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Sample records for increased opioid dependence

  1. Increased Opioid Dependence in a Mouse Model of Panic Disorder

    PubMed Central

    Gallego, Xavier; Murtra, Patricia; Zamalloa, Teresa; Canals, Josep Maria; Pineda, Joseba; Amador-Arjona, Alejandro; Maldonado, Rafael; Dierssen, Mara

    2009-01-01

    Panic disorder is a highly prevalent neuropsychiatric disorder that shows co-occurrence with substance abuse. Here, we demonstrate that TrkC, the high-affinity receptor for neurotrophin-3, is a key molecule involved in panic disorder and opiate dependence, using a transgenic mouse model (TgNTRK3). Constitutive TrkC overexpression in TgNTRK3 mice dramatically alters spontaneous firing rates of locus coeruleus (LC) neurons and the response of the noradrenergic system to chronic opiate exposure, possibly related to the altered regulation of neurotrophic peptides observed. Notably, TgNTRK3 LC neurons showed an increased firing rate in saline-treated conditions and profound abnormalities in their response to met5-enkephalin. Behaviorally, chronic morphine administration induced a significantly increased withdrawal syndrome in TgNTRK3 mice. In conclusion, we show here that the NT-3/TrkC system is an important regulator of neuronal firing in LC and could contribute to the adaptations of the noradrenergic system in response to chronic opiate exposure. Moreover, our results indicate that TrkC is involved in the molecular and cellular changes in noradrenergic neurons underlying both panic attacks and opiate dependence and support a functional endogenous opioid deficit in panic disorder patients. PMID:20204153

  2. Yohimbine Increases Opioid-Seeking Behavior in Heroin-Dependent, Buprenorphine-Maintained Individuals

    PubMed Central

    Greenwald, Mark K.; Lundahl, Leslie H.; Steinmiller, Caren L.

    2012-01-01

    Rationale In laboratory animals, the biological stressor yohimbine (α2-noradrenergic autoreceptor antagonist) promotes drug seeking. Human laboratory studies have demonstrated that psychological stressors can increase drug craving but not that stressors alter drug seeking. Objectives This clinical study tested whether yohimbine increases opioid seeking behavior. Methods Ten heroin-dependent, buprenorphine (8-mg/day) stabilized volunteers, sampled two doses of hydromorphone (12 and 24 mg IM in counterbalanced order, labeled Drug A [session 1] and Drug B [session 2]). During each of six later sessions (within-subject, double blind, randomized crossover design), volunteers could respond on a 12-trial choice progressive ratio task to earn units (1 or 2 mg) of the sampled hydromorphone dose (Drug A or B) vs. money ($2) following different oral yohimbine pretreatment doses (0, 16.2 and 32.4 mg). Results Behavioral economic demand intensity and peak responding (Omax) were significantly higher for hydromorphone 2-mg than 1-mg. Relative to placebo, yohimbine significantly increased hydromorphone demand inelasticity, more so for hydromorphone 1-mg units (Pmax = 909, 3647 and 3225 for placebo, 16.2 and 32.4 mg yohimbine doses, respectively) than hydromorphone 2-mg units (Pmax = 2656, 3193 and 3615, respectively). Yohimbine produced significant but clinically modest dose-dependent increases in blood pressure (systolic ≈15 and diastolic ≈10 mmHg) and opioid withdrawal symptoms, and decreased opioid agonist symptoms and elated mood. Conclusions These findings concur with preclinical data by demonstrating that yohimbine increases drug seeking; in this study, these effects occurred without clinically significant subjective distress or elevated craving, and partly depended on opioid unit dose. PMID:23161001

  3. κ-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats.

    PubMed

    Nealey, Kathryn A; Smith, Alexander W; Davis, Seth M; Smith, Daniel G; Walker, Brendan M

