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Sample records for opioid tolerance development

  1. Opioid tolerance and dependence -- do they matter?

    PubMed

    Jage, Jürgen

    2005-04-01

    The use of opioids has long been accepted as the standard of care in patients with cancer and acute pain. Opioids can further be used effectively in specific subgroups of patients with chronic nonmalignant pain states. While the development of tolerance and physical dependence are known effects of opioids in cancer and noncancer pain populations, these patients can not be regarded as addicted. However, long-term therapy with short-acting opioids predisposes to tolerance and addiction. Recent research has confirmed the important role of psychopathologic and psychosocial conditions as predictors of failed opioid effectiveness in a significant number of noncancer pain subgroups. The clinical picture of failed therapy may be complicated by noncompliance, concealed consumption of psychotropic substances, and diversion of prescribed opioids for various purposes as, e.g., selling for profit, or sharing excess opioids with others. This article discusses the effects of opioid therapy, including tolerance, physical dependence, drug-aberrant behavior, drug history, psychopathology, and somatization.

  2. Oxycodone recycling: a novel hypothesis of opioid tolerance development in humans.

    PubMed

    Linares, Oscar A; Fudin, Jeffrey; Schiesser, William E; Linares, Annemarie Daly; Boston, Raymond C

    2014-09-01

    We hypothesize that oxycodone (OC) recycling promotes sustained synaptic OC content, which prolongs OC's exposure to local μ-opioid receptors (μORs). In that way, OC recycling gives rise to OC tolerance in humans. To pilot test our hypothesis, we developed a whole-body OC mass transport tolerance recovery model. The model derived quantifiable measure of tolerance is TΩ. TΩ estimates OC's tolerance recovery in days; It is defined as the rate of recovery of OC's pharmacologic response after OC is stopped. We studied a random sample of five opioid intolerant healthy male subjects with no history of opioid or illicit drug use, or comorbidities in silico. Subjects were age 24.5 ± 2.3 yr (all values mean ± SD), weight 93 ± 20 kg, and CYP2D6 EM phenotype. Each subject was studied under two experimental conditions: (1) administration of a single oral dose of OC 12 ± 7 mg; and, after complete washout of OC from the intravascular pool, (2) administration of repetitive oral OC doses every 4h for 5 half-lives (t1/2 = 4.5h)-after which time steady-state was assumed. Repetitive OC dose TΩ fell 61% compared to single OC dose TΩ (5.2 ± 1.1 vs. 3.5 ± 0.7 days, p = 0.001). The fall in TΩ was associated with a significant 3-fold increase in extravascular OC content, which was accompanied by 2-fold increase in OC spillover from the extravascular pool, into the intravascular pool. Thus, the model predicted that a single dose of orally administered OC could give rise to tolerance. This is consistent with the widely held view of acute opioid tolerance. In addition, the dynamic changes accompanying repetitive OC dosing suggested that local unbound OC gave rise to both higher extravascular OC content and increased OC spillover. This reflects that OC stimulated endocytosis of μORs was accompanied by a reduction in the availability OC responsive neuroeffector cell surface μOR binding sites. We conclude that our hypothesis extends current concepts of opioid tolerance

  3. Melatonin attenuates the development of antinociceptive tolerance to delta-, but not to mu-opioid receptor agonist in mice.

    PubMed

    Dai, Xu; Cui, Shi-gang; Li, Shi-rong; Chen, Qiang; Wang, Rui

    2007-08-22

    The effects of melatonin (Mel) on the development of tolerance to antinociceptive actions induced by mu- and delta-opioid receptor agonists were determined in male Kunming mice. In the mouse tail-flick tests, selective mu and delta receptor agonists were repeatedly administered to mice supraspinally (intracerebroventricularly, i.c.v.) in the absence or presence of melatonin. Administration of endomorphin-1 (EM-1, a mu-opioid receptor agonist) or deltorphin I (del I, a delta-opioid receptor agonist) twice daily for 4 days produced antinociceptive tolerance compared with vehicle controls. Co-administration with melatonin prevented the development of tolerance to deltorphin I analgesia, and this effect was dose dependent. However, melatonin did not affect the development of antinociceptive tolerance to endomorphin-1. Additionally, the attenuation of deltorphin I tolerance by melatonin was reduced by chronic treatment with luzindole (luz), a selective antagonist on the MT(2) receptor subtype. Taken together, these data suggest that melatonin interferes with the neural mechanisms involved in the development of tolerance to delta-opioid agonist analgesia via its receptor.

  4. Opioid tolerance and dependence in infants and children.

    PubMed

    Anand, K J; Arnold, J H

    1994-02-01

    To review the definitions and scientific basis for opioid tolerance and dependence in neonates and older children; to assess objective methods for the clinical evaluation of opioid abstinence syndromes in this age group; and to suggest therapeutic strategies for the treatment of opioid abstinence in critically ill neonates and children. The published literature on opioid tolerance and dependence in pediatric patients was reviewed. Data from current clinical practices, nursing procedures, and ongoing clinical research were evaluated. Currently proposed mechanisms of opioid tolerance and dependence are assessed, with particular relevance to the developing human central nervous system. The validity and clinical role of currently available objective methods for the assessment of opioid abstinence in neonates and older infants are defined. The efficacy of various pharmacologic and nonpharmacologic modalities for the treatment of opioid abstinence is evaluated and compared, and a therapeutic approach based on receptor mechanisms, clinical monitoring data, and pharmacologic efficacy is suggested. Important parallels for therapeutically-induced opioid tolerance and withdrawal may be drawn from the assessment and management of neonates born from opioid-addicted mothers. Opioid withdrawal can be prevented with appropriate weaning schedules, diagnosed by objective clinical methods, and treated by a variety of pharmacologic and non-pharmacologic means. Pharmacologic therapy includes the use of opioids, with adjuvant drugs such as diazepam, clonidine, or chlorpromazine. The pathophysiology and assessment of therapeutically induced opioid tolerance and withdrawal merit further research in critically ill pediatric patients.

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

    PubMed

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

    2010-05-01

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

  6. Tolerance and Withdrawal From Prolonged Opioid Use in Critically Ill Children

    PubMed Central

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

    2012-01-01

    OBJECTIVE After prolonged opioid exposure, children develop opioid-induced hyperalgesia, tolerance, and withdrawal. Strategies for prevention and management should be based on the mechanisms of opioid tolerance and withdrawal. PATIENTS AND METHODS Relevant manuscripts published in the English language were searched in Medline by using search terms “opioid,” “opiate,” “sedation,” “analgesia,” “child,” “infant-newborn,” “tolerance,” “dependency,” “withdrawal,” “analgesic,” “receptor,” and “individual opioid drugs.” Clinical and preclinical studies were reviewed for data synthesis. RESULTS Mechanisms of opioid-induced hyperalgesia and tolerance suggest important drug- and patient-related risk factors that lead to tolerance and withdrawal. Opioid tolerance occurs earlier in the younger age groups, develops commonly during critical illness, and results more frequently from prolonged intravenous infusions of short-acting opioids. Treatment options include slowly tapering opioid doses, switching to longer-acting opioids, or specifically treating the symptoms of opioid withdrawal. Novel therapies may also include blocking the mechanisms of opioid tolerance, which would enhance the safety and effectiveness of opioid analgesia. CONCLUSIONS Opioid tolerance and withdrawal occur frequently in critically ill children. Novel insights into opioid receptor physiology and cellular biochemical changes will inform scientific approaches for the use of opioid analgesia and the prevention of opioid tolerance and withdrawal. PMID:20403936

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

    PubMed Central

    2012-01-01

    The age-dependency of opioid analgesia and tolerance has been noticed in both clinical observation and laboratory studies. Evidence shows that many molecular and cellular events that play essential roles in opioid analgesia and tolerance are actually age-dependent. For example, the expression and functions of endogenous opioid peptides, multiple types of opioid receptors, G protein subunits that couple to opioid receptors, and regulators of G protein signaling (RGS proteins) change with development and age. Other signaling systems that are critical to opioid tolerance development, such as N-methyl-D-aspartic acid (NMDA) receptors, also undergo age-related changes. It is plausible that the age-dependent expression and functions of molecules within and related to the opioid signaling pathways, as well as age-dependent cellular activity such as agonist-induced opioid receptor internalization and desensitization, eventually lead to significant age-dependent changes in opioid analgesia and tolerance development. PMID:22612909

  8. 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

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

    PubMed Central

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

    2011-01-01

    Repeated injection of opioid analgesics can lead to a progressive loss of effect. This phenomenon is known as tolerance. Several lines of investigations have shown that systemic, intraperitoneal administration or the microinjection of non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) into the midbrain periaqueductal gray matter induces antinociception with some effects of tolerance. Our recent study has revealed that microinjection of three drugs analgin, ketorolac, and xefocam into the central nucleus of amygdala produce tolerance to them and cross-tolerance to morphine. Here we report that repeated administrations of these NSAIDs into the nucleus raphe magnus (NRM) in the following 4 days result in progressively less antinociception compare to the saline control, i.e., tolerance develops to these drugs in male rats. Special control experiments showed that post-treatment with the μ-opioid antagonist naloxone into the NRM significantly decreased antinociceptive effects of NSAIDs on the first day of testing in the tail-flick (TF) reflex and hot plate (HP) latency tests. On the second day, naloxone generally had trend effects in both TF and HP tests and impeded the development of tolerance to the antinociceptive effect of non-opioid analgesics. These findings strongly support the suggestion of endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain-control system. Moreover, repeated injections of NSAIDs progressively lead to tolerance to them, cross-tolerance to morphine, and the risk of a withdrawal syndrome. Therefore, these results are important for human medicine too. PMID:21845173

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

    PubMed

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

    2011-01-01

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

  11. G-protein receptor kinase 3 (GRK3) influences opioid analgesic tolerance but not opioid withdrawal

    PubMed Central

    Terman, Gregory W; Jin, Wenzhen; Cheong, Young-Pyo; Lowe, Janet; Caron, Marc G; Lefkowitz, Robert J; Chavkin, Charles

    2003-01-01

    Tolerance to opioids frequently follows repeated drug administration and affects the clinical utility of these analgesics. Studies in simple cellular systems have demonstrated that prolonged activation of opioid receptors produces homologous receptor desensitization by G-protein receptor kinase mediated receptor phosphorylation and subsequent β-arrestin binding. To define the role of this regulatory mechanism in the control of the electrophysiological and behavioral responses to opioids, we used mice having a targeted disruption of the G-protein receptor kinase 3 (GRK3) gene. Mice lacking GRK3 did not differ from wild-type littermates neither in their response latencies to noxious stimuli on the hot-plate test nor in their acute antinociceptive responses to fentanyl or morphine. Tolerance to the electrophysiological response to the opioid fentanyl, measured in vitro in the hippocampus, was blocked by GRK3 deletion. In addition, tolerance to the antinociceptive effects of fentanyl was significantly reduced in GRK3 knockouts compared to wild-type littermate controls. Tolerance to the antinociceptive effects of morphine was not affected by GRK3 deletion although morphine tolerance in hippocampal slices from GRK3 knockout mice was significantly inhibited. Tolerance developed more slowly in vitro to morphine than fentanyl supporting previous work in in vitro systems showing a correlation between agonist efficacy and GRK3-mediated desensitization. The results of these studies suggest that GRK3-mediated mechanisms are important components of both electrophysiologic and behavioral opioid tolerance. Fentanyl, a high efficacy opioid, more effectively produced GRK3-dependent effects than morphine, a low efficacy agonist. PMID:14662727

  12. T394A Mutation at the μ Opioid Receptor Blocks Opioid Tolerance and Increases Vulnerability to Heroin Self-Administration in Mice.

    PubMed

    Wang, Xiao-Fei; Barbier, Elisabeth; Chiu, Yi-Ting; He, Yi; Zhan, Jia; Bi, Guo-Hua; Zhang, Hai-Ying; Feng, Bo; Liu-Chen, Lee-Yuan; Wang, Jia Bei; Xi, Zheng-Xiong

    2016-10-05

    The etiology and pathophysiology underlying opioid tolerance and dependence are still unknown. Because mu opioid receptor (MOR) plays an essential role in opioid action, many vulnerability-related studies have focused on single nucleotide polymorphisms of MOR, particularly on A118G. In this study, we found that a single-point mutation at the MOR T394 phosphorylation site could be another important susceptive factor in the development of opioid tolerance and dependence in mice. T394A mutation, in which a threonine at 394 was replaced by an alanine, did not alter agonist binding to MOR and opioid analgesia, but resulted in loss of etorphine-induced MOR internalization in spinal dorsal horn neurons and opioid analgesic tolerance induced by either morphine or etorphine. In addition, this mutation also caused an increase in intravenous heroin self-administration and in nucleus accumbens dopamine response to heroin. These findings suggest that T394 phosphorylation following MOR activation causes MOR internalization and desensitization, which subsequently contributes to the development of tolerance in both opioid analgesia and opioid reward. Accordingly, T394A mutation blocks opioid tolerance and leads to an increase in brain dopamine response to opioids and in opioid-taking behavior. Thus, the T394 may serve as a new drug target for modulating opioid tolerance and the development of opioid abuse and addiction.

  13. Medications Development for Opioid Abuse

    PubMed Central

    Negus, S. Stevens; Banks, Matthew L.

    2013-01-01

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

  14. Allostatic Mechanisms of Opioid Tolerance Beyond Desensitization and Downregulation

    PubMed Central

    Cahill, Catherine M.; Walwyn, Wendy; Taylor, Anna M.W.; Pradhan, Amynah A.A.; Evans, Christopher J.

    2017-01-01

    Mechanisms of opioid tolerance have focused on adaptive modifications within cells containing opioid receptors, defined here as cellular allostasis, emphasizing regulation of the opioid receptor signalosome. We review additional regulatory and opponent processes involved in behavioral tolerance, and include mechanistic differences both between agonists (agonist bias), and between μ- and δ-opioid receptors. In a process we will refer to as pass-forward allostasis, cells modified directly by opioid drugs impute allostatic changes to downstream circuitry. Because of the broad distribution of opioid systems, every brain cell may be touched by pass-forward allostasis in the opioid-dependent/tolerant state. We will implicate neurons and microglia as interactive contributors to the cumulative allostatic processes creating analgesic and hedonic tolerance to opioid drugs. PMID:27670390

  15. Allostatic Mechanisms of Opioid Tolerance Beyond Desensitization and Downregulation.

    PubMed

    Cahill, Catherine M; Walwyn, Wendy; Taylor, Anna M W; Pradhan, Amynah A A; Evans, Christopher J

    2016-11-01

    Mechanisms of opioid tolerance have focused on adaptive modifications within cells containing opioid receptors, defined here as cellular allostasis, emphasizing regulation of the opioid receptor signalosome. We review additional regulatory and opponent processes involved in behavioral tolerance, and include mechanistic differences both between agonists (agonist bias), and between μ- and δ-opioid receptors. In a process we will refer to as pass-forward allostasis, cells modified directly by opioid drugs impute allostatic changes to downstream circuitry. Because of the broad distribution of opioid systems, every brain cell may be touched by pass-forward allostasis in the opioid-dependent/tolerant state. We will implicate neurons and microglia as interactive contributors to the cumulative allostatic processes creating analgesic and hedonic tolerance to opioid drugs. Copyright © 2016. Published by Elsevier Ltd.

  16. Inhibition of the development of morphine tolerance by a potent dual mu-delta-opioid antagonist, H-Dmt-Tic-Lys-NH-CH2-Ph.

    PubMed

    Jinsmaa, Yunden; Marczak, Ewa D; Balboni, Gianfranco; Salvadori, Severo; Lazarus, Lawrence H

    2008-10-01

    Three analogues of the dual mu-/delta-antagonist, H-Dmt-Tic-R-NH-CH2-Ph (R = 1, Lys-Z; 2, Lys-Ac; 3, Lys) were examined in vivo: 1 and 2 exhibited weak bioactivity, while 3 injected intracerebroventricularly was a potent dual antagonist for morphine- and deltorphin C-induced antinociception comparable to naltrindole (delta-antagonist), but 93% as effective as naloxone (nonspecific opioid receptor antagonist) and 4% as active as CTOP, a mu antagonist. Subcutaneous or oral administration of 3 antagonized morphine-induced antinociception indicating passage across epithelial and blood-brain barriers. Mice pretreated with 3 before morphine did not develop morphine tolerance indicative of a potential clinical role to inhibit development of drug tolerance.

  17. 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.

  18. Opioid receptor–triggered spinal mTORC1 activation contributes to morphine tolerance and hyperalgesia

    PubMed Central

    Xu, Ji-Tian; Zhao, Jian-Yuan; Zhao, Xiuli; Ligons, Davinna; Tiwari, Vinod; Atianjoh, Fidelis E.; Lee, Chun-Yi; Liang, Lingli; Zang, Weidong; Njoku, Dolores; Raja, Srinivasa N.; Yaster, Myron; Tao, Yuan-Xiang

    2014-01-01

    The development of opioid-induced analgesic tolerance and hyperalgesia is a clinical challenge for managing chronic pain. Adaptive changes in protein translation in the nervous system are thought to promote opioid tolerance and hyperalgesia; however, how opioids drive such changes remains elusive. Here, we report that mammalian target of rapamycin (mTOR), which governs most protein translation, was activated in rat spinal dorsal horn neurons after repeated intrathecal morphine injections. Activation was triggered through μ opioid receptor and mediated by intracellular PI3K/Akt. Spinal mTOR inhibition blocked both induction and maintenance of morphine tolerance and hyperalgesia, without affecting basal pain perception or locomotor functions. These effects were attributed to the attenuation of morphine-induced increases in translation initiation activity, nascent protein synthesis, and expression of some known key tolerance-associated proteins, including neuronal NOS (nNOS), in dorsal horn. Moreover, elevating spinal mTOR activity by knocking down the mTOR-negative regulator TSC2 reduced morphine analgesia, produced pain hypersensitivity, and increased spinal nNOS expression. Our findings implicate the μ opioid receptor–triggered PI3K/Akt/mTOR pathway in promoting morphine-induced spinal protein translation changes and associated morphine tolerance and hyperalgesia. These data suggest that mTOR inhibitors could be explored for prevention and/or reduction of opioid tolerance in chronic pain management. PMID:24382350

  19. Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human

    PubMed Central

    Morgan, Michael M; Christie, MacDonald J

    2011-01-01

    Opioid agonists are the most effective treatment for pain, but their use is limited by side effects, tolerance and fears of addiction and dependence. A major goal of opioid research is to develop agonists that have high analgesic efficacy and a low profile for side effects, tolerance, addiction and dependence. Unfortunately, there is a serious lack of experimental data comparing the degree to which different opioids produce these effects in humans. In contrast, a wide range of experimental techniques from heterologous expression systems to behaviour assessment in whole animals have been developed to study these problems. The objective of this review is to describe and evaluate these techniques as they are used to study opioid efficacy, tolerance, addiction and dependence. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21434879

  20. Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human.

    PubMed

    Morgan, Michael M; Christie, MacDonald J

    2011-10-01

    Opioid agonists are the most effective treatment for pain, but their use is limited by side effects, tolerance and fears of addiction and dependence. A major goal of opioid research is to develop agonists that have high analgesic efficacy and a low profile for side effects, tolerance, addiction and dependence. Unfortunately, there is a serious lack of experimental data comparing the degree to which different opioids produce these effects in humans. In contrast, a wide range of experimental techniques from heterologous expression systems to behaviour assessment in whole animals have been developed to study these problems. The objective of this review is to describe and evaluate these techniques as they are used to study opioid efficacy, tolerance, addiction and dependence.

  1. Thalidomide attenuates the development and expression of antinociceptive tolerance to μ-opioid agonist morphine through l-arginine-iNOS and nitric oxide pathway.

    PubMed

    Khan, Muhammad Imran; Ostadhadi, Sattar; Mumtaz, Faiza; Momeny, Majid; Moghaddaskho, Farima; Hassanipour, Mahsa; Ejtemaei-Mehr, Shahram; Dehpour, Ahmad Reza

    2017-01-01

    Morphine is a μ-opioid analgesic drug which is used in the treatment and management of chronic pain. However, due to development of antinociceptive tolerance its clinical use is limited. Thalidomide is an old glutamic acid derivative which recently reemerged because of its potential to counteract a number of disorders including neurodegenerative disorders. The potential underlying mechanisms and effects of thalidomide on morphine-induced antinociceptive tolerance is still elusive. Hence, the present study was designed to explore the effect of thalidomide on the development and expression of morphine antinociceptive tolerance targeting l-arginine-nitric oxide (NO) pathway in mice and T98G human glioblastoma cell line. When thalidomide was administered in a dose of 17.5mg/kg before each dose of morphine chronically for 5days it prevented the development of antinociceptive tolerance. Also, a single dose of thalidomide 20mg/kg attenuated the expression phase of antinociceptive tolerance. The protective effect of thalidomide was augmented in development phase when co-administration with NOS inhibitors like L-NAME (non- selective NOS inhibitor; 2mg/kg) or aminoguanidine (selective inducible NOS inhibitor; 50mg/kg). Also, the reversal effect of thalidomide in expression phase was potentiated when concomitantly administrated with L-NAME (5mg/kg) or aminoguanidine (100mg/kg). Co-administration of ODQ (a guanylyl cyclase inhibitor) 10mg/kg in developmental phase or 20mg/kg in expression phase also progressively increased the pain threshold. In addition, thalidomide (20μM) also significantly inhibited the overexpression of iNOS gene induced by morphine (2.5μM) in T98G cell line. Hence, our findings suggest that thalidomide has protective effect both in the development and expression phases of morphine antinociceptive tolerance. It is also evident that this effect of thalidomide is induced by the inhibition of NOS enzyme predominantly iNOS. Copyright © 2016 Elsevier Masson

  2. 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

  3. 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.

  4. Do pharmacological approaches that prevent opioid tolerance target different elements in the same regulatory machinery?

    PubMed

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

    2008-06-01

    In the nervous system, the interaction of opioids like heroin and morphine with the G protein-coupled Mu-opioid receptor (MOR) provokes the development of tolerance to these opioids, as well as physical dependence. Tolerance implies that higher doses of these drugs must be consumed in order to obtain an equivalent sensation, a situation that contributes notably to the social problems surrounding recreational opioid abuse. The mechanisms that promote opioid tolerance involve a series of adaptive changes in the MOR and in the post-receptor signalling elements. Pharmacological studies have consistently identified a number of signalling proteins relevant to morphine-induced tolerance, including the delta-opioid receptor (DOR), protein kinase C (PKC), protein kinase A (PKA), calcium/calmodulin-dependent kinase II (CaMKII), nitric oxide synthase (NOS), N-methyl-D-aspartate acid glutamate receptors (NMDAR), and regulators of G-signalling (RGS) proteins. Thus, it is feasible that these treatments which diminish morphine tolerance target distinct elements within the same regulatory machinery. In this scheme, the signals originated at the agonist-activated MORs would be recognised by elements such as the NMDARs, which in turn exert a negative feedback on MOR-evoked signalling. This process involves DOR regulation of MORs, MOR-induced activation of NMDARs (probably via the regulation of Src, recruiting PKC and Galpha subunits) and the NMDAR-mediated activation of CaMKII. The active CaMKII promotes the sequestering of morphine-activated Gbetagamma dimers by phosducin-like proteins (PhLP) and of Galpha subunits by RGS proteins and tolerance to opioids like morphine develops. Future efforts to study these phenomena should focus on fitting additional pieces into this puzzle in order to fully define the mechanism underlying the desensitization of MORs in neural cells.

  5. Neuropathic Pain Activates the Endogenous κ Opioid System in Mouse Spinal Cord and Induces Opioid Receptor Tolerance

    PubMed Central

    Xu, Mei; Petraschka, Michael; McLaughlin, Jay P.; Westenbroek, Ruth E.; Caron, Marc G.; Lefkowitz, Robert J.; Czyzyk, Traci A.; Pintar, John E.; Terman, Gregory W.; Chavkin, Charles

    2008-01-01

    Release of endogenous dynorphin opioids within the spinal cord after partial sciatic nerve ligation (pSNL) is known to contribute to the neuropathic pain processes. Using a phosphoselective antibody [κ opioid receptor (KOR-P)] able to detect the serine 369 phosphorylated form of the KOR, we determined possible sites of dynorphin action within the spinal cord after pSNL. KOR-P immunoreactivity (IR) was markedly increased in the L4 –L5 spinal dorsal horn of wild-type C57BL/6 mice (7–21 d) after lesion, but not in mice pretreated with the KOR antagonist nor-binaltorphimine (norBNI). In addition, knock-out mice lacking prodynorphin, KOR, or G-protein receptor kinase 3 (GRK3) did not show significant increases in KOR-P IR after pSNL. KOR-P IR was colocalized in both GABAergic neurons and GFAP-positive astrocytes in both ipsilateral and contralateral spinal dorsal horn. Consistent with sustained opioid release, KOR knock-out mice developed significantly increased tactile allodynia and thermal hyperalgesia in both the early (first week) and late (third week) interval after lesion. Similarly, mice pretreated with norBNI showed enhanced hyperalgesia and allodynia during the 3 weeks after pSNL. Because sustained activation of opioid receptors might induce tolerance, we measured the antinociceptive effect of the κ agonist U50,488 using radiant heat applied to the ipsilateral hindpaw, and we found that agonist potency was significantly decreased 7 d after pSNL. In contrast, neither prodynorphin nor GRK3 knock-out mice showed U50,488 tolerance after pSNL. These findings suggest that pSNL induced a sustained release of endogenous prodynorphin-derived opioid peptides that activated an anti-nociceptive KOR system in mouse spinal cord. Thus, endogenous dynorphin had both pronociceptive and antinociceptive actions after nerve injury and induced GRK3-mediated opioid tolerance. PMID:15140929

  6. Opioid Analgesics and P-glycoprotein Efflux Transporters: A Potential Systems-Level Contribution to Analgesic Tolerance

    PubMed Central

    Mercer, Susan L.; Coop, Andrew

    2012-01-01

    Chronic clinical pain remains poorly treated. Despite attempts to develop novel analgesic agents, opioids remain the standard analgesics of choice in the clinical management of chronic and severe pain. However, mu opioid analgesics have undesired side effects including, but not limited to, respiratory depression, physical dependence and tolerance. A growing body of evidence suggests that P-glycoprotein (P-gp), an efflux transporter, may contribute a systems-level approach to the development of opioid tolerance. Herein, we describe current in vitro and in vivo methodology available to analyze interactions between opioids and P-gp and critically analyze P-gp data associated with six commonly used mu opioids to include morphine, methadone, loperamide, meperidine, oxycodone, and fentanyl. Recent studies focused on the development of opioids lacking P-gp substrate activity are explored, concentrating on structure-activity relationship development to develop an optimal opioid analgesic lacking this systems-level contribution to tolerance development. Continued work in this area will potentially allow for delineation of the mechanism responsible for opioid-related P-gp up-regulation and provide further support for evidence based medicine supporting clinical opioid rotation. PMID:21050174

  7. Functional Selectivity at the μ-Opioid Receptor: Implications for Understanding Opioid Analgesia and Tolerance

    PubMed Central

    Raehal, Kirsten M.; Schmid, Cullen L.; Groer, Chad E.

    2011-01-01

    Opioids are the most effective analgesic drugs for the management of moderate or severe pain, yet their clinical use is often limited because of the onset of adverse side effects. Drugs in this class produce most of their physiological effects through activation of the μ opioid receptor; however, an increasing number of studies demonstrate that different opioids, while presumably acting at this single receptor, can activate distinct downstream responses, a phenomenon termed functional selectivity. Functional selectivity of receptor-mediated events can manifest as a function of the drug used, the cellular or neuronal environment examined, or the signaling or behavioral measure recorded. This review summarizes both in vitro and in vivo work demonstrating functional selectivity at the μ opioid receptor in terms of G protein coupling, receptor phosphorylation, interactions with β-arrestins, receptor desensitization, internalization and signaling, and details on how these differences may relate to the progression of analgesic tolerance after their extended use. PMID:21873412

  8. Opioid analgesics and P-glycoprotein efflux transporters: a potential systems-level contribution to analgesic tolerance.

    PubMed

    Mercer, Susan L; Coop, Andrew

    2011-01-01

    Chronic clinical pain remains poorly treated. Despite attempts to develop novel analgesic agents, opioids remain the standard analgesics of choice in the clinical management of chronic and severe pain. However, mu opioid analgesics have undesired side effects including, but not limited to, respiratory depression, physical dependence and tolerance. A growing body of evidence suggests that P-glycoprotein (P-gp), an efflux transporter, may contribute a systems-level approach to the development of opioid tolerance. Herein, we describe current in vitro and in vivo methodology available to analyze interactions between opioids and P-gp and critically analyze P-gp data associated with six commonly used mu opioids to include morphine, methadone, loperamide, meperidine, oxycodone, and fentanyl. Recent studies focused on the development of opioids lacking P-gp substrate activity are explored, concentrating on structure-activity relationships to develop an optimal opioid analgesic lacking this systems-level contribution to tolerance development. Continued work in this area will potentially allow for delineation of the mechanism responsible for opioid-related P-gp up-regulation and provide further support for evidence based medicine supporting clinical opioid rotation.

  9. TOLERANCE, OPIOID-INDUCED ALLODYNIA AND WITHDRAWAL ASSOCIATED ALLODYNIA IN INFANT AND YOUNG RATS

    PubMed Central

    Zissen, Maurice H.; Zhang, Guohua; McKelvy, Alvin; Propst, John T.; Kendig, Joan J.; Sweitzer, Sarah M.

    2006-01-01

    Our laboratory has previously characterized age-dependent changes in nociception upon acute morphine withdrawal. This study characterizes changes in mechanical and thermal nociception following acute, intermittent, or continuous morphine administration in infant (postnatal day 5–8) and young (postnatal day 19–21). Morphine was given as a single acute administration (AM), intermittently twice a day for 3 days (IM), or continuously for 72 hours via a subcutaneous pump implanted (CM). AM did not produce long-term changes in mechanical or thermal nociception in either infant or young rats. CM produced changes in mechanical nociception that included the development of tolerance, opioid-induced mechanical allodynia and withdrawal-associated mechanical allodynia in young rats, but only tolerance and a prolonged withdrawal-associated mechanical allodynia in infant rats. IM produced withdrawal-associated mechanical allodynia in both infant and young rats. Measuring paw withdrawal responses to thermal stimuli, infant and young rats showed tolerance without opioid-induced thermal hyperalgesia or withdrawal-associated thermal hyperalgesia following CM. In contrast to CM, withdrawal-associated thermal hyperalgesia was seen in both ages following IM. In conclusion, CM versus IM differentially modified mechanical and thermal nociception, suggesting that opioid-dependent thermal hyperalgesia and mechanical allodynia can be dissociated from each other in infant and young rats. Furthermore, tolerance, opioid-induced hypersensitivity, and withdrawal-associated hypersensitivity are age-specific and may be mediated by distinct mechanisms. PMID:17055659

  10. Tolerance, opioid-induced allodynia and withdrawal associated allodynia in infant and young rats.

    PubMed

    Zissen, M H; Zhang, G; McKelvy, A; Propst, J T; Kendig, J J; Sweitzer, S M

    2007-01-05

    Our laboratory has previously characterized age-dependent changes in nociception upon acute morphine withdrawal. This study characterizes changes in mechanical and thermal nociception following acute, intermittent, or continuous morphine administration in infant (postnatal days 5-8) and young (postnatal days 19-21) rats. Morphine was given as a single acute administration (AM), intermittently twice a day for 3 days (IM), or continuously for 72 h via pump (CM). AM did not produce long-term changes in mechanical or thermal nociception in either infant or young rats. CM produced changes in mechanical nociception that included the development of tolerance, opioid-induced mechanical allodynia and withdrawal-associated mechanical allodynia in young rats, but only tolerance and a prolonged withdrawal-associated mechanical allodynia in infant rats. IM produced withdrawal-associated mechanical allodynia in both infant and young rats. Measuring paw withdrawal responses to thermal stimuli, infant and young rats showed tolerance without opioid-induced thermal hyperalgesia or withdrawal-associated thermal hyperalgesia following CM. In contrast to CM, withdrawal-associated thermal hyperalgesia was seen in both ages following IM. In conclusion, CM versus IM differentially modified mechanical and thermal nociception, suggesting that opioid-dependent thermal hyperalgesia and mechanical allodynia can be dissociated from each other in infant and young rats. Furthermore, tolerance, opioid-induced hypersensitivity, and withdrawal-associated hypersensitivity are age-specific and may be mediated by distinct mechanisms.

  11. 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

  12. Opioid antinociception, tolerance and dependence: interactions with the N-methyl-D-aspartate system in mice.

    PubMed

    Dykstra, Linda A; Fischer, Bradford D; Balter, Rebecca E; Henry, Fredrick E; Schmidt, Karl T; Miller, Laurence L

    2011-09-01

    This study explored the involvement of N-methyl-D-aspartate (NMDA) in the effects of μ-opioid agonists. A hot-plate procedure was used to assess antinociception and tolerance in mice in which the NR1 subunit of the NMDA receptor was reduced [knockdown (KD)] to approximately 10%, and in mice treated with the NMDA antagonist, (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959). The μ opioid agonists, morphine, l-methadone and fentanyl, were approximately three-fold less potent in the NR1 KD mice than in wild-type (WT) controls; however, the development of morphine tolerance and dependence did not differ markedly in the NR1 KD and the WT mice. Acute administration of the NMDA antagonist, LY235959, produced dose-dependent, leftward shifts in the morphine dose-effect curve in the WT mice, but not in the NR1 KD mice. Chronic administration of LY235959 during the morphine tolerance regimen did not attenuate the development of tolerance in the NR1 KD or the WT mice. These results indicate that the NR1 subunit of the NMDA receptor does not play a prominent role in μ opioid tolerance.

  13. Comparison of Pain Tolerance between Opioid Dependent Patients on Methadone Maintenance Therapy (MMT) and Opioid Naive Individuals.

    PubMed

    Zahari, Zalina; Lee, Chee Siong; Ibrahim, Muslih Abdulkarim; Musa, Nurfadhlina; Mohd Yasin, Mohd Azhar; Lee, Yeong Yeh; Tan, Soo Choon; Mohamad, Nasir; Ismail, Rusli

    2016-01-01

    This study compared pain sensitivity among opioid dependent patients on methadone maintenance therapy (MMT) and opioid naive subjects. The three hundred participants comprised 152 opioid naive subjects and 148 opioid dependent patients. Opioid naive subjects had not taken any opioids including morphine and methadone to their best knowledge and were presumed so after two consecutive negative urine screenings for drugs. All opioid dependent patients were stabilized in treatment, defined as having been enrolled in the program for more than one month with no change of methadone dosage over the past one month. Excluded from the study were individuals with chronic or ongoing acute pain and individuals with a history of analgesics ingestion within 3 d before the cold pressor test (CPT). Pain tolerance to CPT was evaluated at 0 h, and at 2, 4, 8, 12, and 24 h post-methadone dose. Patients exhibited a significantly shorter mean pain tolerance time of 34.17 s (95% CI 24.86, 43.49) versus 61.36 (52.23, 70.48) [p < 0.001] compared with opioid naive subjects. Time-dependent mean pain tolerance was also significantly different when naive subjects were compared to patients (p = 0.016). This study revealed hyperalgesia amongst patients on MMT, as manifested by their quicker hand withdrawal. The complaints of pain in this population should not be underestimated and the pain should be evaluated seriously and managed aggressively.

  14. The challenge of perioperative pain management in opioid-tolerant patients

    PubMed Central

    Coluzzi, Flaminia; Bifulco, Francesca; Cuomo, Arturo; Dauri, Mario; Leonardi, Claudio; Melotti, Rita Maria; Natoli, Silvia; Romualdi, Patrizia; Savoia, Gennaro; Corcione, Antonio

    2017-01-01

    The increasing number of opioid users among chronic pain patients, and opioid abusers among the general population, makes perioperative pain management challenging for health care professionals. Anesthesiologists, surgeons, and nurses should be familiar with some pharmacological phenomena which are typical of opioid users and abusers, such as tolerance, physical dependence, hyperalgesia, and addiction. Inadequate pain management is very common in these patients, due to common prejudices and fears. The target of preoperative evaluation is to identify comorbidities and risk factors and recognize signs and symptoms of opioid abuse and opioid withdrawal. Clinicians are encouraged to plan perioperative pain medications and to refer these patients to psychiatrists and addiction specialists for their evaluation. The aim of this review was to give practical suggestions for perioperative management of surgical opioid-tolerant patients, together with schemes of opioid conversion for chronic pain patients assuming oral or transdermal opioids, and patients under maintenance programs with methadone, buprenorphine, or naltrexone. PMID:28919771

  15. 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

  16. No tolerance to peripheral morphine analgesia in presence of opioid expression in inflamed synovia.

    PubMed Central

    Stein, C; Pflüger, M; Yassouridis, A; Hoelzl, J; Lehrberger, K; Welte, C; Hassan, A H

    1996-01-01

    Pain treatment with centrally acting opiates is limited by tolerance. Tolerance is a decreasing effect of a drug with prolonged administration of that drug or of a related (e.g., endogenous) compound acting at the same receptor. This is often associated with a downregulation of receptors. In peripheral inflamed tissue, both locally expressed opioid peptides and morphine can produce powerful analgesia mediated by similar populations of opioid receptors. We hypothesized that the chronic presence of endogenous opioids in inflamed joints might convey downregulation of peripheral opioid receptors and tolerance to the analgesic effects of intraarticular morphine. We assessed these effects after arthroscopic surgery in patients with and without histologically verified synovial cellular infiltration, and we examined synovial opioid peptides and opioid receptors by immunocytochemistry and autoradiography, respectively. We found that, despite an abundance of opioid-containing cells in pronounced synovitis, morphine is at least as effective as in patients without such cellular infiltrations, and there is no major downregulation of peripheral opioid receptors. Thus, opioids expressed in inflamed tissue do not produce tolerance to peripheral morphine analgesia. Tolerance may be less pronounced for peripherally than for centrally acting opioids, which provides a promising perspective for the treatment of chronic pain in arthritis and other inflammatory conditions. PMID:8698872

  17. Reduced Cold Pain Tolerance in Chronic Pain Patients Following Opioid Detoxification

    PubMed Central

    Younger, Jarred; Barelka, Peter; Carroll, Ian; Kaplan, Kim; Chu, Larry; Prasad, Ravi; Gaeta, Ray; Mackey, Sean

    2009-01-01

    Objective One potential consequence of chronic opioid analgesic administration is a paradoxical increase of pain sensitivity over time. Little scientific attention has been given to how cessation of opioid medication affects the hyperalgesic state. In this study, we examined the effects of opioid tapering on pain sensitivity in chronic pain patients. Design Twelve chronic pain patients on long-term opioid analgesic treatment were observed in a 7- to 14-day inpatient pain rehabilitation program, with cold pain tolerance assessed at admission and discharge. The majority of participants were completely withdrawn from their opioids during their stay. Outcome Measures We hypothesized that those patients with the greatest reduction in daily opioid use would show the greatest increases in pain tolerance, as assessed by a cold pressor task. Results A linear regression revealed that the amount of opioid medication withdrawn was a significant predictor of pain tolerance changes, but not in the direction hypothesized. Greater opioid reduction was associated with decreased pain tolerance. This reduction of pain tolerance was not associated with opioid withdrawal symptoms or changes in general pain. Conclusions These findings suggest that the withdrawal of opioids in a chronic pain sample leads to an acute increase in pain sensitivity. PMID:18564998

  18. 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

  19. [Opioids in chronic noncancer pain-are opioids different? A systematic review and meta-analysis of efficacy, tolerability and safety in randomized head-to-head comparisons of opioids of at least four week's duration].

    PubMed

    Lauche, R; Klose, P; Radbruch, L; Welsch, P; Häuser, W

    2015-02-01

    We updated a systematic review on the comparative efficacy, tolerability and safety of opioids and of their routes of application in chronic noncancer pain (CNCP). We screened MEDLINE, Scopus and the Cochrane Central Register of Controlled Trials (CENTRAL) up until October 2013, as well as the reference sections of original studies and systematic reviews of randomized controlled trials (RCTs) of opioids in CNCP. We included randomized head-to-head comparisons of opioids (opioid of the sponsor of the study versus standard opioid) of at least 4 week's duration. Using a random effects model, absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables. The quality of evidence was rated by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. We included 13 RCTs with 6748 participants. Median study duration was 15 weeks (range 4-56 weeks). Hydromorphone, morphine, oxymorphone and tapentadol were compared to oxycodone; fentanyl to morphine and buprenorphine to tramadol. In pooled analysis, there were no significant differences between the two groups of opioids in terms of mean pain reduction (low-quality evidence), the patient global impression to be much or very much improved outcome (low-quality evidence), physical function (very low-quality evidence), serious adverse events (moderate-quality evidence) or mortality (moderate-quality evidence). There was no significant difference between transdermal and oral application of opioids in terms of mean pain reduction, physical function, serious adverse events, mortality (all low-quality evidence) or dropout due to adverse events (very low-quality). Pooled head-to-head comparisons of opioids (opioid of the sponsor of the study versus standard opioid) provide no rational for preferring one opioid and/or administration route over another in the therapy of patients with CNCP. The English full-text version of this

  20. Potentiation of acute opioid-induced respiratory depression and reversal of tolerance by the calcium antagonist nimodipine in awake rats.

    PubMed

    Ruiz, F; Dierssen, M; Flórez, J; Hurlé, M A

    1993-12-01

    The interaction between sufentanil, a mu-opioid agonist, and the Ca2+ antagonist nimodipine on respiration and on the development of opioid tolerance in awake rats has been analyzed. Our previous work demonstrated that chronic treatment with nimodipine together with sufentanil increases the analgesic potency of the opioid 50 fold. Therefore, we have investigated whether the opioid-induced respiratory depression is potentiated in parallel with the analgesia. Ventilation was measured by the whole body plethysmographic method. In naive rats, sufentanil (10-80 micrograms/kg) consistently induced a dose-dependent respiratory depression. Pretreatment with nimodipine (200 micrograms/kg) potentiated this effect but to a lesser extent than it potentiated analgesia. After chronic administration of the opioid (2 micrograms/h, 7 days) tolerance was manifested as a reduction in both the area under the time course curve and in the maximum effect. Nimodipine (1 microgram/h) administered concurrently with sufentanil for 7 days counteracted the tolerance to respiratory depression but no additional potentiation was observed. These results demonstrate that the interaction between nimodipine and sufentanil is not limited to antinociception but also extends to respiratory depression. However, compared with analgesia, the clinical relevance of a potential increase in opioid-induced respiratory depression by nimodipine may be negligible.

  1. Opioid agonist efficacy predicts the magnitude of tolerance and the regulation of μ-opioid receptors and dynamin-2

    PubMed Central

    Pawar, Mohit; Kumar, Priyank; Sunkaraneni, Soujanya; Sirohi, Sunil; Walker, Ellen A.; Yoburn, Byron C.

    2007-01-01

    It has been proposed that opioid agonist efficacy may play a role in tolerance and the regulation of opioid receptor density. To address this issue, the present studies estimated the in vivo efficacy of three opioid agonists and then examined changes in spinal μ-opioid receptor density following chronic treatment in the mouse. In addition, tolerance and regulation of the trafficking protein dynamin-2 were determined. To evaluate efficacy, the method of irreversible receptor alkylation was employed and the efficacy parameter τ estimated. Mice were injected with the irreversible μ-opioid receptor antagonist clocinnamox (0.32–25.6mg/kg, i.p), and 24h later, the analgesic potency of s.c. morphine, oxycodone and etorphine were determined. Clocinnamox dose-dependently antagonized the analgesic effects of morphine, etorphine and oxycodone. The shift to the right of the dose-response curves was greater for morphine and oxycodone compared to etorphine and the highest dose of clocinnamox reduced the maximal effect of morphine and oxycodone, but not etorphine. The order of efficacy calculated from these results was etorphine > morphine > oxycodone. Other mice were infused for 7 days with oxycodone (10–150 mg/kg/day, s.c.) or etorphine (50–250ug/kg/day, s.c.) and the analgesic potency of s.c. morphine determined. The low efficacy agonist (oxycodone) produced more tolerance than the high efficacy agonist (etorphine) at equi-effective infusion doses. In saturation binding experiments, the low efficacy opioid agonists (morphine, oxycodone) did not regulate the density of spinal μ-opioid receptors, while etorphine produced ≈ 40% reduction in μ-opioid receptor density. Furthermore, etorphine increased spinal dynamin-2 abundance, while oxycodone did not produce any significant change in dynamin-2 abundance. Overall, these data indicate that high efficacy agonists produce less tolerance at equi-effective doses. Furthermore, increased efficacy was associated with μ-opioid

  2. Peripartum Anesthetic Management of the Opioid-tolerant or Buprenorphine/Suboxone-dependent Patient.

    PubMed

    Pan, Aileen; Zakowski, Mark

    2017-06-01

    Opioid abuse and dependence continues to rise in both the general population and pregnancy, with opioid overdose deaths having quadrupled in the last 15 years. Illicit drug use in last 30 days of pregnancy was over 4% with almost 0.6% documented maternal opiate use at time of birth. The management of the opioid-tolerant, buprenorphine-dependent or methadone-dependent patient in the peripartum period is reviewed. Options for treatment of opioid dependence, acute pain management, and perioperative multimodal analgesia are discussed. The effects of maternal management on neonatal abstinence syndrome are also reviewed.

  3. Ligand-directed trafficking of the δ-opioid receptor in vivo: two paths toward analgesic tolerance.

    PubMed

    Pradhan, Amynah A A; Walwyn, Wendy; Nozaki, Chihiro; Filliol, Dominique; Erbs, Eric; Matifas, Audrey; Evans, Christopher; Kieffer, Brigitte L

    2010-12-08

    δ-Opioid receptors are G-protein-coupled receptors that regulate nociceptive and emotional responses. It has been well established that distinct agonists acting at the same G-protein-coupled receptor can engage different signaling or regulatory responses. This concept, known as biased agonism, has important biological and therapeutic implications. Ligand-biased responses are well described in cellular models, however, demonstrating the physiological relevance of biased agonism in vivo remains a major challenge. The aim of this study was to investigate the long-term consequences of ligand-biased trafficking of the δ-opioid receptor, at both the cellular and behavioral level. We used δ agonists with similar binding and analgesic properties, but high [SNC80 ((+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide)]- or low [ARM390 (N,N-diethyl-4-(phenyl-piperidin-4-ylidenemethyl)-benzamide)]-internalization potencies. As we found previously, a single SNC80-but not ARM390-administration triggered acute desensitization of the analgesic response in mice. However, daily injections of either compound over 5 d produced full analgesic tolerance. SNC80-tolerant animals showed widespread receptor downregulation, and tolerance to analgesic, locomotor and anxiolytic effects of the agonist. Hence, internalization-dependent tolerance developed, as a result of generalized receptor degradation. In contrast, ARM390-tolerant mice showed intact receptor expression, but δ-opioid receptor coupling to Ca²+ channels was abolished in dorsal root ganglia. Concomitantly, tolerance developed for agonist-induced analgesia, but not locomotor or anxiolytic responses. Therefore, internalization-independent tolerance was produced by anatomically restricted adaptations leading to pain-specific tolerance. Hence, ligand-directed receptor trafficking of the δ-opioid receptor engages distinct adaptive responses, and this study reveals a novel aspect of

  4. Ligand-Directed Trafficking of the δ-Opioid Receptor In Vivo: Two Paths Toward Analgesic Tolerance

    PubMed Central

    Pradhan, Amynah A. A.; Walwyn, Wendy; Nozaki, Chihiro; Filliol, Dominique; Erbs, Eric; Matifas, Audrey; Evans, Christopher; Kieffer, Brigitte L.

    2011-01-01

    δ-Opioid receptors are G-protein-coupled receptors that regulate nociceptive and emotional responses. It has been well established that distinct agonists acting at the same G-protein-coupled receptor can engage different signaling or regulatory responses. This concept, known as biased agonism, has important biological and therapeutic implications. Ligand-biased responses are well described in cellular models, however, demonstrating the physiological relevance of biased agonism in vivo remains a major challenge. The aim of this study was to investigate the long-term consequences of ligand-biased trafficking of the δ-opioid receptor, at both the cellular and behavioral level. We used δ agonists with similar binding and analgesic properties, but high [SNC80 ((+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide)]- or low [ARM390 (N,N-diethyl-4-(phenyl-piperidin-4-ylidenemethyl)-benzamide)]-internalization potencies. As we found previously, a single SNC80—but not ARM390—administration triggered acute desensitization of the analgesic response in mice. However, daily injections of either compound over 5 d produced full analgesic tolerance. SNC80-tolerant animals showed widespread receptor downregulation, and tolerance to analgesic, locomotor and anxiolytic effects of the agonist. Hence, internalization-dependent tolerance developed, as a result of generalized receptor degradation. In contrast, ARM390-tolerant mice showed intact receptor expression, but δ-opioid receptor coupling to Ca2+ channels was abolished in dorsal root ganglia. Concomitantly, tolerance developed for agonist-induced analgesia, but not locomotor or anxiolytic responses. Therefore, internalization-independent tolerance was produced by anatomically restricted adaptations leading to pain-specific tolerance. Hence, ligand-directed receptor trafficking of the δ-opioid receptor engages distinct adaptive responses, and this study reveals a novel aspect of

  5. How to Design an Opioid Drug That Causes Reduced Tolerance and Dependence

    PubMed Central

    Berger, Amy Chang; Whistler, Jennifer L.

    2010-01-01

    Mu opioid receptor (MOR) agonists such as morphine are extremely effective treatments for acute pain. In the setting of chronic pain, however, their long-term utility is limited by the development of tolerance and physical dependence. Drug companies have tried to overcome these problems by simply “dialing up” signal transduction at the receptor, designing more potent and efficacious agonists and more long-lasting formulations. Neither of these strategies has proven to be successful, however, because the net amount of signal transduction, particularly over extended periods of drug use, is a product of much more than the pharmacokinetic properties of potency, efficacy, half-life, and bioavailability, the mainstays of traditional pharmaceutical screening. Both the quantity and quality of signal transduction are influenced by many regulated processes, including receptor desensitization, trafficking, and oligomerization. Importantly, the efficiency with which an agonist first stimulates signal transduction is not necessarily related to the efficiency with which it stimulates these other processes. Here we describe recent findings that suggest MOR agonists with diminished propensity to cause tolerance and dependence can be identified by screening drugs for the ability to induce MOR desensitization, endocytosis, and recycling. We also discuss preliminary evidence that heteromers of the delta opioid receptor and the MOR are pronociceptive, and that drugs that spare such heteromers may also induce reduced tolerance. PMID:20437553

  6. Opioid tolerance induced by metamizol (dipyrone) microinjections into the periaqueductal grey of rats.

    PubMed

    Tortorici, V; Vanegas, H

    2000-11-01

    Non-opioid analgesics have been shown to elicit antinociception by an action upon central nervous system structures, in addition to their well known action upon peripheral tissues. Microinjection of metamizol (dipyrone), a widely used nonopioid analgesic, into the periaqueductal grey matter (PAG) of rats activates pain-modulating systems in the nucleus raphe magnus and inhibits spinal nociceptive neurons and the tail-flick reflex. Since these effects involve an activation of endogenous opioidergic systems, the possibility that metamizol induces opioid tolerance was investigated. Microinjection of metamizol into the ventrolateral PAG in awake rats induced antinociception, as demonstrated in the heat-elicited tail flick and hot plate tests. When microinjected into the ventrolateral PAG twice daily for 2 days, metamizol induced tolerance, i.e. a progressive loss of its antinociceptive effect. In contrast to rats repeatedly microinjected with saline, metamizol-tolerant rats were also tolerant to morphine microinjection into the same PAG site, and displayed signs of opioid withdrawal upon systemic administration of naloxone. These and other results suggest that metamizol activates endogenous opioid systems and that nonopioid analgesics may, by an action upon the central nervous system, lead to opioid tolerance and the risk of opioid withdrawal.

  7. Differential cross-tolerance to mu and kappa opioid agonists in morphine-tolerant rats responding under a schedule of food presentation.

