vivo. To facilitate the determination of the contribution of phosphorylation sites in MOR to opioid-induced analgesic behaviors, we expressed mutant and wild-type human MORs (hMORs) in sensory dorsal root ganglion (DRG) neurons, a major site for nociceptive (pain) signaling and determined morphine- and the full MOR agonist, DAMGO,-induced effects on heat-induced hyperalgesic behaviors and potassium current (IK) desensitization in these rats. Findings A mutant hMOR DNA with the putative phosphorylation threonine site at position 394 replaced by an alanine (T394A), i.e., hMOR-T, or a plasmid containing wild type hMOR (as a positive control) was intrathecally delivered. The plasmid containing GFP or saline was used as the negative control. To limit the expression of exogenous DNA to neurons of DRGs, a neuron-specific promoter was included in the plasmid. Following a plasmid injection, hMOR-T or hMOR receptors were expressed in small and medium DRG neurons. Compared with saline or GFP rats, the analgesic potency of morphine was increased to a similar extent in hMOR-T and hMOR rats. Morphine induced minimum IK desensitization in both rat groups. In contrast, DAMGO increased analgesic potency and elicited IK desensitization to a significantly less extent in hMOR-T than in hMOR rats. The development and extent of acute and chronic tolerance induced by repeated morphine or DAMGO applications were not altered by the T394A mutation. Conclusions These results indicate that phosphorylation of T394

  19. [(35)S]GTPγS binding and opioid tolerance and efficacy in mouse spinal cord.

    PubMed

    Madia, Priyanka A; Navani, Dipesh M; Yoburn, Byron C

    2012-03-01

    The present study examined efficacy of a series of opioid agonists and then using chronic in vivo treatment protocols, determined tolerance to opioid agonist stimulated [(35)S]GTPγS (guanosine 5'-O-(3-[(35)S] thio)triphosphate) binding in mouse spinal cord membranes and compared it directly to spinal analgesic tolerance. The [(35)S]GTPγS binding assay was used to estimate efficacy (E(max) and τ; Operational Model of Agonism) of a series of opioid agonists for G-protein activation in mouse spinal cord. The rank order of opioid agonist efficacy determined in the [(35)S]GTPγS assay using the Operational Model and E(max) was similar. These efficacy estimates correlated with historical analgesic efficacy estimates. For tolerance studies, mice were continuously treated s.c. for 7days with morphine, oxycodone, hydromorphone, etorphine or fentanyl and [(35)S]GTPγS studies were conducted in spinal cord membranes. Other mice were tested in i.t. analgesia dose response studies (tailflick). Tolerance to DAMGO ([D-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin) or morphine stimulated [(35)S]GTPγS binding (decrease in E(max)) was observed following etorphine and fentanyl treatment only. These treatment protocols downregulate μ-opioid receptor density whereas morphine, oxycodone and hydromorphone do not. Spinal analgesic tolerance was observed following all treatment protocols examined (morphine, oxycodone and etorphine). Opioid antagonist treatment that specifically upregulates (chronic naltrexone) or downregulates (clocinnamox) μ-opioid receptor density produced a corresponding change in opioid agonist stimulated [(35)S]GTPγS binding. Although receptor downregulation and G-protein uncoupling are among potential mechanisms of opioid tolerance, the present results suggest that uncoupling in mouse spinal cord plays a minor role and that the [(35)S]GTPγS assay is particularly responsive to changes in μ-opioid receptor density. PMID:22108651

  20. DEVELOPMENT AND IN VITRO CHARACTERIZATION OF A NOVEL BIFUNCTIONAL MU-AGONIST/DELTA-ANTAGONIST OPIOID TETRAPEPTIDE

    PubMed Central

    Purington, Lauren C.; Sobczyk-Kojiro, Katarzyna; Pogozheva, Irina D.; Traynor, John R.; Mosberg, Henry I.

    2011-01-01

    The development of tolerance to and dependence on opioid analgesics greatly reduces their long-term usefulness. Previous studies have demonstrated that co-administration of a mu opioid receptor (MOR) agonist and delta opioid receptor (DOR) antagonist can decrease MOR agonist induced tolerance and dependence development after chronic exposure. Clinically, a single ligand displaying multiple efficacies (e.g. MOR agonism concurrently with DOR antagonism) would be of increased value over two drugs administered simultaneously. Guided by modeling of receptor-ligand complexes we have developed a series of potent non-selective opioid tetrapeptides that have differing efficacy at MOR and DOR. In particular, our lead peptide (KSK-103) binds with equal affinity to MOR and DOR but acts as a MOR agonist with similar efficacy but greater potency than morphine and a DOR antagonist in cellular assays measuring both G protein stimulation and adenylyl cyclase inhibition. PMID:21958158

  1. Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia

    PubMed Central

    Oladosu, Folabomi A.; Conrad, Matthew S.; O’Buckley, Sandra C.; Rashid, Naim U.; Slade, Gary D.; Nackley, Andrea G.

    2015-01-01

    Background A subset of the population receiving opioids for the treatment of acute and chronic clinical pain develops a paradoxical increase in pain sensitivity known as opioid-induced hyperalgesia. Given that opioid analgesics are one of few treatments available against clinical pain, it is critical to determine the key molecular mechanisms that drive opioid-induced hyperalgesia in order to reduce its prevalence. Recent evidence implicates a splice variant of the mu opioid receptor known as MOR-1K in the emergence of opioid-induced hyperalgesia. Results from human genetic association and cell signaling studies demonstrate that MOR-1K contributes to decreased opioid analgesic responses and produces increased cellular activity via Gs signaling. Here, we conducted the first study to directly test the role of MOR-1K in opioid-induced hyperalgesia. Methods and Results In order to examine the role of MOR-1K in opioid-induced hyperalgesia, we first assessed pain responses to mechanical and thermal stimuli prior to, during, and following chronic morphine administration. Results show that genetically diverse mouse strains (C57BL/6J, 129S6, and CXB7/ByJ) exhibited different morphine response profiles with corresponding changes in MOR-1K gene expression patterns. The 129S6 mice exhibited an analgesic response correlating to a measured decrease in MOR-1K gene expression levels, while CXB7/ByJ mice exhibited a hyperalgesic response correlating to a measured increase in MOR-1K gene expression levels. Furthermore, knockdown of MOR-1K in CXB7/ByJ mice via chronic intrathecal siRNA administration not only prevented the development of opioid-induced hyperalgesia, but also unmasked morphine analgesia. Conclusions These findings suggest that MOR-1K is likely a necessary contributor to the development of opioid-induced hyperalgesia. With further research, MOR-1K could be exploited as a target for antagonists that reduce or prevent opioid-induced hyperalgesia. PMID:26270813

  2. A Preliminary Randomized Controlled Trial of a Distress Tolerance Treatment for Opioid Dependent Persons Initiating Buprenorphine

    PubMed Central

    Stein, Michael D.; Herman, Debra S.; Moitra, Ethan; Hecht, Jacki; Lopez, Rosalie; Anderson, Bradley J; Brown, Richard A.

    2014-01-01

    Background Buprenorphine opioid agonist treatment (OAT) has established efficacy for treating opioid dependency but early relapse rates are high and are often associated with withdrawal-related or emotional distress. Methods To determine whether a novel distress tolerance (DT) intervention during buprenorphine initiation decreases opioid relapse, we conducted a preliminary randomized controlled trial with opioid-dependent outpatients. Participants received buprenorphine-naloxone induction and 3-months of maintenance buprenorphine plus seven, 50-minute manualized, individual sessions (DT vs. Health Education (HE) control) over a 28-day period, linked to clinician medication dosing visits, and beginning 2 days prior to buprenorphine induction. Primary outcomes included use of illicit opioids (positive defined as any self-reported use in the prior 28 days or detected by urine toxicology) and treatment drop out. Results Among 49 participants, the mean age was 41 years, 65.3% were male. Persons randomized to DT had lower rates of opioid use at all three monthly assessments, and at 3-months, 72% of HE participants were opioid positive compared with 62.5% of DT participants. Rates of dropout were 24% and 25% in the HE and DT arms, respectively. Conclusions This distress tolerance treatment produced a small, but not statistically significant reduction in opioid use during the first three months of treatment although no differences were found in drop-out rates between conditions. If replicated in a larger study, DT could offer clinicians a useful behavioral treatment to complement the effects of buprenorphine. Trial registered at clinicaltrials.org. Trial number NCT01556087. PMID:25510307

  3. Development and validation of the Patient Opioid Education Measure

    PubMed Central

    Wallace, Lorraine S; Wexler, Randell K; Miser, W Frederick; McDougle, Leon; Haddox, J David

    2013-01-01

    Background Although there are screening tools to aid clinicians in assessing the risk of opioid misuse, an instrument to assess opioid-related knowledge is not currently available. The purpose of this study was to develop a content-valid, understandable, readable, and reliable Patient Opioid Education Measure (POEM). Methods Using concept mapping, clinicians caring for patients with chronic pain participated in brainstorming, sorting, and rating need-to-know information for patients prescribed opioids. Concept mapping analyses identified seven clusters addressing knowledge and expectations associated with opioid use, including medicolegal issues, prescribing policies, safe use and handling, expected outcomes, side effects, pharmacology, and warnings. Results The 49-item POEM was verbally administered to 83 patients (average age 51.3 ± 9.8 years, 77.1% female, 47.1% African American) taking opioids for chronic nonmalignant pain. Patients averaged in total 63.9% ± 14.3% (range 23%–91%) correct responses on the POEM. The POEM demonstrated substantial test-retest reliability (interclass correlation coefficient 0.87). The POEM had a mean readability Lexile (L) score of 805.9 ± 257.3 L (equivalent to approximately a US fifth grade reading level), with individual items ranging from 280 L to 1370 L. Conclusion The POEM shows promise for rapidly identifying patients’ opioid-related knowledge gaps and expectations. Correcting misunderstandings and gaps could result in safer use of opioids in a clinical care setting. PMID:24049456

  4. Remifentanil produces cross-desensitization and tolerance with morphine on the mu-opioid receptor.

    PubMed

    Nowoczyn, M; Marie, N; Coulbault, L; Hervault, M; Davis, A; Hanouz, J L; Allouche, S

    2013-10-01

    Remifentanil is a powerful mu-opioid (MOP) receptor agonist used in anaesthesia with a very short half-life. However, per-operative perfusion of remifentanil was shown to increase morphine consumption during post-operative period to relieve pain. In the present study, we aimed to describe the cellular mechanisms responsible for this apparent reduction of morphine efficacy. For this purpose, we first examined the pharmacological properties of both remifentanil and morphine at the MOP receptor, endogenously expressed in the human neuroblastoma SH-SY5Y cell line, to regulate adenylyl cyclase and the MAP kinase ERK1/2 pathway, their potency to promote MOP receptor phosphorylation, arrestin 3-CFP (cyan fluorescent protein) recruitment and receptor trafficking during acute and sustained exposure. In the second part of this work, we studied the effects of a prior exposure of remifentanil on morphine-induced inhibition of cAMP accumulation, activation of ERK1/2 and analgesia. We showed that sustained exposure to remifentanil promoted a rapid desensitization of opioid receptors on both signalling pathways and a pretreatment with this agonist reduced signal transduction produced by a second challenge with morphine. While both opioid agonists promoted Ser(375) phosphorylation on MOP receptor, remifentanil induced a rapid internalization of opioid receptors compared to morphine but without detectable arrestin 3-CFP translocation to the plasma membrane in our experimental conditions. Lastly, a cross-tolerance between remifentanil and morphine was observed in mice using the hot plate test. Our in vitro and in vivo data thus demonstrated that remifentanil produced a rapid desensitization and internalization of the MOP receptor that would reduce the anti-nociceptive effects of morphine. PMID:23792280

  5. [Pain and opioids].

    PubMed

    Murányi, Marianna; Radák, Zsolt

    2008-12-14

    Noxious stimuli cause pain to protect the body from harmful situations and attract attention to pathophysiologic changes of the body. Specific receptors of pain (nociceptors) can be found all over our body. Pain initiates protecting mechanisms such as vegetative and motor reflexes, and emotional, behavioral changes. However, chronic pain is practically useless and leads to psychopathological changes. There are several ways to relieve pain including non-steroid anti-inflammatory agents, opioids, neurosurgical and non-invasive methods. Central and peripheral effects of opioids can be realized through opioid receptors of the central and the enteric nervous system. In the central nervous system, they can inhibit the perception of pain or change the emotional reactions. Opioids are indicated in postoperative pain, neuropathic pain and cancer. However, the use of opioids has severe side-effects such as breathing depression and the development of tolerance and dependence which do not make opioids optimal painkillers. There are several laboratories in Hungary and abroad working on the design of optimal pain relievers. Furthermore, the euphoric effects of opioids lead to abuse which makes the research important on the mechanisms of opioid addiction. Taken together, opioid research, the design of new compounds and the exploration of the mechanisms of opiate addiction are very important. PMID:19073443

  6. Ligand-biased activation of extracellular signal-regulated kinase 1/2 leads to differences in opioid induced antinociception and tolerance.

    PubMed

    Bobeck, Erin N; Ingram, Susan L; Hermes, Sam M; Aicher, Sue A; Morgan, Michael M

    2016-02-01

    Opioids produce antinociception by activation of G protein signaling linked to the mu-opioid receptor (MOPr). However, opioid binding to the MOPr also activates β-arrestin signaling. Opioids such as DAMGO and fentanyl differ in their relative efficacy for activation of these signaling cascades, but the behavioral consequences of this differential signaling are not known. The purpose of this study was to evaluate the behavioral significance of G protein and internalization dependent signaling within ventrolateral periaqueductal gray (vlPAG). Antinociception induced by microinjecting DAMGO into the vlPAG was attenuated by blocking Gαi/o protein signaling with administration of pertussis toxin (PTX), preventing internalization with administration of dynamin dominant-negative inhibitory peptide (dyn-DN) or direct inhibition of ERK1/2 with administration of the MEK inhibitor, U0126. In contrast, the antinociceptive effect of microinjecting fentanyl into the vlPAG was not altered by administration of PTX or U0126, and was enhanced by administration of dyn-DN. Microinjection of DAMGO, but not fentanyl, into the vlPAG induced phosphorylation of ERK1/2, which was blocked by inhibiting receptor internalization with administration of dyn-DN, but not by inhibition of Gαi/o proteins. ERK1/2 inhibition also prevented the development and expression of tolerance to repeated DAMGO microinjections, but had no effect on fentanyl tolerance. These data reveal that ERK1/2 activation following MOPr internalization contributes to the antinociceptive effect of some (e.g., DAMGO), but not all opioids (e.g., fentanyl) despite the known similarities for these agonists to induce β-arrestin recruitment and internalization. PMID:26497105

  7. Valproate attenuates the development of morphine antinociceptive tolerance.

    PubMed

    Dobashi, Tamae; Tanabe, Serabi; Jin, Hisayo; Nishino, Takashi; Aoe, Tomohiko

    2010-11-19

    Morphine is a potent opioid analgesic. Repeated administration of morphine induces tolerance, thus reducing the effectiveness of analgesic treatment. Although some adjuvant analgesics can increase morphine analgesia, the precise molecular mechanism behind their effects remains unclear. Opioids bind to the mu opioid receptor (MOR). Morphine tolerance may be derived from alterations in the intracellular signal transduction after MOR activation. Chronic morphine treatment activates glycogen synthase kinase 3β (GSK3β), whose inhibition diminishes morphine tolerance. Valproate is widely prescribed as an anticonvulsant and a mood stabilizer for bipolar disorders because it increases the amount of γ-aminobutyric acid (GABA) in the central nervous system. Although the activation of GABAergic neurons may be responsible for the chief pharmacologic effect of valproate, recent studies have shown that valproate also suppresses GSK3β activity. We examined the effect of valproate on the development of morphine antinociceptive tolerance in a mouse model of thermal injury. Mice were treated with morphine alone or with morphine and valproate twice daily for 5 days. The resulting antinociceptive effects were assessed using a hot plate test. While mice treated with morphine developed tolerance, co-administration of valproate attenuated the development of tolerance and impaired the activation of GSK3β in mice brains. Valproate alone did not show analgesic effects; nevertheless, it functioned as an adjuvant analgesic to prevent the development of morphine tolerance. These results suggest that the modulation of GSK3β activity by valproate may be useful and may play a role in the prevention of morphine tolerance. PMID:20816918

  8. Intrathecal morphine attenuates acute opioid tolerance secondary to remifentanil infusions during spinal surgery in adolescents

    PubMed Central

    Tripi, Paul A; Kuestner, Matthew E; Poe-Kochert, Connie S; Rubin, Kasia; Son-Hing, Jochen P; Thompson, George H; Tobias, Joseph D

    2015-01-01

    Introduction The unique pharmacokinetic properties of remifentanil with a context-sensitive half-life unaffected by length of infusion contribute to its frequent use during anesthetic management during posterior spinal fusion in children and adolescents. However, its intraoperative administration can lead to increased postoperative analgesic requirements, which is postulated to be the result of acute opioid tolerance with enhancement of spinal N-methyl-D-aspartate receptor function. Although strategies to prevent or reduce tolerance have included the coadministration of longer acting opioids or ketamine, the majority of these studies have demonstrated little to no benefit. The current study retrospectively evaluates the efficacy of intrathecal morphine (ITM) in preventing hyperalgesia following a remifentanil infusion. Methods We retrospectively analyzed 54 patients undergoing posterior spinal fusion with segmental spinal instrumentation, to evaluate the effects of ITM on hyperalgesia from remifentanil. Patients were divided into two groups based on whether they did or did not receive remifentanil during the surgery: no remifentanil (control group) (n=27) and remifentanil (study group) (n=27). Data included demographics, remifentanil dose and duration, Wong–Baker visual analog scale postoperative pain scores, and postoperative intravenous morphine consumption in the first 48 postoperative hours. Results The demographics of the two study groups were similar. There were no differences in the Wong–Baker visual analog scale pain scores in the postanesthesia care unit and on postoperative days 1 and 3. Pain scores were higher in the remifentanil group on postoperative day 2 (2.9 vs 3.8). Postoperative morphine requirements were similar between the two groups (0.029 vs 0.017 mg/kg/48 h for the control group and the study group, respectively). Conclusion In patients receiving preincisional ITM during spinal surgery, intraoperative remifentanil does not increase

  9. Opioid Analgesics.

    PubMed

    Jamison, Robert N; Mao, Jianren

    2015-07-01

    Chronic pain is an international health issue of immense importance that is influenced by both physical and psychological factors. Opioids are useful in treating chronic pain but have accompanying complications. It is important for clinicians to understand the basics of opioid pharmacology, the benefits and adverse effects of opioids, and related problematic issues of tolerance, dependence, and opioid-induced hyperalgesia. In this article, the role of psychiatric comorbidity and the use of validated assessment tools to identify individuals who are at the greatest risk for opioid misuse are discussed. Additionally, interventional treatment strategies for patients with chronic pain who are at risk for opioid misuse are presented. Specific behavioral interventions designed to improve adherence with prescription opioids among persons treated for chronic pain, such as frequent monitoring, periodic urine screens, opioid therapy agreements, opioid checklists, and motivational counseling, are also reviewed. Use of state-sponsored prescription drug monitoring programs is also encouraged. Areas requiring additional investigation are identified, and the future role of abuse-deterrent opioids and innovative technology in addressing issues of opioid therapy and pain are presented. PMID:26141334

  10. Role of kappa and delta opioid receptors in mediating morphine-induced antinociception in morphine tolerant infant rats

    PubMed Central

    Stoller, Dawn C.; Sim-Selley, Laura J.; Smith, Forrest L.

    2011-01-01

    We have previously noted that the antinociceptive efficacy of morphine was significantly decreased in rat pups chronically infused with morphine from implanted osmotic minipumps. In this study, morphine was fully efficacious (i.e., 100% maximum possible effect, %MPE) in the 52 ºC tail-immersion test after a 72-h infusion from implanted saline-filled osmotic minipumps. However, administration of up to 1000 mg/kg s.c. morphine failed to elicit greater than a 27% MPE in rats infused with morphine at 2 mg/kg/h. Morphine was more efficacious when the water bath temperature was decreased to 49 ºC. Experiments were conducted to determine the mechanisms whereby chronic morphine administration leads to a decrease in antinociceptive efficacy. The kappa-opioid antagonist nor-binalorphimine completely blocked the antinociceptive effects of morphine in morphine-infused rat pups. The kappa agonist U50,488 elicited antinociception however, the requirement to use higher doses in morphine- than saline-infused rats indicates that kappa cross-tolerance was present. Thus, in tolerant rats the antinociceptive effects of high doses of morphine appear to be mediated through kappa-opioid receptors. The delta-opioid antagonist naltrindole was inactive in both treatment groups. DAMGO-stimulated [35S]GTPγS and [3H]naloxone binding reveal that the anatomical distribution of the mu-opioid receptor was consistent with that of the adult rat brain. In adult rats, the mu-opioid receptor is desensitized during morphine tolerance. However, desensitization was not evident in P17 rats based on the lack of significant decreases in [35S]GTPγS binding. Furthermore, [3H]naloxone binding indicated a lack of mu receptor downregulation in morphine-tolerant rat pups. PMID:17300766

  11. The mechanism of μ-opioid receptor (MOR)-TRPV1 crosstalk in TRPV1 activation involves morphine anti-nociception, tolerance and dependence.

    PubMed

    Bao, Yanju; Gao, Yebo; Yang, Liping; Kong, Xiangying; Yu, Jing; Hou, Wei; Hua, Baojin

    2015-01-01

    Initiated by the activation of various nociceptors, pain is a reaction to specific stimulus modalities. The μ-opioid receptor (MOR) agonists, including morphine, remain the most potent analgesics to treat patients with moderate to severe pain. However, the utility of MOR agonists is limited by the adverse effects associated with the use of these drugs, including analgesic tolerance and physical dependence. A strong connection has been suggested between the expression of the transient receptor potential vanilloid type 1 (TRPV1) ion channel and the development of inflammatory hyperalgesia. TRPV1 is important for thermal nociception induction, and is mainly expressed on sensory neurons. Recent reports suggest that opioid or TRPV1 receptor agonist exposure has contrasting consequences for anti-nociception, tolerance and dependence. Chronic morphine exposure modulates TRPV1 activation and induces the anti-nociception effects of morphine. The regulation of many downstream targets of TRPV1 plays a critical role in this process, including calcitonin gene-related peptide (CGRP) and substance P (SP). Additional factors also include capsaicin treatment blocking the anti-nociception effects of morphine in rats, as well as opioid modulation of TRPV1 responses through the cAMP-dependent PKA pathway and MAPK signaling pathways. Here, we review new insights concerning the mechanism underlying MOR-TRPV1 crosstalk and signaling pathways and discuss the potential mechanisms of morphine-induced anti-nociception, tolerance and dependence associated with the TRPV1 signaling pathway and highlight how understanding these mechanisms might help find therapeutic targets for the treatment of morphine induced antinociception, tolerance and dependence. PMID:26176938

  12. Opioid-induced constipation: advances and clinical guidance.

    PubMed

    Nelson, Alfred D; Camilleri, Michael

    2016-03-01

    Currently opioids are the most frequently used medications for chronic noncancer pain. Opioid-induced constipation is the most common adverse effect associated with prolonged use of opioids, having a major impact on quality of life. There is an increasing need to treat opioid-induced constipation. With the recent approval of medications for the treatment of opioid-induced constipation, there are several therapeutic approaches. This review addresses the clinical presentation and diagnosis of opioid-induced constipation, barriers to its diagnosis, effects of opioids in the gastrointestinal tract, differential tolerance to opiates in different gastrointestinal organs, medications approved and in development for the treatment of opioid-induced constipation, and a proposed clinical management algorithm for treating opioid-induced constipation in patients with noncancer pain. PMID:26977281

  13. Opioid-induced constipation: advances and clinical guidance

    PubMed Central

    Nelson, Alfred D.; Camilleri, Michael

    2016-01-01

    Currently opioids are the most frequently used medications for chronic noncancer pain. Opioid-induced constipation is the most common adverse effect associated with prolonged use of opioids, having a major impact on quality of life. There is an increasing need to treat opioid-induced constipation. With the recent approval of medications for the treatment of opioid-induced constipation, there are several therapeutic approaches. This review addresses the clinical presentation and diagnosis of opioid-induced constipation, barriers to its diagnosis, effects of opioids in the gastrointestinal tract, differential tolerance to opiates in different gastrointestinal organs, medications approved and in development for the treatment of opioid-induced constipation, and a proposed clinical management algorithm for treating opioid-induced constipation in patients with noncancer pain. PMID:26977281

  14. Opioid and adjuvant analgesics: compared and contrasted.

    PubMed

    Khan, Mohammed Ilyas Ahmed; Walsh, Declan; Brito-Dellan, Norman

    2011-08-01

    AAs (1-2 days). Rotation among opioids is a useful therapeutic strategy to improve analgesic response or minimize toxicity. Most AAs are unsuitable for rescue dosing because of their pharmacological characteristics. The mu agonist side effect profile is similar among the different opioid agents, regardless of the route of administration. The appropriate use of AAs will reduce opioid-related side effects. No apparent tolerance to analgesia develops with AAs. Abrupt discontinuation of an opioid after chronic repeated use for more than a few days will cause a withdrawal syndrome of variable severity. Adjuvant analgesics are an essential tool in cancer pain. PMID:21622486

  15. Opioid receptor trafficking and interaction in nociceptors

    PubMed Central

    Zhang, X; Bao, L; Li, S

    2015-01-01

    Opiate analgesics such as morphine are often used for pain therapy. However, antinociceptive tolerance and dependence may develop with long-term use of these drugs. It was found that μ-opioid receptors can interact with δ-opioid receptors, and morphine antinociceptive tolerance can be reduced by blocking δ-opioid receptors. Recent studies have shown that μ- and δ-opioid receptors are co-expressed in a considerable number of small neurons in the dorsal root ganglion. The interaction of μ-opioid receptors with δ-opioid receptors in the nociceptive afferents is facilitated by the stimulus-induced cell-surface expression of δ-opioid receptors, and contributes to morphine tolerance. Further analysis of the molecular, cellular and neural circuit mechanisms that regulate the trafficking and interaction of opioid receptors and related signalling molecules in the pain pathway would help to elucidate the mechanism of opiate analgesia and improve pain therapy. LINKED ARTICLES 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 PMID:24611685

  16. Attenuation of tolerance to opioid-induced antinociception and protection against morphine-induced decrease of neurofilament proteins by idazoxan and other I2-imidazoline ligands

    PubMed Central

    Boronat, M Assumpció; Olmos, Gabriel; García-Sevilla, Jesús A

    1998-01-01

    attenuate morphine tolerance. Similarly, the concurrent chronic treatment of moxonidine (1 mg kg−1, i.p.), a mixed I1-imidazoline receptor and α2-adrenoceptor agonist, and morphine (10 mg kg−1, i.p.), did not alter the development of tolerance to the opiate. These results discounted the involvement of α2-adrenoceptors and I1-imidazoline receptors in the modulatory effect of idazoxan on opioid tolerance. Idazoxan and other imidazol(ine) drugs fully inhibited [3H]-(+)-MK-801 binding to N-methyl-D-aspartate (NMDA) receptors in the rat cerebral cortex with low potencies (Ki: 37–190 μM). The potencies of the imidazolines idazoxan, RX821002 and moxonidine were similar, indicating a lack of relationship between potency on NMDA receptors and ability to attenuate opioid tolerance. These results suggested that modulation of opioid tolerance by idazoxan is not related to NMDA receptors blockade. Chronic treatment (13 days) with morphine (10 mg kg−1, i.p.) was associated with a marked decrease (49%) in immunolabelled neurofilament proteins (NF-L) in the frontal cortex of morphine-tolerant rats, suggesting the induction of neuronal damage. Chronic treatment (13 days) with idazoxan (10 mg kg−1) and LSL 60101 (10 mg kg−1) did not modify the levels of NF-L proteins in brain. Interestingly, the concurrent chronic treatment (13 days) of idazoxan or LSL 60101 and morphine, completely reversed the morphine-induced decrease in NF-L immunoreactivity, suggesting a neuroprotective role for these drugs. Together, the results indicate that chronic treatment with I2-imidazoline ligands attenuates the development of tolerance to opiate drugs and may induce neuroprotective effects on chronic opiate treatment. Moreover, these findings offer the I2-imidazoline ligands as promising therapeutic co-adjuvants in the management of chronic pain with opiate drugs. PMID:9776358

  17. Molecular Mechanisms of Opioid Receptor-Dependent Signaling and Behavior

    PubMed Central

    Al-Hasani, Ream; Bruchas, Michael R.

    2013-01-01

    Opioid receptors have been targeted for the treatment of pain and related disorders for thousands of years, and remain the most widely used analgesics in the clinic. Mu (μ), kappa (κ), and delta (δ) opioid receptors represent the originally classified receptor subtypes, with opioid receptor like-1 (ORL1) being the least characterized. All four receptors are G-protein coupled, and activate inhibitory G-proteins. These receptors form homo- and hetereodimeric complexes, signal to kinase cascades, and scaffold a variety of proteins. In this review, we discuss classical mechanisms and developments in understanding opioid tolerance, opioid receptor signaling, and highlight advances in opioid molecular pharmacology, behavioral pharmacology, and human genetics. We put into context how opioid receptor signaling leads to the modulation of behavior with the potential for therapeutic intervention. Finally, we conclude that there is a continued need for more translational work on opioid receptors in vivo. PMID:22020140

  18. Development of concepts on the interaction of drugs with opioid receptors

    NASA Astrophysics Data System (ADS)

    Kuzmina, N. E.; Kuzmin, V. S.

    2011-02-01

    The development of concepts on the molecular mechanisms of the action of medicinal drugs on the opioid receptors is briefly surveyed. The modern point of view on the mechanism of activation of opioid receptors is given based on the data from chimeric and site-directed mutagenesis of the cloned opioid receptors and the computer-aided simulations of the reception zone and ligand-receptor complexes. Three-dimensional models of the opioid pharmacophore derived by both conventional methods and a comparative analysis of molecular fields are described in detail.

  19. Molecular Physiology of Enteric Opioid Receptors

    PubMed Central

    Galligan, James J.; Akbarali, Hamid I.

    2015-01-01

    Opioid drugs have powerful antidiarrheal effects and many patients taking these drugs for chronic pain relief experience chronic constipation that can progress to opioid-induced bowel dysfunction. Three classes of opioid receptors are expressed by enteric neurons: μ-, δ-, and κ-opioid receptors (MOR, DOR, and KOR). MOR and DOR couple to inhibition of adenylate cylase and nerve terminal Ca2+ channels and activation of K+ channels. These effects reduce neuronal activity and neurotransmitter release. KOR couples to inhibition of Ca2+ channels and inhibition of neurotransmitter release. In the human gastrointestinal tract, MOR, DOR, and KOR link to inhibition of acetylcholine release from enteric interneurons and purine/nitric oxide release from inhibitory motorneurons. These actions inhibit propulsive motility. MOR and DOR also link to inhibition of submucosal secretomotor neurons, reducing active Cl− secretion and passive water movement into the colonic lumen. These effects account for the constipation caused by opioid receptor agonists. Tolerance develops to the analgesic effects of opioid receptor agonists but not to the constipating actions. This may be due to differential β-arrestin-2-dependent opioid receptor desensitization and internalization in enteric nerves in the colon compared with the small intestine and in neuronal pain pathways. Further studies of differential opioid receptor desensitization and tolerance in subsets of enteric neurons may identify new drugs or other treatment strategies of opioid-induced bowel dysfunction. PMID:25207608

  20. Molecular physiology of enteric opioid receptors.

    PubMed

    Galligan, James J; Akbarali, Hamid I

    2014-09-10

    Opioid drugs have powerful antidiarrheal effects and many patients taking these drugs for chronic pain relief experience chronic constipation that can progress to opioid-induced bowel dysfunction. Three classes of opioid receptors are expressed by enteric neurons: μ-, δ-, and κ-opioid receptors (MOR, DOR, and KOR). MOR and DOR couple to inhibition of adenylate cylase and nerve terminal Ca(2+) channels and activation of K(+) channels. These effects reduce neuronal activity and neurotransmitter release. KOR couples to inhibition of Ca(2+) channels and inhibition of neurotransmitter release. In the human gastrointestinal tract, MOR, DOR, and KOR link to inhibition of acetylcholine release from enteric interneurons and purine/nitric oxide release from inhibitory motorneurons. These actions inhibit propulsive motility. MOR and DOR also link to inhibition of submucosal secretomotor neurons, reducing active Cl(-) secretion and passive water movement into the colonic lumen. These effects account for the constipation caused by opioid receptor agonists. Tolerance develops to the analgesic effects of opioid receptor agonists but not to the constipating actions. This may be due to differential β-arrestin-2-dependent opioid receptor desensitization and internalization in enteric nerves in the colon compared with the small intestine and in neuronal pain pathways. Further studies of differential opioid receptor desensitization and tolerance in subsets of enteric neurons may identify new drugs or other treatment strategies of opioid-induced bowel dysfunction. PMID:25207608

  1. Adjuncts to opioid therapy.

    PubMed

    Goldstein, Frederick J

    2002-09-01

    Administration of opioids to alleviate moderate to severe acute pain and chronic cancer pain is an established management process. However, advancements in clinical pharmacologic research have shown that opioids are also effective in chronic noncancerous pain. Many patients properly treated for prolonged periods with opioids develop tolerance and subsequently, physical dependence. This process is not necessarily harmful to the patient and will not cause the patient to develop an addiction (properly defined as psychologic dependence). For many patients who have been on opioid therapy for months or years, analgesic effectiveness tragically becomes less. In addition, opioid-induced constipation can be severe and cause pain; patients do not develop tolerance to this adverse reaction. Therefore, such issues become a management problem and require additional intervention. Currently, many different classes of drugs can serve as effective adjuncts to opioids for treatment of pain. Adding adjunctive medication to opioid therapy improves pain management primarily by nonopioid mechanisms of action. Clinical outcomes of such combinations include greater analgesia and attenuation of opioid-induced adverse reactions such as nausea and vomiting, constipation, sedation, and respiratory depression. Adjuncts include acetaminophen, antiarrhythmics, anticonvulsants, antidepressants, antipsychotics, baclofen, benzodiazepines, capsaicin, calcium channel blockers, clonidine hydrochloride, central nervous system stimulants, corticosteroids, local anesthetics, N-methyl-D-aspartate receptor antagonists, nonsteroidal antiinflammatory drugs, pentoxifylline, and scopolamine. Some adjuncts (eg, acetaminophen) are routinely used today, whereas others (eg, nifedipine [calcium channel blocker]) are used on a limited basis but have great potential for more widespread application. All professionals (eg, nurses, pharmacists, physicians, physicians' assistants, social workers, members of the clergy

  2. Delayed Ego Strength Development in Opioid Dependent Adolescents and Young Adults

    PubMed Central

    Abramoff, Benjamin A.; Lange, Hannah L. H.; Matson, Steven C.; Cottrill, Casey B.; Bridge, Jeffrey A.; Abdel-Rasoul, Mahmoud; Bonny, Andrea E.

    2015-01-01

    Objective. To evaluate ego strengths, in the context of Erikson's framework, among adolescents and young adults diagnosed with opioid dependence as compared to non-drug using youth. Methods. Opioid dependent (n = 51) and non-drug using control (n = 31) youth completed the self-administered Psychosocial Inventory of Ego Strengths (PIES). The PIES assesses development in the framework of Erikson's ego strength stages. Multivariate linear regression modeling assessed the independent association of the primary covariate (opioid dependent versus control) as well as potential confounding variables (e.g., psychiatric comorbidities, intelligence) with total PIES score. Results. Mean total PIES score was significantly lower in opioid dependent youth (231.65 ± 30.39 opioid dependent versus 270.67 ± 30.06 control; p < 0.01). Evaluation of the PIES subscores found significant (p < 0.05) delays in all ego strength areas (hope, will, purpose, competence, fidelity, love, care, and wisdom). When adjusting for potential confounders, opioid dependence remained a significant (p < 0.001) independent predictor of total PIES score. Conclusion. Adolescents with opioid dependence demonstrated significant delays in ego strength development. A treatment approach acknowledging this delay may be needed in the counseling and treatment of adolescents with opioid dependence. PMID:26664819

  3. The role of beta-arrestin2 in the severity of antinociceptive tolerance and physical dependence induced by different opioid pain therapeutics

    PubMed Central

    Raehal, Kirsten M.; Bohn, Laura M.

    2010-01-01

    Ligands acting at the same receptor can differentially activate distinct signal transduction pathways, which in turn, can have diverse functional consequences. Further, receptors expressed in different tissues may utilize intracellular signaling proteins in response to a ligand differently as well. The mu opioid receptor (MOR), which mediates many of the pharmacological actions of opiate therapeutics, is also subject to differential signaling in response to diverse agonists. To study the effect of diverse agonists on MOR signaling, we examined the effects of chronic opiate treatment on two distinct physiological endpoints, antinociceptive tolerance and physical dependence, in mice lacking the intracellular regulatory molecule, βarrestin2. While βarrestin2 knockout (βarr2-KO) mice do not become tolerant to the antinociceptive effects of chronic morphine in a hot plate test, tolerance develops to the same degree in both wild type and βarr2-KO mice following chronic infusion with methadone, fentanyl, and oxycodone. Studies here also assess the severity of withdrawal signs precipitated by naloxone following chronic infusions at three different doses of each opiate agonist. While there are no differences in withdrawal responses between genotypes at the highest dose of morphine tested (48 mg/kg/day), the βarr2-KO mice display several less severe withdrawal responses when the infusion dose is lowered (12 or 24 mg/kg/day). Chronic infusion of methadone, fentanyl, and oxycodone all lead to equivalent naloxone-precipitated withdrawal responses in both genotypes at all doses tested. These results lend further evidence that distinct agonists can differentially impact on opioid-mediated responses in vivo in a βarrestin2-dependent manner. PMID:20713067

  4. Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia

    PubMed Central

    Shavit, Yehuda; Grace, Peter M.; Rice, Kenner C.; Maier, Steven F.; Watkins, Linda R.

    2011-01-01

    Vastly stimulated by the discovery of opioid receptors in the early 1970s, preclinical and clinical research was directed at the study of stereoselective neuronal actions of opioids, especially those played in their crucial analgesic role. However, during the past decade, a new appreciation of the non-neuronal actions of opioids has emerged from preclinical research, with specific appreciation for the nonclassic and nonstereoselective sites of action. Opioid activity at Toll-like receptors, newly recognized innate immune pattern recognition receptors, adds substantially to this unfolding story. It is now apparent from molecular and rodent data that these newly identified signaling events significantly modify the pharmacodynamics of opioids by eliciting proinflammatory reactivity from glia, the immunocompetent cells of the central nervous system. These central immune signaling events, including the release of cytokines and chemokines and the associated disruption of glutamate homeostasis, cause elevated neuronal excitability, which subsequently decreases opioid analgesic efficacy and leads to heightened pain states. This review will examine the current preclinical literature of opioid-induced central immune signaling mediated by classic and nonclassic opioid receptors. A unification of the preclinical pharmacology, neuroscience, and immunology of opioids now provides new insights into common mechanisms of chronic pain, naive tolerance, analgesic tolerance, opioid-induced hyperalgesia, and allodynia. Novel pharmacological targets for future drug development are discussed in the hope that disease-modifying chronic pain treatments arising from the appreciation of opioid-induced central immune signaling may become practical. PMID:21752874

  5. Peripartum pain management in opioid dependent women

    PubMed Central

    Höflich, Anna S.; Langer, Martin; Jagsch, Reinhold; Bäwert, Andjela; Winklbaur, Bernadette; Fischer, Gabriele; Unger, Annemarie

    2011-01-01

    Increased pain sensitivity and the development of opioid tolerance complicate the treatment of pain experienced by opioid maintained pregnant women during delivery and the perinatal period. The aim of the present study was to investigate differences in pain management of opioid maintained compared to non-dependent pregnant women during delivery and the postpartum period. 40 deliveries of 37 opioid dependent women enrolled in a double-blind, double-dummy randomized controlled trial (RCT) examining the safety and efficacy of methadone (mean dose at the time of delivery = 63.89 mg) and buprenorphine (mean dose at the time of delivery = 14.05 mg) during pregnancy were analyzed and participants were matched to a non-dependent comparison group of 80 pregnant women. Differences in pain management (opioid and non-opioid analgesic medication) during delivery and perinatal period were analyzed. Following cesarean delivery opioid maintained women received significantly less opioid analgesics (day of delivery p = 0.038; day 1: p = 0.02), NSAIDs were administered more frequently to opioid dependent patients than to the comparison group during cesarean section and on the third day postpartum. Significantly higher nicotine consumption in the group of opioid dependent women had a strong influence on the retrieved results, and might be considered as an independent factor of altered pain experience. Differences in pain treatment became evident when comparing opioid maintained women to healthy controls. These differences might be based on psychosocial consequences of opioid addiction along with the lack of an interdisciplinary consensus on pain treatment protocols for opioid dependent patients. PMID:22396085

  6. Newer generation fentanyl transmucosal products for breakthrough pain in opioid-tolerant cancer patients.

    PubMed

    Elsner, Frank; Zeppetella, Giovambattista; Porta-Sales, Josep; Tagarro, Ignacio

    2011-01-01

    Oral normal-release morphine has long been considered the gold-standard treatment for cancer breakthrough pain. However, its relatively long time to analgesic onset, delay in maximal analgesic effect and prolonged duration of action make it unsuitable for the management of breakthrough pain episodes. These limitations led to the development of an oral transmucosal formulation of the fast-acting opioid fentanyl (oral transmucosal fentanyl citrate [OTFC] lozenge on a plastic handle; Actiq®), which has been shown to produce more rapid and effective pain relief than oral morphine. However, the formulation itself has some limitations. Consequently, investigators have continued to develop other, newer generation, transmucosal formulations of fentanyl to further improve the management of breakthrough pain. Recently, five such compounds (Effentora®/Fentora®, Abstral®, Instanyl®, Breakyl®/OnsolisTM and PecFent®) have been concurrently approved in Europe and/or the US, and have documented efficacy in quickly relieving breakthrough pain episodes. All of the available pivotal efficacy trials of these agents are randomized, double-blind comparisons with placebo. There are no head-to-head trials comparing any of the newer transmucosal formulations with each other. Only one non-pivotal study of intranasal fentanyl spray used a transmucosal preparation as an active comparator. However, that comparator was OTFC, not one of the newer transmucosal products. Close examination of the existing trials assessing these newer transmucosal preparations reveals significant variation in many study parameters, such as patient selection criteria, severity of breakthrough pain episodes, proportions of patients with a neuropathic pain component, titration protocols, choice of the primary endpoints, protocols for repeat dosing and rescue medication, the separation of treated episodes and the extent of the placebo response, all of which may have affected efficacy results. It is therefore

  7. Efficacy and tolerability of oral oxycodone and oxycodone/naloxone combination in opioid-naïve cancer patients: a propensity analysis

    PubMed Central

    Lazzari, Marzia; Greco, Maria Teresa; Marcassa, Claudio; Finocchi, Simona; Caldarulo, Clarissa; Corli, Oscar

    2015-01-01

    Background World Health Organization step III opioids are required to relieve moderate-to-severe cancer pain; constipation is one of the most frequent opioid-induced side effects. A fixed combination, prolonged-release oxycodone/naloxone (OXN), was developed with the aim of reducing opioid-related gastrointestinal side effects. The objective of this study was to compare the efficacy and safety of prolonged-release oxycodone (OXY) alone to OXN in opioid-naïve cancer patients with moderate-to-severe pain. Methods Propensity analysis was utilized in this observational study, which evaluated the efficacy, safety, and quality of life. Results Out of the 210 patients recruited, 146 were matched using propensity scores and included in the comparative analysis. In both groups, pain intensity decreased by ≈3 points after 60 days, indicating comparable analgesic efficacy. Responder rates were similar between groups. Analgesia was achieved and maintained with similarly low and stable dosages over time (12.0–20.4 mg/d for OXY and 11.5–22.0 mg/d for OXN). Bowel Function Index (BFI) and laxative use per week improved from baseline at 30 days and 60 days in OXN recipients (−16, P<0.0001 and −3.5, P=0.02, respectively); BFI worsened in the OXY group. The overall incidence of drug-related adverse events was 28.9% in the OXY group and 8.2% in the OXN group (P<0.01); nausea and vomiting were two to five times less frequent with OXN. Quality of life improved to a significantly greater extent in patients receiving OXN compared to OXY (increase in Short Form-36 physical component score of 7.1 points vs 3.2 points, respectively; P<0.001). Conclusion In patients with chronic cancer pain, OXN provided analgesic effectiveness that is similar to OXY, with early and sustained benefits in tolerability. The relationship between responsiveness to OXN and clinical characteristics is currently being investigated. PMID:26586937

  8. Mu opioid receptors in developing human spinal cord

    PubMed Central

    RAY, SUBRATA BASU; WADHWA, SHASHI

    1999-01-01

    The distribution of mu opioid receptors was studied in human fetal spinal cords between 12–13 and 24–25 wk gestational ages. Autoradiographic localisation using [3H] DAMGO revealed the presence of mu receptors in the dorsal horn at all age groups with a higher density in the superficial laminae (I–II). A biphasic expression was noted. Receptor density increased in the dorsal horn, including the superficial laminae, between 12–13 and 16–17 wk. This could be associated with a spurt in neurogenesis. The density increased again at 24–25 wk in laminae I–II which resembled the adult pattern of distribution. A dramatic proliferation of cells was noted from the region of the ventricular zone between 16–17 and 24–25 wk. These were considered to be glial cells from their histological features. Mu receptor expression was noted over a large area of the spinal cord including the lateral funiculus at 24–25 wk. This may be due to receptor expression by glial cells. The study presents evidence of mu receptor expression by both neurons and glia during early development of human spinal cord. PMID:10473288

  9. Opioid Peptidomimetics: Leads for the Design of Bioavailable Mixed Efficacy Mu Opioid Receptor (MOR) Agonist/Delta Opioid Receptor (DOR) Antagonist Ligands

    PubMed Central

    Mosberg, Henry I.; Yeomans, Larisa; Harland, Aubrie A.; Bender, Aaron M.; Sobczyk-Kojiro, Katarzyna; Anand, Jessica P.; Clark, Mary J.; Jutkiewicz, Emily M.; Traynor, John R.

    2013-01-01

    We have previously described opioid peptidomimetic, 1, employing a tetrahydroquinoline scaffold and modeled on a series of cyclic tetrapeptide opioid agonists. We have recently described modifications to these peptides that confer a mu opioid receptor (MOR) agonist, delta opioid receptor (DOR) antagonist profile, which has been shown to reduce the development of tolerance to the analgesic actions of MOR agonists. Several such bifunctional ligands have been reported, but none has been demonstrated to cross the blood brain barrier. Here we describe the transfer of structural features that evoked MOR agonist/DOR antagonist behavior in the cyclic peptides to the tetrahydroquinoline scaffold and show that the resulting peptidomimetics maintain the desired pharmacological profile. Further, the 4R diastereomer of 1 was fully efficacious and approximately equipotent to morphine in the mouse warm water tail withdrawal assay following intraperitoneal administration and thus a promising lead for the development of opioid analgesics with reduced tolerance. PMID:23419026

  10. Switching Opioid-Dependent Patients From Methadone to Morphine: Safety, Tolerability, and Methadone Pharmacokinetics.

    PubMed

    Glue, Paul; Cape, Gavin; Tunnicliff, Donna; Lockhart, Michelle; Lam, Fred; Gray, Andrew; Hung, Noelyn; Hung, C Tak; Harland, Sarah; Devane, Jane; Howes, John; Weis, Holger; Friedhoff, Lawrence

    2016-08-01

    The aim of this study was to switch patients established on methadone opioid substitution therapy (OST) to morphine over 1 week. Subjects established on daily methadone OST (mean dose 60 mg/day) were switched to morphine slow-release capsules, dosed at 4× the previous total daily methadone dose, for 6 days, then given morphine syrup dosed q3h. All 27 subjects enrolled in this study completed the switch from methadone to morphine. Opioid withdrawal symptoms (OWS) peaked within 12-24 hours of starting morphine, and 24/27 subjects required higher daily morphine doses (mean 5.2× multiple). Pharmacokinetic evaluation showed that 91% of methadone was cleared during this time, with a mean elimination half-life of 59 hours. The most frequent treatment-emergent non-OWS adverse events were headache, nausea, constipation, and neck pain. The method described here appears to be a safe and acceptable approach to switch subjects from methadone to morphine. PMID:26763764

  11. Strategic pain management: the identification and development of the IAHPC opioid essential prescription package.

    PubMed

    Vignaroli, Ernesto; Bennett, Michael I; Nekolaichuk, Cheryl; De Lima, Liliana; Wenk, Roberto; Ripamonti, Carla I; Bruera, Eduardo

    2012-02-01

    The aim of this study was to determine by consensus the components of an opioid essential prescription package (OEPP) to be used when initiating a prescription for the control of moderate to severe chronic pain. Palliative care physicians (n=60) were sampled from the International Association for Hospice and Palliative Care (IAHPC) membership list to represent a range of countries of varying economic levels and diverse geographical regions. Using a Delphi study method, physicians were asked to rank preferences of drug and dosing schedule for first-line opioid, antiemetic, and laxative for the treatment of adults with chronic pain due to cancer and other life-threatening conditions. Overall response rates after two Delphi survey rounds were 95% (n=57) and 82% (n=49), respectively. A consensus (set at ≥75% agreement) was reached to include morphine as first-line opioid at a dose of 5 mg orally every 4 hours. Consensus was reached to include metoclopramide as a first-line antiemetic, but there was no consensus on "regular" or "as needed" administration. No consensus was reached regarding a first-line laxative, but a combination of senna and docusate secured 59% agreement. There was consensus (93% agreement) that laxatives should always be given regularly when opioid treatment is started. Further work is needed to establish a recommended dose of metoclopramide and a type and dose of laxative. The resulting OEPP is international in scope and is designed to ensure that opioids are better tolerated by reducing adverse effects of opioids, which could lead to more sustained improvements in pain management. PMID:22014206

  12. The role of δ-opioid receptors in learning and memory underlying the development of addiction

    PubMed Central

    Klenowski, Paul; Morgan, Michael; Bartlett, Selena E

    2015-01-01

    Opioids are important endogenous ligands that exist in both invertebrates and vertebrates and signal by activation of opioid receptors to produce analgesia and reward or pleasure. The μ-opioid receptor is the best known of the opioid receptors and mediates the acute analgesic effects of opiates, while the δ-opioid receptor (DOR) has been less well studied and has been linked to effects that follow from chronic use of opiates such as stress, inflammation and anxiety. Recently, DORs have been shown to play an essential role in emotions and increasing evidence points to a role in learning actions and outcomes. The process of learning and memory in addiction has been proposed to involve strengthening of specific brain circuits when a drug is paired with a context or environment. The DOR is highly expressed in the hippocampus, amygdala, striatum and other basal ganglia structures known to participate in learning and memory. In this review, we will focus on the role of the DOR and its potential role in learning and memory underlying the development of addiction. LINKED ARTICLES 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 PMID:24641428

  13. 75 years of opioid research: the exciting but vain quest for the Holy Grail

    PubMed Central

    Corbett, Alistair D; Henderson, Graeme; McKnight, Alexander T; Paterson, Stewart J

    2006-01-01

    Over the 75-year lifetime of the British Pharmacological Society there has been an enormous expansion in our understanding of how opioid drugs act on the nervous system, with much of this effort aimed at developing powerful analgesic drugs devoid of the side effects associated with morphine – the Holy Grail of opioid research. At the molecular and cellular level multiple opioid receptors have been cloned and characterised, their potential for oligomerisation determined, a large family of endogenous opioid agonists has been discovered, multiple second messengers identified and our understanding of the adaptive changes to prolonged exposure to opioid drugs (tolerance and physical dependence) enhanced. In addition, we now have greater understanding of the processes by which opioids produce the euphoria that gives rise to the intense craving for these drugs in opioid addicts. In this article, we review the historical pathway of opioid research that has led to our current state of knowledge. PMID:16402099

  14. Co-activation of μ- and δ-opioid receptors elicits tolerance to morphine-induced ventilatory depression via generation of peroxynitrite.

    PubMed

    Young, Alex P; Gruber, Ryan B; Discala, Joe F; May, Walter J; McLaughlin, Dylan; Palmer, Lisa A; Lewis, Stephen J

    2013-05-01

    We determined whether pretreatment with (1) the μ-/δ-opioid receptor (μ-/δ-OR) antagonist, naloxone, (2) the δ1,2-OR antagonist, naltrindole, or (3) the peroxynitrite scavenger, d-penicillamine, affects the development of tolerance to the ventilatory depressant effects of morphine in rats. The injection of morphine in vehicle-pretreated rats decreased minute ventilation predominantly via decreases in tidal volume. Pretreatment with naloxone blunted the responses to morphine whereas pretreatment with naltrindole or d-penicillamine did not. A second injection of morphine, given one day later, elicited markedly smaller responses in vehicle rats whereas it elicited pronounced ventilatory depression in rats that were pretreated with naloxone, naltrindole or d-penicillamine (prior to morphine) the day before. Moreover, the ventilatory responses elicited by subsequent exposure to a hypoxic-hypercapnic challenge were markedly depressed in naloxone- or d-penicillamine-pretreated rats compared to vehicle-pretreated rats. These findings suggest that activation of μ- and δ-ORs causes tolerance to the ventilatory depressant effects of morphine at least partly via the generation of peroxynitrite. PMID:23473921

  15. Treating Opioid-Induced Constipation in Older Adults: New Options.

    PubMed

    Sani, Halima; Mahan, Rebecca J

    2015-10-01

    Numerous factors, such as changes in gastrointestinal physiology, reduced mobility, decreased liquid and nutritional intake, and certain comorbidities, predispose older adults to constipation. Use of opioid medications further compounds this problem. Unlike other side effects associated with opioid use, patients do not develop tolerance to constipation and other opioid-induced bowel dysfunctions. Although opioid-induced constipation has a prevalence rate of 80% in this population, it remains highly undertreated. Despite this problem, there have been limited therapeutic options available for older adults suffering from opioid-induced constipation. On September 16, 2014, a new oral agent, naloxegol, a peripherally acting muopioid receptor antagonist (PAMORA), approved by the Food and Drug Administration, provides new hope for patients. This paper explores clinical complications associated with opioid-induced constipation in older adults, analyzes the efficacy and safety of laxatives and PAMORAs, and defines the future role of naloxegol in this vulnerable population. PMID:26450143

  16. PET and SPECT imaging of the opioid system: receptors, radioligands and avenues for drug discovery and development.

    PubMed

    Lever, John R

    2007-01-01

    As we celebrate the bicentennial of the isolation of morphine by Sertürner, opioids continue to dominate major sectors of the analgesic market worldwide. The pharmaceutical industry stands to benefit greatly from molecular imaging in preclinical and early clinical trials of new or improved opioid drugs. At this juncture, it seems fitting to summarize the past twenty or so years of research on molecular imaging of the opioid system from the viewpoint of drug discovery and development. Opioid receptors were first imaged in human volunteers by positron emission tomography (PET) in 1984. Now, quantitative PET imaging of the major opioid receptor types (micro, delta , kappa) is possible in the brain and peripheral organs of healthy persons and patient populations. Radioligands are under development for single photon emission computed tomography (SPECT) of opioid receptors as well. These functional, nuclear imaging techniques can trace the fate of radiolabeled molecules directly, but non-invasively, and allow precise pharmacokinetic and pharmacodynamic measurements. Molecular imaging provides unique data that can aid in selecting the best drug candidates, determining optimal dosing regimens, clearing regulatory hurdles and lowering risks of failure. Using a historical perspective, this review touches on opioid receptors as drug targets, and focuses on the status and use of radiotracers for opioid receptor PET and SPECT. Selected studies are discussed to illustrate the power of molecular imaging for facilitating opioid drug discovery and development. PMID:17266587

  17. Evaluation of the Tolerability of Switching Patients on Chronic Full μ-Opioid Agonist Therapy to Buccal Buprenorphine

    PubMed Central

    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 μ-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 by naloxone challenge. Study doses were substituted at the time of the regular dose schedule for each patient. The primary endpoint was the proportion of patients with a maximum Clinical Opiate Withdrawal Scale score ≥ 13 (moderate withdrawal) or use of rescue medication. Results. 35 subjects on ≥ 80 mg morphine sulfate equivalent per day were evaluable for opioid withdrawal. One patient during buccal buprenorphine treatment and two during 50% full μ-opioid agonist treatment experienced opioid withdrawal of at least moderate intensity. The mean maximum Clinical Opiate Withdrawal Scale scores were similar, and numerically lower on buccal buprenorphine. There were no significant differences in pain ratings between treatments. The most frequent adverse events with buccal buprenorphine were headache (19%), vomiting (13%), nausea, diarrhea, and drug withdrawal syndrome (each 9%), and with full μ-opioid agonist were headache (16%), drug withdrawal syndrome (13%), and nausea (6%). Conclusions. Chronic pain patients treated with around-the-clock full μ-opioid agonist therapy can be switched to buccal buprenorphine (a partial μ-opioid agonist) at approximately 50% of the full μ-opioid agonist dose without an increased risk of opioid withdrawal or loss of pain control. PMID:26917621

  18. New developments in the management of opioid dependence: focus on sublingual buprenorphine-naloxone.

    PubMed

    Soyka, Michael

    2015-01-01

    Opioid maintenance therapy is a well-established first-line treatment approach in opioid dependence. Buprenorphine, a partial opioid agonist, has been found by numerous studies to be an effective and safe medication in the treatment of opioid dependence. At present, buprenorphine is available as a monodrug or in a fixed 4:1 ratio combination with naloxone. A diminished risk of diversion and abuse for the buprenorphine-naloxone combination is likely but not firmly established. Conventional formulations are given sublingually to avoid the hepatic first-pass effect. A novel film tablet is available only in the US and Australia. Other novel, sustained-release formulations (implant, depot) are currently being developed and tested. Recent studies, including a Cochrane meta-analysis, suggest that the retention with buprenorphine is lower than for methadone, but that buprenorphine may be associated with less drug use. Higher doses of buprenorphine are associated with better retention rates. Buprenorphine has a ceiling effect at the opioid receptor with regard to respiratory depression, and may cause fewer fatal intoxications than methadone. Possible antidepressant effects of buprenorphine and its use in comorbid psychiatric patients has not been studied in much detail. Clinical implications are discussed. PMID:25610012

  19. New developments in the management of opioid dependence: focus on sublingual buprenorphine–naloxone

    PubMed Central

    Soyka, Michael

    2015-01-01

    Opioid maintenance therapy is a well-established first-line treatment approach in opioid dependence. Buprenorphine, a partial opioid agonist, has been found by numerous studies to be an effective and safe medication in the treatment of opioid dependence. At present, buprenorphine is available as a monodrug or in a fixed 4:1 ratio combination with naloxone. A diminished risk of diversion and abuse for the buprenorphine–naloxone combination is likely but not firmly established. Conventional formulations are given sublingually to avoid the hepatic first-pass effect. A novel film tablet is available only in the US and Australia. Other novel, sustained-release formulations (implant, depot) are currently being developed and tested. Recent studies, including a Cochrane meta-analysis, suggest that the retention with buprenorphine is lower than for methadone, but that buprenorphine may be associated with less drug use. Higher doses of buprenorphine are associated with better retention rates. Buprenorphine has a ceiling effect at the opioid receptor with regard to respiratory depression, and may cause fewer fatal intoxications than methadone. Possible antidepressant effects of buprenorphine and its use in comorbid psychiatric patients has not been studied in much detail. Clinical implications are discussed. PMID:25610012

  20. Blocking mammalian target of rapamycin alleviates bone cancer pain and morphine tolerance via µ-opioid receptor.

    PubMed

    Jiang, Zongming; Wu, Shaoyong; Wu, Xiujuan; Zhong, Junfeng; Lv, Anqing; Jiao, Jing; Chen, Zhonghua

    2016-04-15

    The current study was to examine the underlying mechanisms responsible for the role of mammalian target of rapamycin (mTOR) in regulating bone cancer-evoked pain and the tolerance of systemic morphine. Breast sarcocarcinoma Walker 256 cells were implanted into the tibia bone cavity of rats and this evoked significant mechanical and thermal hyperalgesia. Our results showed that the protein expression of p-mTOR, mTOR-mediated phosphorylation of 4E-binding protein 4 (4E-BP1), p70 ribosomal S6 protein kinase 1 (S6K1) as well as phosphatidylinositide 3-kinase (p-PI3K) pathways were amplified in the superficial dorsal horn of the spinal cord of bone cancer rats compared with control rats. Blocking spinal mTOR by using rapamycin significantly attenuated activities of PI3K signaling pathways as well as mechanical and thermal hyperalgesia. Additionally, rapamycin enhanced attenuations of protein kinase Cɛ (PKCɛ)/protein kinase A (PKA) induced by morphine and further extended analgesia of morphine via µ-opioid receptor (MOR). Our data for the first time revealed specific signaling pathways leading to bone cancer pain, including the activation of mTOR and PI3K and downstream PKCɛ/PKA, and resultant sensitization of MOR. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of bone cancer pain often observed in clinics. PMID:26566757

  1. Development of a Community Readiness Survey for Coalitions to Address Prescription Opioid Misuse

    ERIC Educational Resources Information Center

    Trudeau, Kimberlee J.

    2015-01-01

    A community readiness survey for coalitions to address the growing epidemic of prescription opioid misuse was developed in this four-part study. A total of 70 coalition members participated. 1) We conducted 30-minute phone interviews with coalition members (n = 30) and a literature review to develop an item list. 2) Coalition members rated these…

  2. Reversal of morphine analgesic tolerance by ethanol in the mouse.

    PubMed

    Hull, L C; Gabra, B H; Bailey, C P; Henderson, G; Dewey, W L

    2013-06-01

    The chronic use of opioids in humans, accompanied by the development of tolerance, is a dangerous phenomenon in its own right. However, chronic opioid use is often made more dangerous by the coconsumption of other substances. It has been observed that the blood level of opioids in postmortem analyses of addicts, who consumed ethanol along with the opioid, was much less than that observed in individuals who died from opioids alone. This relationship between ethanol and opioids led us to investigate the hypothesis that ethanol alters tolerance to opioids. In the present study, we report that ethanol significantly and dose-dependently reduced the antinociceptive tolerance produced by morphine and the cross-tolerance between [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) and morphine in the mouse tail-flick test. The reversal of morphine tolerance was partially blocked by both the gamma receptor blocker bicuculline and by the γ-aminobutyric acid (GABA)(B) receptor blocker phaclofen and the administration of both inhibitors completely reversed the effects of ethanol on morphine tolerance. Diazepam, like ethanol, decreased morphine tolerance. However, this inhibition was reversed by the GABA(A) antagonist bicuculline but not by the GABA(B) antagonist phaclofen. These findings have important implications for individuals who abuse opioids and ethanol as well as suggest a mechanism to reduce the amount of opioid needed in chronic pain treatment. PMID:23528610

  3. Reversal of Morphine Analgesic Tolerance by Ethanol in the Mouse

    PubMed Central

    Hull, L. C.; Gabra, B. H.; Bailey, C. P.; Henderson, G.

    2013-01-01

    The chronic use of opioids in humans, accompanied by the development of tolerance, is a dangerous phenomenon in its own right. However, chronic opioid use is often made more dangerous by the coconsumption of other substances. It has been observed that the blood level of opioids in postmortem analyses of addicts, who consumed ethanol along with the opioid, was much less than that observed in individuals who died from opioids alone. This relationship between ethanol and opioids led us to investigate the hypothesis that ethanol alters tolerance to opioids. In the present study, we report that ethanol significantly and dose-dependently reduced the antinociceptive tolerance produced by morphine and the cross-tolerance between [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) and morphine in the mouse tail-flick test. The reversal of morphine tolerance was partially blocked by both the gamma receptor blocker bicuculline and by the γ-aminobutyric acid (GABA)B receptor blocker phaclofen and the administration of both inhibitors completely reversed the effects of ethanol on morphine tolerance. Diazepam, like ethanol, decreased morphine tolerance. However, this inhibition was reversed by the GABAA antagonist bicuculline but not by the GABAB antagonist phaclofen. These findings have important implications for individuals who abuse opioids and ethanol as well as suggest a mechanism to reduce the amount of opioid needed in chronic pain treatment. PMID:23528610

  4. Intracerebroventricular opioids for intractable pain

    PubMed Central

    Raffa, Robert B; Pergolizzi, Joseph V

    2012-01-01

    When pain is refractory to systemic opioid and non-opioid analgesic therapy and palliative chemoradiation or ablative or stimulant neurosurgical procedures are not possible, palliative treatment becomes limited, particularly if the patient wishes to be at home at the end of life. Intracerebroventricular (ICV) infusion of morphine in the home setting might be presented as an option. The present article reviews the basic and clinical evidence of the efficacy and safety of ICV administration of opioids. Information was gathered from various bibliographic sources, including PubMed and others, and summarized and evaluated to assess the efficacy and safety of ICV opioids for pain relief. Results from ICV infusion of morphine into terminally ill patients refractory to other pain treatments have been reported since the early 1980s. Good efficacy has been achieved for the vast majority of patients, without serious development of analgesic tolerance. There have also been a low incidence of adverse effects, such as constipation and respiratory depression, and a significant retention of alertness associated with this route of administration. Intracerebroventricular infusion of opioid analgesics thus appears to be a safe and effective therapy for the palliative treatment of refractory pain. PMID:22295988

  5. Pharmacology of Nonsteroidal Antiinflammatory Drugs and Opioids

    PubMed Central

    Slater, Dick; Kunnathil, Sushama; McBride, Joseph; Koppala, Rajah

    2010-01-01

    Chronic pain affects up to 50 million Americans every day. Traditional treatment has included acetaminophen, nonsteroidal antiinflammatory drugs (NSAIDs), or opioids. The combination of NSAIDs and opioids can provide effective treatment for up to 90% of patients with chronic pain, but the NSAIDs have the potential for significant, even life-threatening side effects. Additionally, the nonselective cyclooxygenase inhibitors with 16,000 deaths per year in the United States might not be any safer. The opioids are great for short-term pain, but may need to be adjusted or changed frequently due to the development of tolerance. Understanding of the mechanism of opioids and NSAIDs has improved greatly over the past decade, but is still incomplete. PMID:22550382

  6. Developing Political Tolerance. ERIC Digest.

    ERIC Educational Resources Information Center

    Avery, Patricia G.

    Political tolerance is the willingness to extend basic rights and civil liberties to persons and groups whose viewpoints differ from one's own. It is a central tenet of a liberal democracy. The individual rights and freedoms that U.S. citizens value encourage a wide array of ideas and beliefs, some of which may offend segments of the population.…

  7. An overview of prodrug technology and its application for developing abuse-deterrent opioids.

    PubMed

    Gudin, Jeffrey A; Nalamachu, Srinivas R

    2016-01-01

    The Centers for Disease Control and Prevention has classified prescription drug abuse and overdose deaths as an epidemic. Prescription drug overdose is now the leading cause of injury death, with rates that have more than doubled since 1999. This crisis has developed concurrently with the increased prescribing and availability analgesic drugs, especially opioids, resulting from an effort on the part of clinicians to address a critical need for improved pain assessment and treatment. Clinicians have recognized that oftentimes, opioid analgesics are one of the few remaining options for patients who suffer with severe pain. A 2015 fact sheet issued by the Office of National Drug Policy stated: "While we must ensure better access to prescription medications to alleviate suffering, it is also vital that we do all we can to reduce the diversion and abuse of pharmaceuticals." The US Food and Drug Administration has issued guidance that encourages the research and development of abuse-deterrent formulation of opioids which have the potential to curtail abuse. Included among the recommended formulations for development of abuse-deterrent opioids are prodrugs. Prodrugs are chemically modified versions of pharmacological agents that must undergo a biochemical conversion following administration, often by enzymatic cleavage, to free the active drug. Prodrugs may be inherently abuse-deterrent because they are inactive or significantly less active until conversion to the active drug. This requirement for conversion in the GI tract can modify the pharmacokinetic profile and eliminate or reduce the euphoria when abusers change the route of administration. Abusers often attempt to extract the active drug for injection or insufflation. Prodrugs can be designed to be resistant to crushing or dissolving. In this article, we review the concept of prodrugs and introduce and examine the potential of abuse-deterrent opioid prodrugs. PMID:26615852

  8. Recent developments toward the safer use of opioids, with a focus on hydrocodone.

    PubMed

    Covvey, Jordan R

    2015-01-01

    Opioids have become a mainstay of treatment for pain in the United States, with over 250 million prescription issued in 2012 alone. The increased prescribing of these medications has also contributed to the unintended consequence of a widening prevalence of abuse and misuse, and therefore safety has become a top agenda item for both government and health care providers alike. The move toward new abuse-deterrent formulation technologies, enhanced regulatory requirements from the Food and Drug Administration (FDA) and Drug Enforcement Administration (DEA), and developments in national/state policies have worked together to target a goal of promoting safer clinician prescribing, pharmacy dispensing and patient use of opioids. Hydrocodone in particular, as the most widely prescribed opioid product, has recently been subject to a myriad of changes, both through the federal rescheduling of hydrocodone-combination products (HCPs) to Schedule II, as well as the introduction of two new extended-release formulations to the USA market. These efforts represent a first step toward tackling the opioid harms epidemic, although continuing follow-up through research and policy implementation is needed to see any measureable impact on safety in the future. PMID:25769501

  9. Opioid intoxication

    MedlinePlus

    Intoxication - opioids ... In the United States, the most commonly abused opioids are heroin and methadone. People who become addicted ... of these drugs. Also, the use of prescription opioids for nonmedical reasons is an extensive and growing ...

  10. Opioid intoxication

    MedlinePlus

    ... use of opioid-based drugs. These include morphine, heroin, oxycodone, and synthetic (man-made) opioid narcotics. Prescription ... United States, the most commonly abused opioids are heroin and methadone. People who become addicted to these ...