    2011-01-01

    Previously, it was shown that ethanol-dependent animals display increased sensitivity to the general opioid receptor antagonist nalmefene compared to naltrexone. It was hypothesized that the dissociable effects of the two antagonists were attributable to a κ-opioid receptor mechanism. Nucleus accumbens dynorphin is upregulated following chronic ethanol exposure and such neuroadaptations could contribute to nalmefene's increased potency in ethanol-dependent animals. To test this hypothesis, male Wistar rats were trained to self-administer ethanol using an operant conditioning procedure. Animals were then implanted with bilateral intra-accumbens shell guide cannulae and assigned to either a chronic intermittent ethanol vapor-exposure condition (to induce dependence) or an air-exposed control group. Following a one-month exposure period, nalmefene, nor-binaltorphimine (nor-BNI; selective for κ-opioid receptors) or a combination of the selective opioid receptor antagonists CTOP and naltrindole (selective for the μ- and δ-opioid receptors, respectively) were site-specifically infused into the nucleus accumbens shell prior to ethanol self-administration sessions during acute withdrawal. Nalmefene and CTOP/naltrindole dose-dependently reduced ethanol self-administration in nondependent and dependent animals, whereas nor-BNI selectively attenuated ethanol self-administration in ethanol-dependent animals without affecting the self-administration of nondependent animals. Further analysis indentified that intra-accumbens shell nalmefene was more potent in ethanol-dependent animals and that the increased potency was attributable to a κ-opioid receptor mechanism. These data support the concept that dysregulation of DYN/κ-opioid receptor systems contributes to the excessive self-administration observed in dependent animals and suggest that pharmacotherapeutics for ethanol dependence that target κ-opioid receptors, in addition to μ- and δ-opioid receptors, are preferable

  4. Shedding "UV" light on endogenous opioid dependence.

    PubMed

    Tejeda, Hugo A; Bonci, Antonello

    2014-06-19

    Excessive sun tanning can result in addictive behavior. In this issue of Cell, Fell et al. utilize a combination of behavioral pharmacology and transgenic mice to demonstrate that chronic UV light exposure recruits p53 signaling in keratinocytes, subsequently increasing β-endorphin signaling at opioid receptors, and produces an endogenous opioid-dependent state.

  5. Shedding "UV" light on endogenous opioid dependence.

    PubMed

    Tejeda, Hugo A; Bonci, Antonello

    2014-06-19

    Excessive sun tanning can result in addictive behavior. In this issue of Cell, Fell et al. utilize a combination of behavioral pharmacology and transgenic mice to demonstrate that chronic UV light exposure recruits p53 signaling in keratinocytes, subsequently increasing β-endorphin signaling at opioid receptors, and produces an endogenous opioid-dependent state. PMID:24949960

  6. Parenthood and opioid dependence

    PubMed Central

    Pihkala, Heljä; Sandlund, Mikael

    2015-01-01

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

  7. Common Surgeries Raise Risk for Opioid Dependence

    MedlinePlus

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

  8. Denial of urinalysis-confirmed opioid use in prescription opioid dependence

    PubMed Central

    Hilario, E. Yvette; Griffin, Margaret L.; McHugh, R. Kathryn; McDermott, Katherine A.; Connery, Hilary S.; Fitzmaurice, Garrett M.; Weiss, Roger D.

    2014-01-01

    Although research has generally supported the validity of substance use self-reports, some patients deny urine-verified substance use. We examined the prevalence and patterns of denying urinalysis-confirmed opioid use in a sample of prescription opioid dependent patients. We also identified characteristics associated with denial in this population of increasing public health concern. Opioid use self-reports were compared with weekly urinalysis results in a 12-week multi-site treatment study for prescription opioid dependence. Among those who used opioids during the trial (n=246/360), 44.3% (n=109) denied urinalysis-confirmed opioid use, although usually only once (78%). Overall, 22.9% of opioid-positive urine tests (149/650) were denied on self-report. Multivariable analysis found that initially using opioids to relieve pain was associated with denying opioid use. These findings support the use of both self-reports and urine testing in treating prescription opioid dependence. PMID:25115135

  9. [Opioid tolerance and dependence--pharmacological aspects].