    PubMed

    Picker, M J; Negus, S S; Powell, K R

    1991-01-01

    If different populations of opioid receptors mediate the actions of mu and kappa opioid agonists, then tolerance induced by the chronic administration of a mu agonist should confer cross-tolerance to other mu agonists but not necessarily to those compounds whose effects are mediated by the kappa receptor. This hypothesis was evaluated in the present investigation by examining the effects of the mu agonists morphine, l-methadone and fentanyl, the kappa agonists U50,488 and bremazocine, and the mixed kappa/mu agonist ethylketocyclazocine in rats responding under a fixed-ratio 30 schedule of food presentation before, during and after exposure to a regimen of chronic morphine administration. For comparison, naloxone was evaluated as a representative mu antagonist and the phenothiazine chlorpromazine as a control drug. During all phases of the experiment, each of these compounds produced dose-related decreases in rate of responding. During the daily administration of 40 mg/kg morphine, tolerance developed to the rate-decreasing effects of morphine, l-methadone and fentanyl, and an enhanced sensitivity to the effects of naloxone. In contrast to the effects obtained with these mu opioids, there was no evidence that chronic morphine administration produced tolerance or enhanced sensitivity to the rate-decreasing effects of U50,488, bremazocine, ethylketocyclazocine and chlorpromazine. The present findings demonstrate that the chronic administration of morphine results in the selective development of tolerance to other mu agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

  8. A preliminary randomized controlled trial of a distress tolerance treatment for opioid dependent persons initiating buprenorphine.

    PubMed

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

    2015-02-01

    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. 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-min 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. 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. 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. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  9. Involvement of cholecystokinin in the opioid tolerance induced by dipyrone (metamizol) microinjections into the periaqueductal gray matter of rats.

    PubMed

    Tortorici, Victor; Nogueira, Lourdes; Aponte, Yexica; Vanegas, Horacio

    2004-11-01

    The analgesic effect of non-steroidal anti-inflammatory drugs (NSAIDs) is partly due to an action upon the periaqueductal gray matter (PAG), which triggers the descending pain control system and thus inhibits nociceptive transmission. This action of NSAIDs engages endogenous opioids at the PAG, the nucleus raphe magnus and the spinal cord. Repeated administration of NSAIDs such as dipyrone (metamizol) and acetylsalicylate thus induces tolerance to these compounds and cross-tolerance to morphine. Since cholecystokinin plays a key role in opioid tolerance, the present study in rats investigated whether PAG cholecystokinin is also responsible for tolerance to PAG-microinjected dipyrone. Microinjection of cholecystokinin (1 ng/0.5 microl) into PAG blocked the antinociceptive effect of a subsequent microinjection of dipyrone (150 microg/0.5 microl) into the same site, as evaluated by the tail flick and hot plate tests. Microinjection of proglumide (0.4 microg/0.5 microl), a non-selective cholecystokinin antagonist, into PAG prevented the development of tolerance to subsequent microinjections of dipyrone, as well as cross-tolerance to microinjection of morphine (5 microg/0.5 microl) into the same site. In rats tolerant to PAG dipyrone, a PAG microinjection of proglumide restored the antinociceptive effect of a subsequent microinjection of dipyrone or morphine. These results suggest that PAG-microinjected dipyrone triggers and/or potentiates local opioidergic circuits leading to descending inhibition of nociception, on the one hand, and to a local antiopioid action by cholecystokinin, on the other. Reiteration of these events would then result in an enhancement of cholecystokinin's antiopioid action and thus tolerance to opioids and dipyrone in the PAG.

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

    PubMed Central

    Henrie-Barrus, Patricia; Averill, Lynnette A; Sudweeks, Richard R; Averill, Christopher L; Mota, Natalie

    2016-01-01

    Prescription opioid drug abuse has reached epidemic proportions. Individuals with chronic pain represent a large population at considerable risk of abusing opioids. The Opioid Abuse Risk Screener was developed as a comprehensive self-administered measure of potential risk that includes a wide range of critical elements noted in the literature to be relevant to opioid risk. The creation, refinement, and preliminary modeling of the item pool, establishment of preliminary concurrent validity, and the determination of the factor structure are presented. The initial development and validation of the Opioid Abuse Risk Screener shows promise for effective risk stratification. PMID:28070401

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

    PubMed

    Henrie-Barrus, Patricia; Averill, Lynnette A; Sudweeks, Richard R; Averill, Christopher L; Mota, Natalie

    2016-01-01

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

  12. Development of Kappa Opioid Receptor Antagonists

    PubMed Central

    Carroll, F. Ivy; Carlezon, William A.

    2013-01-01

    Kappa opioid receptors (KORs) belong to the G-protein coupled class of receptors (GPCRs). They are activated by the endogenous opioid peptide dynorphin (DYN) and expressed at particularly high levels within brain areas implicated in modulation of motivation, emotion, and cognitive function. Chronic activation of KORs in animal models has maladaptive effects including increases in behaviors that reflect depression, the propensity to engage in drug-seeking behavior, and drug craving. The fact that KOR activation has such a profound influence on behaviors often triggered by stress has led to interest in selective KOR antagonists as potential therapeutic agents. This perspective provides a description of preclinical research conducted in the development of several different classes of selective KOR antagonists, a summary of the clinical studies conducted thus far, and recommendations for the type of work needed in the future to determine if these agents would be useful as pharmacotherapies for neuropsychiatric illness. PMID:23360448

  13. Analgesic management of acute pain in the opioid-tolerant patient.

    PubMed

    Shah, Samir; Kapoor, Shruti; Durkin, Brian

    2015-08-01

    The management of acute pain in the opioid-tolerant patient is an area in perioperative medicine that is growing, as the use of opioids for chronic noncancer pain has been tolerated in the USA. Adding to this population is an increase in opioid abusers, addicts and those in recovery and maintenance programmes. These patients will continue to present for surgery and with acute pain that anaesthesiologists and other members of the healthcare team must become more adept at managing. This review covers some of the strategies that may be used by practitioners in the management of acute pain in the opioid-tolerant patient. It is important to collect a detailed history of opioid and drugs of abuse, including the timing of the last dose in order to avoid precipitation of withdrawal. The use of multimodal anaesthetic and analgesic strategies is important for both patient safety and satisfaction and can enhance recovery and discharge home. There is a need for more high-level evidence-based guidelines to help practitioners achieve the best care of this growing high-risk population of patients.

  14. 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

  15. Impact of opioid rescue medication for breakthrough pain on the efficacy and tolerability of long-acting opioids in patients with chronic non-malignant pain

    PubMed Central

    Devulder, J.; Jacobs, A.; Richarz, U.; Wiggett, H.

    2009-01-01

    Background There is little evidence that short-acting opioids as rescue medication for breakthrough pain is an optimal long-term treatment strategy in chronic non-malignant pain. We compared clinical studies of long-acting opioids that allowed short-acting opioid rescue medication with those that did not, to determine the impact of opioid rescue medication use on the analgesic efficacy and tolerability of chronic opioid therapy in patients with chronic non-malignant pain. Methods We searched MEDLINE (1950 to July 2006) and EMBASE (1974 to July 2006) using terms for chronic non-malignant pain and long-acting opioids. Independent review of the search results identified 48 studies that met the study selection criteria. The effect of opioid rescue medication on analgesic efficacy and the incidence of common opioid-related side-effects were analysed using meta-regression. Results After adjusting for potentially confounding variables (study design and type of opioid), the difference in analgesic efficacy between the ‘rescue’ and the ‘no rescue’ studies was not significant, with regression coefficients close to 0 and 95% confidence intervals that excluded an effect of more than 18 points on a 0–100 scale in each case. There was also no significant difference between the ‘rescue’ and the ‘no rescue’ studies for the incidence of nausea, constipation, or somnolence in both the unadjusted and the adjusted analyses. Conclusions We found no evidence that rescue medication with short-acting opioids for breakthrough pain affects analgesic efficacy of long-acting opioids or the incidence of common opioid-related side-effects among chronic non-malignant pain patients. PMID:19736216

  16. Ketamine and remifentanil interactions on the sevoflurane minimum alveolar concentration and acute opioid tolerance in the rat.

    PubMed

    Aguado, Delia; Abreu, Mariana; Benito, Javier; García-Fernández, Javier; Gómez de Segura, Ignacio A

    2011-09-01

    Ketamine is used at low doses for its analgesic and antihyperalgesic properties when combined with opioids but also when opioid-induced hyperalgesia and tolerance appear. In this study we determined the interaction of ketamine and remifentanil on the minimum alveolar concentration (MAC) of sevoflurane in rats and to determine whether ketamine may block acute opioid tolerance (AOT). Male Wistar rats were anesthetized with sevoflurane, and the MAC was determined before and after ketamine administration (10, 20, 40, and 80 mg kg(-1) or saline) alone or combined with remifentanil (120 and 240 μg kg(-1) h(-1), low and high doses, respectively). One additional group received the lowest ketamine dose after starting a remifentanil infusion. Finally, naloxone was administered to determine the potential action of ketamine on opioid receptors. MAC was determined from intratracheal gas samples, and tail clamping was used as a supramaximal stimulus. End-tidal anesthetic concentrations were assayed using a side stream gas analyzer. Statistical analysis was performed with an analysis of variance. Ketamine and remifentanil dose-dependently reduced the MAC. Adding the low dose of remifentanil to ketamine did not improve the MAC reduction, whereas the high dose of remifentanil enhanced ketamine reduction in a subadditive fashion. Nevertheless, ketamine was unable to block the development of AOT to remifentanil at either dose. Finally, naloxone blocked the MAC reduction produced by ketamine. A subadditive effect between ketamine and remifentanil was found on the sevoflurane MAC reduction rats. In addition, ketamine was unable to block AOT. The clinical relevance of these findings should be elucidated in future studies to reduce anesthetic requirements.

  17. Tolerance to non-opioid analgesics in PAG involves unresponsiveness of medullary pain-modulating neurons in male rats.

    PubMed

    Tortorici, Victor; Aponte, Yexica; Acevedo, Humberto; Nogueira, Lourdes; Vanegas, Horacio

    2009-03-01

    Opiate analgesia can be hampered by a reduction in pharmacological effectiveness (tolerance), and this crucially depends on the periaqueductal gray matter (PAG). Non-opioids like metamizol (dipyrone) or aspirin also induce PAG-dependent analgesia and tolerance, but the neuronal bases of this tolerance are unknown. Metamizol is a pyrazolon derivative and cyclooxygenase inhibitor with widespread use as an analgesic in Europe and Latin America. Metamizol was microinjected into the PAG of awake male rats, and antinociception was assessed by the tail flick (TF) and hot plate (HP) tests. Microinjection twice daily for 2.5 days caused tolerance to metamizol. The rats were then anesthetized and recordings from pain-facilitating on-cells and pain-inhibiting off-cells of the rostral ventromedial medulla (RVM) were performed. PAG microinjection of morphine or metamizol depresses on-cells, activates off-cells and thus inhibits nociception, including TF and HP. In metamizol-tolerant rats, however, PAG microinjection of metamizol failed to affect on- or off-cells, and this is interpreted as the reason for tolerance. In metamizol-tolerant rats morphine microinjection into PAG also failed to affect RVM neurons or nociception (cross-tolerance). In naïve, non-tolerant rats the antinociceptive effect of PAG-microinjected metamizol or morphine was blocked when CTOP, a mu-opioid antagonist, was previously microinjected into the same PAG site. These results emphasize a close relationship between opioid and non-opioid analgesic mechanisms in the PAG and show that, like morphine, tolerance to metamizol involves a failure of on- and off-cells to, respectively, disfacilitate and inhibit nociception. Cross-tolerance between non-opioid and opioid analgesics should be important in the clinical setting.

  18. 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

  19. Recent developments in the study of opioid receptors.

    PubMed

    Cox, Brian M

    2013-04-01

    It is now about 40 years since Avram Goldstein proposed the use of the stereoselectivity of opioid receptors to identify these receptors in neural membranes. In 2012, the crystal structures of the four members of the opioid receptor family were reported, providing a structural basis for understanding of critical features affecting the actions of opiate drugs. This minireview summarizes these recent developments in our understanding of opiate receptors. Receptor function is also influenced by amino acid substitutions in the protein sequence. Among opioid receptor genes, one polymorphism is much more frequent in human populations than the many others that have been found, but the functional significance of this single nucleotide polymorphism (SNP) has been unclear. Recent studies have shed new light on how this SNP might influence opioid receptor function. In this minireview, the functional significance of the most prevalent genetic polymorphism among the opioid receptor genes is also considered.

  20. Augmentation of morphine-induced sensitization but reduction in morphine tolerance and reward in delta-opioid receptor knockout mice.

    PubMed

    Chefer, V I; Shippenberg, T S

    2009-03-01

    Studies in experimental animals have shown that individuals exhibiting enhanced sensitivity to the locomotor-activating and rewarding properties of drugs of abuse are at increased risk for the development of compulsive drug-seeking behavior. The purpose of the present study was to assess the effect of constitutive deletion of delta-opioid receptors (DOPr) on the rewarding properties of morphine as well as on the development of sensitization and tolerance to the locomotor-activating effects of morphine. Locomotor activity testing revealed that mice lacking DOPr exhibit an augmentation of context-dependent sensitization following repeated, alternate injections of morphine (20 mg/kg; s.c.; 5 days). In contrast, the development of tolerance to the locomotor-activating effects of morphine following chronic morphine administration (morphine pellet: 25 mg: 3 days) is reduced relative to WT mice. The conditioned rewarding effects of morphine were reduced significantly in DOPrKO mice as compared to WT controls. Similar findings were obtained in response to pharmacological inactivation of DOPr in WT mice, indicating that observed effects are not due to developmental adaptations that occur as a consequence of constitutive deletion of DOPr. Together, these findings indicate that the endogenous DOPr system is recruited in response to both repeated and chronic morphine administration and that this recruitment serves an essential function in the development of tolerance, behavioral sensitization, and the conditioning of opiate reward. Importantly, they demonstrate that DOPr has a distinct role in the development of each of these drug-induced adaptations. The anti-rewarding and tolerance-reducing properties of DOPr antagonists may offer new opportunities for the treatment and prevention of opioid dependence as well as for the development of effective analgesics with reduced abuse liability.

  1. Fentanyl tolerance in the treatment of cancer pain: a case of successful opioid switching from fentanyl to oxycodone at a reduced equivalent dose.

    PubMed

    Sutou, Ichiro; Nakatani, Toshihiko; Hashimoto, Tatsuya; Saito, Yoji

    2015-06-01

    Opioids are not generally deemed to have an analgesic ceiling effect on cancer pain. However, there have been occasional reports of tolerance to opioid development induced by multiple doses of fentanyl. The authors report a case of suspected tolerance to the analgesic effect of opioid, in which an increasing dose of fentanyl failed to relieve the patient's cancer pain symptoms, but opioid switching to oxycodone injections enabled a dose reduction to below the equivalent dose conversion ratio. The patient was a 60-year-old man diagnosed with pancreatic body carcinoma with multiple metastases. The base dose consisted of 12 mg/day of transdermal fentanyl patches (equivalent to 3.6 mg/day, 150 μg/h fentanyl injection), and rescue therapy consisted of 10 mg immediate-release oxycodone powders. Despite the total daily dose of fentanyl reaching 5.6 mg (equivalent to 560 mg oral morphine), the analgesic effect was inadequate; thus, an urgent adjustment was necessary. Due to the moderate dose of fentanyl, the switch to oxycodone injection was done incrementally at a daily dose equivalent to 25% of the fentanyl injection. The total dose of oxycodone was replaced approximately 53.5% of the dose of fentanyl prior to opioid switching.

  2. Differential cross-tolerance to opioid agonists in morphine-tolerant pigeons responding under a schedule of food presentation.

    PubMed

    Craft, R M; Picker, M J; Dykstra, L A

    1989-05-01

    Effects of the opioid agonists morphine, l-methadone, ethylketazocine, U50,488 [trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzeneacetamide methanesulfonate hydrate], cyclazocine and bremazocine, and the nonopioid chlorpromazine were determined in pigeons responding under a fixed-ratio 30 schedule of food presentation before, during and after chronic morphine administration. Before chronic morphine administration, all drugs produced dose-dependent decreases in response rates. After daily administration of up to 56 mg/kg of morphine for 7 weeks, dose-effect curves for the mu agonists morphine and l-methadone, as well as the mu/kappa agonist ethylketazocine shifted to the right approximately 1 1/4, 3/4 and 1/2 log units, respectively. In contrast, dose-effect curves for the mixed agonist/antagonists cyclazocine and bremazocine each shifted to the left approximately 3/4 log unit, whereas dose-effect curves for the kappa agonist U50,488 and the nonopioid chlorpromazine did not shift during chronic morphine administration. Dose-effect curves for all drugs except bremazocine returned to their prechronic positions within the period 3 to 8 weeks after termination of chronic morphine administration. The present study demonstrates that repeated administration of morphine produces tolerance to its rate-decreasing effects as well as cross-tolerance selective to other opioids possessing mu agonist properties. The cross-tolerance to ethylketazocine observed in morphine-tolerant pigeons corroborates studies of the discriminative stimulus effects of ethylketazocine in pigeons, suggesting that in this species ethylketazocine possesses predominantly mu agonist properties.

  3. Autoradiographic mapping of mu-opioid receptors during opiate tolerance and supersensitivity in the rat central nervous system.

    PubMed

    Díaz, A; Pazos, A; Flórez, J; Hurlé, M A

    2000-08-01

    In this autoradiographic study we have analysed the regional changes in the density of mu-opioid receptors produced by the chronic administration of sufentanil alone and after concurrent administration with nimodipine. mu-Opioid receptors in the central nervous system (CNS) of rats were labelled using 5 nM [3H]DAMGO. Sufentanil, a high-efficacy agonist, was administered for 7 days by chronic infusion (2 microg/h). Another group of animals received a simultaneous infusion of sufentanil (2 microg/h) and nimodipine (1 microg/h) for 7 days. These two drug regimes have been previously shown to induce tolerance and supersensitivity to the analgesic effect of the opioid, respectively. Our results clearly demonstrate that opioid tolerance is associated with a generalised down-regulation of mu-opioid binding sites throughout the brain and the spinal cord. Compared with the findings in tolerant animals, the CNS of animals supersensitive to sufentanil showed less down-regulation of mu-opioid receptors, to the extent that, particularly in brain areas related to nociception, such as the somatosensory cortex, central grey, raphe magnus nucleus and dorsal horn of the spinal cord, no down-regulation occurred. These neurochemical findings may contribute to the functional interaction between nimodipine and sufentanil that we have previously observed in analgesic studies.

  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.

  5. Fentanyl sublingual: in breakthrough pain in opioid-tolerant adults with cancer.

    PubMed

    Chwieduk, Claudine M; McKeage, Kate

    2010-12-03

    Fentanyl is a potent opioid with a short duration of action. Fentanyl sublingual has been formulated as a rapidly disintegrating tablet that is quickly absorbed, producing a fast onset of analgesia. In two randomized, double-blind clinical trials, fentanyl sublingual as single fixed or titrated doses reduced pain intensity during breakthrough pain episodes to a significantly greater extent than placebo in opioid-tolerant cancer patients. In a fixed-dose phase II trial and a titrated-dose phase III trial, fentanyl sublingual (as a single 400 μg dose and as titrated doses) reduced mean pain intensity difference (PID) to a significantly greater extent than placebo over the entire treatment period (up to 60 minutes), reaching statistical significance 15 minutes post-dose. In the titrated-dose study, the mean sum of PID (area under the PID vs time curve) at 30 minutes post-dose was significantly greater with fentanyl sublingual than placebo, with significant improvements in PID seen at 10 minutes maintained at 60 minutes post-dose. In the phase III study, patients receiving fentanyl sublingual were more satisfied with their treatment than patients receiving placebo (measured using the Patient Global Evaluation of Medication score), and almost half of all fentanyl sublingual recipients were satisfied or very satisfied with their treatment. Fentanyl sublingual was generally well tolerated in the two trials and most adverse events were mild to moderate in intensity.

  6. Opioid analgesia in mechanically ventilated children: results from the multicenter Measuring Opioid Tolerance Induced by Fentanyl study.

    PubMed

    Anand, Kanwaljeet J S; Clark, Amy E; Willson, Douglas F; Berger, John; Meert, Kathleen L; Zimmerman, Jerry J; Harrison, Rick; Carcillo, Joseph A; Newth, Christopher J L; Bisping, Stephanie; Holubkov, Richard; Dean, J Michael; Nicholson, Carol E

    2013-01-01

    To examine the clinical factors associated with increased opioid dose among mechanically ventilated children in the pediatric intensive care unit. Prospective, observational study with 100% accrual of eligible patients. Seven pediatric intensive care units from tertiary-care children's hospitals in the Collaborative Pediatric Critical Care Research Network. Four hundred nineteen children treated with morphine or fentanyl infusions. None. Data on opioid use, concomitant therapy, demographic and explanatory variables were collected. Significant variability occurred in clinical practices, with up to 100-fold differences in baseline opioid doses, average daily or total doses, or peak infusion rates. Opioid exposure for 7 or 14 days required doubling of the daily opioid dose in 16% patients (95% confidence interval 12%-19%) and 20% patients (95% confidence interval 16%-24%), respectively. Among patients receiving opioids for longer than 3 days (n = 225), this occurred in 28% (95% confidence interval 22%-33%) and 35% (95% confidence interval 29%-41%) by 7 or 14 days, respectively. Doubling of the opioid dose was more likely to occur following opioid infusions for 7 days or longer (odds ratio 7.9, 95% confidence interval 4.3-14.3; p < 0.001) or co-therapy with midazolam (odds ratio 5.6, 95% confidence interval 2.4-12.9; p < 0.001), and it was less likely to occur if morphine was used as the primary opioid (vs. fentanyl) (odds ratio 0.48, 95% confidence interval 0.25-0.92; p = 0.03), for patients receiving higher initial doses (odds ratio 0.96, 95% confidence interval 0.95-0.98; p < 0.001), or if patients had prior pediatric intensive care unit admissions (odds ratio 0.37, 95% confidence interval 0.15-0.89; p = 0.03). Mechanically ventilated children require increasing opioid doses, often associated with prolonged opioid exposure or the need for additional sedation. Efforts to reduce prolonged opioid exposure and clinical practice variation may prevent the complications of

  7. Effect of Tamoxifen and Brain-Penetrant Protein Kinase C and c-Jun N-Terminal Kinase Inhibitors on Tolerance to Opioid-Induced Respiratory Depression in Mice.

    PubMed

    Withey, Sarah L; Hill, Rob; Lyndon, Abigail; Dewey, William L; Kelly, Eamonn; Henderson, Graeme

    2017-04-01

    Respiratory depression is the major cause of death in opioid overdose. We have previously shown that prolonged treatment of mice with morphine induces profound tolerance to the respiratory-depressant effects of the drug (Hill et al., 2016). The aim of the present study was to investigate whether tolerance to opioid-induced respiratory depression is mediated by protein kinase C (PKC) and/or c-Jun N-terminal kinase (JNK). We found that although mice treated for up to 6 days with morphine developed tolerance, as measured by the reduced responsiveness to an acute challenge dose of morphine, administration of the brain-penetrant PKC inhibitors tamoxifen and calphostin C restored the ability of acute morphine to produce respiratory depression in morphine-treated mice. Importantly, reversal of opioid tolerance was dependent on the nature of the opioid ligand used to induce tolerance, as these PKC inhibitors did not reverse tolerance induced by prolonged treatment of mice with methadone nor did they reverse the protection to acute morphine-induced respiratory depression afforded by prolonged treatment with buprenorphine. We found no evidence for the involvement of JNK in morphine-induced tolerance to respiratory depression. These results indicate that PKC represents a major mechanism underlying morphine tolerance, that the mechanism of opioid tolerance to respiratory depression is ligand-dependent, and that coadministration of drugs with PKC-inhibitory activity and morphine (as well as heroin, largely metabolized to morphine in the body) may render individuals more susceptible to overdose death by reversing tolerance to the effects of morphine.

  8. Behavioral Consequences of Delta-Opioid Receptor Activation in the Periaqueductal Gray of Morphine Tolerant Rats

    PubMed Central

    Morgan, Michael M.; Ashley, Michelle D.; Ingram, Susan L.; Christie, MacDonald J.

    2009-01-01

    Chronic morphine administration shifts delta-opioid receptors (DORs) from the cytoplasm to the plasma membrane. Given that microinjection of morphine into the PAG produces antinociception, it is hypothesized that the movement of DORs to the membrane will allow antinociception to the DOR agonist deltorphin II as a way to compensate for morphine tolerance. Tolerance was induced by twice daily injections of morphine (5, 10, or 20 mg/kg, subcutaneous) for 3.5 days. Microinjection of deltorphin into the vPAG 6 hours after the last morphine injection produced a mild antinociception that did not vary in a consistent manner across morphine pretreatment doses or nociceptive tests. In contrast, deltorphin caused a decrease in activity in morphine tolerant rats that was associated with lying in the cage. The decrease in activity and change in behavior indicate that chronic morphine administration alters DORs in the vPAG. However, activation of these receptors does not appear to compensate for the decrease in antinociception caused by morphine tolerance. PMID:19266049

  9. Efficacy, Tolerability, and Dose-Dependent Effects of Opioid Analgesics for Low Back Pain: A Systematic Review and Meta-analysis.

    PubMed

    Abdel Shaheed, Christina; Maher, Chris G; Williams, Kylie A; Day, Richard; McLachlan, Andrew J

    2016-07-01

    Opioid analgesics are commonly used for low back pain, however, to our knowledge there has been no systematic evaluation of the effect of opioid dose and use of enrichment study design on estimates of treatment effect. To evaluate efficacy and tolerability of opioids in the management of back pain; and investigate the effect of opioid dose and use of an enrichment study design on treatment effect. Medline, EMBASE, CENTRAL, CINAHL, and PsycINFO (inception to September 2015) with citation tracking from eligible randomized clinical trials (RCTs). Placebo-controlled RCTs in any language. Two authors independently extracted data and assessed risk of bias. Data were pooled using a random effects model with strength of evidence assessed using the grading of recommendations assessment, development, and evaluation (GRADE). The primary outcome measure was pain. Pain and disability outcomes were converted to a common 0 to 100 scale, with effects greater than 20 points considered clinically important. Of 20 included RCTs of opioid analgesics (with a total of 7925 participants), 13 trials (3419 participants) evaluated short-term effects on chronic low back pain, and no placebo-controlled trials enrolled patients with acute low back pain. In half of these 13 trials, at least 50% of participants withdrew owing to adverse events or lack of efficacy. There was moderate-quality evidence that opioid analgesics reduce pain in the short term; mean difference (MD), -10.1 (95% CI, -12.8 to -7.4). Meta-regression revealed a 12.0 point greater pain relief for every 1 log unit increase in morphine equivalent dose (P = .046). Clinically important pain relief was not observed within the dose range evaluated (40.0-240.0-mg morphine equivalents per day). There was no significant effect of enrichment study design. For people with chronic low back pain who tolerate the medicine, opioid analgesics provide modest short-term pain relief but the effect is not likely to be clinically important

  10. Opioid metabolism.

    PubMed

    Smith, Howard S

    2009-07-01

    Clinicians understand that individual patients differ in their response to specific opioid analgesics and that patients may require trials of several opioids before finding an agent that provides effective analgesia with acceptable tolerability. Reasons for this variability include factors that are not clearly understood, such as allelic variants that dictate the complement of opioid receptors and subtle differences in the receptor-binding profiles of opioids. However, altered opioid metabolism may also influence response in terms of efficacy and tolerability, and several factors contributing to this metabolic variability have been identified. For example, the risk of drug interactions with an opioid is determined largely by which enzyme systems metabolize the opioid. The rate and pathways of opioid metabolism may also be influenced by genetic factors, race, and medical conditions (most notably liver or kidney disease). This review describes the basics of opioid metabolism as well as the factors influencing it and provides recommendations for addressing metabolic issues that may compromise effective pain management. Articles cited in this review were identified via a search of MEDLINE, EMBASE, and PubMed. Articles selected for inclusion discussed general physiologic aspects of opioid metabolism, metabolic characteristics of specific opioids, patient-specific factors influencing drug metabolism, drug interactions, and adverse events.

  11. Opioid Metabolism

    PubMed Central

    Smith, Howard S.

    2009-01-01

    Clinicians understand that individual patients differ in their response to specific opioid analgesics and that patients may require trials of several opioids before finding an agent that provides effective analgesia with acceptable tolerability. Reasons for this variability include factors that are not clearly understood, such as allelic variants that dictate the complement of opioid receptors and subtle differences in the receptor-binding profiles of opioids. However, altered opioid metabolism may also influence response in terms of efficacy and tolerability, and several factors contributing to this metabolic variability have been identified. For example, the risk of drug interactions with an opioid is determined largely by which enzyme systems metabolize the opioid. The rate and pathways of opioid metabolism may also be influenced by genetic factors, race, and medical conditions (most notably liver or kidney disease). This review describes the basics of opioid metabolism as well as the factors influencing it and provides recommendations for addressing metabolic issues that may compromise effective pain management. Articles cited in this review were identified via a search of MEDLINE, EMBASE, and PubMed. Articles selected for inclusion discussed general physiologic aspects of opioid metabolism, metabolic characteristics of specific opioids, patient-specific factors influencing drug metabolism, drug interactions, and adverse events. PMID:19567715

  12. Opioid receptor heteromers in analgesia

    PubMed Central

    Costantino, Cristina M.; Gomes, Ivone; Stockton, Steven D.; Lim, Maribel P.; Devi, Lakshmi A.

    2013-01-01

    Opiates such as morphine and fentanyl, a major class of analgesics used in the clinical management of pain, exert their effects through the activation of opioid receptors. Opioids are among the most commonly prescribed and frequently abused drugs in the USA; however, the prolonged use of opiates often leads to the development of tolerance and addiction. Although blockade of opioid receptors with antagonists such as naltrexone and naloxone can lessen addictive impulses and facilitate recovery from overdose, systemic disruption of endogenous opioid receptor signalling through the use of these antagonistic drugs can have severe side effects. In the light of these challenges, current efforts have focused on identifying new therapeutic targets that selectively and specifically modulate opioid receptor signalling and function so as to achieve analgesia without the adverse effects associated with chronic opiate use. We have previously reported that opioid receptors interact with each other to form heteromeric complexes and that these interactions affect morphine signalling. Since chronic morphine administration leads to an enhanced level of these heteromers, these opioid receptor heteromeric complexes represent novel therapeutic targets for the treatment of pain and opiate addiction. In this review, we discuss the role of heteromeric opioid receptor complexes with a focus on mu opioid receptor (MOR) and delta opioid receptor (DOR) heteromers. We also highlight the evidence for altered pharmacological properties of opioid ligands and changes in ligand function resulting from the heteromer formation. PMID:22490239

  13. Development of opioid formulations with limited diversion and abuse potential.

    PubMed

    Fudala, Paul J; Johnson, Rolley E

    2006-06-01

    Non-medical abuse of prescription opioid medications is not a new phenomenon, but such use has been increasing in recent years. Various methods have been used and continue to be developed in an effort to limit diversion and abuse of opioid medications. A number of these methods will be described for opioid analgesic and addiction treatment formulations using relevant historical examples (e.g. propoxyphene, pentazocine, buprenorphine) as well as examples of formulations currently being considered or under development (e.g. oxycodone plus naltrexone, sustained-release buprenorphine). The focus, though not exclusively, will be on those formulations that represent a combination of an opioid agonist with an antagonist. These methods must take into consideration the pharmacokinetic profile of the agonist and antagonist, the expected primary route of abuse of the medication and the medication combination, the dose of medication that is likely to be abused, the availability of alternative drugs of abuse, and the population of potential abusers that is being targeted with the revised formulation.

  14. Opioid receptor types in the brain of the Afghan pika (Ochotona rufescens), a species which is naturally tolerant to morphine.

    PubMed

    Farges, R C; Puget, A; Moisand, C; Meunier, J C

    1988-01-01

    The rabbit is normally sensitive to morphine while another lagomorph, the Afghan pika Ochotona rufescens is naturally tolerant to the analgesic effects elicited by the opium alkaloid. In spite of the different responsiveness of the two species to morphine we find that the pika brain and the rabbit brain both contain a mixture of mu-, delta- and kappa-opioid sites in nearly the same proportions: 46-47% mu, 23% delta and 28-30% kappa. Moreover, apparent binding of morphine in pika and rabbit brain membranes is inhibited in the presence of Na+ ions and/or of 5-guanylylimidodiphosphate indicating that morphine should behave as an opiate agonist (analgesic) not only in rabbits, which it does but also in pikas, which it does not. Taken together these results suggest that the natural tolerance of the Afghan pika to morphine may not reside in modified opioid receptor types and that its origin should be sought elsewhere.

  15. 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. Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

  16. Opioid analgesics stop the development of clostridial gas gangrene.

    PubMed

    Chakravorty, Anjana; Awad, Milena M; Hiscox, Thomas J; Cheung, Jackie K; Choo, Jocelyn M; Lyras, Dena; Rood, Julian I

    2014-08-01

    Gas gangrene is a potentially fatal disease that is primarily caused by the ubiquitous, anaerobic bacteria Clostridium perfringens and Clostridium septicum. Treatment is limited to antibiotic therapy, debridement of the infected tissue, and, in severe cases, amputation. The need for new treatment approaches is compelling. Opioid-based analgesics such as buprenorphine and morphine also have immunomodulatory properties, usually leading to faster disease progression. However, here we show that mice pretreated with buprenorphine and morphine do not die from clostridial myonecrosis. Treatment with buprenorphine after the onset of infection also arrested disease development. Protection against myonecrotic disease was specific to C. perfringens-mediated myonecrosis; buprenorphine did not protect against disease caused by C. septicum infection even though infections due to both species are very similar. These data provide the first evidence of a protective role for opioids during infection and suggest that new therapeutic strategies may be possible for the treatment of C. perfringens-mediated myonecrosis.

  17. 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

  18. Biomarkers of morphine tolerance and dependence are prevented by morphine-induced endocytosis of a mutant μ-opioid receptor

    PubMed Central

    He, Li; Kim, Joseph A.; Whistler, Jennifer L.

    2009-01-01

    Growing evidence shows that trafficking of the μ-opioid receptor (MOR) is a critical process in functional recovery from desensitization following activation and plays important roles in morphine tolerance and dependence largely because of the failure of morphine to promote such trafficking. However, morphine tolerance and dependence are believed to be mediated by multiple mechanisms, including well-documented biochemical changes in cAMP activity, N-methyl-d-aspartate receptors (NMDARs), glucocorticoid receptors (GRs), and c-fos. Here, we assess the consequences of promoting morphine-induced endocytosis on these biochemical changes utilizing a knock-in mouse model, RMOR, in which MORs undergo morphine-induced endocytosis. Chronic morphine treatment of wild-type (WT) mice promoted superactivation of adenylyl cyclase, alterations in NMDARs, and up-regulation of GR and c-fos in distinct brain regions. Notably, none of these biochemical changes occurred in the RMOR-knock-in mice. Together, these data demonstrate that morphine tolerance and dependence are mediated by multiple biochemical mechanisms and that MOR endocytosis plays a critical role in each of these mechanisms.—He, L., Kim, J. A., Whistler, J. L. Biomarkers of morphine tolerance and dependence are prevented by morphine-induced endocytosis of a mutant μ-opioid receptor. PMID:19679639

  19. 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 th

  20. 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.

  1. 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

  2. Recent advances in the development of 14-alkoxy substituted morphinans as potent and safer opioid analgesics.

    PubMed

    Spetea, M; Schmidhammer, H

    2012-01-01

    Morphine and other opioid morphinans produce analgesia primarily through μ opioid receptors (MORs), which mediate beneficial but also non-beneficial actions. There is a continued search for efficacious opioid analgesics with reduced complications. The cornerstone in the development of 14-alkoxymorphinans as novel analgesic drugs was the synthesis of the highly potent MOR agonist 14-O-methyloxymorphone. This opioid showed high antinociceptive potency but also the adverse effects associated with morphine type compounds. Further developments represent the introduction of a methyl and benzyl group at position 5 of 14-O-methyloxymorphone leading to the strong opioid analgesics 14-methoxymetopon and its 5-benzyl analogue, which exhibited less pronounced side effects than morphine although interacting selectively with MORs. Introduction of arylalkyl substituents such as phenylpropoxy in position 14 led to a series of extremely potent antinociceptive agents with enhanced affinities at all three opioid receptor types. During the past years, medicinal chemistry and opioid research focused increasingly on exploring the therapeutic potential of peripheral opioid receptors by peripheralization of opioids in order to minimize the occurrence of centrally-mediated side effects. Strategies to reduce penetration to the central nervous system (CNS) include chemical modifications that increase hydrophilicity. Zwitterionic 6-amino acid conjugates of 14-Oalkyloxymorphones were developed in an effort to obtain opioid agonists that have limited access to the CNS. These compounds show high antinociceptive potency by interacting with peripheral MORs. Opioid drugs with peripheral site of action represent an important target for the treatment of severe and chronic pain without the adverse actions of centrally acting opioids.

  3. 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.

  4. 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

  5. Long-term safety of fentanyl sublingual spray in opioid-tolerant patients with breakthrough cancer pain.

    PubMed

    Minkowitz, Harold; Bull, Janet; Brownlow, R Charles; Parikh, Neha; Rauck, Richard

    2016-06-01

    The current study assessed the long-term safety of fentanyl sublingual spray for managing breakthrough cancer pain (BTCP). This open-label, multicenter study enrolled both de novo and rollover patients who completed a double-blind, efficacy trial. Eligible patients were ≥18 years of age and experiencing pain that was being managed with an around-the-clock opioid yet were experiencing ≤4 BTCP episodes daily and were opioid-tolerant (i.e., receiving ≥60 mg/day oral morphine or an equivalent dose of another opioid for ≥1 week). De novo patients initially entered a 21-day titration period to identify an effective dose of fentanyl sublingual spray (100-1600 μg), then entered a 90-day maintenance period. The incidence of adverse events (AEs), results of laboratory tests, vital sign assessments, and treatment satisfaction were assessed. Of the 269 patients (de novo, 179; rollover, 90) who entered the maintenance period, 163 (60.6 %) completed the study; the primary reason for discontinuation was an AE (22.3 %). Eighty percent of patients identified an effective dose of fentanyl sublingual spray (median dose, 600 μg). The most common AEs differed from the titration period (nausea (13 %), vomiting (12 %), and somnolence (10 %)) to the maintenance period (malignant neoplasm progression (24 %), vomiting (16 %), and peripheral edema (12 %)). Few changes in laboratory parameters and vital sign assessments were observed. Patients generally reported being more satisfied with fentanyl sublingual spray than with their previous BTCP treatment. This long-term maintenance study demonstrated that fentanyl sublingual spray was generally safe and well tolerated for managing BTCP over a 90-day period.

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

    PubMed

    Raehal, Kirsten M; Bohn, Laura M

    2011-01-01

    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. Copyright © 2010 Elsevier Ltd. All rights reserved.

  7. 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

  8. Re-energizing the Development of Pain Therapeutics in Light of the Opioid Epidemic.

    PubMed

    Skolnick, Phil; Volkow, Nora D

    2016-10-19

    Limited options for treating moderate-severe pain led to an overreliance on opioids and the current opioid epidemic. Addressing the factors contributing to a dearth of effective alternatives and re-energizing the development of pain therapeutics is necessary to quell this epidemic.

  9. Opioid receptor approaches for the development of medications for pregnant women.

    PubMed

    Szeto, H H

    1995-01-01

    It is proposed that receptor selectivity may be used as a rational approach in the design and development of new opioid agents for use in pregnant women. While minimizing placental drug transfer will only reduce the direct effects of opioid drugs on the fetus, the use of selective opioid drugs may, in addition, reduce the indirect effects of opioids secondary to alterations in maternal and placental physiology. By taking advantage of the differential ontogeny of the different receptor subtypes, it may even be able to prevent significant drug effects on the fetus despite considerable placental transfer. The combined use of maternal-fetal pharmacokinetics and receptor selectivity may lead to the development of superior opioid drugs with minimal adverse effects on the mother and fetus. Finally, the approaches proposed here may be suitable for the development of other agents that may be useful in the treatment of pregnant addicts and their infants.

  10. 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

  11. [Dmt(1)]DALDA is highly selective and potent at mu opioid receptors, but is not cross-tolerant with systemic morphine.

    PubMed

    Riba, Pal; Ben, Yong; Nguyen, Thi M-D; Furst, Susanna; Schiller, Peter W; Lee, Nancy M

    2002-01-01

    The clinical effectiveness of morphine is limited by several side effects, including the development of tolerance and dependence. Most of these side effects are believed to be mediated by central opioid receptors; therefore, hydrophilic opioids, which don't cross the blood-brain barrier, may have advantages over morphine in some clinical applications. We recently synthesized several analogues of DALDA (Tyr-D-Arg-Phe-Lys-NH2), a highly hydrophilic peptide derived from the endogenous opioid peptide dermorphin; all of them, particularly [Dmt(1)] DALDA (Dmt - 2',6'-dimethyl tyrosine), had high potency and selectivity at mu receptors, the target of morphine, in activity assays. Here we report the pharmacological characterization of [Dmt(1)] DALDA in the whole animal. [Dmt(1)]DALDA was 40 times more potent than morphine in inducing antinociception in mice when both drugs were given s.c., and 6-14 times more potent than DAMGO, a selective m agonist, when both drugs were given it. However, [Dmt(1)]DALDA showed poor cross-tolerance to morphine; thus chronic morphine treatment of animals increased the antinociceptive AD(50) of systemic [Dmt(1)]DALDA two fold or less, as compared to an 8-9-fold increase for morphine and a 4-5-fold increase for DAMGO. The antinociceptive activity of [Dmt(1)]DALDA (i.t) was blocked by CTAP, a selective mu antagonist, but not by TIPP psi, a selective delta antagonist, nor by nor-BNI, a selective kappa antagonist. [Dmt(1)]DALDA-induced antinociception was also blocked by naloxone methiodide, an antagonist that does not cross the blood-brain barrier, when agonist and antagonist were given i.t. or i.c.v., but not when they were given s.c. We conclude that [Dmt(1)] DALDA is a highly potent analgesic acting at mu receptors. Though it appears to penetrate the blood-brain barrier, it exhibits low cross-tolerance to morphine, suggesting that it may have advantages over the latter in certain clinical applications.

  12. Change in functional selectivity of morphine with the development of antinociceptive tolerance

    PubMed Central

    Macey, T A; Bobeck, E N; Suchland, K L; Morgan, M M; Ingram, S L

    2015-01-01

    BACKGROUND AND PURPOSE Opioids, such as morphine, are the most effective treatment for pain but their efficacy is diminished with the development of tolerance following repeated administration. Recently, we found that morphine activated ERK in opioid-tolerant but not in naïve rats, suggesting that morphine activation of μ-opioid receptors is altered following repeated morphine administration. Here, we have tested the hypothesis that μ-opioid receptor activation of ERK in the ventrolateral periaqueductal gray (vlPAG) is dependent on dynamin, a protein implicated in receptor endocytosis. EXPERIMENTAL APPROACH Rats were made tolerant to repeated microinjections of morphine into the vlPAG. The effects of dynamin on ERK activation and antinociception were assessed by microinjecting myristoylated dominant-negative dynamin peptide (Dyn-DN) or a scrambled control peptide into the vlPAG. Microinjection of a fluorescent dermorphin analogue (DERM-A594) into the vlPAG was used to monitor μ-opioid receptor internalization. KEY RESULTS Morphine did not activate ERK and Dyn-DN administration had no effect on morphine-induced antinociception in saline-pretreated rats. In contrast, morphine-induced ERK activation in morphine-pretreated rats that was blocked by Dyn-DN administration. Dyn-DN also inhibited morphine antinociception. Finally, morphine reduced DERM-A594 internalization only in morphine-tolerant rats indicating that μ-opioid receptors were internalized and unavailable to bind DERM-A594. CONCLUSIONS AND IMPLICATIONS Repeated morphine administration increased μ-opioid receptor activation of ERK signalling via a dynamin-dependent mechanism. These results demonstrate that the balance of agonist signalling to G-protein and dynamin-dependent pathways is altered, effectively changing the functional selectivity of the agonist-receptor complex. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other

  13. Effect of chronic opioid treatment on phagocytosis in Tetrahymena.

    PubMed

    Salaman, A; Roman, M; Renaud, F L; Silva, W I

    1990-07-01

    Opioid inhibition of phagocytosis in the protozoan ciliate Tetrahymena is antagonized by naloxone and this antagonism can be surmounted by increasing agonist concentration, which suggests a receptor-mediated mechanism. Desensitization of the opioid effect is time dependent in addition to concentration dependent. Chronic exposure to opioids results in the development of tolerance to the inhibitory effect of the agonists, and withdrawal of the latter results in a decrease in phagocytic capacity, which suggests that a state akin to dependence has been developed in these cells. Naloxone appears to behave as a partial agonist in tolerant cells, and there seems to exist cross-tolerance to mu and delta agonists.

  14. [Development of physical dependence on nicotine and endogenous opioid system--participation of α7 nicotinic acetylcholine receptor].

    PubMed

    Kishioka, Shiroh; Kiguchi, Norikazu; Kobayashi, Yuka; Saika, Fumihiro; Yamamoto, Chizuko

    2014-10-01

    Nicotine (NIC) regulates various cellular functions acting on the nicotinic acetylcholine receptor (nAChR). And nAChR consists of ligand-gated cation channels with pentameric structure and composed of α and β subunits. In the central nervous system, α 4 β 2 and α 7 nAChRs are the most abundantly expressed as nAChR subtypes. There are several lines of evidence indicating that systemic administration of NIC elicits the release of endogenous opioids, such as, endorphins, enkephalins and dynorphins, in the brain. NIC exerts numerous acute effects, for example, antinociceptive effects and the activating effects of the hypothalamic-pituitary-adrenal (HPA) axis. In these effects, NIC-induced antinociception, but not HPA axis activation, was inhibited by opioid receptor antagonist, naloxone (NLX), and was also suppressed in morphine tolerated mice, indicating the participation of the endogenous opioid system in NIC-induced antinociception, but not HPA axis activation. Moreover, NIC-induced antinociception was antagonized by both α 4 β 2 and α 7 nAChR antagonists, while NIC-induced HPA axis activation was antagonized by α 4 β 2 nAChR antagonist, but not by α 7 nAChR antagonist. These results suggest that the endogenous opioid system may not be located on the downstream of α 4 β 2 nAChR. On the other hand, NIC has substantial physical dependence liability. NLX elicits NIC withdrawal after repeated NIC administration evaluated by corticosterone increase as a withdrawal sign, and NLX-precipitated NIC withdrawal is inhibited by concomitant administration of other opioid receptor antagonist, naltrexone, indicating the participation of endogenous opioid system in the development of physical dependence on NIC. NLX-precipitated NIC withdrawal was also inhibited by concomitant administration of an α 7 nAChR antagonist, but not an α 4 β 2 nAChR antagonist. Taken together, these findings suggest that the endogenous opioid system may be located on the downstream of α 7

  15. Concurrent bullatine A enhances morphine antinociception and inhibits morphine antinociceptive tolerance by indirect activation of spinal κ-opioid receptors.

    PubMed

    Huang, Qian; Sun, Ming-Li; Chen, Yuan; Li, Xin-Yan; Wang, Yong-Xiang

    2017-01-20

    Bullatine A, a C20-diterpenoid alkaloid and one of the major effective ingredients in Aconiti brachypodi Radix (Xue-shang-yi-zhi-hao), can block pain hypersensitivity in a variety of rodent models through expression of spinal microglial dynorphin A. To assess the interaction between bullatine A and morphine on antinociception in acute nociception and pain hypersensitivity states, with the exogenous synthetic dynorphin A as a comparison MATERIALS AND METHODS: Spinal nerve ligation-induced neuropathic rats and naïve mice were used for assessing the acute and chronic interactions of bullatine A/dynorphin A with morphine. Single subcutaneous injection of bullatine A or dynorphin A(1-17) did not either alter formalin- and thermally (hot-plate and water immersion tests)-induced acute nociception or potentiate morphine antinociception in naïve mice. In contrast, bullatine A dose-dependently inhibited formalin-induced tonic pain with the efficacy of 54% inhibition and the half-effective dose of 0.9mg/kg. Concurrent bullatine A additively enhanced morphine antinociception. In neuropathic rats, the antinociceptive effects of multiple bidaily intrathecal injections of bullatine A and dynorphin A remained consistent over 13 days, whereas morphine produced progressive and complete tolerance to antinociception, which was completely inhibited by concurrent bullatine A and dynorphin A. A single intrathecal injection of bullatine A and dynorphin A immediately reversed established morphine tolerance in neuropathic rats, although the blockade was a less degree in the thermally induced mouse acute nociceptive tests. The inhibitory effects of bullatine A and dynorphin A on morphine tolerance were immediately and completely attenuated by intrathecal dynorphin A antibody and/or selective κ-opioid receptor antagonist GNTI. These results suggest that bullatine A produces antinociception without induction of tolerance and inhibits morphine antinociceptive tolerance, and provide

  16. Candidate metrics for evaluating the impact of prescriber education on the safe use of extended-release/long-acting (ER/LA) opioid analgesics.

    PubMed

    Willy, Mary E; Graham, David J; Racoosin, Judith A; Gill, Rajdeep; Kropp, Garner F; Young, Jessica; Yang, Jeff; Choi, Joyce; MaCurdy, Thomas E; Worrall, Chris; Kelman, Jeffrey A

    2014-09-01

    The objective of this study was to develop metrics to assess opioid prescribing behavior as part of the evaluation of the Extended-Release/Long-Acting (ER/LA) Opioid Analgesic Risk Evaluation and Mitigation Strategies (REMS). Candidate metrics were selected using published guidelines, examined using sensitivity analyses, and applied to cross-sectional rolling cohorts of Medicare patients prescribed with extended-release oxycodone (ERO) between July 2, 2006 and July 1, 2011. Potential metrics included prescribing opioid-tolerant-only ER/LA opioid analgesics to non-opioid-tolerant patients, prescribing early fills to patients, and ordering drug screens. Proposed definitions for opioid tolerance were seven continuous days of opioid usage of at least 30 mg oxycodone equivalents, within the 7 days (primary) or 30 days (secondary) prior to first opioid-tolerant-only ERO prescription. Forty-four percent of opioid-tolerant-only ERO episodes met the primary opioid tolerance definition; 56% met the secondary definition. Fills were deemed "early" if a prescription was filled before 70% (primary) or 50% (secondary) of the prior prescription's days' supply was to be consumed. Five percent (primary) and 2% (secondary) of episodes had more than or equal to two early fills during treatment. At least one drug screen was billed in 14% of episodes. Stratified analyses indicated that older patients were less likely to be opioid tolerant at the time of the first opioid-tolerant-only ERO prescription. Investigators propose three metrics to monitor changes in prescribing behaviors for opioid analgesics that might be used to evaluate the ER/LA Opioid Analgesics REMS. Low frequencies of patients, particularly those >85 years, were likely to be opioid tolerant prior to receiving prescriptions for opioid-tolerant-only ERO. Wiley Periodicals, Inc.

  17. 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

  18. 14-Alkoxy- and 14-acyloxypyridomorphinans: μ agonist/δ antagonist opioid analgesics with diminished tolerance and dependence side effects.

    PubMed

    Ananthan, Subramaniam; Saini, Surendra K; Dersch, Christina M; Xu, Heng; McGlinchey, Nicholas; Giuvelis, Denise; Bilsky, Edward J; Rothman, Richard B

    2012-10-11

    In the search for opioid ligands with mixed functional activity, a series of 5'-(4-chlorophenyl)-4,5α-epoxypyridomorphinans possessing alkoxy or acyloxy groups at C-14 was synthesized and evaluated. In this series, the affinity and functional activity of the ligands were found to be influenced by the nature of the substituent at C-14 as well as by the substituent at N-17. Whereas the incorporation of a 3-phenylpropoxy group at C-14 on N-methylpyridomorhinan gave a dual MOR agonist/DOR agonist 17h, its incorporation on N-cyclopropylmethylpyridomorphinan gave a MOR agonist/DOR antagonist 17d. Interestingly, 17d, in contrast to 17h, did not produce tolerance or dependence effects upon prolonged treatment in cells expressing MOR and DOR. Moreover, 17d displayed greatly diminished analgesic tolerance as compared to morphine upon repeated administration, thus supporting the hypothesis that ligands with MOR agonist/DOR antagonist functional activity could emerge as novel analgesics devoid of tolerance, dependence, and related side effects.