  11. 78 FR 31945 - Clinical Development Programs for Opioid Conversion; Public Workshop; Request for Comments

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-28

    ... equianalgesic opioid conversion tables in opioid product labels. Discussion will focus on the available data... the inclusion of equianalgesic opioid conversion tables in opioid product labels. Use of these... tables in the current product labels, we are holding this scientific workshop to bring the...

  12. The pharmacological basis of opioids

    PubMed Central

    Ghelardini, Carla; Di Cesare Mannelli, Lorenzo; Bianchi, Enrica

    2015-01-01

    Summary An opioid is a chemical that binds to opioid receptors, which are widely distributed in the central and peripheral nervous system and gastrointestinal tract. The different effects elicited by activation of these receptors are due to their specific neuronal and extraneuronal distribution. The painkiller effect of opioids is induced by the synergy of the two events, namely reduction of pain threshold and emotional detachment from pain. The opioid effects transcending analgesia include sedation, respiratory depression, constipation and a strong sense of euphoria. There are opioid-like substances endogenously produced by the body. Naturally occurring peptides, called enkephalins, have opioid-like activities but are not derived from opium and exert opioid-like effects by interacting with opioid receptors on cell membranes. Yet, animals do contain the same morphine precursors and metabolites as opium poppy and are able to synthesize endogenous morphine alkaloid. Experimental and clinical studies show that opioids, at doses comparable to those of endogenous opioids, can activate pronociceptive systems, leading to pain hypersensitivity and short-term tolerance, a phenomenon encountered in postoperative pain management by acute opioid administration. Whether endogenous opioids play a role in the acute pain necessary to the survival of the individual, remains an open question. PMID:26811699

  13. The pharmacological basis of opioids.

    PubMed

    Ghelardini, Carla; Di Cesare Mannelli, Lorenzo; Bianchi, Enrica

    2015-01-01

    An opioid is a chemical that binds to opioid receptors, which are widely distributed in the central and peripheral nervous system and gastrointestinal tract. The different effects elicited by activation of these receptors are due to their specific neuronal and extraneuronal distribution. The painkiller effect of opioids is induced by the synergy of the two events, namely reduction of pain threshold and emotional detachment from pain. The opioid effects transcending analgesia include sedation, respiratory depression, constipation and a strong sense of euphoria. There are opioid-like substances endogenously produced by the body. Naturally occurring peptides, called enkephalins, have opioid-like activities but are not derived from opium and exert opioid-like effects by interacting with opioid receptors on cell membranes. Yet, animals do contain the same morphine precursors and metabolites as opium poppy and are able to synthesize endogenous morphine alkaloid. Experimental and clinical studies show that opioids, at doses comparable to those of endogenous opioids, can activate pronociceptive systems, leading to pain hypersensitivity and short-term tolerance, a phenomenon encountered in postoperative pain management by acute opioid administration. Whether endogenous opioids play a role in the acute pain necessary to the survival of the individual, remains an open question. PMID:26811699

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

    PubMed Central

    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

  15. Opioids and rat erythrocyte deformability.

    PubMed

    Rhoads, D L; Wei, L X; Lin, E T; Rezvani, A; Way, E L

    1986-01-01

    In previous studies from this laboratory, it was noted that opioids in vitro reduced human red blood cell deformability. The effect was found to be dose-dependent, naloxone reversible and preferentially selective kappa ligands exhibited the highest potency. To extend these findings studies were carried out using rat erythrocytes. The time required for erythrocytes to pass through a 5.0 um pore membrane was determined and used as an index of deformability. Opioids added in vitro produced inhibition of deformability in a dose-dependent, naloxone reversible manner. Injecting naive animals with morphine or nalbuphine also produced dose related reductions in red cell deformability. The degree of inhibition produced by nalbuphine correlated well with its plasma concentrations as measured by high performance liquid chromatography (HPLC). Chronic morphine treatment by pellet implantation resulted in the development of tolerance as evidenced by a loss in the ability of morphine in vitro to inhibit red cell deformability. Addition of naloxone resulted in a decrease in filtration time. Thus, the data confirm and extend previous findings on human red blood cells. In as much as previous data from this laboratory demonstrated that opioids inhibit calcium flux from erythrocytes by inhibiting calcium-ATPase and calcium efflux is necessary for normal deformability, it is concluded that opioids act to reduce red cell deformability by inhibition of the calcium pump. PMID:3123933

  16. Putative Kappa Opioid Heteromers As Targets for Developing Analgesics Free of Adverse Effects

    PubMed Central

    2015-01-01

    It is now generally recognized that upon activation by an agonist, β-arrestin associates with G protein-coupled receptors and acts as a scaffold in creating a diverse signaling network that could lead to adverse effects. As an approach to reducing side effects associated with κ opioid agonists, a series of β-naltrexamides 3–10 was synthesized in an effort to selectively target putative κ opioid heteromers without recruiting β-arrestin upon activation. The most potent derivative 3 (INTA) strongly activated KOR-DOR and KOR-MOR heteromers in HEK293 cells. In vivo studies revealed 3 to produce potent antinociception, which, when taken together with antagonism data, was consistent with the activation of both heteromers. 3 was devoid of tolerance, dependence, and showed no aversive effect in the conditioned place preference assay. As immunofluorescence studies indicated no recruitment of β-arrestin2 to membranes in coexpressed KOR-DOR cells, this study suggests that targeting of specific putative heteromers has the potential to identify leads for analgesics devoid of adverse effects. PMID:24978316

  17. Glia: novel counter-regulators of opioid analgesia.

    PubMed

    Watkins, Linda R; Hutchinson, Mark R; Johnston, Ian N; Maier, Steven F

    2005-12-01

    Development of analgesic tolerance and withdrawal-induced pain enhancement present serious difficulties for the use of opioids for pain control. Although neuronal mechanisms to account for these phenomena have been sought for many decades, their bases remain unresolved. Within the past four years, a novel non-neuronal candidate has been uncovered that opposes acute opioid analgesia and contributes to development of opioid tolerance and tolerance-associated pain enhancement. This novel candidate is spinal cord glia. Glia are important contributors to the creation of enhanced pain states via the release of neuroexcitatory substances. New data suggest that glia also release neuroexcitatory substances in response to morphine, thereby opposing its effects. Controlling glial activation could therefore increase the clinical utility of analgesic drugs. PMID:16246435

  18. Opioid receptor types involved in the development of nicotine physical dependence in an invertebrate (Planaria) model.

    PubMed

    Raffa, Robert B; Baron, Steve; Bhandal, Jaspreet S; Brown, Tevin; Song, Kevin; Tallarida, Christopher S; Rawls, Scott M

    2013-11-01

    Recent data suggest that opioid receptors are involved in the development of nicotine physical dependence in mammals. Evidence in support of a similar involvement in an invertebrate (Planaria) is presented using the selective opioid receptor antagonist naloxone, and the more receptor subtype-selective antagonists CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2) (μ, MOR), naltrindole (δ, DOR), and nor-BNI (norbinaltorphimine) (κ, KOR). Induction of physical dependence was achieved by 60-min pre-exposure of planarians to nicotine and was quantified by abstinence-induced withdrawal (reduction in spontaneous locomotor activity). Known MOR and DOR subtype-selective opioid receptor antagonists attenuated the withdrawal, as did the non-selective antagonist naloxone, but a KOR subtype-selective antagonist did not. An involvement of MOR and DOR, but not KOR, in the development of nicotine physical dependence or in abstinence-induced withdrawal was thus demonstrated in a sensitive and facile invertebrate model. PMID:24084318

  19. Buprenorphine for opioid dependence.

    PubMed

    Ling, Walter

    2009-05-01

    As a treatment agent for opioid dependence, buprenorphine is a nearly ideal medication at our current stage of medication development. Unlike methadone, buprenorphine dosage can be rapidly adjusted with minimal potential for inducing severe consequences. In addition to its intrinsic safety, buprenorphine's relatively low abuse liability in the combination product (i.e., with naloxone as Suboxone) makes it even more acceptable in regulatory quarters as well as to prescribing physicians. The approval of buprenorphine as a pharmacotherapy for opioid dependence returns to physicians the ability to treat their opioid-dependent patients with an effective opioid-based treatment for the first time in nearly 100 years. Buprenorphine is an opioid, however, and potential for misuse remains, even in combination with naloxone. Whether buprenorphine will be increasingly accepted as a treatment for opioid-dependent patients depends on clinicians recognizing the advantages of its uniquely useful properties while still heeding the need to manage their patients' therapy with reasonable vigilance. PMID:19402772

  20. Prohormone convertase 2 (PC2) null mice have increased mu opioid receptor levels accompanied by altered morphine-induced antinociception, tolerance and dependence.

    PubMed

    Lutfy, K; Parikh, D; Lee, D L; Liu, Y; Ferrini, M G; Hamid, A; Friedman, T C

    2016-08-01

    Chronic morphine treatment increases the levels of prohormone convertase 2 (PC2) in brain regions involved in nociception, tolerance and dependence. Thus, we tested if PC2 null mice exhibit altered morphine-induced antinociception, tolerance and dependence. PC2 null mice and their wild-type controls were tested for baseline hot plate latency, injected with morphine (1.25-10mg/kg) and tested for antinociception 30min later. For tolerance studies, mice were tested in the hot plate test before and 30min following morphine (5mg/kg) on day 1. Mice then received an additional dose so that the final dose of morphine was 10mg/kg on this day. On days 2-4, mice received additional doses of morphine (20, 40 and 80mg/kg on days 1, 2, 3, and 4, respectively). On day 5, mice were tested in the hot plate test before and 30min following morphine (5mg/kg). For withdrawal studies, mice were treated with the escalating doses of morphine (10, 20, 40 and 80mg/kg) for 4days, implanted with a morphine pellet on day 5 and 3 days later injected with naloxone (1mg/kg) and signs of withdrawal were recorded. Morphine dose-dependently induced antinociception and the magnitude of this response was greater in PC2 null mice. Tolerance to morphine was observed in wild-type mice and this phenomenon was blunted in PC2 null mice. Withdrawal signs were also reduced in PC2 null mice. Immunohistochemical studies showed up-regulation of the mu opioid receptor (MOP) protein expression in the periaqueductal gray area, ventral tegmental area, lateral hypothalamus, medial hypothalamus, nucleus accumbens, and somatosensory cortex in PC2 null mice. Likewise, naloxone specific binding was increased in the brains of these mice compared to their wild-type controls. The results suggest that the PC2-derived peptides may play a functional role in morphine-induced antinociception, tolerance and dependence. Alternatively, lack of opioid peptides led to up-regulation of the MOP and altered morphine

  1. Enhanced Accident Tolerant LWR Fuels: Metrics Development

    SciTech Connect

    Shannon Bragg-Sitton; Lori Braase; Rose Montgomery; Chris Stanek; Robert Montgomery; Lance Snead; Larry Ott; Mike Billone

    2013-09-01

    The Department of Energy (DOE) Fuel Cycle Research and Development (FCRD) Advanced Fuels Campaign (AFC) is conducting research and development on enhanced Accident Tolerant Fuels (ATF) for light water reactors (LWRs). This mission emphasizes the development of novel fuel and cladding concepts to replace the current zirconium alloy-uranium dioxide (UO2) fuel system. The overall mission of the ATF research is to develop advanced fuels/cladding with improved performance, reliability and safety characteristics during normal operations and accident conditions, while minimizing waste generation. The initial effort will focus on implementation in operating reactors or reactors with design certifications. To initiate the development of quantitative metrics for ATR, a LWR Enhanced Accident Tolerant Fuels Metrics Development Workshop was held in October 2012 in Germantown, MD. This paper summarizes the outcome of that workshop and the current status of metrics development for LWR ATF.

  2. A prospective multicentre study to evaluate the efficacy and tolerability of osmotic release oral system (OROS®) hydromorphone in opioid-naive cancer patients: Results of the Korean South West Oncology Group study

    PubMed Central

    Song, Eun-Kee; Shim, Hyunjeong; Han, Hye-Suk; Sun, DerSheng; Lee, Soon-Il; Kang, Myung Hee; Lee, KyuTaek; Cho, DoYeun; Cho, In Sung; Park, Suk Young; Kim, Samyong; Yim, Chang-Yeol

    2015-01-01

    BACKGROUND: Osmotic release oral system (OROS®) hydromorphone is a potent, long-acting opioid analgesic, effective and safe for controlling cancer pain in patients who have received other strong opioids. To date, few studies have examined the efficacy of hydromorphone for pain relief in opioid-naive cancer patients. OBJECTIVES: A prospective, open-label, multicentre trial was conducted to determine the efficacy and tolerability of OROS hydromorphone as a single and front-line opioid therapy for patients experiencing moderate to severe cancer pain. METHODS: OROS hydromorphone was administered to patients who had not previously received strong, long-acting opioids. The baseline evaluation (visit 1) was followed by two evaluations (visits 2 and 3) performed two and 14 weeks later, respectively. The starting dose of OROS hydromorphone was 4 mg/day and was increased every two days when pain control was insufficient. Immediate-release hydromorphone was the only accepted alternative strong opioid for relief of breakthrough pain. The efficacy, safety and tolerability of OROS hydromorphone, including the effects on quality of life, and patients’ and investigators’ global impressions on pain relief were evaluated. The primary end point was pain intensity difference (PID) at visit 2 relative to visit 1 (expressed as %PID). RESULTS: A total of 107 patients were enrolled in the present study. An improvement in pain intensity of >50% (≥50% PID) was observed in 51.0% of the full analysis set and 58.6% of the per-protocol set. The mean pain score, measured using a numerical rating scale, was significantly reduced after two weeks of treatment, and most adverse events were manageable. Quality of life also improved, and >70% of patients and investigators were satisfied with the treatment. CONCLUSIONS: OROS hydromorphone provided effective pain relief and improved quality of life in opioid-naive cancer patients. As a single and front-line treatment, OROS hydromorphone delivered

  3. Enhancement of tolerance development to morphine in rats prenatally exposed to morphine, methadone, and buprenorphine

    PubMed Central

    2010-01-01

    Background Abuse of addictive substances is a serious problem that has a significant impact on areas such as health, the economy, and public safety. Heroin use among young women of reproductive age has drawn much attention around the world. However, there is a lack of information on effects of prenatal exposure to opioids on their offspring. In this study, an animal model was established to study effects of prenatal exposure to opioids on offspring. Methods Female pregnant Sprague-Dawley rats were sub-grouped to receive (1) vehicle, (2) 2-4 mg/kg morphine (1 mg/kg increment per week), (3) 7 mg/kg methadone, and (4) 3 mg/kg buprenorphine, subcutaneously, once or twice a day from E3 to E20. The experiments were conducted on animals 8-12 weeks old and with body weight between 250 and 350 g. Results Results showed that prenatal exposure to buprenorphine caused higher mortality than other tested substance groups. Although we observed a significantly lower increase in body weight in all of the opioid-administered dams, the birth weight of the offspring was not altered in all treated groups. Moreover, no obvious behavioral abnormality or body-weight difference was noted during the growing period (8-12 weeks) in all offspring. When the male offspring received morphine injection twice a day for 4 days, the prenatally opioid-exposed rats more quickly developed a tolerance to morphine (as shown by the tail-flick tests), most notably the prenatally buprenorphine-exposed offspring. However, the tolerance development to methadone or buprenorphine was not different in offspring exposed prenatally to methadone or buprenorphine, respectively, when compared with that of the vehicle controlled group. Similar results were also obtained in the female animals. Conclusions Animals prenatally exposed to morphine, methadone, or buprenorphine developed tolerance to morphine faster than their controlled mates. In our animal model, prenatal exposure to buprenorphine also resulted in higher

  4. The role of orexin type-1 receptors in the development of morphine tolerance in locus coeruleus neurons: An electrophysiological perspective.

    PubMed

    Abdollahi, Hakime; Ghaemi-Jandabi, Masoumeh; Azizi, Hossein; Semnanian, Saeed

    2016-09-01

    Long-term exposure to opioid agonists results in tolerance to their analgesic effects, so the effectiveness of opioid agonists in the management of pain becomes limited. The locus coeruleus (LC) nucleus has been involved in the development of tolerance to opiates. Orexin type-1 receptors (OX1Rs) are highly expressed in LC nucleus. Orexin plays a noteworthy role in the occurrence of morphine tolerance. The purpose of the present study is to investigate the role of orexin type-1 receptors in the development of morphine tolerance in LC neurons. In this study, adult male Wistar rats weighing 250-300g were utilized. Induction of morphine tolerance was obtained by single injection of morphine per day for 6 successive days. An orexin type-1 receptor antagonist (SB-334867) was injected into the lateral ventricle instantly prior to morphine injection. On day 7, the effect of morphine on the electrical activity of LC neurons was studied using in vivo extracellular single unit recording. The results demonstrate that morphine injection for 6 consecutive days led to the development of morphine-induced tolerance in LC neurons. In other words, there was a significant decrease in LC neuronal responsiveness to morphine injection. Inhibitory responses of LC neurons to intraperitoneally applied morphine can be observed with the treatment of the SB-334867 prior to morphine injection. This study showed that OX1R blockade by SB-334867 prevents the development of morphine tolerance in LC neurons. We hope that further studies will lead to considerable progress in understanding the molecular adaptations that contribute to morphine tolerance. PMID:27235867

  5. Toward a systematic approach to opioid rotation

    PubMed Central

    Smith, Howard S; Peppin, John F

    2014-01-01

    Patients requiring chronic opioid therapy may not respond to or tolerate the first opioid prescribed to them, necessitating rotation to another opioid. They may also require dose increases for a number of reasons, including worsening disease and increased pain. Dose escalation to restore analgesia using the primary opioid may lead to increased adverse events. In these patients, rotation to a different opioid at a lower-than-equivalent dose may be sufficient to maintain adequate tolerability and analgesia. In published trials and case series, opioid rotation is performed either using a predetermined substitute opioid with fixed conversion methods, or in a manner that appears to be no more systematic than trial and error. In clinical practice, opioid rotation must be performed with consideration of individual patient characteristics, comorbidities (eg, concurrent psychiatric, pulmonary, renal, or hepatic illness), and concurrent medications, using flexible dosing protocols that take into account incomplete opioid cross-tolerance. References cited in this review were identified via a search of PubMed covering all English language publications up to May 21, 2013 pertaining to opioid rotation, excluding narrative reviews, letters, and expert opinion. The search yielded a total of 129 articles, 92 of which were judged to provide relevant information and subsequently included in this review. Through a review of this literature and from the authors’ empiric experience, this review provides practical information on performing opioid rotation in clinical practice. PMID:25378948

  6. Oxycodone/Naloxone: role in chronic pain management, opioid-induced constipation, and abuse deterrence.

    PubMed

    DePriest, Anne Z; Miller, Katie

    2014-06-01

    The use of opioids in the treatment of chronic pain is widespread; the prevalence of specific opioids varies from country to country and depends on product availability, national formulary systems, and provider preferences. Patients often receive opioids for legitimate treatment of pain conditions, but on the opposite side of the spectrum, nonmedical use of opioids is a significant public health concern. Opioids are associated with several side effects, and constipation is the most commonly reported and persistent symptom. Unlike some adverse effects associated with opioid use, tolerance does not develop to constipation. Opioid-induced constipation (OIC) is the most prevalent patient complaint associated with opioid use and has been associated with declines in various quality of life measures. OIC can be extremely difficult for patients to tolerate and may prompt patients to decrease or discontinue opioid treatment. Current management strategies for OIC are often insufficient. A prolonged-release formulation of oxycodone/naloxone (OXN) has been investigated for the treatment of nonmalignant and cancer pain and mitigation of OIC, and evidence is largely favorable. Studies have demonstrated the capability of OXN to alleviate OIC while maintaining pain control comparable to oxycodone-only regimens. There is insufficient evidence for OXN efficacy for patients with mild OIC or patients maintained on high doses of opioids, and use in these populations is controversial. The reduction of costs associated with OIC may provide overall cost effectiveness with OXN. Additionally, the presence of naloxone may deter abuse/misuse by those seeking to misuse the formulation by modes of administration other than oral ingestion. Most studies to date have occurred in European countries, and phase 3 trials continue in the United States. This review will include current therapeutic options for pain and constipation, unique characteristics of OXN, evidence related to use of OXN and its

  7. Toward safe accessibility of opioid pain medicines in Vietnam and other developing countries: a balanced policy method.

    PubMed

    Krakauer, Eric L; Nguyen, Thi Phuong Cham; Husain, Syeda Asra; Nguyen, Thi Hai Yen; Joranson, David E; Luong, Ngoc Khue; Maurer, Martha A

    2015-05-01

    Moderate or severe pain is common among people with advanced cancer and other life-threatening illnesses. Yet despite agreement that pain relief is a human right, the poorest 80% of the world's population rarely have access to strong opioid analgesics. Excessively restrictive opioid policies, especially in developing countries, both stem from and propagate misguided fears about opioids, so-called opiophobia. Because opiophobia, like any norm, is historically, socially, and culturally situated, efforts to change opiophobic policies will be most effective if guided by awareness of their historical, social, and cultural determinants. We describe some of these determinants in Vietnam and report on results of an ongoing project there to allay opiophobia and improve safe access to opioids for medical uses. We used a method that entails working with committed local partners, including a high-level official from the Ministry of Health, to review all Vietnamese policies governing opioid accessibility to identify the barriers; devising an action plan to safely reduce or circumnavigate the barriers; obtaining buy-in for the plan from all stakeholders, including drug regulators and the police; and assisting the Ministry of Health to implement the plan. Since the start of the project, morphine consumption has increased each year and as of 2010 was ninefold greater than in 2003, and the number of hospitals offering palliative care has increased from three to 15. We conclude that this balanced policy method appears to be helping to reduce barriers to opioid access in Vietnam and should be used in other developing countries. PMID:25523889

  8. Development and Initial Testing of a Tailored Telephone Intervention Delivered by Peers to Prevent Recurring Opioid-Overdoses (TTIP-PRO)

    ERIC Educational Resources Information Center

    Winhusen, T.; Theobald, J.; Lewis, D.; Wilder, C. M.; Lyons, M. S.

    2016-01-01

    Individuals with opioid use disorder experiencing a non-fatal opioid-overdose (OOD) are at heightened risk for future OODs; there are no interventions to facilitate treatment enrollment for these patients. Our goal was to develop and initially test the "tailored telephone intervention delivered by peers to prevent recurring…

  9. Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems.

    PubMed

    Toll, Lawrence; Bruchas, Michael R; Calo', Girolamo; Cox, Brian M; Zaveri, Nurulain T

    2016-04-01

    The NOP receptor (nociceptin/orphanin FQ opioid peptide receptor) is the most recently discovered member of the opioid receptor family and, together with its endogenous ligand, N/OFQ, make up the fourth members of the opioid receptor and opioid peptide family. Because of its more recent discovery, an understanding of the cellular and behavioral actions induced by NOP receptor activation are less well developed than for the other members of the opioid receptor family. All of these factors are important because NOP receptor activation has a clear modulatory role on mu opioid receptor-mediated actions and thereby affects opioid analgesia, tolerance development, and reward. In addition to opioid modulatory actions, NOP receptor activation has important effects on motor function and other physiologic processes. This review discusses how NOP pharmacology intersects, contrasts, and interacts with the mu opioid receptor in terms of tertiary structure and mechanism of receptor activation; location of receptors in the central nervous system; mechanisms of desensitization and downregulation; cellular actions; intracellular signal transduction pathways; and behavioral actions with respect to analgesia, tolerance, dependence, and reward. This is followed by a discussion of the agonists and antagonists that have most contributed to our current knowledge. Because NOP receptors are highly expressed in brain and spinal cord and NOP receptor activation sometimes synergizes with mu receptor-mediated actions and sometimes opposes them, an understanding of NOP receptor pharmacology in the context of these interactions with the opioid receptors will be crucial to the development of novel therapeutics that engage the NOP receptor. PMID:26956246

  10. Synthesis, modeling, and pharmacological evaluation of UMB 425, a mixed μ agonist/δ antagonist opioid analgesic with reduced tolerance liabilities.

    PubMed

    Healy, Jason R; Bezawada, Padmavani; Shim, Jihyun; Jones, Jace W; Kane, Maureen A; MacKerell, Alexander D; Coop, Andrew; Matsumoto, Rae R

    2013-09-18

    Opioid narcotics are used for the treatment of moderate-to-severe pain and primarily exert their analgesic effects through μ receptors. Although traditional μ agonists can cause undesired side effects, including tolerance, addition of δ antagonists can attenuate said side effects. Herein, we report 4a,9-dihydroxy-7a-(hydroxymethyl)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (UMB 425) a 5,14-bridged morphinan-based orvinol precursor synthesized from thebaine. Although UMB 425 lacks δ-specific motifs, conformationally sampled pharmacophore models for μ and δ receptors predict it to have efficacy similar to morphine at μ receptors and similar to naltrexone at δ receptors, due to the compound sampling conformations in which the hydroxyl moiety interacts with the receptors similar to orvinols. As predicted, UMB 425 exhibits a mixed μ agonist/δ antagonist profile as determined in receptor binding and [(35)S]GTPγS functional assays in CHO cells. In vivo studies in mice show that UMB 425 displays potent antinociception in the hot plate and tail-flick assays. The antinociceptive effects of UMB 425 are blocked by naloxone, but not by the κ-selective antagonist norbinaltorphimine. During a 6-day tolerance paradigm, UMB 425 maintains significantly greater antinociception compared to morphine. These studies thus indicate that, even in the absence of δ-specific motifs fused to the C-ring, UMB 425 has mixed μ agonist/δ antagonist properties in vitro that translate to reduced tolerance liabilities in vivo. PMID:23713721

  11. Synthesis, Modeling, and Pharmacological Evaluation of UMB 425, a Mixed μ Agonist/δ Antagonist Opioid Analgesic with Reduced Tolerance Liabilities

    PubMed Central

    2013-01-01

    Opioid narcotics are used for the treatment of moderate-to-severe pain and primarily exert their analgesic effects through μ receptors. Although traditional μ agonists can cause undesired side effects, including tolerance, addition of δ antagonists can attenuate said side effects. Herein, we report 4a,9-dihydroxy-7a-(hydroxymethyl)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (UMB 425) a 5,14-bridged morphinan-based orvinol precursor synthesized from thebaine. Although UMB 425 lacks δ-specific motifs, conformationally sampled pharmacophore models for μ and δ receptors predict it to have efficacy similar to morphine at μ receptors and similar to naltrexone at δ receptors, due to the compound sampling conformations in which the hydroxyl moiety interacts with the receptors similar to orvinols. As predicted, UMB 425 exhibits a mixed μ agonist/δ antagonist profile as determined in receptor binding and [35S]GTPγS functional assays in CHO cells. In vivo studies in mice show that UMB 425 displays potent antinociception in the hot plate and tail-flick assays. The antinociceptive effects of UMB 425 are blocked by naloxone, but not by the κ-selective antagonist norbinaltorphimine. During a 6-day tolerance paradigm, UMB 425 maintains significantly greater antinociception compared to morphine. These studies thus indicate that, even in the absence of δ-specific motifs fused to the C-ring, UMB 425 has mixed μ agonist/δ antagonist properties in vitro that translate to reduced tolerance liabilities in vivo. PMID:23713721

  12. Beneficial properties of maraviroc on neuropathic pain development and opioid effectiveness in rats.

    PubMed

    Kwiatkowski, Klaudia; Piotrowska, Anna; Rojewska, Ewelina; Makuch, Wioletta; Jurga, Agnieszka; Slusarczyk, Joanna; Trojan, Ewa; Basta-Kaim, Agnieszka; Mika, Joanna

    2016-01-01

    Targeting chemokine signaling pathways is crucial in neuropathy development. In this study, we investigated the influence of chronic administration of maraviroc (CCR5 antagonist) on nociception and opioid effectiveness during neuropathy, which develops as a result of chronic constriction injury (CCI) of the sciatic nerve. To investigate the mechanism of action of maraviroc, we measured the expression of glial cell markers, CCR5 and certain CCR5 ligands (CCL3, CCL4, CCL5, CCL7, CCL11), in the spinal cord and dorsal root ganglia (DRG) of vehicle- and maraviroc-treated, CCI-exposed rats. Our results demonstrate that chronic intrathecal administration of maraviroc diminished neuropathic pain symptoms on day 7 post-CCI. Western blot analysis showed that maraviroc diminished protein level of Iba-1 and GFAP and reversed the up-regulated CCR5 expression observed in spinal cord and DRG after CCI. Additionally, using qRT-PCR, we demonstrated that CCR5 and some of its pronociceptive ligands (CCL3, CCL4, CCL5) increased in the spinal cord after nerve injury, and maraviroc effectively diminished those changes. However, CCL11 spinal expression was undetectable, even after injury. In vitro primary culture studies showed that CCL3, CCL4, CCL5 and CCL7 (but not CCL11) were of microglial and astroglial origin and were up-regulated after LPS stimulation. Our results indicate that maraviroc not only attenuated the development of neuropathic pain symptoms due to significant modulation of neuroimmune interactions but also intensified the analgesic properties of morphine and buprenorphine. In sum, our results suggest the pharmacological modulation of CCR5 by maraviroc as a novel therapeutic approach for co-treatment of patients receiving opioid therapy for neuropathy. PMID:26190414

  13. Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics.

    PubMed

    Betti, Cecilia; Starnowska, Joanna; Mika, Joanna; Dyniewicz, Jolanta; Frankiewicz, Lukasz; Novoa, Alexandre; Bochynska, Marta; Keresztes, Attila; Kosson, Piotr; Makuch, Wioletta; Van Duppen, Joost; Chung, Nga N; Vanden Broeck, Jozef; Lipkowski, Andrzej W; Schiller, Peter W; Janssens, Frans; Ceusters, Marc; Sommen, François; Meert, Theo; Przewlocka, Barbara; Tourwé, Dirk; Ballet, Steven

    2015-12-10

    Herein, the synthesis and biological evaluation of dual opioid agonists-neurokinin 1 receptor (NK1R) antagonists is described. In these multitarget ligands, the two pharmacophores do not overlap, and this allowed maintaining high NK1R affinity and antagonist potency in compounds 12 and 13. Although the fusion of the two ligands resulted in slightly diminished opioid agonism at the μ- and δ-opioid receptors (MOR and DOR, respectively), as compared to the opioid parent peptide, balanced MOR/DOR activities were obtained. Compared to morphine, compounds 12 and 13 produced more potent antinociceptive effects in both acute (tail-flick) and neuropathic pain models (von Frey and cold plate). Similarly to morphine, analgesic tolerance developed after repetitive administration of these compounds. To our delight, compound 12 did not produce cross-tolerance with morphine and high antihyperalgesic and antiallodynic effects could be reinstated after chronic administration of each of the two compounds. PMID:26713106

  14. In vivo and in vitro evaluation of novel μ-opioid receptor agonist compounds.

    PubMed

    Nikaido, Yoshiaki; Kurosawa, Aya; Saikawa, Hitomi; Kuroiwa, Satoshi; Suzuki, Chiharu; Kuwabara, Nobuo; Hoshino, Hazime; Obata, Hideaki; Saito, Shigeru; Saito, Tamio; Osada, Hiroyuki; Kobayashi, Isao; Sezutsu, Hideki; Takeda, Shigeki

    2015-11-15

    Opioids are the most effective and widely used drugs for pain treatment. Morphine is an archetypal opioid and is an opioid receptor agonist. Unfortunately, the clinical usefulness of morphine is limited by adverse effects such as analgesic tolerance and addiction. Therefore, it is important to study the development of novel opioid agonists as part of pain control. The analgesic effects of opioids are mediated by three opioid receptors, namely opioid μ-, δ-, and κ-receptors. They belong to the G protein-coupled receptor superfamily and are coupled to Gi proteins. In the present study, we developed a ligand screening system to identify novel opioid μ-receptor agonists that measures [(35)S]GTPγS binding to cell membrane fractions prepared from the fat body of transgenic silkworms expressing μ-receptor-Gi1α fusion protein. We screened the RIKEN Natural Products Depository (NPDepo) chemical library, which contains 5848 compounds, and analogs of hit compounds. We successfully identified a novel, structurally unique compound, that we named GUM1, with agonist activity for the opioid μ-receptor (EC50 of 1.2 µM). The Plantar Test (Hargreaves' Method) demonstrated that subcutaneous injection of 3mg/kg of GUM1 into wild-type rats significantly extended latency time. This extension was also observed in a rat model of morphine tolerance and was inhibited by pre-treatment of naloxone. The unique molecular skeleton of GUM1 makes it an attractive molecule for further ligand-opioid receptor binding studies. PMID:26476280

  15. Development and Validation of a Novel LC-MS/MS Opioid Confirmation Assay: Evaluation of β-glucuronidase Enzymes and Sample Cleanup Methods.

    PubMed

    Yang, He S; Wu, Alan H B; Lynch, Kara L

    2016-06-01

    With the rise in the use and misuse of prescription opioids, there is an increasing need for the confirmed identification of opioid analgesics in toxicology laboratories. The goals of this study were to (i) systematically evaluate the hydrolysis efficiency of four β-glucuronidase enzymes under optimized condition; (ii) evaluate compound recovery, matrix effects and precision of three protein precipitation plates and (iii) develop and validate a qualitative liquid-chromatography mass spectrometry (LC-MS/MS) assay to identify 13 opioids in urine. A recombinant β-glucuronidase exhibited the best overall hydrolysis efficiency for seven opioid glucuronide conjugates compared with β-glucuronidase from red abalone, Escherichia coli and Patella vulgata One of the protein precipitation plates tested exhibited overall better recovery of the opioids and lower ion suppression compared with the other two plates. An ESI positive mode LC-MS/MS assay for qualitative opioid analysis was developed and validated. Linearity, LOD, precision, matrix effect, recovery, carryover and interference of the method were evaluated. Sixty-two patient samples were analyzed by both a legacy GC-MS opioid method and the LC-MS/MS method, and 22 samples were analyzed by the LC-MS/MS and an LC-MS/MS reference method. The results of the comparisons showed good concordance. Overall, we described an efficient sample preparation procedure for a sensitive qualitative opioid confirmation assay in urine. PMID:27121711

  16. Opioids for low back pain.

    PubMed

    Deyo, Richard A; Von Korff, Michael; Duhrkoop, David

    2015-01-01

    Back pain affects most adults, causes disability for some, and is a common reason for seeking healthcare. In the United States, opioid prescription for low back pain has increased, and opioids are now the most commonly prescribed drug class. More than half of regular opioid users report back pain. Rates of opioid prescribing in the US and Canada are two to three times higher than in most European countries. The analgesic efficacy of opioids for acute back pain is inferred from evidence in other acute pain conditions. Opioids do not seem to expedite return to work in injured workers or improve functional outcomes of acute back pain in primary care. For chronic back pain, systematic reviews find scant evidence of efficacy. Randomized controlled trials have high dropout rates, brief duration (four months or less), and highly selected patients. Opioids seem to have short term analgesic efficacy for chronic back pain, but benefits for function are less clear. The magnitude of pain relief across chronic non-cancer pain conditions is about 30%. Given the brevity of randomized controlled trials, the long term effectiveness and safety of opioids are unknown. Loss of long term efficacy could result from drug tolerance and emergence of hyperalgesia. Complications of opioid use include addiction and overdose related mortality, which have risen in parallel with prescription rates. Common short term side effects are constipation, nausea, sedation, and increased risk of falls and fractures. Longer term side effects may include depression and sexual dysfunction. Screening for high risk patients, treatment agreements, and urine testing have not reduced overall rates of opioid prescribing, misuse, or overdose. Newer strategies for reducing risks include more selective prescription of opioids and lower doses; use of prescription monitoring programs; avoidance of co-prescription with sedative hypnotics; and reformulations that make drugs more difficult to snort, smoke, or inject. PMID

  17. Opioid use behaviors, mental health and pain-Development of a typology of chronic pain patients*

    PubMed Central

    Banta-Green, Caleb J.; Merrill, Joseph O.; Doyle, Suzanne R.; Boudreau, Denise M.; Calsyn, Donald A.

    2009-01-01

    Background The intersection of pain, addiction and mental health has not been adequately described. We describe the roles of these three conditions in a chronic pain patient population using opioid analgesics. Aims were to improve our understanding of this population as well as to explore ways of identifying different types of patients. Methods We conducted a retrospective cohort study in a large integrated group medical practice in Washington State with persons using opioids chronically (n=704). Patient classes were derived with latent class analysis using factors representing DSM-IV opioid abuse and dependence, opioid misuse, pain, anxiety and depression. Regression analyses explored the utility of automated and interview data to distinguish the empirically-derived patient groups. Results Three classes were identified: a Typical group, the substantial majority that had persistent, moderate mental health and pain symptoms; an Addictive Behaviors group with elevated mental health symptoms and opioid problems, but pain similar to the Typical class; and a Pain Dysfunction class with significantly higher pain interference as well as elevated mental health and opioid problems. Prescribed average daily dose of opioids was three times higher for those in the two atypical groups and was strongly associated with class membership after adjusting for other variables. Conclusion We describe three distinct types of patient classes as well as data elements that could help identify the two atypical types. Further research is needed to confirm these findings and determine the utility of this approach in other clinical settings. PMID:19473786

  18. Opioid-induced central immune signaling: implications for opioid analgesia

    PubMed Central

    Grace, Peter M.; Maier, Steven F.; Watkins, Linda R.

    2015-01-01

    Despite being the mainstay of pain management, opioids are limited in their clinical utility by adverse effects, such as tolerance and paradoxical hyperalgesia. Research of the past 15 years has extended beyond neurons, to implicate central nervous system immune signaling in these adverse effects. This article will provide an overview of these central immune mechanisms in opioid tolerance and paradoxical hyperalgesia, including those mediated by toll like receptor 4, purinergic, ceramide and chemokine signaling. Challenges for the future, as well as new lines of investigation will be highlighted. PMID:25833219

  19. Safety, tolerability, and pharmacokinetic evaluation of single- and multiple-ascending doses of a novel kappa opioid receptor antagonist LY2456302 and drug interaction with ethanol in healthy subjects.

    PubMed

    Lowe, Stephen L; Wong, Conrad J; Witcher, Jennifer; Gonzales, Celedon R; Dickinson, Gemma L; Bell, Robert L; Rorick-Kehn, Linda; Weller, MaryAnn; Stoltz, Randall R; Royalty, Jane; Tauscher-Wisniewski, Sitra

    2014-09-01

    Accumulating evidence indicates that selective antagonism of kappa opioid receptors may provide therapeutic benefit in the treatment of major depressive disorder, anxiety disorders, and substance use disorders. LY2456302 is a high-affinity, selective kappa opioid antagonist that demonstrates >30-fold functional selectivity over mu and delta opioid receptors. The safety, tolerability, and pharmacokinetics (PK) of LY2456302 were investigated following single oral doses (2-60 mg), multiple oral doses (2, 10, and 35 mg), and when co-administered with ethanol. Plasma concentrations of LY2456302 were measured by liquid chromatography-tandem mass spectrometry method. Safety analyses were conducted on all enrolled subjects. LY2456302 doses were well-tolerated with no clinically significant findings. No safety concerns were seen on co-administration with ethanol. No evidence for an interaction between LY2456302 and ethanol on cognitive-motor performance was detected. LY2456302 displayed rapid oral absorption and a terminal half-life of approximately 30-40 hours. Plasma exposure of LY2456302 increased proportionally with increasing doses and reached steady state after 6-8 days of once-daily dosing. Steady-state PK of LY2456302 were not affected by coadministration of a single dose of ethanol. No clinically important changes in maximum concentration (Cmax ) or AUC of ethanol (in the presence of LY2456302) were observed. PMID:24619932

  20. Developing Items to Measure Theory of Planned Behavior Constructs for Opioid Administration for Children: Pilot Testing.

    PubMed

    Vincent, Catherine; Riley, Barth B; Wilkie, Diana J

    2015-12-01

    The Theory of Planned Behavior (TpB) is useful to direct nursing research aimed at behavior change. As proposed in the TpB, individuals' attitudes, perceived norms, and perceived behavior control predict their intentions to perform a behavior and subsequently predict their actual performance of the behavior. Our purpose was to apply Fishbein and Ajzen's guidelines to begin development of a valid and reliable instrument for pediatric nurses' attitudes, perceived norms, perceived behavior control, and intentions to administer PRN opioid analgesics when hospitalized children self-report moderate to severe pain. Following Fishbein and Ajzen's directions, we were able to define the behavior of interest and specify the research population, formulate items for direct measures, elicit salient beliefs shared by our target population and formulate items for indirect measures, and prepare and test our questionnaire. For the pilot testing of internal consistency of measurement items, Cronbach alphas were between 0.60 and 0.90 for all constructs. Test-retest reliability correlations ranged from 0.63 to 0.90. Following Fishbein and Ajzen's guidelines was a feasible and organized approach for instrument development. In these early stages, we demonstrated good reliability for most subscales, showing promise for the instrument and its use in pain management research. Better understanding of the TpB constructs will facilitate the development of interventions targeted toward nurses' attitudes, perceived norms, and/or perceived behavior control to ultimately improve their pain behaviors toward reducing pain for vulnerable children. PMID:26527107

  1. Buprenorphine for opioid dependence

    PubMed Central

    Ling, Walter

    2014-01-01

    As a treatment agent for opioid dependence, buprenorphine is a nearly ideal medication at our current stage of medication development. Unlike methadone, buprenorphine dosage can be rapidly adjusted with minimal potential for inducing severe consequences. In addition to its intrinsic safety, buprenorphine's relatively low abuse liability in the combination product (i.e., with naloxone as Suboxone®) makes it even more acceptable in regulatory quarters as well as to prescribing physicians. The approval of buprenorphine as a pharmacotherapy for opioid dependence returns to physicians the ability to treat their opioid-dependent patients with an effective opioid-based treatment for the first time in nearly 100 years. Buprenorphine is an opioid, however, and potential for misuse remains, even in combination with naloxone. Whether buprenorphine will be increasingly accepted as a treatment for opioid-dependent patients depends on clinicians recognizing the advantages of its uniquely useful properties while still heeding the need to manage their patients' therapy with reasonable vigilance. PMID:19402772

  2. Ketamine as an Adjunct to Postoperative Pain Management in Opioid Tolerant Patients After Spinal Fusions: A Prospective Randomized Trial

    PubMed Central

    Ya Deau, Jacques T.; Wukovits, Barbara; Lipnitsky, Jane Y.

    2007-01-01

    Management of acute postoperative pain is challenging, particularly in patients with preexisting narcotic dependency. Ketamine has been used at subanesthetic doses as a N-methyl d-aspartate (NMDA) receptor antagonist to block the processing of nociceptive input in chronic pain syndromes. This prospective randomized study was designed to assess the use of ketamine as an adjunct to acute pain management in narcotic tolerant patients after spinal fusions. Twenty-six patients for 1–2 level posterior lumbar fusions with segmental instrumentation were randomly assigned to receive ketamine or act as a control. Patients in the ketamine group received 0.2 mg/kg on induction of general anesthesia and then 2 mcg kg−1 hour−1 for the next 24 hours. Patients were extubated in the operating room and within 15 minutes of arriving in the Post Anesthesia Care Unit (PACU) were started on intravenous patient-controlled analgesia (PCA) hydromorphone without a basal infusion. Patients were assessed for pain (numerical rating scale [NRS]), narcotic use, level of sedation, delirium, and physical therapy milestones until discharge. The ketamine group had significantly less pain during their first postoperative hour in the PACU (NRS 4.8 vs 8.7) and continued to have less pain during the first postoperative day at rest (3.6 vs 5.5) and with physical therapy (5.6 vs 8.0). Three patients in the control group failed PCA pain management and were converted to intravenous ketamine infusions when their pain scores improved. Patients in the ketamine group required less hydromorphone than the control group, but the differences were not significant. Subanesthetic doses of ketamine reduced postoperative pain in narcotic tolerant patients undergoing posterior spine fusions. PMID:18751864

  3. Development of Functionally Selective, Small Molecule Agonists at Kappa Opioid Receptors*

    PubMed Central

    Zhou, Lei; Lovell, Kimberly M.; Frankowski, Kevin J.; Slauson, Stephen R.; Phillips, Angela M.; Streicher, John M.; Stahl, Edward; Schmid, Cullen L.; Hodder, Peter; Madoux, Franck; Cameron, Michael D.; Prisinzano, Thomas E.; Aubé, Jeffrey; Bohn, Laura M.

    2013-01-01

    The kappa opioid receptor (KOR) is widely expressed in the CNS and can serve as a means to modulate pain perception, stress responses, and affective reward states. Therefore, the KOR has become a prominent drug discovery target toward treating pain, depression, and drug addiction. Agonists at KOR can promote G protein coupling and βarrestin2 recruitment as well as multiple downstream signaling pathways, including ERK1/2 MAPK activation. It has been suggested that the physiological effects of KOR activation result from different signaling cascades, with analgesia being G protein-mediated and dysphoria being mediated through βarrestin2 recruitment. Dysphoria associated with KOR activation limits the therapeutic potential in the use of KOR agonists as analgesics; therefore, it may be beneficial to develop KOR agonists that are biased toward G protein coupling and away from βarrestin2 recruitment. Here, we describe two classes of biased KOR agonists that potently activate G protein coupling but weakly recruit βarrestin2. These potent and functionally selective small molecule compounds may prove to be useful tools for refining the therapeutic potential of KOR-directed signaling in vivo. PMID:24187130

  4. Methadone Reverses Analgesic Tolerance Induced by Morphine Pretreatment

    PubMed Central

    Posa, Luca; Accarie, Alison; Marie, Nicolas

    2016-01-01

    Background: Opiates such as morphine are the most powerful analgesics, but their protracted use is restrained by the development of tolerance to analgesic effects. Recent works suggest that tolerance to morphine might be due to its inability to promote mu opioid receptor endocytosis, and the co-injection of morphine with a mu opioid receptor internalizing agonist like [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin reduces tolerance to morphine. So far, no studies have been conducted to evaluate the ability of methadone to reduce morphine tolerance in morphine-pretreated animals, a treatment sequence that could be encountered in opiate rotation protocol. We investigated the ability of methadone (a mu opioid receptor internalizing agonist used in therapy) to reverse morphine tolerance and the associated cellular mechanisms in the periaqueductal gray matter, a region involved in pain control. Methods: We measured analgesic response following a challenge dose of morphine in the hot plate test and investigated regulation of mu opioid receptor (coupling and endocytosis) and some cellular mechanisms involved in tolerance such as adenylate cyclase superactivation and changes in N-methyl-d-aspartate receptor subunits expression and phosphorylation state. Results: A chronic treatment with morphine promoted tolerance to its analgesic effects and was associated with a lack of mu opioid receptor endocytosis, adenylate cyclase overshoot, NR2A and NR2B downregulation, and phosphorylation of NR1. We reported that a methadone treatment in morphine-treated mice reversed morphine tolerance to analgesia by promoting mu opioid receptor endocytosis and blocking cellular mechanisms of tolerance. Conclusions: Our data might lead to rational strategies to tackle opiate tolerance in the frame of opiate rotation. PMID:26390873

  5. The emerging therapeutic roles of κ-opioid agonists.

    PubMed

    Jones, Mark R; Kaye, Alan D; Kaye, Aaron J; Urman, Richard D

    2016-01-01

    The current practice of μ-opioid receptor agonists such as morphine as the primary means of acute and chronic pain relief has several dangerous consequences that limit their effectiveness, including respiratory depression, gastrointestinal motility inhibition, addiction, tolerance, and abuse. Several other opioid receptors, notably the μ-opioid (KOP) receptor, have long been known to play a role in pain relief. Recent discoveries and advancements in laboratory techniques have allowed significant developments of KOP agonists as potential novel therapies for pain relief and other pathological processes. These drugs exhibit none of the classic opioid adverse effects and have displayed pronounced analgesia in several different scenarios. New formulations since 2014 have unveiled increased oral bioavailability, exceptional peripheral versus central selectivity, and a positive safety profile. Continued refinements of established μ-opioid agonist formulations have virtually eliminated the centrally mediated side effects of dysphoria and sedation that limited the applicability of previous KOP agonists. Further research is required to better elucidate the potential of these compounds in pain management, as well as in the mediation or modulation of other complex pathophysiological processes as therapeutic agents. PMID:27194194

  6. Opioids in Preclinical and Clinical Trials

    NASA Astrophysics Data System (ADS)

    Nagase, Hiroshi; Fujii, Hideaki

    Since 1952, when Gates determined the stereo structure of morphine, numerous groups have focused on discovering a nonnarcotic opioid drug [1]. Although several natural, semisynthetic, and synthetic opioid ligands (alkaloids and peptides) have been developed in clinical studies, very few were nonnarcotic opioid drugs [2]. One of the most important studies in the opioid field appeared in 1976, when Martin and colleagues [3] established types of opioid receptors (these are now classified into μ, δ, and κ types). Later, Portoghese discovered a highly selective μ type opioid receptor antagonist, β-funaltrexamine [4]. This led to the finding that the μ type opioid receptor was correlated to drug dependence [5]. Consequently, δ, and particularly κ, opioid agonists were expected to lead to ideal opioid drugs. Moreover, opioid antagonists were evaluated for the treatment of symptoms related to undesirable opioid system activation. In this chapter, we provide a short survey of opioid ligands in development and describe the discovery of the two most promising drugs, TRK-851 [6] and TRK-820 (nalfurafine hydrochloride) [7].

  7. Biphalin preferentially recruits peripheral opioid receptors to facilitate analgesia in a mouse model of cancer pain - A comparison with morphine.

    PubMed

    Lesniak, Anna; Bochynska-Czyz, Marta; Sacharczuk, Mariusz; Benhye, Sandor; Misicka, Aleksandra; Bujalska-Zadrozny, Magdalena; Lipkowski, Andrzej W

    2016-06-30

    The search for new drugs for cancer pain management has been a long-standing goal in basic and clinical research. Classical opioid drugs exert their primary antinociceptive effect upon activating opioid receptors located in the central nervous system. A substantial body of evidence points to the relevance of peripheral opioid receptors as potential targets for cancer pain treatment. Peptides showing limited blood-brain-barrier permeability promote peripheral analgesia in many pain models. In the present study we examined the peripheral and central analgesic effect of intravenously administered biphalin - a dimeric opioid peptide in a mouse skin cancer pain model, developed by an intraplantar inoculation of B16F0 melanoma cells. The effect of biphalin was compared with morphine - a golden standard in cancer pain management. Biphalin produced profound, dose-dependent and naloxone sensitive spinal analgesia. Additionally, the effect in the tumor-bearing paw was largely mediated by peripheral opioid receptors, as it was readily attenuated by the blood-brain-barrier-restricted opioid receptor antagonist - naloxone methiodide. On the contrary, morphine facilitated its analgesic effect primarily by activating spinal opioid receptors. Both drugs induced tolerance in B16F0 - implanted paws after chronic treatment, however biphalin as opposed to morphine, showed little decrease in its activity at the spinal level. Our results indicate that biphalin may be considered a future alternative drug in cancer pain treatment due to an enhanced local analgesic activity as well as lower tolerance liability compared with morphine. PMID:27094782

  8. The immune tolerance network: a new paradigm for developing tolerance-inducing therapies.

    PubMed

    Rotrosen, Daniel; Matthews, Jeff B; Bluestone, Jeffrey A

    2002-07-01

    Immune tolerance therapies are designed to reprogram immune cells in a highly specific fashion to eliminate pathogenic responses while preserving protective immunity. A concept that has tantalized immunologists for decades, the development of tolerance-inducing therapies, would revolutionize the management of a wide range of chronic and often debilitating diseases by obviating the need for lifelong immunosuppressive regimens. The advances of the past decade have provided a more detailed understanding of the molecular events associated with T-cell recognition and activation. Building on these advances, immunologists have demonstrated the feasibility of various tolerance-inducing approaches in small- and large-animal models of autoimmunity, allergy, and transplant graft rejection. Unprecedented opportunities to test these approaches in a variety of human diseases have now emerged. To capitalize on these advances, the National Institutes of Health recently established the Immune Tolerance Network (ITN), an international consortium of more than 70 basic and clinical immunologists dedicated to the evaluation of novel tolerance-inducing therapies and associated studies of immunologic mechanisms. By using a unique interactive approach to accelerate the development of clinical tolerance therapies, the ITN is partnering with the biotechnology and pharmaceutical industries to examine innovative tolerogenic approaches in a range of allergic and autoimmune diseases and to prevent graft rejection after transplantation. Two years since its inception, the ITN now has approximately 2 dozen clinical trials or tolerance assays studies ongoing or in later stages of protocol development. This report summarizes the rationale for emphasizing clinical research on immune tolerance and highlights the progress of the ITN. PMID:12110811

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

    PubMed

    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. PMID:26802437

  10. Opioid Use Disorders.

    PubMed

    Sharma, Bikash; Bruner, Ann; Barnett, Gabrielle; Fishman, Marc

    2016-07-01

    Opioid use and addiction in adolescents and young adults is a health problem of epidemic proportions, with devastating consequences for youth and their families. Opioid overdose is a life-threatening emergency that should be treated with naloxone, and respiratory support if necessary. Overdose should always be an opportunity to initiate addiction treatment. Detoxification is often a necessary, but never sufficient, component of treatment for OUDs. Treatment for OUDs is effective but treatment capacity is alarmingly limited and under-developed. Emerging consensus supports the incorporation of relapse prevention medications such as buprenorphine and extended release naltrexone into comprehensive psychosocial treatment including counseling and family involvement. PMID:27338968

  11. Pharmacological Profiles of Oligomerized μ-Opioid Receptors

    PubMed Central

    Lee, Cynthia Wei-Sheng; Ho, Ing-Kang

    2013-01-01

    Opioids are widely prescribed pain relievers with multiple side effects and potential complications. They produce analgesia via G-protein-protein coupled receptors: μ-, δ-, κ-opioid and opioid receptor-like 1 receptors. Bivalent ligands targeted to the oligomerized opioid receptors might be the key to developing analgesics without undesired side effects and obtaining effective treatment for opioid addicts. In this review we will update the biological effects of μ-opioids on homo- or hetero-oligomerized μ-opioid receptor and discuss potential mechanisms through which bivalent ligands exert beneficial effects, including adenylate cyclase regulation and receptor-mediated signaling pathways. PMID:24709876

  12. Development of opioid-induced constipation: post hoc analysis of data from a 12-week prospective, open-label, blinded-endpoint streamlined study in low-back pain patients treated with prolonged-release WHO step III opioids

    PubMed Central

    Ueberall, Michael A; Mueller-Schwefe, Gerhard HH

    2015-01-01

    Background Opioid-induced constipation is the most prevalent patient complaint associated with longer-term opioid use and interferes with analgesic efficacy, functionality, quality of life, and patient compliance. Objectives We aimed to compare the effects of prolonged-release (PR) oxycodone plus PR naloxone (OXN) vs PR oxycodone (OXY) vs PR morphine (MOR) on bowel function under real-life conditions in chronic low-back pain patients refractory to World Health Organization (WHO) step I and/or II analgesics. Research design and methods This was a post hoc analysis of the complete data set from a prospective, randomized, open-label, blinded endpoint (PROBE) streamlined study (German pain study registry: 2012-0012-05; European Union Drug Regulating Authorities Clinical Trials [EudraCT]: 2012-001317-16), carried out in 88 centers in Germany, where a total of 901 patients requiring WHO step III opioids to treat low-back pain were enrolled and prospectively observed for 3 months. Opioid allocation was based on either optional randomization (n=453) or physician decision (n=448). In both groups, treatment doses could be adjusted as per the German prescribing information, and physicians were free to address all side effects and tolerability issues as usual. The primary endpoint was the proportion of patients maintaining normal bowel function throughout the complete treatment period, assessed with the Bowel Function Index (BFI). Secondary analyses addressed absolute and relative BFI changes, complete spontaneous bowel movements, use of laxatives, treatment emergent adverse events, analgesic effects, and differences between randomized vs nonrandomized patient groups. Results BFI changed significantly with all three WHO step III treatments, however significantly less with OXN vs OXY and MOR despite a significantly higher use of laxatives with the latter ones (P<0.001). The percentage of patients who maintained normal BFI scores despite opioid treatment was 54.5% (164/301) with

  13. Effect of prenatal methadone and ethanol on opioid receptor development in rats

    SciTech Connect

    Peters, M.A.; Braun, R.L. )

    1991-03-11

    The current literature shows that the offspring of female rats exposed to methadone or ethanol display similar neurochemical and neurobehavioral alterations, and suggests that these drugs may be operating through a common mechanism. If this hypothesis is true, their effect on the endogenous opioid systems should be qualitatively similar. In this study virgin females were treated with methadone or 10% ethanol oral solution starting prior to conception and continued throughout gestation. When the offspring had reached 15 or 30 days of age they were sacrificed, the brain was removed and prepared for opioid receptor binding studies. ({sup 3}H)DAGO and ({sup 3}H)DADLE were used as ligands for the mu and delta receptors, respectively. These studies show significant treatment-related differences in both the number of mu and delta binding sites as well as in apparent receptor affinity. Significant sex- and age-related differences between treatments were also observed. These data show that methadone and ethanol, while manifesting some similar neurochemical and behavioral effects, have unique effects on opioid receptor binding, suggesting that they may be acting by different mechanisms.

  14. Site and mechanism of morphine tolerance in the gastrointestinal tract

    PubMed Central

    AKBARALI, H. I.; INKISAR, A.; DEWEY, W. L.

    2015-01-01

    Opioid-induced constipation is a major clinical problem. The effects of morphine, and other narcotics, on the gastrointestinal tract persist over long-term use thus limiting the clinical benefit of these excellent pain relievers. The effects of opioids in the gut, including morphine, are largely mediated by the μ-opioid receptors at the soma and nerve terminals of enteric neurons. Recent studies demonstrate that regional differences exist in both acute and chronic morphine along the gastrointestinal tract. While tolerance develops to the analgesic effects and upper gastrointestinal motility upon repeated morphine administration, tolerance does not develop in the colon with chronic opioids resulting in persistent constipation. Here, we review the mechanisms by which tolerance develops in the small but not the large intestine. The regional differences lie in the signaling and regulation of the μopioid receptor in the various segments of the gastrointestinal tract. The differential role of β-arrestin2 in tolerance development between central and enteric neurons defines the potential for therapeutic approaches in developing ligands with analgesic properties and minimal constipating effects. PMID:25257923

  15. Management of opioid-induced constipation.

    PubMed

    Prichard, David; Norton, Christine; Bharucha, Adil E

    Up to 40% of patients taking opioids develop constipation. Opioid-induced constipation (OIC) may limit the adequate dosing of opioids for pain relief and reduce quality of life. Health professionals must therefore inquire about bowel function in patients receiving opioids. The management of OIC includes carefully re-evaluating the necessity, type and dose of opioids at each visit. Lifestyle modification and alteration of aggravating factors, the use of simple laxatives and, when essential, the addition of newer laxatives or opioid antagonists (naloxone, naloxegol or methylnaltrexone) can be used to treat OIC. This review discusses the recent literature regarding the management of OIC and provides a rational approach to assessing and managing constipation in individuals receiving opioids. PMID:27231750

  16. Ellagic acid enhances morphine analgesia and attenuates the development of morphine tolerance and dependence in mice.

    PubMed

    Mansouri, Mohammad Taghi; Naghizadeh, Bahareh; Ghorbanzadeh, Behnam

    2014-10-15

    According to our previous study, ellagic acid has both dose-related central and peripheral antinociceptive effect through the opioidergic and l-arginine-NO-cGMP-ATP sensitive K(+) channel pathways. In the present study, the systemic antinociceptive effects of ellagic acid in animal models of pain, and functional interactions between ellagic acid and morphine in terms of analgesia, tolerance and dependence were investigated. Ellagic acid (1-30mg/kg; i.p.) showed significant and dose-dependent antinociceptive effects in the acetic acid-induced writhing test. Intraperitoneal ellagic acid acutely interacted with morphine analgesia in a synergistic manner in this assay. Ellagic acid (1-10mg/kg; i.p.) also exerted analgesic activity in the hot-plate test. Pre-treatment with naloxone (1mg/kg; i.p.) significantly reversed ellagic acid, morphine as well as ellagic acid-morphine combination-induced antinociceptin in these two tests. More importantly, when co-administered with morphine, ellagic acid (1-10mg/kg) effectively blocked the development of tolerance to morphine analgesia in the hot-plate test. Likewise, ellagic acid dose-dependently prevented naloxone-precipitated withdrawal signs including jumping and weight loss. Ellagic acid treatment (1-30mg/kg; i.p.) had no significant effect on the locomotion activity of animals using open-field task. Therefore, these results showed that ellagic acid has notable systemic antinociceptive activity for both tonic and phasic pain models. Altogether, ellagic acid might be used in pain relief alone or in combination with opioid drugs because of enhancing morphine analgesia and preventing morphine-induced tolerance to analgesia and dependence. PMID:25179576

  17. Advanced development for space robotics with emphasis on fault tolerance

    NASA Technical Reports Server (NTRS)

    Tesar, D.; Chladek, J.; Hooper, R.; Sreevijayan, D.; Kapoor, C.; Geisinger, J.; Meaney, M.; Browning, G.; Rackers, K.

    1995-01-01

    This paper describes the ongoing work in fault tolerance at the University of Texas at Austin. The paper describes the technical goals the group is striving to achieve and includes a brief description of the individual projects focusing on fault tolerance. The ultimate goal is to develop and test technology applicable to all future missions of NASA (lunar base, Mars exploration, planetary surveillance, space station, etc.).

  18. Salvinorin A analogs and other kappa opioid receptor compounds as treatments for cocaine abuse

    PubMed Central

    Kivell, Bronwyn M; Ewald, Amy WM; Prisinzano, Thomas E

    2014-01-01

    Acute activation of κ opioid receptors produces anti-addictive effects by regulating dopamine levels in the brain. Unfortunately, classic κ opioid agonists have undesired side effects such as sedation, aversion and depression which restrict their clinical use. Salvinorin A (Sal A), a novel κ opioid receptor agonist extracted from the plant Salvia divinorum, has been identified as a potential therapy for drug abuse and addiction. Here, we review the preclinical effects of Sal A in comparison with traditional κ opioid agonists and several new analogues. Sal A retains the anti-addictive properties of traditional κ opioid receptors agonists with several improvements including reduced side effects. However, the rapid metabolism of Sal A makes it undesirable for clinical development. In an effort to improve the pharmacokinetics and tolerability of this compound, κ opioid receptor agonists based on the structure of Sal A have been synthesized. While work in this field is still in progress, several analogues with improved pharmacokinetic profiles have been shown to have anti-addiction effects. While in its infancy, it is clear that these compounds hold promise for the future development of anti-addiction therapeutics. PMID:24484985

  19. Ligand-Directed Functional Selectivity at the Mu Opioid Receptor Revealed by Label-Free Integrative Pharmacology On-Target

    PubMed Central

    Morse, Megan; Tran, Elizabeth; Sun, Haiyan; Levenson, Robert; Fang, Ye

    2011-01-01

    Development of new opioid drugs that provide analgesia without producing dependence is important for pain treatment. Opioid agonist drugs exert their analgesia effects primarily by acting at the mu opioid receptor (MOR) sites. High-resolution differentiation of opioid ligands is crucial for the development of new lead drug candidates with better tolerance profiles. Here, we use a label-free integrative pharmacology on-target (iPOT) approach to characterize the functional selectivity of a library of known opioid ligands for the MOR. This approach is based on the ability to detect dynamic mass redistribution (DMR) arising from the activation of the MOR in living cells. DMR assays were performed in HEK-MOR cells with and without preconditioning with probe molecules using label-free resonant waveguide grating biosensors, wherein the probe molecules were used to modify the activity of specific signaling proteins downstream the MOR. DMR signals obtained were then translated into high resolution heat maps using similarity analysis based on a numerical matrix of DMR parameters. Our data indicate that the iPOT approach clearly differentiates functional selectivity for distinct MOR signaling pathways among different opioid ligands, thus opening new avenues to discover and quantify the functional selectivity of currently used and novel opioid receptor drugs. PMID:22003401

  20. Weighing the Risks and Benefits of Chronic Opioid Therapy.

    PubMed

    Lembke, Anna; Humphreys, Keith; Newmark, Jordan

    2016-06-15

    Evidence supports the use of opioids for treating acute pain. However, the evidence is limited for the use of chronic opioid therapy for chronic pain. Furthermore, the risks of chronic therapy are significant and may outweigh any potential benefits. When considering chronic opioid therapy, physicians should weigh the risks against any possible benefits throughout the therapy, including assessing for the risks of opioid misuse, opioid use disorder, and overdose. When initiating opioid therapy, physicians should consider buprenorphine for patients at risk of opioid misuse, opioid use disorder, and overdose. If and when opioid misuse is detected, opioids do not necessarily need to be discontinued, but misuse should be noted on the problem list and interventions should be performed to change the patient's behavior. If aberrant behavior continues, opioid use disorder should be diagnosed and treated accordingly. When patients are discontinuing opioid therapy, the dosage should be decreased slowly, especially in those who have intolerable withdrawal. It is not unreasonable for discontinuation of chronic opioid therapy to take many months. Benzodiazepines should not be coprescribed during chronic opioid therapy or when tapering, because some patients may develop cross-dependence. For patients at risk of overdose, naloxone should be offered to the patient and to others who may be in a position to witness and reverse opioid overdose. PMID:27304767

  1. Opioid-induced hyperalgesia and burn pain.

    PubMed

    Holtman, Joseph R; Jellish, W Scott

    2012-01-01

    The treatment of pain produced during the management of burn injury has been an ongoing problem for physicians caring for these patients. The main therapeutic option for analgesia has been the repeated and prolonged use of opioids. The adverse effects of opioids are well known but the long term use of opioids which produces tolerance with accompanying dose escalation and dependence is most problematic. Another potentially important consequence of opioid exposure that sometimes masks as tolerance is that of opioid induced hyperalgesia. This syndrome is manifest as enhanced pain, sensitivity and loss of analgesic efficacy in patients treated with opioids who actually become sensitized to painful stimuli. This article focuses on the treatment of burn pain and how current analgesic therapies with opioids may cause hyperalgesia and affect the adequacy of treatment for burn pain. This article also provides possible modalities to help therapeutically manage these patients and considers future analgesic strategies which may help to improve pain management in this complicated patient population. PMID:23143613

  2. Longitudinal cognitive development of children born to mothers with opioid and polysubstance use

    PubMed Central

    Nygaard, Egil; Moe, Vibeke; Slinning, Kari; Walhovd, Kristine B.

    2015-01-01

    Background: Previous studies indicate an increased risk for neuropsychological difficulties in young children prenatally exposed to opioids and polysubstances, but longitudinal information is scarce. The present longitudinal study investigated whether these waned, persisted, or increased over time. Methods: The cognitive functioning of 72 children with prenatal opioid and polysubstance exposure and 58 children without any established prenatal risk was assessed at 1, 2, 3, 4½, and 8½ y. Results: The exposed boys had significantly and stably lower levels of cognitive functioning than the control group, whereas there were increasing differences over time for the girls. The exposed group had significantly lower IQ scores than the control group on Wechsler Intelligence Scale for Children—Revised at 8½ y after controlling for earlier cognitive abilities, and for children who were permanently placed in adoptive/foster homes before 1 y of age and whose mothers used heroin as their main drug during pregnancy (B = 17.04, 95% CI 8.69–25.38, P < 0.001). Conclusion: While effects of prenatal substance exposure cannot be isolated, group effects on cognition rather increased than waned over time, even in adoptive/foster children with minimal postnatal risk. PMID:25978800

  3. Will abuse-deterrent formulations of opioid analgesics be successful in achieving their purpose?

    PubMed

    Bannwarth, Bernard

    2012-09-10

    During the last 2 decades, there has been a dramatic increase in the use of strong opioids for chronic non-cancer pain. This increase has been accompanied by a steep increase in abuse, misuse, and both fatal and non-fatal overdoses involving prescription opioids. The situation is already alarming in the US. Prescription opioid-related harm is a complex, multifactorial issue that requires a multifaceted solution. In this respect, formulations of opioid analgesics designed to resist or deter abuse may be a useful component of a comprehensive opioid risk minimization programme. Such formulations have or are being developed. Abuse-resistant opioids include those that use some kind of physical barrier to prevent tampering with the formulation. Abuse-deterrent opioids are not necessarily resistant to tampering, but contain substances that are designed to make the formulation less attractive to abusers. This article focuses on two products intended to deter abuse that were reviewed by the US Food and Drug Administration (FDA). The first (Embeda®) consists of extended-release morphine with sequestered naltrexone, an opioid antagonist that is released if the tablet is compromised by chewing or crushing. Although Embeda® exhibited abuse-deterrent features, its label warns that it can be abused in a manner similar to other opioid agonists. Furthermore, tampering with Embeda® will result in the release of naltrexone, which may precipitate withdrawal in opioid-tolerant individuals. In March 2011, all dosage forms of Embeda® were recalled because the product failed to meet routine stability standards, and its return date to the market is currently unknown. The second product (Acurox®) was intended to be both tamper resistant and abuse deterrent. It consisted of an immediate-release oxycodone tablet with subtherapeutic niacin as an aversive agent and used a gel-forming ingredient designed to inhibit inhalation and prevent extraction of the drug for injection. The new drug

  4. Molecular Pharmacology of δ-Opioid Receptors.

    PubMed

    Gendron, Louis; Cahill, Catherine M; von Zastrow, Mark; Schiller, Peter W; Pineyro, Graciela

    2016-07-01

    Opioids are among the most effective analgesics available and are the first choice in the treatment of acute severe pain. However, partial efficacy, a tendency to produce tolerance, and a host of ill-tolerated side effects make clinically available opioids less effective in the management of chronic pain syndromes. Given that most therapeutic opioids produce their actions via µ-opioid receptors (MOPrs), other targets are constantly being explored, among which δ-opioid receptors (DOPrs) are being increasingly considered as promising alternatives. This review addresses DOPrs from the perspective of cellular and molecular determinants of their pharmacological diversity. Thus, DOPr ligands are examined in terms of structural and functional variety, DOPrs' capacity to engage a multiplicity of canonical and noncanonical G protein-dependent responses is surveyed, and evidence supporting ligand-specific signaling and regulation is analyzed. Pharmacological DOPr subtypes are examined in light of the ability of DOPr to organize into multimeric arrays and to adopt multiple active conformations as well as differences in ligand kinetics. Current knowledge on DOPr targeting to the membrane is examined as a means of understanding how these receptors are especially active in chronic pain management. Insight into cellular and molecular mechanisms of pharmacological diversity should guide the rational design of more effective, longer-lasting, and better-tolerated opioid analgesics for chronic pain management. PMID:27343248

  5. Inhibition of Spinal Oxidative Stress by Bergamot Polyphenolic Fraction Attenuates the Development of Morphine Induced Tolerance and Hyperalgesia in Mice

    PubMed Central

    Lauro, Filomena; Giancotti, Luigino Antonio; Ilari, Sara; Dagostino, Concetta; Gliozzi, Micaela; Morabito, Chiara; Malafoglia, Valentina; Raffaeli, William; Muraca, Maurizio; Goffredo, Bianca M.; Mollace, Vincenzo; Muscoli, Carolina

    2016-01-01

    Citrus Bergamia Risso, commonly known as Bergamot, is a fruit whose Essential Oil and Bergamot Polyphenolic Fraction have numerous medicinal properties. It is also an excellent antioxidant and in this study, for the first time, its potential effect on morphine induced tolerance in mice has been investigated. Our studies revealed that development of antinociceptive tolerance to repeated doses of morphine in mice is consistently associated with increased formation of superoxide, malondialdehyde and tyrosine-nitrated proteins in the dorsal horn of the spinal cord such as the enzyme glutamine synthase. Nitration of this protein is intimately linked to inactivation of its biological function and resulting increase of glutamate levels in the spinal cord. Administration of Bergamot Polyphenolic Fraction (5–50 mg/kg) attenuated tolerance development. This effect was accompanied by reduction of superoxide and malondialdehyde production, prevention of GS nitration, re-establishment of its activity and of glutamate levels. Our studies confirmed the main role of free radicals during the cascade of events induced by prolonged morphine treatment and the co-administration of natural derivatives antioxidant such as Bergamot Polyphenolic Fraction can be an important therapeutic approach to restore opioids analgesic efficacy. PMID:27227548

  6. Inhibition of Spinal Oxidative Stress by Bergamot Polyphenolic Fraction Attenuates the Development of Morphine Induced Tolerance and Hyperalgesia in Mice.