    PubMed

    Jaba, I M; Luncanu, I; Mungiu, O C

    2001-01-01

    Prolonged opioids administration leads inevitably to tolerance and dependence, a phenomenon we meet more often in healthy people than in ill patients. Tolerance means a hypersensibility of neuronal membranes as well as changes in the number and affinity of opioid receptors, which implies intake of larger doses to obtain the initial effect. Physical dependence, quite different of the psychological one, is the appearance of abstinence syndrome on sudden interruption of opioid administration or on administration of an antagonist. There is usually cross-tolerance in opioids, but it can also be incomplete, when the initial opioid can be replaced with another one that produces a milder abstinence syndrome. Classically, metadone is used in long time therapy, after detoxification with an antagonist is performed (naloxon, naltrexon). Modern pharmacological alternatives are levo-alpha-acetyl-methadol (LAAM) and agonists-antagonists (butorphanol, buprenorphine, pentazocine, nalbuphine). An antagonist can also be used if associated with an alpha--stimulant (clonidine), in order to remove noradrenergic manifestations of abstinence syndrome. Now other therapeutical principles are being studied: enkephalinaze inhibitors to reduce the abstinence syndrome, NMDA receptor antagonists, NO sintetasis inhibitors, that facilitates opioid analgesia and hinders tolerance development; colecystokinin-receptors agonists or antagonists to reduce tolerance on morphine. A recent study showed that the concomitant administration of an opioid agonist (sufentanil) and a calcium channels blocker (nimodipine) not only prevents from tolerance development but also triggers hypersensibility to analgesic effects of the opioid. PMID:12092171

  10. Genetics of Opioid Dependence: A Review of the Genetic Contribution to Opioid Dependence

    PubMed Central

    Mistry, Chetna J; Bawor, Monica; Desai, Dipika; Marsh, David C; Samaan, Zainab

    2014-01-01

    This narrative review aims to provide an overview of the impact of opioid dependence and the contribution of genetics to opioid dependence. Epidemiological data demonstrate that opioid dependence is a global trend with far-reaching effects on the social, economic, and health care systems. A review of classical genetic studies of opioid use suggests significant heritability of drug use behavior, however the evidence from molecular genetic studies is inconclusive. Nonetheless, certain genetic variants are important to consider given their role in the pathophysiology of addictive behavior. We undertook a literature review to identify the current state of knowledge regarding the role of genes in opioid dependence. Determining the association of genetic markers could change the current understanding of the various factors contributing to opioid dependence and therefore may improve recognition of individuals at risk for the disorder and prevention and treatment strategies. PMID:25242908

  11. Neurobiology of opioid dependence in creating addiction vulnerability.

    PubMed

    Evans, Christopher J; Cahill, Catherine M

    2016-01-01

    Opioid drugs are potent modulators of many physiological and psychological processes. When given acutely, they can elicit the signature responses of euphoria and analgesia that societies have coveted for centuries. Repeated, or chronic, use of opioids induces adaptive or allostatic changes that modify neuronal circuitry and create an altered normality - the "drug-dependent" state. This state, at least that exhibited by those maintained continuously on long-acting opioid drugs such as methadone or buprenorphine, is generally indistinguishable from the drug-naïve state for most overt behaviors. The consequences of the allostatic changes (cellular, circuit, and system adaptations) that accompany the drug-dependent state are revealed during drug withdrawal. Drug cessation triggers a temporally orchestrated allostatic re-establishment of neuronal systems, which is manifested as opposing physiological and psychological effects to those exhibited by acute drug intoxication. Some withdrawal symptoms, such as physical symptoms (sweating, shaking, and diarrhea) resolve within days, whilst others, such as dysphoria, insomnia, and anxiety, can linger for months, and some adaptations, such as learned associations, may be established for life. We will briefly discuss the cellular mechanisms and neural circuitry that contribute to the opioid drug-dependent state, inferring an emerging role for neuroinflammation. We will argue that opioid addictive behaviors result from a learned relationship between opioids and relief from an existing or withdrawal-induced anxiogenic and/or dysphoric state. Furthermore, a future stressful life event can recall the memory that opioid drugs alleviate negative affect (despair, sadness, and anxiety) and thereby precipitate craving, resulting in relapse. A learned association of relief of aversive states would fuel drug craving in vulnerable people living in an increasingly stressful society. We suggest that this route to addiction is contributive to