  19. 14-Alkoxy- and 14-Acyloxypyridomorphinans: Mu Agonist/Delta Antagonist Opioid Analgesics with Diminished Tolerance and Dependence Side Effects

    PubMed Central

    Ananthan, Subramaniam; Saini, Surendra K.; Dersch, Christina M.; Xu, Heng; McGlinchey, Nicholas; Giuvelis, Denise; Bilsky, Edward J.; Rothman, Richard B.

    2012-01-01

    In the search for opioid ligands with mixed functional activity, a series of 5′-(4-chlorophenyl)-4,5α-epoxypyridomorphinans possessing alkoxy or acyloxy groups at C-14 was synthesized and evaluated. In this series, the affinity and functional activity of the ligands were found to be influenced by the nature of the substituent at C-14 as well as by the substituent at N-17. Whereas the incorporation of a 3-phenylpropoxy group at C-14 on N-methylpyridomorhinan gave a dual MOR agonist/DOR agonist 17h its incorporation on N-cyclopropylmethylpyridomorphinan gave a MOR agonist/DOR antagonist 17d. Interestingly, 17d, in contrast to 17h, did not produce tolerance or dependence effects on prolonged treatment in cells expressing MOR and DOR. Moreover, 17d displayed greatly diminished analgesic tolerance as compared to morphine on repeated administration, thus supporting the hypothesis that ligands with MOR agonist/DOR antagonist functional activity could emerge as novel analgesics devoid of tolerance, dependence and related side effects. PMID:23016952

  20. 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

  1. Effectiveness and gastrointestinal tolerability during conversion and titration with once-daily OROS® hydromorphone extended release in opioid-tolerant patients with chronic low back pain

    PubMed Central

    Hale, Martin E; Nalamachu, Srinivas R; Khan, Arif; Kutch, Michael

    2013-01-01

    Purpose To describe the efficacy and safety of hydromorphone extended-release tablets (OROS hydromorphone ER) during dose conversion and titration. Patients and methods A total of 459 opioid-tolerant adults with chronic moderate to severe low back pain participated in an open-label, 2- to 4-week conversion/titration phase of a double-blind, placebo-controlled, randomized withdrawal trial, conducted at 70 centers in the United States. Patients were converted to once-daily OROS hydromorphone ER at 75% of the equianalgesic dose of their prior total daily opioid dose (5:1 conversion ratio), and titrated as frequently as every 3 days to a maximum dose of 64 mg/day. The primary outcome measure was change in pain intensity numeric rating scale; additional assessments included the Patient Global Assessment and the Roland–Morris Disability Questionnaire scores. Safety assessments were performed at each visit and consisted of recording and monitoring all adverse events (AEs) and serious AEs. Results Mean (standard deviation) final daily dose of OROS hydromorphone ER was 37.5 (17.8) mg. Mean (standard error of the mean [SEM]) numeric rating scale scores decreased from 6.6 (0.1) at screening to 4.3 (0.1) at the final titration visit (mean [SEM] change, −2.3 [0.1], representing a 34.8% reduction). Mean (SEM) change in Patient Global Assessment was −0.6 (0.1), and mean change (SEM) in the Roland–Morris Disability Questionnaire was −2.8 (0.3). Patients achieving a stable dose showed greater improvement than patients who discontinued during titration for each of these measures (P < 0.001). Almost 80% of patients achieving a stable dose (213/268) had a ≥30% reduction in pain. Commonly reported AEs were constipation (15.4%), nausea (11.9%), somnolence (8.7%), headache (7.8%), and vomiting (6.5%); 13.0% discontinued from the study due to AEs. Conclusion The majority of opioid-tolerant patients with chronic low back pain were successfully converted to effective doses of

  2. New opioids.

    PubMed

    Mercadante, Sebastiano; Porzio, Giampiero; Gebbia, Vittorio

    2014-06-01

    Despite the skilled use of opioid analgesics, which is crucial to the relief of cancer pain, there is a lack of evidence to support many aspects of current clinical practice. Therefore, there is a significant need for more effective treatment options. New opioids have been marketed in the past years, including hydrocodone and oxymorphone. Moreover, mixed opioids with combined mechanisms of action have been developed; one such agent, tapentadol, is a centrally acting oral analgesic that possesses a combined mechanism of action: μ-opioid receptor activation with norepinephrine reuptake inhibition. Drug development strategies involving naloxone have been initiated to reduce peripheral opioid-related adverse effects. The rationale is based on the local antagonist activity of naloxone in intestinal opioid receptors and the negligible oral bioavailability of naloxone, particularly in a prolonged-release formulation. New delivery systems have been developed to provide rapid analgesia with potent opioid drugs such as fentanyl. Despite the upcoming availability of these new drugs and technologies that will add to existing types of opioid medication, their benefits and liabilities will ultimately need to be determined by the individual physician and individual patient experiencing pain.

  3. Endomorphins: potential roles and therapeutic indications in the development of opioid peptide analgesic drugs.

    PubMed

    Liu, Wei X; Wang, Rui

    2012-05-01

    The application of endomorphins as clinical available analgesic drugs has been impeded by their relatively poor receptor selectivity compared with alkaloid analgesics, rapid degradation in vivo, inefficient to penetrate the blood-brain barrier (BBB), and undesirable or toxic effects, such as acute tolerance and physical dependence, respiratory depression, and inhibition of gastrointestinal motility. Extensive studies have been performed so far striving to conquer these problems. In this article we review and discuss conformational and topographical modifications of the peptide amide bond and amino acid side groups to attain the most appropriate receptor binding affinity and high receptor selectivity; diverse strategies such as insertion of unnatural amino acids, covalent or noncovalent constraints as well as cyclization of linear peptides to enhance the enzymatic stability; designing of peptidomimetic ligands, glycopeptides, and N-terminal amidinationed analogues (such as incorporating guanidine into endomorphins) to penetrate the BBB. Also, several pertinent examples of bivalent and/or multivalent (such as mixed µ-agonist/δ-antagonist profile) compounds are discussed based on the existing literature and current data intending to give an insight into the development of opioid peptides expressing low tendency to produce acute tolerance and physical dependence.

  4. Facts about Buprenorphine for Treatment of Opioid Addiction

    MedlinePlus

    ... doctor’s care. Tolerance and dependence also are side effects from misuse of opioids. Addiction is not likely to develop in a person ... away. Also seek help if the following side effects appear, because they may indicate serious liver ... of treatment for opioid addiction. For many people, another important part is counseling : ...

  5. 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.…

  6. 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. © 2016, The American College of Clinical Pharmacology.

  7. Bivalent ligands that target μ opioid (MOP) and cannabinoid1 (CB1) receptors are potent analgesics devoid of tolerance.

    PubMed

    Le Naour, Morgan; Akgün, Eyup; Yekkirala, Ajay; Lunzer, Mary M; Powers, Mike D; Kalyuzhny, Alexander E; Portoghese, Philip S

    2013-07-11

    Given that μ opioid (MOP) and canabinoid (CB1) receptors are colocalized in various regions of the central nervous system and have been reported to associate as heteromer (MOP-CB1) in cultured cells, the possibility of functional, endogenous MOP-CB1 in nociception and other pharmacologic effects has been raised. As a first step in investigating this possibility, we have synthesized a series of bivalent ligands 1-5 that contain both μ agonist and CB1 antagonist pharmacophores for use as tools to study the functional interaction between MOP and CB1 receptors in vivo. Immunofluorescent studies on HEK293 cells coexpressing both receptors suggested 5 (20-atom spacer) to be the only member of the series that bridges the protomers of the heteromer. Antinociceptive testing in mice revealed 5 to be the most potent member of the series. As neither a mixture of monovalent ligands 9 + 10 nor bivalents 2-5 produced tolerance in mice, MOR-CB1 apparently is not an important target for reducing tolerance.

  8. 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

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

    PubMed

    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. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. © 2014 The British Pharmacological Society.

  10. Development of dependence following treatment with opioid analgesics for pain relief: a systematic review.

    PubMed

    Minozzi, Silvia; Amato, Laura; Davoli, Marina

    2013-04-01

    To assess the incidence or prevalence of opioid dependence syndrome in adults (with and without previous history of substance abuse) following treatment with opioid analgesics for pain relief. Medline, Embase, CINHAL and the Cochrane Library were searched up to January 2011. Systematic reviews and primary studies were included if they reported data about incidence or prevalence of opioid dependence syndrome (as defined by DSM-IV or ICD-10) in patients receiving strong opioids (or opioid-type analgesics) for treatment of acute or chronic pain due to any physical condition. The data were abstracted, and the methodological quality was assessed using validated checklists. Data were extracted from 17 studies involving a total of 88 235 participants. The studies included three systematic reviews, one randomized controlled trial, eight cross-sectional studies and four uncontrolled case series. Most studies included adult patients with chronic non-malignant pain; two also included patients with cancer pain; only one included patients with a previous history of dependence. Incidence ranged from 0 to 24% (median 0.5%); prevalence ranged from 0 to 31% (median 4.5%). The available evidence suggests that opioid analgesics for chronic pain conditions are not associated with a major risk for developing dependence. © 2012 The Authors, Addiction © 2012 Society for the Study of Addiction.

  11. 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

  12. Opioid overdose education and naloxone distribution: Development of the Veterans Health Administration's national program.

    PubMed

    Oliva, Elizabeth M; Christopher, Melissa L D; Wells, Daina; Bounthavong, Mark; Harvey, Michael; Himstreet, Julianne; Emmendorfer, Thomas; Valentino, Michael; Franchi, Mariano; Goodman, Francine; Trafton, Jodie A

    To prevent opioid-related mortality, the Veterans Health Administration (VHA) developed a national Opioid Overdose Education and Naloxone Distribution (OEND) program. VHA's OEND program sought national implementation of OEND across all medical facilities (n = 142). This paper describes VHA's efforts to facilitate nationwide health care system-based OEND implementation, including the critical roles of VHA's national pharmacy services and academic detailing services. VHA is the first large health care system in the United States to implement OEND nationwide. Launching the national program required VHA to translate a primarily community-based public health approach to OEND into a health care system-based approach that distributed naloxone to patients with opioid use disorders as well as to patients prescribed opioid analgesics. Key innovations included developing steps to implement OEND, pharmacy developing standard naloxone rescue kits, adding those kits to the VHA National Formulary, centralizing kit distribution, developing clinical guidance for issuing naloxone kits, and supporting OEND as a focal campaign of academic detailing. Other innovations included the development of patient and provider education resources (e.g., brochures, videos, accredited training) and implementation and evaluation resources (e.g., technical assistance, clinical decision support tools). Clinical decision support tools that leverage VHA national data are available to clinical staff with appropriate permissions. These tools allow staff and leaders to evaluate OEND implementation and provide actionable next steps to help them identify patients who could benefit from OEND. Through fiscal year 2016, VHA dispensed 45,178 naloxone prescriptions written by 5693 prescribers to 39,328 patients who were primarily prescribed opioids or had opioid use disorder. As of February 2, 2016, there were 172 spontaneously reported opioid overdose reversals with the use of VHA naloxone prescriptions. VHA

  13. In vitro and in vivo pharmacological profile of UFP-512, a novel selective delta-opioid receptor agonist; correlations between desensitization and tolerance.

    PubMed

    Aguila, B; Coulbault, L; Boulouard, M; Léveillé, F; Davis, A; Tóth, G; Borsodi, A; Balboni, G; Salvadori, S; Jauzac, P; Allouche, S

    2007-12-01

    Delta-opioid receptors (DOP receptors) could represent a novel target in the treatment of depressive disorders. To explore this new field of interest, the development of highly selective DOP receptor agonists is essential. UFP-512 [H-Dmt-Tic-NH-CH(CH2-COOH)-Bid], was recently shown to behave in vitro as a selective and potent DOP receptor agonist and to promote antidepressant- and anxiolytic-like effects in vivo (Vergura et al., 2007). Here, we have characterized the pharmacological properties of UFP-512 and established a link between desensitization and tolerance. Studies were performed in the human neuroblastoma SK-N-BE cells to establish i) binding parameters for UFP-512 ii) signalling pathways activated after acute and chronic treatment iii) regulation (phosphorylation and trafficking) of human DOP (hDOP) receptors after sustained activation by UFP-512. In vivo, we studied UFP-512-induced antidepressant-like effects after acute or chronic treatment in the mouse forced swimming test. In vitro, UFP-512 was a high affinity agonist for DOP receptors. While UFP-512 induced marked phosphorylation of DOP receptors on Ser363, we observed a low desensitization of the cAMP pathway, associated with receptor endocytosis and recycling without any reduction on extracellular signal-regulated protein kinase 1/2 activation. In vivo, acute administration of UFP-512 produced an antidepressant-like effect, without any sign of tolerance after chronic administration. There was a correlation between weak desensitization, significant internalization and recycling of the human DOP receptors and lack of tolerance to UFP-512. This suggests that this compound would be a promising drug prototype for exploring innovative treatments for mood disorders.

  14. In vitro and in vivo pharmacological profile of UFP-512, a novel selective δ-opioid receptor agonist; correlations between desensitization and tolerance

    PubMed Central

    Aguila, B; Coulbault, L; Boulouard, M; Lιveillι, F; Davis, A; Tσth, G; Borsodi, A; Balboni, G; Salvadori, S; Jauzac, P; Allouche, S

    2007-01-01

    Background and purpose: δ-Opioid receptors (DOP receptors) could represent a novel target in the treatment of depressive disorders. To explore this new field of interest, the development of highly selective DOP receptor agonists is essential. UFP-512 [H-Dmt-Tic-NH-CH(CH2-COOH)-Bid], was recently shown to behave in vitro as a selective and potent DOP receptor agonist and to promote antidepressant- and anxiolytic-like effects in vivo (Vergura et al., 2007). Here, we have characterized the pharmacological properties of UFP-512 and established a link between desensitization and tolerance. Experimental approach: Studies were performed in the human neuroblastoma SK-N-BE cells to establish i) binding parameters for UFP-512 ii) signalling pathways activated after acute and chronic treatment iii) regulation (phosphorylation and trafficking) of human DOP (hDOP) receptors after sustained activation by UFP-512. In vivo, we studied UFP-512-induced antidepressant-like effects after acute or chronic treatment in the mouse forced swimming test. Key results: In vitro, UFP-512 was a high affinity agonist for DOP receptors. While UFP-512 induced marked phosphorylation of DOP receptors on Ser363, we observed a low desensitization of the cAMP pathway, associated with receptor endocytosis and recycling without any reduction on extracellular signal-regulated protein kinase 1/2 activation. In vivo, acute administration of UFP-512 produced an antidepressant-like effect, without any sign of tolerance after chronic administration. Conclusions and implications: There was a correlation between weak desensitization, significant internalization and recycling of the human DOP receptors and lack of tolerance to UFP-512. This suggests that this compound would be a promising drug prototype for exploring innovative treatments for mood disorders. PMID:17982482

  15. Differential opioid agonist regulation of the mouse mu opioid receptor.

    PubMed

    Blake, A D; Bot, G; Freeman, J C; Reisine, T

    1997-01-10

    Mu opioid receptors mediate the analgesia induced by morphine. Prolonged use of morphine causes tolerance development and dependence. To investigate the molecular basis of tolerance and dependence, the cloned mouse mu opioid receptor with an amino-terminal epitope tag was stably expressed in human embryonic kidney (HEK) 293 cells, and the effects of prolonged opioid agonist treatment on receptor regulation were examined. In HEK 293 cells the expressed mu receptor showed high affinity, specific, saturable binding of radioligands and a pertussis toxin-sensitive inhibition of adenylyl cyclase. Pretreatment (1 h, 3 h, or overnight) of cells with 1 microM morphine or [D-Ala2MePhe4,Gly(ol)5]enkephalin (DAMGO) resulted in no apparent receptor desensitization, as assessed by opioid inhibition of forskolin-stimulated cAMP levels. In contrast, the morphine and DAMGO pretreatments (3 h) resulted in a 3-4-fold compensatory increase in forskolin-stimulated cAMP accumulation. The opioid agonists methadone and buprenorphine are used in the treatment of addiction because of a markedly lower abuse potential. Pretreatment of mu receptor-expressing HEK 293 cells with methadone or buprenorphine abolished the ability of opioids to inhibit adenylyl cyclase. No compensatory increase in forskolin-stimulated cAMP accumulation was found with methadone or buprenorphine; these opioids blocked the compensatory effects observed with morphine and DAMGO. Taken together, these results indicate that methadone and buprenorphine interact differently with the mouse mu receptor than either morphine or DAMGO. The ability of methadone and buprenorphine to desensitize the mu receptor and block the compensatory rise in forskolin-stimulated cAMP accumulation may be an underlying mechanism by which these agents are effective in the treatment of morphine addiction.

  16. Reversal of oxycodone and hydrocodone tolerance by diazepam.

    PubMed

    Gonek, Maciej; Akbarali, Hamid I; Henderson, Graeme; Dewey, William L

    2017-11-01

    The Centers for Disease Control has declared opioid abuse to be an epidemic. Overdose deaths are largely assumed to be the result of excessive opioid consumption. In many of these cases, however, opioid abusers are often polydrug abusers. Benzodiazepines are one of the most commonly co-abused substances and pose a significant risk to opioid users. In 2016, the FDA required boxed warnings - the FDA's strongest warning - for prescription opioid analgesics and benzodiazepines about the serious risks associated with using these medications at the same time. The point of our studies was to evaluate the interactions between these two classes of drugs. We investigated whether diazepam adds to the depressant effects of opioids or do they alter the levels of tolerance to opioids. In the present study, we have found that the antinociceptive tolerance that developed to repeated administration of oxycodone was reversed by an acute dose of diazepam. Antinociceptive tolerance to hydrocodone was also reversed by acute injection of diazepam; however, a fourfold higher dose of diazepam was required when compared to reversal of oxycodone-induced tolerance. These doses of diazepam did not potentiate the acute antinociceptive effect of either opioid. The same dose of diazepam that reversed oxycodone antinociceptive tolerance also reversed oxycodone locomotor tolerance while having no potentiating effects. These studies show that diazepam does not potentiate the acute effect of prescription opioids but reverses the tolerance developed after chronic administration of the drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Vermont Hub-and-Spoke Model of Care for Opioid Use Disorder: Development, Implementation, and Impact.

    PubMed

    Brooklyn, John R; Sigmon, Stacey C

    Opioid use disorders (OUDs) are reaching epidemic proportions in the United States, and many geographic areas struggle with a persistent shortage in availability of opioid agonist treatment. Over the past 5 years, Vermont addiction medicine physicians and public health leaders have responded to these challenges by developing an integrated hub-and-spoke opioid treatment network. In the present report, we review the development, implementation, and impact of this novel hub-and-spoke model for expanding OUD treatment in Vermont. Vermont's hub-and-spoke system has been implemented state-wide and well-received by providers and patients alike. Adoption of this model has been associated with substantial increases in the state's OUD treatment capacity, with Vermont now having the highest capacity for treating OUD in the United States with 10.56 people in treatment per 1000. There has been a 64% increase in physicians waivered to prescribe buprenorphine, a 50% increase in patients served per waivered physician, and a robust bidirectional transfer of patients between hubs and spokes based upon clinical need. Challenges to system implementation and important future directions are discussed. Development and implementation of a hub-and-spoke system of care has contributed substantially to improvements in opioid agonist treatment capacity in Vermont. This system may serve as a model for other states grappling with the current opioid use epidemic.

  18. 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

  19. 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.

  20. Markers of tolerance development to food allergens.

    PubMed

    Ponce, M; Diesner, S C; Szépfalusi, Z; Eiwegger, T

    2016-10-01

    IgE-mediated reactions to food allergens are the most common cause of anaphylaxis in childhood. Although allergies to cow's milk, egg, or soy proteins, in contrast to peanut and tree nut allergens, resolve within the first 6 years of life in up to 60% due to natural tolerance development, this process is not well understood. At present, there is no cure or treatment for food allergy that would result in an induction of tolerance to the symptom-eliciting food. Avoidance, providing an emergency plan and education, is the standard of treatment. Oral immunotherapeutic approaches have been proven reasonable efficacy; however, they are associated with high rates of side-effects and low numbers of patients achieving tolerance. Nevertheless, mechanisms that take place during oral immunotherapy may help to understand tolerance development. On the basis of these therapeutic interventions, events like loss of basophil activation and induction of regulatory lymphocyte subsets and of blocking antibodies have been described. Their functional importance at a clinical level, however, remains to be investigated in detail. Consequently, there is eminent need to understand the process of tolerance development to food allergens and define biomarkers to develop and monitor new treatment strategies for food allergy.

  1. Opioid Basics: Prescription Opioids

    MedlinePlus

    ... relievers for acute pain, and high daily doses. Addiction and Overdose Anyone who takes prescription opioids can ... in a primary care setting struggles with opioid addiction. 4,5,6 Once addicted, it can be ...

  2. 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

  3. 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…

  4. [Opioids in chronic noncancer pain-are opioids superior to nonopioid analgesics? A systematic review and meta-analysis of efficacy, tolerability and safety in randomized head-to-head comparisons of opioids versus nonopioid analgesics of at least four week's duration].

    PubMed

    Welsch, P; Sommer, C; Schiltenwolf, M; Häuser, W

    2015-02-01

    Some leading German pain medicine experts postulate that there is a type of chronic non-cancer pain (CNCP) with an opioid requirement. We tested whether opioids are superior to nonopioid analgesics in the management of CNCP in studies of at least 4 week's duration. We screened MEDLINE, Scopus and the Cochrane Central Register of Controlled Trials (CENTRAL) up until October 2013, as well as the reference sections of original studies and systematic reviews of randomised controlled trials (RCTs) of opioids in CNCP. We included double-blind RTCs comparing opioids to nonopioid analgesics of at least 4 week's duration. Relative risks differences (RD) of categorical data and standardized mean differences (SMD) of continuous variables were calculated using a random effects model. We included 10 RCTs with 3046 participants. Median study duration was 6 weeks (range 4-12 weeks). Five studies compared tramadol with nonsteroidal anti-inflammatory drugs (NSAIDs) in osteoarthritis pain and one trial compared tramadol to flupirtine in low back pain. Morphine was compared to antidepressants (two studies), an anticonvulsant (one study) and an antiarrhythmic (one study) in different neuropathic pain syndromes. There was no significant difference between opioids and nonopioid analgesics in pain reduction (SMD 0.03 [95 % confidence interval, CI - 0.18, 0.24]; p = 0.76). Nonopioid analgesics were superior to opioids in improving physical function (SMD 0.17 [95 % CI 0.02, 0.32]; p = 0.03). Patients dropped out due to adverse events more frequently with opioids than with nonopioid analgesics (RD 0.09 [95 % CI 0.06, 0.13]; p < 0.0001). There was no significant difference between opioids and nonopioid analgesics in terms of serious adverse events or dropout rates due to lack of efficacy. Nonopioid analgesics are superior to opioids in terms of improvement of physical function and tolerability in short-term (4-12 weeks) therapy of neuropathic, low back

  5. Disruption of δ-opioid receptor phosphorylation at threonine 161 attenuates morphine tolerance in rats with CFA-induced inflammatory hypersensitivity.

    PubMed

    Chen, Hai-Jing; Xie, Wei-Yan; Hu, Fang; Zhang, Ying; Wang, Jun; Wang, Yun

    2012-04-01

    Our previous study identified Threonine 161 (Thr-161), located in the second intracellular loop of the δ-opioid receptor (DOR), as the only consensus phosphorylation site for cyclin-dependent kinase 5 (Cdk5). The aim of this study was to assess the function of DOR phosphorylation by Cdk5 in complete Freund's adjuvant (CFA)-induced inflammatory pain and morphine tolerance. Dorsal root ganglion (DRG) neurons of rats with CFA-induced inflammatory pain were acutely dissociated and the biotinylation method was used to explore the membrane localization of phosphorylated DOR at Thr-161 (pThr-161-DOR), and paw withdrawal latency was measured after intrathecal delivery of drugs or Tat-peptide, using a radiant heat stimulator in rats with CFA-induced inflammatory pain. Both the total amount and the surface localization of pThr-161-DOR were significantly enhanced in the ipsilateral DRG following CFA injection. Intrathecal delivery of the engineered Tat fusion-interefering peptide corresponding to the second intracellular loop of DOR (Tat-DOR-2L) increased inflammatory hypersensitivity, and inhibited DOR- but not µ-opioid receptor-mediated spinal analgesia in CFA-treated rats. However, intrathecal delivery of Tat-DOR-2L postponed morphine antinociceptive tolerance in rats with CFA-induced inflammatory pain. Phosphorylation of DOR at Thr-161 by Cdk5 attenuates hypersensitivity and potentiates morphine tolerance in rats with CFA-induced inflammatory pain, while disruption of the phosphorylation of DOR at Thr-161 attenuates morphine tolerance.

  6. Differentiation of δ, μ, and κ opioid receptor agonists based on pharmacophore development and computed physicochemical properties

    NASA Astrophysics Data System (ADS)

    Filizola, Marta; Villar, Hugo O.; Loew, Gilda H.

    2001-04-01

    Compounds that bind with significant affinity to the opioid receptor types, δ, μ, and κ, with different combinations of activation and inhibition at these three receptors could be promising behaviorally selective agents. Working on this hypothesis, the chemical moieties common to three different sets of opioid receptor agonists with significant affinity for each of the three receptor types δ, μ, or κ were identified. Using a distance analysis approach, common geometric arrangements of these chemical moieties were found for selected δ, μ, or κ opioid agonists. The chemical and geometric commonalities among agonists at each opioid receptor type were then compared with a non-specific opioid recognition pharmacophore recently developed. The comparison provided identification of the additional requirements for activation of δ, μ, and κ opioid receptors. The distance analysis approach was able to clearly discriminate κ-agonists, while global molecular properties for all compounds were calculated to identify additional requirements for activation of δ and μ receptors. Comparisons of the combined geometric and physicochemical properties calculated for each of the three sets of agonists allowed the determination of unique requirements for activation of each of the three opioid receptors. These results can be used to improve the activation selectivity of known opioid agonists and as a guide for the identification of novel selective opioid ligands with potential therapeutic usefulness.

  7. 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.

  8. Factors Predicting Development of Opioid Use Disorders among Individuals who Receive an Initial Opioid Prescription: Mathematical Modeling Using a Database of Commercially-insured Individuals

    PubMed Central

    Cochran, Bryan N.; Flentje, Annesa; Heck, Nicholas C.; Van Den Bos, Jill; Perlman, Dan; Torres, Jorge; Valuck, Robert; Carter, Jean

    2014-01-01

    Background Prescription drug abuse in the United States and elsewhere in the world is increasing at an alarming rate with non-medical opioid use, in particular, increasing to epidemic proportions over the past two decades. It is imperative to identify those most likely to develop opioid abuse or dependence to inform large-scale, targeted prevention efforts. Methods The present investigation utilized a large commercial insurance claims database to identify demographic, mental health, physical health, and healthcare service utilization variables that differentiate persons who receive an opioid abuse or dependence diagnosis within two years of filling an opioid prescription (OUDs) from those who do not receive such a diagnosis within the same time frame (non-OUDs). Results When compared to non-OUDs, OUDs were more likely to: 1) be male (59.9% vs. 44.2% for non-OUDs) and younger (M=37.9 vs. 47.7); 2) have a prescription history of more opioids (1.7 vs. 1.2), and more days supply of opioids (M=272.5, vs. M=33.2; 3) have prescriptions filled at more pharmacies (M=3.3 per year vs. M=1.3); 4) have greater rates of psychiatric disorders; 5) utilize more medical and psychiatric services; and 6) be prescribed more concomitant medications. A predictive model incorporating these findings was 79.5% concordant with actual OUDs in the data set. Conclusions Understanding correlates of OUD development can help to predict risk and inform prevention efforts. PMID:24679839

  9. Development of an integrated cognitive behavioral therapy for anxiety and opioid use disorder: Study protocol and methods.

    PubMed

    McHugh, R Kathryn; Votaw, Victoria R; Barlow, David H; Fitzmaurice, Garrett M; Greenfield, Shelly F; Weiss, Roger D

    2017-09-01

    Opioid use disorder is a highly disabling psychiatric disorder, and is associated with both significant functional disruption and risk for negative health outcomes such as infectious disease and fatal overdose. Even among those who receive evidence-based pharmacotherapy for opioid use disorder, many drop out of treatment or relapse, highlighting the importance of novel treatment strategies for this population. Over 60% of those with opioid use disorder also meet diagnostic criteria for an anxiety disorder; however, efficacious treatments for this common co-occurrence have not be established. This manuscript describes the rationale and methods for a behavioral treatment development study designed to develop and test an integrated cognitive-behavioral therapy for those with co-occurring opioid use disorder and anxiety disorders. The aims of the study are (1) to develop and pilot test a new manualized cognitive behavioral therapy for co-occurring opioid use disorder and anxiety disorders, (2) to test the efficacy of this treatment relative to an active comparison treatment that targets opioid use disorder alone, and (3) to investigate the role of stress reactivity in both prognosis and recovery from opioid use disorder and anxiety disorders. Our overarching aim is to investigate whether this new treatment improves both anxiety and opioid use disorder outcomes relative to standard treatment. Identifying optimal treatment strategies for this population are needed to improve outcomes among those with this highly disabling and life-threatening disorder. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Tolerance to the anticonvulsant effect of morphine in mice: blockage by ultra-low dose naltrexone.

    PubMed

    Roshanpour, Maryam; Ghasemi, Mehdi; Riazi, Kiarash; Rafiei-Tabatabaei, Neda; Ghahremani, Mohammad Hossein; Dehpour, Ahmad Reza

    2009-02-01

    The present study evaluated the development of tolerance to the anticonvulsant effect of morphine in a mouse model of clonic seizures induced by pentylenetetrazole, and whether ultra-low doses of the opioid receptor antagonist naltrexone which selectively block G(s) opioid receptors were capable of preventing the observed tolerance. The results showed that the morphine anticonvulsant effect could be subject to tolerance after repeated administration. Both the development and expression of tolerance were inhibited by ultra-low doses of naltrexone, suggesting the possible involvement of G(s)-coupled opioid receptors in the development of tolerance to the anticonvulsant effect of morphine.

  11. Differential development of antinociceptive tolerance to morphine and fentanyl is not linked to efficacy in the ventrolateral periaqueductal gray of the rat

    PubMed Central

    Bobeck, Erin N.; Haseman, Rachel A.; Hong, Dana; Ingram, Susan L.; Morgan, Michael M.

    2012-01-01

    Systemic administration of morphine typically produces greater tolerance than higher efficacy mu-opioid receptor (MOPr) agonists, such as fentanyl. The objective of the present study was to test this relationship by measuring antinociceptive efficacy and tolerance to morphine and fentanyl microinjected into the ventrolateral periaqueductal gray (vlPAG). MOPr agonist efficacy was evaluated by microinjecting the irreversible opioid receptor antagonist β-funaltrexamine hydrochloride (β-FNA) into the vlPAG prior to a dose-response analysis of morphine and fentanyl antinociception. In contrast to systemic administration of morphine and fentanyl, microinjection of these drugs into the vlPAG had similar efficacy as measured by similar reductions in maximal antinociception following β-FNA administration. Analysis of tolerance revealed a rightward shift in the dose-response curve to a single pretreatment with morphine, but not fentanyl. Moreover, the magnitude of tolerance to morphine was comparable following one, four, or eight pretreatments. Tolerance to fentanyl also was evident following four or eight microinjections. These data are surprising in that antinociceptive efficacy appears to vary depending on the site of administration. Moreover, the similar efficacy following microinjection of morphine and fentanyl into the vlPAG was associated with comparable tolerance, with the one exception of no tolerance to acute administration of fentanyl. Perspective These data reveal that antinociceptive tolerance following vlPAG administration of opioids develops rapidly, is evident with both morphine and fentanyl, and the magnitude is relatively consistent regardless of the number of pretreatments. PMID:22766006

  12. 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

  13. 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

  14. Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations.

    PubMed

    Arout, Caroline A; Edens, Ellen; Petrakis, Ismene L; Sofuoglu, Mehmet

    2015-06-01

    Opioid analgesics have become a cornerstone in the treatment of moderate to severe pain, resulting in a steady rise of opioid prescriptions. Subsequently, there has been a striking increase in the number of opioid-dependent individuals, opioid-related overdoses, and fatalities. Clinical use of opioids is further complicated by an increasingly deleterious profile of side effects beyond addiction, including tolerance and opioid-induced hyperalgesia (OIH), where OIH is defined as an increased sensitivity to already painful stimuli. This paradoxical state of increased nociception results from acute and long-term exposure to opioids, and appears to develop in a substantial subset of patients using opioids. Recently, there has been considerable interest in developing an efficacious treatment regimen for acute and chronic pain. However, there are currently no well-established treatments for OIH. Several substrates have emerged as potential modulators of OIH, including the N-methyl-D-aspartate and γ-aminobutyric acid receptors, and most notably, the innate neuroimmune system. This review summarizes the neurobiology of OIH in the context of clinical treatment; specifically, we review evidence for several pathways that show promise for the treatment of pain going forward, as prospective adjuvants to opioid analgesics. Overall, we suggest that this paradoxical state be considered an additional target of clinical treatment for chronic pain.

  15. 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.

  16. Revisiting the 'paradigm shift' in opioid use: Developments and implications 10 years later.

    PubMed

    Fischer, Benedikt; Rehm, Jürgen

    2017-03-23

    A decade ago, we queried the unfolding of a 'paradigm shift' in illicit opioid use in North America, specifically involving a shift away from heroin to prescription opioid (PO) use. Today, this situation is more acute than ever, with prescription opioid misuse, morbidity and mortality amounting to one of the most severe substance use-related public health crises ever, now even impacting life expectancy in key population segments. Despite medical system-based PO dispensing and practices being recognised as core drivers of the PO crisis, effective policy measures have been long absent or limited-including those to reduce medical PO use to levels supported by best evidence for pain care. At the same time, heroin use has been increasing again, now commonly tied into interdependent opioid use trajectories, initiated with POs yet shifting to heroin as influenced by economic or availability factors. For policy, there are now two major and urgent-yet partly conflicting-tasks: one is to reduce the determinants of PO misuse and harms by reducing medical prescribing to levels supported by good evidence, while the other is to effectively protect those many active problematic PO users from acute harms (including overdose mortality) by providing effective treatment and survival aids (e.g. naloxone). Surprisingly, it appears that a major 'homemade' and medical system-induced drug crisis has been at least as challenging for North American policy systems to address as other, more conventional illicit drug problems. Lessons for policy hence need to be urgently identified and applied for the future. [Fischer B, Rehm J. Revisiting the 'paradigm shift' in opioid use: Developments and implications 10 years later. Drug Alcohol Rev 2017;00:000-000].

  17. Development and applications of the Veterans Health Administration's Stratification Tool for Opioid Risk Mitigation (STORM) to improve opioid safety and prevent overdose and suicide.

    PubMed

    Oliva, Elizabeth M; Bowe, Thomas; Tavakoli, Sara; Martins, Susana; Lewis, Eleanor T; Paik, Meenah; Wiechers, Ilse; Henderson, Patricia; Harvey, Michael; Avoundjian, Tigran; Medhanie, Amanuel; Trafton, Jodie A

    2017-02-01

    Concerns about opioid-related adverse events, including overdose, prompted the Veterans Health Administration (VHA) to launch an Opioid Safety Initiative and Overdose Education and Naloxone Distribution program. To mitigate risks associated with opioid prescribing, a holistic approach that takes into consideration both risk factors (e.g., dose, substance use disorders) and risk mitigation interventions (e.g., urine drug screening, psychosocial treatment) is needed. This article describes the Stratification Tool for Opioid Risk Mitigation (STORM), a tool developed in VHA that reflects this holistic approach and facilitates patient identification and monitoring. STORM prioritizes patients for review and intervention according to their modeled risk for overdose/suicide-related events and displays risk factors and risk mitigation interventions obtained from VHA electronic medical record (EMR)-data extracts. Patients' estimated risk is based on a predictive risk model developed using fiscal year 2010 (FY2010: 10/1/2009-9/30/2010) EMR-data extracts and mortality data among 1,135,601 VHA patients prescribed opioid analgesics to predict risk for an overdose/suicide-related event in FY2011 (2.1% experienced an event). Cross-validation was used to validate the model, with receiver operating characteristic curves for the training and test data sets performing well (>.80 area under the curve). The predictive risk model distinguished patients based on risk for overdose/suicide-related adverse events, allowing for identification of high-risk patients and enrichment of target populations of patients with greater safety concerns for proactive monitoring and application of risk mitigation interventions. Results suggest that clinical informatics can leverage EMR-extracted data to identify patients at-risk for overdose/suicide-related events and provide clinicians with actionable information to mitigate risk. (PsycINFO Database Record

  18. Region-dependent attenuation of mu opioid receptor-mediated G-protein activation in mouse CNS as a function of morphine tolerance.

    PubMed

    Sim-Selley, L J; Scoggins, K L; Cassidy, M P; Smith, L A; Dewey, W L; Smith, F L; Selley, D E

    2007-08-01

    Chronic morphine administration produces tolerance in vivo and attenuation of mu opioid receptor (MOR)-mediated G-protein activation measured in vitro, but the relationship between these adaptations is not clear. The present study examined MOR-mediated G-protein activation in the CNS of mice with different levels of morphine tolerance. Mice were implanted with morphine pellets, with or without supplemental morphine injections, to induce differing levels of tolerance as determined by a range of MOR-mediated behaviours. MOR function was measured using agonist-stimulated [(35)S]guanylyl-5'-O-(gamma-thio)-triphosphate ([(35)S]GTPgammaS) and receptor binding throughout the CNS. Morphine pellet implantation produced 6-12-fold tolerance in antinociceptive assays, hypothermia and Straub tail, as measured by the ratio of morphine ED(50) values between morphine-treated and control groups. Pellet implantation plus supplemental injections produced 25-50-fold tolerance in these tests. In morphine pellet-implanted mice, MOR-stimulated [(35)S]GTPgammaS binding was significantly reduced only in the nucleus tractus solitarius (NTS) and spinal cord dorsal horn in tissue sections from morphine pellet-implanted mice. In contrast, MOR-stimulated [(35)S]GTPgammaS binding was significantly decreased in most regions examined in morphine pellet+morphine injected mice, including nucleus accumbens, caudate-putamen, periaqueductal gray, parabrachial nucleus, NTS and spinal cord. Tolerance and the regional pattern of apparent MOR desensitization were influenced positively by the level of morphine exposure. These results indicate that desensitization of MOR-mediated G-protein activity is more regionally widespread upon induction of high levels of tolerance, suggesting that this response contributes more to high than low levels of tolerance to CNS-mediated effects of morphine.

  19. 78 FR 31945 - Clinical Development Programs for Opioid Conversion; Public Workshop; Request for Comments

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-28

    ... strategies used in clinical practice to convert patients from one opioid analgesic product to another. The... mechanisms for communicating safe opioid analgesic conversion strategies to prescribers. Date and Time: The... knowledge regarding equianalgesic opioid analgesic doses and opioid conversion in clinical practice....

  20. Novel Molecular Strategies and Targets for Opioid Drug Discovery for the Treatment of Chronic Pain

    PubMed Central

    Olson, Keith M.; Lei, Wei; Keresztes, Attila; LaVigne, Justin; Streicher, John M.

    2017-01-01

    Opioid drugs like morphine and fentanyl are the gold standard for treating moderate to severe acute and chronic pain. However, opioid drug use can be limited by serious side effects, including constipation, tolerance, respiratory suppression, and addiction. For more than 100 years, we have tried to develop opioids that decrease or eliminate these liabilities, with little success. Recent advances in understanding opioid receptor signal transduction have suggested new possibilities to activate the opioid receptors to cause analgesia, while reducing or eliminating unwanted side effects. These new approaches include designing functionally selective ligands, which activate desired signaling cascades while avoiding signaling cascades that are thought to provoke side effects. It may also be possible to directly modulate downstream signaling through the use of selective activators and inhibitors. Separate from downstream signal transduction, it has also been found that when the opioid system is stimulated, various negative feedback systems are upregulated to compensate, which can drive side effects. This has led to the development of multi-functional molecules that simultaneously activate the opioid receptor while blocking various negative feedback receptor systems including cholecystokinin and neurokinin-1. Other novel approaches include targeting heterodimers of the opioid and other receptor systems which may drive side effects, and making endogenous opioid peptides druggable, which may also reduce opioid mediated side effects. Taken together, these advances in our molecular understanding provide a path forward to break the barrier in producing an opioid with reduced or eliminated side effects, especially addiction, which may provide relief for millions of patients. PMID:28356897

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

    PubMed

    Chiang, Yao-Chang; Hung, Tsai-Wei; Lee, Cynthia Wei-Sheng; Yan, Jia-Ying; Ho, Ing-Kang

    2010-06-07

    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. 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 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. 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 mortality and much less sensitivity to

  2. 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

  3. 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. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Development of 5-Substituted N-Methylmorphinan-6-ones as Potent Opioid Analgesics with Improved Side-Effect Profile.

    PubMed

    Schmidhammer, Helmut; Spetea, Mariana

    2012-01-01

    One of the most important functions of the opioid system is the control of pain. Among the three main opioid receptor classes (μ, δ, κ), the μ (MOR) is the main type targeted for pharmacotherapy of pain. Opioid analgesics such as morphine, oxycodone and fentanyl are agonists at the MOR and are the mainstay for the treatment of moderate-to-severe pain. However, adverse effects related to opioid use are severe and often lead to early discontinuation and inadequate analgesia. The development of more effective and safer medications for the management of pain still remains a major direction in pharmaceutical research. Chemical approaches towards the identification of novel MOR analgesics with reduced side effects include structural modifications of 14-alkoxy-N-methylmorphinan-6-ones in key positions that are important for binding, selectivity, potency, and efficacy at opioid receptors. This paper describes a representative strategy to improve the therapeutic usefulness of opioid analgesics from the morphinan class of drugs by targeting position 5. The focus is on chemical and biological studies and structure-activity relationships of this series of ligands. We report on 14-alkoxymorphinan-6-ones having a methyl and benzyl group at position 5 as strong opioid antinociceptive agents with reduced propensity to cause undesired effects compared to morphine although interacting selectively with MORs.

  5. Development of 5-Substituted N-Methylmorphinan-6-ones as Potent Opioid Analgesics with Improved Side-Effect Profile

    PubMed Central

    Schmidhammer, Helmut; Spetea, Mariana

    2012-01-01

    One of the most important functions of the opioid system is the control of pain. Among the three main opioid receptor classes (μ, δ, κ), the μ (MOR) is the main type targeted for pharmacotherapy of pain. Opioid analgesics such as morphine, oxycodone and fentanyl are agonists at the MOR and are the mainstay for the treatment of moderate-to-severe pain. However, adverse effects related to opioid use are severe and often lead to early discontinuation and inadequate analgesia. The development of more effective and safer medications for the management of pain still remains a major direction in pharmaceutical research. Chemical approaches towards the identification of novel MOR analgesics with reduced side effects include structural modifications of 14-alkoxy-N-methylmorphinan-6-ones in key positions that are important for binding, selectivity, potency, and efficacy at opioid receptors. This paper describes a representative strategy to improve the therapeutic usefulness of opioid analgesics from the morphinan class of drugs by targeting position 5. The focus is on chemical and biological studies and structure-activity relationships of this series of ligands. We report on 14-alkoxymorphinan-6-ones having a methyl and benzyl group at position 5 as strong opioid antinociceptive agents with reduced propensity to cause undesired effects compared to morphine although interacting selectively with MORs. PMID:25954525

  6. New trends in the development of opioid peptide analogues as advanced remedies for pain relief.

    PubMed

    Gentilucci, Luca

    2004-01-01

    The search for new peptides to be used as analgesics in place of morphine has been mainly directed to develop peptide analogues or peptidomimetics having higher biological stability and receptor selectivity. Indeed, most of the alkaloid opioid counterindications are due to the scarce stability and the contemporary activation of different receptor types. However, the development of several extremely stable and selective peptide ligands for the different opioid receptors, and the recent discovery of the micro-receptor selective endomorphins, rendered this search less fundamental. In recent years, other opioid peptide properties have been investigated in the search for new pharmacological tools. The utility of a drug depends on its ability to reach appropriate receptors at the target tissue and to remain metabolically stable in order to produce the desired effect. This review deals with the recent investigations on peptide bioavailability, in particular barrier penetration and resistance against enzymatic degradation; with the development of peptides having activity at different receptors; with chimeric peptides, with propeptides, and with non-conventional peptides, lacking basic pharmacophoric features.

  7. 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

  8. Putative kappa opioid heteromers as targets for developing analgesics free of adverse effects.

    PubMed

    Le Naour, Morgan; Lunzer, Mary M; Powers, Michael D; Kalyuzhny, Alexander E; Benneyworth, Michael A; Thomas, Mark J; Portoghese, Philip S

    2014-08-14

    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.

  9. 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 ...

  10. 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

  11. 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

    2016-08-04

    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

  12. Mice lacking δ-opioid receptors resist the development of diet-induced obesity

    PubMed Central

    Czyzyk, Traci A.; Romero-Picó, Amparo; Pintar, John; McKinzie, Jaime H.; Tschöp, Matthias H.; Statnick, Michael A.; Nogueiras, Ruben

    2012-01-01

    Pharmacological manipulation of opioid receptors alters feeding behavior. However, the individual contributions of each opioid receptor subtype on energy balance remain largely unknown. Herein, we investigated whether genetic disruption of the δ-opioid receptor (DOR) also controls energy homeostasis. Mice lacking DOR and wild-type mice were fed with standard diet and high-energy diet (HED). Mice were analyzed in vivo with the indirect calorimetry system, and tissues were analyzed by real-time PCR and Western blot analysis. DOR-knockout (KO) mice gained less weight (P<0.01) and had lower fat mass (P<0.01) when compared to WT mice fed an HED. Although DOR-KO mice were hyperphagic, they showed higher energy expenditure (P<0.05), which was the result of an increased activation of the thermogenic program in brown adipose tissue. The increased nonshivering thermogenesis involved the stimulation of uncoupling protein 1 (UCP1; P<0.01), peroxisome proliferator-activated receptor γ coactivator (PGC1α; P<0.05), and fibroblast growth factor 21 (FGF21; P<0.01). DOR deficiency also led to an attenuation of triglyceride content in the liver (P<0.05) in response to an HED. These findings reveal a novel role of DOR in the control of thermogenic markers and energy expenditure, and they provide a potential new therapeutic approach for the treatment of obesity.—Czyzyk, T. A., Romero-Picó, A., Pintar, J., McKinzie, J. H., Tschöp, M. H., Statnick, M. A., Nogueiras, R. Mice lacking δ-opioid receptors resist the development of diet-induced obesity. PMID:22593549

  13. 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

  14. Defining clinical issues around tolerance, hyperalgesia, and addiction: a quantitative and qualitative outcome study of long-term opioid dosing in a chronic pain practice.

    PubMed

    Schneider, Jennifer P; Kirsh, Kenneth L

    2010-01-01

    Treatment with opioid medications has grown over the past decades, but has been surrounded by some ongoing controversy and debate to whether it is causing more harm than good for patients. To this end, the field of pain management has suffered from a lack of clarity about some basic definitions on concepts such as tolerance and hyperalgesia. Some characterize these issues as inevitable parts of opioid therapy while other schools of thought look at these issues as relatively rare occurrences. Unfortunately, most of the rhetoric around these topics has occurred with very little in the realm of real world data. To this end, the authors have reviewed the charts of 197 patients treated by a pain specialist for at least 1 year to better illustrate whether notions of tolerance and hyperalgesia are common occurrences and, more importantly, whether they occur within any type of specified timeframe. A total of 197 patient charts were reviewed. The sample had an average age of 49.39 years (range = 19-87 years; standard deviation [SD] = 12.48) and comprised 66 men (33.5 percent) and 131 women (66.5 percent). The patients were seen in the pain practice for an average of 56.52 months (range = 12-155 months; SD = 31.26). On average, the patients maintained an average daily dose of 180 mg morphine equivalents for a period of 35.1 months (range = 3-101 months; SD = 21.3). Looking at the pattern of medication usage change over time, 34.5 percent experienced dose stabilization after the initial titration, 13.2 percent had early dose stabilization within one dose change, and an additional 14.7 percent actually had dose decreases after surgeries or other interventional procedures. Only 6.6 percent of the sample had to be discharged or weaned from controlled substances over time in the clinic. Thus, it appears that tolerance and hyperalgesia are not foregone conclusions when considering placing a patient on long-term opioid therapy.

  15. Development of the Chronic Pain Coding System (CPCS) for Characterizing Patient-Clinician Discussions About Chronic Pain and Opioids.

    PubMed

    Henry, Stephen G; Chen, Meng; Matthias, Marianne S; Bell, Robert A; Kravitz, Richard L

    2016-10-01

    To describe the development and initial application of the Chronic Pain Coding System. Secondary analysis of data from a randomized clinical trial. Six primary care clinics in northern California. Forty-five primary care visits involving 33 clinicians and 45 patients on opioids for chronic noncancer pain. The authors developed a structured coding system to accurately and objectively characterize discussions about pain and opioids. Two coders applied the final system to visit transcripts. Intercoder agreement for major coding categories was moderate to substantial (kappa = 0.5-0.7). Mixed effects regression was used to test six hypotheses to assess preliminary construct validity. Greater baseline pain interference was associated with longer pain discussions (P = 0.007) and more patient requests for clinician action (P = 0.02) but not more frequent negative patient evaluations of pain (P = 0.15). Greater clinician-reported visit difficulty was associated with more frequent disagreements with clinician recommendations (P = 0.003) and longer discussions of opioid risks (P = 0.049) but not more frequent requests for clinician action (P = 0.11). Rates of agreement versus disagreement with patient requests and clinician recommendations were similar for opioid-related and non-opioid-related utterances. This coding system appears to be a reliable and valid tool for characterizing patient-clinician communication about opioids and chronic pain during clinic visits. Objective data on how patients and clinicians discuss chronic pain and opioids are necessary to identify communication patterns and strategies for improving the quality and productivity of discussions about chronic pain that may lead to more effective pain management and reduce inappropriate opioid prescribing. © 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  16. 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

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

    PubMed

    Wachholtz, Amy; Gonzalez, Gerardo

    2014-12-01

    Medication assisted treatment for opioid dependence alters the pain experience. This study will evaluate changes pain sensitivity and tolerance with opioid treatments; and duration of this effect after treatment cessation. 120 Individuals with chronic pain were recruited in 4 groups (N = 30): 1-methadone for opioid addiction; 2-buprenorphine for opioid addiction; 3-history of opioid maintenance treatment for opioid addiction but with prolonged abstinence (M = 121 weeks; SD = 23.3); and 4-opioid naïve controls. Participants completed a psychological assessment and a cold water task including, time to first pain (sensitivity) and time to stopping the pain task (tolerance). Data analysis used survival analyses. A Kaplan-Meier-Cox survival analysis showed group differences for both pain sensitivity (log rank = 15.50; p < .001) and tolerance (log rank = 20.11; p < .001). Current or historical use of opioid maintenance resulted in differing pain sensitivity compared to opioid naïve (p's < .01). However, tolerance to pain was better among those with a history of opioid maintenance compared to active methadone patients (p < .05), with the highest tolerance found among opioid naïve control group participants (p's < .001). Correlations within the prolonged abstinent group indicated pain tolerance was significantly improved as length of opioid abstinence increased (R = .37; p < .05); but duration of abstinence did not alter sensitivity (ns). Among individuals with a history of prolonged opioid maintenance, there appears to be long-term differences in pain sensitivity that do not resolve with discontinuation of opioid maintenance. Although pain sensitivity does not change, pain tolerance does improve after opioid maintenance cessation. Implications for treating co-morbid opioid addiction and pain (acute and chronic) are discussed. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  18. Targeting multiple opioid receptors - improved analgesics with reduced side effects?