    PubMed

    Lauro, Filomena; Giancotti, Luigino Antonio; Ilari, Sara; Dagostino, Concetta; Gliozzi, Micaela; Morabito, Chiara; Malafoglia, Valentina; Raffaeli, William; Muraca, Maurizio; Goffredo, Bianca M; Mollace, Vincenzo; Muscoli, Carolina

    2016-01-01

    Citrus Bergamia Risso, commonly known as Bergamot, is a fruit whose Essential Oil and Bergamot Polyphenolic Fraction have numerous medicinal properties. It is also an excellent antioxidant and in this study, for the first time, its potential effect on morphine induced tolerance in mice has been investigated. Our studies revealed that development of antinociceptive tolerance to repeated doses of morphine in mice is consistently associated with increased formation of superoxide, malondialdehyde and tyrosine-nitrated proteins in the dorsal horn of the spinal cord such as the enzyme glutamine synthase. Nitration of this protein is intimately linked to inactivation of its biological function and resulting increase of glutamate levels in the spinal cord. Administration of Bergamot Polyphenolic Fraction (5-50 mg/kg) attenuated tolerance development. This effect was accompanied by reduction of superoxide and malondialdehyde production, prevention of GS nitration, re-establishment of its activity and of glutamate levels. Our studies confirmed the main role of free radicals during the cascade of events induced by prolonged morphine treatment and the co-administration of natural derivatives antioxidant such as Bergamot Polyphenolic Fraction can be an important therapeutic approach to restore opioids analgesic efficacy. PMID:27227548

  7. MicroRNAs Are Involved in the Development of Morphine-Induced Analgesic Tolerance and Regulate Functionally Relevant Changes in Serpini1

    PubMed Central

    Tapocik, Jenica D.; Ceniccola, Kristin; Mayo, Cheryl L.; Schwandt, Melanie L.; Solomon, Matthew; Wang, Bi-Dar; Luu, Truong V.; Olender, Jacqueline; Harrigan, Thomas; Maynard, Thomas M.; Elmer, Greg I.; Lee, Norman H.

    2016-01-01

    Long-term opioid treatment results in reduced therapeutic efficacy and in turn leads to an increase in the dose required to produce equivalent pain relief and alleviate break-through or insurmountable pain. Altered gene expression is a likely means for inducing long-term neuroadaptations responsible for tolerance. Studies conducted by our laboratory (Tapocik et al., 2009) revealed a network of gene expression changes occurring in canonical pathways involved in neuroplasticity, and uncovered miRNA processing as a potential mechanism. In particular, the mRNA coding the protein responsible for processing miRNAs, Dicer1, was positively correlated with the development of analgesic tolerance. The purpose of the present study was to test the hypothesis that miRNAs play a significant role in the development of analgesic tolerance as measured by thermal nociception. Dicer1 knockdown, miRNA profiling, bioinformatics, and confirmation of high value targets were used to test the proposition. Regionally targeted Dicer1 knockdown (via shRNA) had the anticipated consequence of eliminating the development of tolerance in C57BL/6J (B6) mice, thus supporting the involvement of miRNAs in the development of tolerance. MiRNA expression profiling identified a core set of chronic morphine-regulated miRNAs (miR's 27a, 9, 483, 505, 146b, 202). Bioinformatics approaches were implemented to identify and prioritize their predicted target mRNAs. We focused our attention on miR27a and its predicted target serpin peptidase inhibitor clade I (Serpini1) mRNA, a transcript known to be intricately involved in dendritic spine density regulation in a manner consistent with chronic morphine's consequences and previously found to be correlated with the development of analgesic tolerance. In vitro reporter assay confirmed the targeting of the Serpini1 3′-untranslated region by miR27a. Interestingly miR27a was found to positively regulate Serpini1 mRNA and protein levels in multiple neuronal cell lines

  8. Ethanol Reversal of Tolerance to the Respiratory Depressant Effects of Morphine.

    PubMed

    Hill, Rob; Lyndon, Abi; Withey, Sarah; Roberts, Joanne; Kershaw, Yvonne; MacLachlan, John; Lingford-Hughes, Anne; Kelly, Eamonn; Bailey, Chris; Hickman, Matthew; Henderson, Graeme

    2016-02-01

    Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO2 in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths. PMID:26171718

  9. Ethanol Reversal of Tolerance to the Respiratory Depressant Effects of Morphine

    PubMed Central

    Hill, Rob; Lyndon, Abi; Withey, Sarah; Roberts, Joanne; Kershaw, Yvonne; MacLachlan, John; Lingford-Hughes, Anne; Kelly, Eamonn; Bailey, Chris; Hickman, Matthew; Henderson, Graeme

    2016-01-01

    Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO2 in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths. PMID:26171718

  10. Prescription Opioids during Pregnancy

    MedlinePlus

    ... brand names ConZip®, Ryzolt®, Ultram®) The street drug heroin also is an opioid. What problems can opioids ... to buy them illegally. People often start using heroin after becoming addicted to prescription opioids. Sometimes opioids ...

  11. Development of a biotin-avidin probe for detecting opioid receptors.

    PubMed

    Hochhaus, G; Gibson, B W; Sadée, W

    1986-01-01

    Biotinylated derivatives of beta h-endorphin (beta h-EP) with C6 spacer arm, inserted between biotin and beta h-EP, were synthesized and isolated by HPLC. Liquid secondary ion mass spectrometry (LSIMS) indicated the presence of 1 to 4 biotin substituents per beta h-EP molecule, and in combination with the analysis of tryptic peptide fragments, specified the location of the biotinylated lysine residue. Affinities to mu receptors decreased with increasing biotinylation number. Association of the biotinylated ligands with avidin retained or even enhanced IC50 values at the mu site, thus, matching the relative binding affinity of underivatized beta h-EP with the monobiotinylated derivatives. Hence, monobiotinylated beta h-EP represents a versatile opioid receptor probe. PMID:2828982

  12. Novel developments in the mechanisms of immune tolerance to allergens.

    PubMed

    Eiwegger, Thomas; Gruber, Saskia; Szépfalusi, Zsolt; Akdis, Cezmi A

    2012-10-01

    Allergy is the result of a disbalanced immune response to environmental innocuous antigens. Despite of accumulating data to define the pathomechanisms that take place in case of allergic diseases a detailed understanding of sequence of events that lead to the "normal" scenario of tolerance development are still under debate. Allergen-specific immunotherapy is the only causal treatment of allergic diseases. It modifies the immune response to a particular antigen to achieve tolerance against the symptom-causing allergen. This process is considered to mirror physiological peripheral tolerance induction. A number of immunological changes have been described to occur under allergen immunotherapy, including the generation of allergen-specific regulatory T cells, the induction of allergen-specific IgG4, an increase in the Th1/Th2 cytokine ratio and decreased activation and function of effector cells such as mast cells, basophils and eosinophils. PMID:23095863

  13. Responsible opioid use.

    PubMed

    Compton, Peggy; Weaver, Michael F

    2015-06-01

    Editor's Note The journal is delighted to introduce a new feature in this issue that focuses on the complex and multifaceted issue of managing pain and related symptoms while responsibly attending to minimizing substance abuse. How should the seemingly disparate disciplines of drug abuse and symptom control interact? Should these be two separate fields or should practitioners/investigators in one also be qualified in the other? Is that even feasible? We are honored to have two leading, academically based clinician scientists coordinating this new feature. Peggy Compton is Professor and Associate Dean for Academic Affairs at the School of Nursing & Health Studies, Georgetown University in Washington, DC. Many readers know of Peggy's work from her years on the faculty of the University of California at Los Angeles (UCLA). Peggy brings both clinical and scientific addictionology expertise as well as the invaluable perspective of nursing to this arena. Her collaborator is Michael F. Weaver. Mike is Professor of Psychiatry and Behavioral Sciences, and Medical Director of the Center for Neurobehavioral Research on Addictions, at the University of Texas Health Sciences Center at Houston. Prior to moving to Texas, Dr. Weaver became internationally known for his work in addiction medicine at the Medical College of Virginia. We look forward to detailed explorations of many interacting issues in symptom control and substance abuse in the articles featured in this new journal feature in coming issues. The commentary below, the article by Kanouse and Compton, the Issue Brief issued by the U.S. Department of Health and Human Services, and my editorial, all of which appear in this journal issue, introduce the new feature, which I am confident will make valuable contributions to the pain management and substance abuse literature. Arthur G. Lipman, Editor ABSTRACT Abusers of prescription opioids represent two distinct populations: those who develop addiction via opioids prescribed

  14. Update on extended-release opioids in pain management.

    PubMed

    Sloan, Paul

    2014-02-01

    Chronic pain is frequently treated with our most potent analgesics, the opioids. While immediate-release opioids given every 3 - 4 h provide adequate analgesia for most patients with cancer pain and some patients with chronic nonmalignant pain, extended-release (ER) opioid formulations have been developed in the hope that patients with chronic pain would have improved analgesia, reduced side effects, more convenience, improved compliance, improved sleep and reduced nighttime pain. A more recent goal of the ER opioid product is to reduce prescription opioid addiction risk. This editorial will review the evidence that modern ER opioid formulations have advanced toward these goals. PMID:24299558

  15. Early Phase in the Development of Cannabidiol as a Treatment for Addiction: Opioid Relapse Takes Initial Center Stage.

    PubMed

    Hurd, Yasmin L; Yoon, Michelle; Manini, Alex F; Hernandez, Stephanie; Olmedo, Ruben; Ostman, Maria; Jutras-Aswad, Didier

    2015-10-01

    Multiple cannabinoids derived from the marijuana plant have potential therapeutic benefits but most have not been well investigated, despite the widespread legalization of medical marijuana in the USA and other countries. Therapeutic indications will depend on determinations as to which of the multiple cannabinoids, and other biologically active chemicals that are present in the marijuana plant, can be developed to treat specific symptoms and/or diseases. Such insights are particularly critical for addiction disorders, where different phytocannabinoids appear to induce opposing actions that can confound the development of treatment interventions. Whereas Δ(9)-tetracannabinol has been well documented to be rewarding and to enhance sensitivity to other drugs, cannabidiol (CBD), in contrast, appears to have low reinforcing properties with limited abuse potential and to inhibit drug-seeking behavior. Other considerations such as CBD's anxiolytic properties and minimal adverse side effects also support its potential viability as a treatment option for a variety of symptoms associated with drug addiction. However, significant research is still needed as CBD investigations published to date primarily relate to its effects on opioid drugs, and CBD's efficacy at different phases of the abuse cycle for different classes of addictive substances remain largely understudied. Our paper provides an overview of preclinical animal and human clinical investigations, and presents preliminary clinical data that collectively sets a strong foundation in support of the further exploration of CBD as a therapeutic intervention against opioid relapse. As the legal landscape for medical marijuana unfolds, it is important to distinguish it from "medical CBD" and other specific cannabinoids, that can more appropriately be used to maximize the medicinal potential of the marijuana plant. PMID:26269227

  16. [Pharmacotherapy of cancer pain : 2. Use of opioids.].

    PubMed

    Cherny, N I; Portenoy, R K; Raber, M; Zenz, M

    1995-01-01

    as sedation and confusion, will arise with systemic opioids. Morphine, hydromorphone, fentanyl and sufentanil have been used, as have other additional compounds (e.g. local anaesthetics, clonidine). Intracerebroventricular application of morphine has been used only occasionally. In all cases, opioids should be given on to a fixed time schedule thereby, preventing pain from recurring. Additional rescue doses (approximately 50% of baseline single dose) are given for break-through pain. The most frequent side effect of opioids is constipation, and the administration of laxatives is often recommended (Table 5). Nausea, vomiting, sedation and confusion mostly occur in the beginning of opioid therapy. In contrast to constipation, tolerance to these effects develops within days or weeks. True dependence or psychological addiction rarely occurs in patients with chronic cancer pain. In most cases, progression of the underlying disease associated with increasing tissue damage and increasing pain is found. Fear of dependence and addiction often contributes to undertreatment of patients suffering from chronic cancer pain. PMID:18415494

  17. Development and initial testing of a tailored telephone intervention delivered by peers to prevent recurring opioid-overdoses (TTIP-PRO).

    PubMed

    Winhusen, T; Theobald, J; Lewis, D; Wilder, C M; Lyons, M S

    2016-04-01

    Individuals with opioid use disorder experiencing a non-fatal opioid-overdose (OOD) are at heightened risk for future OODs; there are no interventions to facilitate treatment enrollment for these patients. Our goal was to develop and initially test the 'tailored telephone intervention delivered by peers to prevent recurring opioid-overdoses' (TTIP-PRO), a computer-facilitated, peer-delivered, individually tailored secondary prevention intervention designed to: (i) encourage patients to initiate medication-assisted treatment (MAT) and (ii) increase OOD knowledge. A pre-post-study assessed TTIP-PRO-content acceptability and software performance. Two Peer Interventionists, who were abstinent from illicit opioids, enrolled in MAT and had experience with OOD, were recruited from a MAT clinic. Recruitment letters were sent to patients treated for OOD in a hospital emergency department within the prior 8 months. Eight patients received TTIP-PRO and completed pre-/post-assessment. Peer Interventionists completed training within 4 h and reported high satisfaction with TTIP-PRO. There were no performance issues with the software. All participants rated TTIP-PRO as 'very helpful'. Participants' OOD knowledge increased significantly, with 69.9% correct responses pre-TTIP-PRO and 93.6% post-TTIP-PRO. Interest in receiving MAT, measured on a 10-point scale, increased from 8.1 to 9.5, but this change was not statistically significant. Further development and testing of TTIP-PRO appears warranted. PMID:27004905

  18. Multiscale Multiphysics Developments for Accident Tolerant Fuel Concepts

    SciTech Connect

    Gamble, K. A.; Hales, J. D.; Yu, J.; Zhang, Y.; Bai, X.; Andersson, D.; Patra, A.; Wen, W.; Tome, C.; Baskes, M.; Martinez, E.; Stanek, C. R.; Miao, Y.; Ye, B.; Hofman, G. L.; Yacout, A. M.; Liu, W.

    2015-09-01

    U3Si2 and iron-chromium-aluminum (Fe-Cr-Al) alloys are two of many proposed accident-tolerant fuel concepts for the fuel and cladding, respectively. The behavior of these materials under normal operating and accident reactor conditions is not well known. As part of the Department of Energy’s Accident Tolerant Fuel High Impact Problem program significant work has been conducted to investigate the U3Si2 and FeCrAl behavior under reactor conditions. This report presents the multiscale and multiphysics effort completed in fiscal year 2015. The report is split into four major categories including Density Functional Theory Developments, Molecular Dynamics Developments, Mesoscale Developments, and Engineering Scale Developments. The work shown here is a compilation of a collaborative effort between Idaho National Laboratory, Los Alamos National Laboratory, Argonne National Laboratory and Anatech Corp.

  19. Chronic exercise decreases sensitivity to mu opioids in female rats: correlation with exercise output.

    PubMed

    Smith, Mark A; Lyle, Megan A

    2006-09-01

    Aerobic exercise stimulates the release of endogenous opioid peptides and increases nociceptive (i.e., pain) threshold in a naloxone-reversible manner. During chronic exercise, sensitivity to the antinociceptive effects of morphine and other mu opioids decreases, leading some investigators to propose that exercise may lead to the development of cross-tolerance to exogenously administered opioid agonists. The purpose of the present study was to examine the effects of chronic exercise on sensitivity to mu opioids, and to determine if changes in opioid sensitivity during chronic exercise are correlated with exercise output. Eight female rats were obtained at weaning and housed in standard laboratory cages that did not permit any exercise beyond normal cage ambulation. Following 6 weeks under these conditions, opioids possessing a range of relative efficacies at the mu receptor (morphine, levorphanol, buprenorphine, butorphanol) were examined in a warm-water, tail-withdrawal procedure. Under sedentary conditions, all opioids produced dose-dependent increases in tail-withdrawal latencies, and high levels of antinociception were observed for all drugs. Following these tests, rats were reassigned to exercise conditions and transferred to cages equipped with running wheels. Under these conditions, rats ran an average of 7154 rev/day (7869 m/day), with a range across rats from 4501 to 10,164 rev/day (4951-11,180 m/day). Sensitivity to all four opioids decreased significantly during the exercise period, resulting in 2- to 5-fold decreases in the potency of morphine, levorphanol and buprenorphine, and decreases in the effectiveness of buprenorphine and butorphanol. When rats were returned to sedentary conditions, sensitivity to all four opioids increased significantly and returned to that observed prior to the exercise period. For all drugs, there was a positive correlation between exercise output and changes in opioid sensitivity between sedentary and exercise conditions

  20. The research and development of damage tolerant carbon fiber composites

    NASA Astrophysics Data System (ADS)

    Miranda, John Armando

    This record of study takes a first hand look at corporate research and development efforts to improve the damage tolerance of two unique composite materials used in high performance aerospace applications. The professional internship with The Dow Chemical Company---Dow/United Technologies joint venture describes the intern's involvement in developing patentable process technologies for interleave toughening of high temperature resins and their composites. The subsequent internship with Hexcel Corporation describes the intern's involvement in developing the damage tolerance of novel and existing honeycomb sandwich structure technologies. Through the Doctor of Engineering professional internship experience this student exercised fundamental academic understanding and methods toward accomplishing the corporate objectives of the internship sponsors in a resource efficient and cost-effective manner. Also, the student gained tremendous autonomy through exceptional training in working in focused team environments with highly trained engineers and scientists in achieving important corporate objectives.

  1. Novel in situ gelling ocular films for the opioid growth factor-receptor antagonist-naltrexone hydrochloride: fabrication, mechanical properties, mucoadhesion, tolerability and stability studies.

    PubMed

    Abdelkader, Hamdy; Pierscionek, Barbara; Alany, Raid G

    2014-12-30

    Naltrexone hydrochloride (NTX) is an innovative drug used in ophthalmology for treatment of ocular surface diseases such as impaired corneal wound healing and severe dry eye. Poor chemical stability has been a major limitation for development of NTX in solution form. The aim of this study was to develop and characterise NTX in situ ocular films for enhanced chemical stability and improved ocular tolerability. The films were prepared from different amorphous polymers and characterised for physicochemical compatibility, moisture-sorption, surface pH, mechanical properties, sterilisability, surface morphology, mucoadhesion, in vitro release, conjunctival irritation and accelerated stability at 40°C/75% relative humidity for 3 months. Glycerin (GLY)-plasticised films exhibited significantly better mechanical properties, compared with polyethylene glycol (PEG) 400 and triethylcitrate (TEC)-plasticised formulations. Superior mucoadhesion was recorded for F7 and F9 plasticised with GLY and PEG 400, respectively. The stability of NTX was significantly enhanced more than 18-times, compared with the solution form. Combination of carboxymethylcellulose sodium (CMC) and sodium alginate (ALG) in a film formulation demonstrated minimal % moisture sorption, good mechanical properties, in vitro release, excellent chemical stability and minimal conjunctival irritation lending them as promising ocular formulations. PMID:25445974

  2. The diverse clinical uses of opioid receptor drugs.

    PubMed

    Howland, Robert H

    2010-05-01

    Opioid receptors are widely distributed throughout the nervous system. In addition to their central role in brain pathways mediating pain, endogenous opioid peptides function as neuromodulators and opioid systems are involved in many physiological functions. Opioid receptor drugs, including methadone (Dolophine), buprenorphine (Buprenex, Subutex), naltrexone (Revia), naloxone (Narcan), and buprenorphine/naloxone (Suboxone), are the focus of this article. This class of drugs is likely to be further developed for the treatment of addictions and mood disorders. PMID:20415289

  3. Biokinetics and tolerance development of toxic metals in Daphnia magna.

    PubMed

    Tsui, Martin Tsz-Ki; Wang, Wen-Xiong

    2007-05-01

    Daphnia magna is widespread in many freshwater systems of temperate regions and frequently is used to test metal toxicity. Recently, studies have been performed to determine metal biokinetics and development of tolerance in this important zooplankton species. In the present paper, we review the recent progress in these areas and suggest possible directions for future studies. Substantial differences exist in aqueous uptake, dietary assimilation, and elimination of several metals (Cd, Se, Zn, Ag, Hg, and MeHg) by D. magna. The routes of uptake are metal-specific, with Se and MeHg being accumulated predominantly through diet. All metals except Ag can be biomagnified from algae to D. magna, providing that metal concentrations in algae and algal food density are relatively low. Methylmercury is biomagnified in all situations. As a route for metal elimination in D. magna, maternal transfer is especially important for Se, Zn, and MeHg. On the other hand, the effect of single-generation exposure to metals on D. magna is very different from multigeneration exposure, which often results in a significantly higher metal tolerance. Moreover, D. magna easily loses metal tolerance developed through long-term exposure. Recovery from metal stress can temporarily increase the sensitivity of D. magna to metal toxicity. Finally, metallothionein-like protein is responsible for minimizing metal toxicity in D. magna. The results inferred from these studies can be extrapolated to other aquatic invertebrates as well as to other pollutants in the aquatic environment. PMID:17521151

  4. Revolution in GPCR signalling: opioid receptor heteromers as novel therapeutic targets: IUPHAR Review 10

    PubMed Central

    Fujita, Wakako; Gomes, Ivone; Devi, Lakshmi A

    2014-01-01

    GPCRs can interact with each other to form homomers or heteromers. Homomers involve interactions with the same receptor type while heteromers involve interactions between two different GPCRs. These receptor–receptor interactions modulate not only the binding but also the signalling and trafficking properties of individual receptors. Opioid receptor heteromerization has been extensively investigated with the objective of identifying novel therapeutic targets that are as potent as morphine but without the side effects associated with chronic morphine use. In this context, studies have described heteromerization between the different types of opioid receptors and between opioid receptors and a wide range of GPCRs including adrenoceptors, cannabinoid, 5-HT, metabotropic glutamate and sensory neuron-specific receptors. Recent advances in the field involving the generation of heteromer-specific reagents (antibodies or ligands) or of membrane-permeable peptides that disrupt the heteromer interaction are helping to elucidate the physiological role of opioid receptor heteromers and the contribution of the partner receptor to the side effects associated with opioid use. For example, studies using membrane-permeable peptides targeting the heteromer interface have implicated μ and δ receptor heteromers in the development of tolerance to morphine, and heteromers of μ and gastrin-releasing peptide receptors in morphine-induced itch. In addition, a number of ligands that selectively target opioid receptor heteromers exhibit potent antinociception with a decrease in the side effects commonly associated with morphine use. In this review, we summarize the latest findings regarding the biological and functional characteristics of opioid receptor heteromers both in vitro and in vivo. PMID:24916280

  5. Only modest long-term opioid dose escalation occurs over time in chronic nonmalignant pain management.

    PubMed

    Chapman, C Richard; Bradshaw, David H

    2013-12-01

    Clinical experience and the literature increasingly support differentiating chronic pain associated with malignant disease from chronic pain associated with nonmalignant conditions when defining optimal pharmacotherapy. The use of opioids for chronic nonmalignant pain has grown steadily despite the lack of a strong evidence base that can guide practice. A fundamental question is whether patients develop tolerance and need repeated dose escalations to sustain pain control. We examined opioid prescribing data from United Kingdom Clinical Practice Research Datalink longitudinal database of general practice records and tracked dose changes but not pain reports in a sample of 4035 patients who received oral or transdermal-extended release opioids for chronic nonmalignant pain. The median number of days on opioid pharmacotherapy for all patients was 311. Thirty percent of patients never changed doses during the course of treatment. In patients who never changed medications, the mean morphine equivalent 24-hour dose increased from beginning to end of opioid pharmacotherapy only by 1.4 fold, t = 25.73, Cohen's d = .427 and was independent of both age and gender. Comparison across extended release morphine, oxycodone, and fentanyl revealed that it was significantly greatest for patients using fentanyl and least for those using morphine. PMID:24143927

  6. Prescription Opioid Epidemic and Infant Outcomes

    PubMed Central

    Dudley, Judith; Martin, Peter R.; Harrell, Frank E.; Warren, Michael D.; Hartmann, Katherine E.; Ely, E. Wesley; Grijalva, Carlos G.; Cooper, William O.

    2015-01-01

    BACKGROUND AND OBJECTIVES: Although opioid pain relievers are commonly prescribed in pregnancy, their association with neonatal outcomes is poorly described. Our objectives were to identify neonatal complications associated with antenatal opioid pain reliever exposure and to establish predictors of neonatal abstinence syndrome (NAS). METHODS: We used prescription and administrative data linked to vital statistics for mothers and infants enrolled in the Tennessee Medicaid program between 2009 and 2011. A random sample of NAS cases was validated by medical record review. The association of antenatal exposures with NAS was evaluated by using multivariable logistic regression, controlling for maternal and infant characteristics. RESULTS: Of 112 029 pregnant women, 31 354 (28%) filled ≥1 opioid prescription. Women prescribed opioid pain relievers were more likely than those not prescribed opioids (P < .001) to have depression (5.3% vs 2.7%), anxiety disorder (4.3% vs 1.6%) and to smoke tobacco (41.8% vs 25.8%). Infants with NAS and opioid-exposed infants were more likely than unexposed infants to be born at a low birth weight (21.2% vs 11.8% vs 9.9%; P < .001). In a multivariable model, higher cumulative opioid exposure for short-acting preparations (P < .001), opioid type (P < .001), number of daily cigarettes smoked (P < .001), and selective serotonin reuptake inhibitor use (odds ratio: 2.08 [95% confidence interval: 1.67–2.60]) were associated with greater risk of developing NAS. CONCLUSIONS: Prescription opioid use in pregnancy is common and strongly associated with neonatal complications. Antenatal cumulative prescription opioid exposure, opioid type, tobacco use, and selective serotonin reuptake inhibitor use increase the risk of NAS. PMID:25869370

  7. The opioid receptor selectivity for trimebutine in isolated tissues experiments and receptor binding studies.

    PubMed

    Kaneto, H; Takahashi, M; Watanabe, J

    1990-07-01

    Differences of affinity to and selectivity for trimebutine between peripheral and central opioid receptors have been investigated. Trimebutine inhibited electrically induced contraction of guinea-pig ileum (GPI) and mouse vas deferens (MVD) but not of rabbit vas deferens, and the inhibition was antagonized by naloxone and, to lesser extent, by nor-binaltorphimine (nor-BNI). The pA2 values for morphine and trimebutine with naloxone were higher than the values for these compounds with nor-BNI in both GPI and MVD preparations. GPI preparations incubated with a high concentration of morphine or trimebutine developed tolerance; however, there was no cross-tolerance between them, suggesting difference in the underlying mechanisms. In mouse and guinea-pig brain homogenate trimebutine was about 1/13 as potent as morphine to displace the [3H]naloxone binding, while it has no appreciable affinity for kappa-opioid receptors in [3H]U-69593, a selective kappa-receptor agonist. These results suggest that trimebutine, showing its low affinity to opioid receptors, possesses mu-receptor selective properties rather than those of kappa-opioid receptor in the peripheral tissues and in the central brain homogenate. PMID:1963196

  8. Effects of the kappa-opioid receptor agonist, U69593, on the development of sensitization and on the maintenance of cocaine self-administration.

    PubMed

    Schenk, S; Partridge, B; Shippenberg, T S

    2001-04-01

    Previous studies showed that prior administration of kappa-opioid agonists decreased the development of sensitization to some of the behavioral effects of cocaine. The present study sought to determine whether the development of sensitization to cocaine's reinforcing effects was also sensitive to antagonism by kappa-opioid agonists. During a pretreatment phase, the kappa-opioid agonist, U69593 (0.0 or 0.32 mg/kg) was administered prior to (1) 2 daily injections of cocaine (0.0 or 20.0 mg/kg), or (2) cocaine or saline administered via a yoking procedure. Cocaine pretreatment decreased the latency to acquisition of cocaine self-administration. However, prior administration of U69593 during the pretreatment phase failed to attenuate the development of this sensitized response to cocaine's reinforcing effect. In other groups, the effect of acute U69593 pretreatment on the maintenance of cocaine self-administration was examined during a 10 hr session. During training and testing, a stimulus was associated with each self-administered cocaine infusion for one group whereas responding of another group was reinforced by a cocaine infusion alone. On the test day, pretreatment with U69593 (0.32 mg/kg) decreased responding during each hour of the 10 hr session for the group that was reinforced with cocaine plus the cocaine-associated stimulus. U69593 failed to produce a long-lasting disruption of cocaine self-administration for rats that were trained and tested without the cocaine-associated stimulus. These data suggest that the acquisition and maintenance of cocaine self-administration are differentially sensitive to manipulations of kappa-opioid systems. Further, the disruption of cocaine self-administration by U69593 may be due to interactions with mechanisms that underlie facilitative effects of stimuli that have been associated with self-administered cocaine infusions. PMID:11182539

  9. Analgesic tolerance to morphine is regulated by PPARγ

    PubMed Central

    de Guglielmo, Giordano; Kallupi, Marsida; Scuppa, Giulia; Stopponi, Serena; Demopulos, Gregory; Gaitanaris, George; Ciccocioppo, Roberto

    2014-01-01

    Background and Purpose Opioid drugs are potent analgesics. However, their chronic use leads to the rapid development of tolerance to their analgesic effects and subsequent increase of significant side effects, including drug dependence and addiction. Here, we investigated the role of PPARγ in the development of analgesic tolerance to morphine in mice. Experimental Approach We monitored analgesia on alternate days using the tail immersion test. Key Results Daily administration of morphine (30 mg·kg−1, bid) resulted in the rapid development of tolerance to thermal analgesia. Co-administration of pioglitazone (10 and 30 mg·kg−1, bid) significantly attenuated the development and expression of tolerance. However, pretreatment with GW-9662 (5 mg·kg−1, bid), a selective PPARγ antagonist, completely abolished this effect. Injection of GW-9662 and a lower dose of morphine (15 mg·kg−1, bid) accelerated the development of tolerance to its antinociceptive effect. Subsequently, we found that conditional neuronal PPARγ knockout (KO) mice develop a more rapid and pronounced tolerance to morphine antinociception compared with wild-type (WT) controls. Moreover, in PPARγ KO mice, pioglitazone was no longer able to prevent the development of morphine tolerance. Conclusions and Implications Overall, our results demonstrate that PPARγ plays a tonic role in the modulation of morphine tolerance, and its pharmacological activation may help to reduce its development. These findings provide new information about the role of neuronal PPARγ and suggest that combining PPARγ agonists with opioid analgesics may reduce the development of tolerance and possibly attenuate the potential for opioid abuse. PMID:25048682

  10. Antinociception, tolerance and withdrawal symptoms induced by 7-hydroxymitragynine, an alkaloid from the Thai medicinal herb Mitragyna speciosa.

    PubMed

    Matsumoto, Kenjiro; Horie, Syunji; Takayama, Hiromitsu; Ishikawa, Hayato; Aimi, Norio; Ponglux, Dhavadee; Murayama, Toshihiko; Watanabe, Kazuo

    2005-11-19

    7-Hydroxymitragynine is a potent opioid analgesic alkaloid isolated from the Thai medicinal herb Mitragyna speciosa. In the present study, we investigated the opioid receptor subtype responsible for the analgesic effect of this compound. In addition, we tested whether development of tolerance, cross-tolerance to morphine and naloxone-induced withdrawal signs were observed in chronically 7-hydroxymitragynine-treated mice. Subcutaneous (s.c.) administration of 7-hydroxymitragynine produced a potent antinociceptive effect mainly through activation of mu-opioid receptors. Tolerance to the antinociceptive effect of 7-hydroxymitragynine developed as occurs to morphine. Cross-tolerance to morphine was evident in mice rendered tolerant to 7-hydroxymitragynine and vice versa. Naloxone-induced withdrawal signs were elicited equally in mice chronically treated with 7-hydroxymitragynine or morphine. 7-Hydroxymitragynine exhibited a potent antinociceptive effect based on activation of mu-opioid receptors and its morphine-like pharmacological character, but 7-hydroxymitragynine is structurally different from morphine. These interesting characters of 7-hydroxymitragynine promote further investigation of it as a novel lead compound for opioid studies. PMID:16169018

  11. How to Maximize Patient Safety When Prescribing Opioids.

    PubMed

    Kirpalani, Dhiruj

    2015-11-01

    Opioid prescribing and deaths in the United States have increased exponentially in the past couple of decades. This increase has occurred amidst growing awareness of the lack of long-term efficacy of opioids, as well as the significant long- and short-term risks associated with these medications. The scope of the opioid epidemic has led to the development of extensive clinical screening and monitoring tools recommended for health care providers who prescribe opioids to patients for chronic nonmalignant pain. The purpose of this review is to summarize the latest guidelines and evidence that will assist in maximizing patient safety while using chronic opioid therapy as part of pain management. PMID:26568502

  12. An opioid growth factor regulates the replication of microorganisms.

    PubMed

    Zagon, I S; McLaughlin, P J

    1992-01-01

    An opioid growth factor (OGF), [Met5]-enkephalin, interacts with the zeta (zeta) opioid receptor to modulate development of eukaryotes. We have found that [Met5]-enkephalin, an endogenous opioid peptide serves to inhibit the growth of S. aureus. This effect on growth involves cell proliferative events and is under tonic control, since potent opioid antagonists accelerate cell replication. Both the OGF and zeta opioid receptor were associated with these microorganisms. Other opioid receptors (mu, delta and kappa) were not detected. OGF also controlled the growth of other bacteria: P. aeruginosa and S. marcesans. These results indicate that OGF and its receptor, known to be important in the regulation of mammalian development, also function in the growth of simple unicellular organisms. We suggest that the endogenous opioid system related to growth originated billions of years ago. PMID:1313136

  13. Development and Evaluation of Fault-Tolerant Flight Control Systems

    NASA Technical Reports Server (NTRS)

    Song, Yong D.; Gupta, Kajal (Technical Monitor)

    2004-01-01

    The research is concerned with developing a new approach to enhancing fault tolerance of flight control systems. The original motivation for fault-tolerant control comes from the need for safe operation of control elements (e.g. actuators) in the event of hardware failures in high reliability systems. One such example is modem space vehicle subjected to actuator/sensor impairments. A major task in flight control is to revise the control policy to balance impairment detectability and to achieve sufficient robustness. This involves careful selection of types and parameters of the controllers and the impairment detecting filters used. It also involves a decision, upon the identification of some failures, on whether and how a control reconfiguration should take place in order to maintain a certain system performance level. In this project new flight dynamic model under uncertain flight conditions is considered, in which the effects of both ramp and jump faults are reflected. Stabilization algorithms based on neural network and adaptive method are derived. The control algorithms are shown to be effective in dealing with uncertain dynamics due to external disturbances and unpredictable faults. The overall strategy is easy to set up and the computation involved is much less as compared with other strategies. Computer simulation software is developed. A serious of simulation studies have been conducted with varying flight conditions.

  14. Toll-Like Receptor 4 Mutant and Null Mice Retain Morphine-Induced Tolerance, Hyperalgesia, and Physical Dependence

    PubMed Central

    Mattioli, Theresa Alexandra; Leduc-Pessah, Heather; Skelhorne-Gross, Graham; Nicol, Christopher J. B.; Milne, Brian; Trang, Tuan; Cahill, Catherine M.

    2014-01-01

    The innate immune system modulates opioid-induced effects within the central nervous system and one target that has received considerable attention is the toll-like receptor 4 (TLR4). Here, we examined the contribution of TLR4 in the development of morphine tolerance, hyperalgesia, and physical dependence in two inbred mouse strains: C3H/HeJ mice which have a dominant negative point mutation in the Tlr4 gene rendering the receptor non-functional, and B10ScNJ mice which are TLR4 null mutants. We found that neither acute antinociceptive response to a single dose of morphine, nor the development of analgesic tolerance to repeated morphine treatment, was affected by TLR4 genotype. Likewise, opioid induced hyperalgesia and opioid physical dependence (assessed by naloxone precipitated withdrawal) were not altered in TLR4 mutant or null mice. We also examined the behavioural consequence of two stereoisomers of naloxone: (−) naloxone, an opioid receptor antagonist, and (+) naloxone, a purported antagonist of TLR4. Both stereoisomers of naloxone suppressed opioid induced hyperalgesia in wild-type control, TLR4 mutant, and TLR4 null mice. Collectively, our data suggest that TLR4 is not required for opioid-induced analgesic tolerance, hyperalgesia, or physical dependence. PMID:24824631

  15. Differential effects of LY235959, a competitive antagonist of the NMDA receptor on kappa-opioid receptor agonist induced responses in mice and rats.

    PubMed

    Bhargava, H N; Thorat, S N

    1997-02-01

    The effects of the competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, LY235959, were determined on the analgesic and hypothermic effects as well as on the development of tolerance to these effects of U-50,488H, a kappa-opioid receptor agonist in mice and rats. In the mouse, a single injection of LY235959 given 10 min prior to U-50,488H did not modify the analgesic action of the latter. Similarly, chronic administration of LY235959 twice a day for 4 days did not modify U-50,488H-induced analgesia in mice. Repeated pretreatment of mice with LY235959 dose-dependently attenuated the development of tolerance to the analgesic actions of U-50,488H. In the rat, LY235959 by itself produced a significant analgesia and prior treatment of rats with LY235959 enhanced the analgesic action of U-50,488H. Similar effects were seen with the hypothermic action. Pretreatment of rats with LY235959 attenuated the development of tolerance to the analgesic but not to the hypothermic action of U-50,488H. These results provide evidence that LY235959 produces differential actions on nociception and thermic responses by itself and when given acutely with U-50,488H in mice and rats. However, when the animals are pretreated with LY235959, similar inhibitory effects are observed on the development of tolerance to the analgesic action of U-50,488H in both the species. These studies demonstrate an involvement of the NMDA receptor in the development of kappa-opioid tolerance and suggest that the biochemical consequences of an opioid's interaction with the opioid receptor are not the only factors that contribute to the acute and chronic actions of opioid analgesic drugs. PMID:9045999

  16. Fault model development for fault tolerant VLSI design

    NASA Astrophysics Data System (ADS)

    Hartmann, C. R.; Lala, P. K.; Ali, A. M.; Visweswaran, G. S.; Ganguly, S.

    1988-05-01

    Fault models provide systematic and precise representations of physical defects in microcircuits in a form suitable for simulation and test generation. The current difficulty in testing VLSI circuits can be attributed to the tremendous increase in design complexity and the inappropriateness of traditional stuck-at fault models. This report develops fault models for three different types of common defects that are not accurately represented by the stuck-at fault model. The faults examined in this report are: bridging faults, transistor stuck-open faults, and transient faults caused by alpha particle radiation. A generalized fault model could not be developed for the three fault types. However, microcircuit behavior and fault detection strategies are described for the bridging, transistor stuck-open, and transient (alpha particle strike) faults. The results of this study can be applied to the simulation and analysis of faults in fault tolerant VLSI circuits.

  17. The opioid receptors as targets for drug abuse medication

    PubMed Central

    Noble, Florence; Lenoir, Magalie; Marie, Nicolas

    2015-01-01

    The endogenous opioid system is largely expressed in the brain, and both endogenous opioid peptides and receptors are present in areas associated with reward and motivation. It is well known that this endogenous system plays a key role in many aspects of addictive behaviours. The present review summarizes the modifications of the opioid system induced by chronic treatment with drugs of abuse reported in preclinical and clinical studies, as well as the action of opioid antagonists and agonists on the reinforcing effects of drugs of abuse, with therapeutic perspectives. We have focused on the effects of chronic psychostimulants, alcohol and nicotine exposure. Taken together, the changes in both opioid peptides and opioid receptors in different brain structures following acute or chronic exposure to these drugs of abuse clearly identify the opioid system as a potential target for the development of effective pharmacotherapy for the treatment of addiction and the prevention of relapse. PMID:25988826

  18. The opioid receptors as targets for drug abuse medication.

    PubMed

    Noble, Florence; Lenoir, Magalie; Marie, Nicolas

    2015-08-01

    The endogenous opioid system is largely expressed in the brain, and both endogenous opioid peptides and receptors are present in areas associated with reward and motivation. It is well known that this endogenous system plays a key role in many aspects of addictive behaviours. The present review summarizes the modifications of the opioid system induced by chronic treatment with drugs of abuse reported in preclinical and clinical studies, as well as the action of opioid antagonists and agonists on the reinforcing effects of drugs of abuse, with therapeutic perspectives. We have focused on the effects of chronic psychostimulants, alcohol and nicotine exposure. Taken together, the changes in both opioid peptides and opioid receptors in different brain structures following acute or chronic exposure to these drugs of abuse clearly identify the opioid system as a potential target for the development of effective pharmacotherapy for the treatment of addiction and the prevention of relapse. PMID:25988826

  19. Proteomics of seed development, desiccation tolerance, germination and vigor.

    PubMed

    Wang, Wei-Qing; Liu, Shu-Jun; Song, Song-Quan; Møller, Ian Max

    2015-01-01

    Proteomics, the large-scale study of the total complement of proteins in a given sample, has been applied to all aspects of seed biology mainly using model species such as Arabidopsis or important agricultural crops such as corn and rice. Proteins extracted from the sample have typically been separated and quantified by 2-dimensional polyacrylamide gel electrophoresis followed by liquid chromatography and mass spectrometry to identify the proteins in the gel spots. In this way, qualitative and quantitative changes in the proteome during seed development, desiccation tolerance, germination, dormancy release, vigor alteration and responses to environmental factors have all been studied. Many proteins or biological processes potentially important for each seed process have been highlighted by these studies, which greatly expands our knowledge of seed biology. Proteins that have been identified to be particularly important for at least two of the seed processes are involved in detoxification of reactive oxygen species, the cytoskeleton, glycolysis, protein biosynthesis, post-translational modifications, methionine metabolism, and late embryogenesis-abundant (LEA) proteins. It will be useful for molecular biologists and molecular plant breeders to identify and study genes encoding particularly interesting target proteins with the aim to improve the yield, stress tolerance or other critical properties of our crop species. PMID:25461695

  20. Opioids and endocrine dysfunction

    PubMed Central

    Hester, Joan

    2012-01-01

    The endocrine effects of opioids used for the management of persistent pain are poorly understood by clinicians and patients, and hormone levels are rarely measured. It is recognized that opioids exert this effect via the hypothalamic-pituitary-gonadal axis. Additional effects on adrenal hormones, weight, blood pressure and bone density may also occur. Symptoms and signs of sex hormone deficiency occur in both men and women but are under-reported and are often clinically unrecognized. The potential effects of long term opioid therapy on the endocrine system should be explained to patients before opioid therapy is commenced. Monitoring of sex hormones is recommended; if there are deficiencies opioids should be tapered and withdrawn, if this is clinically acceptable. If opioid therapy has to continue, hormone replacement therapy should be initiated and monitored by an endocrinologist. PMID:26516462

  1. Opioids, Exertion, and Dyspnea: A Review of the Evidence.

    PubMed

    Johnson, Miriam J; Hui, David; Currow, David C

    2016-03-01

    The aim of this paper is to review the evidence for a role for opioids as an intervention for exertion induced breathlessness with regard to exercise tolerance and breathlessness intensity. Current knowledge about exogenous opioids in exertion-induced breathlessness due to disease comes from a variety of phase 2 feasibility or pilot designs with differing duration, doses, drugs, exercise regimes, underlying aetiologies, and outcome measures. They provide interesting data but firm conclusions for either breathlessness severity or exercise endurance cannot be drawn. There are no adequately powered phase 3 trials of opioids which show improved exercise tolerance and/or exertion induced breathlessness. Low dose oral morphine seems well tolerated by most, and is beneficial for breathlessness intensity. Current work to investigate the effect on exercise tolerance is ongoing. PMID:25294225

  2. Non-Medical Prescription Opioid Use and Prescription Opioid Use Disorder: A Review

    PubMed Central

    Tetrault, Jeanette M.; Butner, Jenna L.

    2015-01-01

    Over the past few decades, there has been a rise in the non-medical use of prescription opioids, which has now reached epidemic proportions in the United States. In some cases, this non-medical use progresses to prescription opioid use disorder, heroin use, injection, and inhalation drug use, all of which may have further devastating consequences. The purpose of this review article is to discuss the epidemiology of the non-medical use of prescription opioids; discuss the potential progression to subsequent prescription opioid use disorder; review the state and national efforts in development to address addiction and diversion in the United States; discuss treatment options; and, lastly, to evaluate the impact of the related stigma to the development of opioid use disorder. Many unanswered questions remain, and we will explore future possibilities in how the medical community can play a role in curbing this epidemic. PMID:26339205

  3. Non-Medical Prescription Opioid Use and Prescription Opioid Use Disorder: A Review.

    PubMed

    Tetrault, Jeanette M; Butner, Jenna L

    2015-09-01

    Over the past few decades, there has been a rise in the non-medical use of prescription opioids, which has now reached epidemic proportions in the United States. In some cases, this non-medical use progresses to prescription opioid use disorder, heroin use, injection, and inhalation drug use, all of which may have further devastating consequences. The purpose of this review article is to discuss the epidemiology of the non-medical use of prescription opioids; discuss the potential progression to subsequent prescription opioid use disorder; review the state and national efforts in development to address addiction and diversion in the United States; discuss treatment options; and, lastly, to evaluate the impact of the related stigma to the development of opioid use disorder. Many unanswered questions remain, and we will explore future possibilities in how the medical community can play a role in curbing this epidemic. PMID:26339205

  4. Label-free integrative pharmacology on-target of opioid ligands at the opioid receptor family

    PubMed Central

    2013-01-01

    Background In vitro pharmacology of ligands is typically assessed using a variety of molecular assays based on predetermined molecular events in living cells. Many ligands including opioid ligands pose the ability to bind more than one receptor, and can also provide distinct operational bias to activate a specific receptor. Generating an integrative overview of the binding and functional selectivity of ligands for a receptor family is a critical but difficult step in drug discovery and development. Here we applied a newly developed label-free integrative pharmacology on-target (iPOT) approach to systematically survey the selectivity of a library of fifty-five opioid ligands against the opioid receptor family. All ligands were interrogated using dynamic mass redistribution (DMR) assays in both recombinant and native cell lines that express specific opioid receptor(s). The cells were modified with a set of probe molecules to manifest the binding and functional selectivity of ligands. DMR profiles were collected and translated to numerical coordinates that was subject to similarity analysis. A specific set of opioid ligands were then selected for quantitative pharmacology determination. Results Results showed that among fifty-five opioid ligands examined most ligands displayed agonist activity in at least one opioid receptor expressing cell line under different conditions. Further, many ligands exhibited pathway biased agonism. Conclusion We demonstrate that the iPOT effectively sorts the ligands into distinct clusters based on their binding and functional selectivity at the opioid receptor family. PMID:23497702

  5. Opioid drugs: what is next for Lebanon?

    PubMed

    Yamout, Rana; Ayoub, Eliane; Naccache, Nicole; Abou Zeid, Hicham; Matar, Marie-Thérèse; Antakly, Marie-Claire

    2013-01-01

    Opioids remain essential drugs for the treatment of severe cancerous pain. However, many countries have developed new regulations and policies for a better availability and accessibility of these drugs. Lebanon is not too far from these advanced strategies. The Ministry of Health and specifically the Narcotic Department have adjusted regulations related to opioid prescriptions and have registered many new opioid drugs in 2012 for a better pain-free life for our patients. However, there is still a lot to do in this field. PMID:24428075

  6. Imaging opioid analgesia in the human brain and its potential relevance for understanding opioid use in chronic pain

    PubMed Central

    Lee, Michael C.; Wanigasekera, Vishvarani; Tracey, Irene

    2014-01-01

    Opioids play an important role for the management of acute pain and in palliative care. The role of long-term opioid therapy in chronic non-malignant pain remains unclear and is the focus of much clinical research. There are concerns regarding analgesic tolerance, paradoxical pain and issues with dependence that can occur with chronic opioid use in the susceptible patient. In this review, we discuss how far human neuroimaging research has come in providing a mechanistic understanding of pain relief provided by opioids, and suggest avenues for further studies that are relevant to the management of chronic pain with opioids. This article is part of the Special Issue Section entitled ‘Neuroimaging in Neuropharmacology’. PMID:23891639

  7. Pleasure-related analgesia activates opioid-insensitive circuits.

    PubMed

    Kut, Elvan; Candia, Victor; von Overbeck, Jan; Pok, Judit; Fink, Daniel; Folkers, Gerd

    2011-03-16

    Recent findings suggest that pain and pleasure share common neurochemical circuits, and studies in animals and humans show that opioid-mediated descending pathways can inhibit or facilitate pain. We explored the role of endogenous opioid neurotransmission in pleasure-related analgesia. μ-Opioidergic activity was blocked with 0.2 mg/kg naloxone to assess its effects on hedonic responses to pleasant emotional pictures (International Affective Picture System) and its modulating effects on heat pain tolerance. Naloxone did not alter subjective and autonomous reactions to pleasure induction or overall mood of participants. In addition, pleasure-related increases in pain tolerance persisted after reversal of endogenous μ-opioidergic neurotransmission. Subjective pain intensity and unpleasantness ratings increased after naloxone administration. These findings suggest that, in addition to opioid-sensitive circuits, mainly opioid-insensitive pain-modulating circuits are activated during pleasure-related analgesia. PMID:21411655

  8. Naloxegol: First oral peripherally acting mu opioid receptor antagonists for opioid-induced constipation

    PubMed Central

    Anantharamu, Tejus; Sharma, Sushil; Gupta, Ajay Kumar; Dahiya, Navdeep; Singh Brashier, Dick B.; Sharma, Ashok Kumar

    2015-01-01

    Opioid-induced constipation (OIC) is one of the most troublesome and the most common effects of opioid use leading to deterioration in quality of life of the patients and also has potentially deleterious repercussions on adherence and compliance to opioid therapy. With the current guidelines advocating liberal use of opioids by physicians even for non-cancer chronic pain, the situation is further complicated as these individuals are not undergoing palliative care and hence there cannot be any justification to subject these patients to the severe constipation brought on by opioid therapy which is no less debilitating than the chronic pain. The aim in these patients is to prevent the opioid-induced constipation but at the same time allow the analgesic activity of opioids. Many drugs have been used with limited success but the most specific among them were the peripherally acting mu opioid receptor antagonists (PAMORA). Methylnaltrexone and alvimopan were the early drugs in this group but were not approved for oral use in OIC. However naloxegol, the latest PAMORA has been very recently approved as the first oral drug for OIC. This article gives an overview of OIC, its current management and more specifically the development and approval of naloxegol, including pharmacokinetics, details of various clinical trials, adverse effects and its current status for the management of OIC. PMID:26312011

  9. Evaluation of opioid modulation in major depressive disorder.

    PubMed

    Ehrich, Elliot; Turncliff, Ryan; Du, Yangchun; Leigh-Pemberton, Richard; Fernandez, Emilio; Jones, Reese; Fava, Maurizio

    2015-05-01

    Although opioids have known antidepressant activity, their use in major depressive disorder (MDD) has been greatly limited by risk of abuse and addiction. Our aim was to determine whether opioid modulation achieved through a combination of a μ-opioid partial agonist, buprenorphine (BUP), and a potent μ-opioid antagonist, samidorphan (SAM), would demonstrate antidepressant activity without addictive potential. A placebo-controlled crossover study assessed the opioid pharmacodynamic profile following escalating doses of SAM co-administered with BUP in opioid-experienced adults. A subsequent 1-week, placebo-controlled, parallel-group study was conducted in subjects with MDD and an inadequate response to standard antidepressant therapy. This second study evaluated safety and efficacy of ratios of BUP/SAM that were associated with partial and with maximal blockade of opioid responses in the initial study. Pupillometry, visual analog scale assessments, and self-reported questionnaires demonstrated that increasing amounts of SAM added to a fixed dose of BUP resulted in dose-dependent reductions in objective and subjective opioid effects, including euphoria and drug liking, in opioid-experienced adults. Following 7 days of treatment in subjects with MDD, a 1 : 1 ratio of BUP and SAM, the ratio associated with maximal antagonism of opioid effects, exhibited statistically significant improvement vs placebo in HAM-D17 total score (p=0.032) and nearly significant improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) total score (p=0.054). Overall, BUP/SAM therapy was well tolerated. A combination of BUP and SAM showed antidepressant activity in subjects with MDD. Balanced agonist-antagonist opioid modulation represents a novel and potentially clinically important approach to the treatment of MDD and other psychiatric disorders. PMID:25518754

  10. Evaluation of Opioid Modulation in Major Depressive Disorder

    PubMed Central

    Ehrich, Elliot; Turncliff, Ryan; Du, Yangchun; Leigh-Pemberton, Richard; Fernandez, Emilio; Jones, Reese; Fava, Maurizio

    2015-01-01

    Although opioids have known antidepressant activity, their use in major depressive disorder (MDD) has been greatly limited by risk of abuse and addiction. Our aim was to determine whether opioid modulation achieved through a combination of a μ-opioid partial agonist, buprenorphine (BUP), and a potent μ-opioid antagonist, samidorphan (SAM), would demonstrate antidepressant activity without addictive potential. A placebo-controlled crossover study assessed the opioid pharmacodynamic profile following escalating doses of SAM co-administered with BUP in opioid-experienced adults. A subsequent 1-week, placebo-controlled, parallel-group study was conducted in subjects with MDD and an inadequate response to standard antidepressant therapy. This second study evaluated safety and efficacy of ratios of BUP/SAM that were associated with partial and with maximal blockade of opioid responses in the initial study. Pupillometry, visual analog scale assessments, and self-reported questionnaires demonstrated that increasing amounts of SAM added to a fixed dose of BUP resulted in dose-dependent reductions in objective and subjective opioid effects, including euphoria and drug liking, in opioid-experienced adults. Following 7 days of treatment in subjects with MDD, a 1 : 1 ratio of BUP and SAM, the ratio associated with maximal antagonism of opioid effects, exhibited statistically significant improvement vs placebo in HAM-D17 total score (p=0.032) and nearly significant improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) total score (p=0.054). Overall, BUP/SAM therapy was well tolerated. A combination of BUP and SAM showed antidepressant activity in subjects with MDD. Balanced agonist–antagonist opioid modulation represents a novel and potentially clinically important approach to the treatment of MDD and other psychiatric disorders. PMID:25518754

  11. Antihyperalgesic effect of [(±)-(2,4,6-cis)-4-chloro-6-(naphthalen-1-yl)-tetrahydro-2H-pyran-2-yl]methanol: participation of the NO/cGMP/KATP pathway and κ-opioid receptor.

    PubMed

    Gonçalves, Gabriela M; Capim, Saulo L; Vasconcellos, Mário L A A; Marinho, Bruno G

    2016-09-01

    The present study used behavioral analyses to investigate the involvement of the NO/cGMP/KATP pathway, serotoninergic, and opioid systems in the antinociceptive action of [(±)-(2,4,6-cis)-4-chloro-6-(naphthalen-1-yl)-tetrahydro-2H-pyran-2-yl]methanol (CTHP) in mice. Oral administration of CTHP (1, 5, 10, and 30 mg/kg) exerted effects at higher doses in chemical models of nociception (the acetic acid writhing and formalin tests) as well as a thermal model (the tail-flick test). It was also found that pretreatment with L-N-nitroarginine methyl ester (nonselective nitric oxide synthase inhibitor), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (selective inhibitor of nitric oxide-sensitive guanosyl cyclase), glibenclamide (selective ATP-sensitive K channel blocker), naloxone (nonselective opioid receptor blocker), and nor-binaltorphimine (selective κ-opioid receptor blocker), but not methylnaltrexone (peripheral μ-opioid receptor blocker) or naltrindole (selective δ-opioid receptor blocker), reversed the antinociceptive effect of CTHP. In addition, CTHP induced the development of tolerance in the tail-flick test: the tolerance appeared later compared with morphine, and was only observed with a higher dose. Taken together, the present study showed that the systemic administration of CTHP reduced pain induced by chemical and thermal stimuli. We also suggest that the possible mechanisms include the involvement of the NO/cGMP/KATP pathway and the κ-opioid receptor. PMID:27035064

  12. Development of displacement binding and GTPgammaS scintillation proximity assays for the identification of antagonists of the micro-opioid receptor.

    PubMed

    Rodgers, George; Hubert, Cassandra; McKinzie, Jamie; Suter, Todd; Statnick, Michael; Emmerson, Paul; Stancato, Louis

    2003-10-01

    This article describes the development of micro-opioid receptor (MOR) binding and GTPgammaS functional SPAs as improved screening tools for the identification of MOR antagonists. Opioid receptors are members of the seven-transmembrane G protein-coupled receptor (GPCR) family and are involved in the control of various aspects of human physiology, including pain, stress, reward, addiction, respiration, gastric motility, and pituitary hormone secretion. Activation of the MOR initiates intracellular signaling pathways leading to a reduction in intracellular cyclic AMP levels, inhibition of calcium channels, and activation of potassium channels resulting in a reduction of the excitability of neurons. Characterization of opioid receptor ligand binding has traditionally been accomplished through the use of low throughput filtration-based binding assays, whereas functional activity has been based upon cyclic AMP measurements or filtration-based GTPgammaS functional assays. This report describes the development of a MOR displacement binding SPA using the radiolabeled antagonist [(3)H]diprenorphine ((3)H-DPN). The assay was optimized using statistical experimental design and demonstrates the stability and robustness necessary for HTS. The assay was biased toward the identification of MOR antagonists through the addition of Na(+). Our assay conditions also minimized the phenomenon of ligand depletion, a problem commonly observed in low-volume assays using high receptor-expressing cell lines. The optimized procedure revealed (3)H-DPN affinity constants at the MOR that were consistent with results obtained using filtration methods (K(D) (SPA) = 1.89 +/- 0.24 nM, K(D) (filtration) = 1.88 +/- 0.35 nM). The binding SPA identified known opioid receptor modulators contained within the Library of Pharmacological Active Compounds (LOPAC) cassette, and the GTPgammaS scintillation proximity assay (SPA) was used to confirm the functional activity of the LOPAC antagonists acting at the

  13. Chronic Morphine Reduces Surface Expression of δ-Opioid Receptors in Subregions of Rostral Striatum.

    PubMed

    Leah, Paul M; Heath, Emily M L; Balleine, Bernard W; Christie, Macdonald J

    2016-03-01

    The delta opioid receptor (DOPr), whilst not the primary target of clinically used opioids, is involved in development of opioid tolerance and addiction. There is growing evidence that DOPr trafficking is involved in drug addiction, e.g., a range of studies have shown increased plasma membrane DOPr insertion during chronic treatment with opioids. The present study used a transgenic mouse model in which the C-terminal of the DOPr is tagged with enhanced-green fluorescence protein to examine the effects of chronic morphine treatment on surface membrane expression in striatal cholinergic interneurons that are implicated in motivated learning following both chronic morphine and morphine sensitization treatment schedules in male mice. A sex difference was noted throughout the anterior striatum, which was most prominent in the nucleus accumbens core region. Incontrast with previous studies in other neurons, chronic exposure to a high dose of morphine for 6 days had no effect, or slightly decreased (anterior dorsolateral striatum) surface DOPr expression. A morphine sensitization schedule produced similar results with a significant decrease in surface DOPr expression in nucleus accumbens shell. These results suggest that chronic morphine and morphine sensitisation treatment may have effects on instrumental reward-seeking behaviours and learning processes related to drug addiction, via effects on striatal DOPr function. PMID:26093651

  14. Opioid-induced redistribution of 6TM and 7TM μ opioid receptors: A hypothesized mechanistic facilitator model of opioid-induced hyperalgesia.

    PubMed

    Wang, Wei; Wang, Yan; Zhang, Wei; Jin, Xiaoju; Liu, Yusheng; Xu, Shiqin; Lei, Liming; Shen, Xiaofeng; Guo, Xirong; Xia, Xiaoqiong; Wang, Fuzhou

    2016-08-01

    Opioids are still the most popular form of pain treatment, but many unavoidable side effects make opioids a big challenge in effective pain management. Opioid-induced hyperalgesia (OIH), a paradoxical phenomenon, portrays an increased sensitivity to harmful stimuli caused by opioid exposure. Changes in the neural modulation are considered a major contributor to the development of OIH. Activation of opioid receptors (ORs) and corresponding downstream molecules are the vital composition of functional performance of opioids. Increasing interests were proposed of the interaction between ORs and other neural transmitter systems such as glutamatergic, GABAergic and adrenergic ones to the genesis of OIH. G protein coupled μ-opioid receptor (MOR) was studied comprehensively on its role in the development of OIH. In addition to the relationship between MOR and other neurotransmitter receptors, a new intracellular MOR that has six transmembrane (6TM) domains was identified, and found to perform a pro-nociceptive task in contrast to the counterpart 7TM isoform. A mechanistic model of OIH in which both 6TM and 7TM MORs undergoing membrane redistribution upon opioid exposure is proposed which eventually facilitates the neurons more sensitive to nociceptive stimulation than that of the preceding opioid exposure. PMID:27116700

  15. Guideline for Prescribing Opioids for Chronic Pain.

    PubMed

    Centers For Disease Control And Prevention Public Health Service U S Department Of Health And Human Services

    2016-06-01

    Improving the way opioids are prescribed through clinical practice guidelines can ensure patients have access to safer, more effective chronic pain treatment while reducing the number of people who misuse, abuse, or overdose from these drugs. The Centers for Disease Control and Prevention (CDC) developed and published the Guideline for Prescribing Opioids for Chronic Pain to provide recommendations for the prescribing of opioid pain medication for patients 18 and older in primary care settings. Recommendations focus on the use of opioids in treating chronic pain (pain lasting longer than 3 months or past the time of normal tissue healing) outside of active cancer treatment, palliative care, and end-of-life care. PMID:27301691

  16. Buprenorphine for opioid addiction

    PubMed Central

    Ling, Walter; Mooney, Larissa; Torrington, Matthew

    2014-01-01

    SUMMARY Buprenorphine is a partial opioid agonist of the µ-receptor, and is used as a daily dose sublingual tablet or filmstrip for managing opioid addiction. In the USA, the Drug Addiction Treatment Act of 2000 made buprenorphine the only opioid medication for opioid addiction that can be prescribed in an office-based setting. Owing to its high affinity for the µ-receptor, buprenorphine inhibits the reinforcing effect of exogenous opioids. The ceiling effect of buprenorphine's µ-agonist activity reduces the potential for drug overdose and confers low toxicity even at high doses. Buprenorphine pharmacotherapy has proven to be a treatment approach that supports recovery from addiction while reducing or curtailing the use of opioids. This article examines buprenorphine pharmacotherapy for opioid addiction, focusing on the situation in the USA, and is based on a review of pertinent literature, and the authors’ research and clinical experience. The references in this paper were chosen according to the authors’ judgment of quality and relevance, and with respect to their familiarity and involvement in related research. PMID:24654720

  17. Suicide by means of opioid overdose in patients with chronic pain.

    PubMed

    Madadi, Parvaz; Persaud, Nav

    2014-11-01

    Deaths from prescription opioid use continue to rise in North America. The main focus to date has been developing strategies to prevent nonintentional (accidental) fatalities, which constitute the majority of opioid deaths across all jurisdictions. Often overlooked is the complex group of individuals whose cause of death was suicide by opioid overdose. Although most opioid prescribing tools focus on identifying risk factors for potential abuse, diversion, and propensity for opioid addiction, physicians who consider prescribing opioids should also screen and optimize chronic pain treatment for patients at risk for suicide. PMID:25249422

  18. Development of a fish assemblage tolerance index for the National Rivers and Streams Assessment

    EPA Science Inventory

    Whittier et al (Trans. Amer. Fish. Soc. 136:254-271) developed an assemblage tolerance index (ATI) for stream fishes in the western US based on quantitative tolerance values developed for individual fish and amphibian species. The ATI is conceptually similar to the Hilsenhoff Bi...