  12. State-dependent μ-opioid modulation of social motivation

    PubMed Central

    Loseth, Guro E.; Ellingsen, Dan-Mikael; Leknes, Siri

    2014-01-01

    Social mammals engage in affiliative interactions both when seeking relief from negative affect and when searching for pleasure and joy. These two motivational states are both modulated by μ-opioid transmission. The μ-opioid receptor (MOR) system in the brain mediates pain relief and reward behaviors, and is implicated in social reward processing and affiliative bonding across mammalian species. However, pharmacological manipulation of the μ-opioid system has yielded opposite effects on rodents and primates: in rodents, social motivation is generally increased by MOR agonists and reduced by antagonists, whereas the opposite pattern has been shown in primates. Here, we address this paradox by taking into account differences in motivational state. We first review evidence for μ-opioid mediation of reward processing, emotion regulation, and affiliation in humans, non-human primates, rodents and other species. Based on the consistent cross-species similarities in opioid functioning, we propose a unified, state-dependent model for μ-opioid modulation of affiliation across the mammalian species. Finally, we show that this state-dependent model is supported by evidence from both rodent and primate studies, when species and age differences in social separation response are taken into account. PMID:25565999

  13. Neurobiology of opioid dependence in creating addiction vulnerability

    PubMed Central

    Evans, Christopher J.; Cahill, Catherine M.

    2016-01-01

    Opioid drugs are potent modulators of many physiological and psychological processes. When given acutely, they can elicit the signature responses of euphoria and analgesia that societies have coveted for centuries. Repeated, or chronic, use of opioids induces adaptive or allostatic changes that modify neuronal circuitry and create an altered normality — the “drug-dependent” state. This state, at least that exhibited by those maintained continuously on long-acting opioid drugs such as methadone or buprenorphine, is generally indistinguishable from the drug-naïve state for most overt behaviors. The consequences of the allostatic changes (cellular, circuit, and system adaptations) that accompany the drug-dependent state are revealed during drug withdrawal. Drug cessation triggers a temporally orchestrated allostatic re-establishment of neuronal systems, which is manifested as opposing physiological and psychological effects to those exhibited by acute drug intoxication. Some withdrawal symptoms, such as physical symptoms (sweating, shaking, and diarrhea) resolve within days, whilst others, such as dysphoria, insomnia, and anxiety, can linger for months, and some adaptations, such as learned associations, may be established for life. We will briefly discuss the cellular mechanisms and neural circuitry that contribute to the opioid drug-dependent state, inferring an emerging role for neuroinflammation. We will argue that opioid addictive behaviors result from a learned relationship between opioids and relief from an existing or withdrawal-induced anxiogenic and/or dysphoric state. Furthermore, a future stressful life event can recall the memory that opioid drugs alleviate negative affect (despair, sadness, and anxiety) and thereby precipitate craving, resulting in relapse. A learned association of relief of aversive states would fuel drug craving in vulnerable people living in an increasingly stressful society. We suggest that this route to addiction is

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

    PubMed

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

    2016-08-01

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

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

    PubMed Central

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

    2015-01-01

    Background Research grounded in behavioral economics has previously linked addictive behavior to disrupted decision-making and reward-processing, but these principles have not been examined in prescription opioid addiction, which is currently a major public health problem. This study examined whether pre-treatment drug reinforcement value predicted opioid use during outpatient treatment of prescription opioid addiction. Methods Secondary analyses examined participants with prescription opioid dependence who received 12 weeks of buprenorphine-naloxone and counseling in a multi-site clinical trial (N = 353). Baseline measures assessed opioid source and indices of drug reinforcement value, including the total amount and proportion of income spent on drugs. Weekly urine drug screens measured opioid use. Results Obtaining opioids from doctors was associated with lower pre-treatment drug spending, while obtaining opioids from dealers/patients was associated with greater spending. Controlling for demographics, opioid use history, and opioid source frequency, patients who spent a greater total amount (OR = 1.30, p < .001) and a greater proportion of their income on drugs (OR = 1.31, p < .001) were more likely to use opioids during treatment. Conclusions Individual differences in drug reinforcement value, as indicated by pre-treatment allocation of economic resources to drugs, reflects propensity for continued opioid use during treatment among individuals with prescription opioid addiction. Future studies should examine disrupted decision-making and reward-processing in prescription opioid users more directly and test whether reinforcer pathology can be remediated in this population. PMID:25622776

  16. Pharmacologically assisted treatment of opioid-dependent youth.

    PubMed

    Pecoraro, Anna; Fishman, Marc; Ma, Michelle; Piralishvili, Gvantsa; Woody, George E