    PubMed

    Günther, Thomas; Dasgupta, Pooja; Mann, Anika; Miess, Elke; Kliewer, Andrea; Fritzwanker, Sebastian; Steinborn, Ralph; Schulz, Stefan

    2017-04-05

    Classical opioid analgesics, including morphine, mediate all of their desired and undesired effects by specific activation of the μ-opioid receptor (μ receptor). The use of morphine for treating chronic pain, however, is limited by the development of constipation, respiratory depression, tolerance and dependence. Analgesic effects can also be mediated through other members of the opioid receptor family such as the κ-opioid receptor (κ receptor), δ-opioid receptor (δ receptor) and the nociceptin/orphanin FQ peptide receptor (NOP receptor). Currently, a new generation of opioid analgesics is being developed that can simultaneously bind with high affinity to multiple opioid receptors. With this new action profile, it is hoped that additional analgesic effects and fewer side effects can be achieved. Recent research is mainly focused on the development of bifunctional μ/NOP receptor agonists, which has already led to novel lead structures such as the spiroindole-based cebranopadol and a compound class with a piperidin-4-yl-1,3-dihydroindol-2-one backbone (SR16835/AT-202 and SR14150/AT-200). In addition, the ornivol BU08028 is an analogue of the clinically well-established buprenorphine. Moreover, the morphinan-based nalfurafine exerts its effect with a dominant κ receptor-component and is therefore utilized in the treatment of pruritus. The very potent dihydroetorphine is a true multi-receptor opioid ligand in that it binds to μ, κ and δ receptor. The main focus of this review is to assess the paradigm of opioid ligands targeting multiple receptors with a single chemical entity. We reflect on this rationale by discussing the biological actions of selected multi-opioid receptor ligands, but not on their medicinal chemistry and design.

  19. The opioid system and brain development: methadone effects on the oligodendrocyte lineage and the early stages of myelination

    PubMed Central

    Vestal-Laborde, Allison A.; Eschenroeder, Andrew C.; Bigbee, John W.; Robinson, Susan E.; Sato-Bigbee, Carmen

    2014-01-01

    Oligodendrocytes express opioid receptors throughout development but the role of the opioid system in myelination remains poorly understood. This is a significant problem as opioid use and abuse continue to increase in two particular populations: pregnant addicts where drug effects could target early myelination in the fetus and newborns; and adolescents and young adults where late myelination of “higher-order” regions takes place. Maintenance treatments for opioid addicts include the long-lasting opioids methadone and buprenorphine. Similar to our previous findings on buprenorphine effects, we now find that early myelination in the developing rat brain is also altered by perinatal exposure to therapeutic doses of methadone. Pups exposed to this drug exhibit elevated brain levels of the four major splicing variants of myelin basic proteins (MBPs), myelin proteolipid protein (PLP), and myelin-oligodendrocyte glycoprotein (MOG). Consistent with the enrichment and function of these proteins in mature myelin, analysis of the corpus callosum in these young animals also indicated elevated number of axons with already highly compacted myelin sheaths. Moreover, studies in cultured cells showed that methadone exerts direct effects at specific stages of the oligodendrocyte lineage, stimulating the proliferation of the progenitor cells while on the other hand accelerating the maturation of the more differentiated but still immature pre-oligodendrocytes. While the long-term effects of these observations remain unknown, accelerated or increased oligodendrocyte maturation and myelination could both disrupt the complex sequence of synchronized events leading to normal connectivity in the developing brain. Together with our previous observations on buprenorphine effects, the present findings further underscore a crucial function of the endogenous opioid system in the control of oligodendrocyte development and the timing of myelination. Interference with these regulatory

  20. The opioid system and brain development: effects of methadone on the oligodendrocyte lineage and the early stages of myelination.

    PubMed

    Vestal-Laborde, Allison A; Eschenroeder, Andrew C; Bigbee, John W; Robinson, Susan E; Sato-Bigbee, Carmen

    2014-01-01

    Oligodendrocytes express opioid receptors throughout development, but the role of the opioid system in myelination remains poorly understood. This is a significant problem as opioid use and abuse continue to increase in two particular populations: pregnant addicts (in whom drug effects could target early myelination in the fetus and newborn) and adolescents and young adults (in whom late myelination of 'higher-order' regions takes place). Maintenance treatments for opioid addicts include the long-lasting opioids methadone and buprenorphine. Similar to our previous findings on the effects of buprenorphine, we have now found that early myelination in the developing rat brain is also altered by perinatal exposure to therapeutic doses of methadone. Pups exposed to this drug exhibited elevated brain levels of the 4 major splicing variants of myelin basic protein, myelin proteolipid protein, and myelin-oligodendrocyte glycoprotein. Consistent with the enrichment and function of these proteins in mature myelin, analysis of the corpus callosum in these young animals also indicated an elevated number of axons with already highly compacted myelin sheaths. Moreover, studies in cultured cells showed that methadone exerts direct effects at specific stages of the oligodendrocyte lineage, stimulating the proliferation of progenitor cells while on the other hand accelerating the maturation of the more differentiated but still immature preoligodendrocytes. While the long-term effects of these observations remain unknown, accelerated or increased oligodendrocyte maturation and myelination could both disrupt the complex sequence of synchronized events leading to normal connectivity in the developing brain. Together with our previous observations on the effects of buprenorphine, the present findings further underscore a crucial function of the endogenous opioid system in the control of oligodendrocyte development and the timing of myelination. Interference with these regulatory

  1. Relationship between pain and opioid analgesics on the development of delirium following hip fracture.

    PubMed

    Morrison, R Sean; Magaziner, Jay; Gilbert, Marvin; Koval, Kenneth J; McLaughlin, Mary Ann; Orosz, Gretchen; Strauss, Elton; Siu, Albert L

    2003-01-01

    Delirium and pain are common following hip fracture. Untreated pain has been shown to increase the risk of delirium in older adults undergoing elective surgery. This study was performed to examine the relationship among pain, analgesics, and other factors on delirium in hip fracture patients. We conducted a prospective cohort study at four New York hospitals that enrolled 541 patients with hip fracture and without delirium. Delirium was identified prospectively by patient interview supplemented by medical record review. Multiple logistic regression was used to identify risk factors. Eighty-seven of 541 patients (16%) became delirious. Among all subjects, risk factors for delirium were cognitive impairment (relative risk, or RR, 3.6; 95% confidence interval, or CI, 1.8-7.2), abnormal blood pressure (RR 2.3, 95% CI 1.2-4.7), and heart failure (RR 2.9, 95% CI 1.6-5.3). Patients who received less than 10 mg of parenteral morphine sulfate equivalents per day were more likely to develop delirium than patients who received more analgesia (RR 5.4, 95% CI 2.4-12.3). Patients who received meperidine were at increased risk of developing delirium as compared with patients who received other opioid analgesics (RR 2.4, 95% CI 1.3-4.5). In cognitively intact patients, severe pain significantly increased the risk of delirium (RR 9.0, 95% CI 1.8-45.2). Using admission data, clinicians can identify patients at high risk for delirium following hip fracture. Avoiding opioids or using very low doses of opioids increased the risk of delirium. Cognitively intact patients with undertreated pain were nine times more likely to develop delirium than patients whose pain was adequately treated. Undertreated pain and inadequate analgesia appear to be risk factors for delirium in frail older adults.

  2. Establishing "abuse-deterrence equivalence" for generic abuse-deterrent opioid formulations: A proposed development framework.

    PubMed

    Setnik, Beatrice; Cone, Edward J

    2016-01-01

    Abuse-deterrent formulations are one strategy for mitigating the epidemic of prescription opioid abuse. Regulatory guidance documents describe the requirements for developing abuse-deterrent formulations of novel drugs and formulations; however, they do not address "abuse-deterrence equivalence" for generic formulations. As generics may be produced with different excipients and formulations compared to reference drugs, differences in their properties may impact their abuse-deterrent features. Currently, it is unclear what specific studies are needed to support generic abuse-deterrence claims. This commentary outlines several recommendations on the in vitro and in vivo testing required, including the conditions for conducting a human abuse potential study.

  3. Chronic Opioid Use is a Risk Factor for the Development of Central Sleep Apnea and Ataxic Breathing

    PubMed Central

    Walker, James M.; Farney, Robert J.; Rhondeau, Steven M.; Boyle, Kathleen M; Valentine, Karen; Cloward, Tom V.; Shilling, Kevin C.

    2007-01-01

    Background: Chronic opioid therapy for pain management has increased dramatically without adequate study of potential deleterious effects on breathing during sleep. Methods: A retrospective cohort study comparing 60 patients taking chronic opioids matched for age, sex, and body mass index with 60 patients not taking opioids was conducted to determine the effect of morphine dose equivalent on breathing patterns during sleep. Results: The apnea-hypopnea index was greater in the opioid group (43.5/h vs 30.2/h, p < .05) due to increased central apneas (12.8/h vs 2.1/h; p < .001). Arterial oxygen saturation (SpO2) in the opioid group was significantly lower during both wakefulness (difference 2.1%, p < .001) and non-rapid eye movement (NREM) sleep (difference 2.2%, p < .001) but not during rapid eye movement (REM) sleep (difference 1.2%) than in the nonopioid group. Within the opioid group, and after controlling for body mass index, age, and sex, there was a dose-response relationship between morphine dose equivalent and apnea-hypopnea (p < .001), obstructive apnea (p < .001), hypopnea (p < .001), and central apnea indexes (p < .001). Body mass index was inversely related to apnea-hypopnea index severity in the opioid group. Ataxic or irregular breathing during NREM sleep was also more prevalent in patients who chronically used opioids (70% vs 5.0%, p < .001) and more frequent (92%) at a morphine dose equivalent of 200 mg or higher (odds ratio = 15.4, p = .017). Conclusions: There is a dose-dependent relationship between chronic opioid use and the development of a peculiar pattern of respiration consisting of central sleep apneas and ataxic breathing. Although potentially significant, the clinical relevance of these observations remains to be established. Citation: Walker JM; Farney RJ; Rhondeau SM; Boyle KM; Cloward TV; Shilling KC. Chronic opioid use is a risk factor for the development of central sleep apnea and ataxic breathing. J Clin Sleep Med 2007

  4. [Opioid overdose].

    PubMed

    Reingardiene, Dagmara; Vilcinskaite, Jolita

    2002-01-01

    The dangers of opioid overdose have been recognized for as long as the use of opium itself. When used correctly for medical purposes, opioids are remarkably safe and effective agents. However, excessive dosing, whether with therapeutic, suicidal, or euphoric intent, may results in significant toxicity. In a number of countries the use of heroin and other opioids in nonmedical contexts in associated with on increasing rate of overdose and often of fatal opioid overdose. This review article discusses opioid-receptor pharmacology, which is necessary for understanding of the signs and symptoms of opioid ingestion and management principles, clinical and toxic effects mediated with the opioids, the diagnosis and management guidelines in opioid intoxication, a clinical prediction rule to identify patients who can be safely discharge from hospital, the problems of the significant morbidity and mortality associated with opioid overdose.

  5. Developing a framework of care for opioid medication misuse in community pharmacy

    PubMed Central

    Gordon, Adam J.; Field, Craig; Bacci, Jennifer; Dhital, Ranjita; Ylioja, Thomas; Stitzer, Maxine; Kelly, Thomas; Tarter, Ralph

    2016-01-01

    Background Prescription opioid misuse is a major public health concern in the US. Few resources exist to support community pharmacists engaging patients who misuse or are at risk for misuse. Objectives This report describes the results of the execution of the ADAPT-ITT model (a model for modifying evidence-based behavioral interventions to new populations and service settings) to guide the development of a behavioral health framework for opioid medication misuse in the community pharmacy setting. Methods Pharmacy, addiction, intervention, and treatment experts were convened to attend a one-day meeting to review the empirical knowledgebase and discuss adapting the screening, brief intervention, and referral to treatment (SBIRT) protocol for addressing opioid medication misuse in community pharmacy. Qualitative data gathered from the meeting were analyzed by 2 independent coders in a 2-cycle process using objective coding schemes. Percentage of agreement and Cohen’s Kappa were calculated to assess coder agreement. Results First-cycle coding identified 4 distinct themes, with coder percentage of agreement ranging from 93.5–99.6% and with Kappa values between 0.81–0.93. Second-cycle coding identified 10 sub-themes, with coder percentage of agreement ranging from 83–99.8% and with Kappa values between 0.58–0.93. Identified themes and sub-themes encompassed patient identification, intervention, prevention, and referral to treatment. Conclusions Focus of screening efforts in the emerging model should capitalize on pharmacists’ knowledge of medication management. Screening likewise should be multidimensional in order to facilitate patient-centered interventions that activate additional disciplines able to interface with patients at risk or involved in medication misuse. PMID:26048710

  6. Developing a framework of care for opioid medication misuse in community pharmacy.

    PubMed

    Cochran, Gerald; Gordon, Adam J; Field, Craig; Bacci, Jennifer; Dhital, Ranjita; Ylioja, Thomas; Stitzer, Maxine; Kelly, Thomas; Tarter, Ralph

    2016-01-01

    Prescription opioid misuse is a major public health concern in the US. Few resources exist to support community pharmacists engaging patients who misuse or are at risk for misuse. This report describes the results of the execution of the ADAPT-ITT model (a model for modifying evidence-based behavioral interventions to new populations and service settings) to guide the development of a behavioral health framework for opioid medication misuse in the community pharmacy setting. Pharmacy, addiction, intervention, and treatment experts were convened to attend a one-day meeting to review the empirical knowledgebase and discuss adapting the screening, brief intervention, and referral to treatment (SBIRT) protocol for addressing opioid medication misuse in community pharmacy. Qualitative data gathered from the meeting were analyzed by 2 independent coders in a 2-cycle process using objective coding schemes. Percentage of agreement and Cohen's Kappa were calculated to assess coder agreement. First-cycle coding identified 4 distinct themes, with coder percentage of agreement ranging from 93.5 to 99.6% and with Kappa values between 0.81 and 0.93. Second-cycle coding identified 10 sub-themes, with coder percentage of agreement ranging from 83 to 99.8% and with Kappa values between 0.58 and 0.93. Identified themes and sub-themes encompassed patient identification, intervention, prevention, and referral to treatment. Focus of screening efforts in the emerging model should capitalize on pharmacists' knowledge of medication management. Screening likewise should be multidimensional in order to facilitate patient-centered interventions that activate additional disciplines able to interface with patients at risk or involved in medication misuse. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Phased Development of Accident Tolerant Fue

    SciTech Connect

    Bragg-Sitton, Shannon M.; Carmack, W. Jon

    2016-09-01

    The United States Department of Energy (U.S. DOE) Advanced Fuels Campaign (AFC) has adopted a three-phase approach for the development and eventual commercialization of enhanced, accident tolerant fuel (ATF) for light water reactors (LWRs). Extending from 2012 to 2016, AFC is currently coming to the end of Phase 1 research that has entailed Feasibility Assessment and Prioritization for a large number of proposed fuel systems (fuel and cladding) that could provide improved performance under accident conditions. Phase 1 activities will culminate with a prioritization of concepts for both near-term and long-term development based on the available experimental data and modeling predictions. This process will provide guidance to DOE on what concepts should be prioritized for investment in Phase 2 Development/Qualification activities based on technical performance improvements and probability of meeting the aggressive schedule to insert a lead fuel rod (LFR) in a commercial power reactor by 2022. While Phase 1 activities include small-scale fabrication work, materials characterization, and limited irradiation of samples, Phase 2 will require development teams to expand to industrial fabrication methods, conduct irradiation tests under more prototypic reactor conditions (i.e. in contact with reactor primary coolant at LWR conditions and in-pile transient testing), conduct additional characterization and post-irradiation examination, and develop a fuel performance code for the candidate ATF. Phase 2 will culminate in the insertion of an LFR (or lead fuel assembly) in a commercial power reactor. The Phase 3 Commercialization work will extend past 2022. Following post-irradiation examination of LFRs, partial-core reloads will be demonstrated. The commercialization phase will further entail the establishment of commercial fabrication capabilities and the transition of LWR cores to the new fuel. The three development phases described roughly correspond to the technology

  8. Opioid Receptors.

    PubMed

    Stein, Christoph

    2016-01-01

    Opioids are the oldest and most potent drugs for the treatment of severe pain. Their clinical application is undisputed in acute (e.g., postoperative) and cancer pain, but their long-term use in chronic pain has met increasing scrutiny. This article reviews mechanisms underlying opioid analgesia and other opioid actions. It discusses the structure, function, and plasticity of opioid receptors; the central and peripheral sites of analgesic actions and side effects; endogenous and exogenous opioid receptor ligands; and conventional and novel opioid compounds. Challenging clinical situations, such as the tension between chronic pain and addiction, are also illustrated.

  9. [Opioids in chronic neuropathic pain. A systematic review and meta-analysis of efficacy, tolerability and safety in randomized placebo-controlled studies of at least 4 weeks duration].

    PubMed

    Sommer, C; Welsch, P; Klose, P; Schaefert, R; Petzke, F; Häuser, W

    2015-02-01

    The efficacy and safety of opioid therapy in chronic neuropathic pain (CNP) is under debate. We updated a recent Cochrane systematic review on the efficacy, tolerability and safety of opioids in CNP. We screened MEDLINE, Scopus and the Cochrane Central Register of Controlled Trials (CENTRAL) up until October 2013, as well as the reference sections of original studies and systematic reviews of randomized controlled trials (RCTs) of opioids in CNP. We included double-blind randomized placebo-controlled studies of at least 4 weeks duration. Using a random effects model, absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables. We included 12 RCTs with 1192 participants. The included diagnostic entities were painful diabetic neuropathy (four studies), postherpetic neuralgia (three studies), mixed polyneuropathic pain (two studies), and lumbar root, spinal cord injury and postamputation pain (one study each). Mean study duration was 6 (4-12) weeks. Four studies tested morphine, three studies tramadol, two studies oxycodone and one study tapentadol. These are the pooled results of studies with a parallel or cross-over design: opioids were superior to placebo in reducing pain intensity (SMD - 0.64 [95 % confidence interval, CI - 0.81, - 0.46], p < 0.0001; 11 studies with 1040 participants). Opioids were not superior to placebo in 50 % pain reduction (RD 0.16 [95 % CI - 0.04, 0.35], p = 0.11; one study with 93 participants). Opioids were not superior to placebo in reports of much or very much improved pain (RD 0.17 [95 % CI - 0.01, 0.36], p = 0.07; one study with 53 participants). Opioids were superior to placebo in improving physical functioning (SMD - 0.28 [95 % CI - 0.43, - 0.13], p < 0.0001; seven studies with 680 participants). Patients dropped out less frequently due to lack of efficacy with opioids than with placebo (RD - 0

  10. [Opioids in chronic osteoarthritis pain. A systematic review and meta-analysis of efficacy, tolerability and safety in randomized placebo-controlled studies of at least 4 weeks duration].

    PubMed

    Schaefert, R; Welsch, P; Klose, P; Sommer, C; Petzke, F; Häuser, W

    2015-02-01

    The efficacy, tolerability and safety of opioid therapy in chronic osteoarthritis (OA) pain is under debate. We updated a Cochrane systematic review on the efficacy and safety of opioids in chronic OA pain published in 2009. We screened MEDLINE, Scopus and the Cochrane Central Register of Controlled Trials (CENTRAL) up until October 2013, as well as reference sections of original studies and systematic reviews of randomized controlled trials (RCTs) of opioids in chronic osteoarthritis (OA) pain. We included double-blind randomized placebo-controlled studies lasting ≥ 4 weeks. Using a random effects model, absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables. We included 20 RCTs with 33 treatment arms and 8545 participants. Median study duration was 12 (4-24) weeks. Oxycodone and tramadol were each tested in six studies; buprenorphine, hydromorphone, morphine and tapentadol each in two studies and codeine, fentanyl and oxymorphone in one study each. Results are reported with 95 % confidence intervals (CIs). Opioids were superior to placebo in reducing pain intensity (SMD - 0.22 [- 0.28, - 0.17], p < 0.00001; 16 studies with 6743 participants). Opioids were not superior to placebo in 50 % pain reduction (RD - 0.00 [- 0.07, 0.07], p = 0.96; two studies with 2684 participants). Opioids were superior to placebo in terms of reports of much or very much global improvement (RD 0.13 [0.05, 0.21], p = 0.002; three studies with 2251 participants). Opioids were superior to placebo in improving physical functioning (SMD - 0.22 [- 0.28, - 0.17], p < 0.00001; 14 studies with 5887 participants). Patients dropped out more frequently with opioids than with placebo (RD 0.17 [0.14, 0.21], p < 0.00001; 15 studies with 6834 participants; number needed to harm 5 [4-6]. There was no significant difference between opioids and placebo in the

  11. Development of an opioid self-administration assay to study drug seeking in zebrafish.

    PubMed

    Bossé, Gabriel D; Peterson, Randall T

    2017-09-29

    The zebrafish (Danio rerio) has become an excellent tool to study mental health disorders, due to its physiological and genetic similarity to humans, ease of genetic manipulation, and feasibility of small molecule screening. Zebrafish have been shown to exhibit characteristics of addiction to drugs of abuse in non-contingent assays, including conditioned place preference, but contingent assays have been limited to a single assay for alcohol consumption. Using inexpensive electronic, mechanical, and optical components, we developed an automated opioid self-administration assay for zebrafish, enabling us to measure drug seeking and gain insight into the underlying biological pathways. Zebrafish trained in the assay for five days exhibited robust self-administration, which was dependent on the function of the μ-opioid receptor. In addition, a progressive ratio protocol was used to test conditioned animals for motivation. Furthermore, conditioned fish continued to seek the drug despite an adverse consequence and showed signs of stress and anxiety upon withdrawal of the drug. Finally, we validated our assay by confirming that self-administration in zebrafish is dependent on several of the same molecular pathways as in other animal models. Given the ease and throughput of this assay, it will enable identification of important biological pathways regulating drug seeking and could lead to the development of new therapeutic molecules to treat addiction. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Efficacy and tolerability of buccal buprenorphine in opioid-experienced patients with moderate to severe chronic low back pain: results of a phase 3, enriched enrollment, randomized withdrawal study

    PubMed Central

    Gimbel, Joseph; Spierings, Egilius L.H.; Katz, Nathaniel; Xiang, Qinfang; Tzanis, Evan; Finn, Andrew

    2016-01-01

    Abstract A buccal film of buprenorphine (BBUP) was evaluated for safety and efficacy in a multicenter, double-blind, placebo-controlled, enriched-enrollment, randomized-withdrawal study in opioid-experienced patients (30 to ≤160 mg/d morphine sulfate equivalent) with moderate to severe chronic low back pain taking around-the-clock opioid analgesics. Patients' opioid doses were tapered to ≤30 mg morphine sulfate equivalent before open-label titration with BBUP (range, 150-900 μg every 12 hours). Patients who responded (received adequate analgesia that was generally well tolerated for 14 days) were randomized to receive buprenorphine (n = 254) or placebo (n = 257) buccal film. The primary efficacy variable was the change from baseline to week 12 of double-blind treatment in mean average daily pain-intensity scores using a rating scale of 0 (no pain) to 10 (worst pain imaginable). In the intent-to-treat population, mean pain scores were 6.7 after opioid taper and declined to 2.8 after the BBUP titration period. After randomization, mean pain scores were lower in the BBUP group than in the placebo group; the difference between groups in the mean change from baseline to week 12 was −0.98 (95% CI, −1.32 to −0.64; P < 0.001). A significantly larger percentage of patients receiving BBUP than placebo had pain reductions ≥30% and ≥50% (P < 0.001 for both). In the double-blind portion of the study, the only adverse event reported more frequently with BBUP than placebo and in ≥5% of patients was vomiting (5.5% vs 2.3%). These findings demonstrate the efficacy and tolerability of BBUP in opioid-experienced patients taking around-the-clock opioid treatment for chronic low back pain. PMID:27434505

  13. Characterization of 6α- and 6β-N-Heterocyclic Substituted Naltrexamine Derivatives as Novel Leads to Development of Mu Opioid Receptor Selective Antagonists

    PubMed Central

    2011-01-01

    As important pharmacological probes, highly selective opioid receptor antagonists are essential in opioid receptor structural characterization and opioid agonist functional studies. At present, a nonpeptidyl, highly selective, and reversible mu opioid receptor antagonist is still not available. Among a series of novel naltrexamine derivatives that have been designed and synthesized following molecular modeling studies, two compounds, NAP and NAQ, were identified as leads based on the results of in vitro and in vivo pharmacological assays. Both of them displayed high binding affinity and selectivity to the mu opioid receptor. Further pharmacokinetic and functional characterization revealed that NAP seems to be a peripheral nervous system agent while NAQ seems to be a central one. Such characteristics provide two distinguished potential application routes for these two agents and their derivatives. These results also supported our hypothesis that they may serve as leads to develop more potent and selective antagonists for the mu opioid receptor. PMID:22816021

  14. 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.

  15. 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

  16. DEVELOPMENT OF CRYSTAL-TOLERANT WASTE GLASSES

    SciTech Connect

    Matyas, Josef; Vienna, John D.; Kimura, Akihiko; Schaible, Micah J.; Tate, Rachel M.

    2010-10-26

    The loading of high-level waste in borosilicate glasses is limited by crystallinity constraints that cannot prevent crystal accumulation on the melter bottom and in the glass discharge riser of the melter. Pacific Northwest National Laboratory is studying variations in composition that are designed to constrain high-level waste glass compositions and develop the crystal-tolerant high-level waste glasses. These glasses will allow high waste loading without decreasing the lifetime of the melter by keeping the small spinel crystals suspended in the molten glass. Adding ~1 wt% of NiO to the baseline glass caused large spinel crystals to form up to 210 µm in size and resulted in the highest accumulation rate, ~ 227 mm/year, of all tested glasses. Noble metals that were added to high-Ni glass prevented large spinel crystals from forming and decreased the accumulation rate ~ 8.5 times. Adding ~5 wt% of Fe2O3 to the baseline glass resulted in a high number density of ~10-μm spinel crystals that remained suspended in the glass melt even after 17 days at 850°C. The accumulation rate of spinel crystals in high-chromia crucibles was only slightly higher compared with the accumulation rate in double crucibles. Only baseline glass exhibited about 2.6 times faster accumulation rate because of increased number of bigger crystals. These crystals were the result of glass enrichment with chromium that was leached out from the walls of high-chromia crucibles.

  17. Opioid use in young veterans.

    PubMed

    Wu, Phipson C; Lang, Courtney; Hasson, Noelle K; Linder, Steven H; Clark, David J

    2010-01-01

    Data suggest an increase in prescription opioid abuse in recent years. Young veterans represent a group with major risk factors for prescription opioid abuse. The objectives of this study are: (A) to determine the prevalence of chronic opioid use in young veterans over time; (B) to describe the prescribing patterns and monitoring of chronic opioid therapy in young veterans; and (C) to assess opioid management within Veterans Affairs Palo Alto Health Care System (VAPAHCS) with an emphasis on effectiveness and safety. This is a Veterans Affairs Research and Development (R&D) Committee and IRB-approved retrospective, single-center study of young veterans aged 18-30 years on chronic opioid therapy during the study years January 1, 2003, to October 1, 2008. A subset of the study population who were receiving long-acting opioids for a minimum of 6 months was included in the effectiveness and safety analyses. Data were obtained from the Veterans Integrated Service Network (VISN 21) data warehouse, outpatient prescription records, and from electronic chart review. The prevalence of chronic opioid use in young veterans has increased from 3 percent in 2003 to 4.5 percent in 2007. Patients on average were exposed to two different opioids and had three different opioid prescribers. Nearly 80 percent of the opioid prescriptions during the study were prescribed by primary care providers and less than 1 percent was from pain specialists. Only 31 percent of patients on chronic opioids had undergone urine drug testing and only 5 percent had signed opioid treatment agreements. No difference in median pain score was observed following initiation of long-acting opioid therapy, and 22 percent of patients (4 of 18) met the prespecified definition of being a responder to long-acting opioid therapy. Five patients (28 percent) on long-acting opioids experienced adverse drug reactions. The prevalence of chronic opioid use in young veterans has been on the rise in recent years. Young

  18. Opioid switch in palliative care, opioid choice by clinical need and opioid availability.

    PubMed

    Müller-Busch, H C; Lindena, G; Tietze, K; Woskanjan, S

    2005-10-01

    Availability of different WHO-step 3 opioids has encouraged the discussion on their value and led to the concepts of opioid rotation. Rotation is suggested, when other measures fail to achieve optimal analgesia and tolerability in cancer pain treatment. Opioid use was assessed in a prospective cohort study of 412 palliative care patients from 14 inpatient and outpatient palliative care facilities in Germany. The most frequently used opioids at baseline were morphine and fentanyl. The most frequent changes in medication (N=106) occurred from oral to parenteral morphine. Only in 49 cases true switches to other long acting opioids were recorded. This is far less than expected from other reports. True switches and adverse side effects were found to occur more frequently in inpatients, while efficacy problems were more frequently recorded in outpatients. There was no correlation between the opioid used at baseline and switch frequency, but numbers of cases receiving other opioids than fentanyl or morphine were low. Reasons for and frequencies of changes in medication were found to be largely shaped by the setting reflecting patients' needs and clinical necessities. Recommendation of first line therapy and availability of opioid formulations define the frequency of opioid use. This impedes evaluation of specific differences between the opioids.

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

    PubMed Central

    Trudeau, Kimberlee J.

    2016-01-01

    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 60 items for three criteria: importance, confidence in own answer, confidence in others’ answer. 3) Highly rated items were included in a revised survey that was tested with coalition members (n=10) using in-person cognitive interviewing to assess how coalition members were interpreting the questions. 4) Lastly, pre-testing and satisfaction testing with additional coalition members (n=30). Most (83%) of the respondents reported positive overall impressions of the survey. PMID:27516644

  20. Combination opioid analgesics.

    PubMed

    Smith, Howard S

    2008-01-01

    Although there is no "ideal analgesic," scientists and clinicians alike continue to search for compounds with qualities which may approach the "ideal analgesic." Characteristics of an "ideal" analgesic may include: the agent is a full agonist providing optimal/maximal analgesia for a wide range/variety of pain states (e.g., broad spectrum analgesic activity), it does not exhibit tolerance, it produces no unwanted effects and minimal adverse effects, it has no addictive potential, it does not facilitate pain/hyperalgesia, it has a long duration, it has high oral bioavailability, it is not vulnerable to important drug interactions, it is not significantly bound to plasma proteins, it has no active metabolites, it has linear kinetics, and it is eliminated partly by hydrolysis to an inactive metabolite (without involvement of oxidative and conjugative enzymes). Investigators have concentrated on ways to alter existing analgesics or to combine existing analgesic compounds with compounds which may improve efficacy over time or minimize adverse effects. The addition of an analgesic with a second agent (which may or may not also be an analgesic) to achieve a "combination analgesic" is a concept which has been exploited for many years. Although there may be many reasons to add 2 agents together in efforts to achieve analgesia, for purposes of this article - reasons for combining an opioid with a second agent to produce a combination opioid analgesic may be classified into 6 major categories: 1.) combinations to prolong analgesic duration; 2.) combinations to enhance or optimize analgesic efficacy (e.g., analgesic synergy); 3.) combinations to diminish or minimize adverse effects; 4.) combinations to diminish opioid effects which are not beneficial (or contrariwise to or enhance beneficial opioid effects); 5.) combinations to reduce opioid tolerance/opioid-induced hyperalgesia; and 6.) combinations to combat dependency issues/addiction potential/craving sensations

  1. 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

  2. [Opioids in chronic low back pain. A systematic review and meta-analysis of efficacy, tolerability and safety in randomized placebo-controlled studies of at least 4 weeks duration].

    PubMed

    Petzke, F; Welsch, P; Klose, P; Schaefert, R; Sommer, C; Häuser, W

    2015-02-01

    dropped out more frequently with opioids than with placebo due to adverse events (RD 0.12 [0.05, 0.19], p = 0.0007; six studies with 2910 participants; number needed to harm (NNTH) 7 [95 % CI 6-8]). There was no significant difference between opioids and placebo in terms of the frequency of serious adverse events or deaths. Opioids were superior to placebo in terms of efficacy and inferior in terms of tolerability. Opioids and placebo did not differ in terms of safety during the study period. The conclusion on the safety of opioids compared to placebo is limited by the low number of serious adverse events and deaths. Short-term and intermediate-term opioid therapy may be considered in selected CLBP patients. The English full-text version of this article is freely available at SpringerLink (under "Supplemental").

  3. Development and implementation of a pharmacist-managed, neonatal and pediatric, opioid-weaning protocol.

    PubMed

    Johnson, Melissa R; Nash, David R; Laird, Mary R; Kiley, Robert C; Martinez, Michael A

    2014-07-01

    To compare the length of wean and abstinence severity in neonatal and pediatric patients with neonatal abstinence syndrome or iatrogenic opioid dependence treated with a pharmacist-managed, methadone-based protocol compared with physician-managed patients treated with either methadone or dilute tincture of opium (DTO). This was a prospective, single-centered, interventional evaluation of 54 pharmacist-managed patients versus 53 retrospective, physician-managed patients. Wean duration and severity of neonatal abstinence syndrome were compared between groups using the Student t test. Significantly shorter wean duration in in utero-exposed pharmacist-managed patients compared with patients on physician-managed DTO (11.7 days vs 24.2 days, p < 0.001), but not compared with patients on physician-managed methadone (11.7 days vs 47 days, p = 0.101). No statistically significant difference was seen in wean duration in iatrogenic-exposed pharmacist-managed patients compared with patients on either physician-managed DTO or methadone (8.69 days vs 14 days, p = 0.096) and (8.69 days vs 9.82 days, p = 0.34), respectively. There were significantly fewer abstinence scores >12 in pharmacist-managed patients versus physician-managed DTO, but not physician-managed methadone (2.05 vs 17.3, p = 0.008 and 2.05 vs 74.3, p = 0.119, respectively). Significantly fewer abstinence scores ≥8 × 3 consecutively were seen in pharmacist-managed patients compared with patients on either physician-managed DTO or methadone (2.89 vs 11.9, p = 0.01 and 2.89 vs 24, p < 0.001, respectively). Use of a pharmacist-managed, methadone-based weaning protocol standardizes patient care and has the potential to decrease abstinence severity and shorten duration of wean versus physician-managed patients exposed to opioids in utero. Additionally, a methadone wean of 10% to 20% per day was well tolerated in both neonatal and pediatric patients.

  4. Development of transgenic imazapyr-tolerant cowpea (Vigna unguiculata).

    PubMed

    Citadin, C T; Cruz, A R R; Aragão, F J L

    2013-04-01

    Here we present the development of cowpea lines tolerant to a herbicide from imidazoline class (imazapyr). Plants presented tolerance to fourfold the commercial recommended dose for weed control. Cowpea is one of the most important and widely cultivated legumes in many parts of the world. Its cultivation is drastically affected by weeds, causing damages during growth and development of plants, competing for light, nutrients and water. Consequently, weed control is critical, especially using no-tillage farming systems. In tropical regions, no-till farming is much easier with the use of herbicides to control weeds. This study was conducted to evaluate the possibility of obtaining transgenic cowpea plants resistant to imidazolinone, which would facilitate weed control during the summer season. The biolistic process was used to insert a mutated acetohydroxyacid synthase coding gene (Atahas) which confers tolerance to imazapyr. The transgene integration was confirmed by Southern blot analysis. Out of ten lines tested for tolerance to 100 g ha(-1) imazapyr, eight presented some tolerance. One line (named 59) revealed high herbicide tolerance and developmental growth comparable to non-transgenic plants. This line was further tested for tolerance to higher herbicide concentrations and presented tolerance to 400 g ha(-1) imazapyr (fourfold the commercial recommended dose) with no visible symptoms. Line 59 will be the foundation for generating imidazolinone-tolerant cowpea varieties, which will facilitate cultivation of this crop in large areas.

  5. Opioid-induced Cardioprotection

    PubMed Central

    Tanaka, Katsuya; Kersten, Judy R.; Riess, Matthias L.

    2014-01-01

    Ischemic heart disease and myocardial infarction continue to be leading causes of cardiovascular morbidity and mortality. Activation of opioid, adenosine, bradykinin, adrenergic and other G-protein coupled receptors have been found to be cardioprotective. κ- and/or δ-opioid receptor activation is involved in direct myocardial protection, while the role of μ-opioid receptors seems less clear. In addition, differential affinities to the three opioid-receptor subtypes by various agonists and cross-talk among different G-protein coupled receptors render conclusions regarding opioid-mediated cardioprotection challenging. The present review will focus on the protective effects of endogenously released opioid peptides as well as exogenously administered opioids such as morphine, fentanyl, remifentanil, butorphanol, and methadone against myocardial ischemia/reperfusion injury. Receptor heterodimerization and cross-talk as well as interactions with other cardioprotective techniques will be discussed. Implications for opioid-induced cardioprotection in humans and for future drug development to improve myocardial salvage will be provided. PMID:24502571

  6. 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…

  7. 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…

  8. 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

    2016-01-04

    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.

  9. On subclasses of opioid analgesics.

    PubMed

    Raffa, Robert B

    2014-12-01

    The history of discovery of analgesic drugs has followed a trajectory from original serendipitous discovery of plant-derived substances to laboratory creation of customized molecules that are intentionally designed to interact with specific receptors of neurotransmitters involved in either the transmission of the pain signal or the attenuation of such a signal. The drugs most recently developed have been designed to provide incremental greater separation between pain relief and adverse effects. The result has been drugs that have individualized pharmacodynamic and pharmacokinetic characteristics that represent specific advances in basic science and translate into unique clinical profiles. Several of the drugs include non-opioid components. They retain some of the features of opioids, but have distinct clinical characteristics that differentiate them from traditional opioids. Thus they defy simple classification as opioids. A summary is provided of the development of the modern view of multi-mechanistic pain and its treatment using analgesics that have multi-mechanisms of action (consisting of both opioid and non-opioid components). Descriptions of examples of such current analgesics and of those that have pharmacokinetic characteristics that result in atypical opioid clinical profiles are given. By serendipity or design, several current strong analgesics have opioid components of action, but have an additional non-opioid mechanism of action or some pharmacokinetic feature that gives them an atypical opioid clinical profile and renders them not easily classified as classical opioids. An appreciation that there are now opioid analgesics that differentiate from classical opioids in ways that defy their simplistic classification as opioids suggests that recognition of subclasses of opioid analgesics would be more accurate scientifically and would be more informative for healthcare providers and regulators. This would likely lead to positive outcomes for the clinical

  10. High-fat diet alters the dopamine and opioid systems: effects across development

    PubMed Central

    Reyes, T M

    2012-01-01

    Consumption of a high-fat diet has been linked to obesity, dyslipidemia and cardiovascular disease. Less well appreciated are adverse effects on the brain and behavior. Recent research has shown that consumption of a high-fat diet can alter gene expression within the brain, and the dopamine and opioid neurotransmitter systems appear to be vulnerable to dysregulation. This review will focus on recent reports in both humans and animal models that describe adverse effects of high-fat diet consumption on the central reward circuitry. In addition, the importance of different development windows will be discussed, with effects observed in both the prenatal/perinatal time period and with chronic high-fat diet consumption in adulthood. PMID:27152150

  11. Expression of delta- and mu-opioid receptors in the ventricular and subventricular zones of the developing human neocortex.

    PubMed

    Tripathi, Anushree; Khurshid, Nazia; Kumar, Praveen; Iyengar, Soumya

    2008-07-01

    Recent research has documented the involvement of the endogenous opioid system in neural development, including neurogenesis and neuronal differentiation. However, the expression of opioid receptors (ORs) in different cell types of the human ventricular and subventricular zones (VZ and SVZ) has not been studied during early gestation. In the present study, we have used immunohistochemistry and quantified the results to demonstrate that the levels of delta- and mu-OR subtypes were high in the VZ and SVZ between 11 and 16 gestation weeks (GW) and decreased by 20GW. These results have also been confirmed by studying OR mRNA expression in the VZ and SVZ. Both delta- and mu-OR subtypes were expressed by multipotential stem cells, newly differentiated neurons and developing glial cells to different extents. However, migrating neurons expressed negligible levels of both OR subtypes. Our results suggest that the opioid system may affect cellular proliferation and/or differentiation of stem cells into neurons and glia during the first and second trimesters of gestation in humans. Since layers II and III of the cerebral cortex are being formed during the second trimester, their development is most likely affected by the opioid system mediated through delta- and mu-ORs.

  12. Use of Ultra Rapid Opioid Detoxification in the Treatment of US Military Burn Casualties

    DTIC Science & Technology

    2011-07-01

    physical dependence or addiction often develop tolerance from chronic use of exogenous opioid medications, requiring escalating doses to control pain...detoxification trials have been viewed as high-risk from sedative and anesthetic complications but low -yield or benefit because relapse rates are often...discontinuation or decrement in opioid dosing . Although the efficacy of URODA is debated, careful patient selection may predict successful therapeutic

  13. Tolerance and sensitization to chronic escalating-dose heroin following extended withdrawal in Fischer rats: possible role of mu-opioid receptors

    PubMed Central

    Seip-Cammack, Katharine M.; Reed, Brian; Zhang, Yong; Ho, Ann; Kreek, Mary Jeanne

    2012-01-01

    Rationale/objectives Heroin addiction is characterized by recurrent cycles of drug use, abstinence and relapse. It is likely that neurobiological changes during chronic heroin exposure persist across withdrawal and impact behavioral responses to re-exposure. We hypothesized that, after extended withdrawal, heroin-withdrawn rats would express behavioral tolerance and/or sensitization in response to heroin re-exposure and that these responses might be associated with altered mu-opioid receptor (MOPr) activity. Methods Male Fischer rats were exposed chronically to escalating doses of heroin (7.5–75mg/kg/day), experienced acute spontaneous withdrawal and extended (10-day) abstinence, and were re-exposed chronically to heroin. Homecage behaviors and locomotor activity in response to heroin, as well as somatic withdrawal signs, were recorded. Separate groups of rats were sacrificed after extended abstinence and MOPr expression and G-protein coupling were analyzed using [3H]DAMGO and [35S]GTPγS assays. Results The depth of behavioral stupor was lower during the initial days of heroin re-exposure compared to the initial days of the first exposure period. Behavioral responses (e.g., stereotypy) and locomotion were elevated in response to heroin re-exposure at low doses. Rats conditioned for heroin place preference during the chronic re-exposure period expressed heroin preference during acute withdrawal; this preference was stronger than rats conditioned during chronic heroin exposure that followed chronic saline and injection-free periods. Extended withdrawal was associated with increased MOPr expression in the caudate-putamen and frontal and cingulate cortices. No changes in G-protein coupling were identified. Conclusions Aspects of tolerance/sensitization to heroin are present even after extended abstinence and may be associated with altered MOPr density. PMID:22829433

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

    PubMed Central

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

    2016-01-01

    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

  15. Examining the role of mu opioid receptor endocytosis in the beneficial and side-effects of prolonged opioid use: From a symposium on new concepts in mu-opioid pharmacology

    PubMed Central

    Whistler, Jennifer L.

    2014-01-01

    Opioid drugs remain the gold standard for the treatment of severe pain, both acute/post-surgical and chronic. However, the utility of opioid drugs for the treatment of chronic pain is compromised by the development of analgesic tolerance which, in turn, leads to dose-escalation and increased likelihood of dangerous side effects, including dependence. Consequently, there remains resistance among clinicians and the general population to using opiates for pain management because of risk of “addiction.” These fears are not unwarranted. More than 2.5 million people begin abusing opioid painkillers each year, and prescription opioid abuse is now the second most common type of illegal drug use after marijuana. Some abusers become dependent due to recreational use of prescription painkillers. However, many abusers are among the 40 million people suffering from chronic pain, and developed dependence while using the drugs for legitimate purposes. Both of these trends highlight the need to develop opioid therapeutics with a reduced liability to cause tolerance, dependence and addiction. Identifying the ideal properties of opioid drugs that would retain analgesia but reduce these side-effects has been a goal of my laboratory for more than a decade. During this time, we have proposed the novel hypothesis that opioid drugs that promote desensitization, endocytosis and recycling of the mu-opioid-receptor (MOR) will retain analgesic efficacy, but will have a reduced liability to cause tolerance, dependence and addiction. We have generated substantial data, both pharmacological and genetic to suggest that our hypothesis is a valid one. These data are summarized in this review. PMID:22226706

  16. Blockade of NMDA receptors prevents analgesic tolerance to repeated transcutaneous electrical nerve stimulation (TENS) in rats

    PubMed Central

    Hingne, Priyanka M.; Sluka, Kathleen A.

    2008-01-01

    Repeated daily application transcutaneous electrical nerve stimulation (TENS) results in tolerance, at spinal opioid receptors, to the anti-hyperalgesia produced by TENS. Since N-Methyl-D-Aspartate (NMDA) receptor antagonists prevent analgesic tolerance to opioid agonists we hypothesized that blockade of NMDA receptors will prevent tolerance to TENS. In rats with knee joint inflammation, TENS was applied for 20 minute daily at high frequency (100 Hz), low frequency (4 Hz), or sham TENS. Rats were treated with the NMDA antagonist MK-801 (0.01 mg/kg-0.1 mg/kg) or vehicle daily before TENS. Paw withdrawal thresholds were tested before and after inflammation, and before and after TENS treatment for 4 days. On day 1 TENS reversed the decreased mechanical withdrawal threshold induced by joint inflammation. On day 4 TENS had no effect on the decreased withdrawal threshold in the group treated with vehicle demonstrating development of tolerance. However, in the group treated with 0.1 mg/kg MK-801, TENS significantly reversed the mechanical withdrawal thresholds on day 4 demonstrating that tolerance did not develop. Vehicle treated animals developed cross-tolerance at spinal opioid receptors. Treatment with MK-801 reversed this cross-tolerance at spinal opioid receptors. In summary, blockade of NMDA receptors prevents analgesic tolerance to daily TENS by preventing tolerance at spinal opioid receptors. Perspective Tolerance observed to the clinical treatment of TENS could be prevented by administration of pharmaceutical agents with NMDA receptors activity such as ketamine or dextromethorphan. PMID:18061543

  17. 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. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. Development of imidazolinone herbicide tolerant borage (Borago officinalis L.).

    PubMed

    Song, Dongyan; Wu, Guohai; Vrinten, Patricia; Qiu, Xiao

    2017-09-01

    Borage (Borago officinalis) is an annual herb that produces a high level of gamma-linolenic acid (GLA) in its seed oil. Due to the recognized health benefits of GLA, borage is now commercially cultivated worldwide. However, an herbicide-tolerant variety for effective weed management has not yet been developed. Here we report the generation and characterization of ethyl methanesulfonate (EMS) induced borage mutant lines tolerant to the herbicide imidazolinone. An EMS-mutagenized borage population was generated by using a series of concentrations of EMS to treat mature borage seeds. Screening of the M2 and M3 borage plants using an herbicide treatment resulted in the identification of two imidazolinone-tolerant lines. Sequence analysis of two acetohydroxyacid synthase (AHAS) genes, AHAS1 and AHAS2, from the mutant (tolerant) and wild type (susceptible) borage plants showed that single nucleotide substitutions which resulted in amino acid changes occurred in AHAS1 and AHAS2, respectively in the two tolerant lines. A KASP marker was then developed to differentiate the homozygous susceptible, homozygous tolerant and heterozygous borage plants. An in vitro assay showed that homozygous tolerant borage carrying the AHAS1 mutation retained significantly higher AHAS activity than susceptible borage across different imazamox concentrations. A herbicide dose response test indicated that the line with the AHAS1 mutation could tolerate four times the normally used field concentration of "Solo" herbicide. Copyright © 2017. Published by Elsevier B.V.

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

    PubMed Central

    2015-01-01

    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

  20. 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.

  1. Opioids and efflux transporters. Part 3: P-glycoprotein substrate activity of 3-hydroxyl addition to meperidine analogs.

    PubMed

    Mercer, Susan L; Cunningham, Christopher W; Eddington, Natalie D; Coop, Andrew

    2008-06-15

    Numerous studies have shown that many clinically employed opioid analgesics are substrates for P-glycoprotein (P-gp), suggesting that up-regulation of P-gp may contribute to the development of central tolerance to opioids. The studies herein focus on the development of SAR for P-gp substrate activity in the meperidine series of opioids. Addition of a 3-OH to meperidine and the ketone analog of meperidine yielding bemidone and ketobemidone, respectively, significantly increased P-gp substrate affinity. The results of this study have implications in the development of novel analgesics to be utilized as tools to study the contribution of P-gp on the development of central tolerance to opioids.

  2. Development of a Risk Index for Serious Prescription Opioid-Induced Respiratory Depression or Overdose in Veterans' Health Administration Patients.

    PubMed

    Zedler, Barbara; Xie, Lin; Wang, Li; Joyce, Andrew; Vick, Catherine; Brigham, Janet; Kariburyo, Furaha; Baser, Onur; Murrelle, Lenn

    2015-08-01

    Develop a risk index to estimate the likelihood of life-threatening respiratory depression or overdose among medical users of prescription opioids. A case-control analysis of administrative health care data from the Veterans' Health Administration identified 1,877,841 patients with a pharmacy record for an opioid prescription between October 1, 2010 and September 30, 2012. Overdose or serious opioid-induced respiratory depression (OSORD) occurred in 817. Ten controls were selected per case (n = 8,170). Items for an OSORD risk index (RIOSORD) were selected through logistic regression modeling, with point values assigned to each predictor. Modeling of risk index scores produced predicted probabilities of OSORD; risk classes were defined by the predicted probability distribution. Fifteen variables most highly associated with OSORD were retained as items, including mental health disorders and pharmacotherapy; impaired drug metabolism or excretion; pulmonary disorders; specific opioid characteristics; and recent hospital visits. The average predicted probability of experiencing OSORD ranged from 3% in the lowest risk decile to 94% in the highest, with excellent agreement between predicted and observed incidence across risk classes. The model's C-statistic was 0.88 and Hosmer-Lemeshow goodness-of-fit statistic 10.8 (P > 0.05). RIOSORD performed well in identifying medical users of prescription opioids within the Veterans' Health Administration at elevated risk of overdose or life-threatening respiratory depression, those most likely to benefit from preventive interventions. This novel, clinically practical, risk index is intended to provide clinical decision support for safer pain management. It should be assessed, and refined as necessary, in a more generalizable population, and prospectively evaluated. © 2015 The Authors Pain Medicine published by Wiley Periodicals, Inc. on behalf of American Academy of Pain Medicine.

  3. Preclinical pharmacology and opioid combinations.

    PubMed

    Pasternak, Gavril W

    2012-03-01

    Although effective alone, opioids are often used in combination with other drugs for relief of moderate to severe pain. Guidelines for acute perioperative pain recommend the use of multimodal therapy for pain management, although combinations of opioids are not specifically recommended. Mu opioid drugs include morphine, heroin, fentanyl, methadone, and morphine 6β-glucuronide (M6G). Their mechanism of action is complex, resulting in subtle pharmacological differences among them and with unpredictable differences in their potency, effectiveness, and tolerability among patients. Highly selective mu opioids do not bind to a single receptor. Rather, they interact with a large number of mu receptor subtypes with different activation profiles for the various drugs. Thus, mu-receptor-based drugs are not all the same and it may be possible to utilize these differences for enhanced pain control in a clinical setting. These differences among the drugs raise the question of whether combinations might result in better pain relief with fewer side effects. This concept has already been demonstrated between two mu opioids in preclinical studies and clinical trials on other combinations are ongoing. This article reviews the current state of knowledge about mu opioid receptor pharmacology, summarizes preclinical evidence for synergy from opioid combinations, and highlights the complex nature of the mu opioid receptor pharmacology.

  4. 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.).

  5. 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.

  6. Engagement of signaling pathways of protease-activated receptor 2 and μ-opioid receptor in bone cancer pain and morphine tolerance.