  19. Opioids and Viral Infections: A Double-Edged Sword

    PubMed Central

    Tahamtan, Alireza; Tavakoli-Yaraki, Masoumeh; Mokhtari-Azad, Talat; Teymoori-Rad, Majid; Bont, Louis; Shokri, Fazel; Salimi, Vahid

    2016-01-01

    Opioids and their receptors have received remarkable attention because they have the ability to alter immune function, which affects disease progression. In vitro and in vivo findings as well as observations in humans indicate that opioids and their receptors positively or negatively affect viral replication and virus-mediated pathology. The present study reviews recent insights in the role of opioids and their receptors in viral infections and discusses possible therapeutic opportunities. This review supports the emerging concept that opioids and their receptors have both favorable and unfavorable effects on viral disease, depending on the type of virus. Targeting of the opioid system is a potential option for developing effective therapies; however caution is required in relation to the beneficial functions of opioid systems. PMID:27446011

  20. Behavioral effects of perinatal opioid exposure.

    PubMed

    Fodor, Anna; Tímár, Júlia; Zelena, Dóra

    2014-05-28

    Opioids are among the world's oldest known drugs used mostly for pain relief, but recreational use is also widespread. A particularly important problem is opioid exposure in females, as their offspring can also be affected. Adverse intrauterine and postnatal environments can affect offspring development and may lead to various disabilities later in life. It is clear that repetitive painful experiences, such as randomly occurring invasive procedures during neonatal intensive care, can permanently alter neuronal and synaptic organization and therefore later behavior. At the same time, analgesic drugs can also be harmful, inducing neuronal apoptosis or withdrawal symptoms in the neonate and behavioral alterations in adulthood. Hence, risk-benefit ratios should be taken into consideration when pain relief is required during pregnancy or in neonates. Recreational use of opioids can also alter many aspects of life. Intrauterine opioid exposure has many toxic effects, inducing poor pregnancy outcomes due to underdevelopment, but it is believed that later negative consequences are more related to environmental factors such as a chaotic lifestyle and inadequate prenatal care. One of the crucial components is maternal care, which changes profoundly in addicted mothers. In substance-dependent mothers, pre- and postnatal care has special importance, and controlled treatment with a synthetic opioid (e.g., methadone) could be beneficial. We aimed to summarize and compare human and rodent data, as it is important to close the gap between scientific knowledge and societal policies. Special emphasis is given to gender differences in the sensitivity of offspring to perinatal opioid exposure. PMID:24746901

  1. Morphine-induced antinociception and reward in "humanized" mice expressing the mu opioid receptor A118G polymorphism.

    PubMed

    Henderson-Redmond, Angela N; Yuill, Matthew B; Lowe, Tammy E; Kline, Aaron M; Zee, Michael L; Guindon, Josée; Morgan, Daniel J

    2016-05-01

    The rewarding and antinociceptive effects of opioids are mediated through the mu-opioid receptor. The A118G single nucleotide polymorphism in this receptor has been implicated in drug addiction and differences in pain response. Clinical and preclinical studies have found that the G allele is associated with increased heroin reward and self-administration, elevated post-operative pain, and reduced analgesic responsiveness to opioids. Male and female mice homozygous for the "humanized" 118AA or 118GG alleles were evaluated to test the hypothesis that 118GG mice are less sensitive to the rewarding and antinociceptive effects of morphine. We found that 118AA and 118GG mice of both genders developed conditioned place preference for morphine. All mice developed tolerance to the antinociceptive and hypothermic effects of morphine. However, morphine tolerance was not different between AA and GG mice. We also examined sensitivity to the antinociceptive and hypothermic effects of cumulative morphine doses. We found that 118GG mice show reduced hypothermic and antinociceptive responses on the hotplate for 10mg/kg morphine. Finally, we examined basal pain response and morphine-induced antinociception in the formalin test for inflammatory pain. We found no gender or genotype differences in either basal pain response or morphine-induced antinociception in the formalin test. Our data suggests that homozygous expression of the GG allele in mice blunts morphine-induced hypothermia and hotplate antinociception but does not alter morphine CPP, morphine tolerance, or basal inflammatory pain response. PMID:26521067

  2. The Useage of Opioids and their Adverse Effects in Gastrointestinal Practice: A Review

    PubMed Central

    Khansari, MahmoudReza; Sohrabi, MasourReza; Zamani, Farhad

    2013-01-01

    Opium is one of the oldest herbal medicines currently used as an analgesic, sedative and antidiarrheal treatment. The effects of opium are principally mediated by the μ-, κ- and δ-opioid receptors. Opioid substances consist of all natural and synthetic alkaloids that are derived from opium. Most of their effects on gastrointestinal motility and secretion result from suppression of neural activity. Inhibition of gastric emptying, increase in sphincter tone, changes in motor patterns, and blockage of peristalsis result from opioid use. Common adverse effects of opioid administration include sedation, dizziness, nausea, vomiting, constipation, dependency and tolerance, and respiratory depression. The most common adverse effect of opioid use is constipation. Although stool softeners are frequently used to decrease opioid-induced bowel dysfunction, however they are not efficacious. Possibly, the use of specific opioid receptor antagonists is a more suitable approach. Opioid antagonists, both central and peripheral, could affect gastrointestinal function and visceromotor sensitivity, which suggests an important role for endogenous opioid peptides in the control of gastrointestinal physiology. Underlying diseases or medications known to influence the central nervous system (CNS) often accelerate the opioid’s adverse effects. However, changing the opioid and/or route of administration could also decrease their adverse effects. Appropriate patient selection, patient education and discussion regarding potential adverse effects may assist physicians in maximizing the effectiveness of opioids, while reducing the number and severity of adverse effects. PMID:24829664

  3. New opioid prescribing guidelines favor non-opioid alternatives.

    PubMed

    2016-05-01

    Determined to make a dent in the growing problem of opioid addiction, the CDC has unveiled new guidelines for opioid prescribing for chronic pain. The recommendations urge providers to be more judicious in their prescribing, opting for opioids only after carefully weighing substantial risks and benefits. Public health authorities note the rampant use and misuse of opioids have "blurred the lines" between prescription opioids and illicit opioids. The new guidelines are designed to help frontline providers balance the need to manage their patients' chronic pain with the duty to curb dangerous prescribing practices. The recommendations are built around three principles: favor non-opioid alternatives for most cases of chronic pain, use the lowest effective dose when prescribing opioids, and exercise caution/monitor patients who are treated with opioids. PMID:27266000

  4. Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain

    PubMed Central

    Chou, Roger; Fanciullo, Gilbert J.; Fine, Perry G.; Adler, Jeremy A.; Ballantyne, Jane C.; Davies, Pamela; Donovan, Marilee I.; Fishbain, David A.; Foley, Kathy M.; Fudin, Jeffrey; Gilson, Aaron M.; Kelter, Alexander; Mauskop, Alexander; O'Connor, Patrick G.; Passik, Steven D.; Pasternak, Gavril W.; Portenoy, Russell K.; Rich, Ben A.; Roberts, Richard G.; Todd, Knox H.; Miaskowski, Christine

    2014-01-01

    Use of chronic opioid therapy for chronic noncancer pain has increased substantially. The American Pain Society and the American Academy of Pain Medicine commissioned a systematic review of the evidence on chronic opioid therapy for chronic noncancer pain and convened a multidisciplinary expert panel to review the evidence and formulate recommendations. Although evidence is limited, the expert panel concluded that chronic opioid therapy can be an effective therapy for carefully selected and monitored patients with chronic noncancer pain. However, opioids are also associated with potentially serious harms, including opioid-related adverse effects and outcomes related to the abuse potential of opioids. The recommendations presented in this document provide guidance on patient selection and risk stratification; informed consent and opioid management plans; initiation and titration of chronic opioid therapy; use of methadone; monitoring of patients on chronic opioid therapy; dose escalations, high-dose opioid therapy, opioid rotation, and indications for discontinuation of therapy; prevention and management of opioid-related adverse effects; driving and work safety; identifying a medical home and when to obtain consultation; management of breakthrough pain; chronic opioid therapy in pregnancy; and opioid-related polices. Perspective: Safe and effective chronic opioid therapy for chronic noncancer pain requires clinical skills and knowledge in both the principles of opioid prescribing and on the assessment and management of risks associated with opioid abuse, addiction, and diversion. Although evidence is limited in many areas related to use of opioids for chronic noncancer pain, this guideline provides recommendations developed by a multidisciplinary expert panel following a systematic review of the evidence. PMID:19187889

  5. Parent and Metabolite Opioid Drug Concentrations in Unintentional Deaths Involving Opioid and Benzodiazepine Combinations.

    PubMed

    Fields, Marcia D; Abate, Marie A; Hu, Lan; Long, D Leann; Blommel, Matthew L; Haikal, Nabila A; Kraner, James C

    2015-07-01

    Effects of benzodiazepines on postmortem opioid parent and parent/metabolite blood concentration ratios were determined for fentanyl-, hydrocodone-, methadone-, or oxycodone-related accidental deaths. These opioids are partially metabolized by the CYP3A4 enzyme system, which is also affected by diazepam and alprazolam. Opioid/metabolite combinations examined were as follows: fentanyl/norfentanyl, hydrocodone/dihydrocodeine, methadone/EDDP, and oxycodone/oxymorphone. Parent opioid concentrations were analyzed for 877 deaths. Parent/metabolite concentration ratios were analyzed for 349 deaths, excluding cases with co-intoxicants present known to interfere with opioid elimination. Alprazolam in combination with diazepam significantly decreased median hydrocodone concentrations by 48% (p = 0.01) compared to hydrocodone alone. The methadone parent/metabolite concentration ratio was reduced by 35% in the presence of diazepam compared to methadone alone (p = 0.03). Benzodiazepines did not statistically significantly affect fentanyl or oxycodone concentrations. Possible factors affecting opioid concentrations and possible toxicity development, including any differential effects on specific opioids, should continue to be explored. PMID:26223761

  6. 2012 David W. Robertson Award for Excellence in Medicinal Chemistry: Neoclerodanes as Atypical Opioid Receptor Ligands⊥

    PubMed Central

    Prisinzano, Thomas E.

    2013-01-01

    The neoclerodane diterpene salvinorin A is the major active component of the hallucinogenic mint plant Salvia divinorum Epling & Játiva (Lamiaceae). Since the finding that salvinorin A exerts its potent psychotropic actions through the activation of opioid receptors, the site of action of morphine and related analogues, there has been much interest in elucidating the underlying mechanisms behind its effects. These effects are particularly remarkable, because (1) salvinorin A is the first reported non-nitrogenous opioid receptor agonist, and (2) its effects are not mediated through the previously investigated targets of psychotomimetics. This perspective outlines our research program, illustrating a new direction to the development of tools to further elucidate the biological mechanisms of drug tolerance and dependence. The information gained from these efforts is expected to facilitate the design of novel agents to treat pain, drug abuse, and other CNS disorders. PMID:23548164

  7. Quantitative evaluation of human delta opioid receptor desensitization using the operational model of drug action.

    PubMed

    Navratilova, Edita; Waite, Sue; Stropova, Dagmar; Eaton, Miriam C; Alves, Isabel D; Hruby, Victor J; Roeske, William R; Yamamura, Henry I; Varga, Eva V

    2007-05-01

    Agonist-mediated desensitization of the opioid receptors is thought to function as a protective mechanism against sustained opioid signaling and therefore may prevent the development of opioid tolerance. However, the exact molecular mechanism of opioid receptor desensitization remains unresolved because of difficulties in measuring and interpreting receptor desensitization. In the present study, we investigated deltorphin II-mediated rapid desensitization of the human delta opioid receptors (hDOR) by measuring guanosine 5'-O-(3-[(35)S]thio)-triphosphate binding and inhibition of cAMP accumulation. We developed a mathematical analysis based on the operational model of agonist action (Black et al., 1985) to calculate the proportion of desensitized receptors. This approach permits a correct analysis of the complex process of functional desensitization by taking into account receptor-effector coupling and the time dependence of agonist pretreatment. Finally, we compared hDOR desensitization with receptor phosphorylation at Ser363, the translocation of beta-arrestin2, and hDOR internalization. We found that in Chinese hamster ovary cells expressing the hDOR, deltorphin II treatment leads to phosphorylation of Ser363, translocation of beta-arrestin2 to the plasma membrane, receptor internalization, and uncoupling from G proteins. It is noteworthy that mutation of the primary phosphorylation site Ser363 to alanine had virtually no effect on agonist-induced beta-arrestin2 translocation and receptor internalization yet significantly attenuated receptor desensitization. These results strongly indicate that phosphorylation of Ser363 is the primary mechanism of hDOR desensitization. PMID:17322005

  8. Opioid-induced respiratory depression: reversal by non-opioid drugs.

    PubMed

    van der Schier, Rutger; Roozekrans, Margot; van Velzen, Monique; Dahan, Albert; Niesters, Marieke

    2014-01-01

    The human body is critically dependent on the ventilatory control system for adequate uptake of oxygen and removal of carbon dioxide (CO2). Potent opioid analgesics, through their actions on μ-opioid receptor (MOR) expressed on respiratory neurons in the brainstem, depress ventilation. Opioid-induced respiratory depression (OIRD) is potentially life threatening and the cause of substantial morbidity and mortality. One possible way of prevention of OIRD is by adding a respiratory stimulant to the opioid treatment, which through activation of non-opioidergic pathways will excite breathing and consequently will offset OIRD and should not affect analgesia. Various new respiratory stimulants are currently under investigation including (a) potassium channel blockers acting at the carotid bodies, and (b) ampakines and (c) serotonin receptor agonists acting within the brainstem. (a) GAL-021 targets BKCa-channels. Initial animal and human experimental evidence indicates that this potassium channel blocker is a potent respiratory stimulant that reverses OIRD without affecting antinociception. GAL021 is safe and better tolerated than the older K(+)-channel blocker doxapram and more efficacious in its effect on respiration. (b) Ampakines modulate glutamatergic respiratory neurons in brainstem respiratory centers. Various ampakines have been studied showing their ability to increase respiratory drive during OIRD by increasing respiratory rate. Currently, CX717 is the most promising ampakine for use in humans as it is safe and does not affect opioid analgesia. (c) While animal studies show that serotonin receptor agonists increase respiratory drive via activation of serotonin receptors in brainstem respiratory centers, human studies are without success. Further clinical studies are required to improve our care of patients that are treated with potent opioid analgesics. The use of non-opioid adjuvants may reduce the probability of OIRD but does never relieve us of our duty to

  9. Opioid-induced respiratory depression: reversal by non-opioid drugs

    PubMed Central

    van der Schier, Rutger; Roozekrans, Margot; van Velzen, Monique; Niesters, Marieke

    2014-01-01

    The human body is critically dependent on the ventilatory control system for adequate uptake of oxygen and removal of carbon dioxide (CO2). Potent opioid analgesics, through their actions on μ-opioid receptor (MOR) expressed on respiratory neurons in the brainstem, depress ventilation. Opioid-induced respiratory depression (OIRD) is potentially life threatening and the cause of substantial morbidity and mortality. One possible way of prevention of OIRD is by adding a respiratory stimulant to the opioid treatment, which through activation of non-opioidergic pathways will excite breathing and consequently will offset OIRD and should not affect analgesia. Various new respiratory stimulants are currently under investigation including (a) potassium channel blockers acting at the carotid bodies, and (b) ampakines and (c) serotonin receptor agonists acting within the brainstem. (a) GAL-021 targets BKCa-channels. Initial animal and human experimental evidence indicates that this potassium channel blocker is a potent respiratory stimulant that reverses OIRD without affecting antinociception. GAL021 is safe and better tolerated than the older K+-channel blocker doxapram and more efficacious in its effect on respiration. (b) Ampakines modulate glutamatergic respiratory neurons in brainstem respiratory centers. Various ampakines have been studied showing their ability to increase respiratory drive during OIRD by increasing respiratory rate. Currently, CX717 is the most promising ampakine for use in humans as it is safe and does not affect opioid analgesia. (c) While animal studies show that serotonin receptor agonists increase respiratory drive via activation of serotonin receptors in brainstem respiratory centers, human studies are without success. Further clinical studies are required to improve our care of patients that are treated with potent opioid analgesics. The use of non-opioid adjuvants may reduce the probability of OIRD but does never relieve us of our duty to

  10. Physicians Experience with and Expectations of the Safety and Tolerability of WHO-Step III Opioids for Chronic (Low) Back Pain: Post Hoc Analysis of Data from a German Cross-Sectional Physician Survey

    PubMed Central

    Ueberall, Michael A.; Eberhardt, Alice; Mueller-Schwefe, Gerhard H. H.

    2015-01-01

    Objective. To describe physicians' daily life experience with WHO-step III opioids in the treatment of chronic (low) back pain (CLBP). Methods. Post hoc analysis of data from a cross-sectional online survey with 4.283 Germany physicians. Results. With a reported median use in 17% of affected patients, WHO-step III opioids play a minor role in treatment of CLBP in daily practice associated with a broad spectrum of positive and negative effects. If prescribed, potent opioids were reported to show clinically relevant effects (such as ≥50% pain relief) in approximately 3 of 4 patients (median 72%). Analgesic effects reported are frequently related with adverse events (AEs). Only 20% of patients were reported to remain free of any AE. Most frequently reported AE was constipation (50%), also graded highest for AE-related daily life restrictions (median 46%). Specific AE countermeasures were reported to be necessary in approximately half of patients (median 45%); nevertheless AE-related premature discontinuation rates reported were high (median 22%). Fentanyl/morphine were the most/least prevalently prescribed potent opioids mentioned (median 20 versus 8%). Conclusion. Overall, use of WHO-step III opioids for CLBP is low. AEs, especially constipation, are commonly reported and interfere significantly with analgesic effects in daily practice. Nevertheless, beneficial effects outweigh related AEs in most patients with CLBP. PMID:26568890

  11. Role of the lipid peroxidation product, 4-hydroxynonenal, in the development of nitrate tolerance.

    PubMed

    D'Souza, Yohan; Kawamoto, Toshihiro; Bennett, Brian M

    2014-04-21

    Tolerance to nitrates such as nitroglycerin (GTN) is associated with oxidative stress, inactivation of aldehyde dehydrogenase 2 (ALDH2), and decreased GTN-induced cGMP accumulation and vasodilation. We hypothesized that GTN-induced inactivation of ALDH2 results in increased 4-hydroxy-2-nonenal (HNE) adduct formation of key proteins involved in GTN bioactivation, and, consequently, an attenuated vasodilator response to GTN (i.e., tolerance). We used an in vivo GTN tolerance model, a cell culture model of nitrate action, and Aldh2(-/-) mice to assess whether GTN exposure resulted in HNE adduct formation, and whether exogenous HNE affected GTN-induced relaxation and cGMP accumulation. Immunoblot analysis indicated a marked increase in HNE adduct formation in GTN-tolerant porcine kidney epithelial cells (PK1) and in aortae from GTN-tolerant rats and untreated Aldh2(-/-) mice. Preincubation of PK1 cells with HNE resulted in a dose-dependent decrease in GTN-induced cGMP accumulation, and pretreatment of isolated rat aorta with HNE resulted in dose-dependent decreases in the vasodilator response to GTN, thus mimicking GTN-tolerance. Pretreatment of aortae from Aldh2(-/-) mice with 10 μM HNE resulted in a desensitized vasodilator response to GTN. In the in vivo rat tolerance model, changes in HNE adduct formation correlated well with the onset of GTN tolerance and tolerance reversal. Furthermore, coadministration of an HNE scavenger during the tolerance induction protocol completely prevented HNE adduct formation and GTN tolerance but did not prevent the inactivation of ALDH2. The data are consistent with a novel mechanism of GTN tolerance suggesting a primary role of HNE adduct formation in the development of GTN tolerance. PMID:24555687

  12. Effect of chronic pentobarbital treatment on the development of cross-tolerance to ethanol and barbital.

    PubMed

    Khanna, J M; Lê, A D; Gougos, A; Kalant, H

    1988-09-01

    Recently, we reported that a chronic regimen of ethanol by intubation, which produced clear tolerance to ethanol-induced hypothermia, ataxia and sleep, produced only a marginal degree of cross-tolerance to these effects of pentobarbital. The present experiments were designed to test the reverse process by examining cross-tolerance to pentobarbital after chronic pretreatment with ethanol, chronic pentobarbital treatment by gavage conferred clear cross-tolerance to both barbital- and ethanol-induced hypothermia, ataxia and sleep. In a separate experiment, cross-tolerance to barbital- and ethanol-induced hypothermia and ataxia was demonstrated over a wide range of test doses. Determination of ethanol blood levels as well as a complete time course of absorption, distribution and elimination of ethanol suggested that pharmacokinetic alterations may play a role in the development of cross-tolerance to ethanol in pentobarbital-treated subjects. The asymmetry of cross-tolerance raises the possibility that pentobarbital and ethanol invoke tolerance by mechanisms that are not wholly identical. This possibility requires further exploration. Conceivably the actions of ethanol which mediate the measured effects form a subset of a larger range of pentobarbital actions that could provide a stronger stimulus to tolerance development. PMID:3252249

  13. Endogenous opioids and excessive alcohol consumption.

    PubMed Central

    Gianoulakis, C

    1993-01-01

    Alcohol is one of the most popular drugs of abuse in our society, and alcoholism is an important cause of absenteeism at work and a major health and social problem. Ethanol induces a number of effects, such as disinhibition, a feeling of general well-being, tolerance and physical dependence. Since there are no specific receptors with which ethanol interacts, it has been proposed that ethanol exerts its effects by altering the activity of a number of neuronal and neuroendocrine systems. Studies have indicated that alcohol influences the activity of the dopaminergic, serotonergic and opioidergic systems. The implication of the endogenous opioid system in mediating some of the effects of ethanol is indicated by the observations that some of the behavioral and pharmacological effects of ethanol are similar to those of the opiates. Indeed, injections of small amounts of morphine increased ethanol consumption, while the administration of naltrexone decreased ethanol consumption among rats and other experimental animals, in a number of experimental paradigms, suggesting that endogenous opioids may play an important role in controlling voluntary ethanol consumption. This paper reviews studies of the effects of ethanol on the activity of the endogenous opioid system and on the importance of endogenous opioids in controlling alcohol consumption. PMID:7690585

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

    PubMed

    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

  15. Development of Peanut Germplasm with Improved Drought Tolerance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We have observed significant reductions in preharvest aflatoxin contamination (PAC) in peanut genotypes with drought tolerance. These sources of resistance to drought and PAC have been entered into a hybridization program. They have been crossed with cultivars and breeding lines that have high yie...

  16. Opioids and sexual reward.

    PubMed

    Paredes, R G

    2014-06-01

    Various lines of research indicate that sexual reward is mediated by opioids in both males and females. In the first part I review basic ideas about sexual reward in humans followed by a description of what is known in rodents, where most of the studies have been done. Although a direct method to measure opioid release during mating is not yet available, there is a substantial amount of indirect evidence in humans and animals indicating that opioids are released during the execution of sexual behavior. Studies using the conditioned place preference (CPP) method where the effects of opioids upon sex induced reward have been evaluated will also be described. Evidence will also be presented indicating that the medial preoptic area (MPOA) plays a crucial role in the expression of opioid mediated sex-reward in males and females. This area is also important in other naturally occurring reward related behaviors such as singing. Opioids might be part of a system that mediates the rewarding properties of natural behaviors that are intrinsically rewarding. PMID:24239788

  17. Development of tolerance to and physical dependence on ethanol: daily versus repeated cycles treatment with ethanol.

    PubMed

    Pohorecky, L A; Roberts, P

    1991-10-01

    We examined the effect of various treatment schedules with ethanol on the development of tolerance and the severity of withdrawal in rats. Tolerance to ethanol was examined after a challenge dose of ethanol using rectal temperature, dowel performance, and tail flick response; open field activity and the startle response were determined during withdrawal. Animals treated daily with ethanol developed greater tolerance, and also lost it faster, compared with animals subjected to repeated cycles of 3 days of ethanol treatment followed by 3 drug-free days. Also, the severity of withdrawal was greater in animals treated daily with ethanol. In the second study, we examined the development of tolerance and withdrawal severity of animals subjected to three different schedules of daily ethanol administration. Overall, the animals receiving continuous infusion of ethanol showed the most severe withdrawal and had, except for dowel performance, the fastest loss of tolerance to ethanol. PMID:1755516

  18. Faculty Development in Small-Group Teaching Skills Associated with a Training Course on Office-Based Treatment of Opioid Dependence

    ERIC Educational Resources Information Center

    Wong, Jeffrey G.; Holmboe, Eric S.; Becker, William C.; Fiellin, David A.; Jara, Gail B.; Martin, Judith

    2005-01-01

    The Drug Addiction Treatment Act of 2000 (DATA-2000) allows qualified physicians to treat opioid-dependent patients with schedule III-V medications, such as buprenorphine, in practices separate from licensed, accredited opioid treatment programs. Physicians may attain this qualification by completing 8-hours of training in treating opioid…

  19. TGF-β in tolerance, development and regulation of immunity

    PubMed Central

    Johnston, Chris J.C.; Smyth, Danielle J.; Dresser, David W.; Maizels, Rick M.

    2016-01-01

    The TGF-β superfamily is an ancient metazoan protein class which cuts across cell and tissue differentiation, developmental biology and immunology. Its many members are regulated at multiple levels from intricate control of gene transcription, post-translational processing and activation, and signaling through overlapping receptor structures and downstream intracellular messengers. We have been interested in TGF-β homologues firstly as key players in the induction of immunological tolerance, the topic so closely associated with Ray Owen. Secondly, our interests in how parasites may manipulate the immune system of their host has also brought us to study the TGF-β pathway in infections with longlived, essentially tolerogenic, helminth parasites. Finally, within the spectrum of mammalian TGF-β proteins is an exquisitely tightly-regulated gene, anti-Müllerian hormone (AMH), whose role in sex determination underpins the phenotype of freemartin calves that formed the focus of Ray’s seminal work on immunological tolerance. PMID:26617281

  20. Opioid analgesics: does potency matter?

    PubMed

    Passik, Steven D; Webster, Lynn

    2014-01-01

    Prescription opioid analgesics with a wide range of potencies are currently used for the treatment of chronic pain. Yet understanding the clinical relevance and therapeutic consequences of opioid potency remains ill defined. Both patients and clinicians alike have misperceptions about opioid potency, expecting that less-potent opioids will be less effective or fearing that more-potent opioids are more dangerous or more likely to be abused. In this review, common myths about the potency of opioid analgesics will be discussed. Clinicians should understand that pharmacologic potency per se does not necessarily imply more effective analgesia or higher abuse liability. Published dose conversion tables may not accurately calculate the dose for effective and safe rotation from one opioid to another in patients receiving long-term opioid therapy because they are based on limited data that may not apply to chronic pain. Differences in pharmacologic potency are largely accounted for by the actual doses prescribed, according to individualized patient need. Factors for achieving effective analgesia and reducing the risks involved with opioid use include careful medication selection based on patient characteristics, appropriate dosing titration and opioid rotation practices, knowledge of product formulation characteristics (eg, extended release, immediate release, and tamper-resistant features), and an awareness of differences in opioid pharmacokinetics and metabolism. Clinicians should remain vigilant in monitoring patients on any opioid medication, regardless of classification along the opioid potency continuum. PMID:25162606

  1. Development of LWR Fuels with Enhanced Accident Tolerance

    SciTech Connect

    Lahoda, Edward J.; Boylan, Frank A.

    2015-10-30

    Significant progress was made on the technical, licensing, and business aspects of the Westinghouse Electric Company’s Enhanced Accident Tolerant Fuel (ATF) by the Westinghouse ATF team. The fuel pellet options included waterproofed U15N and U3Si2 and the cladding options SiC composites and zirconium alloys with surface treatments. Technology was developed that resulted in U3Si2 pellets with densities of >94% being achieved at the Idaho National Laboratory (INL). The use of U3Si2 will represent a 15% increase in U235 loadings over those in UO₂ fuel pellets. This technology was then applied to manufacture pellets for 6 test rodlets which were inserted in the Advanced Test Reactor (ATR) in early 2015 in zirconium alloy cladding. The first of these rodlets are expected to be removed in about 2017. Key characteristics to be determined include verification of the centerline temperature calculations, thermal conductivity, fission gas release, swelling and degree of amorphization. Waterproofed UN pellets have achieved >94% density for a 32% U3Si2/68% UN composite pellet at Texas A&M University. This represents a U235 increase of about 31% over current UO2 pellets. Pellets and powders of UO2, UN, and U3Si2the were tested by Westinghouse and Los Alamos National Laboratory (LANL) using differential scanning calorimetry to determine what their steam and 20% oxygen corrosion temperatures were as compared to UO2. Cold spray application of either the amorphous steel or the Ti2AlC was successful in forming an adherent ~20 micron coating that remained after testing at 420°C in a steam autoclave. Tests at 1200°C in 100% steam on coatings for Zr alloy have not been successful, possibly due to the low density of the coatings which allowed steam transport to the base zirconium metal. Significant modeling and testing

  2. A review of opioid prescription in a teaching hospital in Colombia

    PubMed Central

    Moyano, Jairo; Figueras, Albert

    2012-01-01

    Introduction: Review of opioid prescriptions in a hospital provides valuable information to health care professionals which may contribute to proper pain management; opioid utilization studies may help uncover factors that can be improved for better prescribing. To evaluate the use of opioid analgesics in a university hospital, a review of opioids prescribed in hospitalized patients was developed. Methods: Information was obtained from the pharmacy database and medical records. The study period was 1 month. Results: Medical records of 1156 patients admitted in July 2009 were analyzed. The most widely prescribed opioid was tramadol; the preferred administration route was intravenous; the main indication was severe pain; and major prescribers were from surgical departments. Discussion: Underutilization of potent opioids for acute and chronic pain seems to occur. Conclusion: Most prescribers prefer weak opioids, given intravenously to treat acute and chronic pain, while some patients may benefit from the prescription of more potent opioids. PMID:23049273

  3. Expression and Localization of Opioid Receptors in Male Germ Cells and the Implication for Mouse Spermatogenesis

    PubMed Central

    Gianzo, Marta; Urizar-Arenaza, Itziar; Casis, Luis; Irazusta, Jon; Subirán, Nerea

    2016-01-01

    The presence of endogenous opioid peptides in different testicular cell types has been extensively characterized and provides evidence for the participation of the opioid system in the regulation of testicular function. However, the exact role of the opioid system during the spermatogenesis has remained controversial since the presence of the mu-, delta- and kappa-opioid receptors in spermatogenic cells was yet to be demonstrated. Through a combination of quantitative real-time PCR, immunofluorescence, immunohistochemistry and flow cytometry approaches, we report for the first time the presence of active mu-, delta- and kappa-opioid receptors in mouse male germ cells. They show an exposition time-dependent response to opioid agonist, hence suggesting their active involvement in spermatogenesis. Our results contribute to understanding the role of the opioid receptors in the spermatogenesis and could help to develop new strategies to employ the opioid system as a biochemical tool for the diagnosis and treatment of male infertility. PMID:27031701

  4. Effect of Iboga Alkaloids on µ-Opioid Receptor-Coupled G Protein Activation

    PubMed Central

    Antonio, Tamara; Childers, Steven R.; Rothman, Richard B.; Dersch, Christina M.; King, Christine; Kuehne, Martin; Bornmann, William G.; Eshleman, Amy J.; Janowsky, Aaron; Simon, Eric R.; Reith, Maarten E. A.; Alper, Kenneth

    2013-01-01

    Objective The iboga alkaloids are a class of small molecules defined structurally on the basis of a common ibogamine skeleton, some of which modify opioid withdrawal and drug self-administration in humans and preclinical models. These compounds may represent an innovative approach to neurobiological investigation and development of addiction pharmacotherapy. In particular, the use of the prototypic iboga alkaloid ibogaine for opioid detoxification in humans raises the question of whether its effect is mediated by an opioid agonist action, or if it represents alternative and possibly novel mechanism of action. The aim of this study was to independently replicate and extend evidence regarding the activation of μ-opioid receptor (MOR)-related G proteins by iboga alkaloids. Methods Ibogaine, its major metabolite noribogaine, and 18-methoxycoronaridine (18-MC), a synthetic congener, were evaluated by agonist-stimulated guanosine-5´-O-(γ-thio)-triphosphate ([35S]GTPγS) binding in cells overexpressing the recombinant MOR, in rat thalamic membranes, and autoradiography in rat brain slices. Results And Significance In rat thalamic membranes ibogaine, noribogaine and 18-MC were MOR antagonists with functional Ke values ranging from 3 uM (ibogaine) to 13 uM (noribogaine and 18MC). Noribogaine and 18-MC did not stimulate [35S]GTPγS binding in Chinese hamster ovary cells expressing human or rat MORs, and had only limited partial agonist effects in human embryonic kidney cells expressing mouse MORs. Ibogaine did not did not stimulate [35S]GTPγS binding in any MOR expressing cells. Noribogaine did not stimulate [35S]GTPγS binding in brain slices using autoradiography. An MOR agonist action does not appear to account for the effect of these iboga alkaloids on opioid withdrawal. Taken together with existing evidence that their mechanism of action also differs from that of other non-opioids with clinical effects on opioid tolerance and withdrawal, these findings suggest a

  5. Elevated Pain Sensitivity in Chronic Pain Patients at Risk for Opioid Misuse

    PubMed Central

    Edwards, Robert R.; Wasan, Ajay D.; Michna, Ed; Greenbaum, Seth; Ross, Ed; Jamison, Robert N.

    2011-01-01

    This study employed quantitative sensory testing (QST) to evaluate pain responses in chronic spinal pain patients at low risk and high risk for opioid misuse, with risk classification based on scores on the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R). Patients were further sub-grouped according to current use of prescription opioids. Of the 276 chronic pain patients tested, approximately 65% were taking opioids; a median split was used to further categorize these patients as being on lower or higher doses of opioids. The highrisk group (n= 161) reported higher levels of clinical pain, had lower pressure and thermal pain thresholds at multiple body sites, had lower heat pain tolerance, and rated repetitive mechanical stimuli as more painful relative to the low-risk group (n= 115; p’s< .01). In contrast, QST measures did not differ across opioid groups. Multiple linear regression analysis suggested that indices of pain-related distress (i.e., anxiety and catastrophizing about pain) were also predictive of hyperalgesia, particularly in patients taking opioids. Collectively, regardless of opioid status, the high-risk group was hyperalgesic relative to the low-risk group; future opioid treatment studies may benefit from the classification of opioid risk, and the examination of pain sensitivity and other factors that differentiate high- and low-risk groups. PMID:21680252

  6. Evidence that tolerance develops to the anxiolytic effect of diazepam in rats.

    PubMed

    Treit, D

    1985-03-01

    The development of tolerance to the anxiolytic effect of diazepam was studied using suppression of defensive burying as an animal model of anxiolytic action. Although tolerance to the suppressive effect of diazepam was not apparent after chronic administration of diazepam when the rats were tested with a low-intensity shock, anxiolytic tolerance was detected under exactly the same drug regimen when the rats were tested with somewhat higher intensity shocks: under the latter conditions, chronically treated rats buried significantly more than acutely treated rats. Furthermore, this tolerance effect did not appear to depend upon the injection environment, the control vehicle, or the strain of rat; under each of these experimental variations rats chronically treated with diazepam buried significantly more than acutely treated rats when they had received a moderately high intensity shock. These results suggested that tolerance to the anxiolytic effects of benzodiazepines may be detectable when the stimuli eliciting anxiety are relatively intense. PMID:2859605

  7. Development of Crystal-Tolerant High-Level Waste Glasses

    SciTech Connect

    Matyas, Josef; Vienna, John D.; Schaible, Micah J.; Rodriguez, Carmen P.; Crum, Jarrod V.; Arrigoni, Alyssa L.; Tate, Rachel M.

    2010-12-17

    Twenty five glasses were formulated. They were batched from HLW AZ-101 simulant or raw chemicals and melted and tested with a series of tests to elucidate the effect of spinel-forming components (Ni, Fe, Cr, Mn, and Zn), Al, and noble metals (Rh2O3 and RuO2) on the accumulation rate of spinel crystals in the glass discharge riser of the high-level waste (HLW) melter. In addition, the processing properties of glasses, such as the viscosity and TL, were measured as a function of temperature and composition. Furthermore, the settling of spinel crystals in transparent low-viscosity fluids was studied at room temperature to access the shape factor and hindered settling coefficient of spinel crystals in the Stokes equation. The experimental results suggest that Ni is the most troublesome component of all the studied spinel-forming components producing settling layers of up to 10.5 mm in just 20 days in Ni-rich glasses if noble metals or a higher concentration of Fe was not introduced in the glass. The layer of this thickness can potentially plug the bottom of the riser, preventing glass from being discharged from the melter. The noble metals, Fe, and Al were the components that significantly slowed down or stopped the accumulation of spinel at the bottom. Particles of Rh2O3 and RuO2, hematite and nepheline, acted as nucleation sites significantly increasing the number of crystals and therefore decreasing the average crystal size. The settling rate of ≤10-μm crystal size around the settling velocity of crystals was too low to produce thick layers. The experimental data for the thickness of settled layers in the glasses prepared from AZ-101 simulant were used to build a linear empirical model that can predict crystal accumulation in the riser of the melter as a function of concentration of spinel-forming components in glass. The developed model predicts the thicknesses of accumulated layers quite well, R2 = 0.985, and can be become an efficient tool for the formulation

  8. Parenthood and opioid dependence

    PubMed Central

    Pihkala, Heljä; Sandlund, Mikael

    2015-01-01

    Introduction Many patients in maintenance treatment programs for opioid dependence are parents to underage children. Objective The aim of this study was to explore how parents who are regular patients in maintenance treatment perceive their parenthood. Methods The study used a qualitative approach. The informants were recruited by staff at a substance abuse clinic in Sweden. Criteria for inclusion were participation in the local maintenance treatment program, having a child or children younger than 18 years, and being in contact with the child or children. Data were collected in 2012–2013 by in-depth interviews of seven fathers and five mothers and analyzed using concepts and procedures of qualitative content analysis. Results The central findings of the study were: 1) the parents’ concerns about possible future discrimination against their children, ie, stigma by association; and 2) the patients’ own parents’ role as the most important support in parenthood. Conclusion The issue of anticipated discrimination against the children of parents undergoing maintenance treatment might be an aspect to consider in the development of interventions and support. Considering the role of the patients’ own parents also seems important. PMID:25709518

  9. [Advanced Development for Space Robotics With Emphasis on Fault Tolerance Technology

    NASA Technical Reports Server (NTRS)

    Tesar, Delbert

    1997-01-01

    This report describes work developing fault tolerant redundant robotic architectures and adaptive control strategies for robotic manipulator systems which can dynamically accommodate drastic robot manipulator mechanism, sensor or control failures and maintain stable end-point trajectory control with minimum disturbance. Kinematic designs of redundant, modular, reconfigurable arms for fault tolerance were pursued at a fundamental level. The approach developed robotic testbeds to evaluate disturbance responses of fault tolerant concepts in robotic mechanisms and controllers. The development was implemented in various fault tolerant mechanism testbeds including duality in the joint servo motor modules, parallel and serial structural architectures, and dual arms. All have real-time adaptive controller technologies to react to mechanism or controller disturbances (failures) to perform real-time reconfiguration to continue the task operations. The developments fall into three main areas: hardware, software, and theoretical.

  10. Nutrient supplementation key to inhibitor-tolerant yeast development and fermentation performance on switchgrass hydrolyzates

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Inhibitory compounds generated during acid hydrolysis pretreatment of lignocellulosic biomass interfere with subsequent fermentation to ethanol. Tolerant yeast strains have recently been developed by targeted evolution in the presence of biomass hydrolyzate inhibitors. In order to optimize performan...

  11. Nutrient supplementation key to inhibitor-tolerant yeast development and fermentation performance on switchgrass hydrolyzates

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Inhibitory compounds generated during acid hydrolysis pretreatment of lignocellulosic biomass interfere with subsequent fermentation to ethanol. Tolerant yeast strains have recently been developed by targeted evolution in the presence of biomass hydrolyzate inhibitors. In order to optimize perform...

  12. Oregon's strategy to confront prescription opioid misuse: a case study.

    PubMed

    McCarty, Dennis; Bovett, Rob; Burns, Thomas; Cushing, Judy; Glynn, Mary Ellen; Kruse, Senator Jeff; Millet, Lisa M; Shames, Jim

    2015-01-01

    Governor John Kitzhaber appointed a Prescription Drug Taskforce to address Oregon's opioid epidemic. This case study reviews the Taskforce's participation in the National Governors Association State Policy Academy on Reducing Prescription Drug Abuse. To address the challenge of the misuse and abuse of prescription opioids, the Taskforce developed a strategy for practice change, community education and enhanced access to safe opioid disposal using stakeholder meetings, consensus development, and five action steps: (1) fewer pills in circulation, (2) educate prescribers and the public on the risks of opioid use, (3) foster safe disposal of unused medication, (4) provide treatment for opioid dependence, and (5) continued leadership from the Governor, health plans and health professionals. Although the story is ongoing, there are lessons for leadership in other states and for public health and medical practitioners throughout the country. PMID:25168199

  13. Lack of effect of chronic dextromethorphan on experimental pain tolerance in methadone-maintained patients.

    PubMed

    Compton, Peggy A; Ling, Walter; Torrington, Matt A

    2008-09-01

    Good evidence exists to suggest that individuals on opioid maintenance for the treatment of addiction (i.e. methadone) are less tolerant of experimental pain than are matched controls or ex-opioid addicts, a phenomenon theorized to reflect opioid-induced hyperalgesia (OIH). Agonist activity at the excitatory ionotropic N-methyl-D-aspartate (NMDA) receptor on dorsal horn neurons has been implicated in the development of both OIH and its putative expression at the clinical level-opioid tolerance. The aim of this study was to evaluate the potential utility of the NMDA-receptor antagonist, dextromethorphan (DEX), to reverse or treat OIH in methadone-maintenance (MM) patients. Utilizing a clinical trial design and double-blind conditions, changes in pain threshold and tolerance [cold pressor (CP) and electrical stimulation (ES)] following a 5-week trial of DEX (titrated to 480 mg/day) in comparison with placebo was evaluated in a well-characterized sample of MM patients. The sample (n = 40) was 53% male and ethnically diverse (53% Latino, 28% African American, 10% White, 9% other), with a mean age of 48.0 years (SD = 6.97). Based on t-test analyses, no difference was found between groups on CP pain threshold, CP pain tolerance, ES pain threshold or ES pain tolerance, both pre- and postmedication. Notably, DEX-related changes significantly differed by gender, with women tending to show diminished tolerance for pain with DEX therapy. These results support that chronic high-dose NMDA antagonism does not improve tolerance for pain in MM patients, although a gender effect on DEX response is suggested. PMID:18507735

  14. Proteomic Analysis of Anoxia Tolerance in the Developing Zebrafish Embryo

    PubMed Central

    Mendelsohn, Bryce A.; Malone, James P.; Townsend, R. Reid; Gitlin, Jonathan D.

    2009-01-01

    While some species and tissue types are injured by oxygen deprivation, anoxia tolerant organisms display a protective response that has not been fully elucidated and is well-suited to genomic and proteomic analysis. However, such methodologies have focused on transcriptional responses, prolonged anoxia, or have used cultured cells or isolated tissues. In this study of intact zebrafish embryos, a species capable of >24 h survival in anoxia, we have utilized 2D difference in gel electrophoresis to identify changes in the proteomic profile caused by near-lethal anoxic durations as well as acute anoxia (1 h), a timeframe relevant to ischemic events in human disease when response mechanisms are largely limited to post-transcriptional and post-translational processes. We observed a general stabilization of the proteome in anoxia. Proteins involved in oxidative phosphorylation, antioxidant defense, transcription, and translation changed over this time period. Among the largest proteomic alterations was that of muscle cofilin 2, implicating the regulation of the cytoskeleton and actin assembly in the adaptation to acute anoxia. These studies in an intact embryo highlight proteomic components of an adaptive response to anoxia in a model organism amenable to genetic analysis to permit further mechanistic insight into the phenomenon of anoxia tolerance. PMID:20403745

  15. Deficits in neuronal cytochrome P450 activity attenuate opioid analgesia but not opioid side effects.

    PubMed

    Hough, Lindsay B; Nalwalk, Julia W; Cleary, Rachel A; Phillips, James G; Fang, Cheng; Yang, Weizhu; Ding, Xinxin

    2014-10-01

    Morphine-like analgesics act on µ opioid receptors in the CNS to produce highly effective pain relief, but the same class of receptors also mediates non-therapeutic side effects. The analgesic properties of morphine were recently shown to require the activity of a brain neuronal cytochrome P450 epoxygenase, but the significance of this pathway for opioid side effects is unknown. Here we show that brain P450 activity is not required for three of morphine׳s major side effects (respiratory depression, constipation, and locomotor stimulation). Following systemic or intracerebroventricular administration of morphine, transgenic mice with brain neuron - specific reductions in P450 activity showed highly attenuated analgesic responses as compared with wild-type (control) mice. However, brain P450-deficient mice showed normal morphine-induced side effects (respiratory depression, locomotor stimulation, and inhibition of intestinal motility). Pretreatment of control mice with the P450 inhibitor CC12 similarly reduced the analgesia, but not these side effects of morphine. Because activation of brain µ opioid receptors produces both opioid analgesia and opioid side effects, dissociation of the mechanisms for the therapeutic and therapy-limiting effects of opioids has important consequences for the development of analgesics with reduced side effects and/or limited addiction liability. PMID:25062792

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

    PubMed Central

    Huber, Elizabeth; Robinson, Richard C.; Noe, Carl E.; Van Ness, Olivia

    2016-01-01

    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. PMID:27417617

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

    PubMed

    Huber, Elizabeth; Robinson, Richard C; Noe, Carl E; Van Ness, Olivia

    2016-01-01

    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. PMID:27417617

  18. Endogenous opioids and reward.

    PubMed

    Van Ree, J M; Niesink, R J; Van Wolfswinkel, L; Ramsey, N F; Kornet, M M; Van Furth, W R; Vanderschuren, L J; Gerrits, M A; Van den Berg, C L

    2000-09-29

    The discovery of endogenous opioids has markedly influenced the research on the biology of addiction and reward brain processes. Evidence has been presented that these brain substances modulate brain stimulation reward, self-administration of different drugs of abuse, sexual behaviour and social behaviour. There appears to be two different domains in which endogenous opioids, present in separate and distinct brain regions, are involved. One is related to the modulation of incentive motivational processes and the other to the performance of certain behaviours. It is concluded that endogenous opioids may play a role in the vulnerability to certain diseases, such as addiction and autism, but also when the disease is present, such as alcoholism. PMID:11033317

  19. Olea Europea-derived phenolic products attenuate antinociceptive morphine tolerance: an innovative strategic approach to treat cancer pain.

    PubMed

    Muscoli, C; Lauro, F; Dagostino, C; D'Agostino, C; Ilari, S; Giancotti, L A; Gliozzi, M; Costa, N; Carresi, C; Musolino, V; Casale, F; Ventrice, D; Oliverio, M; Oliverio, E; Palma, E; Nisticò, S; Nistico', S; Procopio, A; Rizzo, M; Mollace, V

    2014-01-01

    Morphine and related opioid drugs are currently the major drugs for severe pain. Their clinical utility is limited in the management of severe cancer pain due to the rapid development of tolerance. Restoring opioid efficacy is therefore of great clinical importance. A great body of evidence suggests the key role of free radicals and posttranslational modulation in the development of tolerance to the analgesic activity of morphine. Epidemiological studies have shown a relationship between the Mediterranean diet and a reduced incidence of pathologies such as coronary heart disease and cancer. A central hallmark of this diet is the high consumption of virgin olive oil as the main source of fat which contains antioxidant components in the non-saponifiable fraction, including phenolic compounds absent in seed oils. Here, we show that in a rodent model of opiate tolerance, removal of the free radicals with phenolic compounds of olive oil such as hydroxytyrosol and oleuropein reinstates the analgesic action of morphine. Chronic injection of morphine in mice led to the development of tolerance and this was associated with increased nitrotyrosin and malondialdehyde (MDA) formation together with nitration and deactivation of MnSOD in the spinal cord. Removal of free radicals by hydroxytyrosol and oleuropein blocked morphine tolerance by inhibiting nitration and MDA formation and replacing the MnSOD activity. The phenolic fraction of virgin olive oil exerts antioxidant activities in vivo and free radicals generation occurring during chronic morphine administration play a crucial role in the development of opioid tolerance. Our data suggest novel therapeutic approach in the management of chronic cancer pain, in particular for those patients who require long-term opioid treatment for pain relief without development of tolerance. PMID:24750796

  20. Effects of footshock stress and morphine on natural killer lymphocytes in rats: studies of tolerance and cross-tolerance.

    PubMed

    Shavit, Y; Terman, G W; Lewis, J W; Zane, C J; Gale, R P; Liebeskind, J C

    1986-05-01

    Exposure to a form of footshock stress known to cause opioid-mediated analgesia suppresses the cytotoxic activity of natural killer (NK) cells in rats. This suppression is blocked by the opioid antagonist, naltrexone and is mimicked by morphine administration, suggesting mediation by opioid receptors. Supporting this hypothesis, we now report that the morphine-induced suppression of NK activity shows tolerance after 14 daily injections. The NK-suppressive effect of stress, however, shows neither tolerance with repetition nor cross-tolerance in morphine-tolerant rats. PMID:3011211

  1. Development of Novel Glyphosate-Tolerant Japonica Rice Lines: A Step Toward Commercial Release.

    PubMed

    Cui, Ying; Huang, Shuqing; Liu, Ziduo; Yi, Shuyuan; Zhou, Fei; Chen, Hao; Lin, Yongjun

    2016-01-01

    Glyphosate is the most widely used herbicide for its low cost and high efficiency. However, it is rarely applied directly in rice field due to its toxicity to rice. Therefore, glyphosate-tolerant rice can greatly decrease the cost of rice production and provide a more effective weed management strategy. Although, several approaches to develop transgenic rice with glyphosate tolerance have been reported, the agronomic performances of these plants have not been well evaluated, and the feasibility of commercial production has not been confirmed yet. Here, a novel glyphosate-tolerant gene cloned from the bacterium Isoptericola variabilis was identified, codon optimized (designated as I. variabilis-EPSPS (*)), and transferred into Zhonghua11, a widely used japonica rice cultivar. After systematic analysis of the transgene integration via PCR, Southern blot and flanking sequence isolation, three transgenic lines with only one intact I. variabilis-EPSPS (*) expression cassette integrated into intergenic regions were identified. Seed test results showed that the glyphosate tolerance of the transgenic rice was about 240 times that of wild type on plant medium. The glyphosate tolerance of transgenic rice lines was further evaluated based on comprehensive agronomic performances in the field with T3 and T5generations in a 2-year assay, which showed that they were rarely affected by glyphosate even when the dosage was 8400 g ha(-1). To our knowledge, this is the first demonstration of the development of glyphosate-tolerant rice lines based on a comprehensive analysis of agronomic performances in the field. Taken together, the results suggest that the selected glyphosate-tolerant rice lines are highly tolerant to glyphosate and have the possibility of commercial release. I. variabilis-EPSPS (*) also can be a promising candidate gene in other species for developing glyphosate-tolerant crops. PMID:27625652

  2. Development of Novel Glyphosate-Tolerant Japonica Rice Lines: A Step Toward Commercial Release

    PubMed Central

    Cui, Ying; Huang, Shuqing; Liu, Ziduo; Yi, Shuyuan; Zhou, Fei; Chen, Hao; Lin, Yongjun

    2016-01-01

    Glyphosate is the most widely used herbicide for its low cost and high efficiency. However, it is rarely applied directly in rice field due to its toxicity to rice. Therefore, glyphosate-tolerant rice can greatly decrease the cost of rice production and provide a more effective weed management strategy. Although, several approaches to develop transgenic rice with glyphosate tolerance have been reported, the agronomic performances of these plants have not been well evaluated, and the feasibility of commercial production has not been confirmed yet. Here, a novel glyphosate-tolerant gene cloned from the bacterium Isoptericola variabilis was identified, codon optimized (designated as I. variabilis-EPSPS*), and transferred into Zhonghua11, a widely used japonica rice cultivar. After systematic analysis of the transgene integration via PCR, Southern blot and flanking sequence isolation, three transgenic lines with only one intact I. variabilis-EPSPS* expression cassette integrated into intergenic regions were identified. Seed test results showed that the glyphosate tolerance of the transgenic rice was about 240 times that of wild type on plant medium. The glyphosate tolerance of transgenic rice lines was further evaluated based on comprehensive agronomic performances in the field with T3 and T5generations in a 2-year assay, which showed that they were rarely affected by glyphosate even when the dosage was 8400 g ha−1. To our knowledge, this is the first demonstration of the development of glyphosate-tolerant rice lines based on a comprehensive analysis of agronomic performances in the field. Taken together, the results suggest that the selected glyphosate-tolerant rice lines are highly tolerant to glyphosate and have the possibility of commercial release. I. variabilis-EPSPS* also can be a promising candidate gene in other species for developing glyphosate-tolerant crops. PMID:27625652

  3. Clinical pharmacokinetics of transdermal opioids: focus on transdermal fentanyl.

    PubMed

    Grond, S; Radbruch, L; Lehmann, K A

    2000-01-01

    Transdermal delivery allows continuous systemic application of opioids through the intact skin. This review analyses the pharmacokinetic properties of transdermal opioid administration in the context of clinical experience, with a focus on fentanyl. A transdermal therapeutic system (TTS) for fentanyl has been developed. The amount of fentanyl released is proportional to the surface area of the TTS, which is available in different sizes. After the first application of a TTS, a fentanyl depot concentrates in the upper skin layers and it takes several hours until clinical effects are observed. The time from application to minimal effective and maximum serum concentrations is 1.2 to 40 hours and 12 to 48 hours, respectively. Steady state is reached on the third day, and can be maintained as long as patches are renewed. Within each 72-hour period, serum concentrations decrease gradually over the second and third days. When a TTS is removed, fentanyl continues to be absorbed into the systemic circulation from the cutaneous depot. The terminal half-life for TTS fentanyl is approximately 13 to 25 hours. The interindividual variability of serum concentrations, partly caused by different clearance rates, is markedly larger than the intraindividual variability. The effectiveness of TTS fentanyl was first demonstrated in acute postoperative pain. However, the slow pharmacokinetics and large variability of TTS fentanyl, together with the relatively short duration of postoperative pain, precluded adequate dose finding and led to inadequate pain relief or, especially, a high incidence of respiratory depression; such use is now contraindicated. Conversely, in cancer pain, TTS fentanyl offers an interesting alternative to oral morphine, and its effectiveness and tolerability in this indication has been demonstrated by a number of trials. Its usefulness in chronic pain of nonmalignant origin remains to be confirmed in controlled trials. In general, TTS fentanyl produces the same

  4. Co-development of early adolescent alcohol use and depressive feelings: The role of the mu-opioid receptor A118G polymorphism.

    PubMed

    Kleinjan, Marloes; Rozing, Mayke; Engels, Rutger C M E; Verhagen, Maaike

    2015-08-01

    Alcohol use and depressive feelings are often related among early adolescents. However, the nature and underlying mechanisms of this association are not yet clear. The aim of this study was to investigate the co-development of alcohol use and depressive feelings over time and to examine the effects of the mu-opioid receptor (OPRM1) A118G genotype on such co-development. Data from a five-wave longitudinal, genetically informed survey study, with intervals of 4 months among a group of 739 normative early adolescents (12-13 years of age at baseline), were analyzed using a dual latent growth curve approach. OPRM1 status was evaluated from saliva-derived DNA samples. The results indicated a positive association between alcohol use and depressive feelings both at the initial levels and over time, indicating co-development in early adolescence. Compared to OPRM1 118G carriers, homozygous 118A carriers showed a greater increase in frequency of alcohol use and higher levels of depressive feelings over time. Evidence for co-development was only found within the group of homozygous 118A carriers, whereas in OPRM1 118G carriers the development of alcohol use and depressive feelings over time were not significantly associated. These results highlight the potential of OPRM1 as a common etiological factor for the development of alcohol use and depressive feelings in early adolescence. PMID:25215437

  5. Tobacco/Nicotine and Endogenous Brain Opioids

    PubMed Central

    Xue, Yue; Domino, Edward F.

    2008-01-01

    Smoking is a major public health problem with devastating health consequences. Although many cigarette smokers are able to quit, equal numbers of others cannot! Standard medications to assist in smoking cessation, such as nicotine replacement therapies and bupropion, are ineffective in many remaining smokers. Recent developments in the neurobiology of nicotine dependence have identified several neurotransmitter systems that may contribute to the process of smoking maintenance and relapse. These include: especially dopamine, but also norepinephrine, 5-hydroxytryptamine, acetylcholine, endogenous opioids, gamma-aminobutyric acid (GABA), glutamate, and endocannabinoids. The present review examines the limited contribution of the endogenous opioid system to the complex effects of nicotine/tobacco smoking. PMID:18215788

  6. Sex differences in the development of airway epithelial tolerance to naphthalene

    PubMed Central

    Sutherland, K. M.; Edwards, P. C.; Combs, T. J.

    2012-01-01

    Exposure to air pollution has been linked to pulmonary diseases. Naphthalene (NA), an abundant polycyclic aromatic hydrocarbon in tobacco smoke and urban air, is a model toxicant for air pollution effects in the lung. Repeated exposures to NA in male mice result in tolerance, defined as the emergence of a resistant cell phenotype after prior exposure. Tolerance has not been studied in females. Females have sex differences in airway epithelial responses and in the prevalence of certain airway diseases. Male and female mice were exposed to a tolerance-inducing regimen of NA, and lungs were examined by airway level to characterize the cellular changes associated with repeated NA exposure and to assess the expression of genes and proteins involved in NA bioactivation and detoxification. The airway epithelium in treated males resembled that of controls. Females in the tolerant state were characterized by dense populations of ciliated cells in midlevel, distal, and bifurcating airways and a lower abundance of Clara cells at all airway levels. Cytotoxicity following a secondary challenge dose was also greater in females than males. Furthermore, females had decreased gene/protein expression of CYP2F2, a P-450 that metabolizes NA to a toxic epoxide, and glutamate-cysteine ligase, the rate-limiting enzyme in glutathione synthesis, than NA-tolerant males at all airway levels examined. We conclude that, while females develop tolerance, sex differences exist in the tolerant state by airway level, and females remain more susceptible than males to repeated exposures to NA. PMID:22003090

  7. Opioid-induced constipation.

    PubMed

    Gyawali, Bishal; Hayashi, Naomi; Tsukuura, Hiroaki; Honda, Kazunori; Shimokata, Tomoya; Ando, Yuichi

    2015-01-01

    Opioid-induced constipation (OIC) is a very troublesome, difficult to manage and a nearly universal complication of chronic opioid use to control pain associated with advanced illness. Some studies have reported that OIC is so intolerable in some patients that they skip their opioid medications and bear pain instead of OIC. Laxatives have commonly been used as a prophylaxis and treatment of OIC but they are frequently ineffective because the commonly available laxatives do not target the underlying mechanism of OIC, which is the blockade of peripheral mu-receptors. Recently, there have been a number of advances in the treatment of OIC, which any physician involved with opioid-prescribing discipline should be aware of. This review will update the new options and strategies available for treating OIC along with the relevant clinical trials. Finally, this review also provides a recommendation on the preferred way to approach a patient with OIC in the modern era as well as highlight on the importance of doctor-patient communication in this setting. PMID:26061717

  8. Treating Pain with Opioids

    MedlinePlus

    ... it costs. Ask if they have a drug discount program that can help you pay less for your medicine. Buy your medicine from the pharmacy that gives you the cheapest price.  Sign up for patient assistance programs: Most companies that make medicines have programs that Opioids: Howhaerleptpheeoypulesetdh? ...

  9. Opioid Antagonist Impedes Exposure.

    ERIC Educational Resources Information Center

    Merluzzi, Thomas V.; And Others

    1991-01-01

    Thirty spider-phobic adults underwent exposure to 17 phobic-related, graded performance tests. Fifteen subjects were assigned to naltrexone, an opioid antagonist, and 15 were assigned to placebo. Naltrexone had a significant effect on exposure, with naltrexone subjects taking significantly longer to complete first 10 steps of exposure and with…

  10. Pharmacotherapy of Pain in the Older Population: The Place of Opioids

    PubMed Central

    Prostran, Milica; Vujović, Katarina Savić; Vučković, Sonja; Medić, Branislava; Srebro, Dragana; Divac, Nevena; Stojanović, Radan; Vujović, Aleksandar; Jovanović, Lepa; Jotić, Ana; Cerovac, Nataša

    2016-01-01

    Pain is a common symptom in older people. It is possible that pain is underreported in older persons due to an incorrect belief that it is an inevitable part of aging. Opioid analgesics are potent medications, with confirmed efficacy for the treatment of moderate to severe pain. These drugs are commonly used in older persons. However, there is insufficient evidence regarding safety of opioids in older patients. One of the reasons for this is the lack of randomized, controlled clinical trials. People of advanced age often have comorbidites and use other prescription drugs, as well as over-the-counter (OTC) compounds, thus making them more suceptible to the risk of interactions with opioids. Significant pharmacokinetic and pharmacodynamic changes that occur with advancing age increase the risk of adverse effects of opioids. There are also some discrepancies between guidelines, which recommend the use of lower doses of opioids in older patients, and the findings in the literature which suggest that pain is often undertreated in this age group. It seems that there are significant variations in the tolerability of different opioid analgesics in older people. Morphine, fentanyl, oxycodone, and buprenorphine are still the preferred evidence-based choices for add-on opioid therapy for these patients. However, the safety and efficacy of other opioids in older patients, especially if comorbidities and polypharmacy are present, is still questionable. This review addresses the most important aspects of the use of opioids in older persons, focusing on pharmacokinetics, pharmacodynamics, adverse effects, and interactions. PMID:27378916

  11. Pharmacotherapy of Pain in the Older Population: The Place of Opioids.

    PubMed

    Prostran, Milica; Vujović, Katarina Savić; Vučković, Sonja; Medić, Branislava; Srebro, Dragana; Divac, Nevena; Stojanović, Radan; Vujović, Aleksandar; Jovanović, Lepa; Jotić, Ana; Cerovac, Nataša

    2016-01-01

    Pain is a common symptom in older people. It is possible that pain is underreported in older persons due to an incorrect belief that it is an inevitable part of aging. Opioid analgesics are potent medications, with confirmed efficacy for the treatment of moderate to severe pain. These drugs are commonly used in older persons. However, there is insufficient evidence regarding safety of opioids in older patients. One of the reasons for this is the lack of randomized, controlled clinical trials. People of advanced age often have comorbidites and use other prescription drugs, as well as over-the-counter (OTC) compounds, thus making them more suceptible to the risk of interactions with opioids. Significant pharmacokinetic and pharmacodynamic changes that occur with advancing age increase the risk of adverse effects of opioids. There are also some discrepancies between guidelines, which recommend the use of lower doses of opioids in older patients, and the findings in the literature which suggest that pain is often undertreated in this age group. It seems that there are significant variations in the tolerability of different opioid analgesics in older people. Morphine, fentanyl, oxycodone, and buprenorphine are still the preferred evidence-based choices for add-on opioid therapy for these patients. However, the safety and efficacy of other opioids in older patients, especially if comorbidities and polypharmacy are present, is still questionable. This review addresses the most important aspects of the use of opioids in older persons, focusing on pharmacokinetics, pharmacodynamics, adverse effects, and interactions. PMID:27378916

  12. Overview of the U.S. DOE Accident Tolerant Fuel Development Program

    SciTech Connect

    Jon Carmack; Frank Goldner; Shannon M. Bragg-Sitton; Lance L. Snead

    2013-09-01

    The United States Fuel Cycle Research and Development Advanced Fuels Campaign has been given the responsibility to conduct research and development on enhanced accident tolerant fuels with the goal of performing a lead test assembly or lead test rod irradiation in a commercial reactor by 2022. The Advanced Fuels Campaign has defined fuels with enhanced accident tolerance as those that, in comparison with the standard UO2-Zircaloy system currently used by the nuclear industry, can tolerate loss of active cooling in the reactor core for a considerably longer time period (depending on the LWR system and accident scenario) while maintaining or improving the fuel performance during normal operations and operational transients, as well as design-basis and beyond design-basis events. This paper provides an overview of the FCRD Accident Tolerant Fuel program. The ATF attributes will be presented and discussed. Attributes identified as potentially important to enhance accident tolerance include reduced hydrogen generation (resulting from cladding oxidation), enhanced fission product retention under severe accident conditions, reduced cladding reaction with high-temperature steam, and improved fuel-cladding interaction for enhanced performance under extreme conditions. To demonstrate the enhanced accident tolerance of candidate fuel designs, metrics must be developed and evaluated using a combination of design features for a given LWR design, potential improvements to that design, and the design of an advanced fuel/cladding system. The aforementioned attributes provide qualitative guidance for parameters that will be considered for fuels with enhanced accident tolerance. It may be unnecessary to improve in all attributes and it is likely that some attributes or combination of attributes provide meaningful gains in accident tolerance, while others may provide only marginal benefits. Thus, an initial step in program implementation will be the development of quantitative

  13. Improved detection of opioid use in chronic pain patients through monitoring of opioid glucuronides in urine.

    PubMed

    Dickerson, Jane A; Laha, Thomas J; Pagano, Monica B; O'Donnell, Brendan R; Hoofnagle, Andrew N

    2012-10-01

    When chronic pain patients are suspected of being non-compliant, their therapy can be withdrawn. Therefore, sensitive and specific confirmatory testing is important for identifying diversion and adherence. This work aimed to develop a novel liquid chromatography tandem mass spectrometry (LC-MS-MS) method to detect 14 opioids and six opioid glucuronide metabolites in urine with minimal sample preparation. Analytes included were morphine, oxymorphone, hydromorphone, oxycodone, hydrocodone, codeine, fentanyl, norfentanyl, 6-monoacetylmorphine, meperidine, normeperidine, propoxyphene, methadone, buprenorphine, morphine-3-glucuronide, morphine-6-glucuronide, oxymorphone glucuronide, hydromorphone glucuronide, codeine-6-glucuronide and norbuprenorphine glucuronide. Samples were processed by centrifugation and diluted in equal volume with a deuterated internal standard containing 14 opioids and four opioid glucuronides. The separation of all compounds was complete in nine minutes. The assay was linear between 10 and 1,000 ng/mL (fentanyl 0.25-25 ng/mL). Intra-assay imprecision (500 ng/mL, fentanyl 12.5 ng/mL) ranged from 1.0 to 8.4% coefficient of variation. Inter-assay precision ranged from 2.9 to 6.0%. Recovery was determined by spiking five patient specimens with opioid and opioid glucuronide standards at 100 ng/mL (fentanyl 2.5 ng/mL). Recoveries ranged from 82 to 107% (median 98.9%). The method correlated with our current quantitative LC-MS-MS assay for opioids, which employs different chromatography. Internal standards were not available for every analyte to critically evaluate for ion suppression. Instead, a novel approach was designed to achieve the most rigorous quality control possible, in which the recovery of each analyte was evaluated in each negative sample. PMID:22833646

  14. Combination of cell culture assays and knockout mouse analyses for the study of opioid partial agonism.

    PubMed

    Ide, Soichiro; Minami, Masabumi; Sora, Ichiro; Ikeda, Kazutaka

    2010-01-01

    Nonselective opioid partial agonists, such as buprenorphine, butorphanol, and pentazocine, have been widely used as analgesics and for anti-addiction therapy. However, the precise molecular mechanisms underlying the therapeutic and rewarding effects of these drugs have not been clearly delineated. Recent success in developing mu-opioid receptor knockout (MOP-KO) mice has elucidated the molecular mechanisms underlying the effects of morphine and other opioids. We have revealed the in vivo roles of MOPs in the effects of opioid partial agonists by using MOP-KO mice for behavioral tests (e.g., several kinds of antinociceptive tests for analgesic effects, conditioned place preference test for dependence). The combination of the cell culture assays using cDNA for mu, delta, and kappa opioid receptors and the behavioral tests using MOP-KO mice has provided novel theories on the molecular mechanisms underlying the effects of opioid ligands, especially opioid partial agonists. PMID:20336435

  15. The competitive N-methyl-D-aspartate receptor antagonist (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959) potentiates the antinociceptive effects of opioids that vary in efficacy at the mu-opioid receptor.

    PubMed

    Allen, Richard M; Granger, Arthur L; Dykstra, Linda A

    2003-11-01

    (-)-6-Phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959) is a competitive N-methyl-D-aspartate receptor antagonist shown to prevent the development of tolerance to the antinociceptive effects of morphine in rodents. Although administration of LY235959 alone generally does not produce antinociception, LY235959 potentiates the antinociceptive effects of morphine in squirrel monkeys. The present study was designed to determine whether LY235959 would potentiate the acute antinociceptive effects of morphine as well those of the opioid receptor agonists l-methadone, levorphanol, butorphanol, and buprenorphine. A squirrel monkey titration procedure was used in which shock (delivered to the tail) increased in intensity every 15 s (0.01-2.0 mA) in 30 increments. Five lever presses during any given 15-s shock period (fixed ratio 5) produced a 15-s shock-free period after which shock resumed at the next lower intensity. Morphine (0.3-3.0 mg/kg i.m.), l-methadone (0.1-0.56 mg/kg i.m.), levorphanol (0.1-1.0 mg/kg i.m.), butorphanol (1.0-10 mg/kg i.m.), and buprenorphine (0.01-0.03 mg/kg i.m.), but not LY235959 (0.1-1.0 mg/kg i.m.), dose and time dependently increased the intensity below which monkeys maintained shock 50% of the time (median shock level, MSL). LY235959 dose dependently potentiated the effect of each opioid agonist on MSL when concurrently administered to monkeys. Although LY235959 potentiated the antinociceptive effect of each opioid examined in a statistically significant manner, LY235959 seemed more potent and effective when combined with higher efficacy opioids. The present data suggest that the N-methyl-D-aspartate antagonist, LY235959, can potentiate the antinociceptive effects of a range of opioid receptor agonists independently of nonspecific motor effects. PMID:12975489

  16. Tolerance to Isoflurane Does Not Occur in Developing Xenopus laevis Tadpoles

    PubMed Central

    Milutinovic, Pavle S.; Zhao, Jing

    2009-01-01

    Introduction Tolerance is observed for a variety of central nervous system depressants including ethanol, which is an anesthetic, but has not been convincingly demonstrated for a potent halogenated volatile anesthetic. Failure to demonstrate tolerance to these agents may be the result of inadequate exposure to anesthetic. In this study, we exposed Xenopus laevis tadpoles to surgical anesthetic concentrations of isoflurane for one week. Methods Xenopus laevis tadpoles were produced by in vitro fertilization, and exposed to isoflurane (0.59%, 0.98%, 1.52%) or oxygen for one week starting from the time of fertilization. Results Changes in anesthetic EC50 were small and not in a consistent direction. Control animals had an anesthetic EC50 of 0.594% ± 0.003% isoflurane. Tadpoles exposed to 1.52% isoflurane had a lower EC50 than controls (by 16%), while tadpoles raised under 0.59 and 0.98% isoflurane had higher EC50s than control (by 4.7% and 7.4%, respectively). Conclusion We provide the first description of week-long exposures of vertebrates to surgical anesthetic concentrations of isoflurane, and the first report of such exposures in developing vertebrates. Tolerance to isoflurane does not occur in developing Xenopus laevis tadpoles. Taken together with studies in other organisms, the development of tolerance to ethanol but not isoflurane suggests that mechanisms these drugs share probably do not account for the development of tolerance. PMID:19095846

  17. Pharmaceutical opioids in the home and youth: implications for adult medical practice

    PubMed Central

    Binswanger, Ingrid A.; Glanz, Jason M.

    2015-01-01

    Pharmaceutical opioid prescribing, opioid use disorders, and related poisonings have increased substantially in the last decade. In particular, pharmaceutical opioid deaths among youth have markedly increased. One area that has received relatively little attention is the role of home safety, given that parents are an important source of opioids for youth. Parents may intentionally share opioids with youth, due to low perceived risks or limited knowledge, and youth may divert opioids from parents’ medicine cabinets. Safe medication storage has long been mandated by treatment programs that provide pharmacologically supported treatment of opioid use disorders, but it is not generally encouraged or required for pharmaceutical opioids prescribed for pain. Greater attention is needed on the development, evaluation and implementation of three preventive strategies. These three strategies can be delivered in or supported by adult medical practices: 1) fully informing adults prescribed opioids about the risks of opioids to family members and others; 2) providing locked medication safe storage devices; and 3) educating parents on safe disposal options. However, a critical evidence base is still lacking for these opioid safety interventions. PMID:25671706

  18. Opioids: The Prescription Drug & Heroin Overdose Epidemic

    MedlinePlus

    ... Resources Law Enforcement Resources Opioids: The Prescription Drug & Heroin Overdose Epidemic Opioids are natural or synthetic chemicals ... in your brain or body. Common opioids include heroin and prescription drugs such as oxycodone, hydrocodone, and ...

  19. Treating Chronic Pain with Opioids: Comparing Effectiveness and Cost

    MedlinePlus

    Treating Chronic Pain with Opioids: Comparing Effectiveness and Cost What are opioids? Opioids are very strong prescription ... using opioids. We compared the effectiveness, safety, and cost of different opioids. We chose these as Consumer ...