    2013-12-01

    Opioid misuse, abuse, and dependence are global problems whose patterns vary across cultures. In the USA, the non-medical use of prescription opioids has become particularly serious because of its association with addiction and overdose death. Agonist and antagonist medications have been shown to be effective for opioid-dependent adults, and there is a growing body of data that they are also effective for youth. Here, we summarize evidence that detoxification alone results in high rates of treatment dropout and relapse but that the limited but growing data on the extended use of medication-assisted treatment for opioid-dependent youth have been positive. The implementation of medication-assisted treatment as a standard practice is feasible, easily integrated with counseling or psychotherapy, and has potential to greatly improve outcomes. Although concerns about safety and efficacy with youth require more research, and we do not advocate indefinite maintenance, we suggest that opioid-dependent youth should be considered as candidates for medication-assisted treatment delivered in a comprehensive, developmentally appropriate context, beginning at the first episode of care, with the strength of the recommendation to use medication increasing with each care episode.

  17. Prescription Opioid Abuse and Dependence: Assessment Strategies for Counselors

    ERIC Educational Resources Information Center

    Weigel, Daniel J.; Donovan, Kimberly A.; Krug, Kevin S.; Dixon, Wayne A.

    2007-01-01

    The authors review the article "Prescription Drug Use and Abuse: Risk Factors, Red Flags, and Prevention Strategies" (J. H. Isaacson, J. A. Hopper, D. P. Alford, & T. Parran, 2005), which provides an overview of the recent increase in prescription opioid abuse and dependence from the physician's perspective. In the present article, the authors…

  18. Satisfaction with life and opioid dependence

    PubMed Central

    Luty, Jason; Arokiadass, Sujaa Mary Rajagopal

    2008-01-01

    Background Serious substance misuse and dependence is widely seen as damaging to an individual and to society in general. Whereas the medical and society effects of substance misuse are widely described, some commentators suggest substance misuse may be an "alternative lifestyle". Aim To assess general life satisfaction amongst treatment-seeking people with substance dependence. Methods The Satisfaction With Life Scale (SWLS) was administered to a sample of opioid-dependent people receiving substitute medication. Results 105 subjects and 105 age-sex matched subjects in a comparison group completed the questionnaire. The mean SWLS score was 7.12 (SD = 10.6; median = 6) for patients compared to 22.6 (SD = 6.8) in the comparison group. (Two sided p < 0.0001; Median difference = -13.5; Wilcoxon signed rank test.) Conclusion The study used a validated instrument and objective reports to confirm significantly higher rates of dissatisfaction with life among opioid dependent people in treatment when compared to members of the general population. PMID:18226241

  19. The Role of Opioid Prescription in Incident Opioid Abuse and Dependence Among Individuals with Chronic Non-Cancer Pain: The Role of Opioid Prescription

    PubMed Central

    Edlund, Mark J.; Martin, Bradley C.; Russo, Joan E.; Devries, Andrea; Braden, Jennifer Brennan; Sullivan, Mark D.

    2014-01-01

    Objective Increasing rates of opioid use disorders (abuse and dependence) among patients prescribed opioids are a significant public health concern. We investigated the association between exposure to prescription opioids and incident opioid use disorders (OUDs) among individuals with a new episode of a chronic non-cancer pain (CNCP) condition. Methods We utilized claims data from the HealthCore Database for 2000–2005. The dataset included all individuals aged 18 and over with a new CNCP episode (no diagnosis in the prior 6 months), and no opioid use or OUD in the prior 6 months (n=568,640). We constructed a single multinomial variable describing prescription opioid days supply (none, acute, and chronic) and average daily dose (none, low dose, medium dose, and high dose), and examined the association between this variable and an incident OUD diagnosis. Results Patients with CNCP prescribed opioids had significantly higher rates of OUDs compared to those not prescribed opioids. Effects varied by average daily dose and days supply: low dose, acute (odds ratio (OR)=3.03, 95% confidence interval (CI)= 2.32, 3.95); low dose, chronic (OR=14.92, 95% CI=10.38, 21.46); medium dose, acute (OR=2.80, 95% CI=2.12, 3.71); medium dose, chronic (OR=28.69, 95% CI=20.02, 41.13); high dose, acute (OR=3.10 95% CI=1.67, 5.77); and high dose, chronic (OR=122.45, 95% CI=72.79, 205.99). Conclusion Among individuals with a new CNCP episode, prescription opioid exposure was a strong risk factor for incident OUDs; magnitudes of effects were large. Duration of opioid therapy was more important than daily dose in determining OUD risk. PMID:24281273