    PubMed

    Bao, Yanju; Gao, Yebo; Hou, Wei; Yang, Liping; Kong, Xiangying; Zheng, Honggang; Li, Conghuang; Hua, Baojin

    2015-09-15

    Pain is one of the most common and distressing symptoms suffered by patients with progression of cancer. Using a rat model of bone cancer, recent findings suggest that proteinase-activated receptor 2 (PAR2) signaling pathways contribute to neuropathic pain and blocking PAR2 amplifies antinociceptive effects of systemic morphine. The purpose of our study was to examine the underlying mechanisms responsible for the role of PAR2 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 PAR2 and its downstream pathways (protein kinases namely, PKCε and PKA) and transient receptor potential vanilloid 1 (TRPV1) were amplified in the dorsal horn of the spinal cord of bone cancer rats compared to control rats. Blocking spinal PAR2 by using FSLLRY-NH2 significantly attenuated the activities of PKCε/PKA signaling pathways and TRPV1 expression as well as mechanical and thermal hyperalgesia. Also, inhibition of PKCε/PKA and TRPV1 significantly diminished the hyperalgesia observed in bone cancer rats. Additionally, blocking PAR2 enhanced the attenuations of PKCε/PKA and cyclic adenosine monophosphate induced by morphine and further extended analgesia of morphine via μ-opioid receptor (MOR). Our data revealed specific signaling pathways, leading to bone cancer pain, including the activation of PAR2, downstream PKCε/PKA, TRPV1 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.

  7. Opioid-free anaesthesia in three dogs

    PubMed Central

    White, Donna M.; Mair, Alastair R.; Martinez-Taboada, Fernando

    2017-01-01

    Opioid-free anaesthesia (OFA) is a relatively new and growing field in human medicine. There are multiple motivations behind this emerging practice with the recognition of several serious potential opioid-related adverse effects including opioid induced hyperalgesia, opioid tolerance and immunomodulatory effects of opioids. Opioids have long been the mainstay of veterinary anaesthesia and pain management practice. The feasibility of OFA in veterinary patients is presented here. A case series of three dogs that underwent OFA for canine ovariohysterectomy is reported. The authors conclude OFA is possible in veterinary medicine; however the move away from the familiar effects of opioids perioperatively is challenging. Gaining experience with these types of protocols for standard procedures in healthy animals, such as neutering, will provide the anaesthetist with the building blocks for more invasive surgeries. PMID:28616391

  8. 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

  9. Magnesium enhances opioid-induced analgesia - What we have learnt in the past decades?

    PubMed

    Bujalska-Zadrożny, Magdalena; Tatarkiewicz, Jan; Kulik, Kamila; Filip, Małgorzata; Naruszewicz, Marek

    2017-03-01

    Opioids are increasingly used in alleviating pain, including cancer-related pain and postoperative pain. Unfortunately, the development of tolerance, the resistance of neuropathic pain on opioid analgesia or other undesirable effects may limit their utility. In order to reduce opioid doses, and thereby to avoid the risk of side effects and sudden deaths due to overdosing, attempts have been made to introduce co-analgesics. Due to an increasing amount of data concerning a potential enhance of opioid analgesia by the physiological antagonist of N-methyl-d-aspartate receptors, magnesium ions (Mg(2+)), a concomitant use of such a combination seems to be interesting from a clinical point of view. Therefore, the aim of this review is to provide an analysis of existing preclinical and clinical studies in the context of the benefits of using this combination in clinical practice. A potential mechanism of magnesium - opioid interaction is also suggested. The potential influence of Mg on opioid adverse/side effects as well as conclusions on the safety of combined administration of magnesium and opioid drugs were also summarized. Data from animal studies indicate that magnesium increases opioid analgesia in chronic (e.g., neuropathic, inflammatory) as well as acute pain. In clinical trials, most authors confirmed that magnesium reduces opioid consumption and alleviates postoperative pain scores while not increasing the risk of side effects after opioids. However, more clinical studies are needed concerning an influence of Mg on opioid activity in other difficult to treat types of pain, especially neuropathic and inflammatory. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2.

    PubMed

    Váradi, András; Marrone, Gina F; Palmer, Travis C; Narayan, Ankita; Szabó, Márton R; Le Rouzic, Valerie; Grinnell, Steven G; Subrath, Joan J; Warner, Evelyn; Kalra, Sanjay; Hunkele, Amanda; Pagirsky, Jeremy; Eans, Shainnel O; Medina, Jessica M; Xu, Jin; Pan, Ying-Xian; Borics, Attila; Pasternak, Gavril W; McLaughlin, Jay P; Majumdar, Susruta

    2016-09-22

    Natural products found in Mitragyna speciosa, commonly known as kratom, represent diverse scaffolds (indole, indolenine, and spiro pseudoindoxyl) with opioid activity, providing opportunities to better understand opioid pharmacology. Herein, we report the pharmacology and SAR studies both in vitro and in vivo of mitragynine pseudoindoxyl (3), an oxidative rearrangement product of the corynanthe alkaloid mitragynine. 3 and its corresponding corynantheidine analogs show promise as potent analgesics with a mechanism of action that includes mu opioid receptor agonism/delta opioid receptor antagonism. In vitro, 3 and its analogs were potent agonists in [(35)S]GTPγS assays at the mu opioid receptor but failed to recruit β-arrestin-2, which is associated with opioid side effects. Additionally, 3 developed analgesic tolerance more slowly than morphine, showed limited physical dependence, respiratory depression, constipation, and displayed no reward or aversion in CPP/CPA assays, suggesting that analogs might represent a promising new generation of novel pain relievers.

  11. Constant light exposure impairs immune tolerance development in mice.

    PubMed

    Mizutani, Hiromi; Tamagawa-Mineoka, Risa; Minami, Yoichi; Yagita, Kazuhiro; Katoh, Norito

    2017-04-01

    An intrinsic daily physiological rhythm called circadian rhythm has been indicated to affect the immune system and its related diseases. Immune tolerance development is closely associated with the onset of immunological disorders. However, the effect of circadian rhythm in the mechanisms of immune tolerance development has not yet been fully understood. The purpose of this study was to investigate the effects of circadian rhythm disruption on the development of immune tolerance by the perturbation of light environment, using a mouse model of neonatally induced cutaneous tolerance. Mice were kept under constant light (LL) or light-dark (LD) conditions, and hapten was applied at 2days after birth. Six weeks later, hapten was reapplied to abdominal skin, followed by hapten application to ear skin 5days later. The ear-swelling responses and cell infiltration into inflamed skin significantly increased in LL mice compared with those in LD mice. Interestingly, the percentage and the number of Foxp3(+)-regulatory T cells notably decreased in inflamed skin and draining lymph nodes of LL mice compared with that in LD mice. Loss-of-function mutation of a key circadian gene, Bmal1, also exacerbated the ear-swelling responses and cell infiltration into inflamed skin in mice. These results suggest that circadian rhythm may be implicated in immune tolerance development in allergic inflammation. Copyright © 2016 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

  12. Neuroendocrine effects of dexmedetomidine: evidence of cross-tolerance between a mu-opioid agonist and an alpha 2-adrenoceptor agonist in growth hormone secretion of the male rat.

    PubMed

    Idänpään-Heikkilä, J J; Rauhala, P; Männistö, P T

    1996-03-01

    The role of alpha 2-adrenergic receptors (adrenoceptors) in the secretion of growth hormone, prolactin and thyrotropin was studied using highly selective agonists and antagonists of the alpha 2-adrenoceptor. The interplay between opiates and alpha 2-adrenergic drugs in the acute secretion of growth hormone and prolactin, as well as the possible cross-tolerance between morphine (mu-opioid receptor agonist) and dexmedetomidine (alpha 2-adrenoceptor agonist) in growth hormone secretion were also evaluated. Dexmedetomidine dose-dependently increased plasma growth hormone and prolactin levels and decreased thyrotropin levels. The enhanced secretion of both growth hormone and prolactin was antagonized by atipamezole (an alpha 2-adrenoceptor antagonist) but not by prazosin (an alpha 1-adrenoceptor antagonist). Morphine (5 mg/kg)-induced stimulation of growth hormone secretion was antagonized by both naloxone (mu-opioid antagonist) and atipamezole. Naloxone, but not atipamezole, antagonized the morphine-induced increase in prolactin secretion. Dexmedetomidine increased growth hormone secretion in the saline pretreated rats, but did not do so in the morphine-tolerant rats. The stimulation of alpha 2-adrenoceptor enhances secretion of both growth hormone and prolactin. The adrenergic regulation of thyrotropin secretion still remains unclear. Evidently, adrenergic mechanisms are involved in the morphine-induced stimulation of growth hormone secretion, but not in the morphine-induced stimulation of prolactin secretion. In addition, there is a clear cross-tolerance between dexmedetomidine and morphine in growth hormone secretion of the rat.

  13. 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. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. Interactions between opioids and anabolic androgenic steroids: implications for the development of addictive behavior.

    PubMed

    Nyberg, Fred; Hallberg, Mathias

    2012-01-01

    Over the past decades, research on doping agents, such as anabolic androgenic steroids (AAS), has revealed that these compounds are often used in combination with other drugs of abuse. It seems that misuse of AAS probably involves more than a desire to enhance appearance or sports performance and studies have revealed that steroids are commonly connected with alcohol, opioids, tobacco, and psychotropic drugs. We have observed that AAS may interact with the endogenous opioids, excitatory amino acids, and dopaminergic pathways involved in the brain reward system. Furthermore, our studies provide evidence that AAS may induce an imbalance in these signal systems leading to an increased sensitivity toward opioid narcotics and central stimulants. In fact, studies performed in various clinics have shown that individuals taking AAS are likely to get addicted to opioids like heroin. This chapter reviews current knowledge on interactions between AAS and endogenous as well as exogenous opioids based not only on research in our laboratory but also on research carried out by several other clinical and preclinical investigators.

  15. Opioid dependence

    PubMed Central

    2009-01-01

    Introduction Dependence on opioids is a multifactorial condition involving genetic and psychosocial factors. There are three approaches to treating opioid dependence. Stabilisation is usually by opioid substitution treatments, and aims to ensure that the drug use becomes independent of mental state (such as craving and mood) and independent of circumstances (such as finance and physical location). The next stage is to withdraw (detox) from opioids. The final aim is relapse prevention. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments for stabilisation (maintenance) in people with opioid dependence? What are the effects of drug treatments for withdrawal in people with opioid dependence? What are the effects of drug treatments for relapse prevention in people with opioid dependence? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2008 (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: buprenorphine; clonidine; lofexidine; methadone; naltrexone; and ultra-rapid withdrawal regimes. PMID:21696648

  16. Low Molecular Weight Opioid Peptide Esters Could be Developed as a New Class of Analgesics.

    PubMed

    Goldberg, Joel S

    2011-01-01

    Low molecular weight opioid peptide esters (OPE) could become a class of analgesics with different side effect profiles than current opiates. OPE may have sufficient plasma stability to cross the blood brain barrier (BBB), undergo ester hydrolysis and produce analgesia. OPE of dipeptides, tyr-pro and tyr-gly conjugated to ethanol have a structure similar to the anesthestic agent, etomidate. Based upon the analgesic activity of dipeptide opioids, Lipinski's criteria, and permeability of select GABA esters to cross the BBB, opioid peptides (OP) conjugated to ethanol, cholesterol or 3-glucose are lead recommendations. Preliminary animal data suggests that tyr-pro-ethyl ester crosses the BBB and unexpectedly produces hyperalgesia. Currently, there are no approved OP analgesics available for clinical use. Clinical trials of good manufacturing practice OP administered to patients suffering from chronic pain with indwelling intrathecal pumps could resolve the issue that OP may be superior to opiates and may redirect research.

  17. Opioid Use Disorders

    PubMed Central

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

    2016-01-01

    Opioid use and addiction in adolescents and young adults, including heroin and non-medical use of prescription opioids, is a serious and growing health problem of epidemic proportions. Opioid use has devastating consequences for youth and their families, including: progression to full addiction, severe psychosocial impairment, HCV and HIV transmission with injection use, exacerbation of co-occurring psychiatric disorders, overdose, and death. This chapter will provide an overview of opioid use disorders (OUDs) in youth, including: etiologic factors, epidemiology, consequences, clinical presentation and course, assessment and diagnosis, overdose, detoxification, and treatment. Opioid overdose is a life-threatening emergency. Respiratory depression should be treated with naloxone, and respiratory support if necessary. Overdose should always be utilized as an opportunity to initiate addiction treatment. Opioid withdrawal management (detoxification) is often a necessary, but never sufficient, component of treatment for OUDs. Medications used in the treatment of withdrawal may include buprenorphine, clonidine and others for relief of symptoms. Treatment for OUDs is effective but treatment capacity is alarmingly limited and under-developed. Although there is a limited evidence base for youth specific treatment, 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

  18. Development of pharmaceutical heroin preparations for medical co-prescription to opioid dependent patients.

    PubMed

    Klous, Marjolein G; Van den Brink, Wim; Van Ree, Jan M; Beijnen, Jos H

    2005-12-12

    Presently, there is a considerable interest in heroin-assisted treatment: co-prescription of heroin to certain subgroups of chronic, treatment-resistant, opioid dependent patients. In 2002, nine countries had planned (Australia, Belgium, Canada, France, Spain) or ongoing (Germany, The Netherlands, Switzerland, United Kingdom) clinical trials on this subject. These trials (and the routine heroin-assisted treatment programs that might result) will need pharmaceutical heroin (diacetylmorphine) to prescribe to the patients. Research into the development of pharmaceutical forms of heroin for prescription to addicts can benefit from the large amount of knowledge that already exists regarding this substance. Therefore, in this paper we review the physicochemical and pharmaceutical properties of diacetylmorphine and the clinically investigated routes of administration, as well as routes of administration utilised on the street in the context of developing pharmaceutical heroin formulations for prescription to addicts. Patient acceptability of the formulation is essential, because heroin-assisted treatment is aimed at treatment-resistant addicts, who often have to be encouraged to participate (or to maintain participation) in a treatment program. This means that the most suitable products would have pharmacokinetic profiles mimicking that of diacetylmorphine for injection, with rapid peak concentrations of diacetylmorphine and 6-acetylmorphine, ensuring the 'rush effect' and the sustained presence of morphine(-6-glucuronide) creating the prolonged euphoria. Diacetylmorphine for inhalation after volatilisation (via 'chasing the dragon') seems to be a suitable candidate, while intranasal and oral diacetylmorphine are currently thought to be unsuitable. However, oral and intranasal delivery systems might be improved and become suitable for use by heroin dependent patients.

  19. Opioids and efflux transporters. Part 1: P-glycoprotein substrate activity of N-substituted analogs of meperidine.

    PubMed

    Mercer, Susan L; Hassan, Hazem E; Cunningham, Christopher W; Eddington, Natalie D; Coop, Andrew

    2007-03-01

    P-Glycoprotein (P-gp) is an efflux transporter which is up-regulated at the blood-brain barrier in both morphine- and oxycodone-tolerant rats. Numerous studies have shown that many clinically employed opioid analgesics are substrates for P-gp, suggesting that up-regulation of P-gp may contribute to the development of central tolerance to opioids. The studies herein focus on the development of SAR for P-gp substrate activity in the meperidine series of compounds, and show that a meperidine analog of greater potency, N-phenylbutyl-N-normeperidine, has low activity as a P-gp substrate and has the potential to be utilized as a tool to study the contribution of P-gp to the development of central tolerance to opioids.

  20. New 2',6'-dimethyl-L-tyrosine (Dmt) opioid peptidomimetics based on the Aba-Gly scaffold. Development of unique mu-opioid receptor ligands.

    PubMed

    Ballet, Steven; Salvadori, Severo; Trapella, Claudio; Bryant, Sharon D; Jinsmaa, Yunden; Lazarus, Lawrence H; Negri, Lucia; Giannini, Elisa; Lattanzi, Roberta; Tourwé, Dirk; Balboni, Gianfranco

    2006-06-29

    The Aba-Gly scaffold, incorporated into Dmt-Tic ligands (H-Dmt-Tic-Gly-NH-CH2-Ph, H-Dmt-Tic-Gly-NH-Ph, H-Dmt-Tic-NH-CH2-Bid), exhibited mixed micro/delta or delta opioid receptor activities with micro agonism. Substitution of Tic by Aba-Gly coupled to -NH-CH2-Ph (1), -NH-Ph (2), or -Bid (Bid=1H-benzimidazole-2-yl) (3) shifted affinity (Ki(micro)=0.46, 1.48, and 19.9 nM, respectively), selectivity, and bioactivity to micro-opioid receptors. These compounds represent templates for a new class of lead opioid agonists that are easily synthesized and suitable for therapeutic pain relief.

  1. Involvement of moesin in the development of morphine analgesic tolerance through P-glycoprotein at the blood-brain barrier.

    PubMed

    Kobori, Takuro; Fujiwara, Shuhei; Miyagi, Kei; Harada, Shinichi; Nakamoto, Kazuo; Nakagawa, Takayuki; Takahashi, Hideo; Narita, Minoru; Tokuyama, Shogo

    2014-01-01

    Altered expression of P-glycoprotein (P-gp), a drug efflux transporter expressed by brain capillary endothelial cells (BCECs), may contribute to the development of opioid analgesic tolerance, as demonstrated by cumulative evidence from research. However, the detailed mechanism by which chronic morphine treatment increases P-gp expression remains unexplained. Ezrin/radixin/moesin (ERM) are scaffold proteins that are known to regulate the plasma membrane localization of some drug transporters such as P-gp in peripheral tissues, although a few reports suggest its role in the central nervous system as well. In this study, we investigated the involvement of ERM in the development of morphine analgesic tolerance through altered P-gp expression in BCECs. Repeated treatment with morphine (10 mg/kg/day, s.c. for 5 days) decreased its analgesic effect in the tail-flick test and increased P-gp protein expression in BCECs, as determined by Western blotting. Furthermore, moesin protein expression increased in the same fraction whereas that of ezrin decreased; no change was observed in the radixin expression. Furthermore, immunoprecipitation and immunofluorescence assays revealed interaction between moesin and P-gp molecules, along with co-localization, in BCECs. In conclusion, an increase in moesin expression may contribute to the increased expression of P-gp in BCECs, leading to the development of morphine analgesic tolerance.

  2. Fibromyalgia, autism, and opioid addiction as natural and induced disorders of the endogenous opioid hormonal system.

    PubMed

    Johnson, Brian; Ulberg, Scott; Shivale, Swati; Donaldson, Jeffrey; Milczarski, Ben; Faraone, Stephen V

    2014-10-01

    Because of their circulation through the blood, the multiplicity of receptor sites, and the diversity of functions, opioids may most accurately be designated as a hormone. Opioids modulate the intensity of pain. In mammals, the opioid system has been modified to modulate social interactions as well (Panksepp and Watt, 2011). Over 10,000 patient encounters were observed on a neuropsychoanalytic addiction medicine service. Cold pressor times (CPT) were recorded before and after stimulation of the opioid system with low-dose naltrexone (LDN) for patients after opioid detoxification and for fibromyalgia patients. Patients maintained on opioids relate autistically. The cold, unrelated nature of their human interactions was reversed by detoxification from opioids. Fibromyalgia patients have difficulty participating in human relationships, as if they lack an ability to respond interpersonally, as do post-detoxification patients. LDN improved pain tolerance as shown by a significant increase on CPT for post detoxification patients from 16 seconds to 55 seconds and in fibromyalgia patients from 21 seconds to 42 seconds, and improved relatedness. The correlation of opioid prescribing increasing over time and autism prevalence increasing over time is highly significant. 1. Opioid-maintained patients relate autistically. 2. Autism is a hyperopioidergic disorder. 3. Fibromylagia is a hypoopioidergic disorder. 4. Low opioid tone caused by opioid maintenance or fibromyalgia can usually be reversed with low-dose naltrexone. 5. The increase in the incidence of autism may have been caused by the increase in use of opioids for analgesia during childbirth.

  3. Opioid Abuse and Addiction

    MedlinePlus

    ... oxycodone, hydrocodone, fentanyl, and tramadol. The illegal drug heroin is also an opioid. Some opioids are made ... NAS). Opioid abuse may sometimes also lead to heroin use, because some people switch from prescription opioids ...

  4. Opioid Basics: Fentanyl

    MedlinePlus

    ... Basics Understanding the Epidemic Overdose Prevention Prescription Opioids Heroin Fentanyl Data Opioid Data Analysis Drug Overdose Death Data Prescribing Data Prescription Opioid Overdose Data Heroin Overdose Data Synthetic Opioid Data Fentanyl Encounters Data ...

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

    PubMed

    Famoso, Adam N; Clark, Randy T; Shaff, Jon E; Craft, Eric; McCouch, Susan R; Kochian, Leon V

    2010-08-01

    The genetic and physiological mechanisms of aluminum (Al) tolerance have been well studied in certain cereal crops, and Al tolerance genes have been identified in sorghum (Sorghum bicolor) and wheat (Triticum aestivum). Rice (Oryza sativa) has been reported to be highly Al tolerant; however, a direct comparison of rice and other cereals has not been reported, and the mechanisms of rice Al tolerance are poorly understood. To facilitate Al tolerance phenotyping in rice, a high-throughput imaging system and root quantification computer program was developed, permitting quantification of the entire root system, rather than just the longest root. Additionally, a novel hydroponic solution was developed and optimized for Al tolerance screening in rice and compared with the Yoshida's rice solution commonly used for rice Al tolerance studies. To gain a better understanding of Al tolerance in cereals, comparisons of Al tolerance across cereal species were conducted at four Al concentrations using seven to nine genetically diverse genotypes of wheat, maize (Zea mays), sorghum, and rice. Rice was significantly more tolerant than maize, wheat, and sorghum at all Al concentrations, with the mean Al tolerance level for rice found to be 2- to 6-fold greater than that in maize, wheat, and sorghum. Physiological experiments were conducted on a genetically diverse panel of more than 20 rice genotypes spanning the range of rice Al tolerance and compared with two maize genotypes to determine if rice utilizes the well-described Al tolerance mechanism of root tip Al exclusion mediated by organic acid exudation. These results clearly demonstrate that the extremely high levels of rice Al tolerance are mediated by a novel mechanism, which is independent of root tip Al exclusion.

  6. Development of a Novel Aluminum Tolerance Phenotyping Platform Used for Comparisons of Cereal Aluminum Tolerance and Investigations into Rice Aluminum Tolerance Mechanisms1[C][W][OA

    PubMed Central

    Famoso, Adam N.; Clark, Randy T.; Shaff, Jon E.; Craft, Eric; McCouch, Susan R.; Kochian, Leon V.

    2010-01-01

    The genetic and physiological mechanisms of aluminum (Al) tolerance have been well studied in certain cereal crops, and Al tolerance genes have been identified in sorghum (Sorghum bicolor) and wheat (Triticum aestivum). Rice (Oryza sativa) has been reported to be highly Al tolerant; however, a direct comparison of rice and other cereals has not been reported, and the mechanisms of rice Al tolerance are poorly understood. To facilitate Al tolerance phenotyping in rice, a high-throughput imaging system and root quantification computer program was developed, permitting quantification of the entire root system, rather than just the longest root. Additionally, a novel hydroponic solution was developed and optimized for Al tolerance screening in rice and compared with the Yoshida's rice solution commonly used for rice Al tolerance studies. To gain a better understanding of Al tolerance in cereals, comparisons of Al tolerance across cereal species were conducted at four Al concentrations using seven to nine genetically diverse genotypes of wheat, maize (Zea mays), sorghum, and rice. Rice was significantly more tolerant than maize, wheat, and sorghum at all Al concentrations, with the mean Al tolerance level for rice found to be 2- to 6-fold greater than that in maize, wheat, and sorghum. Physiological experiments were conducted on a genetically diverse panel of more than 20 rice genotypes spanning the range of rice Al tolerance and compared with two maize genotypes to determine if rice utilizes the well-described Al tolerance mechanism of root tip Al exclusion mediated by organic acid exudation. These results clearly demonstrate that the extremely high levels of rice Al tolerance are mediated by a novel mechanism, which is independent of root tip Al exclusion. PMID:20538888

  7. Development and application of diagnostic systems to achieve fault tolerance

    SciTech Connect

    King, R.W.; Singer, R.M.

    1989-01-01

    Much work is currently being done to develop and apply diagnostic systems that are tolerant to faulted conditions in the process being monitored and in the sensors that measure the critical parameters associated with the process. A fault-tolerant diagnostic system based on state-determination, pattern-recognition techniques is currently undergoing testing and evaluation in certain applications at the EBR-II reactor. Testing and operational experience with the system to date has shown a high degree of tolerance to sensor failures, while being sensitive to very slight changes in the plant operational state. This paper briefly mentions related work being done by others, and describes in more detail the pattern-recognition system and the results of the testing and operational experience with the system at EBR-II. 9 refs., 10 figs.

  8. [Colitis ulcerosa and opioid addiction].

    PubMed

    Häuser, W; Lachiheb, H; Grandt, D

    2002-05-01

    The occurrence of an opioid addiction within an opioid treatment of pain or diarrhoea in inflammatory bowel disease is rarely reported. We report on a 36-year-old male with a 14 years lasting left sided chronic ulcerative colitis who developed after the initiation of a therapy with tincture of opium because of abdominal pain and diarrhoea an opioid addiction with the consumption of opium and later buprenorphin. Additionally to the diagnostics and therapy of the ulcerative colitis a detoxication was carried out. The diarrhoea slightly increased during the buprenorphin withdrawal. Diarrhoea refractory to other treatment should be treated by loperamid because of its lacking effects on the central nervous system. In chronic abdominal or musculoskeletal pain in inflammatory bowel disease opioids can be used if no surgical or other medical pain relief is possible. A consequent control of the therapeutic and side effects of the opioid therapy is necessary, especially of an abuse of opioid medication. The published case reports of a therapeutic induction of opioid addiction demonstrate that psychiatric comorbidity is an essential or even necessary risk factor. A checklist with seven criteria of opioid addiction during opioid therapy is presented.

  9. Cannabinoid-opioid interactions during neuropathic pain and analgesia

    PubMed Central

    Bushlin, Ittai; Rozenfeld, Raphael; Devi, Lakshmi A

    2009-01-01

    Opiates and exogenous cannabinoids, both potent analgesics used for the treatment of patients with neuropathic pain, bind to and activate class A G-protein coupled receptors (GPCRs). Several lines of evidence have recently suggested that opioid and cannabinoid receptors can functionally interact in the central nervous system (CNS). These interactions may be direct, such as through receptor heteromerization, or indirect, such as through signaling cross-talk that includes agonist-mediated release and/or synthesis of endogenous ligands that can activate downstream receptors. Interactions between opioid and cannabinoid receptors may mediate many of the behavioral phenomena associated with use of these drugs, including the production of acute antinociception and the development of tolerance and cross-tolerance to the antinociceptive effects of opioid and cannabinoid-specific ligands. This review summarizes behavioral, anatomical, and molecular data characterizing these interactions during the development of neuropathic pain and during antinociceptive treatment with these drugs alone or in combination. These studies are critical for understanding how the receptor systems involved in pain relief are altered during acute or chronic pain, and for designing better antinociceptive drug therapies, such as the combined use of opioid and cannabinoid receptor agonists or selective activation of receptor heteromers, that directly target the altered neurophysiology of patients experiencing pain. PMID:19857996

  10. Increased glutamate synaptic transmission in the nucleus raphe magnus neurons from morphine-tolerant rats

    PubMed Central

    Bie, Bihua; Pan, Zhizhong Z

    2005-01-01

    Currently, opioid-based drugs are the most effective pain relievers that are widely used in the treatment of pain. However, the analgesic efficacy of opioids is significantly limited by the development of tolerance after repeated opioid administration. Glutamate receptors have been reported to critically participate in the development and maintenance of opioid tolerance, but the underlying mechanisms remain unclear. Using whole-cell voltage-clamp recordings in brainstem slices, the present study investigated chronic morphine-induced adaptations in glutamatergic synaptic transmission in neurons of the nucleus raphe magnus (NRM), a key supraspinal relay for pain modulation and opioid analgesia. Chronic morphine significantly increased glutamate synaptic transmission exclusively in one class of NRM cells that contains μ-opioid receptors in a morphine-tolerant state. The adenylyl cyclase activator forskolin and the cAMP analog 8-bromo-cAMP mimicked the chronic morphine effect in control neurons and their potency in enhancing the glutamate synaptic current was significantly increased in neurons from morphine-tolerant rats. MDL12330a, an adenylyl cyclase inhibitor, and H89, a protein kinase A (PKA) inhibitor, reversed the increase in glutamate synaptic transmission induced by chronic morphine. In addition, PMA, a phorbol ester activator of protein kinase C (PKC), also showed an increased potency in enhancing the glutamate synaptic current in these morphine-tolerant cells. The PKC inhibitor GF109203X attenuated the chronic morphine effect. Taken together, these results suggest that chronic morphine increases presynaptic glutamate release in μ receptor-containing NRM neurons in a morphine-tolerant state, and that the increased glutamate synaptic transmission appears to involve an upregulation of both the cAMP/PKA pathway and the PKC pathway. This glutamate-mediated activation of these NRM neurons that are thought to facilitate spinal pain transmission may contribute to

  11. Increased glutamate synaptic transmission in the nucleus raphe magnus neurons from morphine-tolerant rats.

    PubMed

    Bie, Bihua; Pan, Zhizhong Z

    2005-02-09

    Currently, opioid-based drugs are the most effective pain relievers that are widely used in the treatment of pain. However, the analgesic efficacy of opioids is significantly limited by the development of tolerance after repeated opioid administration. Glutamate receptors have been reported to critically participate in the development and maintenance of opioid tolerance, but the underlying mechanisms remain unclear. Using whole-cell voltage-clamp recordings in brainstem slices, the present study investigated chronic morphine-induced adaptations in glutamatergic synaptic transmission in neurons of the nucleus raphe magnus (NRM), a key supraspinal relay for pain modulation and opioid analgesia. Chronic morphine significantly increased glutamate synaptic transmission exclusively in one class of NRM cells that contains mu-opioid receptors in a morphine-tolerant state. The adenylyl cyclase activator forskolin and the cAMP analog 8-bromo-cAMP mimicked the chronic morphine effect in control neurons and their potency in enhancing the glutamate synaptic current was significantly increased in neurons from morphine-tolerant rats. MDL12330a, an adenylyl cyclase inhibitor, and H89, a protein kinase A (PKA) inhibitor, reversed the increase in glutamate synaptic transmission induced by chronic morphine. In addition, PMA, a phorbol ester activator of protein kinase C (PKC), also showed an increased potency in enhancing the glutamate synaptic current in these morphine-tolerant cells. The PKC inhibitor GF109203X attenuated the chronic morphine effect. Taken together, these results suggest that chronic morphine increases presynaptic glutamate release in mu receptor-containing NRM neurons in a morphine-tolerant state, and that the increased glutamate synaptic transmission appears to involve an upregulation of both the cAMP/PKA pathway and the PKC pathway. This glutamate-mediated activation of these NRM neurons that are thought to facilitate spinal pain transmission may contribute to

  12. Supraspinal Inactivation of Mitochondrial Superoxide Dismutase is a Source of Peroxynitrite in the Development of Morphine Antinociceptive Tolerance

    PubMed Central

    Doyle, Timothy; Bryant, Leesa; Batinic-Haberle, Ines; Little, Joshua; Cuzzocrea, Salvatore; Masini, Emanuela; Spasojevic, Ivan; Salvemini, Daniela

    2010-01-01

    Effective treatment of chronic pain with morphine is limited by decreases in the drug’s analgesic action with chronic administration (antinociceptive tolerance). Because opioids are mainstays of pain management, restoring their efficacy has great clinical importance. We have recently reported that formation of peroxynitrite (ONOO−, PN) in the dorsal horn of the spinal cord plays a critical role in the development of morphine antinociceptive tolerance and have further documented that nitration and enzymatic inactivation of mitochondrial superoxide dismutase (MnSOD) at that site provides a source for this nitroxidative species. We now report for the first time that antinociceptive tolerance is also associated with the inactivation of MnSOD at supraspinal sites. Inactivation of MnSOD led to nitroxidative stress as evidenced by increased levels of products of oxidative DNA damage and activation of the nuclear factor poly (ADP-ribose) polymerase in whole brain homogenates. Co-administration of morphine with potent Mn porphyrin-based peroxynitrite scavengers, (MnTE-2-PyP5+ and MnTnHex-2-PyP5+) (1) restored the enzymatic activity of MnSOD, (2) attenuated PN derived nitroxidative stress, and (3) blocked the development of morphine induced antinociceptive tolerance. The more lipophilic analogue, MnTnHex-2-PyP5+ was able to cross the blood brain barrier at higher levels than its lipophylic counterpart MnTE-2-PyP5+ and was about 30 fold more efficacious. Collectively, these data suggest that peroxynitrite mediated enzymatic inactivation of supraspinal MnSOD provides a source of nitroxidative stress, which in turn contributes to central sensitization associated with the development of morphine antinociceptive tolerance. These results support our general contention that PN-targeted therapeutics may have potential as adjuncts to opiates in pain management. PMID:19607887

  13. Modulation Between High- and Low-Frequency Transcutaneous Electric Nerve Stimulation Delays the Development of Analgesic Tolerance in Arthritic Rats

    PubMed Central

    DeSantana, Josimari M.; Santana-Filho, Valter J.; Sluka, Kathleen A.

    2009-01-01

    Objective To investigate whether repeated administration of modulating frequency transcutaneous electric nerve stimulation (TENS) prevents development of analgesic tolerance. Design Knee joint inflammation (3% carrageenan and kaolin) was induced in rats. Either mixed or alternating frequency was administered daily (20min) for 2 weeks to the inflamed knee under light halothane anesthesia (1%–2%). Setting Laboratory. Animals Adult male Sprague-Dawley rats (N=36). Intervention Mixed- (4Hz and 100Hz) or alternating- (4Hz on 1 day; 100Hz on the next day) frequency TENS at sensory intensity and 100μs pulse duration. Main Outcome Measures Paw and joint withdrawal thresholds to mechanical stimuli were assessed before induction of inflammation, and before and after daily application of TENS. Results The reduced paw and joint withdrawal thresholds that occur 24 hours after the induction of inflammation were significantly reversed by the first administration of TENS when compared with sham treatment or to the condition before TENS treatment, which was observed through day 9. By the tenth day, repeated daily administration of either mixed- or alternating-frequency TENS did not reverse the decreased paw and joint withdrawal thresholds. Conclusions These data suggest that repeated administration of modulating frequency TENS leads to a development of opioid tolerance. However, this tolerance effect is delayed by approximately 5 days compared with administration of low- or high-frequency TENS independently. Clinically, we can infer that a treatment schedule of repeated daily TENS administration will result in a tolerance effect. Moreover, modulating low and high frequency TENS seems to produce a better analgesic effect and tolerance is slower to develop. PMID:18374009

  14. Modulation between high- and low-frequency transcutaneous electric nerve stimulation delays the development of analgesic tolerance in arthritic rats.

    PubMed

    Desantana, Josimari M; Santana-Filho, Valter J; Sluka, Kathleen A

    2008-04-01

    To investigate whether repeated administration of modulating frequency transcutaneous electric nerve stimulation (TENS) prevents development of analgesic tolerance. Knee joint inflammation (3% carrageenan and kaolin) was induced in rats. Either mixed or alternating frequency was administered daily (20min) for 2 weeks to the inflamed knee under light halothane anesthesia (1%-2%). Laboratory. Adult male Sprague-Dawley rats (N=36). Mixed- (4Hz and 100Hz) or alternating- (4Hz on 1 day; 100Hz on the next day) frequency TENS at sensory intensity and 100micros pulse duration. Paw and joint withdrawal thresholds to mechanical stimuli were assessed before induction of inflammation, and before and after daily application of TENS. The reduced paw and joint withdrawal thresholds that occur 24 hours after the induction of inflammation were significantly reversed by the first administration of TENS when compared with sham treatment or to the condition before TENS treatment, which was observed through day 9. By the tenth day, repeated daily administration of either mixed- or alternating-frequency TENS did not reverse the decreased paw and joint withdrawal thresholds. These data suggest that repeated administration of modulating frequency TENS leads to a development of opioid tolerance. However, this tolerance effect is delayed by approximately 5 days compared with administration of low- or high-frequency TENS independently. Clinically, we can infer that a treatment schedule of repeated daily TENS administration will result in a tolerance effect. Moreover, modulating low and high frequency TENS seems to produce a better analgesic effect and tolerance is slower to develop.

  15. 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

  16. 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.

  17. PTI-609: a novel analgesic that binds filamin A to control opioid signaling.

    PubMed

    Burns, Lindsay H; Wang, Hoau-Yan

    2010-11-01

    Binding a critical pentapeptide region on the scaffolding protein filamin A regulates signaling of mu opioid receptors (MORs) so that their activation should not result in the opioid tolerance, dependence and addiction associated with current opioid painkillers. Additionally, we show that compounds that bind this site on filamin A reduce release of inflammatory cytokines. PTI-609 is a new chemical entity that binds filamin A with picomolar affinity and also activates opioid receptors via a novel binding domain. PTI-609 and analogs have similar analgesic efficacy to morphine by oral administration in mice, provide some anti-inflammatory activity in the rat collagen-induced arthritis model, and show no conditioned place preference at analgesic doses, suggesting no potential for abuse and addiction. PTI-609 was designed after discovering filamin A as the high-affinity target of naltrexone or naloxone. Combined with opiates, ultra-low-dose naloxone or naltrexone can enhance and prolong the analgesia of the opiate alone and prevent or attenuate opioid tolerance, dependence and addictive properties. We will review here the mechanism of action of ultra-low-dose naltrexone and naloxone, the discovery of filamin A as their high-affinity target, and the rationale as to why the current, dualfunction new chemical entity should not only be easier to develop but also more consistently efficacious than opioids combined with ultra-low-dose naltrexone. This new class of compounds, as well as the concept, screening assay and pharmacophore model, are covered in a family of recent patent applications.

  18. Discovery of positive allosteric modulators and silent allosteric modulators of the μ-opioid receptor

    PubMed Central

    Burford, Neil T.; Clark, Mary J.; Wehrman, Tom S.; Gerritz, Samuel W.; Banks, Martyn; O’Connell, Jonathan; Traynor, John R.; Alt, Andrew

    2013-01-01

    μ-Opioid receptors are among the most studied G protein-coupled receptors because of the therapeutic value of agonists, such as morphine, that are used to treat chronic pain. However, these drugs have significant side effects, such as respiratory suppression, constipation, allodynia, tolerance, and dependence, as well as abuse potential. Efforts to fine tune pain control while alleviating the side effects of drugs, both physiological and psychological, have led to the development of a wide variety of structurally diverse agonist ligands for the μ-opioid receptor, as well as compounds that target κ- and δ-opioid receptors. In recent years, the identification of allosteric ligands for some G protein-coupled receptors has provided breakthroughs in obtaining receptor subtype-selectivity that can reduce the overall side effect profiles of a potential drug. However, positive allosteric modulators (PAMs) can also have the specific advantage of only modulating the activity of the receptor when the orthosteric agonist occupies the receptor, thus maintaining spatial and temporal control of receptor signaling in vivo. This second advantage of allosteric modulators may yield breakthroughs in opioid receptor research and could lead to drugs with improved side-effect profiles or fewer tolerance and dependence issues compared with orthosteric opioid receptor agonists. Here, we describe the discovery and characterization of μ-opioid receptor PAMs and silent allosteric modulators, identified from high-throughput screening using a β-arrestin–recruitment assay. PMID:23754417

  19. 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.

  20. Vicia villosa agglutinin labels a subset of neurons coexpressing both the mu opioid receptor and parvalbumin in the developing rat subiculum.

    PubMed

    Bausch, S B; Chavkin, C

    1996-12-23

    Vicia villosa agglutinin (VVA), anti-parvalbumin antiserum and an affinity-purified anti-mu opioid receptor antibody were used to triple-label neurons in the postnatal rat subiculum. VVA labeled a subset of mu opioid receptor-positive neurons that were also immunoreactive for parvalbumin. The morphology of the triple-labeled neurons was heterogeneous, and included multipolar, ovoid and pyramidal-shaped neurons. Neurons single-labeled for the mu opioid receptor, VVA or parvalbumin were also morphologically heterogeneous. The postnatal development of mu opioid receptor immunoreactivity (IR), parvalbumin-IR and VVA binding was investigated using triple-labeling immunocytochemistry. Mu opioid receptor-IR appeared first and was present at postnatal day 1 (P1). Parvalbumin-IR was first observed in somata at P10, followed by proximal and distal dendrites at P15 and P20 respectively. Faint VVA labeling was seen first at P10 and surrounded a limited number of neurons. The intensity of labeling and the number of neurons labeled with VVA increased between P10 and P20; however, both measures remained below adult levels at P20. This study further illustrates the neurochemical heterogeneity of interneurons in the hippocampal formation and shows the developmentally early appearance of mu opioid receptor-IR compared to the late appearance of VVA binding and parvalbumin-IR.

  1. Subcellular protein overexpression to develop abiotic stress tolerant plants

    PubMed Central

    Nouri, Mohammad-Zaman; Komatsu, Setsuko

    2012-01-01

    Environmental stresses are major factors limiting growth and development of crops. Plants respond to the stresses through a wide range of reactions from morphological changes to alterations in the patterns of protein expression. Understanding the mechanisms involved in the stress response is the first step to develop abiotic stress tolerant crops. Proteomics is a powerful tool in evaluating regulated proteins in the cell under stress and it is an efficient technique in studying stress tolerant plants. Because of the nature of abiotic stress, intracellular compartments play a main role in the stress response. Subcellular proteins such as ion and water transporters, reactive oxygen species (ROS) scavengers, and the proteins related to signaling and transcriptional regulation are frequently reported as being involved in stress tolerance. Overexpression of stress-responsive protein through generation of transgenic plants is one the main practical approaches in production of tolerant plants. In this article, recent studies on transgenic plants overexpressing subcellular proteins are reviewed and the role of organelles and over-expressed proteins is classified. PMID:23346093

  2. Opioid dependence

    PubMed Central

    2011-01-01

    Introduction Dependence on opioids is a multifactorial condition involving genetic and psychosocial factors. There are three stages to treating opioid dependence. Stabilisation is usually by opioid substitution treatments, and aims to ensure that the drug use becomes independent of mental state (such as craving and mood) and independent of circumstances (such as finance and physical location). The next stage is to withdraw (detox) from opioids. The final stage is relapse prevention. This treatment process contributes to recovery of the individual, which also includes improved overall health and wellbeing, as well as engagement in society. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments for stabilisation (maintenance) in people with opioid dependence? What are the effects of drug treatments for withdrawal in people with opioid dependence? What are the effects of drug treatments for relapse prevention in people with opioid dependence? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2011 (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 26 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: buprenorphine; clonidine; lofexidine; methadone; naltrexone; and ultra-rapid withdrawal regimens. PMID:21929827

  3. Neurokinin 1 and opioid receptors: relationships and interactions in nervous system

    PubMed Central

    Xiao, Jie; Zeng, Si; Wang, Xiangrui; Babazada, Hasan; Li, Zhanchun; Liu, Renyu; Yu, Weifeng

    2017-01-01

    Opioid receptors and neurokinin 1 receptor (NK1R) are found highly expressed in the central nervous system. The co-localization of these two kinds of receptors suggests that they might interact with each other in both the transmission and modulation of the pain signal. In this review, we explore the relationships between opioid receptors and NK1R. Substance P (SP) plays a modulatory role in the pain transmission by activating the NK1R. Opioid receptor activation can inhibit SP release. NK1R is found participating in the mechanisms of the side effects of the opioids, including opioid analgesic tolerance, hyperalgesia, anxiety behaviors of morphine reward and opioids related respiratory depression. A series of compounds such as NK1R antagonists and ligands works on both mu/delta opioid receptor (MOR/DOR) and NK1R were synthesized as novel analgesics that enhance the clinical pain management efficacy and reduce the dosage and side effects. The current status of these novel ligands and the limitations are discussed in this review. Although the working mechanisms of these ligands remained unclear, they could be used as research tool for developing novel analgesic drugs in the future.

  4. 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

  5. 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.

  6. Opioid pharmacology.

    PubMed

    Trescot, Andrea M; Datta, Sukdeb; Lee, Marion; Hansen, Hans

    2008-03-01

    Mu agonists have been an important component of pain treatment for thousands of years. The usual pharmacokinetic parameters (half-life, clearance, volume of distribution) of opioids have been known for some time. However, the metabolism has, until recently, been poorly understood, and there has been recent interest in the role of metabolites in modifying the pharmacodynamic response in patients, in both analgesia and adverse effects. A number of opioids are available for clinical use, including morphine, hydromorphone, levorphanol, oxycodone, and fentanyl. Advantages and disadvantages of various opioids in the management of chronic pain are discussed. This review looks at the structure, chemistry, and metabolism of opioids in an effort to better understand the side effects, drug interactions, and the individual responses of patients receiving opioids for the treatment of intractable pain. Mu receptor agonists and agonist-antagonists have been used throughout recent medical history for the control of pain and for the treatment of opiate induced side effects and even opiate withdrawal syndromes.

  7. Development of a substance abuse program for opioid-dependent nonurban pregnant women improves outcome.

    PubMed

    Meyer, Marjorie; Benvenuto, Anna; Howard, Diantha; Johnston, Anne; Plante, Dawn; Metayer, Jerilyn; Mandell, Todd

    2012-06-01

    The goal of this study was to determine whether improved access to medication assisted therapy in the general population, with improved coordination of ancillary services for pregnant women, improved perinatal outcomes in a nonurban area. The cohort of women treated for opioid dependence during pregnancy with medication-assisted therapy and delivered at a single institution between 2000 and 2006 were retrospectively identified (n = 149 women; n = 151 neonates). Access to opioid agonist therapy for the general population was determined as the combined number of available treatment positions for medication-assisted therapy. Treatment during pregnancy (interim substitution therapy vs opioid treatment program) and pregnancy outcomes were noted from chart review. The primary outcome of trend of prenatal care indices and newborn birth weight over time was determined by Kendall's tau. As access to treatment in the general population expanded from 2000 to 2006, the number of women receiving treatment increased, the proportion of women receiving interim substitution therapy decreased (P < 0.001), gestational age at the initiation of treatment decreased (P < 0.001), and the proportion of women receiving treatment before pregnancy increased (P < 0.001). Infants delivered to mothers in a treatment program had improved birth weight z score compared with those receiving interim substitution therapy (P = 0.007). The proportion of infants discharged to the care of the mother and remaining in maternal care at 1 year improved both over time (P = 0.03; P = 0.004) and with treatment within a treatment program (P < 0.001; P = 0.004). Improved access to opioid agonist treatment programs for the general population in nonurban areas improves perinatal outcome and retention of maternal guardianship.

  8. 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].

  9. Opioids in preclinical and clinical trials.

    PubMed

    Nagase, Hiroshi; Fujii, Hideaki

    2011-01-01

    Since 1952, when Gates determined the stereo structure of morphine, numerous groups have focused on discovering a nonnarcotic opioid drug. Although several natural, semisynthetic, and synthetic opioid ligands (alkaloids and peptides) have been developed in clinical studies, very few were nonnarcotic opioid drugs. One of the most important studies in the opioid field appeared in 1976, when Martin and colleagues established types of opioid receptors (these are now classified into mu, delta, and kappa types). Later, Portoghese discovered a highly selective mu type opioid receptor antagonist, beta-funaltrexamine. This led to the finding that the mu type opioid receptor was correlated to drug dependence. Consequently, delta, and particularly kappa, 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 and TRK-820 (nalfurafine hydrochloride).

  10. Naltrexone in the treatment of opioid-dependent pregnant women: the case for a considered and measured approach to research.

    PubMed

    Jones, Hendrée E; Chisolm, Margaret S; Jansson, Lauren M; Terplan, Mishka

    2013-02-01

    The present paper considers naltrexone to treat opioid dependence during pregnancy. The public health problem of opioid dependence and its treatment during pregnancy is reviewed first. Next, the naltrexone and opioid dependence treatment literature is summarized, with overviews of the pre-clinical and clinical research on prenatal naltrexone exposure. Finally, considerations and recommendations for future medication research for the treatment of opioid dependence in pregnant women are provided. The efficacy of long-acting injectable naltrexone relative to placebo, its blockade of opioid agonist euphoric effects, its lack of abuse and tolerance development and its modest adverse effect profile make it a potential medication for opioid-dependent pregnant women. However, it is not without seriously concerning potential drawbacks, including the difficulty surrounding medication induction that may lead to vulnerability with regard to relapse, physical dependence re-establishment, increased risk behaviors, treatment dropout and resulting opioid overdose. Before embarking on future research with this medication, the benefits and risks for the mother-embryo/fetus/child dyad should be weighed carefully. Should future research be conducted, a multi-level commitment to proactive ethical research is needed to reach the ultimate goal of improving the lives of women and children affected by opioid dependence. © 2012 The Authors, Addiction © 2012 Society for the Study of Addiction.

  11. 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.

  12. Dietary immunomodulatory factors in the development of immune tolerance.

    PubMed

    West, Christina E; D'Vaz, Nina; Prescott, Susan L

    2011-08-01

    Emerging evidence suggests that exposures during pregnancy and the early postnatal period can modify gene expression and disease propensity. Diet is a major environmental exposure, and dietary factors, including polyunsaturated fatty acids, probiotics, oligosaccharides, antioxidants, folate, and other vitamins, have effects on immune function. Some also have been implicated in reduced risk of allergy in observational studies. Intervention trials with polyunsaturated fatty acids, probiotics, and oligosaccharides suggest preliminary but as-of-yet-unconfirmed benefits. Food allergen avoidance during pregnancy, lactation, or infancy has provided no consistent evidence in allergy prevention and is no longer recommended. Rather, there is now a focus on food allergens in tolerance induction. Specific nutrients can induce changes in gene expression during early development and have been implicated in potentially heritable "epigenetic" changes in disease predisposition. Collectively, these observations emphasize that early exposures may modify tolerance development and that further research on these exposures should remain a priority.

  13. 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

  14. A novel alternatively spliced isoform of the mu-opioid receptor: functional antagonism

    PubMed Central

    2010-01-01

    Background Opioids are the most widely used analgesics for the treatment of clinical pain. They produce their therapeutic effects by binding to μ-opioid receptors (MORs), which are 7 transmembrane domain (7TM) G-protein-coupled receptors (GPCRs), and inhibiting cellular activity. However, the analgesic efficacy of opioids is compromised by side-effects such as analgesic tolerance, dependence and opioid-induced hyperalgesia (OIH). In contrast to opioid analgesia these side effects are associated with cellular excitation. Several hypotheses have been advanced to explain these phenomena, yet the molecular mechanisms underlying tolerance and OIH remain poorly understood. Results We recently discovered a new human alternatively spliced isoform of MOR (MOR1K) that is missing the N-terminal extracellular and first transmembrane domains, resulting in a 6TM GPCR variant. To characterize the pattern of cellular transduction pathways activated by this human MOR1K isoform, we conducted a series of pharmacological and molecular experiments. Results show that stimulation of MOR1K with morphine leads to excitatory cellular effects. In contrast to stimulation of MOR1, stimulation of MOR1K leads to increased Ca2+ levels as well as increased nitric oxide (NO) release. Immunoprecipitation experiments further reveal that unlike MOR1, which couples to the inhibitory Gαi/o complex, MOR1K couples to the stimulatory Gαs complex. Conclusion The major MOR1 and the alternative MOR1K isoforms mediate opposite cellular effects in response to morphine, with MOR1K driving excitatory processes. These findings warrant further investigations that examine animal and human MORK1 expression and function following chronic exposure to opioids, which may identify MOR1K as a novel target for the development of new clinically effective classes of opioids that have high analgesic efficacy with diminished ability to produce tolerance, OIH, and other unwanted side-effects. PMID:20525224

  15. 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

  16. Opioids and cancer recurrence.

    PubMed

    Juneja, Rohit

    2014-06-01

    With the majority of deaths from cancer because of their metastases, strategies to reduce this from occurring are at the forefront of treatment. It has been hypothesized that morphine may result in an increase in cancer metastases, following many in-vitro and animal studies, but the evidence from human retrospective data is inconclusive. This article will explore the possible mechanisms by which opioids can impact on the natural history of the cancer cell and whether they are likely to be harmful in individuals with cancer. Although there have been trials demonstrating benefits with regional anaesthesia techniques (opioid sparing) in the surgical population, it is not clear whether the source of the benefit arises directly from the avoidance of opioids or an added benefit afforded by regional anaesthesia. Research has shown that in particular cancer cell types, morphine may actually be beneficial and that the μ-opioid receptor (MOR) plays a role in cancer disease. With the crystal structure of the MOR having recently been elucidated, this may offer new opportunities for treatments aimed at reducing cancer metastasis. The role opioids play in the development of cancer metastasis and recurrence is far from clear and appears to differ depending on the cancer cell type in question. Prospective randomized controlled trials are currently underway in humans to help clarify the situation further and there results are awaited with anticipation. The negative impact of pain on the immune system is well documented and it appears that appropriate analgesia is paramount in minimizing this. Opioids still constitute a central role in the management of moderate-to-severe cancer pain.