  20. Opioid-Induced Androgen Deficiency (OPIAD): Diagnosis, Management, and Literature Review.

    PubMed

    O'Rourke, Timothy K; Wosnitzer, Matthew S

    2016-10-01

    Opioid-induced androgen deficiency (OPIAD) was initially recognized as a possible consequence of opioid use roughly four decades ago. Long-acting opioid use carries risks of addiction, tolerance, and systemic side effects including hypogonadotropic hypogonadism with consequent testosterone depletion leading to multiple central and peripheral effects. Hypogonadism is induced through direct inhibitory action of opioids on receptors within the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes as well as testosterone production within the testes. Few studies have systematically investigated hormonal changes induced by long-term opioid administration or the effects of testosterone replacement therapy (TRT) in patients with OPIAD. Clomiphene citrate, a selective estrogen receptor modulator (SERM), is a testosterone enhancement treatment which upregulates endogenous hypothalamic function. This review will focus on the pathophysiology, diagnosis, and management of OPIAD, including summary of literature evaluating OPIAD treatment with TRT, and areas of future investigation. PMID:27586511

  1. Prospects for Creation of Cardioprotective and Antiarrhythmic Drugs Based on Opioid Receptor Agonists.

    PubMed

    Maslov, Leonid N; Khaliulin, Igor; Oeltgen, Peter R; Naryzhnaya, Natalia V; Pei, Jian-Ming; Brown, Stephen A; Lishmanov, Yury B; Downey, James M

    2016-09-01

    It has now been demonstrated that the μ, δ1 , δ2 , and κ1 opioid receptor (OR) agonists represent the most promising group of opioids for the creation of drugs enhancing cardiac tolerance to the detrimental effects of ischemia/reperfusion (I/R). Opioids are able to prevent necrosis and apoptosis of cardiomyocytes during I/R and improve cardiac contractility in the reperfusion period. The OR agonists exert an infarct-reducing effect with prophylactic administration and prevent reperfusion-induced cardiomyocyte death when ischemic injury of heart has already occurred; that is, opioids can mimic preconditioning and postconditioning phenomena. Furthermore, opioids are also effective in preventing ischemia-induced arrhythmias. PMID:27197922

  2. Oligodendrocyte Responses to Buprenorphine Uncover Novel and Opposing Roles of μ-Opioid- and Nociceptin/Orphanin FQ Receptors in Cell Development: Implications for Drug Addiction Treatment During Pregnancy

    PubMed Central

    Eschenroeder, Andrew C.; Vestal-Laborde, Allison A.; Sanchez, Emilse S.; Robinson, Susan E.; Sato-Bigbee, Carmen

    2011-01-01

    While the classical function of myelin is the facilitation of saltatory conduction, this membrane and the oligodendrocytes, the cells that make myelin in the central nervous system (CNS), are now recognized as important regulators of plasticity and remodeling in the developing brain. As such, oligodendrocyte maturation and myelination are among the most vulnerable processes along CNS development. We have shown previously that rat brain myelination is significantly altered by buprenorphine, an opioid analogue currently used in clinical trials for managing pregnant opioid addicts. Perinatal exposure to low levels of this drug induced accelerated and increased expression of myelin basic proteins (MBPs), cellular and myelin components that are markers of mature oligodendrocytes. In contrast, supra-therapeutic drug doses delayed MBP brain expression and resulted in a decreased number of myelinated axons. We have now found that this biphasic-dose response to buprenorphine can be attributed to the participation of both the μ-opioid receptor (MOR) and the nociceptin/orphanin FQ receptor (NOP receptor) in the oligodendrocytes. This is particularly intriguing because the NOP receptor/nociceptin system has been primarily linked to behavior and pain regulation, but a role in CNS development or myelination has not been described before. Our findings suggest that balance between signaling mediated by (a) MOR activation and (b) a novel, yet unidentified pathway that includes the NOP receptor, plays a crucial role in the timing of oligodendrocyte maturation and myelin synthesis. Moreover, exposure to opioids could disrupt the normal interplay between these two systems altering the developmental pattern of brain myelination. PMID:22002899

  3. Oligodendrocyte responses to buprenorphine uncover novel and opposing roles of μ-opioid- and nociceptin/orphanin FQ receptors in cell development: implications for drug addiction treatment during pregnancy.

    PubMed

    Eschenroeder, Andrew C; Vestal-Laborde, Allison A; Sanchez, Emilse S; Robinson, Susan E; Sato-Bigbee, Carmen

    2012-01-01

    Although the classical function of myelin is the facilitation of saltatory conduction, this membrane and the oligodendrocytes, the cells that make myelin in the central nervous system (CNS), are now recognized as important regulators of plasticity and remodeling in the developing brain. As such, oligodendrocyte maturation and myelination are among the most vulnerable processes along CNS development. We have shown previously that rat brain myelination is significantly altered by buprenorphine, an opioid analogue currently used in clinical trials for managing pregnant opioid addicts. Perinatal exposure to low levels of this drug induced accelerated and increased expression of myelin basic proteins (MBPs), cellular and myelin components that are markers of mature oligodendrocytes. In contrast, supra-therapeutic drug doses delayed MBP brain expression and resulted in a decreased number of myelinated axons. We have now found that this biphasic-dose response to buprenorphine can be attributed to the participation of both the μ-opioid receptor (MOR) and the nociceptin/orphanin FQ receptor (NOP receptor) in the oligodendrocytes. This is particularly intriguing because the NOP receptor/nociceptin system has been primarily linked to behavior and pain regulation, but a role in CNS development or myelination has not been described before. Our findings suggest that balance between signaling mediated by (a) MOR activation and (b) a novel, yet unidentified pathway that includes the NOP receptor, plays a crucial role in the timing of oligodendrocyte maturation and myelin synthesis. Moreover, exposure to opioids could disrupt the normal interplay between these two systems altering the developmental pattern of brain myelination. PMID:22002899

  4. Combating an Epidemic of Prescription Opioid Abuse.

    PubMed

    Pon, Doreen; Awuah, Kwaku; Curi, Danielle; Okyere, Ernest; Stern, Craig S

    2015-11-01

    The past decade has witnessed an alarming increase in the number of deaths due to prescription opioids that has paralleled the rise in the number of opioid prescriptions dispensed. Prescription drug monitoring programs, abuse-deterrent formulations and proper disposal of opioids have been promoted to help combat the opioid epidemic. We discuss changes that dentists, the third most frequent prescribers of opioids, can implement to help reduce the risk of prescription opioid abuse in their communities. PMID:26798885

  5. Synthesis and biological activity of small peptides as NOP and opioid receptors' ligands: view on current developments.

    PubMed

    Naydenova, Emilia; Todorov, Petar; Zamfirova, Rositza

    2015-01-01

    The heptadecapeptide nociceptin, also called orphanin FQ (N/OFQ), is the endogenous agonist of the N/OFQ peptide receptor (NOP receptor) and is involved in several central nervous system pathways, such as nociception, reward, tolerance, and feeding. The discovery of small molecule ligands for NOP is being actively pursued for several therapeutic applications. This review presents overview of the several recently reported NOP ligands (agonists and antagonists), with an emphasis of the structural features that may be important for modulating the intrinsic activity of these ligands. In addition, a brief account on the characterization of newly synthesized ligands of NOP receptor with aminophosphonate moiety and β-tryptophan analogues will be presented. PMID:25677770

  6. Opioid-induced secondary adrenal insufficiency presenting as hypercalcaemia

    PubMed Central

    Lee, Angela S

    2015-01-01

    Summary Adrenal insufficiency is a rare cause of hypercalcaemia and should be considered when more common causes such as primary hyperparathyroidism and malignancy are excluded. Opioid therapy as a cause of adrenal insufficiency is a possibly under-recognised endocrinopathy with potentially life-threatening adverse effects. We report on a case of opioid-induced secondary adrenal insufficiency presenting as hypercalcaemia. The patient was a 25-year-old man who developed hypercalcaemia during the recovery stage after a period of critical illness. Systematic investigation of his hypercalcaemia found it to be due to secondary adrenal insufficiency, developing as a consequence of methadone opioid analgesia. Treatment with i.v. saline and subsequent glucocorticoid replacement led to resolution of the hypercalcaemia. The hypoadrenalism resolved when opioids were subsequently weaned and ceased. These two interacting endocrinopathies of opioid-induced adrenal insufficiency and consequent hypercalcaemia highlight the importance of maintaining awareness of the potentially serious adverse clinical outcomes which can occur as a result of opioids, particularly considering that symptoms of hypoadrenalism can overlap with those of concomitant illness. Treatment with hydration and glucocorticoid replacement is effective in promptly resolving the hypercalcaemia due to hypoadrenalism. Hypoadrenalism due to prescribed and recreational opioids may be more common than is currently recognised. Learning points Opioid therapy can cause clinically significant secondary adrenal insufficiency, and this may be more common than is currently recognised.Adrenal insufficiency is reversible after discontinuation of the opioid therapy.Hypercalcaemia can occur as a consequence of adrenal insufficiency, and may be the presenting feature.Treatment of hypercalcaemia due to adrenal insufficiency involves i.v. saline and glucocorticoid replacement. PMID:26161260

  7. Pain sensitivity and opioid analgesia: a pharmacogenomic twin study.

    PubMed

    Angst, Martin S; Phillips, Nicholas G; Drover, David R; Tingle, Martha; Ray, Amrita; Swan, Gary E; Lazzeroni, Laura C; Clark, J David

    2012-07-01

    Opioids are the cornerstone medication for the management of moderate to severe pain. Unfortunately, vast inter-individual differences in dose requirements complicate their effective and safe clinical use. Mechanisms underlying such differences are incompletely understood, are likely multifactorial, and include genetic and environmental contributions. While accumulating evidence suggests that variants of several genes account for some of the observed response variance, the relative contribution of these factors remains unknown. This study used a twin paradigm to provide a global estimate of the genetic and environmental contributions to inter-individual differences in pain sensitivity and analgesic opioid effects. Eighty one monozygotic and 31 dizygotic twin pairs successfully underwent a computer-controlled infusion with the μ-opioid agonist alfentanil in a single occasion, randomized, double-blind and placebo-controlled study design. Pain sensitivity and analgesic effects were assessed with experimental heat and cold pressor pain models along with important covariates including demographic factors, depression, anxiety, and sleep quality. Significant heritability was detected for cold pressor pain tolerance and opioid-mediated elevations in heat and cold pressor pain thresholds. Genetic effects accounted for 12-60% of the observed response variance. Significant familial effects accounting for 24-32% of observed variance were detected for heat and cold pressor pain thresholds and opioid-mediated elevation in cold pressor pain tolerance. Significant covariates included age, gender, race, education, and anxiety. Results provide a strong rationale for more detailed molecular genetic studies to elucidate mechanisms underlying inter-individual differences in pain sensitivity and analgesic opioid responses. Such studies will require careful consideration of the studied pain phenotype. PMID:22444188

  8. Prescription Opioid Abuse: Challenges and Opportunities for Payers

    PubMed Central

    Katz, Nathaniel P.; Birnbaum, Howard; Brennan, Michael J.; Freedman, John D.; Gilmore, Gary P.; Jay, Dennis; Kenna, George A.; Madras, Bertha K.; McElhaney, Lisa; Weiss, Roger D.; White, Alan G.

    2013-01-01

    Objective Prescription opioid abuse and addiction are serious problems with growing societal and medical costs, resulting in billions of dollars of excess costs to private and governmental health insurers annually. Though difficult to accurately assess, prescription opioid abuse also leads to increased insurance costs in the form of property and liability claims, and costs to state and local governments for judicial, emergency, and social services. This manuscript’s objective is to provide payers with strategies to control these costs, while supporting safe use of prescription opioid medications for patients with chronic pain. Method A Tufts Health Care Institute Program on Opioid Risk Management meeting was convened in June 2010 with private and public payer representatives, public health and law enforcement officials, pain specialists, and other stakeholders to present research, and develop recommendations on solutions that payers might implement to combat this problem. Results While protecting access to prescription opioids for patients with pain, private and public payers can implement strategies to mitigate financial risks associated with opioid abuse, using internal strategies, such as formulary controls, claims data surveillance, and claims matching; and external policies and procedures that support and educate physicians on reducing opioid risks among patients with chronic pain. Conclusion Reimbursement policies, incentives, and health technology systems that encourage physicians to use universal precautions, to consult prescription monitoring program (PMP) data, and to implement Screening, Brief Intervention, and Referral to6Treatment protocols, have a high potential to reduce insurer risks while addressing a serious public health problem. PMID:23725361

  9. Vermont responds to its opioid crisis.

    PubMed

    Simpatico, Thomas A

    2015-11-01

    Vermont is one of the more forward-thinking states in the nation with a history of taking groundbreaking approaches to complex social issues. In his Jan 8, 2014 State of the State Address, Vermont Governor Peter Shumlin announced that Vermont was in the midst of an opioid addiction epidemic. Though Vermont had called attention to its opioid crisis, it soon became clear that many other states shared this problem. Economic modeling of expanded access to maintenance therapy with either methadone or buprenorphine is felt to have "high value" because the added health care costs of treatment are offset by reductions in other health care costs that occur when individuals with opioid dependence begin treatment. Moreover, when broader societal costs such as criminal activity and work productivity are included, maintenance treatment is estimated to produce substantial overall savings. Coordinated efforts between the Vermont Department of Health's Division of Alcohol and Drug Abuse Programs (ADAP) and the Department of Vermont Health Access (DVHA-Vermont Medicaid Authority) have resulted in the creation of the Care Alliance for Opioid Addiction (or Hub & Spoke model). Vermont intends to develop a reproducible and exportable model based on cost effective, outcomes driven public policy. PMID:25869219

  10. Spatiotemporal control of opioid signaling and behavior

    PubMed Central

    Siuda, Edward R.; Copits, Bryan A.; Schmidt, Martin J.; Baird, Madison A.; Al-Hasani, Ream; Planer, William J.; Funderburk, Samuel C.; McCall, Jordan G.; Gereau, Robert W.; Bruchas, Michael R.

    2015-01-01

    Summary Optogenetics is now a widely accepted tool for spatiotemporal manipulation of neuronal activity. However, a majority of optogenetic approaches use binary on/off control schemes. Here we extend the optogenetic toolset by developing a neuromodulatory approach using a rationale-based design to generate a Gi-coupled, optically-sensitive, mu-opioid-like receptor, we term opto-MOR. We demonstrate that opto-MOR engages canonical mu-opioid signaling through inhibition of adenylyl cyclase, activation of MAPK and G protein-gated inward rectifying potassium (GIRK) channels, and internalizes with similar kinetics as the mu-opioid receptor. To assess in vivo utility we expressed a Cre-dependent viral opto-MOR in RMTg/VTA GABAergic neurons, which led to a real-time place preference. In contrast, expression of opto-MOR in GABAergic neurons of the ventral pallidum hedonic cold spot, led to real-time place aversion. This tool has generalizable application for spatiotemporal control of opioid signaling and, furthermore, can be used broadly for mimicking endogenous neuronal inhibition pathways. PMID:25937173

  11. Pneumococcal pneumonia suppresses allergy development but preserves respiratory tolerance in mice.

    PubMed

    Hartmann, Carolin; Behrendt, Ann-Kathrin; Henken, Stefanie; Wölbeling, Florian; Maus, Ulrich A; Hansen, Gesine

    2015-03-01

    Colonization with Streptococcus pneumoniae (S. pneumoniae) is associated with an increased risk for recurrent wheeze and asthma. Killed S. pneumoniae showed some potential as an effective immunomodulatory therapy in a murine model of asthma. Murine studies demonstrated protection against allergic asthma by symbiotic bacteria via triggering regulatory T cell response: treatment with killed S. pneumoniae resulted in suppressed levels of allergen-specific Th2 cytokines, while early immunization generated a protective Th1 response. We investigated the impact of lung infection with live S. pneumoniae on both the development and maintenance of allergic airway inflammation and respiratory tolerance in mice. BALB/c mice were infected intratracheally with S. pneumoniae either prior to or after tolerance or allergy were induced, using ovalbumin (OVA) as model allergen. Infection of mice with S. pneumoniae prior to sensitization or after manifestation of allergic airway inflammation suppressed the development of an allergic phenotype as judged by reduced eosinophil counts in bronchoalveolar lavage fluid, decreased IgE serum levels and Th2 cytokines, relative to non-infected allergic control mice. In contrast, infection of mice with S. pneumoniae after manifestation of allergic airway inflammation combined with late mucosal re-challenge did not affect the allergic response. Moreover, induction and maintenance of respiratory tolerance to OVA challenge were not altered in S. pneumoniae-infected mice, demonstrating that mice remained tolerant to the model allergen and were protected from the development of allergic airway inflammation regardless of the time point of infection. Our results suggest that a bacterial infection may decrease the manifestation of an allergic phenotype not only prior to sensitization but also after manifestation of allergic airway inflammation in mice, whereas both, induction and maintenance of respiratory tolerance are not affected by pneumococcal

  12. Defining problematic pharmaceutical opioid use among people prescribed opioids for chronic noncancer pain: do different measures identify the same patients?

    PubMed

    Campbell, Gabrielle; Bruno, Raimondo; Lintzeris, Nicholas; Cohen, Milton; Nielsen, Suzanne; Hall, Wayne; Larance, Briony; Mattick, Richard P; Blyth, Fiona; Farrell, Michael; Degenhardt, Louisa

    2016-07-01

    The International Classification of Diseases (ICD) and the Diagnostic and Statistical Manual (DSM) are routinely used in diagnosing illicit substance use disorders, but for people taking prescribed opioids they remain controversial. In pain medicine, the concept of "Addiction" is preferred with reduced emphasis on tolerance and withdrawal. This article examines the prevalence and characteristics of pharmaceutical opioid dependence/disorder according to ICD, DSM, and the pain medicine concept of "Addiction," among chronic noncancer pain (CNCP) patients prescribed opioids. In the current study, we used data from a national sample of 1134 people prescribed opioids for CNCP. Past 12-month "Addiction" (based on Pain Medicine definition), DSM, and ICD dependence definitions were assessed using the Composite International Diagnostic Interview. Twenty-four percent of the cohort met the criteria for "Addiction," 18% for DSM-5 use disorder and 19% for ICD-11 dependence. There was "substantial" concordance between "Addiction" and both DSM-5 use disorder and ICD-11 dependence, although concordance was much greater with ICD-11 dependence (kappa = 0.63 and 0.79, respectively). Participants meeting the criteria for "Addiction" only were older, less likely to engage in nonadherent behaviours, self-reported fewer problems or concerns with their medication, and had lower rates of psychological distress than those who also met the DSM-5 and ICD-11 criteria. The definition of "Addiction" captures a larger group of patients than other classification systems and includes people with fewer "risk" behaviours. Despite removal of tolerance and withdrawal for prescribed opioid use for DSM-5, we found that "Addiction" was more closely related to an ICD-11 diagnosis of pharmaceutical opioid dependence. PMID:26963848

  13. Influence of shade tolerance and development stage on the allometry of ten temperate tree species.

    PubMed

    Franceschini, Tony; Schneider, Robert

    2014-11-01

    Allometry studies the change in scale between two dimensions of an organism. The metabolic theory of ecology predicts invariant allometric scaling exponents, while empirical studies evidenced inter- and intra-specific variations. This work aimed at identifying the sources of variations of the allometric exponents at both inter- and intra-specific levels using stem analysis from 9,363 trees for ten Eastern Canada species with a large shade-tolerance gradient. Specifically, the yearly allometric exponents, α(v,DBH) [volume (v) and diameter at breast height (DBH)], β(v,h) [v and height (h)], and γ(h,DBH) (h and DBH) were modelled as a function of tree age for each species. α(v,DBH), and γ(h,DBH) increased with tree age and then reached a plateau ranging from 2.45 to 3.12 for α(v,DBH), and 0.874-1.48 for γ(h,DBH). Pine species presented a local maximum. No effect of tree age on β(v,h) was found for conifers, while it increased until a plateau ranging from 3.71 to 5.16 for broadleaves. The influence of shade tolerance on the growth trajectories was then explored. In the juvenile stage, α(v,DBH), and γ(h,DBH) increased with shade tolerance while β(v,h) was shade-tolerance independent. In the mature stage, β(v,h) increased with shade tolerance, whereas γ(h,DBH) decreased and α(v,DBH) was shade-tolerance independent. The interaction between development stage and shade tolerance for allometric exponents demonstrates the importance of the changing functional requirements of trees for resource allocation at both the inter- and intra-specific level. These results indicate the need to also integrate specific functional traits, growth strategies and allocation, in allometric theoretical frameworks. PMID:25168006

  14. Parent and Metabolite Opioid Drug Concentrations in Unintentional Deaths Involving Opioid and Benzodiazepine Combinations*†‡

    PubMed Central

    Fields, Marcia D.; Abate, Marie A.; Hu, Lan; Long, D. Leann; Blommel, Matthew L.; Haikal, Nabila A.; Kraner, James C.

    2016-01-01

    Effects of benzodiazepines on postmortem opioid parent and parent/metabolite blood concentration ratios were determined for fentanyl-, hydrocodone-, methadone-, or oxycodone-related accidental deaths. These opioids are partially metabolized by the CYP3A4 enzyme system, which is also affected by diazepam and alprazolam. Opioid/metabolite combinations examined were as follows: fentanyl/norfentanyl, hydrocodone/dihydrocodeine, methadone/EDDP, and oxycodone/oxymorphone. Parent opioid concentrations were analyzed for 877 deaths. Parent/metabolite concentration ratios were analyzed for 349 deaths, excluding cases with co-intoxicants present known to interfere with opioid elimination. Alprazolam in combination with diazepam significantly decreased median hydrocodone concentrations by 48% (p = 0.01) compared to hydrocodone alone. The methadone parent/metabolite concentration ratio was reduced by 35% in the presence of diazepam compared to methadone alone (p = 0.03). Benzodiazepines did not statistically significantly affect fentanyl or oxycodone concentrations. Possible factors affecting opioid concentrations and possible toxicity development, including any differential effects on specific opioids, should continue to be explored. PMID:26223761

  15. HLW Glass Studies: Development of Crystal-Tolerant HLW Glasses

    SciTech Connect

    Matyas, Josef; Huckleberry, Adam R.; Rodriguez, Carmen P.; Lang, Jesse B.; Owen, Antionette T.; Kruger, Albert A.

    2012-04-02

    In our study, a series of lab-scale crucible tests were performed on designed glasses of different compositions to further investigate and simulate the effect of Cr, Ni, Fe, Al, Li, and RuO2 on the accumulation rate of spinel crystals in the glass discharge riser of the HLW melter. The experimental data were used to expand the compositional region covered by an empirical model developed previously (Matyáš et al. 2010b), improving its predictive performance. We also investigated the mechanism for agglomeration of particles and impact of agglomerates on accumulation rate. In addition, the TL was measured as a function of temperature and composition.

  16. Progress towards developing neutron tolerant magnetostrictive and piezoelectric transducers

    NASA Astrophysics Data System (ADS)

    Reinhardt, Brian; Tittmann, Bernhard; Rempe, Joy; Daw, Joshua; Kohse, Gordon; Carpenter, David; Ames, Michael; Ostrovsky, Yakov; Ramuhalli, Pradeep; Montgomery, Robert; Chien, Hualte; Wernsman, Bernard

    2015-03-01

    Current generation light water reactors (LWRs), sodium cooled fast reactors (SFRs), small modular reactors (SMRs), and next generation nuclear plants (NGNPs) produce harsh environments in and near the reactor core that can severely tax material performance and limit component operational life. To address this issue, several Department of Energy Office of Nuclear Energy (DOE-NE) research programs are evaluating the long duration irradiation performance of fuel and structural materials used in existing and new reactors. In order to maximize the amount of information obtained from Material Testing Reactor (MTR) irradiations, DOE is also funding development of enhanced instrumentation that will be able to obtain in-situ, real-time data on key material characteristics and properties, with unprecedented accuracy and resolution. Such data are required to validate new multi-scale, multi-physics modeling tools under development as part of a science-based, engineering driven approach to reactor development. It is not feasible to obtain high resolution/microscale data with the current state of instrumentation technology. However, ultrasound-based sensors offer the ability to obtain such data if it is demonstrated that these sensors and their associated transducers are resistant to high neutron flux, high gamma radiation, and high temperature. To address this need, the Advanced Test Reactor National Scientific User Facility (ATR-NSUF) is funding an irradiation, led by PSU, at the Massachusetts Institute of Technology Research Reactor to test the survivability of ultrasound transducers. As part of this effort, PSU and collaborators have designed, fabricated, and provided piezoelectric and magnetostrictive transducers that are optimized to perform in harsh, high flux, environments. Four piezoelectric transducers were fabricated with either aluminum nitride, zinc oxide, or bismuth titanate as the active element that were coupled to either Kovar or aluminum waveguides and two

  17. Progress towards developing neutron tolerant magnetostrictive and piezoelectric transducers

    SciTech Connect

    Reinhardt, Brian; Tittmann, Bernhard; Rempe, Joy; Daw, Joshua; Kohse, Gordon; Carpenter, David; Ames, Michael; Ostrovsky, Yakov; Ramuhalli, Pradeep; Montgomery, Robert; Chien, Hualte; Wernsman, Bernard

    2015-03-31

    Current generation light water reactors (LWRs), sodium cooled fast reactors (SFRs), small modular reactors (SMRs), and next generation nuclear plants (NGNPs) produce harsh environments in and near the reactor core that can severely tax material performance and limit component operational life. To address this issue, several Department of Energy Office of Nuclear Energy (DOE-NE) research programs are evaluating the long duration irradiation performance of fuel and structural materials used in existing and new reactors. In order to maximize the amount of information obtained from Material Testing Reactor (MTR) irradiations, DOE is also funding development of enhanced instrumentation that will be able to obtain in-situ, real-time data on key material characteristics and properties, with unprecedented accuracy and resolution. Such data are required to validate new multi-scale, multi-physics modeling tools under development as part of a science-based, engineering driven approach to reactor development. It is not feasible to obtain high resolution/microscale data with the current state of instrumentation technology. However, ultrasound-based sensors offer the ability to obtain such data if it is demonstrated that these sensors and their associated transducers are resistant to high neutron flux, high gamma radiation, and high temperature. To address this need, the Advanced Test Reactor National Scientific User Facility (ATR-NSUF) is funding an irradiation, led by PSU, at the Massachusetts Institute of Technology Research Reactor to test the survivability of ultrasound transducers. As part of this effort, PSU and collaborators have designed, fabricated, and provided piezoelectric and magnetostrictive transducers that are optimized to perform in harsh, high flux, environments. Four piezoelectric transducers were fabricated with either aluminum nitride, zinc oxide, or bismuth titanate as the active element that were coupled to either Kovar or aluminum waveguides and two

  18. Molecular breeding for developing drought tolerant and disease resistant maize in sub Saharan Africa

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The International Maize and Wheat Improvement Center (CIMMYT), in collaboration with public and private partners, is working on developing and disseminating drought tolerant maize for sub Saharan Africa (SSA) using pedigree selection and molecular breeding. In this paper, we provide an overview of ...

  19. Development and analysis of the Software Implemented Fault-Tolerance (SIFT) computer

    NASA Technical Reports Server (NTRS)

    Goldberg, J.; Kautz, W. H.; Melliar-Smith, P. M.; Green, M. W.; Levitt, K. N.; Schwartz, R. L.; Weinstock, C. B.

    1984-01-01

    SIFT (Software Implemented Fault Tolerance) is an experimental, fault-tolerant computer system designed to meet the extreme reliability requirements for safety-critical functions in advanced aircraft. Errors are masked by performing a majority voting operation over the results of identical computations, and faulty processors are removed from service by reassigning computations to the nonfaulty processors. This scheme has been implemented in a special architecture using a set of standard Bendix BDX930 processors, augmented by a special asynchronous-broadcast communication interface that provides direct, processor to processor communication among all processors. Fault isolation is accomplished in hardware; all other fault-tolerance functions, together with scheduling and synchronization are implemented exclusively by executive system software. The system reliability is predicted by a Markov model. Mathematical consistency of the system software with respect to the reliability model has been partially verified, using recently developed tools for machine-aided proof of program correctness.

  20. Inflammatory Pain Promotes Increased Opioid Self-Administration: Role of Dysregulated Ventral Tegmental Area μ Opioid Receptors

    PubMed Central

    Hipólito, Lucia; Wilson-Poe, Adrianne; Campos-Jurado, Yolanda; Zhong, Elaine; Gonzalez-Romero, Jose; Virag, Laszlo; Whittington, Robert; Comer, Sandra D.; Carlton, Susan M.; Walker, Brendan M.; Bruchas, Michael R.

    2015-01-01

    inflammatory pain and opioid abuse liability, and should help to facilitate the development of novel and safer opioid-based strategies for treating chronic pain. PMID:26338332

  1. Tolerance of developing salmonid eggs and fry to nitrate exposure

    USGS Publications Warehouse

    Kincheloe, John W.; Wedemeyer, Gary A.; Koch, David L.

    1979-01-01

    This paper reports on tests which show significant effects on early salmonid life stages of nitrates at levels commonly found in groundwaters in geographical areas that are influenced by fertilizer application. It has long been known, from fish cultural experience, that in certain site specific locations, chronic problems can be expected with salmonid egg development and early fry mortality. However, fingerlings which survive usually grow normally. A complete explanation is lacking although several environmental factors have been proposed to account for this phenomenon. One, which has so far received little attention, is that nitrate levels in the ground and surface waters of many areas have been increasing significantly over historical background levels. Ammonia, urea, and other potential sources of nitrate can enter natural waters from a variety of sources, such as domestic or industrial sewage, animal feedlots, or seepage and return flows from agricultural lands. The latter may be the largest contributor, since billions of tons of nitrate fertilizers are applied to agricultural crops on a worldwide basis each year. In addition, intensive forest management techniques include the aerial application of nitrate fertilizer to increase the yield of wood products, while range management practices call for use of nitrates to increase forage production. The nitrate that is not taken up by plants ultimately appears in ground or surface waters.

  2. Progress towards developing neutron tolerant magnetostrictive and piezoelectric transducers

    SciTech Connect

    Reinhardt, Brian; Tittmann, Bernhard; Rempe, Joy; Daw, Joshua; Kohse, Gordon; Carpenter, David; Ames, Micheal; Ostrovsky, Yakov; Ramuhalli, Pradeep; Montgomery, Robert; Chien, Hualte; Wernsman, Bernard

    2014-07-01

    Current generation light water reactors (LWRs), sodium cooled fast reactors (SFRs), small modular reactors (SMRs), and next generation nuclear plants (NGNPs) provide harsh environments in and near the core that can severely test material performance and limit their operational life. To address this issue, several Department of Energy Office of Nuclear Energy (DOE-NE) research programs are evaluating the long duration radiation performance of fuels and materials. In To reduce the amount of Material and Test Reactor (MTR) irradiations required, DOE is also funding development of enhanced instrumentation that will be able to obtain data, with unprecedented accuracy and resolution, that are required to validate new multi-scale multiphysics modeling tools . It is not feasible to obtain such data with the current state of instrumentation technology. To address this need, PSU and collaborators have started an experiment to test the potential for utilizing ultrasonic instruments in-pile. Ultrasonic sensors must be resistant to high neutron flux, high gamma radiation, and high temperature. PSU and collaborators have designed, fabricated, and started to irradiate piezoelectric and magnetostrictive transducers designed to perform in such harsh environments. Three piezoelectric transducers were fabricated with aluminum nitride, zinc oxide, and bismuth titanate as the active element. The transducers are coupled kovar and aluminum waveguides of which pulse-echo ultrasonic measurements are made in-situ. Two magnetostrictive transducers were fabricated with Remendur and Arnokrome as the active elements. These devices will be pulsed and monitored in-situ. (1) Selection of candidate sensor materials as well as optimization of test assembly parameters (2) High temperature benchmark testing and (3) initial data from the irradiation will be reported.

  3. Opioid pharmaceuticals and addiction: The issues, and research directions seeking solutions

    PubMed Central

    Walwyn, Wendy M.; Miotto, Karen A.; Evans, Christopher J.

    2011-01-01

    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. PMID:20188495

  4. Pain tolerance predicts human social network size

    PubMed Central

    Johnson, Katerina V.-A.; Dunbar, Robin I. M.

    2016-01-01

    Personal social network size exhibits considerable variation in the human population and is associated with both physical and mental health status. Much of this inter-individual variation in human sociality remains unexplained from a biological perspective. According to the brain opioid theory of social attachment, binding of the neuropeptide β-endorphin to μ-opioid receptors in the central nervous system (CNS) is a key neurochemical mechanism involved in social bonding, particularly amongst primates. We hypothesise that a positive association exists between activity of the μ-opioid system and the number of social relationships that an individual maintains. Given the powerful analgesic properties of β-endorphin, we tested this hypothesis using pain tolerance as an assay for activation of the endogenous μ-opioid system. We show that a simple measure of pain tolerance correlates with social network size in humans. Our results are in line with previous studies suggesting that μ-opioid receptor signalling has been elaborated beyond its basic function of pain modulation to play an important role in managing our social encounters. The neuroplasticity of the μ-opioid system is of future research interest, especially with respect to psychiatric disorders associated with symptoms of social withdrawal and anhedonia, both of which are strongly modulated by endogenous opioids. PMID:27121297

  5. Pain tolerance predicts human social network size.

    PubMed

    Johnson, Katerina V-A; Dunbar, Robin I M

    2016-01-01

    Personal social network size exhibits considerable variation in the human population and is associated with both physical and mental health status. Much of this inter-individual variation in human sociality remains unexplained from a biological perspective. According to the brain opioid theory of social attachment, binding of the neuropeptide β-endorphin to μ-opioid receptors in the central nervous system (CNS) is a key neurochemical mechanism involved in social bonding, particularly amongst primates. We hypothesise that a positive association exists between activity of the μ-opioid system and the number of social relationships that an individual maintains. Given the powerful analgesic properties of β-endorphin, we tested this hypothesis using pain tolerance as an assay for activation of the endogenous μ-opioid system. We show that a simple measure of pain tolerance correlates with social network size in humans. Our results are in line with previous studies suggesting that μ-opioid receptor signalling has been elaborated beyond its basic function of pain modulation to play an important role in managing our social encounters. The neuroplasticity of the μ-opioid system is of future research interest, especially with respect to psychiatric disorders associated with symptoms of social withdrawal and anhedonia, both of which are strongly modulated by endogenous opioids. PMID:27121297

  6. Development of a new multi-analyte assay for the simultaneous detection of opioids in serum and other body fluids using liquid chromatography-tandem mass spectrometry.

    PubMed

    Eckart, K; Röhrich, J; Breitmeier, D; Ferner, M; Laufenberg-Feldmann, R; Urban, R

    2015-09-15

    A liquid chromatography-tandem mass spectrometry method using electrospray ionization in positive ionization mode was developed for the simultaneous detection of multiple opioid-type drugs in plasma. The presented assay allows the quantitative determination of alfentanil, buprenorphine, codeine, desomorphine, dextromethorphan, dextrorphan, dihydrocodeine, dihydromorphine, ethylmorphine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, naloxone, naltrexone, oxycodone, oxymorphone, pentazocine, pethidine, pholcodine, piritramide, remifentanil, sufentanil, and tramadol as well as the metabolites 6-monoacetylmorphine, bisnortilidine, morphine-3-glucuronide, morphine-6-glucuronide, naltrexol, norbuprenorphine, norfentanyl, norpethidine, nortilidine, and O-desmethyltramadol. Serum and blood samples were purified by solid-phase extraction. The analytes were separated on a phenyl-hexyl (100mm) column by formic acid/acetonitrile gradient elution using an UPLC 1290 Infinity coupled with a 6490 Triple Quadrupole mass spectrometer. The limits of detection ranged from 0.02 to 0.6ng/mL and the lower limits of quantification ranged from 0.1 to 2.0ng/mL. The calibration curves were linear between Calibration Levels 1-6 for all 35 substances. Recovery rates ranged between 51 and 88% for all compounds except alfentanil, bisnortilidine, pethidine, and morphine-3-glucuronide. The matrix effect ranged from 86% for ethylmorphine to 105% for desomorphine. Using the validation procedure proposed by the German Society of Toxicological and Forensic Chemistry, acceptable precision and accuracy data for almost all analytes were obtained. The method was successfully applied to 206 authentic serum samples provided by the palliative and intensive care units of the University Medical Center and the police authorities. Furthermore, a suspected fatal intoxication is demonstrated by an analysis of the sufentanil in post mortem body fluids and tissues. PMID:26241181

  7. Medication-assisted therapy for opioid addiction.

    PubMed

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

    2013-12-01

    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). PMID:25264415

  8. Pharmacological characterization of EN-9, a novel chimeric peptide of endomorphin-2 and neuropeptide FF that produces potent antinociceptive activity and limited tolerance.

    PubMed

    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. PMID:26970017

  9. Development of a novel aluminum tolerance phenotyping platform used for comparisons of cereal aluminum tolerance and investigations into rice aluminum tolerance mechanisms

    Technology Transfer Automated Retrieval System (TEKTRAN)

    It has been suggested that rice is the most Al-tolerant cereal crop under field conditions, capable of withstanding significantly higher concentrations of Al compared to other major cereals. Therefore, rice may provide novel genetic and/or physiological mechanisms that confer significantly higher l...

  10. Safe management of chronic pain in pregnancy in an era of opioid misuse and abuse.

    PubMed

    Pritham, Ursula A; McKay, Laura

    2014-01-01

    Safe and effective management of chronic pain in pregnancy is challenging. Use of over-the-counter analgesics, opioids, opioid substitution therapies, complementary and alternative therapies, antidepressants, and anxiolytics each have benefits and risks for the mother and neonate that must be considered. Because of their potency, opioids are often used despite associated risks for adverse effects, abuse, diversion, and addiction. Development of a pain management protocol for the counsel and care of pregnant women with pain is necessary. PMID:25123962

  11. Structure-activity relationships and discovery of a G protein biased μ opioid receptor ligand, [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro-[4.5]decan-9-yl]ethyl})amine (TRV130), for the treatment of acute severe pain.

    PubMed

    Chen, Xiao-Tao; Pitis, Philip; Liu, Guodong; Yuan, Catherine; Gotchev, Dimitar; Cowan, Conrad L; Rominger, David H; Koblish, Michael; Dewire, Scott M; Crombie, Aimee L; Violin, Jonathan D; Yamashita, Dennis S

    2013-10-24

    The concept of "ligand bias" at G protein coupled receptors has been introduced to describe ligands which preferentially stimulate one intracellular signaling pathway over another. There is growing interest in developing biased G protein coupled receptor ligands to yield safer, better tolerated, and more efficacious drugs. The classical μ opioid morphine elicited increased efficacy and duration of analgesic response with reduced side effects in β-arrestin-2 knockout mice compared to wild-type mice, suggesting that G protein biased μ opioid receptor agonists would be more efficacious with reduced adverse events. Here we describe our efforts to identify a potent, selective, and G protein biased μ opioid receptor agonist, TRV130 ((R)-30). This novel molecule demonstrated an improved therapeutic index (analgesia vs adverse effects) in rodent models and characteristics appropriate for clinical development. It is currently being evaluated in human clinical trials for the treatment of acute severe pain. PMID:24063433

  12. In vivo profiling of seven common opioids for antinociception, constipation and respiratory depression: no two opioids have the same profile

    PubMed Central

    Kuo, A; Wyse, B D; Meutermans, W; Smith, M T

    2015-01-01

    BACKGROUND AND PURPOSE For patients experiencing inadequate analgesia and intolerable opioid-related side effects on one strong opioid analgesic, pain relief with acceptable tolerability is often achieved by rotation to a second strong opioid. These observations suggest subtle pharmacodynamic differences between opioids in vivo. This study in rats was designed to assess differences between opioids in their in vivo profiles. EXPERIMENTAL APPROACH Male Sprague Dawley rats were given single i.c.v. bolus doses of morphine, morphine-6-glucuronide (M6G), fentanyl, oxycodone, buprenorphine, DPDPE ([D-penicillamine2,5]-enkephalin) or U69,593. Antinociception, constipation and respiratory depression were assessed using the warm water tail-flick test, the castor oil-induced diarrhoea test and whole body plethysmography respectively. KEY RESULTS These opioid agonists produced dose-dependent antinociception, constipation and respiratory depression. For antinociception, morphine, fentanyl and oxycodone were full agonists, buprenorphine and M6G were partial agonists, whereas DPDPE and U69,593 had low potency. For constipation, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, morphine produced a bell-shaped dose–response curve, whereas DPDPE and U69,593 were inactive. For respiratory depression, morphine, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, whereas DPDPE and U69,593 were inactive. The respiratory depressant effects of fentanyl and oxycodone were of short duration, whereas morphine, M6G and buprenorphine evoked prolonged respiratory depression. CONCLUSION AND IMPLICATIONS For the seven opioids we assessed, no two had the same profile for evoking antinociception, constipation and respiratory depression, suggesting that these effects are differentially regulated. Our findings may explain the clinical success of ‘opioid rotation’. LINKED ARTICLES This article is part of a themed section on

  13. Drug Interaction and Serotonin Toxicity with Opioid Use: Another Reason to Avoid Opioids in Headache and Migraine Treatment.

    PubMed

    Ansari, Hossein; Kouti, Leila

    2016-08-01

    Treatment of headache, specifically migraine attacks, has always been a challenging subject, especially for neurologist and pain specialists. Triptans are generally underutilized, despite being the gold standard abortive medication for migraine attacks. On the other hand, opioid analgesics are overused as a treatment for headache. One reason for this could be physician unfamiliarity with drug interactions between opioids and other medications, especially the possibility of serotonin toxicity. The general awareness of potential serotonin toxicity with using opioid analgesics is low. In this review, we will conduct a theoretic and evidence-based review of the potential for developing serotonin syndrome in patients who are using opioids analgesics, especially in combination with antidepressants, a common co-prescribed combination. We also review the current diagnostic criteria for serotonin syndrome and identify possible shortcomings of those criteria. Our aim is to increase the awareness of health care providers about potential drug interaction of opioid analgesics with other classes of medication. We place particular emphasis on tramadol since this drug is one of the most commonly used opioid analgesics for headache. The potential for developing serotonin syndrome is relatively high in the patients who are using opioid for pain control. The use of opioids in migraine headache is already discouraged due to the high risk of medication overuse headache and also an increase in headache-related disability (Katsarava et al. Neurology 62:788-790, 2004; Bigal and Lipton. Neurology 71:1821-8, 2008; Casucci and Cevoli. Neurol Sci. 34 Suppl 1:S125-8, 2013). This is another reason that physicians and health care providers should avoid using this class of medication for pain, specifically headache and migraine treatment. PMID:27457368

  14. Glial TLR4 signaling does not contribute to opioid-induced depression of respiration

    PubMed Central

    Zwicker, Jennifer D.; Zhang, Yong; Ren, Jun; Hutchinson, Mark R.; Rice, Kenner C.; Watkins, Linda R.; Greer, John J.

    2014-01-01

    Opioids activate glia in the central nervous system in part by activating the toll-like receptor 4 (TLR4)/myeloid differentiation 2 (MD2) complex. TLR4/MD2-mediated activation of glia by opioids compromises their analgesic actions. Glial activation is also hypothesized as pivotal in opioid-mediated reward and tolerance and as a contributor to opioid-mediated respiratory depression. We tested the contribution of TLR4 to opioid-induced respiratory depression using rhythmically active medullary slices that contain the pre-Bötzinger Complex (preBötC, an important site of respiratory rhythm generation) and adult rats in vivo. Injection with DAMGO (μ-opioid receptor agonist; 50 μM) or bath application of DAMGO (500 nM) or fentanyl (1 μM) slowed frequency recorded from XII nerves to 40%, 40%, or 50% of control, respectively. This DAMGO-mediated frequency inhibition was unaffected by preapplication of lipopolysaccharides from Rhodobacter sphaeroides (a TLR4 antagonist, 2,000 ng/ml) or (+)naloxone (1–10 μM, a TLR4-antagonist). Bath application of (−)naloxone (500 nM; a TLR4 and μ-opioid antagonist), however, rapidly reversed the opioid-mediated frequency decrease. We also compared the opioid-induced respiratory depression in slices in vitro in the absence and presence of bath-applied minocycline (an inhibitor of microglial activation) and in slices prepared from mice injected (ip) 18 h earlier with minocycline or saline. Minocycline had no effect on respiratory depression in vitro. Finally, the respiratory depression evoked in anesthetized rats by tail vein infusion of fentanyl was unaffected by subsequent injection of (+)naloxone, but completely reversed by (−)naloxone. These data indicate that neither activation of microglia in preBötC nor TLR4/MD2-activation contribute to opioid-induced respiratory depression. PMID:25103966

  15. The pharmacological treatment of opioid addiction--a clinical perspective.

    PubMed

    Lobmaier, Philipp; Gossop, Michael; Waal, Helge; Bramness, Jorgen

    2010-06-01

    This article reviews the main pharmacotherapies that are currently being used to treat opioid addiction. Treatments include detoxification using tapered methadone, buprenorphine, adrenergic agonists such as clonidine and lofexidine, and forms of rapid detoxification. In opioid maintenance treatment (OMT), methadone is most widely used. OMT with buprenorphine, buprenorphine-naloxone combination, or other opioid agonists is also discussed. The use of the opioid antagonists naloxone (for the treatment of intoxication and overdose) and oral and sustained-release formulations of naltrexone (for relapse prevention) is also considered. Although recent advances in the neurobiology of addictions may lead to the development of new pharmacotherapies for the treatment of addictive disorders, a major challenge lies in delivering existing treatments more effectively. Pharmacotherapy of opioid addiction alone is usually insufficient, and a complete treatment should also include effective psychosocial support or other interventions. Combining pharmacotherapies with psychosocial support strategies that are tailored to meet the patients' needs represents the best way to treat opioid addiction effectively. PMID:20169438

  16. Opioids and skin homeostasis, regeneration and ageing - What's the evidence?

    PubMed

    Bigliardi, Paul L; Dancik, Yuri; Neumann, Christine; Bigliardi-Qi, Mei

    2016-08-01

    What has the opioid receptor system, known for beneficial as well as disastrous effects in the central nervous system, to do with skin? The question is appropriate considering the fact that the nervous system and the skin both derive from the ectoderm. As part of the skin neuroendocrine system, the opioid receptor system exemplifies the closeness between the nervous system and the skin. Overexpression of the δ-opioid receptor in keratinocytes yields dysregulation of involucrin, loricrin, and filaggrin, proteins essential to the integrity of the skin barrier. The μ-opioid receptor ligand β-endorphin, produced in the pituitary gland and a variety of skin cells, promotes wound healing via regulation of cytokeratin 16 and TGF-β type II receptor expression in keratinocytes. These and other published results discussed in this viewpoint are evidence for the fundamental role of the skin opioid receptor system in skin homeostasis, regeneration and ageing. While considerable progress in understanding the opioid receptors' function on the cellular level has been made, there is a need to link these results to physiological observations for the development of local skin therapies. PMID:27060353

  17. Developmental patterns for pancreatic opioids in the rat.

    PubMed

    Powell, A M; Voyles, N R; Wilkins, S D; Zalenski, C M; Timmers, K I; Recant, L

    1989-01-01

    Developmental patterns for rat pancreatic opioid peptides and islet hormones were studied from gestational day 20 through adulthood. Fetal tissue was obtained as well as pancreas at birth (day 0), and postnatal days 3, 7, 14, and 21, and 7 weeks. The hormones measured included insulin, glucagon, and somatostatin. The opioids measured were beta-endorphin, Met- and Leu-enkephalins, and the high molecular weight enkephalin precursors. Pancreata were pooled as necessary and extracted (acid alcohol, or hot acetic acid), and opioids were further purified on reversed-phase C-18 (Sep-pak) cartridges. In all instances measurements were made by radioimmunoassays. Precursor peptides were first digested (with trypsin and carboxypeptidase B) prior to immunoassay. All opioids and hormones except the precursors for enkephalins showed a well-defined surge in pancreatic concentration during the first postnatal week. In contrast, the precursors had the highest concentration in the fetus, and by the seventh day of life had decreased by greater than 50%. This progressive decrease may represent maturation of the enkephalin convertase and trypsin-like enzymes in the islets. The opioid and hormonal surges that we have described are similar to the surge in islet concentration of thyroid-releasing hormone (TRH) previously described in neonatal rat islets. It is suggested that these postnatal alterations in opioid and hormone concentration relate to a specific function in the development of the endocrine pancreas. PMID:2530576

  18. A Response to the Opioid Overdose Epidemic: Naloxone Nasal Spray

    PubMed Central

    Wermeling, Daniel P.

    2012-01-01

    Opioid overdose morbidity and mortality is recognized to have epidemic proportions. Medical and public health agencies are adopting opioid harm reduction strategies to reduce the morbidity and mortality associated with overdose. One strategy developed by emergency medical services and public health agencies is to deliver the opioid antidote naloxone injection intranasally to reverse the effects of opioids. Paramedics have used this route to quickly administer naloxone in a needle-free system and avoiding needle-stick injuries and contracting a blood-born pathogen disease such as hepatitis or human immunodeficiency virus. Public health officials advocate broader lay person access since civilians are likely witnesses or first responders to an opioid overdose in a time-acute setting. The barrier to greater use of naloxone is that a suitable and optimized needlefree drug delivery system is unavailable. The scientific basis for design and study of an intranasal naloxone product is described. Lessons from nasal delivery of opioid analgesics are applied to the consideration of naloxone nasal spray. PMID:23734342

  19. A history of neuraxial administration of local analgesics and opioids.

    PubMed

    Brill, S; Gurman, G M; Fisher, A

    2003-09-01

    The history of intrathecal and epidural anaesthesia is in parallel with the development of general anaesthesia. As ether anaesthesia (1846) is considered the first modern anaesthetic since its use by Morton 157 yr ago, so Bier made history by using cocaine for intrathecal anaesthesia in 1898. The first published report on opioids for intrathecal anaesthesia belongs to a Romanian surgeon, Racoviceanu-Pitesti, who presented his experience at Paris in 1901. It was almost a century before the opioids were used for epidural analgesia. Behar and his colleagues published the first report on the epidural use of morphine for the treatment of pain in The Lancet in 1979. Epidural and intrathecal opioids are today part of a routine regimen for intra- and postoperative analgesia. Over the last 30 yr, the use of epidural opioids has became a standard for analgesia in labour and delivery, and for the management of chronic pain. Finally, epidural opioids have been shown to have a pre-emptive effect, when used before major surgery. We present the evolution of neuraxial anaesthesia and the history of intrathecal and epidural administration of opioids. PMID:12974588

  20. Opioid modulation of taste hedonics within the ventral striatum.

    PubMed

    Kelley, A E; Bakshi, V P; Haber, S N; Steininger, T L; Will, M J; Zhang, M

    2002-07-01

    There is a long-standing interest in the role of endogenous opioid peptides in feeding behavior and, in particular, in the modulation of food reward and palatability. Since drugs such as heroin, morphine, alcohol, and cannabinoids, interact with this system, there may be important common neural substrates between food and drug reward with regard to the brain's opioid systems. In this paper, we review the proposed functional role of opioid neurotransmission and mu opiate receptors within the nucleus accumbens and surrounding ventral striatum. Opioid compounds, particularly those selective for the mu receptor, induce a potent increase in food intake, sucrose, salt, saccharin, and ethanol intake. We have explored this phenomenon with regard to macronutrient selection, regional specificity, role of output structures, Fos mapping, analysis of motivational state, and enkephalin gene expression. We hypothesize that opioid-mediated mechanisms within ventral striatal medium spiny neurons mediate the affective or hedonic response to food ('liking' or food 'pleasure'). A further refinement of this hypothesis is that activation of ventral striatal opioids specifically encodes positive affect induced by tasty and/or calorically dense foods (such as sugar and fat), and promotes behaviors associated with this enhanced palatability. It is proposed that this brain mechanism was beneficial in evolutionary development for ensuring the consumption of relatively scarce, high-energy food sources. However, in modern times, with unlimited supplies of high-calorie food, it has contributed to the present epidemic of obesity. PMID:12117573

  1. Development of pressure containment and damage tolerance technology for composite fuselage structures in large transport aircraft

    NASA Technical Reports Server (NTRS)

    Smith, P. J.; Thomson, L. W.; Wilson, R. D.

    1986-01-01

    NASA sponsored composites research and development programs were set in place to develop the critical engineering technologies in large transport aircraft structures. This NASA-Boeing program focused on the critical issues of damage tolerance and pressure containment generic to the fuselage structure of large pressurized aircraft. Skin-stringer and honeycomb sandwich composite fuselage shell designs were evaluated to resolve these issues. Analyses were developed to model the structural response of the fuselage shell designs, and a development test program evaluated the selected design configurations to appropriate load conditions.

  2. Ubiquitination pathway as a target to develop abiotic stress tolerance in rice

    PubMed Central

    Dametto, Andressa; Buffon, Giseli; Dos Reis Blasi, Édina Aparecida; Sperotto, Raul Antonio

    2015-01-01

    Abiotic stresses may result in significant losses in rice grain productivity. Protein regulation by the ubiquitin/proteasome system has been studied as a target mechanism to optimize adaptation and survival strategies of plants to different environmental stresses. This article aimed at highlighting recent discoveries about the roles ubiquitination may play in the exposure of rice plants to different abiotic stresses, enabling the development of modified plants tolerant to stress. Responses provided by the ubiquitination process include the regulation of the stomatal opening, phytohormones levels, protein stabilization, cell membrane integrity, meristematic cell maintenance, as well as the regulation of reactive oxygen species and heavy metals levels. It is noticeable that ubiquitination is a potential means for developing abiotic stress tolerant plants, being an excellent alternative to rice (and other cultures) improvement programs. PMID:26236935

  3. The effects of ibudilast, a glial activation inhibitor, on opioid withdrawal symptoms in opioid-dependent volunteers.

    PubMed

    Cooper, Ziva D; Johnson, Kirk W; Pavlicova, Martina; Glass, Andrew; Vosburg, Suzanne K; Sullivan, Maria A; Manubay, Jeanne M; Martinez, Diana M; Jones, Jermaine D; Saccone, Phillip A; Comer, Sandra D

    2016-07-01

    Glial activation is hypothesized to contribute directly to opioid withdrawal. This study investigated the dose-dependent effects of a glial cell modulator, ibudilast, on withdrawal symptoms in opioid-dependent volunteers after abrupt discontinuation of morphine administration. Non-treatment-seeking heroin-dependent volunteers (n = 31) completed the in-patient, double-blind, placebo-controlled, within-subject and between-group study. Volunteers were maintained on morphine (30 mg, QID) for 14 days and placebo (0 mg, QID) for the last 7 days of the 3-week study. Volunteers also received placebo (0 mg, PO, BID) capsules on days 1-7. On days 8-21, volunteers were randomized to receive ibudilast (20 or 40 mg, PO, BID) or placebo capsules. Subjective and clinical ratings of withdrawal symptoms were completed daily using daily using the Subjective Opioid Withdrawal Scale (SOWS) and Clinical Opioid Withdrawal Scale (COWS). Medication side effects were also monitored. Relative to the first 2 weeks, all groups exhibited withdrawal during the third week as assessed by the SOWS and COWS (P ≤ 0.0001). Although overall SOWS scores did not differ between groups, exploratory analyses pooling the two ibudilast groups demonstrated that they had lower ratings of withdrawal symptoms on SOWS items ('anxious,' 'perspiring,' 'restless,' 'stomach cramps') during detoxification relative to the placebo group. Ibudilast was well tolerated; no serious adverse events occurred during the study. Pharmacological modulation of glial activity with ibudilast decreased some subjective ratings of opioid withdrawal symptoms. These exploratory findings are the first to demonstrate the potential clinical utility of glial modulators for treating opioid withdrawal in humans. PMID:25975386

  4. Role of Maternal Dietary Peanut Exposure in Development of Food Allergy and Oral Tolerance

    PubMed Central

    Järvinen, Kirsi M.; Westfall, Jennifer; De Jesus, Magdia; Mantis, Nicholas J.; Carroll, Jessica A.; Metzger, Dennis W.; Sampson, Hugh A.; Berin, M. Cecilia

    2015-01-01

    Background The impact of maternal ingestion of peanut during pregnancy and lactation on an offspring’s risk for peanut allergy is under debate. Objective To investigate the influence of maternal dietary peanut exposure and breast milk on an offspring’s allergy risk. Methods Preconceptionally peanut-exposed C3H/HeJ females were either fed or not fed peanut during pregnancy and lactation. The offsprings’ responses to peanut sensitization or oral tolerance induction by feeding antigen prior to immunization were assessed. We also assessed the impact of immune murine milk on tolerance induction pre- or post-weaning. For antigen uptake studies, mice were gavaged with fluorescent peanut in the presence or absence of immune murine milk; Peyer’s patches were harvested for immunostaining. Results Preconceptional peanut exposure resulted in the production of varying levels of maternal antibodies in serum (and breast milk), which were transferred to the offspring. Despite this, maternal peanut exposure either preconceptionally or during pregnancy and lactation, when compared to no maternal exposure, had no impact on peanut allergy. When offspring were fed peanut directly, dose-dependent tolerance induction, unaltered by maternal feeding of peanut, was seen. Although peanut uptake into the gut-associated lymphoid tissues was enhanced by immune milk as compared to naïve milk, tolerance induction was not affected by the co-administration of immune milk either pre- or post-weaning. Conclusion Maternal peanut exposure during pregnancy and lactation has no impact on the development of peanut allergy in the offspring. Tolerance to peanut can be induced early, even pre-weaning, by giving moderate amounts of peanut directly to the infant, and this is neither enhanced nor impaired by concurrent exposure to immune milk. PMID:26656505

  5. Proglumide exhibits delta opioid agonist properties.

    PubMed

    Rezvani, A; Stokes, K B; Rhoads, D L; Way, E L

    1987-01-01

    Recently, it was reported that proglumide, a cholecystokinin (CCK) antagonist, potentiates the analgetic effects of morphine and endogenous opioid peptides and reverses morphine tolerance by antagonizing the CCK system in the central nervous system of the rat. In order to provide additional insight into the mode of action of this agent, we assessed the effect of proglumide in the isolated guinea pig ileum and the mouse, rat and rabbit vas deferens. Furthermore, we studied the in vitro binding affinity of this substance to mouse brain synaptosomes. Our results show that proglumide inhibits, dose dependently, the electrically stimulated twitches in the mouse vas deferens and guinea pig ileum, but not in the rat or rabbit vas deferens. The inhibitory action of proglumide on the mouse vas deferens, but not on the guinea pig ileum, is antagonized by naloxone and by the selective delta-antagonist, ICI 174,864, in a competitive fashion. Other CCK antagonists were found to be devoid of such activity on the mouse vas deferens. In vitro binding studies showed that proglumide displaces D-ala-D-[leucine]5-enkephalin (DADLE), a delta agonist, but not ethylketocyclazocine (EKC), a preferentially selective kappa agonist. The effect of proglumide appeared to be elicited presynaptically since it did not alter the norepinephrine-induced contractions of the mouse vas deferens. Our results suggest that proglumide might exert its opiate-like effects by activation of delta-opioid receptors. PMID:3030338

  6. Semisynthetic Neoclerodanes as Kappa Opioid Receptor Probes

    PubMed Central

    Lovell, Kimberly M.; Vasiljevik, Tamara; Araya, Juan J.; Lozama, Anthony; Prevatt-Smith, Katherine M.; Day, Victor W.; Dersch, Christina M.; Rothman, Richard B.; Butelman, Eduardo R.; Kreek, Mary Jeanne; Prisinzano, Thomas E.

    2012-01-01

    Modification of the furan ring of salvinorin A (1), the main active component of Salvia divinorum, has resulted in novel neoclerodane diterpenes with opioid receptor affinity and activity. Conversion of the furan ring to an aldehyde at the C-12 position (5) has allowed for the synthesis of analogues with new carbon-carbon bonds at that position. Previous methods for forming these bonds, such as Grignard and Stille conditions, have met with limited success. We report a palladium catalyzed Liebeskind-Srogl cross-coupling reaction of a thioester and a boronic acid that occurs at neutral pH and ambient temperature to produce ketone analogs at C-12. To the best of our knowledge, this is the first reported usage of the Liebeskind-Srogl reaction to diversify a natural product scaffold. We also describe a one-step protocol for the conversion of 1 to 12-epi-1 (3) through microwave irradiation. Previously, this synthetically challenging process has required multiple steps. Additionally, we report in this study that alkene 9 and aromatic analogues 12, 19, 23, 25, and 26 were discovered to retain affinity and selectivity at kappa opioid receptors (KOP). Finally, we report that the furan-2-yl analog of 1 (31) has similar affinity to 1. Collectively, these findings suggest that different aromatic groups appended directly to the decalin core may be well tolerated by KOP receptors, and may generate further ligands with affinity and activity at KOP receptors. PMID:22464684

  7. Road Map for Development of Crystal-Tolerant High Level Waste Glasses

    SciTech Connect

    Matyas, Josef; Vienna, John D.; Peeler, David; Fox, Kevin; Herman, Connie; Kruger, Albert A.

    2014-05-31

    This road map guides the research and development for formulation and processing of crystal-tolerant glasses, identifying near- and long-term activities that need to be completed over the period from 2014 to 2019. The primary objective is to maximize waste loading for Hanford waste glasses without jeopardizing melter operation by crystal accumulation in the melter or melter discharge riser. The potential applicability to the Savannah River Site (SRS) Defense Waste Processing Facility (DWPF) is also addressed in this road map.

  8. Prescription Opioids in Pregnancy and Birth Outcomes: A Review of the Literature

    PubMed Central

    Yazdy, Mahsa M.; Desai, Rishi J.; Brogly, Susan B.

    2015-01-01

    Prescription opioids are used prenatally for the management of pain, as well as for opiate dependency. Opioids are known to cross the placenta and despite the evidence of possible adverse effects on fetal development, studies have consistently shown prescription opioids are among the most commonly prescribed medications and the prevalence of use is increasing among pregnant women. This article summarizes the available literature documenting potential harms associated with prescription opioid use during pregnancy, including poor fetal growth, preterm birth, birth defects, and neonatal abstinence syndrome. PMID:26998394

  9. Previous Homologous and Heterologous Stress Exposure Induces Tolerance Development to Pulsed Light in Listeria monocytogenes.

    PubMed

    Heinrich, Victoria; Zunabovic, Marija; Petschnig, Alice; Müller, Horst; Lassenberger, Andrea; Reimhult, Erik; Kneifel, Wolfgang

    2016-01-01

    As one of the emerging non-thermal technologies, pulsed light (PL) facilitates rapid, mild and residue-free microbial surface decontamination of food and food contact materials. While notable progress has been made in the characterization of the inactivation potential of PL, experimental data available on the tolerance development to the same (homologous) stress or to different (heterologous) stresses commonly applied in food manufacturing (e.g., acid, heat, salt) is rather controversial. The findings of the present study clearly indicate that both the homologous tolerance development against PL as well as the heterologous tolerance development from heat to PL can be triggered in Listeria monocytogenes. Further, conducted kinetic analysis confirmed that the conventionally applied log-linear model is not well suited to describe the inactivation of L. monocytogenes, when exposed to PL. Instead, the Weibull model as well as the log-linear + tail model were identified as suitable models. Transmission electron microscopic (TEM) approaches allow suggestions on the morphological alterations in L. monocytogenes cells after being subjected to PL. PMID:27092137

  10. Previous Homologous and Heterologous Stress Exposure Induces Tolerance Development to Pulsed Light in Listeria monocytogenes

    PubMed Central

    Heinrich, Victoria; Zunabovic, Marija; Petschnig, Alice; Müller, Horst; Lassenberger, Andrea; Reimhult, Erik; Kneifel, Wolfgang

    2016-01-01

    As one of the emerging non-thermal technologies, pulsed light (PL) facilitates rapid, mild and residue-free microbial surface decontamination of food and food contact materials. While notable progress has been made in the characterization of the inactivation potential of PL, experimental data available on the tolerance development to the same (homologous) stress or to different (heterologous) stresses commonly applied in food manufacturing (e.g., acid, heat, salt) is rather controversial. The findings of the present study clearly indicate that both the homologous tolerance development against PL as well as the heterologous tolerance development from heat to PL can be triggered in Listeria monocytogenes. Further, conducted kinetic analysis confirmed that the conventionally applied log-linear model is not well suited to describe the inactivation of L. monocytogenes, when exposed to PL. Instead, the Weibull model as well as the log-linear + tail model were identified as suitable models. Transmission electron microscopic (TEM) approaches allow suggestions on the morphological alterations in L. monocytogenes cells after being subjected to PL. PMID:27092137

  11. Enhanced development of dispositional tolerance to methadone by desipramine given together with methadone

    SciTech Connect

    Liu, S.J.; Wang, R.I.H.

    1985-02-25

    Rats given 2-day oral administration of methadone (15 mg/kg, twice on day 1 and once on day 2) by gastric tube developed dispositional tolerance to methadone analgesia as demonstrated by a decrease in analgesic response and by an increase in methadone metabolism. The increased metabolism of methadone was evidenced by a decrease in brain concentration of /sup 14/C-methadone and increases in the percentages of total /sup 14/C in liver or urine as /sup 14/C-water-soluble metabolites (/sup 14/C-WSM) after the rats were challenged with a test dose of /sup 14/C-methadone. Two-day pretreatment with a combination of desipramine (DMI) (10 mg/kg, ip) and methadone (15 mg/kg, po) enhanced the development of dispositional tolerance to methadone analgesia which was evidenced by a greater decrease in the brain concentration of methadone and a greater increase in methadone metabolism as compared to those changes in rats pretreated with only methadone. Repeated treatment with DMI alone neither decreased the analgesic effect of methadone nor stimulated methadone metabolism. It is suggested that DMI given together with methadone promoted the induction of methadone metabolism in the liver by prolonging the enzyme-stimulating state of methadone, thus enhancing the development of dispositional tolerance to methadone. 20 references, 1 figure, 1 table.

  12. Nonpeptidic Delta (δ) Opioid Agonists and Antagonists of the Diarylmethylpiperazine Class: What Have We Learned?

    NASA Astrophysics Data System (ADS)

    Calderon, Silvia N.

    The discovery of the selective delta (δ) opioid agonists SNC 80 and BW373U86, which possess a diarylmethylpiperazine structure unique among opioids, represented a major advance in the field of δ-opioid ligands. Extensive research has recently been performed to uncover the structure-activity relationships (SAR) of this class of ligands, thereby providing valuable tools for the pharmacological characterization of the δ opioid receptor. This review focuses on the SAR of this unique series of ligands, and provides an overview of the various chemical routes that have been developed and optimized through the years to allow the syntheses of these ligands on a multigram scale. The search for selective δ opioid agonists and antagonists, as well as for those with mixed opioid agonist properties with potential therapeutic value, continues. Several questions regarding the interaction at the molecular level of diphenylmethylpiperazine derivatives and related analogs with opioid receptors and in particular with the δ opioid system still remain unanswered. Indeed, the development and pharmacological characterization of novel nonpeptidic δ opioid ligands remains an active area of research, as it may provide a better understanding of the role of this receptor in multiple disease states and disorders.

  13. Assessment and treatment of abuse risk in opioid prescribing for chronic pain.

    PubMed

    Jamison, Robert N; Serraillier, Juliana; Michna, Edward

    2011-01-01

    Opioid analgesics provide effective treatment for noncancer pain, but many physicians have concerns about adverse effects, tolerance, and addiction. Misuse of opioids is prominent in patients with chronic back pain and early recognition of misuse risk could help physicians offer adequate patient care while implementing appropriate levels of monitoring to reduce aberrant drug-related behaviors. In this review, we discuss opioid abuse and misuse issues that often arise in the treatment of patients with chronic back pain and present an overview of assessment and treatment strategies that can be effective in improving compliance with the use of prescription opioids for pain. Many persons with chronic back pain have significant medical, psychiatric and substance use comorbidities that affect treatment decisions and a comprehensive evaluation that includes a detailed history, physical, and mental health evaluation is essential. Although there is no "gold standard" for opioid misuse risk assessment, several validated measures have been shown to be useful. Controlled substance agreements, regular urine drug screens, and interventions such as motivational counseling have been shown to help improve patient compliance with opioids and to minimize aberrant drug-related behavior. Finally, we discuss the future of abuse-deterrent opioids and other potential strategies for back pain management. PMID:22110936

  14. Assessment and Treatment of Abuse Risk in Opioid Prescribing for Chronic Pain

    PubMed Central

    Jamison, Robert N.; Serraillier, Juliana; Michna, Edward

    2011-01-01

    Opioid analgesics provide effective treatment for noncancer pain, but many physicians have concerns about adverse effects, tolerance, and addiction. Misuse of opioids is prominent in patients with chronic back pain and early recognition of misuse risk could help physicians offer adequate patient care while implementing appropriate levels of monitoring to reduce aberrant drug-related behaviors. In this review, we discuss opioid abuse and misuse issues that often arise in the treatment of patients with chronic back pain and present an overview of assessment and treatment strategies that can be effective in improving compliance with the use of prescription opioids for pain. Many persons with chronic back pain have significant medical, psychiatric and substance use comorbidities that affect treatment decisions and a comprehensive evaluation that includes a detailed history, physical, and mental health evaluation is essential. Although there is no “gold standard” for opioid misuse risk assessment, several validated measures have been shown to be useful. Controlled substance agreements, regular urine drug screens, and interventions such as motivational counseling have been shown to help improve patient compliance with opioids and to minimize aberrant drug-related behavior. Finally, we discuss the future of abuse-deterrent opioids and other potential strategies for back pain management. PMID:22110936

  15. Opioids in chronic noncancer pain: More faces from the crowd

    PubMed Central

    Watson, C Peter N

    2012-01-01

    BACKGROUND: The use of opioids for chronic noncancer pain (CNCP) remains very controversial. There are several randomized controlled trials, mostly in neuropathic pain, reporting efficacy and safety in the short term, but more long-term data are needed. Randomized controlled trials may be limited in providing data about the patients who benefit from often high-dose opioids over the long term. The present article provides details of these patients and adds to a previous case series. METHODS: The present article contains 17 case reports of 11 CNCP conditions (followed to 2011) selected to illustrate specific issues from a survey of 84 patients with intractable CNCP treated with opioids and followed every three months for a median of 11 years. The previous published survey of this group reported outcomes of pain severity, adverse effects, pain relief, satisfaction, mood, problematic opioid use, tolerance, physical dependency, functional status, health-related quality of life (HRQL), immune status and sexual function. The outcome measures for that study included a numerical rating scale for pain, the Hospital Anxiety and Depression Scale, the Brief Pain Inventory Interference Scale, the Pain Disability Index and, for HRQL, the Short-Form Health Survey 12 version 2. Most patients in the total sample reported 50% or greater relief and a moderate improvement in disability. Scores for functional status and HRQL were not severely affected. Problematic use, tolerance and serious adverse effects, including constipation, were not major issues. These selected patient reports were chosen, not to illustrate optimal results, but rather important aspects of the diagnoses, opioids and doses, the paucity of intolerable adverse effects, particular issues (concurrent addiction history, bipolar disorder and combination therapy), disease-specific and other outcomes and duration of follow-up with complex pain problems. RESULTS: Opioids were found to be safe and useful in the long term for

  16. Attentional Bias For Prescription Opioid Cues Among Opioid Dependent Chronic Pain Patients

    PubMed Central

    Garland, Eric L.; Froeliger, Brett; Passik, Steven D.; Howard, Matthew O.