  20. Increases in Drug and Opioid Overdose Deaths--United States, 2000-2014.

    PubMed

    Rudd, Rose A; Aleshire, Noah; Zibbell, Jon E; Gladden, R Matthew

    2016-01-01

    The United States is experiencing an epidemic of drug overdose (poisoning) deaths. Since 2000, the rate of deaths from drug overdoses has increased 137%, including a 200% increase in the rate of overdose deaths involving opioids (opioid pain relievers and heroin). CDC analyzed recent multiple cause-of-death mortality data to examine current trends and characteristics of drug overdose deaths, including the types of opioids associated with drug overdose deaths. During 2014, a total of 47,055 drug overdose deaths occurred in the United States, representing a 1-year increase of 6.5%, from 13.8 per 100,000 persons in 2013 to 14.7 per 100,000 persons in 2014. The rate of drug overdose deaths increased significantly for both sexes, persons aged 25-44 years and ≥55 years, non-Hispanic whites and non-Hispanic blacks, and in the Northeastern, Midwestern, and Southern regions of the United States. Rates of opioid overdose deaths also increased significantly, from 7.9 per 100,000 in 2013 to 9.0 per 100,000 in 2014, a 14% increase. Historically, CDC has programmatically characterized all opioid pain reliever deaths (natural and semisynthetic opioids, methadone, and other synthetic opioids) as "prescription" opioid overdoses (1). Between 2013 and 2014, the age-adjusted rate of death involving methadone remained unchanged; however, the age-adjusted rate of death involving natural and semisynthetic opioid pain relievers, heroin, and synthetic opioids, other than methadone (e.g., fentanyl) increased 9%, 26%, and 80%, respectively. The sharp increase in deaths involving synthetic opioids, other than methadone, in 2014 coincided with law enforcement reports of increased availability of illicitly manufactured fentanyl, a synthetic opioid; however, illicitly manufactured fentanyl cannot be distinguished from prescription fentanyl in death certificate data. These findings indicate that the opioid overdose epidemic is worsening. There is a need for continued action to prevent opioid

  1. Profile of dependence symptoms among extramedical opioid analgesic users.

    PubMed

    Martins, Silvia S; Ghandour, Lilian A; Chilcoat, Howard D

    2007-10-01

    Little is known about the extent of problems due to extramedical opioid analgesic use ('analgesic misuse') in the US general population. This study explores the distribution of the seven DSM-IV-defined past-year dependence symptoms in a total household sample of 7,810 past-year extramedical opioid analgesic users using the 2002-2003 National Survey on Drug Use and Health (NSDUH). We tested for differences in opioid analgesic dependence symptom profiles across four subgroups of opioid analgesic users, different levels of deviant behaviors, and presence/absence of serious mental health problems quantified by the Composite International Diagnostic Interview Short Form (CIDI-sf). Generalized Estimated Equations (GEE) models were used to analyze the data. The most common opioid analgesic dependence symptoms were 'tolerance' (17.0%) and 'salience' (13.3%). Opioid analgesic dependence symptom profiles were 'parallel' across the groups of past-year opioid analgesic users, across deviant behavior groups and across presence/absence of serious mental health problems. Extramedical use of opioid analgesics associated with prescription drug use, having high levels of deviant behaviors, and having serious mental health problems were more strongly associated with endorsement of opioid analgesics dependence symptoms.

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

    PubMed

    Todadze, Kh; Mosia, S

    2016-05-01

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

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

    PubMed

    Todadze, Kh; Mosia, S

    2016-05-01

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

  4. Peripheral Sensitization Increases Opioid Receptor Expression and Activation by Crotalphine in Rats

    PubMed Central

    Zambelli, Vanessa Olzon; Fernandes, Ana Carolina de Oliveira; Gutierrez, Vanessa Pacciari; Ferreira, Julio Cesar Batista; Parada, Carlos Amilcar; Mochly-Rosen, Daria; Cury, Yara