  17. 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

  18. The activation of μ-opioid receptor potentiates LPS-induced NF-kB promoting an inflammatory phenotype in microglia.

    PubMed

    Gessi, Stefania; Borea, Pier Andrea; Bencivenni, Serena; Fazzi, Debora; Varani, Katia; Merighi, Stefania

    2016-09-01

    Increased production of proinflammatory cytokines has a prominent role in tolerance to opioids. The objectives of this study were to examine whether μ-opioid receptor affects proinflammatory signalling through the activation of NF-kB in microglia. The novelty of the described research is that a low dose of morphine, exerting its effects via the μ-opioid receptor, increases the DNA-binding activity of NF-kB via PKCε, while a high dose of morphine triggers a nonopiate receptor response mediated by TLR4 and, interestingly, PKCε signalling. The identification of morphine as a crucial upstream regulator of PKCε-NF-κB signalling in microglia argues for a central role of these pathways in neuroinflammation development and progression. Therefore, the morphine-PKCε-NF-κB pathway may provide novel targets to induce neuroprotective mechanisms, thereby reducing tolerance to opioids.

  19. Salvinorin A analogs and other κ-opioid receptor compounds as treatments for cocaine abuse.

    PubMed

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

    2014-01-01

    Acute activation of kappa-opioid receptors produces anti-addictive effects by regulating dopamine levels in the brain. Unfortunately, classic kappa-opioid agonists have undesired side effects such as sedation, aversion, and depression, which restrict their clinical use. Salvinorin A (Sal A), a novel kappa-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 kappa-opioid agonists and several new analogs. Sal A retains the anti-addictive properties of traditional kappa-opioid receptor 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, kappa-opioid receptor agonists based on the structure of Sal A have been synthesized. While work in this field is still in progress, several analogs with improved pharmacokinetic profiles have been shown to have anti-addictive effects. While in its infancy, it is clear that these compounds hold promise for the future development of anti-addictive therapeutics.

  20. 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

  1. Opioid peptides in peripheral pain control.

    PubMed

    Lesniak, Anna; Lipkowski, Andrzej W

    2011-01-01

    Opioids have a long history of therapeutic use as a remedy for various pain states ranging from mild acute nociceptive pain to unbearable chronic advanced or end-stage disease pain. Analgesia produced by classical opioids is mediated extensively by binding to opioid receptors located in the brain or the spinal cord. Nevertheless, opioid receptors are also expressed outside the CNS in the periphery and may become valuable assets in eliciting analgesia devoid of shortcomings typical for the activation of their central counterparts. The discovery of endogenous opioid peptides that participate in the formation, transmission, modulation and perception of pain signals offers numerous opportunities for the development of new analgesics. Novel peptidic opioid receptor analogs, which show limited access through the blood brain barrier may support pain therapy requiring prolonged use of opioid drugs.

  2. 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.

  3. Cross-talk between cardiac kappa-opioid and beta-adrenergic receptors in developing hypertensive rats.

    PubMed

    Yu, X C; Wang, H X; Zhang, W M; Wong, T M

    1999-03-01

    The kappa-opioid receptor exerts a negative modulatory action on the beta-adrenoceptor and the action is blunted in adult spontaneously hypertensive rats (SHR). In order to determine whether the blunted negative modulation of the beta-adrenoceptor by the kappa-opioid receptor contributes to the development of hypertension, the electrically induced intracellular calcium ([Ca2+]i) transient was measured in single ventricular myocytes of SHR at 4, 6, 8 and 13-week-old and the age-matched Wistar Kyoto (WKY) rats. The electrically induced [Ca2+]i transients were augmented by norepinephrine (NE), a beta-adrenoceptor agonist, over four-fold in WKY rats of all ages studied and in SHR of 4 and 6 weeks of age. The enhancing effect of NE in 8- and 13-week-old SHR was, however, only approximately three-fold, significantly lower than the corresponding values in age-matched WKY rats. Similarly, the electrically induced [Ca2+]i transients were also augmented by forskolin, an activator of adenylate cyclase, by approximately two-fold in WKY rats of all ages and SHR aged 4 and 6 weeks. In SHR aged 8 and 13 weeks, the effect of forskolin was only 1.5-fold, significantly lower than the two-fold increase in the corresponding WKY rats. The enhancing effects of NE and forskolin were attenuated by U50,488H, a selective kappa-opioid agonist, by approximately 50 and 25%, respectively, in both types of rats of all ages studied, with the exception of 13-week-old rats. In rats of this age group, the attenuations by U50,488H on the enhancing effects of NE and forskolin were 17 and 9% in SHR, respectively, significantly less than the corresponding 54 and 29% in WKY. The fact that attenuation of U50,488H on the enhancing effects of NE and forskolin only occurs in 13-week-old SHR when hypertension has been fully developed indicates that the attenuated inhibitory modulation of kappa-opioid receptor stimulation does not contribute to the initiation of hypertension. Interestingly, the enhancing

  4. Cholecystokinin receptors mediate tolerance to the analgesic effect of TENS in arthritic rats ✩

    PubMed Central

    DeSantana, Josimari M.; da Silva, Luis Felipe S.; Sluka, Kathleen A.

    2014-01-01

    Transcutaneous electrical nerve stimulation (TENS) is a treatment for pain that involves placement of electrical stimulation through the skin for pain relief. Previous work from our laboratory shows that repeated application of TENS produces analgesic tolerance by the fourth day and a concomitant cross-tolerance at spinal opioid receptors. Prior pharmacological studies show that blockade of cholecystokinin (CCK) receptors systemically and spinally prevents the development of analgesic tolerance to repeated doses of opioid agonists. We therefore hypothesized that systemic and intrathecal blockade of CCK receptors would prevent the development of analgesic tolerance to TENS, and cross-tolerance at spinal opioid receptors. In animals with knee joint inflammation (3% kaolin/carrageenan), high (100 Hz) or low frequency (4 Hz) TENS was applied daily and the mechanical withdrawal thresholds of the muscle and paw were examined. We tested thresholds before and after inflammation, and before and after TENS. Animals treated systemically, prior to TENS, with the CCK antagonist, proglumide, did not develop tolerance to repeated application of TENS on the fourth day. Spinal blockade of CCK-A or CCK-B receptors blocked the development of tolerance to high and low frequency TENS, respectively. In the same animals we show that spinal blockade of CCK-A receptors prevents cross-tolerance at spinal delta-opioid receptors that normally occurs with high frequency TENS; and blockade of CCK-B receptors prevents cross-tolerance at spinal mu-opioid receptors that normally occurs with low frequency TENS. Thus, we conclude that blockade of CCK receptors prevents the development of analgesic tolerance to repeated application of TENS in a frequency-dependent manner. PMID:19944533

  5. 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

  6. Feeding Releases Endogenous Opioids in Humans.

    PubMed

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

    2017-08-23

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

  7. Morphine mediates a proinflammatory phenotype via μ-opioid receptor-PKCɛ-Akt-ERK1/2 signaling pathway in activated microglial cells.

    PubMed

    Merighi, Stefania; Gessi, Stefania; Varani, Katia; Fazzi, Debora; Stefanelli, Angela; Borea, Pier Andrea

    2013-08-15

    Anti-nociceptive tolerance to opioids severely limits their clinical efficacy for the treatment of chronic pain syndromes. Glia has a central role in the development of morphine tolerance. Here, we characterized the receptor-proximal signaling events that link μ-opioid receptors to activation of Akt and ERKs in lipopolysaccharide (LPS)-stimulated murine microglial cells with the aim to define the molecular mechanism contributing to the ability of morphine to increase inflammatory mediators such as nitric oxide (NO), tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in activated microglial cells. In particular, the role of PKCɛ isoform in μ-opioid-induced inflammatory response in microglia was investigated. The results indicate that morphine increases the LPS-induced expression and activation of PKCɛ and stimulates Akt pathway upstream of ERK1/2 and iNOS. Furthermore, we found that morphine enhanced the release of IL-1β, TNF-α, IL-6, and of NO via μ-opioid receptor-PKCɛ signaling pathway in activated microglial cells, mediating a proinflammatory phenotype in mouse microglial cells. Together, these data suggest that the modulation of μ-opioid receptor signaling on microglia through PKCɛ selective inhibition may provide a means to attenuate glial activation and, as a consequence, to treat opioid development of tolerance and dependence.

  8. Designing Opioids That Deter Abuse

    PubMed Central

    Raffa, Robert B.; Pergolizzi, Joseph V.; Muñiz, Edmundo; Taylor, Robert; Pergolizzi, Jason

    2012-01-01

    Prescription opioid formulations designed to resist or deter abuse are an important step in reducing opioid abuse. In creating these new formulations, the paradigm of drug development target should be introduced. Biological targets relating to the nature of addiction may pose insurmountable hurdles based on our current knowledge and technology, but products that use behavioral targets seem logical and feasible. The population of opioid abusers is large and diverse so behavioral targets are more challenging than they appear at first glance. Furthermore, we need to find ways to correlate behavioral observations of drug liking to actual use and abuse patterns. This may involve revisiting some pharmacodynamic concepts in light of drug effect rather than peak concentration. In this paper we present several new opioid analgesic agents designed to resist or deter abuse using physical barriers, the inclusion of an opioid agonist or antagonist, an aversive agent, and a prodrug formulation. Further, this paper also provides insight into the challenges facing drug discovery in this field. Designing and screening for opioids intended to resist or deter abuse is an important step to meet the public health challenge of burgeoning prescription opioid abuse. PMID:23213510

  9. Dextromethorphan attenuated inflammation and combined opioid use in humans undergoing methadone maintenance treatment.

    PubMed

    Chen, Shiou-Lan; Lee, Sheng-Yu; Tao, Pao-Luh; Chang, Yun-Hsuan; Chen, Shih-Heng; Chu, Chun-Hsien; Chen, Po See; Lee, I Hui; Yeh, Tzung Lieh; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band

    2012-12-01

    Recent studies show that proinflammatory cytokines might be related to the development of opioid dependence (physiological, psychological, or both). In a double-blind, randomly stratified clinical trial investigating whether add-on dextromethorphan (60-120 mg/day) attenuated inflammation and the combined use of opioids in heroin-dependent patients undergoing methadone maintenance treatment, we evaluated whether inflammation is related to the progression of opioid dependence. All participants (107 heroin-dependent patients and 84 nondependent healthy controls) were recruited from National Cheng Kung University Hospital. Their plasma cytokine levels were measured to evaluate the effect of add-on dextromethorphan. Plasma TNF-α and IL-8 levels were significantly higher in long-term heroin-dependent patients than in healthy controls (p < 0.001). Chronic heroin-use-induced TNF-α and IL-8 levels were significantly (p < 0.05) attenuated in patients treated for 12 weeks with add-on dextromethorphan. Moreover, both tolerance to methadone and the combined use of opioids were significantly (p < 0.05) attenuated in patients taking dextromethorphan. We conclude that dextromethorphan might be a feasible adjuvant therapeutic for attenuating inflammation and inhibiting methadone tolerance and combined opioid use in heroin-dependent patients.

  10. 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.

  11. Pressure Pain Sensitivity in Patients With Suspected Opioid-Induced Hyperalgesia

    PubMed Central

    Wasserman, Ronald A.; Hassett, Afton L.; Harte, Steven E.; Goesling, Jenna; Malinoff, Herbert L.; Berland, Daniel W.; Zollars, Jennifer; Moser, Stephanie E.; Brummett, Chad M.

    2015-01-01

    Background and Objectives This study was designed to test whether a brief quantitative sensory testing (QST) assessment could be used to detect hyperalgesia in patients with suspected opioid-induced hyperalgesia. Methods Twenty patients on long-term opioid therapy with suspected opioid-induced hyperalgesia were recruited along with and 20 healthy controls. Pressure pain threshold, Pain50, a measure of intermediate suprathreshold pressure pain sensitivity, and tolerance levels, were evaluated. As a secondary outcome, changes in pressure pain sensitivity following intravenous administration of placebo (saline) and fentanyl (1.5 μg/kg) were assessed. Results There were no significant differences in pain measures between healthy controls and patients. However, there was an association between higher doses of opioids and having a lower pain tolerance (r= -0.46, P=0.041) and lower Pain50 (r=-0.46, P = 0.044), which was consistent with the hypothesis. Patients on >100 mg oral morphine equivalents (OME) displayed decreased pressure pain tolerance compared to patients taking <100 mg OME (P = 0.042). In addition, male patients showed a hyperalgesic response to fentanyl administration, which was significant for the Pain50 measure (P=0.002). Conclusions Whereas there were no differences between patients suspected of having opioid-induced hyperalgesia and the healthy controls, the finding that higher doses of opioids were associated with more sensitivity suggests that dose might be an important factor in the development of hyperalgesia. In addition, male patients demonstrated a hyperalgesic response after a bolus of fentanyl. Future studies are needed to develop better diagnostics for detecting hyperalgesia in the clinical setting. PMID:26469365

  12. Long-term efficacy, safety and tolerability of Remoxy for the management of chronic pain.

    PubMed

    Pergolizzi, Joseph V; Zampogna, Gianpietro; Taylor, Robert; Raffa, Robert B

    2015-03-01

    Historically, chronic pain generally went under-treated for a variety of objective and subjective reasons, including difficulty to objectively diagnose and manage over a long period of time, potential serious adverse effects of commonly available medications, and patient, healthcare and societal concerns over opioid medications. More recently, in an effort to redress the under-treatment of pain, the number of prescriptions of opioid analgesics has risen dramatically. However, paralleling the increased legitimate use has been a concomitant increase in opioid abuse, misuse and diversion. Pharmaceutical companies have responded by developing a variety of opioid formulations designed to deter abuse by making the products more difficult to tamper with. One such product is Remoxy(®), an extended-release formulation of the strong opioid oxycodone. We review the efficacy, safety and tolerability of this formulation based on the available published literature.

  13. 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

  14. Glia as the “bad guys”: Implications for improving clinical pain control and the clinical utility of opioids

    PubMed Central

    Watkins, Linda R.; Hutchinson, Mark R.; Ledeboer, Annemarie; Wieseler-Frank, Julie; Milligan, Erin D.; Maier, Steven F.

    2007-01-01

    Within the past decade, there has been increasing recognition that glia are far more than simply “housekeepers” for neurons. This review explores two recently recognized roles of glia (microglia and astrocytes) in: (a) creating and maintaining enhanced pain states such as neuropathic pain, and (b) compromising the efficacy of morphine and other opioids for pain control. While glia have little-to-no role in pain under basal conditions, pain is amplified when glia become activated, inducing the release of proinflammatory products, especially proinflammatory cytokines. How glia are triggered to become activated is a key issue, and appears to involve a number of neuron-to-glia signals including neuronal chemokines, neurotransmitters, and substances released by damaged, dying and dead neurons. In addition, glia become increasingly activated in response to repeated administration of opioids. Products of activated glia increase neuronal excitability via numerous mechanisms, including direct receptor-mediated actions, upregulation of excitatory amino acid receptor function, downregulation of GABA receptor function, and so on. These downstream effects of glial activation amplify pain, suppress acute opioid analgesia, contribute to the apparent loss of opioid analgesia upon repeated opioid administration (tolerance), and contribute to the development of opioid dependence. The potential implications of such glial regulation of pain and opioid actions are vast, suggestive that targeting glia and their proinflammatory products may provide a novel and effective therapy for controlling clinical pain syndromes and increasing the clinical utility of analgesic drugs. PMID:17175134

  15. Molecular Pharmacology of δ-Opioid Receptors

    PubMed Central

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

    2016-01-01

    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

  16. [Management of adverse effects of opioid therapy].

    PubMed

    Wirz, Stefan

    2017-04-01

    More than 6 million people in Germany suffer from chronic pain which greatly impairs their wellbeing. Often the only therapeutic option is to use class 2 or 3 analgesic opioids in the WHO classification, as class 1 analgesics may be toxic or of limited efficacy. However, the high incidence of opioid side effects leads to high discontinuation rates. Thus, the success of opioid treatment is also highly dependent on the management of the safety and tolerability of the treatment. Most opioid side effects, such as nausea and sedation, predominantly occur in the initial phase of therapy. In contrast, opioid-induced constipation can last throughout opioid therapy. First-line treatment with laxatives does not solve the problem in all patients. Possible second-line therapies include opioid receptor antagonists, such as Naloxone, oral-administered Naloxegol, or subcutaneously given Methylnaltrexone. The discussion also covers the management of other common side effects of opioids, such as nausea, vomiting, sedation, pruritus, micturition disorder, and further symptoms. © Georg Thieme Verlag KG Stuttgart · New York.

  17. Development and in vitro characterization of self-emulsifying drug delivery system (SEDDS) for oral opioid peptide delivery.

    PubMed

    Zupančič, Ožbej; Rohrer, Julia; Thanh Lam, Hung; Grießinger, Julia Anita; Bernkop-Schnürch, Andreas

    2017-10-01

    In this study, self-emulsifying drug delivery system (SEDDS) for oral delivery of opioid peptide dalargin were developed and characterized in vitro. Dalargin lipophilicity was increased by O-esterification of tyrosine OH group, hydrophobic ion pairing, or a combination thereof. Distribution coefficients (log D) of lipidized dalargin derivatives were determined. Then, dalargin was incorporated in chosen SEDDS, namely SEDDS-1, composed of 50% Capmul 907, 40% Cremophor EL, and 10% propylene glycol and comparatively more lipophilic SEDDS-2 composed of 30% Captex 8000, 30% Capmul MCM, 30% Cremophor EL, and 10% propylene glycol. Additionally, SEDDS were characterized regarding droplet size, polydispersity index (PDI), cloudy point, physical stability and stability against pancreatic lipase. Furthermore, mucus permeating properties of SEDDS and their ability to protect the incorporated dalargin against proteolysis by trypsin, α-chymotrypsin, elastase, simulated gastric fluid (SGF), and simulated intestinal fluid (SIF) were evaluated. The highest dalargin drug payload of 4.57% in SEDDS-2 was achieved when dalargin palmitate (pDAL) was ion paired with sodium dodecyl sulfate (SDS) in molar ratio 1:1. Moreover, SEDDS-1 and SEDDS-2 had a narrow droplet size distribution with average droplet sizes of 42.1 and 33.1 nm with PDI of 0.042 and 0.034, respectively. Lipolysis study showed that within 30 min 78.5% of SEDDS-1 and 92.1% of SEDDS-2 were digested. In addition, both SEDDS exhibited mucus permeating properties as well as a protective effect against enzymatic degradation by trypsin, α-chymotrypsin, elastase, SGF and SIF. The results of this study suggest that the developed SEDDS could be considered for oral opioid peptide delivery.

  18. 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.

  19. μ-Opioid Receptor-Induced Ca2+ Mobilization and Astroglial Development: Morphine Inhibits DNA Synthesis and Stimulates Cellular Hypertrophy through a Ca2+-Dependent Mechanism

    PubMed Central

    Hauser, Kurt F.; Stiene-Martin, Anne; Mattson, Mark P.; Elde, Robert P.; Ryan, S. Eric; Godleske, Chrystal C.

    2015-01-01

    Morphine, a preferential μ opioid receptor agonist, alters astroglial development by inhibiting cell proliferation and by promoting cellular differentiation. Although morphine affects cellular differentiation through a Ca2+-dependent mechanism, few studies have examined whether Ca2+ mediates the effect of opioids on cell proliferation, or whether a particular Ca2+ signal transduction pathway mediates opioid actions. Moreover, it is uncertain whether one or more opioid receptor types mediates the developmental effects of opioids. To address these questions, the present study examined the role of μ opioid receptors and Ca2+ mobilization in morphine-induced astrocyte development. Morphine (1 μM) and non-morphine exposed cultures enriched in murine astrocytes were incubated in Ca2+-free media supplemented with < 0.005, 0.3, 1.0, or 3.0 mM Ca2+ ([Ca2+]o), or in unmodified media containing Ca2+ ionophore (A23187), nifedipine (1 μM), dantrolene (10 μM), thapsigargin (100 nM), or L-glutamate (100 μM) for 0–72 h. μ-Opioid receptor expression was examined immunocytochemically using specific (MOR1) antibodies. Intracellular Ca2+ ([Ca2+]i) was measured by microfluorometric analysis using fura-2. Astrocyte morphology and bromodeoxyuridine (BrdU) incorporation (DNA synthesis) were assessed in glial fibrillary acidic protein (GFAP) immunoreactive astrocytes. The results showed that morphine inhibited astroglial growth by activating μ opioid receptors. Astrocytes expressed MOR1 immunoreactivity and morphine’s actions were mimicked by the selective μ agonist PL017. In addition, morphine inhibited DNA synthesis by mobilizing [Ca2+]i in developing astroglia. At normal [Ca2+]o, morphine attenuated DNA synthesis by increasing [Ca2+]i; low [Ca2+]o (0.3 mM) blocked this effect, while treatment with Ca2+ ionophore or glutamate mimicked morphine’s actions. At extremely low [Ca2+]o (<0.005 mM), morphine paradoxically increased BrdU incorporation. Although opioids can increase

  20. 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.

  1. 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. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  2. Constitutive opioid receptor activation: a prerequisite mechanism involved in acute opioid withdrawal.

    PubMed

    Freye, E; Levy, Jv

    2005-06-01

    The opioid receptor antagonist naltrexone, which is used in detoxification and rehabilitation programmes in opioid addicts, can precipitate opioid withdrawal symptoms even in patients who have no opioid present. We tested the hypothesis that in order to precipitate withdrawal, opioids need to convert the inactive opioid receptor site via protein kinase C into a constitutively active form on which the antagonist precipitates withdrawal. Acute microg/kg), given for 6 days, which was followed by the antagonist naltrexone (20 microg/kg i.v.) in the awake trained canine (n = 10). Abrupt displacement of opioid binding resulted in acute withdrawal symptoms: increase in blood pressure, heart rate, increase in amplitude height of somatosensory evoked potential, reduced tolerance to colon distention and a significant increase in grading of vegetative variables (restlessness, panting, thrashing of the head, whining, yawning, gnawing, salivation and/or rhinorrhoea, mydriasis, stepping of extremities and vomiting). Following a washout period of 14 days, the same animals were given the highly specific protein kinase C inhibitor H7 (250 microg/kg) prior to the same dosages of sufentanil and naltrexone. Such pretreatment was able to either attenuate or completely abolish the acute withdrawal symptoms. The data suggest that for precipitation of withdrawal, intracellular phosphorylation is a prerequisite in order to activate the opioid mu-receptor. In such a setting, naltrexone acts like an 'inverse agonist' relative to the action of the antagonist on a non-preoccupied receptor site not being exposed previously to a potent opioid agonist.

  3. 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.

  4. Current Research on Opioid Receptor Function

    PubMed Central

    Feng, Yuan; He, Xiaozhou; Yang, Yilin; Chao, Dongman; Lazarus, Lawrence H.; Xia, Ying

    2012-01-01

    The use of opioid analgesics has a long history in clinical settings, although the comprehensive action of opioid receptors is still less understood. Nonetheless, recent studies have generated fresh insights into opioid receptor-mediated functions and their underlying mechanisms. Three major opioid receptors (μ-opioid receptor, MOR; δ-opioid receptor, DOR; and κ-opioid receptor, KOR) have been cloned in many species. Each opioid receptor is functionally sub-classified into several pharmacological subtypes, although, specific gene corresponding each of these receptor subtypes is still unidentified as only a single gene has been isolated for each opioid receptor. In addition to pain modulation and addiction, opioid receptors are widely involved in various physiological and pathophysiological activities, including the regulation of membrane ionic homeostasis, cell proliferation, emotional response, epileptic seizures, immune function, feeding, obesity, respiratory and cardiovascular control as well as some neurodegenerative disorders. In some species, they play an essential role in hibernation. One of the most exciting findings of the past decade is the opioid-receptor, especially DOR, mediated neuroprotection and cardioprotection. The up-regulation of DOR expression and DOR activation increase the neuronal tolerance to hypoxic/ischemic stress. The DOR signal triggers (depending on stress duration and severity) different mechanisms at multiple levels to preserve neuronal survival, including the stabilization of homeostasis and increased pro-survival signaling (e.g., PKC-ERK-Bcl 2) and anti-oxidative capacity. In the heart, PKC and KATP channels are involved in the opioid receptor-mediated cardioprotection. The DOR-mediated neuroprotection and cardioprotection have the potential to significantly alter the clinical pharmacology in terms of prevention and treatment of life-threatening conditions like stroke and myocardial infarction. The main purpose of this article

  5. In vivo antinociception of potent mu opioid agonist tetrapeptide analogues and comparison with a compact opioid agonist - neurokinin 1 receptor antagonist chimera

    PubMed Central

    2012-01-01

    Background An important limiting factor in the development of centrally acting pharmaceuticals is the blood-brain barrier (BBB). Transport of therapeutic peptides through this highly protective physiological barrier remains a challenge for peptide drug delivery into the central nervous system (CNS). Because the most common strategy to treat moderate to severe pain consists of the activation of opioid receptors in the brain, the development of active opioid peptide analogues as potential analgesics requires compounds with a high resistance to enzymatic degradation and an ability to cross the BBB. Results Herein we report that tetrapeptide analogues of the type H-Dmt1-Xxx2-Yyy3-Gly4-NH2 are transported into the brain after intravenous and subcutaneous administration and are able to activate the μ- and δ opioid receptors more efficiently and over longer periods of time than morphine. Using the hot water tail flick test as the animal model for antinociception, a comparison in potency is presented between a side chain conformationally constrained analogue containing the benzazepine ring (BVD03, Yyy3: Aba), and a "ring opened" analogue (BVD02, Yyy3: Phe). The results show that in addition to the increased lipophilicity through amide bond N-methylation, the conformational constraint introduced at the level of the Phe3 side chain causes a prolonged antinociception. Further replacement of NMe-D-Ala2 by D-Arg2 in the tetrapeptide sequence led to an improved potency as demonstrated by a higher and maintained antinociception for AN81 (Xxx2: D-Arg) vs. BVD03 (Xxx2: NMe-D-Ala). A daily injection of the studied opioid ligands over a time period of 5 days did however result in a substantial decrease in antinociception on the fifth day of the experiment. The compact opioid agonist - NK1 antagonist hybrid SBCHM01 could not circumvent opioid induced tolerance. Conclusions We demonstrated that the introduction of a conformational constraint has an important impact on opioid receptor

  6. A chronic opioid therapy dose reduction policy in primary care.

    PubMed

    Weimer, Melissa B; Hartung, Daniel M; Ahmed, Sharia; Nicolaidis, Christina

    2016-01-01

    High-dose opioids prescribed for the treatment of chronic pain have been associated with increased risk of opioid overdose. Health systems and states have responded by developing opioid dose limitation policies. Little is known about how these policies affect prescribing practices or characteristics of patients who respond best to opioid tapers from high-dose opioids. We conducted a retrospective cohort study to evaluate change in total opioid dose after the implementation of a provider education intervention and a 120 mg morphine equivalents per day (MED) opioid dose limitation policy in one academic primary care clinic. We compared opioid prescriptions 1 year before and 1 year after the intervention. We used univariate and multivariate logistic regression to assess which patient characteristics predicted opioid dose reduction from high opioid dose. Out of a total of 516 patients prescribed chronic opioid therapy, 116 patients (22%) were prescribed high-dose opioid therapy (>120 mg MED). After policy adoption, the average daily dose of opioids declined by 64 mg MED (95% confidence interval [CI]: 32-96; P < .001) and 41 patients (37%) on high-dose opioids tapered their doses below 120 mg MED (Tapered to Safer Dose group). In multivariate analyses, female sex was the only significant association with dose taper; female patients were less likely to taper to a safer dose (adjusted odds ratio [aOR] = 0.28, 95% CI: 0.11-0.70). A combined intervention of education and a practice policy that limits opioid doses for patients prescribed chronic opioid therapy may be an important component of system-level strategies to reduce opioid misuse and overdose; it may also help identify patients suitable for medication-assisted treatment for opioid use disorder. Specific strategies may be needed to assist women with opioid dose tapers.

  7. [Long-term opioid therapy in chronic noncancer pain. A systematic review and meta-analysis of efficacy, tolerability and safety in open-label extension trials with study duration of at least 26 weeks].

    PubMed

    Häuser, W; Bernardy, K; Maier, C

    2015-02-01

    aberrant drug behavior by independent expert assessment. There was no significant change (p = 0.50) in pain intensity between the end of the randomized period and the end of open-label phase (SMD 0.19 [- 0.03, 0.41]; six studies with 1360 participants). Only a minority of patients selected for opioid therapy at randomization finished the long-term open-label study. However, sustained effects of pain reduction could be demonstrated in these patients. LtOT can be considered in carefully selected and monitored CNCP patients who experience clinically meaningful pain reduction with at least tolerable AE in short-term opioid therapy. The English full-text version of this article is freely available at SpringerLink (under "Supplementary Material").

  8. 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 ...

  9. A double-blind, randomized, parallel group study to compare the efficacy, safety and tolerability of slow-release oral morphine versus methadone in opioid-dependent in-patients willing to undergo detoxification

    PubMed Central

    Madlung-Kratzer, Ekkehard; Spitzer, Berhard; Brosch, Renate; Dunkel, Dirk; Haring, Christian

    2009-01-01

    Aims Evaluation of the efficacy and safety of slow-release oral morphine (SROM) compared with methadone for detoxification from methadone and SROM maintenance treatment. Design Randomized, double-blind, double-dummy, comparative multi-centre study with parallel groups. Setting Three psychiatric hospitals in Austria specializing in in-patient detoxification. Participants Male and female opioid dependents (age > 18 years) willing to undergo detoxification from maintenance therapy in order to reach abstinence. Interventions Abstinence was reached from maintenance treatment by tapered dose reduction of either SROM or methadone over a period of 16 days. Measurements Efficacy analyses were based on the number of patients per treatment group completing the study, as well as on the control of signs and symptoms of withdrawal [measured using Short Opioid Withdrawal Scale (SOWS)] and suppression of opiate craving. In addition, self-reported somatic and psychic symptoms (measured using Symptom Checklist SCL-90-R) were monitored. Findings Of the 208 patients enrolled into the study, 202 were eligible for analysis (SROM: n = 102, methadone: n = 100). Completion rates were 51% in the SROM group and 49% in the methadone group [difference between groups: 2%; 95% confidence interval (CI): −12% to 16%]. The rate of discontinuation in the study was high mainly because of patients voluntarily withdrawing from treatment. No statistically significant differences between treatment groups were found in terms of signs and symptoms of opiate withdrawal, craving for opiates or self-reported symptoms. SROM and methadone were both well tolerated. Conclusions Detoxification from maintenance treatment with tapered dose reduction of SROM is non-inferior to methadone. PMID:19686525

  10. 6β-N-heterocyclic substituted naltrexamine derivative NAP as a potential lead to develop peripheral mu opioid receptor selective antagonists.

    PubMed

    Yuan, Yunyun; Stevens, David L; Braithwaite, Amanda; Scoggins, Krista L; Bilsky, Edward J; Akbarali, Hamid I; Dewey, William L; Zhang, Yan

    2012-07-15

    A 6β-N-heterocyclic substituted naltrexamine derivative, NAP, was proposed as a peripheral mu opioid receptor (MOR) selective antagonist based on the in vitro and in vivo pharmacological and pharmacokinetic studies. To further validate this notion, several functional assays were carried out to fully characterize this compound. In the charcoal gavage and intestinal motility assay in morphine-pelleted mice, when administered 0.3 mg/kg or higher doses up to 3 mg/kg subcutaneously, NAP significantly increased the intestinal motility compared to the saline treatment. The comparative opioid withdrawal precipitation study and the lower locomotor assay demonstrated that NAP showed only marginal intrinsic effect in the central nervous system either given subcutaneously or intravenously: no jumps were witnessed for the tested animals even given up to a dose of 50 mg/kg, while similar noticeable wet-dog shakes only occurred at the dose 50 times of those for naloxone or naltrexone, and significant reduction of the hyper-locomotion only happened at the dose as high as 32 mg/kg. Collectively, these results suggested that NAP may serve as a novel lead to develop peripheral MOR selective antagonist which might possess therapeutic potential for opioid-induced bowel dysfunction (OBD), such as opioid-induced constipation (OIC).

  11. Pharmacogenetics of opioid analgesics in dogs.

    PubMed

    Kongara, K

    2017-09-11

    Genetic variation causes interindividual variability in drug absorption, distribution, metabolism and excretion. These pharmacokinetic processes will influence the observed efficacy and toxicity of a drug. Polymorphisms in the genes encoding the metabolizing enzymes, transport proteins and receptors have been linked to the inconsistency in responses to opioid treatment in humans and laboratory animals. Pharmacogenetics is relatively less developed field in veterinary medicine compared to significant advances in knowledge on genetic basis of variation in drug responses and clinical applications in human medicine. This review discusses the opioid drug metabolism and possible genetic polymorphism of metabolizing enzymes in dogs. Polymorphism of genes encoding opioid drug transporter proteins and its effect on opioid response and opioid receptor gene variants are also discussed. Due to the scarcity of studies reported on opioid pharmacogenetics in dogs, relevant studies in humans and rodents have also been discussed to indicate current trends and potential targets for research in dogs. © 2017 John Wiley & Sons Ltd.

  12. Simultaneous determination of 18 abused opioids and metabolites in human hair using LC-MS/MS and illegal opioids abuse proven by hair analysis.

    PubMed

    Kim, Jihyun; Ji, Dajeong; Kang, Soyoung; Park, Meejung; Yang, Wonkyung; Kim, Eunmi; Choi, Hwakyung; Lee, Sooyeun

    2014-02-01

    Natural and synthetic opioids have efficient analgesic activity but can also be addictive. Thus, the determination of opioids and their metabolites in biological specimens is of interest in clinical and forensic toxicology laboratories. The analysis of drugs in hair provides valuable information on previous chronic drug use and has been successfully applied to the diagnosis of drug abuse, tolerance, compliance and gestational drug exposure. Despite the abuse of prescription opioids along with heroin and other illegal opiates, few studies have been conducted on the simultaneous determination of the broad range of opioids covering those drugs in hair. In the present study, an analytical method for the simultaneous detection in hair of 18 opioids and metabolites considered to have a high abuse risk based on the results of urine drug screening was established and validated using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the purpose of clinical and forensic applications. The drugs and metabolites were extracted from hair using methanol and analyzed using LC-MS/MS. The validation results proved that the method was selective, accurate and precise with acceptable linearity within calibration ranges. No significant variation was observed by different sources of matrices. The limits of detection and the limits of quantification ranged from 0.05 to 0.25ng/10mg hair and from 0.05 to 0.5ng/10mg hair, respectively. The developed method was successfully applied to 15 hair samples from opioids users. This method will be very useful for monitoring the inappropriate use of opioid drugs.

  13. Different mechanisms of homologous and heterologous μ-opioid receptor phosphorylation.

    PubMed

    Mann, Anika; Illing, Susann; Miess, Elke; Schulz, Stefan

    2015-01-01

    The efficiency of μ-opioid receptor signalling is tightly regulated and ultimately limited by the coordinated phosphorylation of intracellular serine and threonine residues. Here, we review and discuss recent progress in the generation and application of phosphosite-specific μ-opioid receptor antibodies, which have proved to be excellent tools for monitoring the spatial and temporal dynamics of receptor phosphorylation and dephosphorylation. Agonist-induced phosphorylation of μ-opioid receptors occurs at a conserved 10 residue sequence (370) TREHPSTANT(379) in the receptor's carboxyl-terminal cytoplasmic tail. Diverse opioids induce receptor phosphorylation at S375, present in the middle of this sequence, but only high-efficacy opioids have the ability to drive higher order phosphorylation on flanking residues (T370, T376 and T379). S375 is the initiating residue in a hierarchical phosphorylation cascade. In contrast, agonist-independent heterologous μ-opioid receptor phosphorylation occurs primarily at T370. The combination of phosphosite-specific antibodies and siRNA knockdown screening also facilitated the identification of relevant kinases and phosphatases. In fact, morphine induces a selective S375 phosphorylation that is predominantly catalysed by GPCR kinase 5 (GRK5), whereas multisite phosphorylation induced by high-efficacy opioids specifically requires GRK2/3. By contrast, T370 phosphorylation stimulated by phorbol esters or heterologous activation of Gq -coupled receptors is mediated by PKCα. Rapid μ-opioid receptor dephosphorylation occurs at or near the plasma membrane and is catalysed by protein phosphatase 1γ (PP1γ). These findings suggest that there are distinct phosphorylation motifs for homologous and heterologous regulation of μ-opioid receptor phosphorylation. However, it remains to be seen to what extent different μ-opioid receptor phosphorylation patterns contribute to the development of tolerance and dependence in vivo. This article

  14. Methadone as first-line opioid treatment for cancer pain in a developing country palliative care unit.

    PubMed

    Peirano, Gabriela P; Mammana, Guillermo P; Bertolino, Mariela S; Pastrana, Tania; Vega, Gloria F; Russo, Jorgelina; Varela, Gabriela; Vignaroli, Ernesto; Ruggiero, Raúl; Armesto, Arnaldo; Camerano, Gabriela; Dran, Graciela

    2016-08-01

    The use of methadone for cancer pain is limited by the need of expertise and close titration due to variable half-life. Yet, it is a helpful palliative strategy in low-resources countries given its long-acting effect at low cost and worth additional study. Our aim was to describe the prescription and outcomes of methadone as a first-line treatment for cancer pain in a tertiary palliative care unit (PCU) in Argentina. Retrospective review of medical records of patients with moderate to severe cancer pain seen at the PCU in 1-year period, who initiated strong opioids at the first consultation. Data collected during the first month of treatment included disease and pain characteristics, initial and final opioid type and dose and need for opioid rotation. Methadone was the most frequent opioid both at the initial and last assessment (71 and 66 % of the prescriptions). In all, treatment with strong opioids provided considerable decrease in pain intensity (p < 0.001) with low and stable opioid dose. Median and interquartile range (IR) of oral morphine equivalent daily dose (OMEDD) was 26 (16-32) and 39 (32-55) mg for initial and final assessments, respectively (p = 0.3). In patients initiated with methadone, the median (IR) daily methadone dose was 5 (4-6) mg at first and 7.5 (6-10) mg at final assessment, and the median (IR) index of opioid escalation was 0 (0-4) mg; (p < 0.05). Patients on methadone underwent less percentage of opioid rotation (15 versus 50 %; p < 0.001) and longer time to rotation (20.6 ± 4.4 versus 9.0 ± 2.7 days; p < 0.001) than patients on other opioids. Results indicate the preference of methadone as first-line strong opioid treatment in a PCU, providing good pain relief at low doses with low need for rotation. Several considerations about the costs of strong opioids in the region are given.

  15. Management of neonatal abstinence syndrome from opioids.

    PubMed

    Grim, Kendra; Harrison, Tracy E; Wilder, Robert T

    2013-09-01

    Most infants at risk for neonatal abstinence syndrome have opioid plus another drug exposure; polypharmacy is the rule rather than the exception. Scales for evaluation of neonatal abstinence syndrome are primarily based for opioid withdrawal. A standard protocol to treat neonatal abstinence syndrome has not been developed. Institute nonpharmacologic strategies for all neonates at risk. The American Academy of Pediatrics recommends mechanism-directed therapy (treat opioid withdrawal with an opioid) as the first-line therapy. Second-line medications are currently under evaluation. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Use of methadone in a highly tolerant patient receiving parenteral hydromorphone.

    PubMed

    Thomas, Z; Bruera, E

    1995-05-01

    A 59-year-old woman with metastatic breast cancer experienced a poor response to increasing doses of hydromorphone, possibly related to the neuropathic nature of her pain. Ultimately, the cost of this treatment was more than $1000 per day. Administration of methadone, initially as an adjuvant and eventually as the sole analgesic, at a much smaller dose than expected resulted in very satisfactory analgesia, without the development of serious side effects. In addition, the cost of treatment decreased to less than $25 per day. This case illustrates the rationale and advantages for the use of methadone. Intraindividual variability in the response to various opioids is a factor to be considered when selecting analgesics. Methadone is a useful second-line or third-line opioid for the patient who is highly tolerant to other opioids, as it may demonstrate incomplete cross-tolerance with other agonist opioids. Switching of the opioid to methadone may be a worthwhile option to consider in managing patients who are highly tolerant to other opioids.

  17. A randomized clinical trial of the effects of ultra-low-dose naloxone infusion on postoperative opioid requirements and recovery.

    PubMed

    Xiao, Y; Wu, L; Zhou, Q; Xiong, W; Duan, X; Huang, X

    2015-10-01

    Tolerance to remifentanil during sevoflurane anesthesia may increase postoperative analgesic requirements. Low-dose naloxone not only has been shown to block the development of acute opioid tolerance but also to ameliorate undesired opioid-induced side effects. We hypothesized that naloxone prevents the acute opioid tolerance produced by a large dose of remifentanil, and reduces the incidence of opioid-induced side effects. Seventy-two patients undergoing open colorectal surgery were randomly assigned to receive intraoperative remifentanil (1) small dose at 0.1 μg/kg/min; (2) large dose at 0.30 μg/kg/min; or (3) large dose at 0.30 μg/kg/min combined with low-dose naloxone at 0.25 μg/kg/h just after the induction. Cumulative morphine consumption, postoperative pain scores, incidence of opioid-related side effects, time to recovery of bowel function, and length of hospital stay were recorded. Cumulative morphine consumption at 24 h after surgery was higher in the large-dose remifentanil group (28 ± 12 mg) compared with the small-dose remifentanil group (17 ± 12 mg), and large-dose remifentanil-naloxone group (18 ± 9 mg), (P < 0.001). The median time to return of bowel function was shorter in the large-dose remifentanil-naloxone group than the other two groups (P < 0.05). The median length of hospital stay was lower in the large-dose remifentanil-naloxone group (8 [interquartile range: 8-12] days) compared with the small-dose remifentanil group (12 [interquartile range: 9-15] days) and large-dose remifentanil group (12 [interquartile range: 10-13] days), (P < 0.001). Naloxone infusion prevented the acute opioid tolerance, provided a quicker recovery of bowel function, and reduced the length of hospital stay after open colorectal surgery. © 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  18. Development of a common 3D pharmacophore for δ-opioid recognition from peptides and non-peptides using a novel computer program

    NASA Astrophysics Data System (ADS)

    Huang, Ping; Kim, Susan; Loew, Gilda

    1997-01-01

    A unified three-dimensional (3D) pharmacophore for recognition of the δ-opioid receptorby families of structurally diverse δ-opioid ligands, including peptides and non-peptides,has been determined. An additional structural feature required for δ-selectivity was alsocharacterized using a subset of these ligands that are highly selective for the δ-opioidreceptor. To obtain these pharmacophores, we have used a recently developed computerprogram that performs systematic and automated comparisons of molecules to determinewhether any common 3D relationships exist among candidate recognition moieties in high-affinity analogs. All the low-energy conformations of each ligand are included in thesecomparisons. The program developed should be applicable in general to molecular super-imposition problems in rational drug design and to develop both 3D recognition and activationpharmacophores for any receptor for which high- and low-affinity analogs and agonists andantagonists have been identified.

  19. Use of prescription opioids with abuse-deterrent technology to address opioid abuse.

    PubMed

    Michna, Edward; Kirson, Noam Y; Shei, Amie; Birnbaum, Howard G; Ben-Joseph, Rami

    2014-08-01

    The development of new formulations of extended-release (ER) opioids with abuse-deterrent technology attempts to deter prescription opioid abuse while maintaining appropriate access to care for pain patients. This study examined the degree to which some patients may avoid switching to reformulated ER opioids with abuse-deterrent technology and the extent to which those patients are more likely to be abusers. We analyzed Truven MarketScan pharmacy and medical claims data following the introduction of two reformulated ER opioids with abuse-deterrent technology. Adults aged 18-64 who were continuous users of extended-release oxycodone HCl (ER oxycodone) or extended-release oxymorphone HCl (ER oxymorphone) in a 6 month period prior to the introduction of the respective reformulations of those products were identified and categorized based on whether they switched to the reformulation, switched to other ER/long-acting (LA) opioids (without abuse-deterrent technology), or discontinued ER/LA opioid treatment in a 6 month post-reformulation period. Abusers were identified using ICD-9-CM diagnosis codes for opioid abuse/dependence. Pearson's chi-squared tests and Fisher's exact tests were then used to compare rates of abuse between patients who avoided switching to a reformulated ER opioid. Sensitivity analyses examined several definitions used in this analysis. ER/LA opioid utilization; rates of diagnosed opioid abuse. A total of 31%-50% of patients avoided switching to reformulated ER opioids. Rates of diagnosed opioid abuse were higher among these patients compared to patients who transitioned to the reformulated ER opioids. Due to the observational research design, caution is warranted in causal interpretation of the findings. The study was conducted among commercially insured continuous ER oxycodone or ER oxymorphone users; future research should consider additional patient populations, such as non-continuous users and those without commercial insurance (i.e., Medicare

  20. Targeting peripheral opioid receptors to promote analgesic and anti-inflammatory actions

    PubMed Central

    Iwaszkiewicz, Katerina S.; Schneider, Jennifer J.; Hua, Susan

    2013-01-01

    Mechanisms of endogenous pain control are significant. Increasing studies have clearly produced evidence for the clinical usefulness of opioids in peripheral analgesia. The immune system uses mechanisms of cell migration not only to fight pathogens but also to control pain and inflammation within injured tissue. It has been demonstrated that peripheral inflammatory pain can be effectively controlled by an interaction of immune cell-derived opioid peptides with opioid receptors on peripheral sensory nerve terminals. Experimental and clinical studies have clearly shown that activation of peripheral opioid receptors with exogenous opioid agonists and endogenous opioid peptides are able to produce significant analgesic and anti-inflammatory effects, without central opioid mediated side effects (e.g., respiratory depression, sedation, tolerance, dependence). This article will focus on the role of opioids in peripheral inflammatory conditions and the clinical implications of targeting peripheral opioid receptors. PMID:24167491

  1. Implications of opioid analgesia for medically complicated patients.

    PubMed

    Smith, Howard; Bruckenthal, Patricia

    2010-05-01

    Opioid analgesics have an established role in the management of postoperative pain and cancer pain, and are gaining acceptance for the management of moderate to severe chronic noncancer pain, most notably chronic low back pain and osteoarthritis, that does not respond to other interventions. Many patients with chronic pain have co-morbid medical conditions that may complicate opioid therapy. Selecting the appropriate opioid requires knowledge of how individual opioids differ with respect to metabolism and interaction with concurrent medications, as well as the reasons why specific medical conditions may influence their efficacy and tolerability. Polypharmacy is a common complicating condition in the elderly and in patients with psychiatric illness, cancer, cardiovascular disease, diabetes mellitus or other chronic illnesses. Polypharmacy, though often necessary for patients with multiple medical conditions, also multiplies the risk of drug interactions. Pharmacokinetic drug interactions can increase or reduce exposure to the opioid or concurrent medications, reducing efficacy and/or tolerability and increasing toxicity. Pharmacodynamic interactions can enhance the depressive effects of opioids, compromising safety. Patients with impaired renal or hepatic function may have difficulty clearing or metabolizing opioids and concurrent medications, leading to increased risk of adverse events. Patients with cardiovascular, cerebrovascular or respiratory disease (including smokers of >/=2 packs/day with no other diagnosis) may be more susceptible to respiratory depression, bradycardia and hypotension with any opioid, and a few specific opioids pose additional risks. Patients with cerebrovascular disease, dementia, brain injury or psychiatric illness are more susceptible to opioid effects on the CNS, which can include euphoria, cognitive impairment and sedation. Appropriate opioid selection may mitigate these effects. Even in older patients, addiction, abuse and

  2. Neonatal opioid withdrawal syndrome.

    PubMed

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

    2014-06-01

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

  3. Dextromethorphan differentially affects opioid antinociception in rats

    PubMed Central

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

    2005-01-01

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

  4. 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.

  5. Opioids and Opioid Maintenance Therapies: Their Impact on Monocyte-Mediated HIV Neuropathogenesis

    PubMed Central

    Jaureguiberry-Bravo, Matias; Wilson, Rebecca; Carvallo, Loreto; Berman, Joan W.

    2017-01-01

    Background HIV-1 enters the CNS within two weeks after peripheral infection and results in chronic neuroinflammation that leads to HIV associated neurocognitive disorders (HAND) in more than 50% of infected people. HIV enters the CNS by transmigration of infected monocytes across the blood brain barrier. Intravenous drug abuse is a major risk factor for HIV-1 infection, and opioids have been shown to alter the progression and severity of HAND. Methadone and buprenorphine are opioid derivates that are used as opioid maintenance therapies. They are commonly used to treat opioid dependency in HIV infected substance abusers, but their effects on monocyte migration relevant to the development of cognitive impairment are not well characterized. Conclusion Here, we will discuss the effects of opioids and opioid maintenance therapies on the inflammatory functions of monocytes and macrophages that are related to the development of neuroinflammation in the context of HIV infection. PMID:27009099

  6. 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

  7. Revolution in GPCR signalling: opioid receptor heteromers as novel therapeutic targets: IUPHAR review 10.

    PubMed

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

    2014-09-01

    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.

  8. 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...

  9. 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...

  10. Functionally Selective Signaling for Morphine and Fentanyl Antinociception and Tolerance Mediated by the Rat Periaqueductal Gray

    PubMed Central

    Morgan, Michael M.; Reid, Rachel A.; Saville, Kimber A.

    2014-01-01

    Functionally selective signaling appears to contribute to the variability in mechanisms that underlie tolerance to the antinociceptive effects of opioids. The present study tested this hypothesis by examining the contribution of G protein-coupled receptor kinase (GRK)/Protein kinase C (PKC) and C-Jun N-terminal kinase (JNK) activation on both the expression and development of tolerance to morphine and fentanyl microinjected into the ventrolateral periaqueductal gray of the rat. Microinjection of morphine or fentanyl into the periaqueductal gray produced a dose-dependent increase in hot plate latency. Microinjection of the non-specific GRK/PKC inhibitor Ro 32-0432 into the periaqueductal gray to block mu-opioid receptor phosphorylation enhanced the antinociceptive effect of morphine but had no effect on fentanyl antinociception. Microinjection of the JNK inhibitor SP600125 had no effect on morphine or fentanyl antinociception, but blocked the expression of tolerance to repeated morphine microinjections. In contrast, a microinjection of Ro 32-0432 blocked the expression of fentanyl, but not morphine tolerance. Repeated microinjections of Ro 32-0432 blocked the development of morphine tolerance and inhibited fentanyl antinociception whether rats were tolerant or not. Repeated microinjections of SP600125 into the periaqueductal gray blocked the development of tolerance to both morphine and fentanyl microinjections. These data demonstrate that the signaling molecules that contribute to tolerance vary depending on the opioid and methodology used to assess tolerance (expression vs. development of tolerance). This signaling difference is especially clear for the expression of tolerance in which JNK contributes to morphine tolerance and GRK/PKC contributes to fentanyl tolerance. PMID:25503060

  11. Possible involvement of Toll-Like Receptor 4/MD-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences

    PubMed Central

    Hutchinson, Mark R.; Lewis, Susannah S.; Coats, Benjamen D.; Rezvani, Niloofar; Zhang, Yingning; Wieseler, Julie L.; Somogyi, Andrew A.; Yin, Hang; Maier, Steven F.; Rice, Kenner C.; Watkins, Linda R.