    2012-01-01

    Recurrent use of prescription opioid analgesics by chronic pain patients may result in opioid dependence, which involves implicit neurocognitive operations that organize and impel craving states and compulsive drug taking behavior. Prior studies have identified an attentional bias (AB) towards heroin among heroin dependent individuals. The aim of this study was to determine whether opioid-dependent chronic pain patients exhibit an AB towards prescription opioidrelated cues. Opioid-dependent chronic pain patients (n = 32) and a comparison group of non-dependent opioid users with chronic pain (n = 33) completed a dot probe task designed to measure opioid AB. Participants also rated their opioid craving and self-reported arousal associated with opioid-related and neutral images, pain severity, and relief from pain treatments. Repeated-measures ANOVA revealed a significant group (opioid-dependent vs. non-dependent opioid user) × presentation duration (200 ms. vs. 2000 ms.) interaction, such that opioid-dependent individuals evidenced a significant AB towards opioid cues presented for 200 ms but not for cues presented for 2000 ms, whereas non-dependent opioid users did not exhibit a significant mean AB at either stimulus duration. Among opioid-dependent individuals, 200 ms opioid AB was significantly associated with opioid craving, while among non-dependent opioid users, 200 ms opioid AB was significantly associated with relief from pain treatments. Furthermore, dependent and non-dependent opioid users experienced opioid cues as significantly more arousing than neutral cues. Opioid dependence among chronic pain patients appears to involve an automatic AB towards opioid-related cues. When coupled with chronic pain, attentional fixation on opioid cues may promote compulsive drug use and addictive behavior. PMID:22968666

  17. Nurses' Role in Preventing Prescription Opioid Diversion.

    PubMed

    Manworren, Renee C B; Gilson, Aaron M

    2015-08-01

    Prescription opioid abuse is at epidemic levels. Opioids diverted from friends and family members who have legitimate prescriptions are a major source of abused prescription opioids. Nurses are vital to any effort to combat this public health crisis because they have the opportunity to provide essential anticipatory guidance every time a patient receives prescription medication. The purpose of this article is to inform nurses of the magnitude of opioid diversion, the nonmedical use of opioids, and opioids' inappropriate disposal. The authors propose three potential interventions in which nurses can play a critical role: teaching patients about the risks of opioid diversion, providing patients with information on the safekeeping and proper disposal of opioids, and tracking patients' analgesic use to improve our knowledge of prescription analgesic requirements for pain management. Nurses are in an ideal position to help reverse the occurrence and potentially fatal consequences of prescription opioid diversion. PMID:26186473

  18. Effects of Combined Opioids on Pain and Mood in Mammals

    PubMed Central

    Rech, Richard H.; Mokler, David J.; Briggs, Shannon L.

    2012-01-01

    The authors review the opioid literature for evidence of increased analgesia and reduced adverse side effects by combining mu-opioid-receptor (MOR) agonists, kappa-opioid-receptor (KOR) agonists, and nonselective low-dose-opioid antagonists (LD-Ant). We tested fentanyl (MOR agonist) and spiradoline (KOR agonist), singly and combined, against somatic and visceral pain models. Combined agonists induced additive analgesia in somatic pain and synergistic analgesia in visceral pain. Other investigators report similar effects and reduced tolerance and dependence with combined MOR agonist and KOR agonist. LD-Ant added to either a MOR agonist or KOR agonist markedly enhanced analgesia of either agonist. In accordance with other place-conditioning (PC) studies, our PC investigations showed fentanyl-induced place preference (CPP) and spiradoline-induced place aversion (CPA). We reduced fentanyl CPP with a low dose of spiradoline and reduced spiradoline CPA with a low dose of fentanyl. We propose combined MOR agonist, KOR agonist, and LD-Ant to produce superior analgesia with reduced adverse side effects, particularly for visceral pain. PMID:22550575

  19. Orally active opioid compounds from a non-poppy source.

    PubMed

    Raffa, Robert B; Beckett, Jaclyn R; Brahmbhatt, Vivek N; Ebinger, Theresa M; Fabian, Chrisjon A; Nixon, Justin R; Orlando, Steven T; Rana, Chintan A; Tejani, Ali H; Tomazic, Robert J

    2013-06-27

    The basic science and clinical use of morphine and other "opioid" drugs are based almost exclusively on the extracts or analogues of compounds isolated from a single source, the opium poppy (Papaver somniferum). However, it now appears that biological diversity has evolved an alternative source. Specifically, at least two alkaloids isolated from the plant Mitragyna speciosa, mitragynine ((E)-2-[(2S,3S)-3-ethyl-8-methoxy-1,2,3,4,6,7,12,12b-octahydroindolo[3,2-h]quinolizin-2-yl]-3-methoxyprop-2-enoic acid methyl ester; 9-methoxy coryantheidine; MG) and 7-hydroxymitragynine (7-OH-MG), and several synthetic analogues of these natural products display centrally mediated (supraspinal and spinal) antinociceptive (analgesic) activity in various pain models. Several characteristics of these compounds suggest a classic "opioid" mechanism of action: nanomolar affinity for opioid receptors, competitive interaction with the opioid receptor antagonist naloxone, and two-way analgesic cross-tolerance with morphine. However, other characteristics of the compounds suggest novelty, particularly chemical structure and possible greater separation from side effects. We review the chemical and pharmacological properties of these compounds. PMID:23517479

  20. Prescription opioid misuse in the United States and the United Kingdom: cautionary lessons.

    PubMed

    Weisberg, Daniel F; Becker, William C; Fiellin, David A; Stannard, Cathy

    2014-11-01

    In the United States, opioid analgesics have increasingly been prescribed in the treatment of chronic pain, and this trend has accompanied increasing rates of misuse and overdose. Lawmakers have responded with myriad policies to curb the growing epidemic of opioid misuse, and a global alarm has been sounded among countries wishing to avoid this path. In the United Kingdom, a similar trend of increasing opioid consumption, albeit at lower levels, has been observed without an increase in reported misuse or drug-related deaths. The comparison between these two countries in opioid prescribing and opioid overdose mortality underscores important features of prescribing, culture, and health systems that may be permissive or protective in the development of a public health crisis. As access to opioid medications increases around the world, it becomes vitally important to understand the forces impacting opioid use and misuse. Trends in benzodiazepine and methadone use in the UK as well as structural elements of the National Health Service may serve to buffer opioid-related harms in the face of increasing prescriptions. In addition, the availability and price of heroin, as well as the ease of access to opioid agonist treatment in the UK may limit the growth of the illicit market for prescription opioids. The comparison between the US and the UK in opioid consumption and overdose rates should serve as a call to action for UK physicians and policymakers. Basic, proactive steps in the form of surveillance - of overdoses, marketing practices, prescribers, and patients - and education programs may help avert a public health crisis as opioid prescriptions increase. PMID:25190034

  1. Identifying and assessing the risk of opioid abuse in patients with cancer: an integrative review

    PubMed Central

    Carmichael, Ashley-Nicole; Morgan, Laura; Del Fabbro, Egidio

    2016-01-01

    Background The misuse and abuse of opioid medications in many developed nations is a health crisis, leading to increased health-system utilization, emergency department visits, and overdose deaths. There are also increasing concerns about opioid abuse and diversion in patients with cancer, even at the end of life. Aims To evaluate the current literature on opioid misuse and abuse, and more specifically the identification and assessment of opioid-abuse risk in patients with cancer. Our secondary aim is to offer the most current evidence of best clinical practice and suggest future directions for research. Materials and methods Our integrative review included a literature search using the key terms “identification and assessment of opioid abuse in cancer”, “advanced cancer and opioid abuse”, “hospice and opioid abuse”, and “palliative care and opioid abuse”. PubMed, PsycInfo, and Embase were supplemented by a manual search. Results We found 691 articles and eliminated 657, because they were predominantly non cancer populations or specifically excluded cancer patients. A total of 34 articles met our criteria, including case studies, case series, retrospective observational studies, and narrative reviews. The studies were categorized into screening questionnaires for opioid abuse or alcohol, urine drug screens to identify opioid misuse or abuse, prescription drug-monitoring programs, and the use of universal precautions. Conclusion Screening questionnaires and urine drug screens indicated at least one in five patients with cancer may be at risk of opioid-use disorder. Several studies demonstrated associations between high-risk patients and clinical outcomes, such as aberrant behavior, prolonged opioid use, higher morphine-equivalent daily dose, greater health care utilization, and symptom burden. PMID:27330340

  2. Like parent, like child? Development of prejudice and tolerance towards immigrants.

    PubMed

    Miklikowska, Marta

    2016-02-01

    Although intergroup attitudes are assumed to develop due to the influence of parents, there is no longitudinal evidence supporting this claim. In addition, research on socialization of intergroup attitudes has omitted possible effects of adolescents on their parents. We also know little about the conditions under which intergroup attitudes are transmitted. This two-wave, 2 years apart, study of adolescents (N = 507) and their parents examined the relations between parents and adolescents' prejudice and tolerance from a longitudinal perspective. The study tested whether parental prejudice and tolerance would predict over-time changes in adolescents' attitudes and whether adolescents' prejudice and tolerance would elicit changes in parental attitudes. Additionally, it explored whether some of the effects would depend on perceived parental support. Results showed significant bidirectional influences between parents and adolescents' attitudes. In addition, adolescents who perceived their parents as supportive showed higher parent-adolescent correspondence in prejudice than youth with low parental support. These findings show that intergroup attitudes develop as a result of mutual influences between parents and adolescents. Hence, the unidirectional transmission model and previous research findings should be revisited. The results also suggest that parents' prejudice influence adolescents' attitudes to the extent that youth perceive their parents as supportive. PMID:25702782

  3. Development of Sulfur and Carbon Tolerant Reforming Alloy Catalysts Aided Fundamental Atomistic Insights

    SciTech Connect

    Suljo Linic

    2008-12-31

    Current hydrocarbon reforming catalysts suffer from rapid carbon and sulfur poisoning. Even though there is a tremendous incentive to develop more efficient catalysts, these materials are currently formulated using inefficient trial and error experimental approaches. We have utilized a hybrid experimental/theoretical approach, combining quantum Density Functional Theory (DFT) calculations and various state-of-the-art experimental tools, to formulate carbon tolerant reforming catalysts. We have employed DFT calculations to develop molecular insights into the elementary chemical transformations that lead to carbon poisoning of Ni catalysts. Based on the obtained molecular insights, we have identified, using DFT quantum calculation, various Ni alloy catalysts as potential carbon tolerant reforming catalysts. The alloy catalysts were synthesized and tested in steam reforming and partial oxidation of methane, propane, and isooctane. We demonstrated that the alloy catalysts are much more carbon-tolerant than monometallic Ni catalysts under nearly stoichiometric steam-to-carbon ratios. Under these conditions, monometallic Ni is rapidly poisoned by sp2 carbon deposits. The research approach is distinguished by two characteristics: (a) knowledge-based, bottomup approach, compared to the traditional trial and error approach, allows for a more efficient and systematic discovery of improved catalysts. (b) the focus is on exploring alloy materials which have been largely unexplored as potential reforming catalysts.

  4. Development of Sulfur and Carbon Tolerant Reforming Alloy Catalysts Aided by Fundamental Atomistics Insights

    SciTech Connect

    Suljo Linic

    2006-08-31

    Current hydrocarbon reforming catalysts suffer from rapid carbon and sulfur poisoning. Even though there is a tremendous incentive to develop more efficient catalysts, these materials are currently formulated using inefficient trial and error experimental approaches. We have utilized a novel hybrid experimental/theoretical approach, combining quantum Density Functional Theory (DFT) calculations and various state-of-the-art experimental tools, to formulate carbon tolerant reforming catalysts. We have employed DFT calculations to develop molecular insights into the elementary chemical transformations that lead to carbon poisoning of Ni catalysts. Based on the obtained molecular insights, we have identified, using DFT quantum calculation, Sn/Ni alloy as a potential carbon tolerant reforming catalyst. Sn/Ni alloy was synthesized and tested in steam reforming of methane, propane, and isooctane. We demonstrated that the alloy catalyst is carbon-tolerant under nearly stoichiometric steam-to-carbon ratios. Under these conditions, monometallic Ni is rapidly poisoned by sp2 carbon deposits. The research approach is distinguished by a few characteristics: (a) Knowledge-based, bottom-up approach, compared to the traditional trial and error approach, allows for a more efficient and systematic discovery of improved catalysts. (b) The focus is on exploring alloy materials which have been largely unexplored as potential reforming catalysts.

  5. Brain acetylcholinesterase diurnal variations during the rapid development of tolerance to the hypothermic effect of ethanol

    SciTech Connect

    Wang, O.; Soliman, K.F.A. )

    1991-03-11

    Male Sprague-Dawley rats maintained under controlled environmental conditions were used. Acetylcholinesterase (AChE) activity was determined in the cerebral cortex, midbrain, hypothalamus, hippocampus, cerebellum, pons and medulla oblongata of saline control and ethanol-treated rats, either after a single dose at 06:0 or 18:00h, or after a second dose administered 24 hrs later at the same time scheduled. Results of this experiment indicate that repeated administration with ethanol was associated with the rapid development of tolerance to the hypothermic action of ethanol. A single injection of ethanol at 0600h resulted in a significant decrease in AChE activity in the hypothalamus, medulla, cerebellum, hippocampus and the cortex. However, ethanol administration at 18.00h was associated with significant increases in AChE activity in the same brain regions. The repeated administration of ethanol at 06.00h was associated with tolerance in AChE response to ethanol in the hypothalamus and hippocampus. However, there was no tolerance development in AChE activity in brain regions when ethanol was administered at 18.00h. The results indicate that chronotolerance to ethanol might be related to the brain cholinergic system.

  6. Development of tolerance against toxic Microcystis aeruginosa in three cladocerans and the ecological implications.

    PubMed

    Guo, Nichun; Xie, Ping

    2006-10-01

    This is the first experimental study to compare difference in the development of tolerance against toxic Microcystis among multi-species of cladocerans (Daphnia, Moina and Ceriodaphnia) pre-exposed to two M. aeruginosa PCC7820 strains (MC-containing and MC-free). Zooplankton were divided into S population (fed Scenedesmus), M-F population (fed Scenedesmus+MC-free Microcystis), and M-C population (fed Scenedesmus+MC-containing Microcystis). M-F and M-C populations were pre-exposed to Microcystis strains for 4 weeks, and their newborns were collected for experiments. A pre-exposure to MC-containing or MC-free Microcystis increased tolerance against toxic Microcystis. The marked increases in survival rate and median lethal time (LT(50), 100-194% increase) in the M-C population of Ceriodaphnia suggest that small-sized cladocerans may develop stronger tolerance against Microcystis than large-sized ones when both groups are exposed to toxic Microcystis. This may explain why dominant Daphnia is usually replaced by small-sized cladocerans when cyanobacteria bloomed in summer in eutrophic lakes. PMID:16448731

  7. Brain cholinergic involvement during the rapid development of tolerance to morphine

    NASA Technical Reports Server (NTRS)

    Wahba, Z. Z.; Oriaku, E. T.; Soliman, S. F. A.

    1987-01-01

    The effect of repeated administration of morphine on the activities of the cholinergic enzymes, choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), in specific brain regions were studied in rats treated with 10 mg/kg morphine for one or two days. Repeated administration of morphine was associated with a decline in the degree of analgesia produced and with a significant increase of AChE activity of the medulla oblongata. A single injection of morphine resulted in a significant decline in ChAT activity in the hypothalamus, cerebellum, and medulla oblongata regions. After two consecutive injections, no decline in ChAT was observed in these regions, while in the cerebral cortex the second administration elicited a significant decline. The results suggest that the development of tolerance to morphine may be mediated through changes in ChAT activity and lend support to the involvement of the central cholinergic system in narcotic tolerance.

  8. The opioid/nonopioid nature of stress-induced analgesia and learned helplessness.

    PubMed

    Maier, S F; Sherman, J E; Lewis, J W; Terman, G W; Liebeskind, J C

    1983-01-01

    Exposure to a variety of stressors produces a subsequent analgesic reaction. This stress-induced analgesia (SIA) is sometimes opioid in nature (reversed by opiate antagonists and cross-tolerant with morphine) and sometimes nonopioid. Both 30 min of intermittent footshock and 60-80 five-sec tailshocks have been shown to produce opioid SIA, whereas 3 min of continuous footshock and 5-40 tailshocks produce nonopioid SIA. We report that both of the opioid SIA procedures produce a learned helplessness effect as assessed by shuttlebox escape acquisition and an analgesia that is reinstatable 24 hr. later. The nonopioid procedures produce neither a learned helplessness effect nor a reinstatable analgesia. It is argued that these data implicate the learning of uncontrollability in the activation of opioid systems. PMID:6682435

  9. Prescription opioid use and misuse

    PubMed Central

    Srivastava, Anita; Kahan, Meldon; Jiwa, Ashifa

    2012-01-01

    Abstract Objective To evaluate the feasibility and effectiveness of a multifaceted educational intervention to improve the opioid prescribing practices of rural family physicians in a remote First Nations community. Design Prospective cohort study. Setting Sioux Lookout, Ont. Participants Family physicians. Interventions Eighteen family physicians participated in a 1-year study of a series of educational interventions on safe opioid prescribing. Interventions included a main workshop with a lecture and interactive case discussions, an online chat room, video case conferencing, and consultant support. Main outcome measures Responses to questionnaires at baseline and after 1 year on knowledge, attitudes, and practices related to opioid prescribing. Results The main workshop was feasible and was well received by primary care physicians in remote communities. At 1 year, physicians were less concerned about getting patients addicted to opioids and more comfortable with opioid dosing. Conclusion Multifaceted education and consultant support might play an important role in improving family physician comfort with opioid prescribing, and could improve the treatment of chronic pain while minimizing the risk of addiction. PMID:22611608

  10. Constipation in people prescribed opioids

    PubMed Central

    2010-01-01

    Introduction Constipation is reported in 52% of people with advanced malignancy. This figure rises to 87% in people who are terminally ill and taking opioids. Constipation may be the most common adverse effect of opioids. There is no reason to believe that people with chronic non-malignant disease who take opioids will be any less troubled by this adverse effect. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of: oral laxatives, rectally applied medications, and opioid antagonists for constipation in people prescribed opioids? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2009 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 23 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: arachis oil enemas, bisacodyl, co-danthrusate/co-danthramer, docusate, glycerol suppositories, ispaghula husk, lactulose, liquid paraffin, macrogols plus electrolyte solutions, magnesium salts, methylcellulose, opioid antagonists, phosphate enemas, senna, sodium citrate micro-enema, and sodium picosulfate. PMID:21718572

  11. Mu Opioid Receptors on Primary Afferent Nav1.8 Neurons Contribute to Opiate-Induced Analgesia: Insight from Conditional Knockout Mice

    PubMed Central

    Karchewski, Laurie; Gardon, Olivier; Matifas, Audrey; Filliol, Dominique; Becker, Jérôme A. J.; Wood, John N.; Kieffer, Brigitte L.; Gaveriaux-Ruff, Claire

    2013-01-01

    Opiates are powerful drugs to treat severe pain, and act via mu opioid receptors distributed throughout the nervous system. Their clinical use is hampered by centrally-mediated adverse effects, including nausea or respiratory depression. Here we used a genetic approach to investigate the potential of peripheral mu opioid receptors as targets for pain treatment. We generated conditional knockout (cKO) mice in which mu opioid receptors are deleted specifically in primary afferent Nav1.8-positive neurons. Mutant animals were compared to controls for acute nociception, inflammatory pain, opiate-induced analgesia and constipation. There was a 76% decrease of mu receptor-positive neurons and a 60% reduction of mu-receptor mRNA in dorsal root ganglia of cKO mice. Mutant mice showed normal responses to heat, mechanical, visceral and chemical stimuli, as well as unchanged morphine antinociception and tolerance to antinociception in models of acute pain. Inflammatory pain developed similarly in cKO and controls mice after Complete Freund’s Adjuvant. In the inflammation model, however, opiate-induced (morphine, fentanyl and loperamide) analgesia was reduced in mutant mice as compared to controls, and abolished at low doses. Morphine-induced constipation remained intact in cKO mice. We therefore genetically demonstrate for the first time that mu opioid receptors partly mediate opiate analgesia at the level of Nav1.8-positive sensory neurons. In our study, this mechanism operates under conditions of inflammatory pain, but not nociception. Previous pharmacology suggests that peripheral opiates may be clinically useful, and our data further demonstrate that Nav1.8 neuron-associated mu opioid receptors are feasible targets to alleviate some forms of persistent pain. PMID:24069332

  12. Rapid Crown Root Development Confers Tolerance to Zinc Deficiency in Rice

    PubMed Central

    Nanda, Amrit K.; Wissuwa, Matthias

    2016-01-01

    Zinc (Zn) deficiency is one of the leading nutrient disorders in rice (Oryza sativa). Many studies have identified Zn-efficient rice genotypes, but causal mechanisms for Zn deficiency tolerance remain poorly understood. Here, we report a detailed study of the impact of Zn deficiency on crown root development of rice genotypes, differing in their tolerance to this stress. Zn deficiency delayed crown root development and plant biomass accumulation in both Zn-efficient and inefficient genotypes, with the effects being much stronger in the latter. Zn-efficient genotypes had developed new crown roots as early as 3 days after transplanting (DAT) to a Zn deficient field and that was followed by a significant increase in total biomass by 7 DAT. Zn-inefficient genotypes developed few new crown roots and did not increase biomass during the first 7 days following transplanting. This correlated with Zn-efficient genotypes retranslocating a higher proportion of shoot-Zn to their roots, compared to Zn-inefficient genotypes. These latter genotypes were furthermore not efficient in utilizing the limited Zn for root development. Histological analyses indicated no anomalies in crown tissue of Zn-efficient or inefficient genotypes that would have suggested crown root emergence was impeded. We therefore conclude that the rate of crown root initiation was differentially affected by Zn deficiency between genotypes. Rapid crown root development, following transplanting, was identified as a main causative trait for tolerance to Zn deficiency and better Zn retranslocation from shoot to root was a key attribute of Zn-efficient genotypes. PMID:27066060

  13. Rapid Crown Root Development Confers Tolerance to Zinc Deficiency in Rice.

    PubMed

    Nanda, Amrit K; Wissuwa, Matthias

    2016-01-01

    Zinc (Zn) deficiency is one of the leading nutrient disorders in rice (Oryza sativa). Many studies have identified Zn-efficient rice genotypes, but causal mechanisms for Zn deficiency tolerance remain poorly understood. Here, we report a detailed study of the impact of Zn deficiency on crown root development of rice genotypes, differing in their tolerance to this stress. Zn deficiency delayed crown root development and plant biomass accumulation in both Zn-efficient and inefficient genotypes, with the effects being much stronger in the latter. Zn-efficient genotypes had developed new crown roots as early as 3 days after transplanting (DAT) to a Zn deficient field and that was followed by a significant increase in total biomass by 7 DAT. Zn-inefficient genotypes developed few new crown roots and did not increase biomass during the first 7 days following transplanting. This correlated with Zn-efficient genotypes retranslocating a higher proportion of shoot-Zn to their roots, compared to Zn-inefficient genotypes. These latter genotypes were furthermore not efficient in utilizing the limited Zn for root development. Histological analyses indicated no anomalies in crown tissue of Zn-efficient or inefficient genotypes that would have suggested crown root emergence was impeded. We therefore conclude that the rate of crown root initiation was differentially affected by Zn deficiency between genotypes. Rapid crown root development, following transplanting, was identified as a main causative trait for tolerance to Zn deficiency and better Zn retranslocation from shoot to root was a key attribute of Zn-efficient genotypes. PMID:27066060

  14. Morphine-induced internalization of the L83I mutant of the rat μ-opioid receptor

    PubMed Central

    Cooke, A E; Oldfield, S; Krasel, C; Mundell, S J; Henderson, G; Kelly, E

    2015-01-01

    BACKGROUND AND PURPOSE Naturally occurring single-nucleotide polymorphisms (SNPs) within GPCRs can result in alterations in various pharmacological parameters. Understanding the regulation and function of endocytic trafficking of the μ-opioid receptor (MOP receptor) is of great importance given its implication in the development of opioid tolerance. This study has compared the agonist-dependent trafficking and signalling of L83I, the rat orthologue of a naturally occurring variant of the MOP receptor. EXPERIMENTAL APPROACH Cell surface elisa, confocal microscopy and immunoprecipitation assays were used to characterize the trafficking properties of the MOP-L83I variant in comparison with the wild-type receptor in HEK 293 cells. Functional assays were used to compare the ability of the L83I variant to signal to several downstream pathways. KEY RESULTS Morphine-induced internalization of the L83I MOP receptor was markedly increased in comparison with the wild-type receptor. The altered trafficking of this variant was found to be specific to morphine and was both G-protein receptor kinase- and dynamin-dependent. The enhanced internalization of L83I variant in response to morphine was not due to increased phosphorylation of serine 375, arrestin association or an increased ability to signal. CONCLUSIONS AND IMPLICATIONS These results suggest that morphine promotes a specific conformation of the L83I variant that makes it more liable to internalize in response to morphine, unlike the wild-type receptor that undergoes significantly less morphine-stimulated internalization, providing an example of a ligand-selective biased receptor. The presence of this SNP within an individual may consequently affect the development of tolerance and analgesic responses. LINKED ARTICLES 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 PMID:24697554

  15. Does selection on increased cold tolerance in the adult stage confer resistance throughout development?

    PubMed

    Dierks, A; Kölzow, N; Franke, K; Fischer, K

    2012-08-01

    Artificial selection is a powerful approach to unravel constraints on genetic adaptation. Although it has been frequently used to reveal genetic trade-offs among different fitness-related traits, only a few studies have targeted genetic correlations across developmental stages. Here, we test whether selection on increased cold tolerance in the adult stage increases cold resistance throughout ontogeny in the butterfly Bicyclus anynana. We used lines selected for decreased chill-coma recovery time and corresponding controls, which had originally been set up from three levels of inbreeding (outbred control, one or two full-sib matings). Four generations after having terminated selection, a response to selection was found in 1-day-old butterflies (the age at which selection took place). Older adults showed a very similar although weaker response. Nevertheless, cold resistance did not increase in either egg, larval or pupal stage in the selection lines but was even lower compared to control lines for eggs and young larvae. These findings suggest a cost of increased adult cold tolerance, presumably reducing resource availability for offspring provisioning and thereby stress tolerance during development, which may substantially affect evolutionary trajectories. PMID:22686583

  16. Long- or short-acting opioids for chronic non-malignant pain? A qualitative systematic review.

    PubMed

    Pedersen, L; Borchgrevink, P C; Riphagen, I I; Fredheim, O M S

    2014-04-01

    In selected patients with chronic non-malignant pain, chronic opioid therapy is indicated. Published guidelines recommend long-acting over short-acting opioids in these patients. The aim of this systematic review was to investigate whether long-acting opioids in chronic non-malignant pain are superior to short-acting opioids in pain relief, physical function, sleep quality, quality of life or adverse events. This review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. PubMed, Embase and Cochrane Central Register of Controlled Trials were searched for relevant trials up to July 2012. Reference lists of included trials and relevant reviews were in addition searched by hand. Of the 1168 identified publications, 6 randomised trials evaluating efficacy and safety filled the criteria for inclusion. None of them found a significantly better pain relief, significantly less consumption of rescue analgesia, improved quality of sleep or improved physical function from long-acting opioids. None of the trials investigated quality of life. None of the trials investigated adverse events properly nor addiction, tolerance or hyperalgesia. Three trials in healthy volunteers with a recreational drug use, found no difference in abuse potential between long- and short-acting opioids. While long term, comparative data are lacking, there is fair evidence from short-term trials that long-acting opioids provide equal pain relief compared with short-acting opioids. Contrary to several guidelines, there is no evidence supporting long-acting opioids superiority to short-acting ones in improving functional outcomes, reducing side effects or addiction. PMID:24617618

  17. Using opioids in general practice for chronic non-cancer pain: an overview of current evidence.

    PubMed

    Currow, David C; Phillips, Jane; Clark, Katherine

    2016-05-01

    Chronic non-cancer pain (lasting more than 3 months) is highly prevalent in Australia (17% of males and 20% of females) and its optimal management is crucial to the health and wellbeing of the community. For 5% of the population, such pain interferes markedly with daily function. Part of the treatment for acute non-cancer pain for many people will include opioid analgesics at least for days to weeks. However, as pain becomes chronic, evidence to support ongoing prescription of opioids is lacking. There is increasing pressure to ensure that prescribing opioid analgesics is minimised to reduce not only the risk of dependence and illicit diversion but also the potential harms associated with tolerance, side effects and complications. Frameworks for considering opioid prescribing include assessing suitability of the patient for opioids; initiating a trial of therapy; and monitoring long term use. There is limited evidence of the long term efficacy of opioids for chronic non-cancer pain, and documented clinical consequences beyond addiction include acceleration of loss of bone mineral density, hypogonadism and an association with increased risk of acute myocardial infarction. Careful clinical selection of patients can help optimise the evidence-based use of opioids for chronic non-cancer pain: only treat pain that has been as well defined as possible when non-opioid therapies have not been effective; consider referral to specialist services for assessment if doses are above 100 mg oral morphine equivalent per 24 hours or the duration of therapy is longer than 4 weeks; limit prescribing to only one practitioner; seek an agreement with the patient for the initiation and potential withdrawal of opioids if the therapeutic trial is not effective. PMID:27125804

  18. The role of ontogeny in physiological tolerance: decreasing hydrostatic pressure tolerance with development in the northern stone crab Lithodes maja

    PubMed Central

    Munro, Catriona; Morris, James P.; Brown, Alastair; Hauton, Chris; Thatje, Sven

    2015-01-01

    Extant deep-sea invertebrate fauna represent both ancient and recent invasions from shallow-water habitats. Hydrostatic pressure may present a significant physiological challenge to organisms seeking to colonize deeper waters or migrate ontogenetically. Pressure may be a key factor contributing to bottlenecks in the radiation of taxa and potentially drive speciation. Here, we assess shifts in the tolerance of hydrostatic pressure through early ontogeny of the northern stone crab Lithodes maja, which occupies a depth range of 4–790 m in the North Atlantic. The zoea I, megalopa and crab I stages were exposed to hydrostatic pressures up to 30.0 MPa (equivalent of 3000 m depth), and the relative fold change of genes putatively coding for the N-methyl-d-aspartate receptor-regulated protein 1 (narg gene), two heat-shock protein 70 kDa (HSP70) isoforms and mitochondrial Citrate Synthase (CS gene) were measured. This study finds a significant increase in the relative expression of the CS and hsp70a genes with increased hydrostatic pressure in the zoea I stage, and an increase in the relative expression of all genes with increased hydrostatic pressure in the megalopa and crab I stages. Transcriptional responses are corroborated by patterns in respiratory rates in response to hydrostatic pressure in all stages. These results suggest a decrease in the acute high-pressure tolerance limit as ontogeny advances, as reflected by a shift in the hydrostatic pressure at which significant differences are observed. PMID:26041343

  19. Opioid-induced hyperalgesia (OIH): a real clinical problem or just an experimental phenomenon?

    PubMed

    Eisenberg, Elon; Suzan, Erica; Pud, Dorit

    2015-03-01

    Although opioid-induced hyperalgesia (OIH) is mentioned as a potential cause of opioid dose escalation without adequate analgesia, true evidence in support of this notion is relatively limited. Most studies conducted in the context of acute and experimental pain, which seemingly demonstrated evidence for OIH, actually might have measured other phenomena such as acute opioid withdrawal or tolerance. OIH studies in patients with chronic pain have used various experimental pain models (such as cold pain tolerance or heat pain intensity). Therefore, the fact that they have yielded inconsistent results is hard to interpret. Thus far, with the exception of a few clinical case reports on OIH in patients with cancer pain and one prospective study in patients with chronic neuropathic pain, evidence for OIH in patients with chronic or cancer-related pain is lacking. Whether experimental pain models are necessary for establishing the clinical diagnosis of OIH, and which specific model is preferred, are yet to be determined. PMID:25128284

  20. Dosakaya Juice Assuages Development of Sucrose Induced Impaired Glucose Tolerance and Imbalance in Antioxidant Defense

    PubMed Central

    Kumar, Dommati Anand; Sweeya, Pisupati S. R.; Shukla, Srishti; Anusha, Sanga Venkata; Akshara, Dasari; Madhusudana, Kuncha; Tiwari, Ashok Kumar

    2015-01-01

    Objective: The objective was to explore the effect of Dosakaya (DK) (Cucumis melo var. chito) juice on sucrose induced dysglycemia and disturbances in antioxidant defense in rats. Materials and Methods: Rats were preconditioned with DK juice before administration of sucrose beverage continuously for 1-month. Blood glucose tolerance test and glutathione (GSH) homeostasis pathways in kidney were analyzed in different group of animals at the end of the study. Results: DK juice diffused (P < 0.001) hypertriglyceridemia inducing effect of sucrose and arrested sucrose induced weight gain. It improved glucose tolerance ability by significantly reducing (P < 0.05) first-hour glycemic excursion and decreasing 2 h glycemic load (P < 0.05) following oral glucose tolerance test in sucrose fed animals. Furthermore, disturbances in antioxidant defense mechanisms in terms of GSH homeostasis in kidney were restored due to juice feeding. DK juice administration checked reduction in GSH-S-transferase and glyoxalase-I activity, thus, significantly mitigated lipid peroxidation (P < 0.05), and formation of advanced glycation end-products (P < 0.001) in kidney and serum (P < 0.01). Quantitative analysis of juice found it a rich source of protein and polyphenols. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis revealed the presence of multiple protein bands in whole fruit juice. Therefore, SDS-PAGE protein fingerprint of DK juice may serve as a quality control tool for standardization of juice. Conclusion: The whole fruit juice of DK may become cost-effective, affordable health beverage in extenuating ill-health effects of sugar consumption. This is the first report identifying DK juice in preventing development dysglycemia, dyslipidemia, and oxidative stress induced due to chronic sucrose feeding in rats. SUMMARY Chronic sucrose consumption induced development of dysglycemia and also impaired antioxidant defense mechanism in rats. The oral administration of

  1. Pain Raises Risk of Opioid Addiction

    MedlinePlus

    ... fullstory_160033.html Pain Raises Risk of Opioid Addiction Men and younger people had higher odds of ... had a 41 percent higher risk of opioid addiction than those with no pain. That increased risk ...

  2. FDA Approves Implant to Battle Opioid Addiction

    MedlinePlus

    ... 159050.html FDA Approves Implant to Battle Opioid Addiction Experts say steady dosing eliminates need to take ... U.S. Food and Drug Administration. "Opioid abuse and addiction have taken a devastating toll on American families. ...

  3. Common Surgeries Raise Risk for Opioid Dependence

    MedlinePlus

    ... fullstory_159815.html Common Surgeries Raise Risk for Opioid Dependence: Study Doctors should explore alternatives for pain ... have an elevated risk of growing dependent on opioid painkillers, a new study finds. These prescription painkillers ...

  4. Challenges for opioid receptor nomenclature: IUPHAR Review 9

    PubMed Central

    Cox, Brian M; Christie, Macdonald J; Devi, Lakshmi; Toll, Lawrence; Traynor, John R

    2015-01-01

    Recent developments in the study of the structure and function of opioid receptors raise significant challenges for the definition of individual receptor types and the development of a nomenclature that precisely describes isoforms that may subserve different functions in vivo. Presentations at the 2013 meeting of the International Narcotics Research Conference in Cairns, Australia, considered some of the new discoveries that are now unravelling the complexities of opioid receptor signalling. Variable processing of opioid receptor messenger RNAs may lead to the presence of several isoforms of the μ receptor. Each opioid receptor type can function either as a monomer or as part of a homo- or heterodimer or higher multimer. Additionally, recent evidence points to the existence of agonist bias in the signal transduction pathways activated through μ receptors, and to the presence of regulatory allosteric sites on the receptors. This brief review summarizes the recent discoveries that raise challenges for receptor definition and the characterization of signal transduction pathways activated by specific receptor forms. LINKED ARTICLES 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 PMID:24528283

  5. Use of Opioids and Sedatives at End-of-Life

    PubMed Central

    Sim, Shin Wei; Ho, Shirlynn; Kumar, Radha Krishna Lalit

    2014-01-01

    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. PMID:25125876

  6. Fault Tolerant Magnetic Bearing Testing and Conical Magnetic Bearing Development for Extreme Temperature Environments

    NASA Technical Reports Server (NTRS)

    Keith, Theo G., Jr.; Clark, Daniel

    2004-01-01

    During the six month tenure of the grant, activities included continued research of hydrostatic bearings as a viable backup-bearing solution for a magnetically levitated shaft system in extreme temperature environments (1000 F), developmental upgrades of the fault-tolerant magnetic bearing rig at the NASA Glenn Research Center, and assisting in the development of a conical magnetic bearing for extreme temperature environments, particularly turbomachinery. It leveraged work from the ongoing Smart Efficient Components (SEC) and the Turbine-Based Combined Cycle (TBCC) program at NASA Glenn Research Center. The effort was useful in providing technology for more efficient and powerful gas turbine engines.

  7. The Development of Design Tools for Fault Tolerant Quantum Dot Cellular Automata Based Logic

    NASA Technical Reports Server (NTRS)

    Armstrong, Curtis D.; Humphreys, William M.

    2003-01-01

    We are developing software to explore the fault tolerance of quantum dot cellular automata gate architectures in the presence of manufacturing variations and device defects. The Topology Optimization Methodology using Applied Statistics (TOMAS) framework extends the capabilities of the A Quantum Interconnected Network Array Simulator (AQUINAS) by adding front-end and back-end software and creating an environment that integrates all of these components. The front-end tools establish all simulation parameters, configure the simulation system, automate the Monte Carlo generation of simulation files, and execute the simulation of these files. The back-end tools perform automated data parsing, statistical analysis and report generation.

  8. Opioid-use disorder among patients on long-term opioid therapy: impact of final DSM-5 diagnostic criteria on prevalence and correlates

    PubMed Central

    Boscarino, Joseph A; Hoffman, Stuart N; Han, John J

    2015-01-01

    Aims Previously, we estimated the prevalence and risk factors for prescription opioid-use disorder among outpatients on opioid therapy using the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 and DSM-4 criteria. However, at the time, the DSM-5 criteria were not finalized. In the current study, we analyzed these data using the final DSM-5 criteria and compared these results. Methods Using electronic records from a large US health care system, we identified outpatients receiving five or more prescription orders for opioid therapy in the past 12 months for noncancer pain (mean prescription orders =10.72; standard deviation =4.96). In 2008, we completed diagnostic interviews with 705 of these patients using the DSM-4 criteria. In the current study, we reassessed these results using the final DSM-5 criteria. Results The lifetime prevalence of DSM-5 opioid-use disorders using the final DSM-5 criteria was 58.7% for no or few symptoms (<2), 28.1% for mild symptoms (2–3), 9.7% for moderate symptoms (4–5), and 3.5% for severe symptoms (six or more). Thus, the lifetime prevalence of “any” prescription opioid-use disorder in this cohort was 41.3% (95% confidence interval [CI] =37.6–45.0). A comparison to the DSM-4 criteria indicated that the majority of patients with lifetime DSM-4 opioid dependence were now classified as having mild opioid-use disorder, based on the DSM-5 criteria (53.6%; 95% CI =44.1–62.8). In ordinal logistic regression predicting no/few, mild, moderate, and severe opioid-use disorder, the best predictors were age <65 years, current pain impairment, trouble sleeping, suicidal thoughts, anxiety disorders, illicit drug use, and history of substance abuse treatment. Conclusion Given the final DSM-5 criteria, including the elimination of tolerance and withdrawal, inclusion of craving and abuse symptoms, and introduction of a new graded severity classification, the prevalence of opioid-use disorders has changed, while many of the DSM-4

  9. Sustained-Release Buprenorphine (RBP-6000) Blocks the Effects of Opioid Challenge With Hydromorphone in Subjects With Opioid Use Disorder.

    PubMed

    Nasser, Azmi F; Greenwald, Mark K; Vince, Bradley; Fudala, Paul J; Twumasi-Ankrah, Philip; Liu, Yongzhen; Jones, J P; Heidbreder, Christian

    2016-02-01

    A major goal for the treatment of opioid use disorder is to reduce or eliminate the use of illicit opioids. Buprenorphine, a μ-opioid receptor partial agonist and kappa opioid receptor antagonist, is now being developed as a monthly, sustained-release formulation (RBP-6000). The objective of this study was to demonstrate that RBP-6000 blocks the subjective effects and reinforcing efficacy of the μ-opioid receptor agonist hydromorphone (intramuscularly administered) in subjects with moderate or severe opioid use disorder. Subjects were first inducted and dose stabilized on sublingual buprenorphine/naloxone (8-24 mg daily; dose expressed as the buprenorphine component), then received two subcutaneous injections of RBP-6000 (300 mg) on Day 1 and Day 29. Hydromorphone challenges (6 mg, 18 mg or placebo administered in randomized order) occurred on 3 consecutive days of each study week before and after receiving RBP-6000. Subjects reported their responses to each challenge on various 100-mm Visual Analogue Scales (VAS). Subjects also completed a choice task to assess the reinforcing efficacy of each hydromorphone dose relative to money. At baseline, mean "drug liking" VAS scores for hydromorphone 18 mg and 6 mg versus placebo were 61 mm (95% confidence interval, 52.3-68.9) and 45 mm (95% confidence interval, 37.2-53.6), respectively. After 300 mg RBP-6000 was administered, mean VAS score differences from placebo were less than 10 mm through week 12. The reinforcing efficacy of hydromorphone decreased in a parallel manner. This study demonstrated that RBP-6000 at a 300 mg dose provides durable and potent blockade of the subjective effects and reinforcing efficacy of hydromorphone in subjects with moderate or severe opioid use disorder. PMID:26650971

  10. A new potent analgesic agent with reduced liability to produce morphine tolerance.

    PubMed

    Kiraly, Kornel; Caputi, Francesca Felicia; Hanuska, Adrienn; Kató, Erzsébet; Balogh, Mihaly; Köles, László; Palmisano, Martina; Riba, Pal; Hosztafi, Sándor; Romualdi, Patrizia; Candeletti, Sanzio; Ferdinandy, Péter; Fürst, Susanna; Al-Khrasani, Mahmoud

    2015-08-01

    The therapeutic use of opioids is limited by the development of tolerance to the analgesic effect and the cellular and molecular mechanisms underlying this phenomenon are still not completely understood. For this reason the search for new analgesic derivatives, endowed with lower tolerance, is always an active field. The newly synthesized 14-O-Methylmorphine-6-sulfate (14-O-MeM6SU) shows high efficacy in in vitro assays and a strong analgesic action in the rat tail flick test. The aim of present work was to investigate: the analgesic effect of 14-O-MeM6SU in mouse tail-flick test; the tolerance to analgesic effect of 14-O-MeM6SU compared to morphine in mice, the effects of test compounds on glutamatergic neurotransmission by measuring spontaneous excitatory postsynaptic currents (sEPSCs) of layer V pyramidal cells from rat prefrontal cortices; and the effect of acute and chronic 14-O-MeM6SU treatments on opioid receptor gene expression in SH-SY5Y neuroblastoma cells expressing μ-opioid (MOP) and nociceptin/opioid receptor-like 1 (NOP) receptors. 14-O-MeM6SU was 17 times more potent than morphine in analgesia and had long duration of action in analgesic dose equipotent to morphine. Mice were treated subcutaneously (s.c.) either with 200 μmol/kg morphine or with 14-O-MeM6SU (12 μmol/kg) twice daily for three days. The magnitude of tolerance or cross-tolerance indicated by the shift in antinociceptive ED50 measured was greater for morphine compared to 14-O-MeM6SU. Subsequent to behavioral testing, patch-clamp experiments in layer V pyramidal neurons of rat prefrontal cortical slices in the presence of bicuculline were performed. Both 14-O-MeM6SU (0.1 μM) and morphine (1 μM) decreased the frequency of sEPSCs, indicating reduction of glutamate release. The effect of the novel compound was reversed by the opioid receptor antagonist naloxone, indicating an opioid mediated action. In contrast, the amplitude was not affected. Finally, gene expression data showed a dose

  11. Development of N-version software samples for an experiment in software fault tolerance

    NASA Technical Reports Server (NTRS)

    Lauterbach, L.

    1987-01-01

    The report documents the task planning and software development phases of an effort to obtain twenty versions of code independently designed and developed from a common specification. These versions were created for use in future experiments in software fault tolerance, in continuation of the experimental series underway at the Systems Validation Methods Branch (SVMB) at NASA Langley Research Center. The 20 versions were developed under controlled conditions at four U.S. universities, by 20 teams of two researchers each. The versions process raw data from a modified Redundant Strapped Down Inertial Measurement Unit (RSDIMU). The specifications, and over 200 questions submitted by the developers concerning the specifications, are included as appendices to this report. Design documents, and design and code walkthrough reports for each version, were also obtained in this task for use in future studies.

  12. Interdose interval effects on the development of contextual tolerance to nicotine's analgesic effects in rats (Rattus norvegicus).

    PubMed

    Cepeda-Benito, Antonio; Reynoso, Jose T; Davis, Kristina W; Susabda, Agnes; Mendez, Ian A; Harraid, James H

    2006-05-01

    Learning models of associative and nonassociative drug tolerance predict that the development of contextual tolerance to drug effects is disrupted when the drug is delivered at short interdose intervals (IDIs). The authors examined the impact of 1 long IDI and 2 short IDIs in the development of contextual nicotine tolerance. Associative tolerance was investigated by giving rats (Rattus norvegicus) 10 subcutaneous injections of nicotine at either long (72-hr) IDIs or short (6-hr and 4.5-hr) IDIs. The delivery of nicotine was either explicitly paired or explicitly unpaired with a distinctive context. A 3rd group of rats was exposed to the experimental procedures but received only saline. Associative tolerance to nicotine's analgesic effects was defined as a shift to the right of the dose-response curve (DRC) of rats in the explicitly paired condition with respect to the DRC of rats in the explicitly unpaired condition. Analgesia was assessed with the tail-flick and hot-plate devices. In the tail-flick assessment, associative tolerance was evident in the 72-hr and the 6-hr IDI conditions only. In the hot-plate assessment, associative tolerance was present in the 72-hr IDI condition only. The findings suggest that contextual tolerance to nicotine's analgesic effects are positively related to IDI length and are more readily demonstrated with the tail-flick method than with the hot-plate method. Overall, the results supported the thesis that nicotine tolerances that develop to different IDIs are qualitatively different and may be mediated by different psychological and physiological mechanisms. PMID:16756422

  13. Emerging therapies for patients with symptoms of opioid-induced bowel dysfunction

    PubMed Central

    Leppert, Wojciech

    2015-01-01

    , and OXN may be also considered as a preventive measure of OIBD development in patients who require opioid administration. PMID:25931815

  14. Nucleus accumbens μ-opioid receptors mediate social reward.

    PubMed

    Trezza, Viviana; Damsteegt, Ruth; Achterberg, E J Marijke; Vanderschuren, Louk J M J

    2011-04-27

    Positive social interactions are essential for emotional well-being and proper behavioral development of young individuals. Here, we studied the neural underpinnings of social reward by investigating the involvement of opioid neurotransmission in the nucleus accumbens (NAc) in social play behavior, a highly rewarding social interaction in adolescent rats. Intra-NAc infusion of morphine (0.05-0.1 μg) increased pinning and pouncing, characteristic elements of social play behavior in rats, and blockade of NAc opioid receptors with naloxone (0.5 μg) prevented the play-enhancing effects of systemic morphine (1 mg/kg, s.c.) administration. Thus, stimulation of opioid receptors in the NAc was necessary and sufficient for morphine to increase social play. Intra-NAc treatment with the selective μ-opioid receptor agonist [D-Ala(2),N-MePhe(4),Gly(5)-ol]enkephalin (DAMGO) (0.1-10 ng) and the μ-opioid receptor antagonist Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) (0.3-3 μg) increased and decreased social play, respectively. The δ-opioid receptor agonist DPDPE ([D-Pen(2),D-Pen(5)]-enkephalin) (0.3-3 μg) had no effects, whereas the κ-opioid receptor agonist U69593 (N-methyl-2-phenyl-N-[(5R,7S,8S)-7-(pyrrolidin-1-yl)-1-oxaspiro[4.5]dec-8-yl]acetamide) (0.01-1 μg) decreased social play. Intra-NAc treatment with β-endorphin (0.01-1 μg) increased social play, but met-enkephalin (0.1-5 μg) and the enkephalinase inhibitor thiorphan (0.1-1 μg) were ineffective. DAMGO (0.1-10 ng) increased social play after infusion into both the shell and core subregions of the NAc. Last, intra-NAc infusion of CTAP (3 μg) prevented the development of social play-induced conditioned place preference. These findings identify NAc μ-opioid receptor stimulation as an important neural mechanism for the attribution of positive value to social interactions in adolescent rats. Altered NAc μ-opioid receptor function may underlie social impairments in psychiatric disorders such as autism

  15. Oregon’s Strategy to Confront Prescription Opioid Misuse: A Case Study

    PubMed Central

    McCarty, Dennis; Bovett, Rob; Burns, Thomas; Cushing, Judy; Glynn, Mary Ellen; Kruse, Senator Jeff; Millet, Lisa M.; Shames, Jim

    2014-01-01

    Governor John Kitzhaber appointed a Prescription Drug Taskforce to address Oregon’s opioid epidemic. This case study reviews the Taskforce’s participation in the National Governors Association State Policy Academy on Reducing Prescription Drug Abuse. To address the challenge of the misuse and abuse of prescription opioids, the Taskforce developed a strategy for practice change, community education and enhanced access to safe opioid disposal using stakeholder meetings, consensus development, and five action steps: 1) fewer pills in circulation, 2) educate prescribers and the public on the risks of opioid use, 3) foster safe disposal of unused medication, 4) provide treatment for opioid dependence, and 5) continued leadership from the Governor, health plans and health professionals. Although the story is ongoing, there are lessons for leadership in other states and for public health and medical practitioners throughout the country. PMID:25168199

  16. Opioid Use in Fibromyalgia: A Cautionary Tale.

    PubMed

    Goldenberg, Don L; Clauw, Daniel J; Palmer, Roy E; Clair, Andrew G

    2016-05-01

    Multiple pharmacotherapies are available for the treatment of fibromyalgia (FM), including opioid analgesics. We postulate that the mechanism of action of traditional opioids predicts their lack of efficacy in FM. Literature searches of the MEDLINE and Cochrane Library databases were conducted using the search term opioid AND fibromyalgia to identify relevant articles, with no date limitations set. Citation lists in returned articles and personal archives of references were also examined for additional relevant items, and articles were selected based on the expert opinions of the authors. We found no evidence from clinical trials that opioids are effective for the treatment of FM. Observational studies have found that patients with FM receiving opioids have poorer outcomes than patients receiving nonopioids, and FM guidelines recommend against the use of opioid analgesics. Despite this, and despite the availability of alternative Food and Drug Administration-approved pharmacotherapies and the efficacy of nonpharmacologic therapies, opioids are commonly used in the treatment of FM. Factors associated with opioid use include female sex; geographic variation; psychological factors; a history of opioid use, misuse, or abuse; and patient or physician preference. The long-term use of opioid analgesics is of particular concern in the United States given the ongoing public health emergency relating to excess prescription opioid consumption. The continued use of opioids to treat FM despite a proven lack of efficacy, lack of support from treatment guidelines, and the availability of approved pharmacotherapy options provides a cautionary tale for their use in other chronic pain conditions. PMID:26975749

  17. THE TREATMENT OF ALCOHOL AND OPIOID DEPENDENCE IN PREGNANT WOMEN

    PubMed Central

    Heberlein, Annemarie; Leggio, Lorenzo; Stichtenoth, Dirk; Thomas, Hillemacher

    2016-01-01

    concurrent drug use need to be considered in order to find the “best opioid substitute”. Further considerations include the expectant mother’s compliance level to the treatment and the degree to which she tolerates the respective substitute. PMID:23037965

  18. CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016.

    PubMed

    Dowell, Deborah; Haegerich, Tamara M; Chou, Roger

    2016-01-01

    This guideline provides recommendations for primary care clinicians who are prescribing opioids for chronic pain outside of active cancer treatment, palliative care, and end-of-life care. The guideline addresses 1) when to initiate or continue opioids for chronic pain; 2) opioid selection, dosage, duration, follow-up, and discontinuation; and 3) assessing risk and addressing harms of opioid use. CDC developed the guideline using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework, and recommendations are made on the basis of a systematic review of the scientific evidence while considering benefits and harms, values and preferences, and resource allocation. CDC obtained input from experts, stakeholders, the public, peer reviewers, and a federally chartered advisory committee. It is important that patients receive appropriate pain treatment with careful consideration of the benefits and risks of treatment options. This guideline is intended to improve communication between clinicians and patients about the risks and benefits of opioid therapy for chronic pain, improve the safety and effectiveness of pain treatment, and reduce the risks associated with long-term opioid therapy, including opioid use disorder, overdose, and death. CDC has provided a checklist for prescribing opioids for chronic pain (http://stacks.cdc.gov/view/cdc/38025) as well as a website (http://www.cdc.gov/drugoverdose/prescribingresources.html) with additional tools to guide clinicians in implementing the recommendations. PMID:26987082

  19. Mechanisms of Non-Opioid Analgesics Beyond Cyclooxygenase Enzyme Inhibition

    PubMed Central

    Hamza, May; Dionne, Raymond A.

    2009-01-01

    Non-opioid analgesics including both selective and non-selective cyclooxygenase (COX) inhibitors and acetaminophen are the most widely used treatments for pain. Inhibition of COX is thought to be largely responsible for both the therapeutic and adverse effects of this class of drugs. Accumulating evidence over the past two decades has demonstrated effects of non-opioids beyond the inhibition of COX and prostaglandin synthesis that might also explain their therapeutic and adverse effects. These include their interaction with endocannabinoids, nitric oxide, monoaminergic, and cholinergic systems. Moreover, the recent development of microarray technology that allows the study of human gene expression suggests multiple pathways that may be related to the analgesic and anti-inflammatory effects of non-opioids. The present review will discuss the multiple actions of non-opioids and their interactions with these systems during inflammation and pain, suggesting that COX inhibition is an incomplete explanation for the actions of non-opioids and proposes the involvement of multiple selective targets for their analgesic, as well as, their adverse effects. PMID:19779578

  20. Borderline personality disorder: a dysregulation of the endogenous opioid system?

    PubMed

    Bandelow, Borwin; Schmahl, Christian; Falkai, Peter; Wedekind, Dirk

    2010-04-01

    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 constitute part of the underlying pathophysiology of BPD. The alarming symptoms and self-destructive behaviors of the affected patients may be explained by uncontrollable and unconscious attempts to stimulate their endogenous opioid system (EOS) and the dopaminergic reward system, regardless of the possible harmful consequences. Neurobiological findings that support this hypothesis are reviewed: Frantic efforts to avoid abandonment, frequent and risky sexual contacts, and attention-seeking behavior may be explained by attempts to make use of the rewarding effects of human attachment mediated by the EOS. Anhedonia and feelings of emptiness may be an expression of reduced activity of the EOS. Patients with BPD tend to abuse substances that target mu-opioid receptors. Self-injury, food restriction, aggressive behavior, and sensation seeking may be interpreted as desperate attempts to artificially set the body to survival mode in order to mobilize the last reserves of the EOS. BPD-associated symptoms, such as substance abuse, anorexia, self-injury, depersonalization, and sexual overstimulation, can be treated successfully with opioid receptor antagonists. An understanding of the neurobiology of BPD may help in developing new treatments for patients with this severe disorder. PMID:20438240

  1. Chronic opioid use in fibromyalgia syndrome: a clinical review.

    PubMed

    Painter, Jacob T; Crofford, Leslie J

    2013-03-01

    Chronic opioid therapy in the treatment of chronic nonmalignant pain has increased drastically over the past decade. This is a worrisome trend in general, but specifically, given pathophysiologic characteristics seen in fibromyalgia (FM) syndrome patients, the use of this class of medication deserves special scrutiny. We first describe the current understanding of the etiology and pathophysiology of FM, including the role of genetic and environmental factors in the development of this syndrome. We then discuss the biologic effects of opioid use. Next, we review the pharmaceutical treatment options for FM, including 3 Food and Drug Administration-approved medications, and the evolution of treatment guidelines since 2004. We then highlight the various consequences associated with the mechanism of action of opioids and the specific concerns for FM patients.Finally, summarizing the existing literature, we make the case that chronic opioid use is inappropriate in the treatment of FM because of the interaction of unique pathophysiologic characteristics of the patients and effects associated with chronic opioid use. PMID:23364665

  2. "Weak" opioid analgesics. Codeine, dihydrocodeine and tramadol: no less risky than morphine.

    PubMed

    2016-02-01

    So-called weak opioid analgesics are often used to treat severe pain, or when paracetamol or a nonsteroidal anti-inflammatory drug (NSAID) proves inadequate. But are weak opioids any more effective than paracetamol or NSAIDs on nociceptive pain, and are they better tolerated than morphine? To answer these questions, we conducted a review of literature using the standard Prescrire methodology. The potency of codeine and tramadol is strongly influenced by the cytochrome P450 isoenzyme CYP2D6 genotype, which varies widely from one person to another. This explains reports of overdosing or underdosing after administration of standard doses of the two drugs. The potency of morphine and that of buprenorphine, an opioid receptor agonist-antagonist, appears to be independent of CYP2D6 activity. All "weak" opioids can have the same dose-dependent adverse effects as morphine. There is no evidence that, at equivalent analgesic efficacy, weak opioids carry a lower risk of addiction than low-dose morphine. Respiratory depression can occur in ultrarapid metabolisers after brief exposure to standard doses of codeine or tramadol. Similar cases have been reported with dihydrocodeine in patients with renal failure. In addition, tramadol can cause a serotonin syndrome, hypoglycaemia, hyponatraemia and seizures. Several trials have compared different weak opioids in patients with post-operative pain. A single dose of a weak opioid, possibly combined with paracetamol, has greater analgesic efficacy than paracetamol alone but is not more effective than an NSAID alone. There is a dearth of evidence on weak opioids in patients with chronic pain. Available trials fail to show that a weak opioid has markedly superior analgesic efficacy to paracetamol or an NSAID. Sublingual buprenorphine at analgesic doses appears less likely to cause respiratory depression, but it seems to have weak analgesic efficacy. In practice, when opioid therapy is needed, there is no evidence that codeine

  3. Development of a fluid bed granulation design space using critical quality attribute weighted tolerance intervals.

    PubMed

    Zacour, Brian M; Drennen, James K; Anderson, Carl A

    2012-08-01

    The fluid bed granulation and drying unit operation were used as a case study for control systems implementation. This single processor was used to blend, granulate, dry, and cool the materials. The current study demonstrated control of each of the phases using a fully automated, hybrid control system that incorporated first-principle modeling, empirical design of experiments (DOE), and process analytical technology to assure the production of constant product quality. The system allowed data to be collected efficiently for the development of a rigorous design space that combined formulation factors, process factors, and their interactions to define a tolerance surface where risk of future product failure was significantly reduced. The DOE incorporated microcrystalline cellulose and lactose monohydrate, excipients with substantially different wetting properties, to elucidate the relationship between the critical process parameters of the unit operation and the material properties of the formulation components. The extended analysis of covariance model enabled these factors and their interaction terms to be described in a single model. The results indicate that the development of a tolerance interval-based weighted design space can enhance product understanding and thereby help to assure future product quality. PMID:22570275

  4. Contribution of opioid receptors on primary afferent versus sympathetic neurons to peripheral opioid analgesia.

    PubMed

    Zhou, L; Zhang, Q; Stein, C; Schäfer, M

    1998-08-01

    Opioid receptors are synthesized in dorsal root ganglia and transported into peripheral terminals of primary afferent neurons. Activation of such receptors results in antinociceptive effects that are most prominent in inflammation. In addition, opioid receptors located on sympathetic postganglionic neuron terminals may be involved in these effects. This study investigates the peripheral analgesic efficacy of the mu, delta and kappa receptor agonists [D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin, [D-Pen2,5]-enkephalin and trans-(+/-)3, 4-Dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamid e, the effective number of peripheral mu, delta and kappa receptors in relation to the development of inflammation and the contribution of sympathetic vs. sensory neurons by use of capsaicin and 6-hydroxydopamine, respectively. In Wistar rats with Freund's adjuvant-induced hindpaw inflammation, antinociceptive effects of intraplantar [D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin (1.0-32 microg), [D-Pen2,5]-enkephalin (10-100 microg) and trans-(+/-)3, 4-Dichloro-N-methyl-N-[2-(l-pyrrolidiny)-cyclohexyl]-benzeneace tam ide (10-100 microg) were evaluated by paw pressure test. These effects increased linearly between 6 and 24 hr, but did not change between 24 and 96 hr of inflammation, whereas the doses of the irreversible antagonists beta-funaltrexamine, [D-Ala2,Leu5,Cys6]enkephalin or (+/-)-(5beta,7a,8beta)-3, 4-dichloro-N-[3-methylene-2-oxo-8-(1-pyrrolidinyl)-1-oxaspir[4, 5]dec-7-yl]benzeneacetamide required to abolish the respective agonist effects increased between 12 and 96 hr. Pretreatment with capsaicin (30, 50, 70 mg/kg s.c. over 3 days) but not with 6-hydroxydopamine (75 mg/kg i.p. over 3 days) reversed the hyperalgesia in inflamed paws and almost abolished antinociceptive effects of all three agonists. These results suggest that the increased opioid agonist efficacy is due to an increased number of peripheral opioid receptors at later stages of inflammation and that

  5. Molecular characterization of opioid receptors

    SciTech Connect

    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.

  6. Dopamine D2/3- and μ-opioid receptor antagonists reduce cue-induced responding and reward impulsivity in humans

    PubMed Central

    Weber, S C; Beck-Schimmer, B; Kajdi, M-E; Müller, D; Tobler, P N; Quednow, B B

    2016-01-01

    Increased responding to drug-associated stimuli (cue reactivity) and an inability to tolerate delayed gratification (reward impulsivity) have been implicated in the development and maintenance of drug addiction. Whereas data from animal studies suggest that both the dopamine and opioid system are involved in these two reward-related processes, their role in humans is less clear. Moreover, dopaminergic and opioidergic drugs have not been directly compared with regard to these functions, even though a deeper understanding of the underlying mechanisms might inform the development of specific treatments for elevated cue reactivity and reward impulsivity. In a randomized, double-blind, between-subject design we administered the selective dopamine D2/D3 receptor antagonist amisulpride (400 mg, n=41), the unspecific opioid receptor antagonist naltrexone (50 mg, n=40) or placebo (n=40) to healthy humans and measured cue-induced responding with a Pavlovian-instrumental transfer task and reward impulsivity with a delay discounting task. Mood was assessed using a visual analogue scale. Compared with placebo, amisulpride significantly suppressed cue-induced responding and reward impulsivity. The effects of naltrexone were similar, although less pronounced. Both amisulpride and naltrexone decreased average mood ratings compared with placebo. Our results demonstrate that a selective blockade of dopamine D2/D3 receptors reduces cue-induced responding and reward impulsivity in healthy humans. Antagonizing μ-opioid receptors has similar effects for cue-induced responding and to a lesser extent for reward impulsivity. PMID:27378550

  7. Dopamine D2/3- and μ-opioid receptor antagonists reduce cue-induced responding and reward impulsivity in humans.

    PubMed

    Weber, S C; Beck-Schimmer, B; Kajdi, M-E; Müller, D; Tobler, P N; Quednow, B B

    2016-01-01

    Increased responding to drug-associated stimuli (cue reactivity) and an inability to tolerate delayed gratification (reward impulsivity) have been implicated in the development and maintenance of drug addiction. Whereas data from animal studies suggest that both the dopamine and opioid system are involved in these two reward-related processes, their role in humans is less clear. Moreover, dopaminergic and opioidergic drugs have not been directly compared with regard to these functions, even though a deeper understanding of the underlying mechanisms might inform the development of specific treatments for elevated cue reactivity and reward impulsivity. In a randomized, double-blind, between-subject design we administered the selective dopamine D2/D3 receptor antagonist amisulpride (400 mg, n=41), the unspecific opioid receptor antagonist naltrexone (50 mg, n=40) or placebo (n=40) to healthy humans and measured cue-induced responding with a Pavlovian-instrumental transfer task and reward impulsivity with a delay discounting task. Mood was assessed using a visual analogue scale. Compared with placebo, amisulpride significantly suppressed cue-induced responding and reward impulsivity. The effects of naltrexone were similar, although less pronounced. Both amisulpride and naltrexone decreased average mood ratings compared with placebo. Our results demonstrate that a selective blockade of dopamine D2/D3 receptors reduces cue-induced responding and reward impulsivity in healthy humans. Antagonizing μ-opioid receptors has similar effects for cue-induced responding and to a lesser extent for reward impulsivity. PMID:27378550

  8. The effects of alcohol on the pharmacokinetics and pharmacodynamics of the selective mu-opioid receptor antagonist GSK1521498 in healthy subjects

    PubMed Central

    Ziauddeen, Hisham; Nathan, Pradeep J; Dodds, Chris; Maltby, Kay; Miller, Sam R; Waterworth, Dawn; Song, Kijoung; Warren, Liling; Hosking, Louise; Zucchetto, Mauro; Bush, Mark; Johnson, Lakshmi Vasist; Sarai, Bhopinder; Mogg, Karin; Bradley, Brendan P; Richards, Duncan B; Fletcher, Paul C; Bullmore, Edward T

    2013-01-01

    The mu-opioid system has a key role in hedonic and motivational processes critical to substance addiction. However, existing mu-opioid antagonists have had limited success as anti-addiction treatments. GSK1521498 is a selective and potent mu-opioid antagonist being developed for the treatment of overeating and substance addictions. In this study, 28 healthy participants were administered single doses of GSK1521498 20 mg, ethanol 0.5 g/kg body weight, or both in combination, in a double blind placebo controlled four-way crossover design. The primary objective was to determine the risk of significant adverse pharmacodynamic and pharmacokinetic (PK) interactions. The effects of GSK1521498 on hedonic and consummatory responses to alcohol and the attentional processing of alcohol-related stimuli, and their modulation by the OPRM1 A118G polymorphism were also explored. GSK1521498 20 mg was well tolerated alone and in combination with ethanol. There were mild transient effects of GSK1521498 on alertness and mood that were greater when it was combined with ethanol. These effects were not of clinical significance. There were no effects of GSK1521498 on reaction time, hedonic or consummatory responses. These findings provide encouraging safety and PK data to support continued development of GSK1521498 for the treatment of alcohol addiction. PMID:23934621

  9. Delay of Morphine Tolerance by Palmitoylethanolamide

    PubMed Central

    Di Cesare Mannelli, Lorenzo; Corti, Francesca; Micheli, Laura; Zanardelli, Matteo; Ghelardini, Carla

    2015-01-01

    In spite of the potency and efficacy of morphine, its clinical application for chronic persistent pain is limited by the development of tolerance to the antinociceptive effect. The cellular and molecular mechanisms underlying morphine tolerance are complex and still unclear. Recently, the activation of glial cells and the release of glia-derived proinflammatory mediators have been suggested to play a role in the phenomenon. N-Palmitoylethanolamine (PEA) is an endogenous compound with antinociceptive effects able to reduce the glial activation. On this basis, 30 mg kg−1 PEA was subcutaneously daily administered in morphine treated rats (10 mg kg−1 intraperitoneally, daily). PEA treatment significantly attenuated the development of tolerance doubling the number of days of morphine antinociceptive efficacy in comparison to the vehicle + morphine group. PEA prevented both microglia and astrocyte cell number increase induced by morphine in the dorsal horn; on the contrary, the morphine-dependent increase of spinal TNF-α levels was not modified by PEA. Nevertheless, the immunohistochemical analysis revealed significantly higher TNF-α immunoreactivity in astrocytes of PEA-protected rats suggesting a PEA-mediated decrease of cytokine release from astrocyte. PEA intervenes in the nervous alterations that lead to the lack of morphine antinociceptive effects; a possible application of this endogenous compound in opioid-based therapies is suggested. PMID:25874232

  10. Very low dose naltrexone addition in opioid detoxification: a randomized, controlled trial

    PubMed Central

    Mannelli, Paolo; Patkar, Ashwin A.; Peindl, Kathi; Gorelick, David A.; Wu, Li-Tzy; Gottheil, Edward

    2008-01-01

    Although current treatments for opioid detoxification are not always effective, medical detoxification remains a required step before long-term interventions. The use of opioid antagonist medications to improve detoxification has produced inconsistent results. Very low dose naltrexone (VLNTX) was recently found to reduce opioid tolerance and dependence in animal and clinical studies. We decided to evaluate safety and efficacy of VLNTX adjunct to methadone in reducing withdrawal during detoxification. In a multi-center, double-blind, randomized study at community treatment programs, where most detoxifications are performed, 174 opioid-dependent subjects received NTX 0.125 mg, 0.250 mg or placebo daily for 6 days, together with methadone in tapering doses. VLNTX-treated individuals reported attenuated withdrawal symptoms [F = 7.24 (2,170); P = 0.001] and reduced craving [F = 3.73 (2,107); P = 0.03]. Treatment effects were more pronounced at discharge and were not accompanied by a significantly higher retention rate. There were no group differences in use of adjuvant medications and no treatment-related adverse events. Further studies should explore the use of VLNTX, combined with full and partial opioid agonist medications, in detoxification and long-term treatment of opioid dependence. PMID:18715283

  11. Aberrant Opioid Use and Urine Drug Testing in Outpatient Palliative Care.

    PubMed

    Arthur, Joseph A; Haider, Ali; Edwards, Tonya; Waletich-Flemming, Jessica; Reddy, Suresh; Bruera, Eduardo; Hui, David

    2016-07-01

    Aberrant opioid use is a public health issue, which has not been adequately described in the palliative care literature. With the increasing integration of palliative care into oncologic care, palliative care clinicians are seeing patients earlier in the disease trajectory, and therefore, more outpatients with chronic pain requiring chronic opioid therapy. This may have resulted in a concomitant rise in the number of patients with aberrant opioid use. In this article, we report on two patients with aberrant opioid-related behavior seen at our palliative care clinic. A high suspicion of opioid abuse, misuse, or diversion based on certain behavioral cues necessitated the ordering of a urine drug test (UDT). The tests helped the medical team to confirm an already existing pattern of maladaptive opioid use. In both cases, we provided ample opioid education and implemented effective strategies to address their aberrant opioid use. These cases suggest the need for palliative care clinicians to develop strategies to effectively address this issue in our field of medicine. It also highlights the usefulness of UDT in the outpatient palliative care setting. PMID:27171327

  12. Opioid abuse-deterrent strategies: role of clinicians in acute pain management.

    PubMed

    Webster, Lynn R; Brennan, Michael J; Kwong, Louis M; Levandowski, Richard; Gudin, Jeffrey A

    2016-01-01

    Opioid abuse is a healthcare and societal problem that burdens individuals, their families and the healthcare professionals who care for them. Restricting access to opioid analgesics is one option to deter abuse, but this may prevent pain patients in need from obtaining effective analgesics. Therefore, strategies that mitigate the risk of opioid abuse while maintaining access are being pursued by several stakeholders including federal agencies, state governments, payors, researchers, the pharmaceutical industry and clinicians. Federal agency efforts have included required licensure and documentation for prescribing opioids, implementation of risk evaluation and mitigation strategies, and guidance on assessment and labeling of opioid abuse-deterrent formulations. In addition, state governments and payors have enacted monitoring programs, and pharmaceutical companies continue to develop abuse-deterrent opioid formulations. Strategies for clinicians to mitigate opioid abuse include comprehensive patient assessment and universal precautions (e.g. use of multimodal analgesia and abuse-deterrent opioid formulations, urine toxicology screening, participation in prescription drug monitoring and risk evaluation and mitigation strategy programs). PMID:26631936

  13. Forages and Pastures Symposium: development of and field experience with drought-tolerant maize.

    PubMed

    Soderlund, S; Owens, F N; Fagan, C

    2014-07-01

    Drought-tolerant maize hybrids currently are being marketed by several seed suppliers. Such hybrids were developed by phenotypic and marker-assisted selection or through genetic modification and tested by exposing these hybrids to various degrees of water restriction. As drought intensifies, crop yields and survival progressively decline. Water need differs among plants due to differences in root structure, evaporative loss, capacity to store water or enter temporary dormancy, and plant genetics. Availability of water differs widely not only with rainfall and irrigation but also with numerous soil and agronomic factors (e.g., soil type, slope, seeding rates, tillage practices). Reduced weed competition, enhanced pollen shed and silk production, and deep, robust root growth help to reduce the negative impacts of drought. Selected drought-tolerant maize hybrids have consistently yielded more grain even when drought conditions are not apparent either due to reduced use of soil water reserves before water restriction or due to greater tolerance of intermittent water shortages. In DuPont Pioneer trials, whole plant NDF digestibility of maize increased with water restriction, perhaps due to an increased leaf to stem ratio. Efficiency of water use, measured as dry matter or potential milk yield from silage per unit of available water, responded quadratically to water restriction, first increasing slightly but then decreasing as water restriction increased. For grain production, water restriction has its greatest negative impact during or after silking through reducing the number of kernels and reducing kernel filling. For silage production, water restriction during the vegetative growth stage negatively impacts plant height and biomass yield. Earlier planting and shorter season maize hybrids help to avoid midsummer heat stress during pollination and can reduce the number of irrigation events needed. Although drought tolerance of maize hybrids has been improved due to

  14. Quantitative conformationally sampled pharmacophore for delta opioid ligands: reevaluation of hydrophobic moieties essential for biological activity.