    2014-01-01

    Inflammation enhances the peripheral analgesic efficacy of opioid drugs, but the mechanisms involved in this phenomenon have not been fully elucidated. Crotalphine (CRP), a peptide that was first isolated from South American rattlesnake C.d. terrificus venom, induces a potent and long-lasting anti-nociceptive effect that is mediated by the activation of peripheral opioid receptors. Because the high efficacy of CRP is only observed in the presence of inflammation, we aimed to elucidate the mechanisms involved in the CRP anti-nociceptive effect induced by inflammation. Using real-time RT-PCR, western blot analysis and ELISA assays, we demonstrate that the intraplantar injection of prostaglandin E2 (PGE2) increases the mRNA and protein levels of the µ- and κ-opioid receptors in the dorsal root ganglia (DRG) and paw tissue of rats within 3 h of the injection. Using conformation state-sensitive antibodies that recognize activated opioid receptors, we show that PGE2, alone does not increase the activation of these opioid receptors but that in the presence of PGE2, the activation of specific opioid receptors by CRP and selective µ- and κ-opioid receptor agonists (positive controls) increases. Furthermore, PGE2 down-regulated the expression and activation of the δ-opioid receptor. CRP increased the level of activated mitogen-activated protein kinases in cultured DRG neurons, and this increase was dependent on the activation of protein kinase Cζ. This CRP effect was much more prominent when the cells were pretreated with PGE2. These results indicate that the expression and activation of peripheral opioid receptors by opioid-like drugs can be up- or down-regulated in the presence of an acute injury and that acute tissue injury enhances the efficacy of peripheral opioids. PMID:24594607

  5. Peripheral sensitization increases opioid receptor expression and activation by crotalphine in rats.

    PubMed

    Zambelli, Vanessa Olzon; Fernandes, Ana Carolina de Oliveira; Gutierrez, Vanessa Pacciari; Ferreira, Julio Cesar Batista; Parada, Carlos Amilcar; Mochly-Rosen, Daria; Cury, Yara

    2014-01-01

    Inflammation enhances the peripheral analgesic efficacy of opioid drugs, but the mechanisms involved in this phenomenon have not been fully elucidated. Crotalphine (CRP), a peptide that was first isolated from South American rattlesnake C.d. terrificus venom, induces a potent and long-lasting anti-nociceptive effect that is mediated by the activation of peripheral opioid receptors. Because the high efficacy of CRP is only observed in the presence of inflammation, we aimed to elucidate the mechanisms involved in the CRP anti-nociceptive effect induced by inflammation. Using real-time RT-PCR, western blot analysis and ELISA assays, we demonstrate that the intraplantar injection of prostaglandin E2 (PGE2) increases the mRNA and protein levels of the µ- and κ-opioid receptors in the dorsal root ganglia (DRG) and paw tissue of rats within 3 h of the injection. Using conformation state-sensitive antibodies that recognize activated opioid receptors, we show that PGE2, alone does not increase the activation of these opioid receptors but that in the presence of PGE2, the activation of specific opioid receptors by CRP and selective µ- and κ-opioid receptor agonists (positive controls) increases. Furthermore, PGE2 down-regulated the expression and activation of the δ-opioid receptor. CRP increased the level of activated mitogen-activated protein kinases in cultured DRG neurons, and this increase was dependent on the activation of protein kinase Cζ. This CRP effect was much more prominent when the cells were pretreated with PGE2. These results indicate that the expression and activation of peripheral opioid receptors by opioid-like drugs can be up- or down-regulated in the presence of an acute injury and that acute tissue injury enhances the efficacy of peripheral opioids.

  6. Current and potential pharmacological treatment options for maintenance therapy in opioid-dependent individuals.

    PubMed

    Tetrault, Jeanette M; Fiellin, David A

    2012-01-22

    Opioid dependence, manifesting as addiction to heroin and pharmaceutical opioids is increasing. Internationally, there are an estimated 15.6 million illicit opioid users. The global economic burden of opioid dependence is profound both in terms of HIV and hepatitis C virus transmission, direct healthcare costs, and indirectly through criminal activity, absenteeism and lost productivity. Opioid agonist medications, such as methadone and buprenorphine, that stabilize neuronal systems and provide narcotic blockade are the most effective treatments. Prolonged provision of these medications, defined as maintenance treatment, typically produces improved outcomes when compared with short-duration tapers and withdrawal. The benefits of opioid agonist maintenance include decreased illicit drug use, improved retention in treatment, decreased HIV risk behaviours and decreased criminal behaviour. While regulations vary by country, these medications are becoming increasingly available internationally, especially in regions experiencing rapid transmission of HIV due to injection drug use. In this review, we describe the rationale for maintenance treatment of opioid dependence, discuss emerging uses of opioid antagonists such as naltrexone and sustained-release formulations of naltrexone and buprenorphine, and provide a description of the experimental therapies.