    2010-01-01

    Opioid-induced glial activation and its proinflammatory consequences have been associated with both reduced acute opioid analgesia and the enhanced development of tolerance, hyperalgesia and allodynia following chronic opioid administration. Intriguingly, recent evidence demonstrates that these effects can result independently from the activation of classical, stereoselective opioid receptors. Here, a structurally disparate range of opioids cause activation of signaling by the innate immune receptor Toll Like Receptor 4 (TLR4), resulting in proinflammatory glial activation. In the present series of studies, we demonstrate that the (+)-isomers of methadone and morphine, which bind with negligible affinity to classical opioid receptors, induced upregulation of proinflammatory cytokine and chemokine production in rat isolated dorsal spinal cord. Chronic intrathecal (+)-methadone produced hyperalgesia and allodynia, which were associated with significantly increased spinal glial activation (TLR4 mRNA and protein) and the expression of multiple chemokines and cytokines. Statistical analysis suggests that a cluster of cytokines and chemokines may contribute to these nociceptive behavioral changes. Acute intrathecal (+)-methadone and (+)-morphine were also found to induce microglial, interleukin-1 and TLR4/MD-2 dependent enhancement of pain responsivity. In silico docking analysis demonstrated (+)-naloxone sensitive docking of (+)-methadone and (+)-morphine to human MD-2. Collectively, these data provide the first evidence of the pro-nociceptive consequences of small molecule xenobiotic activation of spinal TLR4 signaling independent of classical opioid receptor involvement. PMID:20178837

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

    PubMed

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

    2013-10-01

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

  13. 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

  14. Fast Modulation of μ-Opioid Receptor (MOR) Recycling Is Mediated by Receptor Agonists*

    PubMed Central

    Roman-Vendrell, Cristina; Yu, Y. Joy; Yudowski, Guillermo Ariel

    2012-01-01

    The μ-opioid receptor (MOR) is a member of the G protein-coupled receptor family and the main target of endogenous opioid neuropeptides and morphine. Upon activation by ligands, MORs are rapidly internalized via clathrin-coated pits in heterologous cells and dissociated striatal neurons. After initial endocytosis, resensitized receptors recycle back to the cell surface by vesicular delivery for subsequent cycles of activation. MOR trafficking has been linked to opioid tolerance after acute exposure to agonist, but it is also involved in the resensitization process. Several studies describe the regulation and mechanism of MOR endocytosis, but little is known about the recycling of resensitized receptors to the cell surface. To study this process, we induced internalization of MOR with [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) and morphine and imaged in real time single vesicles recycling receptors to the cell surface. We determined single vesicle recycling kinetics and the number of receptors contained in them. Then we demonstrated that rapid vesicular delivery of recycling MORs to the cell surface was mediated by the actin-microtubule cytoskeleton. Recycling was also dependent on Rab4, Rab11, and the Ca2+-sensitive motor protein myosin Vb. Finally, we showed that recycling is acutely modulated by the presence of agonists and the levels of cAMP. Our work identifies a novel trafficking mechanism that increases the number of cell surface MORs during acute agonist exposure, effectively reducing the development of opioid tolerance. PMID:22378794

  15. Fast modulation of μ-opioid receptor (MOR) recycling is mediated by receptor agonists.

    PubMed

    Roman-Vendrell, Cristina; Yu, Y Joy; Yudowski, Guillermo Ariel

    2012-04-27

    The μ-opioid receptor (MOR) is a member of the G protein-coupled receptor family and the main target of endogenous opioid neuropeptides and morphine. Upon activation by ligands, MORs are rapidly internalized via clathrin-coated pits in heterologous cells and dissociated striatal neurons. After initial endocytosis, resensitized receptors recycle back to the cell surface by vesicular delivery for subsequent cycles of activation. MOR trafficking has been linked to opioid tolerance after acute exposure to agonist, but it is also involved in the resensitization process. Several studies describe the regulation and mechanism of MOR endocytosis, but little is known about the recycling of resensitized receptors to the cell surface. To study this process, we induced internalization of MOR with [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO) and morphine and imaged in real time single vesicles recycling receptors to the cell surface. We determined single vesicle recycling kinetics and the number of receptors contained in them. Then we demonstrated that rapid vesicular delivery of recycling MORs to the cell surface was mediated by the actin-microtubule cytoskeleton. Recycling was also dependent on Rab4, Rab11, and the Ca(2+)-sensitive motor protein myosin Vb. Finally, we showed that recycling is acutely modulated by the presence of agonists and the levels of cAMP. Our work identifies a novel trafficking mechanism that increases the number of cell surface MORs during acute agonist exposure, effectively reducing the development of opioid tolerance.

  16. Argon prevents the development of locomotor sensitization to amphetamine and amphetamine-induced changes in mu opioid receptor in the nucleus accumbens.

    PubMed

    David, Hélène N; Dhilly, Martine; Poisnel, Géraldine; Degoulet, Mickael; Meckler, Cédric; Vallée, Nicolas; Blatteau, Jean-Éric; Risso, Jean-Jacques; Lemaire, Marc; Debruyne, Danièle; Abraini, Jacques H

    2014-01-01

    Systemic administration of γ-amino-butyric acid type A (GABA-A) and benzodiazepine receptor agonists has been reported to block the development of locomotor sensitization to amphetamine. Here, we investigated whether the non-anesthetic noble gas argon, shown to possess agonistic properties at these receptors, may block the acquisition of amphetamine-induced locomotor sensitization and mu opioid receptor activation in the nucleus accumbens. Rats were pretreated with saline solution or amphetamine (1 mg/kg) from day 1 to day 3 and then exposed, immediately after injection of amphetamine, to medicinal air or argon at 75 vol% (with the remainder being oxygen). After a 3-day period of withdrawal, rats were challenged with amphetamine on day 7. Rats pretreated with amphetamine and argon had lower locomotor activity (U = 5, P < 0.005) and mu opioid receptor activity in the nucleus accumbens (U = 0, P < 0.001) than rats pretreated with amphetamine and air. In contrast, argon had effect on locomotor and mu receptor activity neither in rats pretreated with saline and challenged with amphetamine (acute amphetamine) nor in rats pretreated and challenged with saline solution (controls). These results indicate that argon inhibits the development of both locomotor sensitization and mu opioid receptor activation induced by repeated administration of amphetamine.

  17. Forskolin promotes the development of ethanol tolerance in 6-hydroxydopamine-treated mice

    SciTech Connect

    Szabo, G.; Hoffman, P.L.; Tabakoff, B.

    1988-01-01

    Partial depletion of brain norepinephrine by 6-hydroxydopamine prevents the development of functional tolerance to ethanol in mice. This blockade of tolerance development was overcome by daily intracerebroventricular injections of forskolin. These results suggest that interaction of norepinephrine with post-synaptic ..beta..-adrenergic receptors, and activation of adenylate cyclase, is important for the development of ethanol tolerance. Interaction of norepinephrine with ..cap alpha../sub 1/-adrenergic receptors may be less crucial, since treatment with a phorbol ester activator of protein kinase C did not restore the development of tolerance in mice treated with 6-hydroxydopamine. The importance of the ..beta..-adrenergic receptor-coupled adenylate cyclase system for development of ethanol tolerance, in addition to its previously-reported role in long-term potentiation, suggests that this system may influence neuroadaptive processes in general. 26 references, 2 figures.

  18. The competence to acquire cellular desiccation tolerance is independent of seed morphological development.

    PubMed

    Golovina, E A; Hoekstra, F A; Van Aelst, A C

    2001-05-01

    Acquisition of desiccation tolerance and the related changes at the cellular level in wheat (Triticum aestivum cv. Priokskaya) kernels during normal development and premature drying on the ear were studied using a spin probe technique and low temperature scanning electron microscopy. During normal development, the ability of embryos to germinate after rapid drying and rehydration was acquired after completion of morphological development, which is a few days before mass maturity. The acquisition of desiccation tolerance, as assessed by germination, was associated with an upsurge in cytoplasmic viscosity, the onset of accumulation of protein and oil bodies, and the retention of membrane integrity upon dehydration/rehydration. These features were also used to assess cellular desiccation tolerance in the cases when germination could not occur. Slow premature drying was used to decouple the acquisition of cellular desiccation tolerance from morphogenesis. Upon premature drying of kernels on the ears of plants cut at 5 d after anthesis, desiccation-tolerant dwarf embryos were formed that were able to germinate. When plants were cut at earlier stages poorly developed embryos were formed that were unable to germinate, but cellular desiccation tolerance was nevertheless acquired. In such prematurely dried kernels, peripheral meristematic endosperm cells had already passed through similar physiological and ultrastructural changes associated with the acquisition of cellular desiccation tolerance. It is concluded that despite the apparent strong integration in seed development, desiccation tolerance can be acquired by the meristematic cells in the developing embryo and cambial layer of endosperm, independently of morphological development.

  19. Effects of ibudilast on oxycodone-induced analgesia and subjective effects in opioid-dependent volunteers.

    PubMed

    Cooper, Z D; Johnson, K W; Vosburg, S K; Sullivan, M A; Manubay, J; Martinez, D; Jones, J D; Saccone, P A; Comer, S D

    2017-09-01

    Opioid-induced glial activation is hypothesized to contribute to the development of tolerance to opioid-induced analgesia. This inpatient, double-blind, placebo-controlled, within-subject and between-groups pilot study investigated the dose-dependent effects of ibudilast, a glial cell modulator, on oxycodone-induced analgesia. Opioid-dependent volunteers were maintained on morphine (30mg, PO, QID) for two weeks and received placebo ibudilast (0mg, PO, BID) during the 1st week (days 1-7). On day 8, participants (N=10/group) were randomized to receive ibudilast (20 or 40mg, PO, BID) or placebo for the remainder of the study. On days 4 (week 1) and 11 (week 2), the analgesic, subjective, and physiological effects of oxycodone (0, 25, 50mg/70kg, PO) were determined. Analgesia was measured using the cold pressor test; participants immersed their hand in cold water (4°C) and pain threshold and pain tolerability were recorded. Oxycodone decreased pain threshold and tolerability in all groups during week 1. During week 2, the placebo group exhibited a blunted analgesic response to oxycodone for pain threshold and subjective pain ratings, whereas the 40mg BID ibudilast group exhibited greater analgesia as measured by subjective pain ratings (p≤0.05). Oxycodone also increased subjective drug effect ratings associated with abuse liability in all groups during week 1 (p≤0.05); ibudilast did not consistently affect these ratings. These findings suggest that ibudilast may enhance opioid-induced analgesia. Investigating higher ibudilast doses may establish the utility of pharmacological modulation of glial activity to maximize the clinical use of opioids. Copyright © 2017. Published by Elsevier B.V.

  20. Personality as a risk factor for illicit opioid use and a protective factor for illicit opioid dependence.

    PubMed

    Zaaijer, Eline R; Bruijel, Jessica; Blanken, Peter; Hendriks, Vincent; Koeter, Maarten W J; Kreek, Mary Jeanne; Booij, Jan; Goudriaan, Anna E; van Ree, Jan M; van den Brink, Wim

    2014-12-01

    Most studies investigating the role of personality as a risk factor for the development of opioid dependence compare dependent opioid users with healthy controls who never used heroin. In order to understand the potential protective role of personality, it is crucial to compare illicit opioid users who never became dependent with dependent opioid users. This study aims to examine the role of personality as a risk factor for opioid use and as a protective factor for the development of opioid dependence. Comparing personality factors between three groups: (1) 161 never-dependent illicit opioid users who have been using illicit opioids but never became opioid dependent; (2) 402 dependent opioid users in methadone maintenance treatment or heroin-assisted treatment; and (3) 135 healthy controls who never used heroin. Personality was assessed with a short version of Cloninger's Temperament and Character Inventory. Never-dependent opioid users reported more Novelty Seeking and Harm Avoidance and less Self-Directedness and Cooperativeness than healthy controls and more Reward Dependence and Self-Directedness, and less Harm Avoidance than dependent opioid users. Furthermore, never-dependent opioid users reported more Self-Transcendence than both dependent opioid users and healthy controls. Never-dependent opioid users may have started to use opioids partly due to their tendency to seek novel and/or spiritual experiences (high Novelty Seeking, high Self-Transcendence) and their tendency to avoid aversive stimuli (high Harm Avoidance), whereas they may have been protected against the development of dependence by their need for social approval (high Reward Dependence) and their self-efficacy (high Self-Directedness). Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  1. Prescription opioid epidemic and infant outcomes.

    PubMed

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

    2015-05-01

    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). 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. 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. 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. Copyright © 2015 by the American Academy of Pediatrics.

  2. 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

  3. [The development of the Japanese pharmaceutical industry (Part 8) - the change of opium alkaloid opioid analgesics in Japanese pharmaceutical companies.].

    PubMed

    Takehara, Jun

    2005-01-01

    After the Japan-England Friendship and Commercial Treaty of 1858 (Ansei 5), narcotic drugs have been strictly regulated by laws. The production of opium alkaloid analgesics, mainly morphine, became active in Japan after World War I (1918, Taisho 7). Having released the "Cancer Pain Relief" guideline by the WHO in 1986 (Showa 61) and the morphine sulfate controlled-release tablet "MS Contin" in 1989 (Heisei 1) in Japan, the demand for morphine in Japan expanded remarkably. Today, several more kinds of strong opioid analgesics are available for cancer pain treatment in Japan. An increase in the use of strong opioid analgesics is expected in the future.

  4. A prospective evaluation of opioid weaning in opioid-dependent pediatric critical care patients.

    PubMed

    Berens, Richard J; Meyer, Michael T; Mikhailov, Theresa A; Colpaert, Krista D; Czarnecki, Michelle L; Ghanayem, Nancy S; Hoffman, George M; Soetenga, Deborah J; Nelson, Thomas J; Weisman, Steven J

    2006-04-01

    Critically ill children are treated with opioid medication in an attempt to decrease stress and alleviate pain during prolonged pediatric intensive care. This treatment plan places children at risk for opioid dependency. Once dependent, children need to be weaned or risk development of a withdrawal syndrome on abrupt cessation of medication. We enrolled opioid-dependent children into a prospective, randomized trial of 5- versus 10-day opioid weaning using oral methadone. Children exposed to opioids for an average of 3 wk showed no difference in the number of agitation events requiring opioid rescue (3 consecutive neonatal abstinence scores >8 every 2 h) in either wean group. Most of the events requiring rescue occurred on day 5 and 6 of the wean in both treatment groups. Patients may be able to be weaned successfully in 5 days once converted to oral methadone, with a follow-up period after medication wean to observe for a delayed withdrawal syndrome.

  5. An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics.

    PubMed

    Johnson, Jeremy R; Lossignol, Dominique; Burnell-Nugent, Mary; Fallon, Marie T

    2013-08-01

    Chronic pain in patients with advanced cancer poses a serious clinical challenge. The Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (U.S. Adopted Name, nabiximols; Sativex(®)) is a novel cannabinoid formulation currently undergoing investigation as an adjuvant therapy for this treatment group. This follow-up study investigated the long-term safety and tolerability of THC/CBD spray and THC spray in relieving pain in patients with advanced cancer. In total, 43 patients with cancer-related pain experiencing inadequate analgesia despite chronic opioid dosing, who had participated in a previous three-arm (THC/CBD spray, THC spray, or placebo), two-week parent randomized controlled trial, entered this open-label, multicenter, follow-up study. Patients self-titrated THC/CBD spray (n=39) or THC spray (n=4) to symptom relief or maximum dose and were regularly reviewed for safety, tolerability, and evidence of clinical benefit. The efficacy end point of change from baseline in mean Brief Pain Inventory-Short Form scores for "pain severity" and "worst pain" domains showed a decrease (i.e., improvement) at each visit in the THC/CBD spray patients. Similarly, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 scores showed a decrease (i.e., improvement) from baseline in the domains of insomnia, pain, and fatigue. No new safety concerns associated with the extended use of THC/CBD spray arose from this study. This study showed that the long-term use of THC/CBD spray was generally well tolerated, with no evidence of a loss of effect for the relief of cancer-related pain with long-term use. Furthermore, patients who kept using the study medication did not seek to increase their dose of this or other pain-relieving medication over time, suggesting that the adjuvant use of cannabinoids in cancer-related pain could provide useful benefit. Copyright © 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc

  6. Development of custom radiation-tolerant DCDC converter ASICs

    NASA Astrophysics Data System (ADS)

    Faccio, F.; Michelis, S.; Orlandi, S.; Blanchot, G.; Fuentes, C.; Saggini, S.; Ongaro, F.

    2010-11-01

    Based on a detailed study of the radiation tolerance of high-voltage transistors, 2 commercial CMOS technologies have been selected for the design of synchronous buck DCDC converter ASICs. Three prototype converters have been produced, embedding increasingly sophisticated functions. The electrical and radiation performance of these prototypes is presented.

  7. Development of Peanut Germplasm with Improved Drought Tolerance

    USDA-ARS?s Scientific Manuscript database

    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...

  8. Non-opioid actions of opioid peptides.

    PubMed

    Wollemann, Mária; Benyhe, Sándor

    2004-06-04

    Beside the well known actions of opioid peptides on mu-, delta- and kappa-opioid receptors, increasing amount of pharmacological and biochemical evidence has recently been published about non-opioid actions of various opioid peptides. These effects are not abolished by naloxone treatments. Such non-opioid effects are observed both in nervous tissues and in the cellular elements of the immune system. Peptides exhibiting non-opioid effects include beta-endorphin, dynorphin A, nociceptin/OFQ, endomorphins, hemorphins and a number of Proenkephalin A derived peptides, such as Met-enkephalin, Met-enkephalin-Arg-Phe (MERF) and bovine adrenal medullary peptide (BAM22). Non-opioid actions are exerted through different neuronal receptors, e.g., dynorphin hyperalgesia through NMDA receptor, Met-enkephalin induced regulation of cell growth through zeta receptors, pain modulation by nociceptin through ORL-1 or NOP receptors, while BAM22 acts through sensory neuron specific G protein-coupled receptors (SNSR). We have investigated Met-enkephalin-Arg-Phe (MERF) and its analogues by the means of direct and indirect radioligand binding assays. It has been found that in addition to kappa(2) and delta-opioid receptors, MERF can act also through sigma(2)- or probably via FMRF-NH(2) receptors in rat cerebellum. A role of functionally assembling heterodimer receptors in mediating the non-conventional actions of these peptide ligands can not be excluded as well.

  9. Opioid Receptors: Toward Separation of Analgesic from Undesirable Effects

    PubMed Central

    Law, P.Y.; Reggio, Patricia H.; Loh, H.H.

    2013-01-01

    The use of opioid analgesics for pain has always been hampered by their many side effects; in particular, the addictive liability associated with chronic use. Recently, attempts to develop analgesic agents with reduced side effects have targeted either the putative opioid receptor splice variants or the receptor heterooligomers. This review discusses the potential for receptor splice variant- and the hetero-oligomer-based discovery of new opioid analgesics. We also examine an alternative approach of using receptor mutants for pain management. Finally, we discuss the role of the biased agonism observed and the recently reported opioid receptor crystal structures in guiding the future development of opioid analgesics PMID:23598157

  10. Opioid receptors: toward separation of analgesic from undesirable effects.

    PubMed

    Law, Ping-Yee; Reggio, Patricia H; Loh, Horace H

    2013-06-01

    The use of opioid analgesics for pain has always been hampered by their many side effects; in particular, the addictive liability associated with chronic use. Recently, attempts to develop analgesic agents with reduced side effects have targeted either the putative opioid receptor splice variants or the receptor hetero-oligomers. This review discusses the potential for receptor splice variant- and the hetero-oligomer-based discovery of new opioid analgesics. We also examine an alternative approach of using receptor mutants for pain management. Finally, we discuss the role of the biased agonism observed and the recently reported opioid receptor crystal structures in guiding the future development of opioid analgesics.

  11. Brief Opioid Overdose Knowledge (BOOK): A Questionnaire to Assess Overdose Knowledge in Individuals Who Use Illicit or Prescribed Opioids

    PubMed Central

    Dunn, Kelly E.; Barrett, Frederick S.; Yepez-Laubach, Claudia; Meyer, Andrew C.; Hruska, Bryce J.; Sigmon, Stacey C.; Fingerhood, Michael; Bigelow, George E.

    2016-01-01

    Background: Opioid overdose is a public health crisis. This study describes efforts to develop and validate the Brief Opioid Overdose Knowledge (BOOK) questionnaire to assess patient knowledge gaps related to opioid overdose risks. Methods: Two samples of illicit opioid users and a third sample of patients receiving an opioid for the treatment of chronic pain (total N = 848) completed self-report items pertaining to opioid overdose risks. Results: A 3-factor scale was established, representing Opioid Knowledge (4 items), Opioid Overdose Knowledge (4 items), and Opioid Overdose Response Knowledge (4 items). The scale had strong internal and face validity. Patients with chronic pain performed worse than illicit drug users in almost all items assessed, highlighting the need to increase knowledge of opioid overdose risk to this population. Conclusions: This study sought to develop a brief, internally valid method for quickly assessing deficits in opioid overdose risk areas within users of illicit and prescribed opioids, to provide an efficient metric for assessing and comparing educational interventions, facilitate conversations between physicians and patients about overdose risks, and help formally identify knowledge deficits in other patient populations. PMID:27504923

  12. Endomorphins and related opioid peptides.

    PubMed

    Okada, Yoshio; Tsuda, Yuko; Bryant, Sharon D; Lazarus, Lawrence H

    2002-01-01

    Opioid peptides and their G-protein-coupled receptors (delta, kappa, mu) are located in the central nervous system and peripheral tissues. The opioid system has been studied to determine the intrinsic mechanism of modulation of pain and to develop uniquely effective pain-control substances with minimal abuse potential and side effects. Two types of endogenous opioid peptides exist, one containing Try-Gly-Gly-Phe as the message domain (enkephalins, endorphins, dynorphins) and the other containing the Tyr-Pro-Phe/Trp sequence (endomorphins-1 and -2). Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2), which has high mu receptor affinity (Ki = 0.36 nM) and remarkable selectivity (4000- and 15,000-fold preference over the delta and kappa receptors, respectively), was isolated from bovine and human brain. In addition, endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), isolated from the same sources, exhibited high mu receptor affinity (Ki = 0.69 nM) and very high selectivity (13,000- and 7500-fold preference relative to delta and kappa receptors, respectively). Both opioids bind to mu-opioid receptors, thereby activating G-proteins, resulting in regulation of gastrointestinal motility, manifestation of antinociception, and effects on the vascular systems and memory. To develop novel analgesics with less addictive properties, evaluation of the structure-activity relationships of the endomorphins led to the design of more potent and stable analgesics. Opioidmimetics and opioid peptides containing the amino acid sequence of the message domain of endomorphins, Tyr-Pro-Phe/Trp, could exhibit unique binding activity and lead to the development of new therapeutic drugs for controlling pain.

  13. The delta opioid receptor tool box.

    PubMed

    Vicente-Sanchez, Ana; Segura, Laura; Pradhan, Amynah A

    2016-12-03

    In recent years, the delta opioid receptor has attracted increasing interest as a target for the treatment of chronic pain and emotional disorders. Due to their therapeutic potential, numerous tools have been developed to study the delta opioid receptor from both a molecular and a functional perspective. This review summarizes the most commonly available tools, with an emphasis on their use and limitations. Here, we describe (1) the cell-based assays used to study the delta opioid receptor. (2) The features of several delta opioid receptor ligands, including peptide and non-peptide drugs. (3) The existing approaches to detect delta opioid receptors in fixed tissue, and debates that surround these techniques. (4) Behavioral assays used to study the in vivo effects of delta opioid receptor agonists; including locomotor stimulation and convulsions that are induced by some ligands, but not others. (5) The characterization of genetically modified mice used specifically to study the delta opioid receptor. Overall, this review aims to provide a guideline for the use of these tools with the final goal of increasing our understanding of delta opioid receptor physiology.

  14. Opioid Dependence Treatment: Options In Pharmacotherapy

    PubMed Central

    Stotts, Angela L.; Dodrill, Carrie L.; Kosten, Thomas R.

    2010-01-01

    The development of effective treatments for opioid dependence is of great importance given the devastating consequences of the disease. Pharmacotherapies for opioid addiction include opioid agonists, partial agonists, opioid antagonists, and alpha-2-adrenergic agonists, which are targeted toward either detoxification or long-term agonist maintenance. Agonist maintenance therapy is currently the recommended treatment for opioid dependence due to its superior outcomes relative to detoxification. Detoxification protocols have limited long term efficacy and patient discomfort remains a significant therapy challenge. Buprenorphine’s effectiveness relative to methadone remains a controversy and may be most appropriate for patients in need of low doses of agonist treatment. Buprenorphine appears superior to alpha-2 agonists, however, and office-based treatment with buprenorphine in the US is gaining support. Studies of sustained-release formulations of naltrexone suggest improved effectiveness for retention and sustained abstinence, however, randomized clinical trials are needed. PMID:19538000

  15. 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

  16. 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

  17. Non-analgesic effects of opioids: opioid-induced respiratory depression.

    PubMed

    Boom, Merel; Niesters, Marieke; Sarton, Elise; Aarts, Leon; Smith, Terry W; Dahan, Albert

    2012-01-01

    Opioids induce respiratory depression via activation of μ-opioid receptors at specific sites in the central nervous system including the pre-Bötzinger complex, a respiratory rhythm generating area in the pons. Full opioid agonists like morphine and fentanyl affect breathing with onset and offset profiles that are primarily determined by opioid transfer to the receptor site, while the effects of partial opioid agonists such as buprenorphine are governed by transfer to the receptor site together with receptor kinetics, in particular dissociation kinetics. Opioid-induced respiratory depression is potentially fatal but may be reversed by the opioid receptor antagonist naloxone, an agent with a short elimination half-life (30 min). The rate-limiting factor in naloxone-reversal of opioid effect is the receptor kinetics of the opioid agonists that requires reversal. Agents with slow dissociation kinetics (buprenorphine) require a continuous naloxone infusion while agents with rapid kinetics (fentanyl) will show complete reversal upon a single naloxone dose. Since naloxone is non-selective and will reverse analgesia as well, efforts are focused on the development of compounds that reverse opioid-induced respiratory depression without affecting analgesic efficacy. Such agents include ampakines and serotonin agonists which are aimed at selectively enhancing central respiratory drive. A novel approach is aimed at the reduction of respiratory depression from opioid-activation of (micro-)glia cells in the pons and brainstem using micro-glia cell stabilizers. Since this approach simultaneously enhances opioid analgesic efficacy it seems an attractive alternative to the classical reversal strategies with naloxone.

  18. Opioid receptor modulation of hedonic taste preference and food intake: a single-dose safety, pharmacokinetic, and pharmacodynamic investigation with GSK1521498, a novel μ-opioid receptor inverse agonist.

    PubMed

    Nathan, Pradeep J; O'Neill, Barry V; Bush, Mark A; Koch, Annelize; Tao, Wenli X; Maltby, Kay; Napolitano, Antonella; Brooke, Allison C; Skeggs, Andrew L; Herman, Craig S; Larkin, Andrew L; Ignar, Diane M; Richards, Duncan B; Williams, Pauline M; Bullmore, Edward T

    2012-04-01

    Endogenous opioids and µ-opioid receptors have been linked to hedonic and rewarding aspects of palatable food intake. The authors examined the safety, pharmacokinetic, and pharmacodynamic profile of GSK1521498, a µ-opioid receptor inverse agonist that is being investigated primarily for the treatment of overeating behavior in obesity. In healthy participants, GSK1521498 oral solution and capsule formulations were well tolerated up to a dose of 100 mg. After single doses (10-150 mg), the maximum concentration (C(max)) and area under the curve (AUC) in plasma increased in a dose-proportional manner. GSK1521498 selectively reduced sensory hedonic ratings of high-sugar and high-fat dairy products and caloric intake of high-fat/high-sucrose snack foods. These findings provide encouraging data in support of the development of GSK1521498 for the treatment of disorders of maladaptive ingestive behavior or compulsive consumption.

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

    PubMed

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

    2010-07-01

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

  20. Opioid overuse pain syndrome (OOPS): the story of opioids, prometheus unbound.

    PubMed

    Mehendale, Anand W; Goldman, Mark P; Mehendale, Rachel P

    2013-01-01

    Throughout history, opioids have effectively alleviated pain but not without the risk of addiction and death. Seductive and dangerous, full of promise and destruction, opioids are both revered and feared by Western culture. Their exponential use in "developed countries" is now an enormous public health problem and requires us to harness their properties with scientific rigor and adequate safeguards. The use of opioids for the treatment of chronic nonterminal pain (CNTP) has been a relatively new phenomenon which has coincided with the proclamation by the Joint Commission on Accreditation of Health Care Organization in 2000 that pain assessment be the "fifth vital sign," notwithstanding the fact that pain is a symptom and not a sign.(1) Nonetheless, this resulted in a culture of a marked increase in use of opioids for acute and chronic pain management. Consequently, there are many unintended outcomes which include opioid-induced hyperalgesia increased diversion, addiction, and death. Understandably, this has resulted in many regulatory responses from such agencies such as the Drug Enforcement Administration (DEA) and state medical boards. This article proposes a clinically relevant paradigm of opioid overuse pain syndrome. The goal of this article is to inform the clinicians of the complicated neurobiology of opioids. It is our hope that scientists rather than government regulators dictate the appropriate response to the epidemic of over prescription of opioids. A similar designation of "medication overuse headache" has resulted in near extinction of excessive use of opioids in the field of headache medicine.

  1. Ontogenetic studies of tolerance development: effects of chronic morphine on the hypothalamic-pituitary-adrenal axis.

    PubMed

    Little, P J; Kuhn, C M

    1995-11-01

    Endogenous opiates are important regulators of the hypothalamic-pituitary-adrenal (HPA) axis in rats. Tolerance clearly develops to morphine-induced stimulation of the HPA axis in adult rats (Ignar and Kuhn 1990). The goal of the present study was to determine whether tolerance to morphine-induced stimulation of the HPA axis developed in neonatal and weanling rats treated chronically with morphine. Rats were injected with morphine or saline between days 4-8 postnatal (pups) or days 21-25 (weanlings) and tolerance assessed by determining dose-response curves for ACTH and corticosterone secretion following an acute morphine challenge. Weanlings displayed marked tolerance to the stimulation of ACTH and corticosterone secretion by morphine. Tolerance was also observed in pups to morphine-stimulated ACTH and corticosterone release. These findings suggest that the relative adaptability of the HPA axis to chronic morphine in neonatal and weanling rats is similar.

  2. Development Status of the Rad-Tolerant TTEthernet Controller

    NASA Astrophysics Data System (ADS)

    Fidi, Christian; van Masar, Ivan

    2016-08-01

    handling of different traffic classes (critical traffic and non-critical traffic, i.e. TT, RC and BE [2]). Also the compatibility to the IEEE1588 synchronization protocol can be used to connect legacy IEEE1588 equipment for GSE equipment.However this commercially available technology currently used in the aviation-, the industrial- and the automotive market needs to be matured for the use in space applications. Therefore a development of the necessary space-grade components, mainly the switch and the end system is needed.This paper presents the current development status of a radiation tolerant integrated circuit for the use in different space applications. It outlines the different steps needed to be performed to ensure the usability of this digital chip in highly reliable as well as in highly available space applications.

  3. Neonatal opioid withdrawal and antenatal opioid prescribing.

    PubMed

    Turner, Suzanne D; Gomes, Tara; Camacho, Ximena; Yao, Zhan; Guttmann, Astrid; Mamdani, Muhammad M; Juurlink, David N; Dhalla, Irfan A

    2015-01-01

    The incidence of neonatal opioid withdrawal is increasing in both Canada and the United States. However, the degree to which the treatment of pain with opioids, rather than the misuse of prescription opioids or heroin, contributes to the prevalence of neonatal opioid withdrawal remains unknown. We conducted a retrospective, population-based, cross-sectional study between 1992 and 2011 in Ontario with 2 objectives. First, we determined the annual incidence of neonatal abstinence syndrome. Second, using data from a subset of women eligible for publicly funded prescription drugs, we determined what proportion of women who deliver an infant with neonatal abstinence syndrome were given a prescription for an opioid before and during pregnancy. The incidence of neonatal abstinence syndrome in Ontario increased 15-fold during the study period, from 0.28 per 1000 live births in 1992 to 4.29 per 1000 live births in 2011. During the final 5 years of the study, we identified 927 deliveries of infants with neonatal abstinence syndrome to mothers who were public drug plan beneficiaries. Of these mothers, 67% had received an opioid prescription in the 100 days preceding delivery, including 53.3% who received methadone, an increase from 28.6% in the interval spanning 1 to 2 years before delivery (p < 0.001). Prescription for nonmethadone opioids decreased from 38% to 17% (p < 0.001). The incidence of neonatal opioid withdrawal in Ontario has increased substantially over the last 20 years. Most of the women in this cohort who delivered an infant with neonatal abstinence syndrome had received a prescription for an opioid both before and during their pregnancy.

  4. Neonatal opioid withdrawal and antenatal opioid prescribing

    PubMed Central

    Gomes, Tara; Camacho, Ximena; Yao, Zhan; Guttmann, Astrid; Mamdani, Muhammad M.; Juurlink, David N.; Dhalla, Irfan A.

    2015-01-01

    Background The incidence of neonatal opioid withdrawal is increasing in both Canada and the United States. However, the degree to which the treatment of pain with opioids, rather than the misuse of prescription opioids or heroin, contributes to the prevalence of neonatal opioid withdrawal remains unknown. Methods We conducted a retrospective, population-based, cross-sectional study between 1992 and 2011 in Ontario with 2 objectives. First, we determined the annual incidence of neonatal abstinence syndrome. Second, using data from a subset of women eligible for publicly funded prescription drugs, we determined what proportion of women who deliver an infant with neonatal abstinence syndrome were given a prescription for an opioid before and during pregnancy. Results The incidence of neonatal abstinence syndrome in Ontario increased 15-fold during the study period, from 0.28 per 1000 live births in 1992 to 4.29 per 1000 live births in 2011. During the final 5 years of the study, we identified 927 deliveries of infants with neonatal abstinence syndrome to mothers who were public drug plan beneficiaries. Of these mothers, 67% had received an opioid prescription in the 100 days preceding delivery, including 53.3% who received methadone, an increase from 28.6% in the interval spanning 1 to 2 years before delivery (p < 0.001). Prescription for nonmethadone opioids decreased from 38% to 17% (p < 0.001). Interpretation The incidence of neonatal opioid withdrawal in Ontario has increased substantially over the last 20 years. Most of the women in this cohort who delivered an infant with neonatal abstinence syndrome had received a prescription for an opioid both before and during their pregnancy. PMID:25844370

  5. 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

  6. [The role of opioids in the treatment of primary headache disorders].

    PubMed

    Totzeck, A; Gaul, C

    2014-04-01

    There is no sufficient evidence for opioids in the acute treatment of primary headache disorders. Controlled clinical trials using triptans as comparator are missing. Data show high frequent headache recurrence, typical side effects of opioids, increased risk of chronification, and development of addiction in primary headache patients treated with opioids. Chronic headache patients with opioid therapy often experience lengthy withdrawal treatment. On the basis of the current scientific data, opioids should be avoided in acute and prophylactic treatment of primary headache disorders.

  7. Role of nitric oxide in the induction and expression of morphine tolerance and dependence in mice.

    PubMed Central

    Dambisya, Y. M.; Lee, T. L.

    1996-01-01

    1. The possible involvement of nitric oxide (NO) in the induction and expression of morphine tolerance and dependence was studied in mice. A two-day repeated injection regimen was used to induce morphine tolerance and dependence. Tolerance was assessed by the tail flick test and physical dependence by naloxone challenge, on the third day. 2. Two days pretreatment with L-arginine (20 mg kg-1, twice daily) or D-NG-nitro arginine methyl ester (D-NAME, 20 mg kg-1, twice daily) alone had no effect on subsequent morphine antinociception. L-NG-monomethyl arginine (L-NMMA, 10 mg kg-1, twice daily) for two days led to a slight increase (not statistically significant) in morphine antinociception; while L-NG-nitro arginine methyl ester (L-NAME, 10 mg kg-1, twice daily) for two days led to attenuation of morphine analgesia. None of the animals treated with these drugs alone showed signs characteristic of the opioid withdrawal syndrome upon naloxone challenge. 3. Induction phase L-arginine slowed the development of opioid tolerance and physical dependence, while L-NAME and L-NMMA led to a higher degree of tolerance but had no effect on the development of physical dependence. 4. L-Arginine and D-NAME had no effect on the expression of morphine tolerance and physical dependence. Expression phase L-NAME and L-NMMA, on the other hand, attenuated morphine tolerance and reduced the incidence of withdrawal signs. 5. NO may, therefore, play a role in both phases of morphine tolerance and dependence: elevation of NO levels during the induction phase delays the development of opioid tolerance/dependence, while inhibition of NO synthase accelerates the development of tolerance. Inhibition of NO attenuates the expression of both tolerance and physical dependence. PMID:8851510

  8. Translation of structure-activity relationships from cyclic mixed efficacy opioid peptides to linear analogues.

    PubMed

    Anand, Jessica P; Porter-Barrus, Vanessa R; Waldschmidt, Helen V; Yeomans, Larisa; Pogozheva, Irina D; Traynor, John R; Mosberg, Henry I

    2014-01-01

    Most opioid analgesics used in the treatment of pain are mu opioid receptor (MOR) agonists. While effective, there are significant drawbacks to opioid use, including the development of tolerance and dependence. However, the coadministration of a MOR agonist with a delta opioid receptor (DOR) antagonist slows the development of MOR-related side effects, while maintaining analgesia. We have previously reported a series of cyclic mixed efficacy MOR agonist/DOR antagonist ligands. Here we describe the transfer of key features from these cyclic analogs to linear sequences. Using the linear MOR/DOR agonist, Tyr-DThr-Gly-Phe-Leu-Ser-NH2 (DTLES), as a lead scaffold, we replaced Phe(4) with bulkier and/or constrained aromatic residues shown to confer DOR antagonism in our cyclic ligands. These replacements failed to confer DOR antagonism in the DTLES analogs, presumably because the more flexible linear ligands can adopt binding poses that will fit in the narrow binding pocket of the active conformations of both MOR and DOR. Nonetheless, the pharmacological profile observed in this series, high affinity and efficacy for MOR and DOR with selectivity relative to KOR, has also been shown to reduce the development of unwanted side effects. We further modified our lead MOR/DOR agonist with a C-terminal glucoserine to improve bioavailability. The resulting ligand displayed high efficacy and potency at both MOR and DOR and no efficacy at KOR.

  9. Variability in Opioid Equivalence Calculations.

    PubMed

    Rennick, Amanda; Atkinson, Timothy; Cimino, Nina M; Strassels, Scott A; McPherson, Mary Lynn; Fudin, Jeffrey

    2015-09-09

    Equianalgesic conversion methods are commonly used to switch patients from one opioid to another due to suboptimal pain relief or adverse events. There is no universally accepted opioid conversion method, however, and there is often significant variability between conversion resources. As a result, patients are at risk for undertreated pain and serious adverse events. The purpose of this survey was to compare the equianalgesic conversion estimates between nurse practitioners, pharmacists, and physicians for commonly prescribed opioids. A survey form was developed using Survey Monkey. Participation was solicited by providing a link to the survey via social media (e.g., Facebook, Twitter, LinkedIn, etc.) and emailing professional organizations for sharing with their members and followers. Data collected included demographics and estimated morphine equivalents (MEQs) of hydrocodone 80 mg, fentanyl transdermal patches 1,800 mcg (as 75 mcg/hour), methadone 40 mg, oxycodone 120 mg, and hydromorphone 48 mg. Participants were also asked to provide their choice of reference utilized to complete the conversions, including personal knowledge. Descriptive analyses were performed using measures of central tendency. Hypothesis testing was performed using Pearson's chi-squared and Fisher's Exact Test for categorical data and the Kruskal-Wallis equality of populations rank test for continuous data to assess differences between median opioid doses by professional groups. The total number of respondents included in the analysis was 319. Physicians, pharmacists, and nurse practitioners/physician assistants comprised 25.4%, 56.7%, and 16.3%, respectively, of respondents. The overall mean (± standard deviation) MEQ doses for fentanyl, hydrocodone, hydromorphone, methadone, and oxycodone were: 176 (±117) mg, 88 (±42) mg, 192 (±55) mg, 193 (±201) mg, and 173 (±39) mg, respectively. For fentanyl, the mean (±standard deviation) MEQ doses were 180 (±122) mg, 178 (±128) mg, and 157

  10. Differential regional development of tolerance to increase in dopamine turnover upon repeated neuroleptic administration.

    PubMed

    Scatton, B

    1977-12-15

    Repeated treatment with haloperidol and sulpiride induced tolerance to the increases in homovanillic and dihydroxyphenyl acetic acids in the striatum, nucleus accumbens, tuberculum olfactorium and frontal cortex of the rat. The threshold dose inducing this effect appeared to be lower in the striatum than in the limbic regions. Similar results were found in the frontal cortex by measuring dopamine utilization. Moreover, tolerance developed earlier in the striatum than in the limbic areas. The possible reasons are discussed for the differential development of tolerance in the various DA areas investigated.

  11. [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.

  12. 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.

  13. 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

  14. Chronic administration of U50,488H fails to produce hypothalamo-pituitary-adrenal axis tolerance in neonatal rats.

    PubMed

    Ignar, D M; Windh, R T; Kuhn, C M

    1992-02-01

    The present study investigated the effect of chronic administration of a kappa opioid receptor agonist on the function of kappa and mu opioid, serotonergic and cholinergic regulation of secretion from the hypothalamo-pituitary-adrenal axis in neonatal rats. After chronic treatment with saline or U50,488H (trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]- benzeneacetamide methane sulfonate), a kappa opioid receptor agonist and subsequent pharmacological challenge, corticosterone (CS) in serum was determined. Kappa tolerance did not develop in pups treated on postnatal days 5-9 with increasing doses of U50,488H (0.5-2.5 mg/kg). When the rats were treated with the same chronic regimen of U50,488H at different stages of development from birth through weaning, only weanling rats became tolerant to U50,488H. In the absence of measurable kappa tolerance, the responses of corticosterone in serum to morphine, quipazine, a serotonin receptor agonist and physostigmine, an inhibitor of acetylcholinesterase, were attenuated in neonatal rats, treated with U50,488H. These studies suggest that kappa tolerance is more difficult to induce in developing rats than in adults and that regulation of the function of the hypothalamo-pituitary-adrenal axis by other neurotransmitter systems is altered by treatment with kappa opioid receptor agonists, even in the apparent absence of tolerance.

  15. Therapeutic manipulation of peroxynitrite attenuates the development of opiate-induced antinociceptive tolerance in mice

    PubMed Central

    Muscoli, Carolina; Cuzzocrea, Salvatore; Ndengele, Michael M.; Mollace, Vincenzo; Porreca, Frank; Fabrizi, Francesca; Esposito, Emanuela; Masini, Emanuela; Matuschak, George M.; Salvemini, Daniela

    2007-01-01

    Severe pain syndromes reduce quality of life in patients with inflammatory and neoplastic diseases, often because chronic opiate therapy results in reduced analgesic effectiveness, or tolerance, leading to escalating doses and distressing side effects. The mechanisms leading to tolerance are poorly understood. Our studies revealed that development of antinociceptive tolerance to repeated doses of morphine in mice was consistently associated with the appearance of several tyrosine-nitrated proteins in the dorsal horn of the spinal cord, including the mitochondrial isoform of superoxide (O2–) dismutase, the glutamate transporter GLT-1, and the enzyme glutamine synthase. Furthermore, antinociceptive tolerance was associated with increased formation of several proinflammatory cytokines, oxidative DNA damage, and activation of the nuclear factor poly(ADP-ribose) polymerase. Inhibition of NO synthesis or removal of O2– blocked these biochemical changes and inhibited the development of tolerance, pointing to peroxynitrite (ONOO–), the product of the interaction between O2– and NO, as a signaling mediator in this setting. Indeed, coadministration of morphine with the ONOO– decomposition catalyst, Fe(III) 5,10,15,20-tetrakis(N-methylpyridinium-4-yl)porphyrin, blocked protein nitration, attenuated the observed biochemical changes, and prevented the development of tolerance in a dose-dependent manner. Collectively, these data suggest a causal role for ONOO– in pathways culminating in antinociceptive tolerance to opiates. Peroxynitrite (ONOO–) decomposition catalysts may have therapeutic potential as adjuncts to opiates in relieving suffering from chronic pain. PMID:17975673

  16. Proteomics of desiccation tolerance during development and germination of maize embryos.

    PubMed

    Huang, Hui; Møller, Ian Max; Song, Song-Quan

    2012-02-02

    Maize seeds were used to identify the key embryo proteins involved in desiccation tolerance during development and germination. Immature maize embryos (28N) during development and mature embryos imbibed for 72 h (72HN) are desiccation sensitive. Mature maize embryos (52N) during development are desiccation tolerant. Thiobarbituric acid reactive substance and hydrogen peroxide contents decreased and increased with acquisition and loss of desiccation tolerance, respectively. A total of 111 protein spots changed significantly (1.5 fold increase/decrease) in desiccation-tolerant and -sensitive embryos before (28N, 52N and 72HN) and after (28D, 52D and 72HD) dehydration. Nine pre-dominantly proteins, 17.4 kDa Class I heat shock protein 3, late embryogenesis abundant protein EMB564, outer membrane protein, globulin 2, TPA:putative cystatin, NBS-LRR resistance-like protein RGC456, stress responsive protein, major allergen Bet v 1.01C and proteasome subunit alpha type 1, accumulated during embryo maturation, decreased during germination and increased in desiccation-tolerant embryos during desiccation. Two proteins, Rhd6-like 2 and low-molecular-weight heat shock protein precursor, showed the inverse pattern. We infer that these eleven proteins are involved in seed desiccation tolerance. We conclude that desiccation-tolerant embryos make more economical use of their resources to accumulate protective molecules and antioxidant systems to deal with maturation drying and desiccation treatment. Copyright © 2011 Elsevier B.V. All rights reserved.

  17. [Functional selectivity of opioid receptors ligands].

    PubMed

    Audet, Nicolas; Archer-Lahlou, Elodie; Richard-Lalonde, Mélissa; Piñeyro-Filpo, Graciela

    2010-01-01

    Opiates are the most effective analgesics available for the treatment of severe pain. However, their clinical use is restricted by unwanted side effects such as tolerance, physical dependence and respiratory depression. The strategy to develop new opiates with reduced side effects has mainly focused on the study and production of ligands that specifically bind to different opiate receptors subtypes. However, this strategy has not allowed the production of novel therapeutic ligands with a better side effects profile. Thus, other research strategies need to be explored. One which is receiving increasing attention is the possibility of exploiting ligand ability to stabilize different receptor conformations with distinct signalling profiles. This newly described property, termed functional selectivity, provides a potential means of directing the stimulus generated by an activated receptor towards a specific cellular response. Here we summarize evidence supporting the existence of ligand-specific active conformations for two opioid receptors subtypes (delta and mu), and analyze how functional selectivity may contribute in the production of longer lasting, better tolerated opiate analgesics. double dagger.

  18. 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

  19. 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.

  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. Indications for Opioid Antagonists.

    PubMed

    Coppes, O J Michael; Sang, Christine N

    2017-06-01

    As opioids have become more common in clinical practice for the treatment of both acute and chronic pain, so too has the need for a deeper understanding of the clinical applications of opioid antagonists. The purpose of this review is to present both the longstanding and potential new indications for the use of drugs that block the effects of opioid receptors. There is a growing body of data demonstrating the modulation of pain by opioid antagonists. Additional clinical studies that show their direct antinociceptive effects and/or enhancement of the analgesic potency of opioid agonists are warranted. We briefly discuss the well-established role that these agents play in the reversal of life-threatening opioid toxicity and explore both existing and expanding clinical applications, including their apparent paradox that they may themselves be associated with analgesia.

  2. Potential misuse and inappropriate prescription practices involving opioid analgesics.

    PubMed

    Liu, Ying; Logan, Joseph E; Paulozzi, Leonard J; Zhang, Kun; Jones, Christopher M

    2013-08-01

    Opioid misuse and abuse are growing concerns among the medical and public health communities. To examine the prevalence of indicators for potential opioid misuse in a large, commercially insured adult population. We adapted existing indicators developed by expert panels to include having overlapping opioid prescriptions, overlapping opioid and benzodiazepine prescriptions, long-acting/ extended release (LA/ER) opioids for acute pain,and high daily doses of opioids (>100 morphine milligram equivalents). These indicators were assessed among continuously enrolled individuals aged 18-64 years from the 2009 Truven Health MarketScan databases. Analyses were stratified by sex. We identified 3,391,599 eligible enrollees who received at least 1 opioid prescription. On average, enrollees obtained 3.3 opioid prescriptions, and the average annual days of supply was 47 days. Twice as many enrollees received opioid prescriptions for acute pain as for chronic pain. About a quarter of the enrollees had at least 1 indicator of either potential misuse by patients or inappropriate prescription practices by providers. About 15% of enrollees had high daily doses;7.8% had opioid overlap; and 7.9% had opioid and benzodiazepine overlap. Among those prescribed LA/ER opioids, 24.3% were treated for acute pain. Overlap indicators were more common among women. Our findings underscore the critical need to develop programs aimed at promoting appropriate use of opioids. Retrospective opioid utilization reviews similar to our analyses can potentially help managed care organizations and healthcare providers improve patient care and reduce the risk of adverse outcomes related to these medications.

  3. 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

  4. A Study on the Development of the Tendency to Tolerance Scale and an Analysis of the Tendencies of Primary School Students to Tolerance through Certain Variables

    ERIC Educational Resources Information Center

    Caliskan, Huseyin; Saglam, Halil Ibrahim

    2012-01-01

    The purpose of this study is to develop the Tendency to Tolerance Scale and to analyze the tendencies of primary school students to tolerance through certain variables. The population of the study was comprised of 899 students who studied at five different primary schools located in Sakarya. The exploratory factor analysis yielded an 18-item…

  5. 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

  6. 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

  7. 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.

  8. Dmt and opioid peptides: a potent alliance.

    PubMed

    Bryant, Sharon D; Jinsmaa, Yunden; Salvadori, Severo; Okada, Yoshio; Lazarus, Lawrence H

    2003-01-01

    The introduction of the Dmt (2',6'-dimethyl-L-tyrosine)-Tic pharmacophore into the design of opioid ligands produced an extraordinary family of potent delta-opioid receptor antagonists and heralded a new phase in opioid research. First reviewed extensively in 1998, the incorporation of Dmt into a diverse group of opioid molecules stimulated the opioid field leading to the development of unique analogues with remarkable properties. This overview will document the crucial role played by this residue in the proliferation of opioid peptides with high receptor affinity (K(i) equal to or less than 1 nM) and potent bioactivity. The discussion will include the metamorphosis between delta-opioid receptor antagonists to delta-agonists based solely on subtle structural changes at the C-terminal region of the Dmt-Tic pharmacophore as well as their behavior in vivo. Dmt may be considered promiscuous due to the acquisition of potent mu-agonism by dermorphin and endomorphin derivatives as well as by a unique class of opioidmimetics containing two Dmt residues separated by alkyl or pyrazinone linkers. Structural studies on the Dmt-Tic compounds were enhanced tremendously by x-ray diffraction data for three potent and biologically diverse Dmt-Tic opioidmimetics that led to the development of pharmacophores for both delta-opioid receptor agonists and antagonists. Molecular modeling studies of other unique Dmt opioid analogues illuminated structural differences between delta- and mu-receptor ligand interactions. The future of these compounds as therapeutic applications for various medical syndromes including the control of cancer-associated pain is only a matter of time and perseverance. Copyright 2003 Wiley Periodicals, Inc.

  9. 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.