    PubMed

    Bernard, Denzil; Coop, Andrew; MacKerell, Alexander D

    2007-04-19

    Recent studies have indicated several therapeutic applications for delta opioid agonists and antagonists. To exploit the therapeutic potential of delta opioids developing a structural basis for the activity of ligands at the delta opioid receptor is essential. The conformationally sampled pharmacophore (CSP) method (Bernard et al. J. Am. Chem. Soc. 2003, 125, 3103-3107) is extended here to obtain quantitative models of delta opioid ligand efficacy and affinity. Quantification is performed via overlap integrals of the conformational space sampled by ligands with respect to a reference compound. Iterative refinement of the CSP model identified hydrophobic groups other than the traditional phenylalanine residues as important for efficacy and affinity in DSLET and ICI 174 864. The obtained models for a structurally diverse set of peptidic and nonpeptidic delta opioid ligands offer good predictions with R2 values>0.9, and the predicted efficacy for a set of test compounds was consistent with the experimental values. PMID:17367120

  15. Pain and Poppies: The Good, the Bad, and the Ugly of Opioid Analgesics

    PubMed Central

    Al-Hasani, Ream; Salvemini, Daniela; Salter, Michael W.; Gutstein, Howard

    2015-01-01

    Treating pain is one of the most difficult challenges in medicine and a key facet of disease management. The isolation of morphine by Friedrich Sertürner in 1804 added an essential pharmacological tool in the treatment of pain and spawned the discovery of a new class of drugs known collectively as opioid analgesics. Revered for their potent pain-relieving effects, even Morpheus the god of dreams could not have dreamt that his opium tincture would be both a gift and a burden to humankind. To date, morphine and other opioids remain essential analgesics for alleviating pain. However, their use is plagued by major side effects, such as analgesic tolerance (diminished pain-relieving effects), hyperalgesia (increased pain sensitivity), and drug dependence. This review highlights recent advances in understanding the key causes of these adverse effects and explores the effect of chronic pain on opioid reward. SIGNIFICANCE STATEMENT Chronic pain is pervasive and afflicts >100 million Americans. Treating pain in these individuals is notoriously difficult and often requires opioids, one of the most powerful and effective classes of drugs used for controlling pain. However, their use is plagued by major side effects, such as a loss of pain-relieving effects (analgesic tolerance), paradoxical pain (hyperalgesia), and addiction. Despite the potential side effects, opioids remain the pharmacological cornerstone of modern pain therapy. This review highlights recent breakthroughs in understanding the key causes of these adverse effects and explores the cellular control of opioid systems in reward and aversion. The findings will challenge traditional views of the good, the bad, and the ugly of opioids. PMID:26468188

  16. The combination of mitragynine and morphine prevents the development of morphine tolerance in mice.

    PubMed

    Fakurazi, Sharida; Rahman, Shamima Abdul; Hidayat, Mohamad Taufik; Ithnin, Hairuszah; Moklas, Mohamad Aris Mohd; Arulselvan, Palanisamy

    2013-01-01

    Mitragynine (MG) is the major active alkaloid found in Mitragyna speciosa Korth. In the present study, we investigated the enhancement of analgesic action of MG when combined with morphine and the effect of the combination on the development of tolerance towards morphine. Mice were administered intraperitoneally with a dose of MG (15 and 25 mg/kg b.wt) combined with morphine (5 mg/kg b.wt) respectively for 9 days. The antinociceptive effect was evaluated by a hot plate test. The protein expression of cyclic adenosine monophosphate (cAMP) and cAMP response element binding (CREB) was analyzed by immunoblot. Toxicological parameters especially liver and kidney function tests were assessed after the combination treatment with MG and morphine. The concurrent administration of MG and morphine showed significant (p < 0.05) increase in latency time when compared to morphine alone group and the outstanding analgesic effects in the combination regimens were maintained until day 9. For the protein expression, there was a significant increment of cAMP and CREB levels (p < 0.05) in group treated with 5 mg/kg morphine but there was no significant change of these protein expressions when MG was combined with morphine. There was a significant changes in toxicological parameters of various treated groups. The combination treatment of MG and morphine effectively reduce the tolerance due to the chronic administration of morphine. PMID:23292329

  17. Aminothiazolomorphinans with Mixed Kappa and Mu Opioid Activitya

    PubMed Central

    Zhang, Tangzhi; Yan, Zhaohua; Sromek, Anna; Knapp, Brian I.; Scrimale, Thomas; Bidlack, Jean M.; Neumeyer, John L.

    2011-01-01

    A series of N-substituted and N′-substituted aminothiazole-derived morphinans (5) were synthesized for expanding the structure-activity relationships of aminothiazolo-morphinans. Although their affinities were somewhat lower than their prototype aminothiazolo-N-cyclopropylmorphinan (3), 3-aminothiazole derivatives of cyclorphan (1) containing a primary amino group displayed high affinity and selectivity at the κ and μ opioid receptors. [35S]GTPγS binding assays showed that the aminothiazolomorphinans were κ agonists with mixed agonist and antagonist activity at the μ opioid receptor. These novel N′-monosubstituted aminothiazole-derived morphinans may be valuable for the development of drug abuse medications. PMID:21351746

  18. The evolution of vertebrate opioid receptors

    PubMed Central

    Stevens, Craig W.

    2011-01-01

    The proteins that mediate the analgesic and other effects of opioid drugs and endogenous opioid peptides are known as opioid receptors. Opioid receptors consist of a family of four closely-related proteins belonging to the large superfamily of G-protein coupled receptors. The three types of opioid receptors shown unequivocally to mediate analgesia in animal models are the mu (MOR), delta (DOR), and kappa (KOR) opioid receptor proteins. The role of the fourth member of the opioid receptor family, the nociceptin or orphanin FQ receptor (ORL), is not as clear as hyperalgesia, analgesia, and no effect was reported after administration of ORL agonists. There are now cDNA sequences for all four types of opioid receptors that are expressed in the brain of six species from three different classes of vertebrates. This review presents a comparative analysis of vertebrate opioid receptors using bioinformatics and data from recent human genome studies. Results indicate that opioid receptors arose by gene duplication, that there is a vector of opioid receptor divergence, and that MOR shows evidence of rapid evolution. PMID:19273128

  19. Advanced Durability and Damage Tolerance Design and Analysis Methods for Composite Structures: Lessons Learned from NASA Technology Development Programs

    NASA Technical Reports Server (NTRS)

    Harris, Charles E.; Starnes, James H., Jr.; Shuart, Mark J.

    2003-01-01

    Aerospace vehicles are designed to be durable and damage tolerant. Durability is largely an economic life-cycle design consideration whereas damage tolerance directly addresses the structural airworthiness (safety) of the vehicle. However, both durability and damage tolerance design methodologies must address the deleterious effects of changes in material properties and the initiation and growth of microstructural damage that may occur during the service lifetime of the vehicle. Durability and damage tolerance design and certification requirements are addressed for commercial transport aircraft and NASA manned spacecraft systems. The state-of-the-art in advanced design and analysis methods is illustrated by discussing the results of several recently completed NASA technology development programs. These programs include the NASA Advanced Subsonic Technology Program demonstrating technologies for large transport aircraft and the X-33 hypersonic test vehicle demonstrating technologies for a single-stage-to-orbit space launch vehicle.

  20. Role of the mu opioid receptor in opioid modulation of immune function

    PubMed Central

    Ninković, Jana; Roy, Sabita

    2014-01-01

    SUMMARY Endogenous opioids are synthesized in vivo in order to modulate pain mechanisms and inflammatory pathways. Endogenous and exogenous opioids mediate analgesia in response to painful stimuli by binding to opioid receptors on neuronal cells. However, wide distribution of opioid receptors on tissues and organ systems outside the CNS, such as the cells of the immune system, indicate that opioids are capable of exerting additional effects in the periphery, such as immunomodulation. The increased prevalence of infections in opioid abusers based epidemiological studies further highlights the immunosuppressive effects of opioids. In spite of their many debilitating side effects, prescription opioids remain a gold standard for treatment of chronic pain. Therefore, given the prevalence of opioid use and abuse, opioid mediated immune suppression presents a serious concern in our society today. It is imperative to understand the mechanisms by which exogenous opioids modulate immune processes. In this review we will discuss the role of opioid receptors and their ligands in mediating immune suppressive functions. We will summarize recent studies on direct and indirect opioid modulation of the cells of the immune system as well as the role of opioids in exacerbation of certain disease states. PMID:22170499

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

    PubMed Central

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

    2015-01-01

    Background 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. Methods 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. Results 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, p < .001) and a greater proportion of their income on drugs (OR = 1.31, p < .001) were more likely to use opioids during treatment. Conclusions Individual differences in drug reinforcement value, as indicated by pre-treatment allocation of economic 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. PMID:25622776

  2. Current State of Opioid Therapy and Abuse.

    PubMed

    Manchikanti, Laxmaiah; Kaye, Adam M; Kaye, Alan D

    2016-05-01

    Currently, there is growing tension between the twin challenges of opioid therapy for chronic pain and adverse consequences of abuse, leading to multiple complications including respiratory failure and death. The recent data from Centers for Disease Control and Prevention (CDC) have shown continued escalation of prescription opioid use with opioid overdose deaths topping all previous estimations. Numerous policy initiatives, advisories, and guidelines have been advanced through the years to control the opioid epidemic. The strategies to prevent opioid abuse and to maintain opioid therapy when medically necessary fall into primary and secondary prevention categories. The primary prevention category is extremely crucial, since it involves education of primary care providers and patients at the starting point of opioid therapy. The education of surgeons and other prescribers is as crucial as the education of primary care physicians. PMID:27048483

  3. Prescription opioid abuse: Problems and responses.

    PubMed

    Compton, Wilson M; Boyle, Maureen; Wargo, Eric

    2015-11-01

    Prescription opioid abuse and addiction, along with consequences such as overdose death and increasing transition to heroin use, constitute a devastating public health problem in the United States. Increasingly it is clear that overprescription of these medications over the past two decades has been a major upstream driver of the opioid abuse epidemic. This commentary considers the factors that have led to overprescription of opioids by clinicians, discusses recent evidence casting doubt on the efficacy of opioids for treating chronic pain, and describes the ongoing efforts by federal and community stakeholders to address this epidemic-for example, supporting prescription drug monitoring programs and improved clinician training in pain management to help reduce the supply of opioids, increasing dissemination of evidence-based primary prevention programs to reduce demand for opioids, and expanding access to effective opioid agonist therapies and antagonist medications for both treatment and overdose prevention. PMID:25871819

  4. Positive allosteric modulators of the μ-opioid receptor: a novel approach for future pain medications

    PubMed Central

    Burford, N T; Traynor, J R; Alt, A

    2015-01-01

    Morphine and other agonists of the μ-opioid receptor are used clinically for acute and chronic pain relief and are considered to be the gold standard for pain medication. However, these opioids also have significant side effects, which are also mediated via activation of the μ-opioid receptor. Since the latter half of the twentieth century, researchers have sought to tease apart the mechanisms underlying analgesia, tolerance and dependence, with the hope of designing drugs with fewer side effects. These efforts have revolved around the design of orthosteric agonists with differing pharmacokinetic properties and/or selectivity profiles for the different opioid receptor types. Recently, μ-opioid receptor-positive allosteric modulators (μ-PAMs) were identified, which bind to a (allosteric) site on the μ-opioid receptor separate from the orthosteric site that binds an endogenous agonist. These allosteric modulators have little or no detectable functional activity when bound to the receptor in the absence of orthosteric agonist, but can potentiate the activity of bound orthosteric agonist, seen as an increase in apparent potency and/or efficacy of the orthosteric agonist. In this review, we describe the potential advantages that a μ-PAM approach might bring to the design of novel therapeutics for pain that may lack the side effects currently associated with opioid therapy. LINKED ARTICLES 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 PMID:24460691

  5. ROAD MAP FOR DEVELOPMENT OF CRYSTAL-TOLERANT HIGH LEVEL WASTE GLASSES

    SciTech Connect

    Fox, K.; Peeler, D.; Herman, C.

    2014-05-15

    The U.S. Department of Energy (DOE) is building a Tank Waste Treatment and Immobilization Plant (WTP) at the Hanford Site in Washington to remediate 55 million gallons of radioactive waste that is being temporarily stored in 177 underground tanks. Efforts are being made to increase the loading of Hanford tank wastes in glass while meeting melter lifetime expectancies and process, regulatory, and product quality requirements. This road map guides the research and development for formulation and processing of crystaltolerant glasses, identifying near- and long-term activities that need to be completed over the period from 2014 to 2019. The primary objective is to maximize waste loading for Hanford waste glasses without jeopardizing melter operation by crystal accumulation in the melter or melter discharge riser. The potential applicability to the Savannah River Site (SRS) Defense Waste Processing Facility (DWPF) will also be addressed in this road map. The planned research described in this road map is motivated by the potential for substantial economic benefits (significant reductions in glass volumes) that will be realized if the current constraints (T1% for WTP and TL for DWPF) are approached in an appropriate and technically defensible manner for defense waste and current melter designs. The basis of this alternative approach is an empirical model predicting the crystal accumulation in the WTP glass discharge riser and melter bottom as a function of glass composition, time, and temperature. When coupled with an associated operating limit (e.g., the maximum tolerable thickness of an accumulated layer of crystals), this model could then be integrated into the process control algorithms to formulate crystal-tolerant high-level waste (HLW) glasses targeting high waste loadings while still meeting process related limits and melter lifetime expectancies. The modeling effort will be an iterative process, where model form and a broader range of conditions, e.g., glass

  6. Independent SCPS-TP development for fault-tolerant, end-to-end communication architectures

    NASA Astrophysics Data System (ADS)

    Edwards, E.; Lamorie, J.; Younghusband, D.; Brunet, C.; Hartman, L.

    2002-07-01

    A fully networked architecture provides for the distribution of computing elements, of all mission components, through the spacecraft. Each node is individually addressable through the network, and behaves as an independent entity. This level of communication also supports individualized Command and Data Handling (C&DH), as well as one-to-one transactions between spacecraft nodes and individual ground segment users. To be effective, fault-tolerance must be applied at the network data transport level, as well as the supporting layers below it. If the network provides fail-safe characteristics independent of the mission applications being executed, then developers need not build in their own systems to ensure network reliability. The Space Communications Protocol Standards (SCPS) were developed to provide robust communications in a space environment, while retaining compatibility with Internet data transport at the ground segment. Although SCPS is a standard of the Consultative Committee for Space Data Systems (CCSDS), the adoption of SCPS was initially delayed by US export regulations that prevented the distribution of reference code. This paper describes the development and test of a fully independent implementation of the SCSP Transport Protocol, SCPS-TP, which has been derived directly from the CCSDS specification. The performance of the protocol is described for a set of geostationary satellite tests, and these results will be compared with those derived from network simulation and laboratory emulation. The work is placed in the context of a comprehensive, fault-tolerant network that potentially surpasses the failsafe performance of a traditional spacecraft control system under similar circumstances.

  7. The effect of alpha-interferon, cyclosporine A, and radiation-induced immune suppression on morphine-induced hypothermia and tolerance.

    PubMed

    Dougherty, P M; Harper, C; Dafny, N

    1986-12-01

    An interconnection between the immune and the central nervous systems has been suggested by investigators studying the actions of several types of immune modifying agents and procedures upon opiate related phenomena. These studies have included the effects of altering immune system function by administration of either alpha-interferon, cyclosporine or radiation exposure upon naloxone-precipitated opiate withdrawal and upon opioid antinociceptive effects. The present study extends these earlier investigations by examining the effect of immune modulation upon opiate induced hypothermia. The results demonstrate that interferon and cyclosporine have no effects on baseline temperature or morphine induced hypothermia, while irradiation exposure elicits hyperthermia without affecting morphine-induced hypothermia. Finally, neither cyclosporine nor irradiation affect the development of tolerance to morphine induced hypothermia, while a single injection of the immune system modifier interferon was able to prevent the development of such tolerance. These observations suggest that yet another opiate-related phenomenon may be regulated at least in part by the immune system. These results together with our previous findings are further evidence of a link between the immune system and the CNS mediated through the opioid system. In addition, these studies further support our earlier hypothesis that "Interferon" is one of the endogenous substances which serves to prevent the development of tolerance and dependence to endogenous opioids. PMID:3784774

  8. Comparing Mindfulness-Based Group Therapy With Treatment as Usual for Opioid Dependents: A Pilot Randomized Clinical Trial Study Protocol

    PubMed Central

    Imani, Saeed; Atef Vahid, Mohammad Kazem; Gharraee, Banafsheh; Habibi, Mojtaba; Bowen, Sarah; Noroozi, Alireza

    2015-01-01

    Background: In response to high burden of opioid abuse in Iran, Ministry of Health has launched a large-scale opioid maintenance treatment program, delivered through a network of certified drug treatment centers. To promote opioid pharmacotherapies, there is an urgent need to develop and introduce evidence-based psychosocial interventions into the network. Patients and Methods: This is a randomized clinical trial (RCT) to investigate feasibility and effectiveness of adding mindfulness-based group therapy to opioid pharmacotherapies as compared to opioid pharmacotherapies alone. The primary outcomes were treatment retention and percentage of weekly morphine, methamphetamine, and benzodiazepine negative tests. Discussion: This is the first RCT that explores the effectiveness of mindfulness-based relapse prevention group therapy among opioid dependent clients in Iran. The feasibility of group therapy and comparison of outcomes in intervention and control groups should be discussed in the outcome article. PMID:26251659

  9. Pain and Opioid Dependence: Is it a Matter of Concern.

    PubMed

    Meera, Agar

    2011-01-01

    Opioids are extremely effective in managing cancer pain, and now are utilized for longer periods of time in cancer patients as the treatment for malignancies has become more successful.[1] The goals in cancer pain treatment includes maintaining function in patients with cancer pain (especially in earlier stage disease), and palliation in advanced disease.[1] The perception of the lay public and inexperienced clinicians that addiction is inevitable, often leads to an inappropriate fear to utilize opioids to appropriately manage pain; resulting in persistent under-treatment of cancer pain internationally.[23] There is much confusion about the phenomenon of physical dependence and how this can be differentiated from the maladaptive behaviors that constitute a diagnosis of substance abuse. The burden of cancer and associated cancer pain is projected to continue to rise, and is often at an advanced stage at diagnosis in less developed countries.[4] To be able to provide quality care for this patient population availability of opioids and skilled clinicians in pain management is paramount. In the majority of cases, the main concern is to abate concerns about risks of opioid addiction; to allow adequate pain relief. To understand the infrequent phenomenon of substance abuse in the setting of cancer pain management clear definitions are needed, and review of the epidemiology of occurrence in cancer populations is needed. It is also important to clearly separate the issues of substance abuse at the patient level and diversion of prescribed opioids. There are principles of managing cancer pain in the rare clinical scenario when the risk of substance abuse is high, which can still allow safe management of cancer pain with opioids. PMID:21811368

  10. Pain and Opioid Dependence: Is it a Matter of Concern

    PubMed Central

    Meera, Agar

    2011-01-01

    Opioids are extremely effective in managing cancer pain, and now are utilized for longer periods of time in cancer patients as the treatment for malignancies has become more successful.[1] The goals in cancer pain treatment includes maintaining function in patients with cancer pain (especially in earlier stage disease), and palliation in advanced disease.[1] The perception of the lay public and inexperienced clinicians that addiction is inevitable, often leads to an inappropriate fear to utilize opioids to appropriately manage pain; resulting in persistent under-treatment of cancer pain internationally.[23] There is much confusion about the phenomenon of physical dependence and how this can be differentiated from the maladaptive behaviors that constitute a diagnosis of substance abuse. The burden of cancer and associated cancer pain is projected to continue to rise, and is often at an advanced stage at diagnosis in less developed countries.[4] To be able to provide quality care for this patient population availability of opioids and skilled clinicians in pain management is paramount. In the majority of cases, the main concern is to abate concerns about risks of opioid addiction; to allow adequate pain relief. To understand the infrequent phenomenon of substance abuse in the setting of cancer pain management clear definitions are needed, and review of the epidemiology of occurrence in cancer populations is needed. It is also important to clearly separate the issues of substance abuse at the patient level and diversion of prescribed opioids. There are principles of managing cancer pain in the rare clinical scenario when the risk of substance abuse is high, which can still allow safe management of cancer pain with opioids. PMID:21811368

  11. Development and evaluation of a Fault-Tolerant Multiprocessor (FTMP) computer. Volume 2: FTMP software

    NASA Technical Reports Server (NTRS)

    Lala, J. H.; Smith, T. B., III

    1983-01-01

    The software developed for the Fault-Tolerant Multiprocessor (FTMP) is described. The FTMP executive is a timer-interrupt driven dispatcher that schedules iterative tasks which run at 3.125, 12.5, and 25 Hz. Major tasks which run under the executive include system configuration control, flight control, and display. The flight control task includes autopilot and autoland functions for a jet transport aircraft. System Displays include status displays of all hardware elements (processors, memories, I/O ports, buses), failure log displays showing transient and hard faults, and an autopilot display. All software is in a higher order language (AED, an ALGOL derivative). The executive is a fully distributed general purpose executive which automatically balances the load among available processor triads. Provisions for graceful performance degradation under processing overload are an integral part of the scheduling algorithms.

  12. High Temperature, Permanent Magnet Biased, Fault Tolerant, Homopolar Magnetic Bearing Development

    NASA Technical Reports Server (NTRS)

    Palazzolo, Alan; Tucker, Randall; Kenny, Andrew; Kang, Kyung-Dae; Ghandi, Varun; Liu, Jinfang; Choi, Heeju; Provenza, Andrew

    2008-01-01

    This paper summarizes the development of a magnetic bearing designed to operate at 1,000 F. A novel feature of this high temperature magnetic bearing is its homopolar construction which incorporates state of the art high temperature, 1,000 F, permanent magnets. A second feature is its fault tolerance capability which provides the desired control forces with over one-half of the coils failed. The construction and design methodology of the bearing is outlined and test results are shown. The agreement between a 3D finite element, magnetic field based prediction for force is shown to be in good agreement with predictions at room and high temperature. A 5 axis test rig will be complete soon to provide a means to test the magnetic bearings at high temperature and speed.

  13. Chronic pain, opioid prescriptions, and mortality in Denmark: A population-based cohort study.

    PubMed

    Ekholm, Ola; Kurita, Geana Paula; Højsted, Jette; Juel, Knud; Sjøgren, Per

    2014-12-01

    This study aimed to investigate the risk of death, development of cancer, and hospital inpatient admissions resulting from injuries and toxicity/poisoning among opioid users with chronic noncancer pain. A population-based cohort of 13,127 adults, who have participated in the Danish Health Interview Surveys in 2000 or 2005 and have been followed up prospectively by registers until the end of 2011, were classified according to the absence or presence of chronic pain (ie, pain lasting ⩾ 6 months) and long-term or short-term opioid use (individuals using at least 1 prescription per month for 6 months in the previous year and at least 1 prescription in the previous year, respectively). The risk of all-cause mortality was 1.72 (95% confidence interval [CI]=1.23-2.41) times higher among long-term opioid users than among individuals without chronic pain. The risk of death was lower, but still significantly higher in short-term (1.36, 95% CI=1.07-1.72) and non-opioid users with chronic pain (1.39, 95% CI=1.22-1.59) than in the background population. There was no statistically significant association between long-term opioid use and cardiovascular and cancer mortality. No deaths among opioid users were caused by accidents or suicides, although opioid users had higher risks of injuries and toxicity/poisoning resulting in hospital inpatient admissions than individuals without chronic pain. The risk of all-cause mortality was significantly higher among long-term opioid users, but no obvious associations between long-term opioid use and cause-specific mortality were observed. However, opioid use increased the risk of injuries and toxicity/poisoning resulting in hospital inpatient admissions. PMID:25020002

  14. Evolving paradigms in the treatment of opioid-induced bowel dysfunction

    PubMed Central

    Poulsen, Jakob Lykke; Brock, Christina; Olesen, Anne Estrup; Nilsson, Matias; Drewes, Asbjørn Mohr

    2015-01-01

    In recent years prescription of opioids has increased significantly. Although effective in pain management, bothersome gastrointestinal adverse effects are experienced by a substantial proportion of opioid-treated patients. This can lead to difficulties with therapy and subsequently inadequate pain relief. Collectively referred to as opioid-induced bowel dysfunction, these adverse effects are the result of binding of exogenous opioids to opioid receptors in the gastrointestinal tract. This leads to disturbance of three important gastrointestinal functions: motility, coordination of sphincter function and secretion. In the clinic this manifests in a wide range of symptoms such as reflux, bloating, abdominal cramping, hard, dry stools, and incomplete evacuation, although the most known adverse effect is opioid-induced constipation. Traditional treatment with laxatives is often insufficient, but in recent years a number of novel pharmacological approaches have been introduced. In this review the pathophysiology, symptomatology and prevalence of opioid-induced bowel dysfunction is presented along with the benefits and caveats of a suggested consensus definition for opioid-induced constipation. Finally, traditional treatment is appraised and compared with the latest pharmacological developments. In conclusion, opioid antagonists restricted to the periphery show promising results, but use of different definitions and outcome measures complicate comparison. However, an international working group has recently suggested a consensus definition for opioid-induced constipation and relevant outcome measures have also been proposed. If investigators within this field adapt the suggested consensus and include symptoms related to dysfunction of the upper gut, it will ease comparison and be a step forward in future research. PMID:26557892

  15. Dual allosteric modulation of opioid antinociceptive potency by α2A-adrenoceptors.

    PubMed

    Chabot-Doré, Anne-Julie; Millecamps, Magali; Naso, Lina; Devost, Dominic; Trieu, Phan; Piltonen, Marjo; Diatchenko, Luda; Fairbanks, Carolyn A; Wilcox, George L; Hébert, Terence E; Stone, Laura S

    2015-12-01

    Opioid and α2-adrenoceptor (AR) agonists are analgesic when administered in the spinal cord and show a clinically beneficial synergistic interaction when co-administered. However, α2-AR antagonists can also inhibit opioid antinociception, suggesting a complex interaction between the two systems. The α2A-AR subtype is necessary for spinal adrenergic analgesia and synergy with opioids for most agonist combinations. Therefore, we investigated whether spinal opioid antinociception and opioid-adrenergic synergy were under allosteric control of the α2A-AR. Drugs were administered intrathecally in wild type (WT) and α2A-knock-out (KO) mice and antinociception was measured using the hot water tail immersion or substance P behavioral assays. The α2A-AR agonist clonidine was less effective in α2A-KO mice in both assays. The absence of the α2A-AR resulted in 10-70-fold increases in the antinociceptive potency of the opioid agonists morphine and DeltII. In contrast, neither morphine nor DeltII synergized with clonidine in α2A-KO mice, indicating that the α2AAR has both positive and negative modulatory effects on opioid antinociception. Depletion of descending adrenergic terminals with 6-OHDA resulted in a significant decrease in morphine efficacy in WT but not in α2A-KO mice, suggesting that endogenous norepinephrine acts through the α2A-AR to facilitate morphine antinociception. Based on these findings, we propose a model whereby ligand-occupied versus ligand-free α2A-AR produce distinct patterns of modulation of opioid receptor activation. In this model, agonist-occupied α2A-ARs potentiate opioid analgesia, while non-occupied α2A-ARs inhibit opioid analgesia. Exploiting such interactions between the two receptors could lead to the development of better pharmacological treatments for pain management. PMID:26254859

  16. Impulsivity and risk for prescription opioid misuse in a chronic pain patient sample.

    PubMed

    Vest, Noel; Reynolds, Caleb J; Tragesser, Sarah L

    2016-09-01

    Misuse of, and addiction to, prescription opioid pain relievers is a growing concern, in both non-clinical samples and chronic pain patients receiving opioid analgesic therapy. Research is needed to identify which patients may be more prone to misuse or dependence on opioids in a chronic pain treatment setting. Based on literature showing the role of impulsivity in substance use disorders generally, we predicted that impulsivity may also be important to understanding which individuals may be at risk for opioid misuse when opioids are prescribed for pain. The present study examined associations between impulsivity facets and measures of prescription opioid misuse and symptoms. Four facets of impulsivity were examined: urgency, sensation seeking, lack of premeditation, and lack of perseverance. 143 patients receiving treatment for chronic pain at a regional pain clinic completed a series of questionnaires including the UPPS and measures of opioid risk and misuse. Consistent with predictions, urgency was associated with risk for future misuse (β=0.246, p<0.05), current misuse (β=0.253, p<0.01), and symptoms of current opioid use disorder (OUD; β=0.206, p<0.05). Sensation seeking was also associated with current misuse (β=0.279, p<0.01). These results suggest that identifying facets of impulsivity is important to understanding and assessing for risk of prescription opioid misuse in the context of chronic pain treatment. These data indicate that patients who react impulsively to negative mood states and cravings may be especially prone to developing aberrant use patterns when taking prescription opioids. This is the first known study to identify the role of urgency in predicting risk for OUDs in chronic pain patients. PMID:27156219

  17. Development of tolerance to nifedipine in patients with stable angina pectoris.

    PubMed Central

    Martsevich, S Y; Metelitsa, V I; Rumiantsev, D O; Piotrovskii, V K; Slastnikova, I D; Egorov, L V; Vygodin, V A

    1990-01-01

    1. The possibility of development of tolerance to the anti-ischaemic and anti-anginal effects of nifedipine during sustained administration for 2 months was studied in 15 patients with stable angina pectoris by means of repeated exercise tests on a treadmill. 2. After acute administration of nifedipine (20-30 mg) substantial anti-ischaemic and anti-anginal effects lasted for at least 4 h in all patients. 3. During sustained nifedipine treatment with a dose schedule which provided continuous anti-ischaemic effect during a day (mean daily dose 82.7 +/- 6.0 mg, range 60-120 mg) a substantial attenuation of this effect was registered. The duration of the anti-ischaemic effect was 5.4 +/- 0.3 h after acute administration, decreasing significantly to 3.6 +/- 0.4 h during sustained administration. 4. The attenuation of the nifedipine effect was not associated with worsening of the patients' condition. 5. Plasma concentrations of nifedipine and its metabolite were similar after acute administration and during sustained treatment. Protein binding of nifedipine also remained constant during the study. 6. There was marked interindividual variation in the degree of attenuation of the nifedipine effect during sustained administration. In five patients nearly complete loss of nifedipine efficacy was registered. Eight to ten days after stopping regular administration of nifedipine only partial restoration of nifedipine effect was observed. 7. We conclude that during sustained nifedipine administration tolerance to its anti-ischaemic, anti-anginal and circulatory effects develops in a substantial number of patients with stable angina pectoris. PMID:2310657

  18. Group Health’s Initiative To Avert Opioid Misuse And Overdose Among Patients With Chronic Noncancer Pain

    PubMed Central

    Trescott, Claire E.; Beck, Randi M.; Seelig, Michelle D.; Von Korff, Michael R.

    2012-01-01

    Increased opioid prescribing for chronic pain that is not due to cancer has been accompanied by large increases in abuse and overdose of prescription opioids. This paper describes how Group Health, a Seattle-based nonprofit health care system, implemented a major initiative to make opioid prescribing safer. In the initiative’s first nine months, clinicians developed documented care plans for almost 6,000 patients receiving long-term opioid therapy for chronic pain. Evaluation of the initiative’s effects on care processes and trends in adverse events is under way. PMID:21821559

  19. Opioid receptors in the gastrointestinal tract

    PubMed Central

    Holzer, Peter

    2011-01-01

    Opium is arguably one of the oldest herbal medicines, being used as analgesic, sedative and antidiarrheal drug for thousands of years. These effects mirror the actions of the endogenous opioid system and are mediated by the principal μ-, κ- and δ-opioid receptors. In the gut, met-enkephalin, leu-enkephalin, β-endorphin and dynorphin occur in both neurons and endocrine cells. When released, opioid peptides activate opioid receptors on the enteric circuitry controlling motility and secretion. As a result, inhibition of gastric emptying, increase in sphincter tone, induction of stationary motor patterns and blockade of peristalsis ensue. Together with inhibition of ion and fluid secretion, these effects cause constipation, one of the most frequent and troublesome adverse reactions of opioid analgesic therapy. Although laxatives are most frequently used to ameliorate opioid-induced bowel dysfunction, their efficacy is unsatisfactory. Specific antagonism of peripheral opioid receptors is a more rational approach. This goal is addressed by the use of opioid receptor antagonists with limited absorption such as oral prolonged-release naloxone and opioid receptor antagonists that do not penetrate the blood-brain barrier such as methylnaltrexone and alvimopan. Preliminary evidence indicates that peripherally restricted opioid receptor antagonists may act as prokinetic drugs in their own right. PMID:19345246

  20. Cytochrome P450 epoxygenase dependence of opioid analgesia: fluconazole does not interfere with remifentanil-mediated analgesia in human subjects.

    PubMed

    Oertel, B G; Vermehren, J; Huynh, T T; Doehring, A; Ferreiros, N; Zimmermann, M; Geisslinger, G; Lötsch, J

    2014-12-01

    Cytochrome P450 (CYP) inhibitors may reduce opioid analgesia by inhibiting CYP activity-dependent post-opioid receptor signaling pathways in the brain. This suggestion was predicated on observations of highly attenuated morphine antinociception in rodents after intracerebroventricular injection of fluconazole or carrying a neuron-specific deletion of the cytochrome P450 reductase. However, based on assessments of thermal and electrical pain tolerance, respiratory function, and side effects in 21 healthy volunteers, before and during steady-state concentrations of 1.5 and 3.0 ng/ml of remifentanil at the effect site (viz., the central nervous system), administration of 400 mg/day fluconazole for 8 days in a double-blind, placebo-controlled manner failed to attenuate opioid effects. Although CYP inhibitors such as fluconazole are unlikely to attenuate remifentanil analgesia in humans, extrapolation of the findings to other opioids is premature because differences among opioid effects, such as ligand-selective biased signaling at opioid receptors, leave the possibility that CYP-dependent opioid signaling in the brain might be limited to morphine and may not extend to remifentanil. PMID:25148377

  1. The effect of a novel pentadecapeptide BPC 157 on development of tolerance and physical dependence following repeated administration of diazepam.

    PubMed

    Jelovac, N; Sikiric, P; Rucman, R; Petek, M; Perovic, D; Marovic, A; Anic, T; Seiwerth, S; Mise, S; Pigac, B; Duplancie, B; Turkovic, B; Dodig, G; Prkacin, I; Stancic-Rokotov, D; Zoricic, I; Aralica, G; Sebecic, B; Ziger, T; Slobodnjak, Z

    1999-09-30

    A novel gastric pentadecapeptide BPC 157 with different beneficial activities and anticonvulsant effect interacting with GABAergic system could improve diazepam efficacy coadministered (10 microg/kg, 10 ng/kg i.p.) with diazepam (5.0 mg/kg i.p.) twice daily for 10 days, since diazepam chronic medication would otherwise predispose for diazepam- tolerance/withdrawal development (shorter latency to convulsion after convulsant). In diazepam chronically treated mice, it attenuated diazepam tolerance (provoked by later acute administration of diazepam together with convulsant) and postponed physical dependence/withdrawal effects (provoked by later administration of isoniazid). In tolerance assay, at 42 h after the end of conditioning regimen, shorter preconvulsive latencies than in healthy (non-diazepam conditioned) mice following isoniazid (800 mg/kg i.p.) (as hallmark of tolerance) were observed if diazepam (5.0 mg/kg i.p.) was again given acutely to mice previously conditioned with diazepam alone (use of picrotoxin 3.0 mg/kg i.p., as convulsant, with acute application of diazepam in previously diazepam conditioned mice did not lead to tolerance hallmark). This was completely avoided in diazepam+BPC 157 10 microg or diazepam+BPC 157 10 ng chronically treated animals. In physical dependence assay (isoniazid challenge assessed at 6, 14, 42 and 72 h after conditioning medication), when compared to diazepam non-conditioned healthy mice, in diazepam conditioned mice residual anticonvulsive activity was not present already at the earliest post-conditioning interval (i.e., not different latency to isoniazid-convulsions), whereas shorter preconvulsive latencies (as physical dependence/withdrawal hallmark) were noted in diazepam conditioned mice following isoniazid challenge at 42 h and at 72 h after end of conditioning treatment. In diazepam+BPC 157 10 microg- conditioned mice, a residual anticonvulsive activity (i.e., longer latency to isoniazid convulsion) was noted at 6 h

  2. Selective review and commentary on emerging pharmacotherapies for opioid addiction.

    PubMed

    Ling, Walter; Mooney, Larissa; Zhao, Min; Nielsen, Suzanne; Torrington, Matthew; Miotto, Karen

    2011-01-01

    Pharmacotherapies for opioid addiction under active development in the US include lofexidine (primarily for managing withdrawal symptoms) and Probuphine®, a distinctive mode of delivering buprenorphine for six months, thus relieving patients, clinicians, and regulatory personnel from most concerns about diversion, misuse, and unintended exposure in children. In addition, two recently approved formulations of previously proven medications are in early phases of implementation. The sublingual film form of buprenorphine + naloxone (Suboxone®) provides a less divertible, more quickly administered, more child-proof version than the buprenorphine + naloxone sublingual tablet. The injectable depot form of naltrexone (Vivitrol®) ensures consistent opioid receptor blockade for one month between administrations, removing concerns about medication compliance. The clinical implications of these developments have attracted increasing attention from clinicians and policymakers in the US and around the world, especially given that human immunodeficiency virus/acquired immunodeficiency syndrome and other infectious diseases are recognized as companions to opioid addiction, commanding more efforts to reduce opioid addiction. While research and practice improvement efforts continue, reluctance to adopt new medications and procedures can be expected, especially considerations in the regulatory process and in the course of implementation. Best practices and improved outcomes will ultimately emerge from continued development efforts that reflect input from many quarters. PMID:24474855

  3. Prescription Opioid Abuse, Prescription Opioid Addiction, and Heroin Abuse among Adolescents in a Recovery High School: A Pilot Study

    ERIC Educational Resources Information Center

    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…

  4. Differences in the Association between Depression and Opioid Misuse in Chronic Low Back Pain versus Chronic Pain at Other Locations.

    PubMed

    Jaiswal, Arpana; Scherrer, Jeffrey F; Salas, Joanne; van den Berk-Clark, Carissa; Fernando, Sheran; Herndon, Christopher M

    2016-01-01

    Patients with chronic pain and depression are more likely to develop opioid abuse compared to patients without depression. It is not known if this association differs by pain location. We compared the strength of association between depression and opioid misuse in patients with chronic low back pain (CLBP) vs. chronic pain of other location (CPOL). Chart abstracted data was obtained from 166 patients seeking care in a family medicine clinic. Depression was measured by the PHQ-9 and opioid misuse was measured using the Current Opioid Misuse Measure. Pain severity and interference questions came from the Brief Pain Inventory. Cross-tabulations were computed to measure the association between depression and opioid misuse stratified on pain location. Exploratory logistic regression modeled the association between depression and opioid misuse after adjusting for pain location and pain severity and interference. Depression was significantly associated with opioid misuse in CPOL but not in CLBP. Regression results indicate pain interference partly accounts for the depression-opioid misuse association. These preliminary results from a small patient sample suggest depression may co-occur with opioid misuse more often in CPOL than in CLBP. Further research is needed to compare this comorbidity in specific pain diagnoses such as arthritis, fibromyalgia and CLBP. PMID:27417622

  5. Differences in the Association between Depression and Opioid Misuse in Chronic Low Back Pain versus Chronic Pain at Other Locations

    PubMed Central

    Jaiswal, Arpana; Scherrer, Jeffrey F.; Salas, Joanne; van den Berk-Clark, Carissa; Fernando, Sheran; Herndon, Christopher M.

    2016-01-01

    Patients with chronic pain and depression are more likely to develop opioid abuse compared to patients without depression. It is not known if this association differs by pain location. We compared the strength of association between depression and opioid misuse in patients with chronic low back pain (CLBP) vs. chronic pain of other location (CPOL). Chart abstracted data was obtained from 166 patients seeking care in a family medicine clinic. Depression was measured by the PHQ-9 and opioid misuse was measured using the Current Opioid Misuse Measure. Pain severity and interference questions came from the Brief Pain Inventory. Cross-tabulations were computed to measure the association between depression and opioid misuse stratified on pain location. Exploratory logistic regression modeled the association between depression and opioid misuse after adjusting for pain location and pain severity and interference. Depression was significantly associated with opioid misuse in CPOL but not in CLBP. Regression results indicate pain interference partly accounts for the depression–opioid misuse association. These preliminary results from a small patient sample suggest depression may co-occur with opioid misuse more often in CPOL than in CLBP. Further research is needed to compare this comorbidity in specific pain diagnoses such as arthritis, fibromyalgia and CLBP. PMID:27417622

  6. Fewer Injured Workers Getting Opioid Prescriptions in Some States

    MedlinePlus

    ... opioids in the 25 states in the study. Simultaneous use of opioids and sedating medications called benzodiazepines ... 1 percent to 9 percent of injured workers. Simultaneous use of opioids and muscle relaxants occurred among ...

  7. [Opioid receptors and their selective ligands].

    PubMed

    Piestrzeniewicz, Mariola Katarzyna; Fichna, Jakub; Michna, Jakub; Janecka, Anna

    2006-01-01

    Opioid receptors (micro, delta, and kappa) belong to a large family of G protein-coupled receptors and play an important physiological role. Stimulation of these receptors triggers analgesic effects and affects the function of gastrointestinal tract. The discovery of opioid peptides, which are endogenous ligands of opioid receptors, including delta-selective enkephalins, kappa-selective dynorphins, and micro-selective endomorphins, initiated their structure-activity relationship studies. For the last 30 years, hundreds of analogs of opioid peptides have been synthesized in an effort to obtain the compounds more active, selective, and resistant to biodegradation than the endogenous ligands. Different unnatural amino acids, as well as cyclisation procedures, leading to conformationaly restricted analogs, were employed. All these modifications resulted in obtaining very selective agonists and antagonists with high affinity at micro-, dlta-, and kappa-opioid receptors, which are extremely useful tools in further studies on the pharmacology of opioid receptors in a mammalian organism. PMID:17201067

  8. Chronic opioid induced constipation in patients with nonmalignant pain: challenges and opportunities

    PubMed Central

    Nelson, Alfred D.

    2015-01-01

    With the recent introduction and approval of medications directed at the treatment of opioid induced constipation (OIC) in patients with nonmalignant pain, there is increased interest and understanding of the unmet need and opportunities to enhance patient management. The high incidence of OIC is associated with rapid increase of narcotic analgesic prescriptions for nonmalignant chronic pain. This review addresses briefly the mechanisms of action of opioids that lead to OIC, the differential tolerance of gastrointestinal organs to the effects of opioids, the size and scope of the problem, the definition and outcome measures for OIC, current differential diagnosis and management algorithms, and the pharmacology and efficacy of treatments for OIC in patients with nonmalignant pain. PMID:26136838

  9. Chronic opioid induced constipation in patients with nonmalignant pain: challenges and opportunities.

    PubMed

    Nelson, Alfred D; Camilleri, Michael

    2015-07-01

    With the recent introduction and approval of medications directed at the treatment of opioid induced constipation (OIC) in patients with nonmalignant pain, there is increased interest and understanding of the unmet need and opportunities to enhance patient management. The high incidence of OIC is associated with rapid increase of narcotic analgesic prescriptions for nonmalignant chronic pain. This review addresses briefly the mechanisms of action of opioids that lead to OIC, the differential tolerance of gastrointestinal organs to the effects of opioids, the size and scope of the problem, the definition and outcome measures for OIC, current differential diagnosis and management algorithms, and the pharmacology and efficacy of treatments for OIC in patients with nonmalignant pain. PMID:26136838

  10. Tolerating Zero Tolerance?

    ERIC Educational Resources Information Center

    Moore, Brian N.

    2010-01-01

    The concept of zero tolerance dates back to the mid-1990s when New Jersey was creating laws to address nuisance crimes in communities. The main goal of these neighborhood crime policies was to have zero tolerance for petty crime such as graffiti or littering so as to keep more serious crimes from occurring. Next came the war on drugs. In federal…

  11. Tetrahydroquinoline derivatives as opioid receptor antagonists.

    PubMed

    Zhang, Cunyu; Westaway, Susan M; Speake, Jason D; Bishop, Michael J; Goetz, Aaron S; Carballo, Luz Helena; Hu, Mike; Epperly, Andrea H

    2011-01-15

    Opioid receptors play an important role in both behavioral and homeostatic functions. We herein report tetrahydroquinoline derivatives as opioid receptor antagonists. SAR studies led to the identification of the potent antagonist 2v, endowed with 1.58nM (K(i)) functional activity against the μ opioid receptor. DMPK data suggest that novel tetrahydroquinoline analogs may be advantageous in peripheral applications. PMID:21193310

  12. Caring for opioid dependent pregnant women: prenatal and postpartum care considerations

    PubMed Central

    Krans, Elizabeth E.; Cochran, Gerald; Bogen, Debra L.

    2015-01-01

    Pregnancy is an opportune time to identify opioid dependence, facilitate conversion to opioid maintenance treatment, and coordinate care with specialists in addiction medicine, behavioral health and social services. Comprehensive prenatal care for opioid dependent women involves the evaluation and management of co-occurring psychiatric disorders, polysubstance use, infectious diseases, social stressors and counseling regarding the importance of breastfeeding, contraception and neonatal abstinence syndrome. While the complex psychiatric, social and environmental factors faced by this population pose significant challenges to obstetric care providers, the development of strong patient-provider relationships can facilitate the ability to deliver efficient and effective health care during pregnancy. PMID:25775440

  13. A case of delayed respiratory depression caused by accidental subcutaneous opioid infusion.

    PubMed

    Okada, Takuya; Egi, Moritoki; Sato, Hitoaki; Nomura, Yuki; Okada, Masako; Izuta, Shinichiro; Mizobuchi, Satoshi

    2016-06-01

    We report a case of delayed respiratory depression due to accidental subcutaneous opioid infusion. A healthy 33-year-old woman underwent orthopedic surgery under general anesthesia. Before the end of the operation, it was noticed that a part of the opioid infusion had been administered subcutaneously. About 15 min after tracheal extubation, the patient developed respiratory depression and loss of consciousness. The patient recovered with the use of jaw lift together with bag-valve-mask ventilation. We believe that accidental subcutaneous opioid accumulation may have caused the respiratory depression. PMID:26762999

  14. The relationship between opioid and sugar intake: Review of evidence and clinical applications

    PubMed Central

    Mysels, David J; Sullivan, Maria A

    2011-01-01

    Opioid dependence poses significant public health risks arising from associated morbidity and mortality caused by accidents, infectious disease, and social ramifications of crime and unemployment, among other complications. Opioid use, acute and chronic, is also associated with weight gain, glycemic dysregulation, and dental pathology. The literature supporting the connection between opiate use and development of preference for sweet tastes is reviewed, and further association with dental pathology, weight gain, and loss of glycemic control are considered. We discuss the impact of sweet tastes on the endogenous opioid system as well as clinical implications for analgesia and treating the opiate-dependent patient. PMID:21269006

  15. Novel pharmacotherapeutic strategies for treatment of opioid-induced neonatal abstinence syndrome

    PubMed Central

    McLemore, Gabrielle L.; Lewis, Tamorah; Jones, Catherine H.; Gauda, Estelle B.

    2014-01-01

    Summary 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 in maternal and fetal/neonatal (M-F/N) medicine. The standard of care for illicit or prescription opioid dependence during pregnancy is opioid agonist (methadone or buprenorphine) substitution therapy, which are also frequently abused. The next generation of pharmacotherapies for the treatment of illicit or prescription opioid addiction in the M-F/N interactional dyad must take into consideration the interplay between genetic, epigenetic, and environmental factors. Addiction to illicit drugs during pregnancy presents unique challenges to effectively treat the mother, and the developing fetus and infant after delivery. New pharmacotherapies should be safe to the developing fetus, effective in treating the physical and psychological consequences of addiction in the mother, and reduce the incidence and severity of NAS in the infant after birth. More pharmacotherapeutic options should be available to the physician such that a more individualized rather than a one-drug/strategy-fits-all approach can be used. A myriad of new and exciting pharmacotherapeutic strategies for the treatment of opioid dependence and addiction are on the horizon. This review focuses on such three strategies: (i) pharmacotherapeutic targeting of the serotoninergic system; (ii) mixed opioid immunotherapeutics (vaccines); (iii) pharmacogenomics as a therapeutic strategy to insure personalized care. We review and discuss how these strategies may offer additional treatment modalities for the treatment

  16. Opioid prescribing pitfalls: medicolegal and regulatory issues

    PubMed Central

    Jammal, Walid; Gown, Grace

    2015-01-01

    Summary Inappropriate opioid prescribing can lead to patient harm as well as a medicolegal risk to prescribers. Prescribers need to be familiar with the indications, contraindications and harms associated with opioids. When prescribing opioids, doctors must be aware of their clinical, ethical and legal responsibilities, particularly the legislative requirements in their state. Failure to comply with these can result in disciplinary action. To avoid potential conflict with differing state regulations on opioid prescribing, doctors should advise patients to get their prescription dispensed in the same state in which it was written. PMID:26843712

  17. Chronic Pain and the Opioid Conundrum.

    PubMed

    Webster, Lynn R

    2016-06-01

    Opioids prescribed for chronic cancer and noncancer pain have been embroiled in public policy debates as to effectiveness and potential for contributing to society's problem with misuse, addiction, and overdose mortality. The conundrum of opioid prescribing is to determine who will most likely benefit from opioids and how medical practitioners may safely provide chronic opioid therapy, while also identifying patients who are unlikely to benefit or could divert illicit pharmaceuticals into society. Risk assessment and monitoring are essential to meet the standard of care, as is compliance with federal controlled substances law as well as state regulations. PMID:27208714

  18. Plant defense response against Fusarium oxysporum and strategies to develop tolerant genotypes in banana.

    PubMed

    Swarupa, V; Ravishankar, K V; Rekha, A

    2014-04-01

    Soil-borne fungal pathogen, Fusarium oxysporum causes major economic losses by inducing necrosis and wilting symptoms in many crop plants. Management of fusarium wilt is achieved mainly by the use of chemical fungicides which affect the soil health and their efficiency is often limited by pathogenic variability. Hence understanding the nature of interaction between pathogen and host may help to select and improve better cultivars. Current research evidences highlight the role of oxidative burst and antioxidant enzymes indicating that ROS act as an important signaling molecule in banana defense response against Fusarium oxysporum f.sp. cubense. The role of jasmonic acid signaling in plant defense against necrotrophic pathogens is well recognized. But recent studies show that the role of salicylic acid is complex and ambiguous against necrotrophic pathogens like Fusarium oxysporum, leading to many intriguing questions about its relationship between other signaling compounds. In case of banana, a major challenge is to identify specific receptors for effector proteins like SIX proteins and also the components of various signal transduction pathways. Significant progress has been made to uncover the role of defense genes but is limited to only model plants such as Arabidopsis and tomato. Keeping this in view, we review the host response, pathogen diversity, current understanding of biochemical and molecular changes that occur during host and pathogen interaction. Developing resistant cultivars through mutation, breeding, transgenic and cisgenic approaches have been discussed. This would help us to understand host defenses against Fusarium oxysporum and to formulate strategies to develop tolerant cultivars. PMID:24420701

  19. Development of a more fish-tolerant turbine runner, advanced hydropower turbine project

    SciTech Connect

    Cook, T.C.; Hecker, G.E.; Faulkner, H.B.; Jansen, W.

    1997-02-01

    Alden Research Laboratory, Inc. (ARL) and Northern Research and Engineering Corporation (NREC) conducted a research program to develop a turbine runner which will minimize fish injury and mortality at hydroelectric projects. ARL?NREC have developed a runner shape which minimizes the number of blade leading edges, reduces the pressure versus time and the velocity versus distance gradients within the runner, minimizes or eliminates the clearance between the runner and runner housing, and maximizes the size of the flow passages, all with minimal penalty on turbine efficiency. An existing pump impeller provided the starting point for developing the fish tolerant turbine runner. The Hidrostal pump is a single bladed combined screw/centrifugal pump which has been proven to transport fish with minimal injury. The focus of the ARL/NREC research project was to develop a new runner geometry which is effective in downstream fish passage and hydroelectric power generation. A flow of 1,000 cfs and a head in the range of 75 ft to 100 ft were selected for conceptual design of the new runner. Conceptual design of the new runner began with a re-evaluation of studies which have been previously conducted to identify probable sources of injury to fish passing through hydraulic turbines. Criteria relative to hydraulic characteristics which are favorable for fish passage were prepared based on a reassessment of the available information. Important criteria used to develop the new runner design included low pressure change rates, minimum absolute pressures, and minimum shear. Other criteria which are reflected in the runner design are a minimum number of blades (only two), minimum total length of leading edges, and large flow passages. 86 figs., 5 tabs.

  20. Validation of a Brief Opioid Compliance Checklist for Patients with Chronic Pain

    PubMed Central

    Jamison, Robert N.; Martel, Marc O.; Edwards, Robert R.; Qian, Jing; Sheehan, Kerry Anne; Ross, Edgar L.

    2014-01-01

    There has been a need for a brief assessment tool to determine compliance with use of prescribed opioids for pain. The purpose of this study was to develop and begin the validation of a brief and simple compliance checklist (Opioid Compliance Checklist; OCC) for chronic pain patients prescribed long-term opioid therapy. A review of the literature of opioid therapy agreements led to a 12-item OCC that was repeatedly administered to 157 patients who were taking opioids for chronic pain and followed for six months. Validation of the OCC was conducted by identifying those patients exhibiting aberrant drug-related behavior as determined by any of the following: positive urine toxicology screen, a positive score on the Prescription Drug Use Questionnaire (PDUQ) interview or Current Opioid Misuse Measure (COMM), and/or ratings by staff on the Addiction Behavior Checklist (ABC). Of the original 12 items, 5 OCC items appeared to best predict subsequent aberrant behaviors based on multivariate logistic regression analyses (cross-validated AUC=.67). Although further testing is needed, these results suggest that the OCC is an easy-to-use, promising measure in monitoring opioid adherence among persons with chronic pain. PMID:25092233

  1. Pharmacogenomic considerations in opioid analgesia

    PubMed Central

    Vuilleumier, Pascal H; Stamer, Ulrike M; Landau, Ruth

    2012-01-01

    Translating pharmacogenetics to clinical practice has been particularly challenging in the context of pain, due to the complexity of this multifaceted phenotype and the overall subjective nature of pain perception and response to analgesia. Overall, numerous genes involved with the pharmacokinetics and dynamics of opioids response are candidate genes in the context of opioid analgesia. The clinical relevance of CYP2D6 genotyping to predict analgesic outcomes is still relatively unknown; the two extremes in CYP2D6 genotype (ultrarapid and poor metabolism) seem to predict pain response and/or adverse effects. Overall, the level of evidence linking genetic variability (CYP2D6 and CYP3A4) to oxycodone response and phenotype (altered biotransformation of oxycodone into oxymorphone and overall clearance of oxycodone and oxymorphone) is strong; however, there has been no randomized clinical trial on the benefits of genetic testing prior to oxycodone therapy. On the other hand, predicting the analgesic response to morphine based on pharmacogenetic testing is more complex; though there was hope that simple genetic testing would allow tailoring morphine doses to provide optimal analgesia, this is unlikely to occur. A variety of polymorphisms clearly influence pain perception and behavior in response to pain. However, the response to analgesics also differs depending on the pain modality and the potential for repeated noxious stimuli, the opioid prescribed, and even its route of administration. PMID:23226064

  2. Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators.

    PubMed

    Kruegel, Andrew C; Gassaway, Madalee M; Kapoor, Abhijeet; Váradi, András; Majumdar, Susruta; Filizola, Marta; Javitch, Jonathan A; Sames, Dalibor

    2016-06-01

    Mu-opioid receptor agonists represent mainstays of pain management. However, the therapeutic use of these agents is associated with serious side effects, including potentially lethal respiratory depression. Accordingly, there is a longstanding interest in the development of new opioid analgesics with improved therapeutic profiles. The alkaloids of the Southeast Asian plant Mitragyna speciosa, represented by the prototypical member mitragynine, are an unusual class of opioid receptor modulators with distinct pharmacological properties. Here we describe the first receptor-level functional characterization of mitragynine and related natural alkaloids at the human mu-, kappa-, and delta-opioid receptors. These results show that mitragynine and the oxidized analogue 7-hydroxymitragynine, are partial agonists of the human mu-opioid receptor and competitive antagonists at the kappa- and delta-opioid receptors. We also show that mitragynine and 7-hydroxymitragynine are G-protein-biased agonists of the mu-opioid receptor, which do not recruit β-arrestin following receptor activation. Therefore, the Mitragyna alkaloid scaffold represents a novel framework for the development of functionally biased opioid modulators, which may exhibit improved therapeutic profiles. Also presented is an enantioselective total synthesis of both (-)-mitragynine and its unnatural enantiomer, (+)-mitragynine, employing a proline-catalyzed Mannich-Michael reaction sequence as the key transformation. Pharmacological evaluation of (+)-mitragynine revealed its much weaker opioid activity. Likewise, the intermediates and chemical transformations developed in the total synthesis allowed the elucidation of previously unexplored structure-activity relationships (SAR) within the Mitragyna scaffold. Molecular docking studies, in combination with the observed chemical SAR, suggest that Mitragyna alkaloids adopt a binding pose at the mu-opioid receptor that is distinct from that of classical opioids. PMID

  3. A Phase 3 Placebo-Controlled, Double Blind, Multi-Site Trial of the alpha-2-adrenergic Agonist, Lofexidine, for Opioid Withdrawal

    PubMed Central

    Yu, Elmer; Miotto, Karen; Akerele, Evaristo; Montgomery, Ann; Elkashef, Ahmed; Walsh, Robert; Montoya, Ivan; Fischman, Marian W.; Collins, Joseph; McSherry, Frances; Boardman, Kathy; Davies, David K.; O’Brien, Charles P.; Ling, Walter; Kleber, Herbert; Herman, Barbara H.

    2008-01-01

    Context Lofexidine is an alpha-2-A noradrenergic receptor agonist that is approved in the United Kingdom for the treatment of opioid withdrawal symptoms. Lofexidine has been reported to have more significant effects on decreasing opioid withdrawal symptoms with less hypotension than clonidine. Objective To demonstrate that lofexidine is well tolerated and effective in the alleviation of observationally-defined opioid withdrawal symptoms in opioid dependent individuals undergoing medically supervised opioid detoxification as compared to placebo. Design An inpatient, Phase 3, placebo-controlled, double blind, randomized multi-site trial with three phases: (1) Opioid Agonist Stabilization Phase (days 1–3), (2) Detoxification/Medication or Placebo Phase (days 4–8), and (3) Post Detoxification/Medication Phase (days 9–11). Subjects Sixty-eight opioid dependent subjects were enrolled at three sites with 35 randomized to lofexidine and 33 to placebo. Main Outcome Measure Modified Himmelsbach Opiate Withdrawal Scale (MHOWS) on study day 5 (2nd opioid detoxification treatment day). Results Due to significant findings, the study was terminated early. On the study day 5 MHOWS, subjects treated with lofexidine had significantly lower scores (equating to fewer/less severe withdrawal symptoms) than placebo subjects (Least squares means 19.5 ± 2.1 versus 30.9 ± 2.7; p=0.0019). Lofexidine subjects had significantly better retention in treatment than placebo subjects (38.2% versus 15.2%; Log rank test p=0.01). Conclusions Lofexidine is well tolerated and more efficacious than placebo for reducing opioid withdrawal symptoms in inpatients undergoing medically supervised opioid detoxification. Trial Registration trial registry name A Phase 3 Placebo-Controlled, Double-Blind Multi-Site Trial of Lofexidine for Opiate Withdrawal, registration number NCT00032942, URL for the registry http://clinicaltrials.gov/ct/show/NCT00032942?order=4. PMID:18508207

  4. Safety and Tolerability of Glucagon-Like Peptide-1 Receptor Agonists Utilizing Data from the Exenatide Clinical Trial Development Program.

    PubMed

    Peng, Hui; Want, Laura L; Aroda, Vanita R

    2016-05-01

    Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated benefits for patients with type 2 diabetes including A1C reduction and weight loss with minimal risk of hypoglycemia. This article provides an evidence-based update of safety and tolerability considerations for the clinical use of GLP-1RAs as a class, with a specific detailed review of data from the exenatide clinical trial development program, which has the longest history and availability of safety and tolerability data as the first-approved GLP-1RA. Specific areas covered include comparative risk of hypoglycemia, as well as pancreatic, thyroid, and cardiovascular safety data; clinical guidance regarding current safety and tolerability data is also reviewed. PMID:27037706

  5. Implementing opioid substitution in Lebanon: Inception and challenges.

    PubMed

    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. PMID:27114000

  6. Ignavine: a novel allosteric modulator of the μ opioid receptor.

    PubMed

    Ohbuchi, Katsuya; Miyagi, Chika; Suzuki, Yasuyuki; Mizuhara, Yasuharu; Mizuno, Keita; Omiya, Yuji; Yamamoto, Masahiro; Warabi, Eiji; Sudo, Yuka; Yokoyama, Akinobu; Miyano, Kanako; Hirokawa, Takatsugu; Uezono, Yasuhito

    2016-01-01

    Processed Aconiti tuber (PAT) is used to treat pain associated with various disorders. Although it has been demonstrated that the κ opioid receptor (KOR) signaling pathway is a mediator of the analgesic effect of PAT, active components affecting opioid signaling have not yet been identified. In this study, we explored candidate components of PAT by pharmacokinetic analysis and identified ignavine, which is a different structure from aconitine alkaloids. A receptor binding assay of opioid receptors showed that ignavine specifically binds the μ opioid receptor (MOR), not the KOR. Receptor internalization assay in MOR-expressing cell lines revealed that ignavine augmented the responses produced by D-Ala(2)-N-Me-Phe(4)-Gly-ol(5)-enkephalin (DAMGO), a representative MOR agonist, at a low concentration and inhibited it at a higher concentration. Ignavine also exerted positive modulatory activity for DAMGO, endomorphin-1 and morphine in cAMP assay. Additionally, ignavine alone showed an analgesic effect in vivo. In silico simulation analysis suggested that ignavine would induce a unique structural change distinguished from those induced by a representative MOR agonist and antagonist. These data collectively suggest the possibility that ignavine could be a novel allosteric modulator of the MOR. The present results may open the way for the development of a novel pain management strategy. PMID:27530869

  7. Ignavine: a novel allosteric modulator of the μ opioid receptor

    PubMed Central

    Ohbuchi, Katsuya; Miyagi, Chika; Suzuki, Yasuyuki; Mizuhara, Yasuharu; Mizuno, Keita; Omiya, Yuji; Yamamoto, Masahiro; Warabi, Eiji; Sudo, Yuka; Yokoyama, Akinobu; Miyano, Kanako; Hirokawa, Takatsugu; Uezono, Yasuhito

    2016-01-01

    Processed Aconiti tuber (PAT) is used to treat pain associated with various disorders. Although it has been demonstrated that the κ opioid receptor (KOR) signaling pathway is a mediator of the analgesic effect of PAT, active components affecting opioid signaling have not yet been identified. In this study, we explored candidate components of PAT by pharmacokinetic analysis and identified ignavine, which is a different structure from aconitine alkaloids. A receptor binding assay of opioid receptors showed that ignavine specifically binds the μ opioid receptor (MOR), not the KOR. Receptor internalization assay in MOR-expressing cell lines revealed that ignavine augmented the responses produced by D-Ala(2)-N-Me-Phe(4)-Gly-ol(5)-enkephalin (DAMGO), a representative MOR agonist, at a low concentration and inhibited it at a higher concentration. Ignavine also exerted positive modulatory activity for DAMGO, endomorphin-1 and morphine in cAMP assay. Additionally, ignavine alone showed an analgesic effect in vivo. In silico simulation analysis suggested that ignavine would induce a unique structural change distinguished from those induced by a representative MOR agonist and antagonist. These data collectively suggest the possibility that ignavine could be a novel allosteric modulator of the MOR. The present results may open the way for the development of a novel pain management strategy. PMID:27530869

  8. Regulation and Functional Implications of Opioid Receptor Splicing in Opioid Pharmacology and HIV Pathogenesis.

    PubMed

    Regan, Patrick M; Langford, Dianne; Khalili, Kamel

    2016-05-01

    Despite the identification and characterization of four opioid receptor subtypes and the genes from which they are encoded, pharmacological data does not conform to the predications of a four opioid receptor model. Instead, current studies of opioid pharmacology suggest the existence of additional receptor subtypes; however, no additional opioid receptor subtype has been identified to date. It is now understood that this discrepancy is due to the generation of multiple isoforms of opioid receptor subtypes. While several mechanisms are utilized to generate these isoforms, the primary mechanism involves alternative splicing of the pre-mRNA transcript. Extensive alternative splicing patterns for opioid receptors have since been identified and discrepancies in opioid pharmacology are now partially attributed to variable expression of these isoforms. Recent studies have been successful in characterizing the localization of these isoforms as well as their specificity in ligand binding; however, the regulation of opioid receptor splicing specificity is poorly characterized. Furthermore, the functional significance of individual receptor isoforms and the extent to which opioid- and/or HIV-mediated changes in the opioid receptor isoform profile contributes to altered opioid pharmacology or the well-known physiological role of opioids in the exacerbation of HIV neurocognitive dysfunction is unknown. As such, the current review details constitutive splicing mechanisms as well as the specific architecture of opioid receptor genes, transcripts, and receptors in order to highlight the current understanding of opioid receptor isoforms, potential mechanisms of their regulation and signaling, and their functional significance in both opioid pharmacology and HIV-associated neuropathology. PMID:26529364

  9. [Nociceptin and the ORL1 receptor: pharmacology of a new opioid receptor].