  10. Clinically Employed Opioid Analgesics Produce Antinociception via μ-δ Opioid Receptor Heteromers in Rhesus Monkeys

    PubMed Central

    2012-01-01

    Morphine and related drugs are widely employed as analgesics despite the side effects associated with their use. Although morphine is thought to mediate analgesia through mu opioid receptors, delta opioid receptors have been implicated in mediating some side effects such as tolerance and dependence. Here we present evidence in rhesus monkeys that morphine, fentanyl, and possibly methadone selectively activate mu-delta heteromers to produce antinociception that is potently antagonized by the delta opioid receptor antagonist, naltrindole (NTI). Studies with HEK293 cells expressing mu-delta heteromeric opioid receptors exhibit a similar antagonism profile of receptor activation in the presence of NTI. In mice, morphine was potently inhibited by naltrindole when administered intrathecally, but not intracerebroventricularly, suggesting the possible involvement of mu-delta heteromers in the spinal cord of rodents. Taken together, these results strongly suggest that, in primates, mu-delta heteromers are allosterically coupled and mediate the antinociceptive effects of three clinically employed opioid analgesics that have been traditionally viewed as mu-selective. Given the known involvement of delta receptors in morphine tolerance and dependence, our results implicate mu-delta heteromers in mediating both antinociception and these side effects in primates. These results open the door for further investigation in humans. PMID:23019498

  11. Clinically employed opioid analgesics produce antinociception via μ-δ opioid receptor heteromers in Rhesus monkeys.

    PubMed

    Yekkirala, Ajay S; Banks, Matthew L; Lunzer, Mary M; Negus, Stevens S; Rice, Kenner C; Portoghese, Philip S

    2012-09-19

    Morphine and related drugs are widely employed as analgesics despite the side effects associated with their use. Although morphine is thought to mediate analgesia through mu opioid receptors, delta opioid receptors have been implicated in mediating some side effects such as tolerance and dependence. Here we present evidence in rhesus monkeys that morphine, fentanyl, and possibly methadone selectively activate mu-delta heteromers to produce antinociception that is potently antagonized by the delta opioid receptor antagonist, naltrindole (NTI). Studies with HEK293 cells expressing mu-delta heteromeric opioid receptors exhibit a similar antagonism profile of receptor activation in the presence of NTI. In mice, morphine was potently inhibited by naltrindole when administered intrathecally, but not intracerebroventricularly, suggesting the possible involvement of mu-delta heteromers in the spinal cord of rodents. Taken together, these results strongly suggest that, in primates, mu-delta heteromers are allosterically coupled and mediate the antinociceptive effects of three clinically employed opioid analgesics that have been traditionally viewed as mu-selective. Given the known involvement of delta receptors in morphine tolerance and dependence, our results implicate mu-delta heteromers in mediating both antinociception and these side effects in primates. These results open the door for further investigation in humans.

  12. Induction of antinociceptive tolerance to the chronic intrathecal administration of apelin-13 in rat.

    PubMed

    Abbasloo, Elham; Najafipour, Hamid; Esmaeili-Mahani, Saeed

    2016-12-01

    Pain represents a major contributing factor to the individual's quality of life. Although pain killers as opioids, endogenous or exogenous peptides can decrease pain perception, the chronic use of them leads to antinociceptive tolerance. It has been demonstrated that neuropeptide apelin has potent antinoceptive effect. However, the possibility of the induction of its antinociceptive tolerance has not yet been clarified. The tail-flick test was used to assess the nociceptive threshold. All experiments were carried out on male Wistar rats which received intrathecal apelin for 7days. To determine the role of apelin and opioid receptors on the development of apelin analgesic tolerance, their receptor antagonists (F-13 A and naloxone, respectively) were injected simultaneously with apelin. The lumbar spinal cord was assayed to determine apelin receptor levels by the western blotting method. Plasma corticosterone levels were assayed using ELISA. Results showed that apelin (3μg/rat) induced strong thermal antinociception. In addition, chronic apelin produced tolerance to its antinociceptive effect and down regulated spinal apelin receptor. F-13 A and naloxone could inhibit apelin tolerance development. The corticosterone levels did not change following drug administration. Taken together, the data indicated that apelin like other analgesic drugs leads to the induction of side effects such as analgesic tolerance which is mediated partly via the apelin and opioid receptors activation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Attenuation of a radiation-induced conditioned taste aversion after the development of ethanol tolerance

    SciTech Connect

    Hunt, W.A.; Rabin, B.M.

    1988-01-01

    An attempt to reduce a radiation-induced conditioned taste aversion (CTA) was undertaken by rendering animals tolerant to ethanol. Ethanol tolerance, developed over 5 days, was sufficient to block a radiation-induced taste aversion, as well as an ethanol-induced CTA. Several intermittent doses of ethanol, which did not induce tolerance but removed the novelty of the conditioning stimulus, blocked an ethanol-induced CTA but not the radiation-induced CTA. A CTA induced by doses of radiation up to 500 rads was attenuated. These data suggest that radioprotection developing in association with ethanol tolerance is a result of a physiological response to the chronic presence of ethanol not to the ethanol itself.

  14. 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

  15. Development of Carbon and Sulphur Tolerant Anodes of Solid Oxide Fuel Cells

    DTIC Science & Technology

    2010-01-14

    ABSTRACT  The objective of the project is to develop carbon and sulfur tolerant anodes of solid oxide fuel cells ( SOFCs ). Due to the complicity...LSCM/YSZ) composite anode is investigated in detail for the direct utilization of ethanol and methane (the main component of natural gas) in SOFCs ...demonstrate that the Pd-impregnated LSCM/YSZ composite is a promising carbon-tolerant anode for natural gas fuel-based SOFCs . The electrochemical

  16. Opioid Prescribing at Hospital Discharge Contributes to Chronic Opioid Use.

    PubMed

    Calcaterra, Susan L; Yamashita, Traci E; Min, Sung-Joon; Keniston, Angela; Frank, Joseph W; Binswanger, Ingrid A

    2016-05-01

    Chronic opioid therapy for chronic pain treatment has increased. Hospital physicians, including hospitalists and medical/surgical resident physicians, care for many hospitalized patients, yet little is known about opioid prescribing at hospital discharge and future chronic opioid use. We aimed to characterize opioid prescribing at hospital discharge among 'opioid naïve' patients. Opioid naïve patients had not filled an opioid prescription at an affiliated pharmacy 1 year preceding their hospital discharge. We also set out to quantify the risk of chronic opioid use and opioid refills 1 year post discharge among opioid naïve patients with and without opioid receipt at discharge. This was a retrospective cohort study. From 1 January 2011 to 31 December 2011, 6,689 opioid naïve patients were discharged from a safety-net hospital. Chronic opioid use 1 year post discharge. Twenty-five percent of opioid naïve patients (n = 1,688) had opioid receipt within 72 hours of discharge. Patients with opioid receipt were more likely to have diagnoses including neoplasm (6.3% versus 3.5%, p < 0.001), acute pain (2.7% versus 1.0 %, p < 0.001), chronic pain at admission (12.1% versus 3.3%, p < 0.001) or surgery during their hospitalization (65.1% versus 18.4%, p < 0.001) compared to patients without opioid receipt. Patients with opioid receipt were less likely to have alcohol use disorders (15.7% versus 20.7%, p < 0.001) and mental health disorders (23.9% versus 31.4%, p < 0.001) compared to patients without opioid receipt. Chronic opioid use 1 year post discharge was more common among patients with opioid receipt (4.1% versus 1.3%, p < 0.0001) compared to patients without opioid receipt. Opioid receipt was associated with increased odds of chronic opioid use (AOR = 4.90, 95% CI 3.22-7.45) and greater subsequent opioid refills (AOR = 2.67, 95% CI 2.29-3.13) 1 year post discharge compared to no opioid receipt. Opioid receipt at hospital

  17. Opioids for restless legs syndrome.

    PubMed

    de Oliveira, César Osório; Carvalho, Luciane Bc; Carlos, Karla; Conti, Cristiane; de Oliveira, Marcio M; Prado, Lucila Bf; Prado, Gilmar F

    2016-06-29

    Restless legs syndrome (RLS) is a distressing and common neurological disorder that may have a huge impact in the quality of life of those with frequent and intense symptoms. Patients complain of unpleasant sensations in the legs, at or before bedtime, and feel an urge to move the legs, which improves with movement, such as walking. Symptoms start with the patient at rest (e.g. sitting or lying down), and follow a circadian pattern, increasing during the evening or at night. Many pharmacological intervention are available for RLS, including drugs used to treat Parkinson's disease (L-Dopa and dopaminergic agonists), epilepsy (anticonvulsants), anxiety (benzodiazepines), and pain (opioids). Dopaminergic drugs are those most frequently used for treatment of RLS, but some patients do not respond effectively and require other medication. Opioids, a class of medications used to treat severe pain, seem to be effective in treating RLS symptoms, and are recommended for patients with severe symptoms, because RLS and pain appear to share the same mechanism in the central nervous system. All available drugs are associated to some degree with side effects, which can impede treatment. Opioids are associated with adverse events such as constipation, tolerance, and dependence. This justifies the conduct of a systematic review to ascertain whether opioids are safe and effective for treatment of RLS. To asses the effects of opioids compared to placebo treatment for restless legs syndrome in adults. We searched the Cochrane Central Register of Controlled trials, CENTRAL 2016, issue 4 and MEDLINE, EMBASE, and LILACS up to April 2016, using a search strategy adapted by Cochraneto identify randomised clinical trials. We checked the references of each study and established personal communication with other authors to identify any additional studies. We considered publications in all languages. Randomised controlled clinical trials of opioid treatment in adults with idiopathic RLS. Two

  18. Early single Aspirin-triggered Lipoxin blocked morphine anti-nociception tolerance through inhibiting NALP1 inflammasome: Involvement of PI3k/Akt signaling pathway.

    PubMed

    Tian, Yu; Liu, Ming; Mao-Ying, Qi-Liang; Liu, Huan; Wang, Zhi-Fu; Zhang, Meng-Ting; Wang, Jun; Li, Qian; Liu, Shen-Bin; Mi, Wen-Li; Ma, Hong-Jian; Wu, Gen-Cheng; Wang, Yan-Qing

    2015-11-01

    Clinical usage of opioids in pain relief is dampened by analgesic tolerance after chronic exposure, which is related to opioid-associated neuroinflammation. In the current study, which is based on a chronic morphine tolerance rat model and sustained morphine treatment on primary neuron culture, it was observed that Akt phosphorylation, cleaved-Caspase-1-dependent NALP1 inflammasome activation and IL-1β maturation in spinal cord neurons were significantly enhanced by morphine. Moreover, treatment with LY294002, a specific inhibitor of PI3k/Akt signaling, significantly reduced Caspase-1 cleavage, NALP1 inflammasome activation and attenuated morphine tolerance. Tail-flick tests demonstrated that pharmacological inhibition on Caspase-1 activation or antagonizing IL-1β dramatically blocked the development of morphine tolerance. The administration of an exogenous analogue of lipoxin, Aspirin-triggered Lipoxin (ATL), caused a decline in Caspase-1 cleavage, inflammasome activation and mature IL-1β production and thus attenuated the development of morphine tolerance by inhibiting upstream Akt phosphorylation. Additionally, treatment with DAMGO, a selective μ-opioid receptor peptide, significantly induced Akt phosphorylation, Caspase-1 cleavage and anti-nociception tolerance, all of which were attenuated by ATL treatment. Taken together, the present study revealed the involvement of spinal NALP1 inflammasome activation in the development of morphine tolerance and the role of the μ-receptor/PI3k-Akt signaling/NALP1 inflammasome cascade in this process. By inhibiting this signaling cascade, ATL blocked the development of morphine tolerance.

  19. Fetal Regulatory T Cells and Peripheral Immune Tolerance in utero: Implications for Development and Disease

    PubMed Central

    Burt, Trevor D.

    2014-01-01

    The developing fetus must actively learn to tolerate benign antigens, or suffer the consequences of broken tolerance. Tolerance of self-antigens prevents development of autoimmune diseases, and is achieved by both deletion of autoreactive T cell clones in the thymus (central tolerance) and by the suppressive influence of CD4+CD25+FoxP3+ regulatory T cells (Tregs) in the periphery. Fetal CD4+ T cells have a strong predisposition to differentiate into tolerogenic Tregs that actively promote self-tolerance, as well as tolerance to non-inherited antigens on chimeric maternal cells that reside in most fetal tissues. As the fetus nears birth, a crucial transition must occur between the tolerogenic fetal immune system and a more defensive adult-type immune system that is able to combat pathogens. This paper will review the unique tolerogenic nature of the human fetal immune system and will examine evidence for a novel model of fetal immune development: the layered immune system hypothesis. PMID:23432802

  20. Identifying ligand-specific signalling within biased responses: focus on δ opioid receptor ligands

    PubMed Central

    Charfi, I; Audet, N; Bagheri Tudashki, H; Pineyro, G

    2015-01-01

    Opioids activate GPCRs to produce powerful analgesic actions but at the same time induce side effects and generate tolerance, which restrict their clinical use. Reducing this undesired response profile has remained a major goal of opioid research and the notion of ‘biased agonism’ is raising increasing interest as a means of separating therapeutic responses from unwanted side effects. However, to fully exploit this opportunity, it is necessary to confidently identify biased signals and evaluate which type of bias may support analgesia and which may lead to undesired effects. The development of new computational tools has made it possible to quantify ligand-dependent signalling and discriminate this component from confounders that may also yield biased responses. Here, we analyse different approaches to identify and quantify ligand-dependent bias and review different types of confounders. Focus is on δ opioid receptor ligands, which are currently viewed as promising agents for chronic pain management. 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:24665881

  1. 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.

  2. Pain Intensity and Opioid Utilization in Response to CPAP Therapy in Veterans with Obstructive Sleep Apnea on Chronic Opioid Treatment

    PubMed Central

    Jaoude, Philippe; Lal, Ashima; Vermont, Leah; Porhomayon, Jahan; El-Solh, Ali A.

    2016-01-01

    Study Objectives: Sleep fragmentation has been linked to poor pain tolerance and lowered pain threshold. Little evidence exists on whether continuous positive airway pressure (CPAP) adherence in veterans with obstructive sleep apnea (OSA) who are taking opioids for non-malignant pain would ameliorate pain and reduce consumption of opioids. Methods: A retrospective case-control study was performed at a VA sleep center. Pain intensity was assessed using the Numerical Categorical Scale prior to CPAP treatment and 12-mo follow-up. Opioids intake was assessed using the morphine equivalent daily dose (MEDD). Adherence to CPAP was evaluated with the built-in meter. Results: We reviewed 113 patients with OSA (apnea-hypopnea index [AHI] 35.9 ± 29.5) using a MEDD of 61.6 mg (range 5–980 mg) and a control group of 113 veterans with OSA (AHI 33.4 ± 27.3) on no opioids treatment. CPAP adherence was significantly lower at 12 mo in opioid-treated patients compared to controls (37% versus 55%; p = 0.01). Greater pain intensity was the only independent variable associated with CPAP non-adherence at 12-mo follow-up (p = 0.03). Compared to baseline, no significant difference was observed in pain intensity or consumption of opioids in CPAP adherent patients. Conclusions: CPAP treatment did not reduce pain intensity or consumption of opioids in veterans with chronic pain who have coexisting OSA. CPAP adherence was lower in opioid-treated veterans with OSA compared to opioid-free veterans with OSA. Pain intensity was the only determinant of CPAP adherence. Future studies are needed to evaluate pain management program on adherence to CPAP. Citation: Jaoude P, Lal A, Vermont L, Porhomayon J, El-Solh AA. Pain intensity and opioid utilization in response to cpap therapy in veterans with obstructive sleep apnea on chronic opioid treatment. J Clin Sleep Med 2016;12(8):1105–1111. PMID:27250815

  3. Development of a conformational search strategy for flexible ligands: A study of the potent μ-selective opioid analgesic fentanyl

    NASA Astrophysics Data System (ADS)

    Cometta-Morini, Chiara; Loew, Gilda H.

    1991-08-01

    An extensive conformational search of the potent opioid analgesic, fentanyl, was performed using the semiempirical quantum mechanical method AM1 and the CHARMm potential energy function. A combination of two procedures was used to search the conformational space for fentanyl, which included nested dihedral scans, geometry optimization and molecular dynamics simulation at different temperatures. In addition, the effect of a continuum solvent environment was taken into account by use of appropriate values for the dielectric constant in the CHARMm computations. The results of the conformational search allowed the determination of the probable conformation of fentanyl in polar and nonpolar solvents and of three candidate conformers for its bioactive form.

  4. 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

  5. Development of a New Scale to Measure Ambiguity Tolerance in Veterinary Students.

    PubMed

    Hammond, Jennifer A; Hancock, Jason; Martin, Margaret S; Jamieson, Susan; Mellor, Dominic J

    The ability to cope with ambiguity and feelings of uncertainty is an essential part of professional practice. Research with physicians has identified that intolerance of ambiguity or uncertainty is linked to stress, and some authors have hypothesized that there could be an association between intolerance of ambiguity and burnout. We describe the adaptation of the TAMSAD (Tolerance of Ambiguity in Medical Students and Doctors) scale for use with veterinary students. Exploratory factor analysis supports a uni-dimensional structure for the Ambiguity tolerance construct. Although internal reliability of the 29-item TAMSAD scale is reasonable (α=.50), an alternative 27-item scale (drawn from the original 41 items used to develop TAMSAD) shows higher internal reliability for veterinary students (α=.67). We conclude that there is good evidence to support the validity of this latter TAVS (Tolerance of Ambiguity in Veterinary Students) scale to study ambiguity tolerance in veterinary students.

  6. Compulsivity in opioid dependence.

    PubMed

    Tolomeo, Serenella; Matthews, Keith; Steele, Douglas; Baldacchino, Alex

    2017-09-14

    This study aimed to investigate the relationship between compulsivity versus impulsivity and structural MRI abnormalities in opioid dependence. We recruited 146 participants: i) patients with a history of opioid dependence due to chronic heroin use (n=24), ii) heroin users stabilised on methadone maintenance treatment (n=48), iii) abstinent participants with a history of opioid dependence due to heroin use (n=24) and iv) healthy controls (n=50). Compulsivity was measured using Intra/Extra-Dimensional (IED) Task and impulsivity was measured using the Cambridge Gambling Task (CGT). Structural Magnetic Resonance Imaging (MRI) data were also obtained. As hypothesised, compulsivity was negatively associated with impulsivity (p<0.02). Testing for the neural substrates of compulsivity versus impulsivity, we found a higher compulsivity/impulsivity ratio associated with significantly decreased white matter adjacent to the nucleus accumbens, bed nucleus of stria terminalis and rostral cingulate in the abstinent group, compared to the other opioid dependent groups. In addition, self-reported duration of opioid exposure correlated negatively with bilateral globus pallidus grey matter reductions. Our findings are consistent with Volkow & Koob's addiction models and underline the important role of compulsivity versus impulsivity in opioid dependence. Our results have implications for the treatment of opioid dependence supporting the assertion of different behavioural and biological phenotypes in the opioid dependence and abstinence syndromes. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Opioid dependence and pregnancy.

    PubMed

    Winklbaur, Bernadette; Jung, Erika; Fischer, Gabriele

    2008-05-01

    The management of opioid dependence during pregnancy has received considerable attention over the past three decades. Recent peer-reviewed literature in the fields of pregnancy and opioid dependence and neonatal abstinence syndrome has been evaluated and discussed. Pregnant opioid-dependent women must be carefully managed to minimize harm to the fetus; therefore, standardized care for maternal health is required. In a multidisciplinary care system opioid maintenance therapy is the recommended treatment approach during pregnancy. Equivalent attention must be given to the treatment of neonatal abstinence syndrome, which occurs in 55-94% of neonates after intrauterine opioid exposure with a 60% likelihood of requiring treatment; heterogeneous rating scales as well as heterogeneous treatment approaches are often responsible for extended hospital stays. Interpretation of available literature is confounded by several methodological flaws. In general, there is still a lack of evidence-based study designs for pharmacological treatment of these patients as well as neonatal abstinence syndrome.

  8. Consequences of prenatal opioid use for newborns.

    PubMed

    Anand, Kanwaljeet J S; Campbell-Yeo, Marsha

    2015-11-01

    One-third of childbearing women take prescription opioids, previously occurring only in 6-7% of pregnant women. Prenatal opioid exposures may cause birth defects, altered brain development and neonatal abstinence syndrome (NAS). NAS incidence increased fourfold and length of stay increased from 13 to 19 days over 10 years (2004-2013), leading to sevenfold increases in NICU days due to NAS. Initial data suggest that recent NAS increases have resulted from increased use of prescription opioids rather than illicit drugs. Paediatricians will have to manage the consequences of prenatal opioid exposures, as the offspring often have complex medical and social issues associated with these families. ©2015 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

  9. Functional coupling, desensitization and internalization of virally expressed mu opioid receptors in cultured dorsal root ganglion neurons from mu opioid receptor knockout mice.

    PubMed

    Walwyn, W M; Keith, D E; Wei, W; Tan, A M; Xie, C W; Evans, C J; Kieffer, B L; Maidment, N T

    2004-01-01

    Although mu opioid receptors desensitize in various cell lines in vitro, the relationship of this change in signaling efficacy to the development of tolerance in vivo remains uncertain. It is clear that a system is needed in which functional mu opioid receptor expression is obtained in appropriate neurons so that desensitization can be measured, manipulated, and mutated receptors expressed in this environment. We have developed a recombinant system in which expression of a flag-tagged mu opioid receptor is returned to dorsal root ganglia neurons from mu opioid receptor knockout mice in vitro. Flow cytometry analysis showed that adenoviral-mediated expression of the amino-terminal flag-tagged mu opioid receptor in neurons resulted in approximately 1.3x10(6) receptors/cell. Many mu opioid receptor cell lines express a similar density of receptors but this is approximately 7x greater than the number of endogenous receptors expressed by matched wild-type neurons. Inhibition of the high voltage-activated calcium currents in dorsal root ganglia neurons by the mu agonist, D-Ala(2), N-MePhe(4), Gly(5)-ol-enkephalin (DAMGO), was not different between the endogenous and flag-tagged receptor at several concentrations of DAMGO used. Both receptors desensitized equally over the first 6 h of DAMGO pre-incubation, but after 24 h the response of the endogenous receptor to DAMGO had desensitized further than the flag- tagged receptor (71+/-3 vs 29+/-7% respectively; P<0.002), indicating less desensitization in neurons expressing a higher density of receptor. Using flow cytometry to quantify the percentage of receptors remaining on the neuronal cell surface, the flag-tagged receptor internalized by 17+/-1% after 20 min and 55+/-2% after 24 h of DAMGO. These data indicate that this return of function model in neurons recapitulates many of the characteristics of endogenous mu opioid receptor function previously identified in non-neuronal cell lines.

  10. Reward processing by the opioid system in the brain.

    PubMed

    Le Merrer, Julie; Becker, Jérôme A J; Befort, Katia; Kieffer, Brigitte L

    2009-10-01

    The opioid system consists of three receptors, mu, delta, and kappa, which are activated by endogenous opioid peptides processed from three protein precursors, proopiomelanocortin, proenkephalin, and prodynorphin. Opioid receptors are recruited in response to natural rewarding stimuli and drugs of abuse, and both endogenous opioids and their receptors are modified as addiction develops. Mechanisms whereby aberrant activation and modifications of the opioid system contribute to drug craving and relapse remain to be clarified. This review summarizes our present knowledge on brain sites where the endogenous opioid system controls hedonic responses and is modified in response to drugs of abuse in the rodent brain. We review 1) the latest data on the anatomy of the opioid system, 2) the consequences of local intracerebral pharmacological manipulation of the opioid system on reinforced behaviors, 3) the consequences of gene knockout on reinforced behaviors and drug dependence, and 4) the consequences of chronic exposure to drugs of abuse on expression levels of opioid system genes. Future studies will establish key molecular actors of the system and neural sites where opioid peptides and receptors contribute to the onset of addictive disorders. Combined with data from human and nonhuman primate (not reviewed here), research in this extremely active field has implications both for our understanding of the biology of addiction and for therapeutic interventions to treat the disorder.

  11. New approaches to the treatment of opioid-induced constipation

    PubMed Central

    Holzer, Peter

    2015-01-01

    Opiates are indispensable for the treatment of moderate to severe pain. The gastrointestinal tract is one of the major victims of the undesired effects of opiates, because the enteric nervous system expresses all major subtypes of opioid receptors. As a result, propulsive motility and secretory processes in the gut are inhibited by opioid analgesics, and the ensuing constipation is one of the most frequent and troublesome adverse reactions. Many treatments involving laxatives, prokinetic drugs and opioid-sparing regimens have been explored to circumvent opioid-induced bowel dysfunction, but the outcome has in general been unsatisfactory. Specific antagonism of peripheral opioid receptors offers a more rational approach to the management of the adverse actions of opioid analgesics in the gut. This goal is currently addressed by the use of opioid receptor antagonists with limited absorption such as oral naloxone and by the development of peripherally restricted opioid receptor antagonists such as methylnaltrexone and alvimopan. These investigational drugs hold considerable promise in preventing constipation due to opiate treatment, whereas the analgesic action of opiates remains unabated. Postoperative ileus associated with opioid-induced postsurgical pain control is likewise ameliorated by the compounds. With this proof of concept, several phase III studies are under way to define optimal dosage, dosing regimen as well as long-term efficacy and safety of methylnaltrexone and alvimopan. In addition, there is preliminary evidence that these peripherally restricted opioid receptor antagonists may act as prokinetic drugs in their own right. PMID:18924451

  12. Reward Processing by the Opioid System in the Brain

    PubMed Central

    MERRER, JULIE LE; BECKER, JÉRÔME A. J.; BEFORT, KATIA; KIEFFER, BRIGITTE L.

    2015-01-01

    The opioid system consists of three receptors, mu, delta, and kappa, which are activated by endogenous opioid peptides processed from three protein precursors, proopiomelanocortin, proenkephalin, and prodynorphin. Opioid receptors are recruited in response to natural rewarding stimuli and drugs of abuse, and both endogenous opioids and their receptors are modified as addiction develops. Mechanisms whereby aberrant activation and modifications of the opioid system contribute to drug craving and relapse remain to be clarified. This review summarizes our present knowledge on brain sites where the endogenous opioid system controls hedonic responses and is modified in response to drugs of abuse in the rodent brain. We review 1) the latest data on the anatomy of the opioid system, 2) the consequences of local intracerebral pharmacological manipulation of the opioid system on reinforced behaviors, 3) the consequences of gene knockout on reinforced behaviors and drug dependence, and 4) the consequences of chronic exposure to drugs of abuse on expression levels of opioid system genes. Future studies will establish key molecular actors of the system and neural sites where opioid peptides and receptors contribute to the onset of addictive disorders. Combined with data from human and nonhuman primate (not reviewed here), research in this extremely active field has implications both for our understanding of the biology of addiction and for therapeutic interventions to treat the disorder. PMID:19789384

  13. Where do the embryos of Riftia pachyptila develop? Pressure tolerances, temperature tolerances, and buoyancy during prolonged embryonic dispersal

    NASA Astrophysics Data System (ADS)

    Brooke, Sandra D.; Young, Craig M.

    2009-09-01

    The giant vent tubeworm Riftia pachyptila releases slightly buoyant lipid-rich zygotes into the water column, where embryos develop and disperse for 21-25 days before they become ciliated larvae capable of controlling their position in the water column. If embryos rise too rapidly, either from their own buoyancy or by being entrained in a buoyant plume, they could encounter warmer temperatures or lower pressures than the embryos can tolerate. Likewise, if they are entrained among the tubes of the adults or in near-bottom currents, the embryos could encounter warm water and adverse chemical conditions. To determine the range of physiological tolerances for normal development of R. pachyptila, we examined survival of embryos at various combinations of pressure and temperature in the laboratory using small pressure vessels. We also used small incubation chambers deployed in and above tubeworm clusters at our study site on the East Pacific Rise. These served as an in situ comparison for the laboratory data. Temperatures were measured at each incubation site with temperature data loggers. The ambient temperature away from the vents at the study site was 2 °C, and the upper thermal limit for 50% normal development was 6 °C for embryos cultured in the pressure vessels and approximately 7 °C in situ. This limited temperature tolerance defines the embryos physiologically as "cold stenotherms". In laboratory experiments conducted at 2 °C, embryos developed normally at the near-ambient vent pressure of 238 and also at 170 atm. Cleavage rates at 170 atm were much slower than at the higher pressure, however, suggesting that the embryos were probably near their low-pressure threshold. No development occurred at 100 or at 1 atm. During upward migration, embryos would encounter a pressure of 170 atm at a significantly greater depth (1700 m) than they would encounter a temperature of 6 °C, suggesting that embryonic survival should be pressure limited before temperature becomes

  14. Minocycline can delay the development of morphine tolerance, but cannot reverse existing tolerance in the maintenance period of neuropathic pain in rats.

    PubMed

    Zhang, Xin; Wang, Jing; Yu, Tingting; Du, Dongping; Jiang, Wei

    2015-01-01

    Neuropathic pain is a challenge for physicians and basic science researchers, because it often does not respond to routine treatment. The administration of morphine has been considered one of the effective recommended treatments, but its wide application is limited because of the development of antinociceptive tolerance. In general, basic science studies focus on neuropathic pain and morphine tolerance separately. However, we tried to investigate the effect of microglial activation on morphine tolerance in spinal nerve ligation (SNL) rats during the maintenance period of neuropathic pain. This study produced the following results. The morphine tolerance model in neuropathic pain was established by repeated administration of morphine twice daily (10 mg/kg s.c) in the maintenance period of SNL rats. Minocycline, the microglial activation inhibitor, was given once daily (30 mg/kg, i.p.) at different time-points. The CD11b protein level was measured by western blot to monitor microglial activation. Rats' mechanical allodynia was assessed using the 50% paw withdrawal threshold, and the tail antinociception was determined using the percentage of the maximal possible antinociceptive effect. First, the repeated administration of morphine induced the development of antinociceptive tolerance during the maintenance period of neuropathic pain. Second, during the development of morphine tolerance, microglial activation, which is related to the analgesic effect of morphine, decreased in the first few days, but this pattern was reversed in the following days with the development of morphine tolerance. Third, the repeated administration of minocycline, a microglial activation inhibitor, did not influence the antinociceptive effect of a single dose of morphine. Fourth, the pre-administration of minocycline can delay the development of morphine tolerance, but repeated minocycline administration cannot reverse existing morphine tolerance. We concluded that microglial activation

  15. From morphine clinics to buprenorphine: regulating opioid agonist treatment of addiction in the United States.

    PubMed

    Jaffe, Jerome H; O'Keeffe, Charles

    2003-05-21

    The practice of prescribing opioid drugs for opioid dependent patients in the U.S. has been subjected to special government scrutiny for almost 100 years. From 1920 until 1964, doctors who used opioids to treat addicts risked federal and/or state criminal prosecution. Although that period ended when oral methadone maintenance was established as legitimate medical practice, public concern about methadone diversion and accidental overdose fatalities, combined with political pressure from both hostile bureaucracies and groups committed to drug-free treatments, led to the development of unprecedented and detailed Food and Drug Administration (FDA) regulations that specified the manner in which methadone (and later, levo-alpha-acetyl methadol, or levomethadyl acetate, (LAAM)) could be provided. In 1974, Congress gave the Drug Enforcement Administration (DEA) additional oversight of methadone treatment programs. Efforts to liberalize the FDA regulations over the past 30 years have been resisted by both the DEA and existing treatment providers. Additional flexibility for clinicians may evolve from the most recent effort to create an accreditation system to replace some of the FDA regulations. The development of buprenorphine, a partial opioid agonist, as an effective treatment for opioid addiction reopened the possibility for having a less burdensome oversight process, especially because of its reduced toxicity if ingested by non-tolerant individuals. New legislation, the Drug Addiction Treatment Act (DATA) of 2000, created an opportunity for clinicians with special training to be exempted from both federal methadone regulations and the requirement to obtain a special DEA license when using buprenorphine to treat addicts. Some details of how the DATA was developed, moved through Congress, and signed into law are described.

  16. Buprenorphine: an analgesic with an expanding role in the treatment of opioid addiction.

    PubMed

    Robinson, Susan E

    2002-01-01

    Buprenorphine, a long-acting opioid with both agonist and antagonist properties, binds to mu-opioid (OP(3)), kappa-opioid (OP(2)), delta-opioid (OP(1)), and nociceptin (ORL-1) receptors. Its actions at these receptors have not been completely characterized, although buprenorphine is generally regarded as a mu-opioid receptor partial agonist and a kappa-opioid receptor antagonist. Its pharmacology is further complicated by an active metabolite, norbuprenorphine. Although buprenorphine can be used as an analgesic agent, it is of greater importance in the treatment of opioid abuse. Because of its partial agonist activity at mu-opioid receptors and its long half-life, buprenorphine has proven to be an excellent alternative to methadone for either maintenance therapy or detoxification of the opioid addict. Although buprenorphine may ultimately prove to be superior to methadone in the maintenance of the pregnant addict, its effects on the developing fetus must be carefully evaluated.

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

    PubMed

    Salsitz, Edwin A

    2016-03-01

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

  18. 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

  19. Opioids switching with transdermal systems in chronic cancer pain.

    PubMed

    Aurilio, C; Pace, M C; Pota, V; Sansone, P; Barbarisi, M; Grella, E; Passavanti, M B

    2009-05-07

    Due to tolerance development and adverse side effects, chronic pain patients frequently need to be switched to alternative opioid therapy To assess the efficacy and tolerability of an alternative transdermally applied (TDS) opioid in patients with chronic cancer pain receiving insufficient analgesia using their present treatment. A total of 32 patients received alternative opioid therapy, 16 were switched from buprenorphine to fentanyl and 16 were switched from fentanyl to buprenorphine. The dosage used was 50% of that indicated in equipotency conversion tables. Pain relief was assessed at weekly intervals for the next 3 weeks Pain relief as assessed by VAS, PPI, and PRI significantly improved (p < 0.0001) in all patients at all 3 follow up visits. After 3 weeks of treatment, the reduction in the mean VAS, PPI, and PRI scores in the fentanyl and buprenorphine groups was 68, 77, 74, and 69, 79, and 62%, respectively. Over the same time period the use of oral morphine as rescue medication was reduced from 27.5 +/- 20.5 (mean +/- SD) to 3.75 +/- 8.06, and 33.8 +/- 18.9 to 3.75 +/- 10.9 mg/day in the fentanyl and buprenorphine groups, respectively. There was no significant difference in either pain relief or rescue medication use between the two patient groups The number of patient with adverse events fell during the study. After the third week of the treatment the number of patients with constipation was reduced from 11 to 5, and 10 to 4 patients in the fentanyl and buprenorphine groups, respectively. There was a similar reduction in the incidence of nausea and vomiting. No sedation was seen in any patient after one week of treatment. Opioid switching at 50% of the calculated equianalgesic dose produced a significant reduction in pain levels and rescue medication. The incidence of side effects decreased and no new side effects were noted. Further studies are required to provide individualized treatment for patients according to their different types of cancer.

  20. Opioids Switching with Transdermal Systems in Chronic Cancer Pain

    PubMed Central

    Aurilio, C; Pace, MC; Pota, V; Sansone, P; Barbarisi, M; Grella, E; Passavanti, MB

    2009-01-01

    Background Due to tolerance development and adverse side effects, chronic pain patients frequently need to be switched to alternative opioid therapy Objective To assess the efficacy and tolerability of an alternative transdermally applied (TDS) opioid in patients with chronic cancer pain receiving insufficient analgesia using their present treatment. Methods A total of 32 patients received alternative opioid therapy, 16 were switched from buprenorphine to fentanyl and 16 were switched from fentanyl to buprenorphine. The dosage used was 50% of that indicated in equipotency conversion tables. Pain relief was assessed at weekly intervals for the next 3 weeks Results Pain relief as assessed by VAS, PPI, and PRI significantly improved (p < 0.0001) in all patients at all 3 follow up visits. After 3 weeks of treatment, the reduction in the mean VAS, PPI, and PRI scores in the fentanyl and buprenorphine groups was 68, 77, 74, and 69, 79, and 62%, respectively. Over the same time period the use of oral morphine as rescue medication was reduced from 27.5 ± 20.5 (mean ± SD) to 3.75 ± 8.06, and 33.8 ± 18.9 to 3.75 ± 10.9 mg/day in the fentanyl and buprenorphine groups, respectively. There was no significant difference in either pain relief or rescue medication use between the two patient groups The number of patient with adverse events fell during the study. After the third week of the treatment the number of patients with constipation was reduced from 11 to 5, and 10 to 4 patients in the fentanyl and buprenorphine groups, respectively. There was a similar reduction in the incidence of nausea and vomiting. No sedation was seen in any patient after one week of treatment. Conclusion Opioid switching at 50% of the calculated equianalgesic dose produced a significant reduction in pain levels and rescue medication. The incidence of side effects decreased and no new side effects were noted. Further studies are required to provide individualized treatment for patients according

  1. 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.

  2. 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

  3. Prescription opioid analgesics increase the risk of depression.

    PubMed

    Scherrer, Jeffrey F; Svrakic, Dragan M; Freedland, Kenneth E; Chrusciel, Timothy; Balasubramanian, Sumitra; Bucholz, Kathleen K; Lawler, Elizabeth V; Lustman, Patrick J

    2014-03-01

    Prescription opioid analgesic use has quintupled recently. Evidence linking opioid use with depression emanates from animal models and studies of persons with co-occurring substance use and major depression. Little is known about depressogenic effects of opioid use in other populations. The purpose of this study was to determine whether prescription opioids are associated with increased risk of diagnosed depression. Retrospective cohort study, new user design. Medical record data from 49,770 US Department of Veterans Affairs (VA) health care system patients with no recent (24-month) history of opioid use or a diagnosis of depression in 1999 and 2000. Propensity scores were used to control for bias by indication, and the data were weighted to balance the distribution of covariates by duration of incident opioid exposure. Cox proportional hazard models with adjustment for painful conditions were used to estimate the association between duration of prescription opioid use and the subsequent risk of development of depression between 2001 and 2007. Of 49,770 patients who were prescribed an opioid analgesic, 91 % had a prescription for < 90 days, 4 % for 90-180 days, and 5 % for > 180 days. Compared to patients whose prescription was for < 90 days, the risk of depression increased significantly as the duration of opioid prescription increased (HR = 1.25; 95 % CI: 1.05-1.46 for 90-180 days, and HR = 1.51; 95 % CI:1.31-1.74 for > 180 days). In this sample of veterans with no recent (24-month) history of depression or opioid analgesic use, the risk of development of depression increased as the duration of opioid analgesic exposure increased. The potential for depressogenic effect should be considered in risk-benefit discussions, and patients initiating opioid treatment should be monitored for development of depression.

  4. 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

  5. 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.

  6. 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

  7. The Opposing Roles of IVS2+691 CC Genotype and AC/AG Diplotype of 118A>G and IVS2+691G>C of OPRM1 Polymorphisms in Cold Pain Tolerance Among Opioid-Dependent Malay Males on Methadone Therapy.

    PubMed

    Zahari, Zalina; Lee, Chee Siong; Ibrahim, Muslih Abdulkarim; Musa, Nurfadhlina; Yasin, Mohd Azhar Mohd; Lee, Yeong Yeh; Tan, Soo Choon; Mohamad, Nasir; Ismail, Rusli

    2015-12-01

    We recently reported that a majority of opioid-dependent Malay males on methadone therapy are cold pain sensitive. It is postulated that common OPRM1 polymorphisms may be responsible. This study investigated the association between 118A>G (dbSNP rs1799971) and IVS2+691G>C (dbSNP rs2075572) variants on cold pain responses among opioid-dependent Malay males on methadone maintenance therapy. Cold pain responses including pain threshold, pain tolerance, and pain intensity were measured using the cold pressor test. DNA was extracted from the venous blood before polymerase chain reaction genotyping. Repeated measures analysis of variance was used to compare the cold pain responses and OPRM1 polymorphisms (118A>G and IVS2+691G>C) using models including genotype dominant and recessive models, allelic additive models, and analysis of haplotypes and diplotypes. A total of 148 participants were recruited. With the recessive model, those with IVS2+691 homozygous CC genotype had a shorter cold pain tolerance time than those without CC genotype (i.e., GG/GC genotype; 29.81 vs. 43.08 s, respectively, P = 0.048). On the other hand, with diplotype analysis, participants with combined homozygous 118 AA genotype and heterozygous IVS2+691 GC genotype (i.e., AC/AG diplotype) had a longer cold pain tolerance time than those without this diplotype (49.34 vs. 31.48 s, respectively, P = 0.043). Cold pain threshold was not associated with any of the 118A>G and IVS2+691G>C variations despite being analyzed using various models (all P > 0.05). The IVS2+691 CC genotype and AC/AG diplotype of 118A>G and IVS2+691G>C seem to have opposing roles in pain tolerance among opioid-dependent Malay males on methadone therapy. Haplotypes of OPRM1 may be associated with altered binding affinity.

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

    PubMed Central

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

    2014-01-01

    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

  9. The Opioid Epidemic: Crisis and Solutions.

    PubMed

    Skolnick, Phil

    2017-10-02

    The widespread abuse of prescription opioids and a dramatic increase in the availability of illicit opioids have created what is commonly referred to as the opioid epidemic. The magnitude of this epidemic is startling: About 4% of the adult US population misuses prescription opioids, and in 2015, more than 33,000 deaths were attributable to overdose with licit and illicit opioids. Increasing the availability of medication-assisted treatments (such as buprenorphine and naltrexone), the use of abuse-deterrent formulations, and the adoption of US Centers for Disease Control and Prevention prescribing guidelines all constitute short-term approaches to quell this epidemic. However, with more than 125 million Americans suffering from either acute or chronic pain, the development of effective alternatives to opioids, enabled at least in part by a fuller understanding of the neurobiological bases of pain, offers the best long-term solution for controlling and ultimately eradicating this epidemic. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 58 is January 6, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  10. Caged Naloxone Reveals Opioid Signaling Deactivation Kinetics

    PubMed Central

    Banghart, Matthew R.; Shah, Ruchir C.; Lavis, Luke D.

    2013-01-01

    The spatiotemporal dynamics of opioid signaling in the brain remain poorly defined. Photoactivatable opioid ligands provide a means to quantitatively measure these dynamics and their underlying mechanisms in brain tissue. Although activation kinetics can be assessed using caged agonists, deactivation kinetics are obscured by slow clearance of agonist in tissue. To reveal deactivation kinetics of opioid signaling we developed a caged competitive antagonist that can be quickly photoreleased in sufficient concentrations to render agonist dissociation effectively irreversible. Carboxynitroveratryl-naloxone (CNV-NLX), a caged analog of the competitive opioid antagonist NLX, was readily synthesized from commercially available NLX in good yield and found to be devoid of antagonist activity at heterologously expressed opioid receptors. Photolysis in slices of rat locus coeruleus produced a rapid inhibition of the ionic currents evoked by multiple agonists of the μ-opioid receptor (MOR), but not of α-adrenergic receptors, which activate the same pool of ion channels. Using the high-affinity peptide agonist dermorphin, we established conditions under which light-driven deactivation rates are independent of agonist concentration and thus intrinsic to the agonist-receptor complex. Under these conditions, some MOR agonists yielded deactivation rates that are limited by G protein signaling, whereas others appeared limited by agonist dissociation. Therefore, the choice of agonist determines which feature of receptor signaling is unmasked by CNV-NLX photolysis. PMID:23960100

  11. Nicotine effects and the endogenous opioid system.

    PubMed

    Kishioka, Shiroh; Kiguchi, Norikazu; Kobayashi, Yuka; Saika, Fumihiro

    2014-01-01

    Nicotine (NIC) is an exogenous ligand of the nicotinic acetylcholine receptor (nAChR), and it influences various functions in the central nervous system. Systemic administration of NIC elicits the release of endogenous opioids (endorphins, enkephalins, and dynorphins) in the supraspinal cord. Additionally, systemic NIC administration induces the release of methionine-enkephalin in the spinal dorsal horn. NIC has acute neurophysiological actions, including antinociceptive effects, and the ability to activate the hypothalamic-pituitary-adrenal (HPA) axis. The endogenous opioid system participates in NIC-induced antinociception, but not HPA axis activation. Moreover, NIC-induced antinociception is mediated by α4β2 and α7 nAChRs, while NIC-induced HPA axis activation is mediated by α4β2, not α7, suggesting that the effects of NIC on the endogenous opioid system are mediated by α7, not α4β2. NIC has substantial physical dependence liability. The opioid-receptor antagonist naloxone (NLX) elicits NIC withdrawal after repeated NIC administration, and NLX-induced NIC withdrawal is inhibited by concomitant administration of an opioid-receptor antagonist. NLX-induced NIC withdrawal is also inhibited by concomitant administration of an α7 antagonist, but not an α4β2 antagonist. Taken together, these findings suggest that NIC-induced antinociception and the development of physical dependence are mediated by the endogenous opioid system, via the α7 nAChR.

  12. 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.

  13. Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting μ Opioid Analgesic with Reduced Abuse Liability.

    PubMed

    Crowley, Rachel Saylor; Riley, Andrew P; Sherwood, Alexander M; Groer, Chad E; Shivaperumal, Nirajmohan; Biscaia, Miguel; Paton, Kelly; Schneider, Sebastian; Provasi, Davide; Kivell, Bronwyn M; Filizola, Marta; Prisinzano, Thomas E

    2016-12-22

    Opioids are widely used to treat millions suffering from pain, but their analgesic utility is limited due to associated side effects. Herein we report the development and evaluation of a chemical probe exhibiting analgesia and reduced opioid-induced side effects. This compound, kurkinorin (5), is a potent and selective μ-opioid receptor (MOR) agonist (EC50 = 1.2 nM, >8000 μ/κ selectivity). 5 is a biased activator of MOR-induced G-protein signaling over β-arrestin-2 recruitment. Metadynamics simulations of 5's binding to a MOR crystal structure suggest energetically preferred binding modes that differ from crystallographic ligands. In vivo studies with 5 demonstrate centrally mediated antinociception, significantly reduced rewarding effects, tolerance, and sedation. We propose that this novel MOR agonist may represent a valuable tool in distinguishing the pathways involved in MOR-induced analgesia from its side effects.

  14. Oxycodone combined with opioid receptor antagonists: efficacy and safety.

    PubMed

    Davis, Mellar; Goforth, Harold W; Gamier, Pam

    2013-05-01

    A mu receptor antagonist combined with oxycodone (OXY) may improve pain control, reduce physical tolerance and withdrawal, minimizing opioid-related bowel dysfunction and act as an abuse deterrent. The authors cover the use of OXY plus ultra-low-dose naltrexone for analgesia and the use of sustained-release OXY plus sustained-release naloxone to reduce the opioid bowel syndrome. The authors briefly describe the use of sustained-release OXY and naltrexone pellets as a drug abuse deterrent formulation. Combinations of ultra-low-dose naltrexone plus OXY have been in separate trials involved in patients with chronic pain from osteoarthritis and idiopathic low back pain. High attrition and marginal differences between ultra-low-dose naltrexone plus OXY and OXY led to discontinuation of development. Prolonged-release (PR) naloxone combined with PR OXY demonstrates a consistent reduction in opioid-related bowel dysfunction in multiple randomized controlled trials. However, gastrointestinal side effects, including diarrhea, were increased in several trials with the combination compared with PR OXY alone. Analgesia appeared to be maintained although non-inferiority to PR OXY is not formally established. There were flaws to trial design and safety monitoring. Naltrexone has been combined with OXY in individual pellets encased in a capsule. This combination has been reported in a Phase II trial and is presently undergoing Phase III studies. Due to the lack of efficacy the combination of altered low-dose naltrexone with oxycodone should cease in development. The combination of sustained release oxycodone plus naloxone reduces constipation with a consistent benefit. Safety has been suboptimally evaluated which is a concern. Although the drug is commercially available in several countries, ongoing safety monitoring particularly high doses would be important.

  15. 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

  16. 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

  17. 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

  18. 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.

  19. 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.

  20. Is periconceptional opioid use safe?

    PubMed Central

    Chan, Felix; Koren, Gideon

    2015-01-01

    Abstract Question A patient in my practice who takes buprenorphine for chronic pain would like to conceive. Is it safe for her to continue taking her medication? Answer The literature regarding periconceptional opioid use is conflicted as to whether opioids pose an elevated risk of birth defects. Confounding factors such as socioeconomic status, stress, and alcohol consumption might play a role. The first trimester of pregnancy is the critical period of development for many organ systems in the embryo. A chemical or environmental insult is more likely to produce major congenital malformations such as neural tube defects or mental retardation if it occurs within this window. Medical practitioners should judiciously consider a risk-benefit analysis before making their decisions. PMID:26167561

  1. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.

    PubMed

    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

    2009-02-01

    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 policies. 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 after a systematic review of the evidence.

  2. Opioid analgesia in neonates following cardiac surgery.

    PubMed

    Hammer, Gregory B; Golianu, Brenda

    2007-03-01

    Pain in the newborn is complex, involving a variety of receptors and mechanisms within the developing nervous system. When pain is generated, a series of sequential neurobiologic changes occur within the central nervous system. If pain is prolonged or repetitive, the developing nervous system could be permanently modified, with altered processing at spinal and supraspinal levels. In addition, pain is associated with a number of adverse physiologic responses that include alterations in circulatory (tachycardia, hypertension, vasoconstriction), metabolic (increased catabolism), immunologic (impaired immune response), and hemostatic (platelet activation) systems. This "stress response" associated with cardiac surgery in neonates could be profound and is associated with increased morbidity and mortality. Neonates undergoing cardiac operations are exposed to extensive tissue damage related to surgery and additional painful stimulation related to endotracheal and thoracostomy tubes that may remain in place for variable periods of time following surgery. In addition, postoperatively neonates endure repeated procedural pain from suctioning of endotracheal tubes, placement of vascular catheters, and manipulation of wounds (eg, sternal closure) and dressings. The treatment and/or prevention of pain are widely considered necessary for humanitarian and physiologic reasons. Improved clinical and developmental outcomes underscore the importance of providing adequate analgesia for newborns who undergo major surgery, mechanical ventilation, and related procedures in the intensive care unit. This article reviews published information regarding opioid administration and associated issues of tolerance and abstinence syndromes (withdrawal) in neonates with an emphasis on those having undergone cardiac surgery.

  3. What Do We Know about Opioids and the Kidney?

    PubMed Central

    Mallappallil, Mary; Sabu, Jacob; Friedman, Eli A.; Salifu, Moro

    2017-01-01

    Evidence suggests a link between opioid use and kidney disease. This review summarizes the known renal manifestations of opioid use including its role in acute and chronic kidney injury. Both the direct and indirect effects of the drug, and the context which leads to the development of renal failure, are explored. While commonly used safely for pain control and anesthesia in those with kidney disease, the concerns with respect to side effects and toxicity of opioids are addressed. This is especially relevant with the worldwide increase in the use of opioids for medical and recreational use. PMID:28117754

  4. 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.

  5. [Opioid Therapy and Management of Side Effects Associated with Opioids].

    PubMed

    Nakatani, Toshihiko

    2017-04-01

    Opioids are very useful medications to reduce suffering of cancer patients such as refractory pain and dyspnea. We physicians have to use opioids to have good management of pain and suffering associated with cancer including management of side effects caused by opioids. Opioids couple opioid receptors and affect several pharmacological effects. Other than analgesic effect, opioids have some side effects of constipation, nausea and vomiting, respiratory depression. In this chapter, I take important side effects of constipation, nausea and vomiting and respiratory depression. Next, serotonin syndrome caused by tramadol combined with anti-depressants is remarked as assignable syndrome. As advancing in chemotherapy for cancer treatment, cancer survivors live longer with opioid therapy. We have to pay attention to the side effects and another dysfunction caused by long use of opioids. It is important that we physician use opioids effectively to keep activity of daily living(ADL) of patients and families as team approach.

  6. Prescription of Opioids for Opioid-Naive Medical Inpatients

    PubMed Central

    Lail, Sharan; Sequeira, Kelly; Lieu, Jenny; Dhalla, Irfan A

    2014-01-01

    Background: Harms associated with prescription opioids are a major and increasing public health concern. Prescribing of opioids for inpatients may contribute to the problem, especially if primary care practitioners continue opioid therapy that is initiated in hospital. Objectives: To describe the extent and nature of opioid prescribing for opioid-naive patients (i.e., no use of opioids within 2 weeks before admission) on an internal medicine unit. Methods: This single-centre study involved chart review for opioid-naive patients admitted to the internal medicine unit of a large academic health sciences centre