    PubMed

    Grond, S; Meuser, T; Pietruck, C; Sablotzki, A

    2002-12-01

    Molecular biological investigations led to the discovery of the ORL1 receptor ( opioid receptor like-1 receptor) and its endogenous ligand nociceptin. Although its sequence and structure are closely related to traditional opioid receptors, the ORL1 receptor shows low binding affinities for selective opioid agonists and antagonists. On the other hand, the ORL1 ligand nociceptin does not bind to the three traditional opioid receptors. The activation of the G protein-coupled ORL1 receptor inhibits adenlylate cyclase activity, reduces the intracellular concentration of the second messenger cAMP and regulates ion channels. The supraspinal administration of nociceptin produces hyperalgesia. unlike opioids. Spinal intrathecal and peripheral administration of nociceptin causes hyperalgesia in low doses and analgesia in high doses. The physiological role and detailed mechanisms of these dose-dependent nociceptin effects in opposite directions are not yet known. In addition, nociceptin modulates other biological phenomena such as feeding, locomotion, gastrointestinal function,memory, cardiovascular function,immunity, renal function, anxiety,dependence and tolerance.Future research on the physiological and pathophysiological importance of the nociceptin/ORL1 receptor systems may provide a target for novel therapeutics. PMID:12486589

  10. Oral opioid use alters DNIC but not cold pain perception in patients with chronic pain - new perspective of opioid-induced hyperalgesia.

    PubMed

    Ram, Kerstin Carlin; Eisenberg, Elon; Haddad, May; Pud, Dorit

    2008-10-15

    Opioids can elicit unexpected changes in pain sensitivity, known as opioid-induced hyperalgesia (OIH). The aim of this study was to explore whether OIH exists in patients with chronic pain treated with oral opioids (OP) versus non-opioid (NOP) analgesics. The sensitivity to cold pain and the magnitude of diffuse noxious inhibitory control (DNIC) were evaluated in 73 OP and 37 NOP treated patients. Pain threshold, intensity and tolerance in response to the cold pressor (1 degrees C) were measured. DNIC was tested by co-administrating conditioned heat stimulation (47 degrees C) to the left forearm and a conditioning stimulation of 12 degrees C for 30s to the right hand. The results showed no differences between the two groups in any of the cold pain measures. In contrast, the magnitude of DNIC was significantly larger in the NOP than in the OP treated patients (p=0.003). A gender based analysis showed a significant difference in DNIC between OP and NOP treated men only. However, a mixed model ANOVA demonstrated a significant effect of treatment (OP versus NOP) (F=5.928, p=0.017) rather than gender on DNIC. A regression analysis showed that opioid dosage and treatment duration had a significant negative effect on the magnitude of DNIC in OP treated men (beta=-2.175, p=0.036 and beta=-2.061, p=0.047, respectively). In conclusion, oral opioids usage for the treatment of chronic pain does not result in abnormal sensitivity to cold pain, but seems to alter pain modulation. The use of 'advanced' psychophysics tests such as evaluation of DNIC can help understanding the phenomenon of OIH. PMID:18583047

  11. It’s MORe exciting than mu: crosstalk between mu opioid receptors and glutamatergic transmission in the mesolimbic dopamine system

    PubMed Central

    Chartoff, Elena H.; Connery, Hilary S.

    2014-01-01

    Opioids selective for the G protein-coupled mu opioid receptor (MOR) produce potent analgesia and euphoria. Heroin, a synthetic opioid, is considered one of the most addictive substances, and the recent exponential rise in opioid addiction and overdose deaths has made treatment development a national public health priority. Existing medications (methadone, buprenorphine, and naltrexone), when combined with psychosocial therapies, have proven efficacy in reducing aspects of opioid addiction. Unfortunately, these medications have critical limitations including those associated with opioid agonist therapies (e.g., sustained physiological dependence and opioid withdrawal leading to high relapse rates upon discontinuation), non-adherence to daily dosing, and non-renewal of monthly injection with extended-release naltrexone. Furthermore, current medications fail to ameliorate key aspects of addiction such as powerful conditioned associations that trigger relapse (e.g., cues, stress, the drug itself). Thus, there is a need for developing novel treatments that target neural processes corrupted with chronic opioid use. This requires a basic understanding of molecular and cellular mechanisms underlying effects of opioids on synaptic transmission and plasticity within reward-related neural circuits. The focus of this review is to discuss how crosstalk between MOR-associated G protein signaling and glutamatergic neurotransmission leads to immediate and long-term effects on emotional states (e.g., euphoria, depression) and motivated behavior (e.g., drug-seeking, relapse). Our goal is to integrate findings on how opioids modulate synaptic release of glutamate and postsynaptic transmission via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate receptors in the nucleus accumbens and ventral tegmental area with the clinical (neurobehavioral) progression of opioid dependence, as well as to identify gaps in knowledge that can be addressed in future studies

  12. Review of naloxone safety for opioid overdose: practical considerations for new technology and expanded public access

    PubMed Central

    2015-01-01

    Opioid overdose and mortality have increased at an alarming rate prompting new public health initiatives to reduce drug poisoning. One initiative is to expand access to the opioid antidote naloxone. Naloxone has a long history of safe and effective use by organized healthcare systems and providers in the treatment of opioid overdose by paramedics/emergency medicine technicians, emergency medicine physicians and anesthesiologists. The safety of naloxone in a prehospital setting administered by nonhealthcare professionals has not been formally established but will likely parallel medically supervised experiences. Naloxone dose and route of administration can produce variable intensity of potential adverse reactions and opioid withdrawal symptoms: intravenous administration and higher doses produce more adverse events and more severe withdrawal symptoms in those individuals who are opioid dependent. More serious adverse reactions after naloxone administration occur rarely and may be confounded by the effects of other co-intoxicants and the effects of prolonged hypoxia. One component of the new opioid harm reduction initiative is to expand naloxone access to high-risk individuals (addicts, abusers, or patients taking high-dose or extended-release opioids for pain) and their close family or household contacts. Patients or their close contacts receive a naloxone prescription to have the medication on their person or in the home for use during an emergency. Contacts are trained on overdose recognition, rescue breathing and administration of naloxone by intramuscular injection or nasal spraying of the injection prior to the arrival of emergency medical personnel. The safety profile of naloxone in traditional medical use must be considered in this new context of outpatient prescribing, dispensing and treatment of overdose prior to paramedic arrival. New naloxone delivery products are being developed for this prehospital application of naloxone in treatment of opioid

  13. Review of naloxone safety for opioid overdose: practical considerations for new technology and expanded public access.

    PubMed

    Wermeling, Daniel P

    2015-02-01

    Opioid overdose and mortality have increased at an alarming rate prompting new public health initiatives to reduce drug poisoning. One initiative is to expand access to the opioid antidote naloxone. Naloxone has a long history of safe and effective use by organized healthcare systems and providers in the treatment of opioid overdose by paramedics/emergency medicine technicians, emergency medicine physicians and anesthesiologists. The safety of naloxone in a prehospital setting administered by nonhealthcare professionals has not been formally established but will likely parallel medically supervised experiences. Naloxone dose and route of administration can produce variable intensity of potential adverse reactions and opioid withdrawal symptoms: intravenous administration and higher doses produce more adverse events and more severe withdrawal symptoms in those individuals who are opioid dependent. More serious adverse reactions after naloxone administration occur rarely and may be confounded by the effects of other co-intoxicants and the effects of prolonged hypoxia. One component of the new opioid harm reduction initiative is to expand naloxone access to high-risk individuals (addicts, abusers, or patients taking high-dose or extended-release opioids for pain) and their close family or household contacts. Patients or their close contacts receive a naloxone prescription to have the medication on their person or in the home for use during an emergency. Contacts are trained on overdose recognition, rescue breathing and administration of naloxone by intramuscular injection or nasal spraying of the injection prior to the arrival of emergency medical personnel. The safety profile of naloxone in traditional medical use must be considered in this new context of outpatient prescribing, dispensing and treatment of overdose prior to paramedic arrival. New naloxone delivery products are being developed for this prehospital application of naloxone in treatment of opioid

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

    PubMed

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

    2011-10-01

    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, low doses of 6β-naltrexol antagonized naltrexone precipitated withdrawal while high doses acted additively. All doses of naltrexone increased 6β-naltrexol's potency to precipitate withdrawal. The next experiment examined changes in antagonist potency to precipitate withdrawal with increasing morphine dependence. Mice were exposed to morphine for 1-6 days and then withdrawal was precipitated. Naltrexone was more potent than 6β-naltrexol at all the time points. The ED(50) of both drugs decreased at the same rate suggesting that increased dependence produced no change in constitutive opioid receptor activity. Taken together these results indicate that the functional efficacy of 6β-naltrexol is dose-dependent and that constitutive opioid receptor activity did not change as opioid dependence increased from 1 to 6 days. PMID:21736895

  15. Identification of desiccation tolerance transcripts potentially involved in rape (Brassica napus L.) seeds development and germination.

    PubMed

    Lang, Sirui; Liu, Xiaoxia; Ma, Gang; Lan, QinYing; Wang, Xiaofeng

    2014-10-01

    To investigate regulatory processes and protective mechanisms leading to desiccation tolerance (DT) in seeds, cDNA amplified fragment length polymorphism (cDNA-AFLP) in conjunction with 128 primer combinations was used to detect differential gene expression in rape seeds in response to DT during seed development and germination. We obtained approximately 8000 transcript-derived fragments (TDFs), of which 394 TDFs with differential expression patterns ("sustained expression", "up-regulated", "couple with seed DT", and "down-regulated") were excised from gels and re-amplified by polymerase chain reaction (PCR). After sequencing and comparison with the National Center for Biotechnology Information database, 176 TDFs presented significant similarity with known genes that could be classified into the following categories: metabolism and energy, stress resistance and defense, storage, signal transduction, and other functional categories. Using semiquantitative reverse-transcription PCR and real-time PCR approaches, the significance of the differences was further confirmed in fresh seeds and dehydrated seeds. The genes that encode superoxide dismutase, peroxiredoxin, caleosin, oleosin S3, steroleosin, late embryogenesis abundant protein, glutathione reductase, β-glucosidase, S23 transcriptional repressor, and some heat-shock proteins could be associated with DT. The results of this study will aid in the identification of candidate genes for future experiments that seek to understand seed DT. PMID:25221920

  16. Protein S-ACYL Transferase10 is critical for development and salt tolerance in Arabidopsis.

    PubMed

    Zhou, Liang-Zi; Li, Sha; Feng, Qiang-Nan; Zhang, Yu-Ling; Zhao, Xinying; Zeng, Yong-lun; Wang, Hao; Jiang, Liwen; Zhang, Yan

    2013-03-01

    Protein S-acylation, commonly known as palmitoylation, is a reversible posttranslational modification that catalyzes the addition of a saturated lipid group, often palmitate, to the sulfhydryl group of a Cys. Palmitoylation regulates enzyme activity, protein stability, subcellular localization, and intracellular sorting. Many plant proteins are palmitoylated. However, little is known about protein S-acyl transferases (PATs), which catalyze palmitoylation. Here, we report that the tonoplast-localized PAT10 is critical for development and salt tolerance in Arabidopsis thaliana. PAT10 loss of function resulted in pleiotropic growth defects, including smaller leaves, dwarfism, and sterility. In addition, pat10 mutants are hypersensitive to salt stresses. We further show that PAT10 regulates the tonoplast localization of several calcineurin B-like proteins (CBLs), including CBL2, CBL3, and CBL6, whose membrane association also depends on palmitoylation. Introducing a C192S mutation within the highly conserved catalytic motif of PAT10 failed to complement pat10 mutants, indicating that PAT10 functions through protein palmitoylation. We propose that PAT10-mediated palmitoylation is critical for vacuolar function by regulating membrane association or the activities of tonoplast proteins. PMID:23482856

  17. Preliminary work toward the development of a dimensional tolerance standard for rapid prototyping

    NASA Technical Reports Server (NTRS)

    Kennedy, W. J.

    1996-01-01

    Rapid prototyping is a new technology for building parts quickly from CAD models. It works by slicing a CAD model into layers, then by building a model of the part one layer at a time. Since most parts can be sliced, most parts can be modeled using rapid prototyping. The layers themselves are created in a number of different ways - by using a laser to cure a layer of an epoxy or a resin, by depositing a layer of plastic or wax upon a surface, by using a laser to sinter a layer of powder, or by using a laser to cut a layer of paper. Rapid prototyping (RP) is new, and a standard part for use in comparing dimensional tolerances has not yet been chosen and accepted by ASTM (the American Society for Testing Materials). Such a part is needed when RP is used to build parts for investment casting or for direct use. The objective of this project was to start the development of a standard part by using statistical techniques to choose the features of the part which show curl - the vertical deviation of a part from its intended horizontal plane.

  18. Acute effects of exposure to orthochlorobenzylidene malononitrile (CS) and the development of tolerance

    PubMed Central

    Beswick, F. W.; Holland, P.; Kemp, K. H.

    1972-01-01

    Beswick, F. W., Holland, P., and Kemp, K. H. (1972).Brit. J. industr. Med.,29, 298-306. Acute effects of exposure to orthochlorobenzylidene malononitrile (CS) and the development of tolerance. Of the many compounds capable of producing irritation of the eyes and upper respiratory tract two, ω-chloroacetophenone and orthochlorobenzylidene malononitrile (CS), have been used as riot control agents. The latter, CS, has been in use for more than 10 years and is currently still in service. When dispersed as a smoke consisting of 1-micron diameter particles CS will produce lachrymation and pain and discomfort in the upper respiratory tract and chest. Exposed individuals become apprehensive and highly motivated to escape from the smoke. Recovery from these effects occurs within minutes of the affected individual reaching fresh air. The present study reports the effects produced by CS aerosol on 35 healthy male volunteers who were exposed in such a way that the total dose of the agent received by each man was greater than that which he might have received in an actual riot; this was achieved by taking advantage of the fact that adaptation to the effects of CS occurs if exposure is gradual and to low concentrations. In addition to the clinical observations, cardiological, respiratory, and biochemical observations were made. No abnormalities were observed in the electrocardiogram, respiratory function tests or the blood biochemistry and cell constitution. Such changes that were observed could be ascribed to the emotional stress and discomfort of the experiment. PMID:5044601

  19. SMAD4 is Involved in the Development of Endotoxin Tolerance in Microglia.

    PubMed

    Liu, Xiaorong; Qin, Yongwei; Dai, Aihua; Zhang, Yu; Xue, Huaqing; Ni, Haidan; Han, Lijian; Zhu, Liang; Yuan, Debin; Tao, Tao; Cao, Maohong

    2016-07-01

    Initial exposure of macrophages to LPS induces hyporesponsiveness to a second challenge with LPS, a phenomenon termed LPS tolerance. Smad4 plays important roles in the induction of LPS tolerance. However, the function of Smad4 in microglia remains unknown. Here we show that expression of Smad4 was highly up-regulated in LPS-tolerized mouse cerebral cortex. Smad4 was mostly colocalized with microglia, rarely with neurons. Using a microglia cell line, BV2, we find that LPS activates endogenous Smad4, inducing its migration into the nucleus and increasing its expression. Smad4 significantly suppressed TLR-triggered production of proinflammatory cytokines (IL-6), increased anti-inflammatory cytokine in LPS-tolerized microglia. Moreover, IL-6 concentrations in culture supernatants after second LPS challenge are higher in SMAD4 small interfering RNA (siRNA) BV2 cells than control siRNA BV2 cells, indicating failure to induce tolerance in absence of Smad4 signaling. In our study, we conclude that both in vivo and in vitro, Smad4 signaling is required for maximal induction of endotoxin tolerance. PMID:26758028

  20. Analgesia and decrement in operant performance in socially defeated mice: selective cross-tolerance to morphine and antagonism by naltrexone.

    PubMed

    Miczek, K A; Winslow, J T

    1987-01-01

    During a social confrontation between a resident and an intruder mouse, only the submissive or defeated intruder shows an opioid-mediated analgesia to which tolerance develops. We investigated the altered morphine responsiveness after different kinds of social experiences. Mice were assessed for performance of operant behavior under the control of a fixed ratio schedule of positive reinforcement as well as for the tail flick response to a heat stimulus before and after one or five consecutive social confrontations. The dose-effect curves for morphine's suppression of schedule-controlled behavior were closely similar before and after defeat in a single or in five social confrontations. However, the concurrently measured response to pain in the tail flick assay produced morphine dose-effect curves that were shifted to the right after defeat in one or five social confrontations. Four to six times higher doses of morphine were necessary to produce analgesia in mice that were defeated in five social confrontations. Naltrexone (1 mg/kg, ip) antagonized the suppressive effects of morphine (10 mg/kg, ip) on rate of responding and the analgesic effects. Naltrexone also blocked the development of analgesia in mice that were defeated for the first time in a social confrontation, but did not prevent the suppressive effects on rate of responding. Specific social experiences such as defeat in a social confrontation appear to alter endogenous opioid process that mediate analgesia; these processes differ from those that suppress positively reinforced behavior. The differential development of morphine tolerance to the analgesic effects, but not the rate-decreasing effects as well as the differential naltrexone antagonism of both effects may indicate the involvement of opioid and non-opioid mechanisms. PMID:3114797

  1. Attenuation of morphine tolerance and dependence by thymoquinone in mice

    PubMed Central

    Hosseinzadeh, Hossein; Parvardeh, Siavash; Masoudi, Alireza; Moghimi, Mahsa; Mahboobifard, Fatemeh

    2016-01-01

    Objective: Dependence and tolerance are major restricting factors in the clinical use of opioid analgesics. In the present study, the effects of thymoquinone, the major constituent of Nigella sativa seeds, on morphine dependence and tolerance were investigated in mice. Materials and Methods: Male adult NMRI mice were made tolerant and dependent by repeated injections of morphine (50, 50, and 75 mg/kg, i.p. on 9 a.m., 1 p.m., and 5 p.m., respectively) during a 3-day administration schedule. The hot-plate test was used to assess tolerance to the analgesic effects of morphine. Naloxone (2 mg/kg, i.p.) was injected to precipitate withdrawal syndrome in order to assess the morphine dependence. To evaluate the effects of thymoquinone on tolerance and dependence to morphine, different single or repeated doses of thymoquinone were administered in mice. Rotarod was used to assess the motor coordination. Results: Administration of single or repeated doses of thymoquinone (20 and 40 mg/kg, i.p.) significantly decreased the number of jumps in morphine dependent animals. Repeated administration of thymoquinone (20 and 40 mg/kg, for 3 days) and also single injection of thymoquinone (40 mg/kg, on the fourth day) attenuated tolerance to the analgesic effect of morphine. None of the thymoquinone doses (10, 20, and 40 mg/kg) produced any antinociceptive effects on their own. Motor coordination of animals was impaired by the high dose of thymoquinone (40 mg/kg). Conclusion: Based on these results, it can be concluded that thymoquinone prevents the development of tolerance and dependence to morphine. PMID:27247922

  2. Examining the Role of Endogenous Opioids in Learned Odor-Stroke Associations in Infant Rats

    PubMed Central

    Roth, Tania L.; Sullivan, Regina M.

    2006-01-01

    Maternal touch profoundly regulates infant neural and behavioral development, and supports learned odor associations necessary for infant attachment. Endogenous opioids are well characterized to mediate the calming and analgesic properties of maternal touch; yet their role in learned odor-touch associations is unknown. We administered naltrexone, an opioid receptor antagonist, before or immediately following classical conditioning with peppermint odor and tactile stimulation (stroking) in rat neonates. Results indicate odor-stroke conditioning produces odor preferences facilitated by endogenous opioids during acquisition and memory consolidation. These results provide additional evidence for the modulatory role of opioids in neonate learning and memory. Disturbances to this system may alter the impact of touch on infant development, particularly in the realm of learning necessary for attachment. PMID:16381030

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

    PubMed Central

    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

  4. Pyrrolo- and Pyridomorphinans: Non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists

    PubMed Central

    Kumar, V.; Clark, M.J.; Traynor, J.R.; Lewis, J.W.; Husbands, S.M.

    2014-01-01

    Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse. PMID:24973818

  5. Pyrrolo- and pyridomorphinans: non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists.

    PubMed

    Kumar, V; Clark, M J; Traynor, J R; Lewis, J W; Husbands, S M

    2014-08-01

    Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse. PMID:24973818

  6. Selectively Promiscuous Opioid Ligands: Discovery of High Affinity/Low Efficacy Opioid Ligands with Substantial Nociceptin Opioid Peptide Receptor Affinity

    PubMed Central

    2015-01-01

    Emerging clinical and preclinical evidence suggests that a compound displaying high affinity for μ, κ, and δ opioid (MOP, KOP, and DOP) receptors and antagonist activity at each, coupled with moderate affinity and efficacy at nociceptin opioid peptide (NOP) receptors will have utility as a relapse prevention agent for multiple types of drug abuse. Members of the orvinol family of opioid ligands have the desired affinity profile but have typically displayed substantial efficacy at MOP and or KOP receptors. In this study it is shown that a phenyl ring analogue (1d) of buprenorphine displays the desired profile in vitro with high, nonselective affinity for the MOP, KOP, and DOP receptors coupled with moderate affinity for NOP receptors. In vivo, 1d lacked any opioid agonist activity and was an antagonist of both the MOP receptor agonist morphine and the KOP receptor agonist ethylketocyclazocine, confirming the desired opioid receptor profile in vivo. PMID:24761755

  7. The endogenous opioid system in cocaine addiction: what lessons have opioid peptide and receptor knockout mice taught us?

    PubMed Central

    Yoo, Ji Hoon; Kitchen, Ian; Bailey, Alexis

    2012-01-01

    Cocaine addiction has become a major concern in the UK as Britain tops the European ‘league table’ for cocaine abuse. Despite its devastating health and socio-economic consequences, no effective pharmacotherapy for treating cocaine addiction is available. Identifying neurochemical changes induced by repeated drug exposure is critical not only for understanding the transition from recreational drug use towards compulsive drug abuse but also for the development of novel targets for the treatment of the disease and especially for relapse prevention. This article focuses on the effects of chronic cocaine exposure and withdrawal on each of the endogenous opioid peptides and receptors in rodent models. In addition, we review the studies that utilized opioid peptide or receptor knockout mice in order to identify and/or clarify the role of different components of the opioid system in cocaine-addictive behaviours and in cocaine-induced alterations of brain neurochemistry. The review of these studies indicates a region-specific activation of the µ-opioid receptor system following chronic cocaine exposure, which may contribute towards the rewarding effect of the drug and possibly towards cocaine craving during withdrawal followed by relapse. Cocaine also causes a region-specific activation of the κ-opioid receptor/dynorphin system, which may antagonize the rewarding effect of the drug, and at the same time, contribute to the stress-inducing properties of the drug and the triggering of relapse. These conclusions have important implications for the development of effective pharmacotherapy for the treatment of cocaine addiction and the prevention of relapse. PMID:22428846

  8. Concept Designed and Developed for Distortion- Tolerant, High-Stability Engine Control

    NASA Technical Reports Server (NTRS)

    1995-01-01

    Engine Control Future aircraft turbine engines, both commercial and military, must be able to successfully accommodate expected increased levels of steady-state and dynamic engine-face distortion. Advanced tactical aircraft are likely to use thrust vectoring to enhance their maneuverability. As a result, the engines will see more extreme aircraft angles-of-attack and sideslip levels than are currently encountered with present-day aircraft. Also, the mixed-compression inlets needed for the High Speed Civil Transport will likely encounter disturbances similar to those seen by tactical aircraft, in addition to planar pulse, inlet buzz, and high distortion levels at low flight speed and off-design operation. The current approach of incorporating a sufficient component design stall margin to tolerate these increased levels of distortion would significantly reduce performance. The objective of the High Stability Engine Control (HISTEC) program is to design, develop, and flight demonstrate an advanced, high-stability, integrated engine-control system that uses measurement-based, real-time estimates of distortion to enhance engine stability. The resulting distortion-tolerant control reduces the required design stall margin, with a corresponding increase in performance and decrease in fuel burn. The HISTEC concept has been designed and developed, and the software implementing the concept has successfully accommodated time-varying distortion. The NASA Lewis Research Center is currently overseeing the development and validation of the hardware and software necessary to flight test the HISTEC concept. HISTEC is a contracted effort with Pratt & Whitney of West Palm Beach, Florida. The HISTEC approach includes two major systems: A Distortion Estimation System (DES) and Stability Management Control (SMC). DES is an aircraft-mounted, high-speed processor that estimates the amount and type of distortion present and its effect on the engine. It uses high-response pressure

  9. Nitrovasodilator-induced relaxation and tolerance development in porcine vena cordis magna: dependence on intact endothelium.

    PubMed Central

    Kojda, G.; Beck, J. K.; Meyer, W.; Noack, E.

    1994-01-01

    1. Isolated segments of porcine vena cordis magna exhibited a reproducible contractile activity upon application of prostaglandin F2 alpha (PGF2 alpha) or KCl, that was independent of the presence of intact endothelium. Substance P (3 nM) elicited strictly endothelium-dependent relaxations amounting to 46.1 +/- 1.4% (n = 206) of contractions induced by 10 microM PGF2 alpha. 2. S-nitroso-N-acetyl-D,L-penicillamine (SNAP), a compound that spontaneously liberates nitric oxide, concentration-dependently relaxed PGF2 alpha-precontracted (50 microM) venous segments. Tolerance induction (incubation with 100 microM SNAP for 30 min) within the same segments resulted in a 3 fold attenuation of this effect, which was not further reduced after additional preincubation with glyceryl trinitrate (GTN). Removal of endothelium or the presence of N omega-nitro-L-arginine methylester (L-NAME) significantly improved the potency of SNAP before and after tolerance induction. 3. Concentration-dependent relaxations induced by GTN in non-tolerant veins were similar in the presence and absence of endothelium but much more reduced in tolerant endothelium-denuded (75 fold) compared to intact (20 fold) segments. In contrast, the presence of L-NAME significantly improved GTN-activity solely in non-tolerant veins, which, therefore, also resulted in a more pronounced attenuation of activity due to tolerance induction (100 fold). Preincubation of intact veins with SNAP also reduced GTN-activity but to a lesser extent (10 fold). 4. The more delayed but much longer, and compared to GTN somewhat weaker, acting new nitrovasodilator N-(3-nitrato-pivaloyl)-1-cysteineethylester (SPM 3672) was more potent in denuded than intact non-tolerant venous segments.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7521258

  10. Development of a Native Escherichia coli Induction System for Ionic Liquid Tolerance

    PubMed Central

    Frederix, Marijke; Hütter, Kimmo; Leu, Jessica; Batth, Tanveer S.; Turner, William J.; Rüegg, Thomas L.; Blanch, Harvey W.; Simmons, Blake A.; Adams, Paul D.; Keasling, Jay D.; Thelen, Michael P.; Dunlop, Mary J.; Petzold, Christopher J.; Mukhopadhyay, Aindrila

    2014-01-01

    The ability to solubilize lignocellulose makes certain ionic liquids (ILs) very effective reagents for pretreating biomass prior to its saccharification for biofuel fermentation. However, residual IL in the aqueous sugar solution can inhibit the growth and function of biofuel-producing microorganisms. In E. coli this toxicity can be partially overcome by the heterologous expression of an IL efflux pump encoded by eilA from Enterobacter lignolyticus. In the present work, we used microarray analysis to identify native E. coli IL-inducible promoters and develop control systems for regulating eilA gene expression. Three candidate promoters, PmarR’, PydfO’, and PydfA’, were selected and compared to the IPTG-inducible PlacUV5 system for controlling expression of eilA. The PydfA’ and PmarR’ based systems are as effective as PlacUV5 in their ability to rescue E. coli from typically toxic levels of IL, thereby eliminating the need to use an IPTG-based system for such tolerance engineering. We present a mechanistic model indicating that inducible control systems reduce target gene expression when IL levels are low. Selected-reaction monitoring mass spectrometry analysis revealed that at high IL concentrations EilA protein levels were significantly elevated under the control of PydfA’ and PmarR’ in comparison to the other promoters. Further, in a pooled culture competition designed to determine fitness, the strain containing pPmarR’-eilA outcompeted strains with other promoter constructs, most significantly at IL concentrations above 150 mM. These results indicate that native promoters such as PmarR’ can provide effective systems for regulating the expression of heterologous genes in host engineering and simplify the development of industrially useful strains. PMID:24983352

  11. Development and evaluation of a treadmill-based exercise tolerance test in cardiac rehabilitation

    PubMed Central

    Adams, Jenny; Cheng, Dunlei; Barton, Stephanie; Bigej-Cerqua, Janet; Mims, Lisa; Molden, Jennifer; Anderson, Valerie

    2013-01-01

    Cardiac rehabilitation exercise prescriptions should be based on exercise stress tests; however, limitations in performing stress tests in this setting typically force reliance on subjective measures like the Duke Activity Status Index (DASI). We developed and evaluated a treadmill-based exercise tolerance test (ETT) to provide objective physiologic measures without requiring additional equipment or insurance charges. The ETT is stopped when the patient's Borg scale rating of perceived exertion (RPE) reaches 15 or when any sign/symptom indicates risk of an adverse event. Outcomes of the study included reasons for stopping; maximum heart rate, systolic blood pressure, and rate pressure product; and adverse events. We tested equivalence to the DASI as requiring the 95% confidence interval for the mean difference between DASI and ETT metabolic equivalents (METs) to fall within the range (–1, 1). Among 502 consecutive cardiac rehabilitation patients, one suffered a panic attack; no other adverse events occurred. Most (80%) stopped because they reached an RPE of 15; the remaining 20% were stopped on indications that continuing risked an adverse event. Mean maximum systolic blood pressure, heart rate, and rate pressure product were significantly (P < 0.001) below thresholds of the American Association of Cardiovascular and Pulmonary Rehabilitation. Two patients’ heart rates exceeded 150 beats per minute, but their rate pressure products remained below 36,000. The mean difference between DASI and ETT METs was −0.8 (−0.98, −0.65), indicating equivalence at our threshold. In conclusion, the ETT can be performed within cardiac rehabilitation, providing a functional capacity assessment equivalent to the DASI and objective physiologic measures for developing exercise prescriptions and measuring progress. PMID:23814381

  12. Development and evaluation of a treadmill-based exercise tolerance test in cardiac rehabilitation.

    PubMed

    Dunagan, Julie; Adams, Jenny; Cheng, Dunlei; Barton, Stephanie; Bigej-Cerqua, Janet; Mims, Lisa; Molden, Jennifer; Anderson, Valerie

    2013-07-01

    Cardiac rehabilitation exercise prescriptions should be based on exercise stress tests; however, limitations in performing stress tests in this setting typically force reliance on subjective measures like the Duke Activity Status Index (DASI). We developed and evaluated a treadmill-based exercise tolerance test (ETT) to provide objective physiologic measures without requiring additional equipment or insurance charges. The ETT is stopped when the patient's Borg scale rating of perceived exertion (RPE) reaches 15 or when any sign/symptom indicates risk of an adverse event. Outcomes of the study included reasons for stopping; maximum heart rate, systolic blood pressure, and rate pressure product; and adverse events. We tested equivalence to the DASI as requiring the 95% confidence interval for the mean difference between DASI and ETT metabolic equivalents (METs) to fall within the range (-1, 1). Among 502 consecutive cardiac rehabilitation patients, one suffered a panic attack; no other adverse events occurred. Most (80%) stopped because they reached an RPE of 15; the remaining 20% were stopped on indications that continuing risked an adverse event. Mean maximum systolic blood pressure, heart rate, and rate pressure product were significantly (P < 0.001) below thresholds of the American Association of Cardiovascular and Pulmonary Rehabilitation. Two patients' heart rates exceeded 150 beats per minute, but their rate pressure products remained below 36,000. The mean difference between DASI and ETT METs was -0.8 (-0.98, -0.65), indicating equivalence at our threshold. In conclusion, the ETT can be performed within cardiac rehabilitation, providing a functional capacity assessment equivalent to the DASI and objective physiologic measures for developing exercise prescriptions and measuring progress. PMID:23814381

  13. Personalized Medicine and Opioid Analgesic Prescribing for Chronic Pain: Opportunities and Challenges

    PubMed Central

    Bruehl, Stephen; Apkarian, A. Vania; Ballantyne, Jane C.; Berger, Ann; Borsook, David; Chen, Wen G.; Farrar, John T.; Haythornthwaite, Jennifer A.; Horn, Susan D.; Iadarola, Michael J.; Inturrisi, Charles E.; Lao, Lixing; Mackey, Sean; Mao, Jianren; Sawczuk, Andrea; Uhl, George R.; Witter, James; Woolf, Clifford J.; Zubieta, Jon-Kar; Lin, Yu

    2013-01-01

    Use of opioid analgesics for pain management has increased dramatically over the past decade, with corresponding increases in negative sequelae including overdose and death. There is currently no well-validated objective means of accurately identifying patients likely to experience good analgesia with low side effects and abuse risk prior to initiating opioid therapy. This paper discusses the concept of data-based personalized prescribing of opioid analgesics as a means to achieve this goal. Strengths, weaknesses, and potential synergism of traditional randomized placebo-controlled trial (RCT) and practice-based evidence (PBE) methodologies as means to acquire the clinical data necessary to develop validated personalized analgesic prescribing algorithms are overviewed. Several predictive factors that might be incorporated into such algorithms are briefly discussed, including genetic factors, differences in brain structure and function, differences in neurotransmitter pathways, and patient phenotypic variables such as negative affect, sex, and pain sensitivity. Currently available research is insufficient to inform development of quantitative analgesic prescribing algorithms. However, responder subtype analyses made practical by the large numbers of chronic pain patients in proposed collaborative PBE pain registries, in conjunction with follow-up validation RCTs, may eventually permit development of clinically useful analgesic prescribing algorithms. Perspective Current research is insufficient to base opioid analgesic prescribing on patient characteristics. Collaborative PBE studies in large, diverse pain patient samples in conjunction with follow-up RCTs may permit development of quantitative analgesic prescribing algorithms which could optimize opioid analgesic effectiveness, and mitigate risks of opioid-related abuse and mortality. PMID:23374939

  14. Involvement of opioid peptides in the regulation of reproduction in the prawn Penaeus indicus

    NASA Astrophysics Data System (ADS)

    Sreenivasula Reddy, P.

    The possible involvement of an endogenous opioid system in the regulation of ovarian development in the prawn Penaeus indicus was investigated. Injection of leucine-enkephalin significantly increased the ovarian index and oocyte diameter in a dose-dependent manner. In contrast, injection of methionine-enkephalin significantly decreased the ovarian index and oocyte diameters. These results provide evidence to support the hypothesis that an opioid system is involved in the regulation of reproduction in crustaceans.

  15. Improving pain management in orthopedic surgical patients with opioid tolerance.

    PubMed

    Doi, Kathleen; Shimoda, Rosanne; Gibbons, Gregory

    2014-09-01

    As increasing numbers of the baby boomer generation seek health care, nursing staff educated in the evidence-based practice process can make significant contributions to successful patient outcomes. Health care providers who anticipate the approaching perfect storm in health care and thoughtfully plan, collaborate, and incorporate evidence-based practice methods will be well prepared to improve the quality of care, realize cost savings, and meet the challenges ahead. PMID:25155539

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

    PubMed Central

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

    2016-01-01

    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. PMID:27605249

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

    PubMed

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

    2016-01-01

    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. PMID:27605249

  18. Combined Treatment with Morphine and Δ9-Tetrahydrocannabinol in Rhesus Monkeys: Antinociceptive Tolerance and Withdrawal.

    PubMed

    Gerak, L R; France, C P

    2016-05-01

    Opioid receptor agonists are effective for treating pain; however, tolerance and dependence can develop with repeated use. Combining opioids with cannabinoids can enhance their analgesic potency, although it is less clear whether combined treatment alters opioid tolerance and dependence. In this study, four monkeys received 3.2 mg/kg morphine alone or in combination with 1 mg/kg Δ(9)-tetrahydrocannabinol (THC) twice daily; the antinociceptive effects (warm water tail withdrawal) of morphine, the cannabinoid receptor agonists WIN 55,212 [(R)-(1)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate] and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol), and the κ opioid receptor agonist U-50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzenacetamide methanesulfonate) were examined before, during, and after treatment. To determine whether concurrent THC treatment altered morphine dependence, behavioral signs indicative of withdrawal were monitored when treatment was discontinued. Before treatment, each drug increased tail withdrawal latency to 20 seconds (maximum possible effect). During treatment, latencies did not reach 20 seconds for morphine or the cannabinoids up to doses 3- to 10-fold larger than those that were fully effective before treatment. Rightward and downward shifts in antinociceptive dose-effect curves were greater for monkeys receiving the morphine/THC combination than monkeys receiving morphine alone. When treatment was discontinued, heart rate and directly observable withdrawal signs increased, although they were generally similar in monkeys that received morphine alone or with THC. These results demonstrated that antinociceptive tolerance was greater during treatment with the combination, and although treatment conditions were sufficient to result in the development of dependence on morphine, withdrawal was not

  19. microRNAs in opioid pharmacology

    PubMed Central

    Hwang, Cheol Kyu; Wagley, Yadav; Law, Ping-Yee; Wei, Li-Na; Loh, Horace H.

    2011-01-01

    MicroRNAs (miRNA), a class of ~22-nucleotide RNA molecules, are important gene regulators that bind to the target sites of mRNAs to inhibit the gene expressions either through translational inhibition or mRNA destabilization. There are growing evidences that miRNAs have played several regulatory roles in opioid pharmacology. Like other research fields such as cancer biology, the area where numerous miRNAs are found to be involved in gene regulation, we assume that in opioid studies including research fields of drug additions and opioid receptor regulation, there may be more miRNAs waiting to be discovered. This review will summarize our current knowledge of miRNA functions on opioids biology and briefly describe future research directions of miRNAs related to opioids. PMID:22068836

  20. Novel approaches for the treatment of psychostimulant and opioid abuse – focus on opioid receptor-based therapies

    PubMed Central

    Bailey, Chris P.; Husbands, Steve M.

    2015-01-01

    Introduction 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. Firstly, there are 3 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 3 stimuli. Secondly, 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. Areas Covered 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 2 categories: ‘memory-based’ and ‘receptor-based’ and the authors discuss the key targets here within. Expert opinion 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’ medications targets - research suggests that a ‘non-selective’ approach to targeting opioid receptors will be the most effective. PMID:25253272

  1. Identification of short-acting κ-opioid receptor antagonists with anxiolytic-like activity.

    PubMed

    Peters, Matthew F; Zacco, Anna; Gordon, John; Maciag, Carla M; Litwin, Linda C; Thompson, Carolann; Schroeder, Patricia; Sygowski, Linda A; Piser, Timothy M; Brugel, Todd A

    2011-07-01

    The κ-opioid receptor plays a central role in mediating the response to stressful life events. Inhibiting κ-opioid receptor signaling is proposed as a mechanism for treating stress-related conditions such as depression and anxiety. Preclinical testing consistently confirms that disruption of κ-opioid signaling is efficacious in animal models of mood disorders. However, concerns about the feasibility of developing antagonists into drugs stem from an unusual pharmacodynamic property of prototypic κ-opioid receptor-selective antagonists; they inhibit receptor signaling for weeks to months after a single dose. Several fundamental questions include - is it possible to identify short-acting antagonists; is long-lasting inhibition necessary for efficacy; and is it safe to develop long-acting antagonists in the clinic. Here, we test representative compounds (AZ-ECPC, AZ-MTAB, and LY-DMPF) from three new chemical series of κ-opioid receptor ligands for long-lasting inhibition. Each compound dose-dependently reversed κ-opioid agonist-induced diuresis. However, unlike the prototypic antagonist, nBNI, which fully inhibited evoked diuresis for at least four weeks, the new compounds showed no inhibition after one week. The two compounds with greater potency and selectivity were tested in prenatally-stressed rats on the elevated plus maze, an exploration-based model of anxiety. Spontaneous exploration of open arms in the elevated plus maze was suppressed by prenatal stress and restored with both compounds. These findings indicate that persistent inhibition is not an inherent property of κ-opioid-selective antagonists and that post-stress dosing with transient inhibitors can be effective in a mood disorder model. This further supports κ-opioid receptor as a promising target for developing novel psychiatric medications. PMID:21539838

  2. Pain pharmacology: focus on opioids

    PubMed Central

    Fornasari, Diego

    2014-01-01

    Summary The incidence of chronic pain is estimated to be 20–25% worldwide. Although major improvements in pain control have been obtained, more than 50% of the patients reports inadequate relief. It is accepted that chronic pain, if not adequately and rapidly treated, can become a disease in itself, often intractable and maybe irreversible. This is mainly due to neuroplasticity of pain pathways. In the present review I will discuss about pain depicting the rational for the principal pharmacological interventions and finally focusing on opioids, that represent a primary class of drug to treat pain. PMID:25568646

  3. Immature hippocampal neuronal networks do not develop tolerance to the excitatory actions of ethanol.

    PubMed

    Galindo, Rafael; Valenzuela, C Fernando

    2006-10-01

    Ethanol (EtOH) damages the hippocampus, a brain region that is involved in learning and memory processes. The mechanisms responsible for this effect of EtOH are not fully understood. We recently demonstrated that acute EtOH exposure potently stimulates oscillatory activity driven by the excitatory actions of GABA in the CA3 region of the neonatal rat hippocampus. This activity can be recorded during the growth spurt period as giant depolarizing potentials (GDPs). Here, we characterized the effects of prolonged EtOH exposure on GDPs. In the first study, we prepared hippocampal coronal slices from neonatal rats and exposed these to control artificial cerebrospinal fluid (ACSF) or ACSF plus 50 mM EtOH for 3-4 h. We then performed whole-cell patch-clamp electrophysiological recordings from CA3 pyramidal neurons, which revealed that tolerance to the GDP stimulating effects of EtOH did not occur after continuous exposure. In the second study, we exposed neonatal rats to air or air plus 1.9 g/dl EtOH in vapor chambers for 4h/day for 1 or 3 days (neonatal peak blood EtOH concentration = 40-45 mM). We then performed slice electrophysiological studies 24 h after the end of EtOH exposure and found that there was no statistically significant difference in the acute effect of 50 mM EtOH on GDP frequency in samples from neonates exposed to air or air plus EtOH. These findings indicate that EtOH persistently stimulates network-driven oscillatory activity in the developing hippocampus. We propose that the lack of adaptive response to continuous EtOH exposure could make immature neuronal networks particularly vulnerable to the actions of this agent. PMID:17307647

  4. Methoprene-tolerant (Met) knockdown in the adult female cockroach, Diploptera punctata completely inhibits ovarian development.

    PubMed

    Marchal, Elisabeth; Hult, Ekaterina F; Huang, Juan; Pang, Zhenguo; Stay, Barbara; Tobe, Stephen S

    2014-01-01

    Independent of the design of the life cycle of any insect, their growth and reproduction are highly choreographed through the action of two versatile hormones: ecdysteroids and juvenile hormones (JH). However, the means by which JH can target tissues and exert its pleiotropic physiological effects is currently still not completely elucidated. Although the identity of the one JH receptor is currently still elusive, recent evidence seems to point to the product of the Methoprene-tolerant gene (Met) as the most likely contender in transducing the action of JH. Studies on the role of this transcription factor have mostly been focused on immature insect stages. In this study we used the viviparous cockroach Diploptera punctata, a favorite model in studying JH endocrinology, to examine the role of Met during reproduction. A tissue distribution and developmental profile of transcript levels was determined for Met and its downstream partners during the first gonadotropic cycle of this cockroach. Using RNA interference, our study shows that silencing Met results in an arrest of basal oocyte development; vitellogenin is no longer transcribed in the fat body and no longer taken up by the ovary. Patency is not induced in these animals which fail to produce the characteristic profile of JH biosynthesis typical of the first gonadotropic cycle. Moreover, the ultrastructure of the follicle cells showed conspicuous whorls of rough endoplasmic reticulum and a failure to form chorion. Our study describes the role of Met on a cellular and physiological level during insect reproduction, and confirms the role of Met as a key factor in the JH signaling pathway. PMID:25197795

  5. Genomic-assisted haplotype analysis and the development of high-throughput SNP markers for salinity tolerance in soybean

    PubMed Central

    Patil, Gunvant; Do, Tuyen; Vuong, Tri D.; Valliyodan, Babu; Lee, Jeong-Dong; Chaudhary, Juhi; Shannon, J. Grover; Nguyen, Henry T.

    2016-01-01

    Soil salinity is a limiting factor of crop yield. The soybean is sensitive to soil salinity, and a dominant gene, Glyma03g32900 is primarily responsible for salt-tolerance. The identification of high throughput and robust markers as well as the deployment of salt-tolerant cultivars are effective approaches to minimize yield loss under saline conditions. We utilized high quality (15x) whole-genome resequencing (WGRS) on 106 diverse soybean lines and identified three major structural variants and allelic variation in the promoter and genic regions of the GmCHX1 gene. The discovery of single nucleotide polymorphisms (SNPs) associated with structural variants facilitated the design of six KASPar assays. Additionally, haplotype analysis and pedigree tracking of 93 U.S. ancestral lines were performed using publically available WGRS datasets. Identified SNP markers were validated, and a strong correlation was observed between the genotype and salt treatment phenotype (leaf scorch, chlorophyll content and Na+ accumulation) using a panel of 104 soybean lines and, an interspecific bi-parental population (F8) from PI483463 x Hutcheson. These markers precisely identified salt-tolerant/sensitive genotypes (>91%), and different structural-variants (>98%). These SNP assays, supported by accurate phenotyping, haplotype analyses and pedigree tracking information, will accelerate marker-assisted selection programs to enhance the development of salt-tolerant soybean cultivars. PMID:26781337

  6. Development of an Immunologically Tolerated Combination of Fluorescent Proteins for In vivo Two-photon Imaging

    PubMed Central

    Gossa, Selamawit; Nayak, Debasis; Zinselmeyer, Bernd H.; McGavern, Dorian B.

    2014-01-01

    Combinations of fluorescent proteins (FPs) are routinely used for multi-parameter in vivo imaging experiments to visualize tagged proteins or cell populations of interest. Studies involving FPs are often limited by spectral overlap, toxicity, relative quantum efficiency, and the potential for immunological rejection upon transfer into a non-tolerant recipient. Here we evaluate the immunologic visibility of several commonly used FPs by the murine immune system and identify a spectrally compatible, immunologically tolerated combination of FPs well suited for in vivo two-photon imaging. PMID:25322934

  7. The SIFT computer and its development. [Software Implemented Fault Tolerance for aircraft control

    NASA Technical Reports Server (NTRS)

    Goldberg, J.

    1981-01-01

    Software Implemented Fault Tolerance (SIFT) is an aircraft control computer designed to allow failure probability of less than 10 to the -10th/hour. The system is based on advanced fault-tolerance computing and validation methodology. Since confirmation of reliability by observation is essentially impossible, system reliability is estimated by a Markov model. A mathematical proof is used to justify the validity of the Markov model. System design is represented by a hierarchy of abstract models, and the design proof comprises mathematical proofs that each model is, in fact, an elaboration of the next more abstract model.

  8. Use of microdoses for induction of buprenorphine treatment with overlapping full opioid agonist use: the Bernese method

    PubMed Central

    Hämmig, Robert; Kemter, Antje; Strasser, Johannes; von Bardeleben, Ulrich; Gugger, Barbara; Walter, Marc; Dürsteler, Kenneth M; Vogel, Marc

    2016-01-01

    Background Buprenorphine is a partial µ-opioid receptor agonist used for maintenance treatment of opioid dependence. Because of the partial agonism and high receptor affinity, it may precipitate withdrawal symptoms during induction in persons on full µ-opioid receptor agonists. Therefore, current guidelines and drug labels recommend leaving a sufficient time period since the last full agonist use, waiting for clear and objective withdrawal symptoms, and reducing pre-existing full agonist therapies before administering buprenorphine. However, even with these precautions, for many patients the induction of buprenorphine is a difficult experience, due to withdrawal symptoms. Furthermore, tapering of the full agonist bears the risk of relapse to illicit opioid use. Cases We present two cases of successful initiation of buprenorphine treatment with the Bernese method, ie, gradual induction overlapping with full agonist use. The first patient began buprenorphine with overlapping street heroin use after repeatedly experiencing relapse, withdrawal, and trauma reactivation symptoms during conventional induction. The second patient was maintained on high doses of diacetylmorphine (ie, pharmaceutical heroin) and methadone during induction. Both patients tolerated the induction procedure well and reported only mild withdrawal symptoms. Discussion Overlapping induction of buprenorphine maintenance treatment with full µ-opioid receptor agonist use is feasible and may be associated with better tolerability and acceptability in some patients compared to the conventional method of induction. PMID:27499655

  9. Denial of urinalysis-confirmed opioid use in prescription opioid dependence

    PubMed Central

    Hilario, E. Yvette; Griffin, Margaret L.; McHugh, R. Kathryn; McDermott, Katherine A.; Connery, Hilary S.; Fitzmaurice, Garrett M.; Weiss, Roger D.

    2014-01-01

    Although research has generally supported the validity of substance use self-reports, some patients deny urine-verified substance use. We examined the prevalence and patterns of denying urinalysis-confirmed opioid use in a sample of prescription opioid dependent patients. We also identified characteristics associated with denial in this population of increasing public health concern. Opioid use self-reports were compared with weekly urinalysis results in a 12-week multi-site treatment study for prescription opioid dependence. Among those who used opioids during the trial (n=246/360), 44.3% (n=109) denied urinalysis-confirmed opioid use, although usually only once (78%). Overall, 22.9% of opioid-positive urine tests (149/650) were denied on self-report. Multivariable analysis found that initially using opioids to relieve pain was associated with denying opioid use. These findings support the use of both self-reports and urine testing in treating prescription opioid dependence. PMID:25115135

  10. Determination of substance overdose in two Iranian centers: comparison between opioids and non-opioids.

    PubMed

    Taghaddosinejad, Fakhreddin; Arefi, Mohammad; Fayaz, Amir Farshid; Tanhaeivash, Roozbeh

    2013-04-01

    Recently, new trend toward non-opioid substances is observed in Iran. This is, therefore, to compare overdose of opioids and non-opioids origin. We performed this investigation to provide more detailed information so that preventive actions are taken in future. Over 18 month, 1876 individuals with opioid (opium, heroin, compact-heroin, buprenorphine and opiates) or non-opioid (MDMA (ecstasy), LSD, hashish and cocaine) overdose were selected. They have been compared regarding sex, age, reason of overdose, method of substance use, occupation, marital status, history of addiction in parents/siblings, duration of hospital admission and educational level. There were 1782 and 94 persons with opioid and non-opioid, respectively. Inhalation was the method of choice and women were found to have more tendencies to hallucinogens rather opioids. Moreover, use of non-opioids was observed more in individuals with university education and moreover in whom none of whose parents/siblings was addict. Policies should be planned by the governments to prevent further addictions especially to non-opioids. PMID:23472794

  11. Denial of urinalysis-confirmed opioid use in prescription opioid dependence.

    PubMed

    Hilario, E Yvette; Griffin, Margaret L; McHugh, R Kathryn; McDermott, Katherine A; Connery, Hilary S; Fitzmaurice, Garrett M; Weiss, Roger D

    2015-01-01

    Although research has generally supported the validity of substance use self-reports, some patients deny urine-verified substance use. We examined the prevalence and patterns of denying urinalysis-confirmed opioid use in a sample of prescription opioid dependent patients. We also identified characteristics associated with denial in this population of increasing public health concern. Opioid use self-reports were compared with weekly urinalysis results in a 12-week multi-site treatment study for prescription opioid dependence. Among those who used opioids during the trial (n=246/360), 44.3% (n=109) denied urinalysis-confirmed opioid use, although usually only once (78%). Overall, 22.9% of opioid-positive urine tests (149/650) were denied on self-report. Multivariable analysis found that initially using opioids to relieve pain was associated with denying opioid use. These findings support the use of both self-reports and urine testing in treating prescription opioid dependence. PMID:25115135

  12. Correlates of prescription opioid initiation and long-term opioid use in veterans with persistent pain

    PubMed Central

    Dobscha, Steven K.; Morasco, Benjamin J.; Duckart, Jonathan P.; Macey, Tara; Deyo, Richard A.

    2012-01-01

    Objectives Little is known about how opioid prescriptions for chronic pain are initiated. We sought to describe patterns of prescription opioid initiation, identify correlates of opioid initiation, and examine correlates of receipt of chronic opioid therapy (COT) among veterans with persistent non-cancer pain. Methods Using Veterans Affairs (VA) administrative data, we identified 5,961 veterans from the Pacific Northwest with persistent elevated pain intensity scores who had not been prescribed opioids in the prior 12 months. We compared veterans not prescribed opioids over the subsequent 12 months to those prescribed any opioid and to those prescribed COT (≥90 consecutive days). Results During the study year, 34% of the sample received an opioid prescription, and 5% received COT. Most first opioid prescriptions were written by primary care clinicians. Veterans prescribed COT were younger, had greater pain intensity, and high rates of psychiatric and substance use disorders (SUDs) compared to veterans in the other two groups. Among patients receiving COT, 29% were prescribed long-acting opioids, 37% received one or more urine drug screens, and 24% were prescribed benzodiazepines. Adjusting for age, sex, and baseline pain intensity, major depression (OR 1.24 [1.10–1.39]; 1.48 [1.14–1.93]) and nicotine dependence (1.34 [1.17–1.53]; 2.02 [1.53–2.67]) were associated with receiving any opioid prescription and with COT, respectively. Discussion Opioid initiations are common among veterans with persistent pain, but most veterans are not prescribed opioids long-term. Psychiatric disorders and SUDs are associated with receiving COT. Many Veterans receiving COT are concurrently prescribed benzodiazepines and many do not receive urine drug screening; additional study regarding practices that optimize safety of COT in this population is indicated. PMID:23269280

  13. Improving the recognition and diagnosis of opioid-induced constipation in clinical practice.

    PubMed

    Gupta, Anita

    2015-10-01

    Opioid-induced constipation is a common side effect of opioid therapy that has been under-recognized and undertreated. With the continued increase in opioid use in the United States, along with the growth of the elderly population, more patients will develop OIC, and family physicians will encounter more patients with OIC. OIC negatively affects patient QOL, daily activity, work productivity, and psychological well-being. If not treated effectively, OIC may result in patients attempting to balance their pain relief against their constipation, by self-adjusting their opioid dose. OIC results from opioid actions at enteric opioid receptors. Although commonly prescribed for OIC, laxatives do not target the pathophysiologic mechanism of OIC and have limited efficacy. Specific, effective treatments for OIC, consisting of a subcutaneously administered PAMORA, an oral PAMORA, and an oral chloride channel activator, have been developed and have received US Food and Drug Administration approval. After recognizing the signs and symptoms of OIC to facilitate diagnosis, family physicians can initiate effective treatments in appropriate patients. PMID:26561554

  14. Low-dose morphine elicits ventilatory excitant and depressant responses in conscious rats: Role of peripheral μ-opioid receptors.

    PubMed

    Henderson, Fraser; May, Walter J; Gruber, Ryan B; Young, Alex P; Palmer, Lisa A; Gaston, Benjamin; Lewis, Stephen J

    2013-08-01

    The systemic administration of morphine affects ventilation via a mixture of central and peripheral actions. The aims of this study were to characterize the ventilatory responses elicited by a low dose of morphine in conscious rats; to determine whether tolerance develops to these responses; and to determine the potential roles of peripheral μ-opioid receptors (μ-ORs) in these responses. Ventilatory parameters were monitored via unrestrained whole-body plethysmography. Conscious male Sprague-Dawley rats received an intravenous injection of vehicle or the peripherally-restricted μ-OR antagonist, naloxone methiodide (NLXmi), and then three successive injections of morphine (1 mg/kg) given 30 min apart. The first injection of morphine in vehicle-treated rats elicited an array of ventilatory excitant (i.e., increases in frequency of breathing, minute volume, respiratory drive, peak inspiratory and expiratory flows, accompanied by decreases in inspiratory time and end inspiratory pause) and inhibitory (i.e., a decrease in tidal volume and an increase in expiratory time) responses. Subsequent injections of morphine elicited progressively and substantially smaller responses. The pattern of ventilatory responses elicited by the first injection of morphine was substantially affected by pretreatment with NLXmi whereas NLXmi minimally affected the development of tolerance to these responses. Low-dose morphine elicits an array of ventilatory excitant and depressant effects in conscious rats that are subject to the development of tolerance. Many of these initial actions of morphine appear to involve activation of peripheral μ-ORs whereas the development of tolerance to these responses does not. PMID:24900948

  15. Medical Student and Junior Doctors' Tolerance of Ambiguity: Development of a New Scale

    ERIC Educational Resources Information Center

    Hancock, Jason; Roberts, Martin; Monrouxe, Lynn; Mattick, Karen

    2015-01-01

    The practice of medicine involves inherent ambiguity, arising from limitations of knowledge, diagnostic problems, complexities of treatment and outcome and unpredictability of patient response. Research into doctors' tolerance of ambiguity is hampered by poor conceptual clarity and inadequate measurement scales. We aimed to create and pilot a…

  16. Development and genetic analyses of early season cold tolerant sorghum germplasm

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sorghum is one of the most versatile & resilient crop species with vast genetic diversity. To date sorghum provides commodity products for grain, forage & bioenergy industries. It is also well-known for excellent drought and high temperature tolerance; and is considered as water and climate susta...

  17. A microbial biomanufacturing platform for natural and semisynthetic opioids.

    PubMed

    Thodey, Kate; Galanie, Stephanie; Smolke, Christina D

    2014-10-01

    Opiates and related molecules are medically essential, but their production via field cultivation of opium poppy Papaver somniferum leads to supply inefficiencies and insecurity. As an alternative production strategy, we developed baker's yeast Saccharomyces cerevisiae as a microbial host for the transformation of opiates. Yeast strains engineered to express heterologous genes from P. somniferum and bacterium Pseudomonas putida M10 convert thebaine to codeine, morphine, hydromorphone, hydrocodone and oxycodone. We discovered a new biosynthetic branch to neopine and neomorphine, which diverted pathway flux from morphine and other target products. We optimized strain titer and specificity by titrating gene copy number, enhancing cosubstrate supply, applying a spatial engineering strategy and performing high-density fermentation, which resulted in total opioid titers up to 131 mg/l. This work is an important step toward total biosynthesis of valuable benzylisoquinoline alkaloid drug molecules and demonstrates the potential for developing a sustainable and secure yeast biomanufacturing platform for opioids. PMID:25151135

  18. CD27 costimulation is not critical for the development of asthma and respiratory tolerance in a murine model.

    PubMed

    Behrendt, Ann-Kathrin; Hansen, Gesine

    2010-09-01

    CD27 is a costimulatory molecule of the TNFR family strongly expressed on activated CD4(+) and CD8(+) T lymphocytes. Binding with its ligand CD70, present on lymphocytes and DCs, leads to enhanced T cell activation and proliferation. Several other costimulatory molecules of the TNFR family like CD30, CD134 (OX40) or CD137 (4-1BB) have been shown to be critically involved in the development of asthma and/or respiratory tolerance. However, the role of CD27/CD70 signalling in these disease models has not been studied intensively. The aim of this study was to directly investigate the role of CD27 for the development of asthma and respiratory tolerance by comparative analysis of wild type (WT) and CD27(-/-) mice in the corresponding murine models. Ovalbumin (OVA)-sensitized and challenged CD27(-/-) mice developed comparably increased airway hyperreactivity (AHR), eosinophilic airway inflammation, mucus hypersecretion and elevated OVA-specific serum IgE levels in response to OVA sensitization as WT mice. In addition, Th2 cytokine production in spleen cell culture supernatants and proliferation of splenocytes after in vitro OVA restimulation was equally enhanced when derived from WT and CD27(-/-) mice. Furthermore, the absence of CD27 had no decisive impact on tolerance induction, so that WT and CD27(-/-) mice were comparably protected from asthma development by mucosal antigen application before sensitization. Our results suggest that CD27 costimulation is dispensable for a Th2 cell mediated allergic asthma response and respiratory tolerance induction in murine models. PMID:20600327

  19. A Framework for Selecting Performance Measures for Opioid Treatment Programs

    PubMed Central

    Pelletier, Luc R.; Hoffman, Jeffrey A.

    2006-01-01

    As a result of new federal regulations released in early 2001 that move the monitoring and evaluation of opioid treatment programs from a government regulation to an accreditation model, program staff members are now being challenged to develop performance measurement systems that improve care and service. Using measurement selection criteria is the first step in developing a performance measurement system as a component of an overall quality management (QM) strategy. Opioid treatment programs can “leapfrog” the development of such systems by using lessons learned from the healthcare quality industry. This article reviews performance measurement definitions, proposes performance measurement selection criteria, and makes a business case for Internet automation and accessibility. Performance measurement sets that are appropriate for opioid treatment programs are proposed, followed by a discussion on how performance measurement can be used within a comprehensive QM program. It is hoped that through development, adoption, and implementation of such a performance measurement program, treatment for clients and their families will continuously improve. PMID:14692185

  20. Immunoreactive opioid peptides in human breast cancer.

    PubMed Central

    Scopsi, L.; Balslev, E.; Brünner, N.; Poulsen, H. S.; Andersen, J.; Rank, F.; Larsson, L. I.

    1989-01-01

    Opioid peptides have a variety of actions on inter alia pituitary hormone secretion and the immune system. Release of endogenous opioids has been found to stimulate growth of experimental breast cancers and opiate receptor blockers have reduced the growth of chemically induced rat breast tumors. Opioid peptides may therefore play a role in human breast cancer. Invasive ductal carcinomas from 61 premenopausal women were immunocytochemically analyzed for the presence of opioid peptide immunoreactivity. Positive staining was unambiguously identified in 34 of the tumors (56%). In addition, a medullary carcinoma was positive. In a smaller series of tumors, opioid peptide immunoreactive cells were detected in both primary tumors and metastases. Positive tumor cells were usually few and scattered. Therefore, underestimates of their true frequency of occurrence are likely to have occurred, making accurate correlations with clinical behavior and estrogen receptor status difficult. No correlations with estrogen receptors were established for the unambiguously opioid peptide-positive tumors. Many of the positive tumors also stained with antibodies to gamma-endorphin and alpha-melanocyte-stimulating hormone, suggesting the presence of proopiomelanocortin-derived peptides in them. However, peptides derived from other opioid precursors also may be present in breast cancer. Images Figure 1 PMID:2464945

  1. A comparison between enriched and nonenriched enrollment randomized withdrawal trials of opioids for chronic noncancer pain

    PubMed Central

    Furlan, Andrea D; Chaparro, Luis E; Irvin, Emma; Mailis-Gagnon, Angela

    2011-01-01

    BACKGROUND: An enriched enrollment randomized withdrawal (EERW) design excludes potential participants who are nonresponders or who cannot tolerate the experimental drug before random assignment. It is unclear whether EERW design has an influence on the efficacy and safety of opioids for chronic noncancer pain (CNCP). OBJECTIVES: The primary objective was to compare the results from EERW and non-EERW trials of opioids for CNCP. Secondary objectives were to compare weak versus strong opioids, subgroups of patients with different types of pain, and the efficacy of opiods compared with placebo versus other drugs. METHODS: MEDLINE, EMBASE and CENTRAL were searched up to July 2009, for randomized controlled trials of any opioid for CNCP. Meta-analyses and meta-regressions were conducted to compare the results. Treatment efficacy was assessed by effect sizes (small, medium and large) and the incidence of adverse effects was assessed by a clinically relevant mean difference of 10% or greater. RESULTS: Sixty-two randomized trials were included. In 61 trials, the duration was less than 16 weeks. There was no difference in efficacy between EERW and non-EERW trials for both pain (P=0.6) and function (P=0.3). However, EERW trials failed to detect a clinically relevant difference for nausea, vomiting, somnolence, dizziness and dry skin/itching compared with non-EERW. Opioids were more effective than placebo in patients with nociceptive pain (effect size=0.60, 95% CI 0.49 to 0.72) and neuropathic pain (effect size=0.56, 95% CI 0.38 to 0.73). CONCLUSION: EERW trial designs appear not to bias the results of efficacy, but they underestimate the adverse effects. The present updated meta-analysis shows that weak and strong opioids are effective for CNCP of both nociceptive and neuropathic origin. PMID:22059206

  2. "Infectious" Transplantation Tolerance

    NASA Astrophysics Data System (ADS)

    Qin, Shixin; Cobbold, Stephen P.; Pope, Heather; Elliott, James; Kioussis, Dimitris; Davies, Joanna; Waldmann, Herman

    1993-02-01

    The maintenance of transplantation tolerance induced in adult mice after short-term treatment with nonlytic monoclonal antibodies to CD4 and CD8 was investigated. CD4^+ T cells from tolerant mice disabled naive lymphocytes so that they too could not reject the graft. The naive lymphocytes that had been so disabled also became tolerant and, in turn, developed the capacity to specifically disable other naive lymphocytes. This process of "infectious" tolerance explains why no further immunosuppression was needed to maintain long-term transplantation tolerance.

  3. Genetics of Opioid Dependence: A Review of the Genetic Contribution to Opioid Dependence

    PubMed Central

    Mistry, Chetna J; Bawor, Monica; Desai, Dipika; Marsh, David C; Samaan, Zainab

    2014-01-01

    This narrative review aims to provide an overview of the impact of opioid dependence and the contribution of genetics to opioid dependence. Epidemiological data demonstrate that opioid dependence is a global trend with far-reaching effects on the social, economic, and health care systems. A review of classical genetic studies of opioid use suggests significant heritability of drug use behavior, however the evidence from molecular genetic studies is inconclusive. Nonetheless, certain genetic variants are important to consider given their role in the pathophysiology of addictive behavior. We undertook a literature review to identify the current state of knowledge regarding the role of genes in opioid dependence. Determining the association of genetic markers could change the current understanding of the various factors contributing to opioid dependence and therefore may improve recognition of individuals at risk for the disorder and prevention and treatment strategies. PMID:25242908

  4. How do physicians adopt and apply opioid prescription guidelines in the emergency department? A qualitative study

    PubMed Central

    Kilaru, Austin S.; Gadsden, Sarah M.; Perrone, Jeanmarie; Paciotti, Breah; Barg, Frances K; Meisel, Zachary F.

    2014-01-01

    Objective A rise in prescriptions for opioid pain medications has coincided with increasing opioid overdose deaths. Guidelines designed to optimize opioid prescriptions written in the emergency department have been implemented with substantial controversy. Little is known about how physicians perceive and apply these guidelines. We sought to identify key themes regarding emergency physicians’ definition, awareness, use, and opinions of opioid prescribing guidelines. Methods We conducted semi-structured qualitative interviews with a convenience sample of 61 emergency physicians attending the American College of Emergency Physicians Scientific Assembly (October 2012; Denver, Colorado). Participants varied with respect to age, gender, geographic region, practice setting, and years of practice experience. We analyzed the interview content using modified grounded theory, an iterative coding process to identify patterns of responses and derive key themes. The study team examined discrepancies in the coding process to ensure reliability and establish consensus. Results When aware of opioid prescribing guidelines, emergency physicians often defined them as policies developed by individual hospitals that sometimes reflected guidelines at the state or national level. Guidelines were primarily used by physicians to communicate decisions to limit prescriptions to patients upon discharge rather than as decision-making tools. Attitudes toward guidelines varied with regard to general attitudes toward opioid medications as well as the perceived effects of guidelines on physician autonomy, public health, liability, and patient diversion. Conclusion These exploratory findings suggest that hospital-based opioid guidelines complement and occasionally supersede state and national guidelines and that emergency physicians apply guidelines primarily as communication tools. The perspectives of providers should inform future policy actions that seek to address the problem of opioid abuse

  5. Opioid receptors and cardioprotection – ‘opioidergic conditioning’ of the heart

    PubMed Central

    Headrick, John P; See Hoe, Louise E; Du Toit, Eugene F; Peart, Jason N

    2015-01-01

    Ischaemic heart disease (IHD) remains a major cause of morbidity/mortality globally, firmly established in Westernized or ‘developed’ countries and rising in prevalence in developing nations. Thus, cardioprotective therapies to limit myocardial damage with associated ischaemia–reperfusion (I–R), during infarction or surgical ischaemia, is a very important, although still elusive, clinical goal. The opioid receptor system, encompassing the δ (vas deferens), κ (ketocyclazocine) and μ (morphine) opioid receptors and their endogenous opioid ligands (endorphins, dynorphins, enkephalins), appears as a logical candidate for such exploitation. This regulatory system may orchestrate organism and organ responses to stress, induces mammalian hibernation and associated metabolic protection, triggers powerful adaptive stress resistance in response to ischaemia/hypoxia (preconditioning), and mediates cardiac benefit stemming from physical activity. In addition to direct myocardial actions, central opioid receptor signalling may also enhance the ability of the heart to withstand I–R injury. The δ- and κ-opioid receptors are strongly implicated in cardio