  7. Evidence of CNIH3 involvement in opioid dependence.

    PubMed

    Nelson, E C; Agrawal, A; Heath, A C; Bogdan, R; Sherva, R; Zhang, B; Al-Hasani, R; Bruchas, M R; Chou, Y-L; Demers, C H; Carey, C E; Conley, E D; Fakira, A K; Farrer, L A; Goate, A; Gordon, S; Henders, A K; Hesselbrock, V; Kapoor, M; Lynskey, M T; Madden, P A F; Moron, J A; Rice, J P; Saccone, N L; Schwab, S G; Shand, F L; Todorov, A A; Wallace, L; Wang, T; Wray, N R; Zhou, X; Degenhardt, L; Martin, N G; Hariri, A R; Kranzler, H R; Gelernter, J; Bierut, L J; Clark, D J; Montgomery, G W

    2016-05-01

    Opioid dependence, a severe addictive disorder and major societal problem, has been demonstrated to be moderately heritable. We conducted a genome-wide association study in Comorbidity and Trauma Study data comparing opioid-dependent daily injectors (N=1167) with opioid misusers who never progressed to daily injection (N=161). The strongest associations, observed for CNIH3 single-nucleotide polymorphisms (SNPs), were confirmed in two independent samples, the Yale-Penn genetic studies of opioid, cocaine and alcohol dependence and the Study of Addiction: Genetics and Environment, which both contain non-dependent opioid misusers and opioid-dependent individuals. Meta-analyses found five genome-wide significant CNIH3 SNPs. The A allele of rs10799590, the most highly associated SNP, was robustly protective (P=4.30E-9; odds ratio 0.64 (95% confidence interval 0.55-0.74)). Epigenetic annotation predicts that this SNP is functional in fetal brain. Neuroimaging data from the Duke Neurogenetics Study (N=312) provide evidence of this SNP's in vivo functionality; rs10799590 A allele carriers displayed significantly greater right amygdala habituation to threat-related facial expressions, a phenotype associated with resilience to psychopathology. Computational genetic analyses of physical dependence on morphine across 23 mouse strains yielded significant correlations for haplotypes in CNIH3 and functionally related genes. These convergent findings support CNIH3 involvement in the pathophysiology of opioid dependence, complementing prior studies implicating the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate system. PMID:26239289

  8. Increased mesolimbic cue-reactivity in carriers of the mu-opioid-receptor gene OPRM1 A118G polymorphism predicts drinking outcome: a functional imaging study in alcohol dependent subjects.

    PubMed

    Bach, Patrick; Vollsta Dt-Klein, Sabine; Kirsch, Martina; Hoffmann, Sabine; Jorde, Anne; Frank, Josef; Charlet, Katrin; Beck, Anne; Heinz, Andreas; Walter, Henrik; Sommer, Wolfgang H; Spanagel, Rainer; Rietschel, Marcella; Kiefer, Falk

    2015-08-01

    The endogenous opioid system is involved in the pathophysiology of alcohol-use disorders. Genetic variants of the opioid system alter neural and behavioral responses to alcohol. In particular, a single nucleotide polymorphism rs1799971 (A118G) in the mu-opioid receptor gene (OPRM1) is suggested to modulate alcohol-related phenotypes and neural response in the mesocorticolimbic dopaminergic system. Little is known about the clinical implications of these changes. The current study investigated the relationship of genotype effects on subjective and neural responses to alcohol cues and relapse in a sample of abstinent alcohol-dependent patients. Functional magnetic resonance imaging (fMRI) was used to investigate alcohol cue-reactivity and drinking outcome of 81 abstinent alcohol-dependent patients. G-allele carriers displayed increased fMRI cue-reactivity in the left dorsal striatum and bilateral insulae. Neural responses to alcohol cues in these brain regions correlated positively with subjective craving for alcohol and positive expectations of alcohol׳s effects. Moreover, alcohol cue-reactivity in the left dorsal striatum predicted time to first severe relapse. Current results show that alcohol-dependent G-allele carriers׳ increased cue-reactivity is associated with an increased relapse risk. This suggests that genotype effects on cue-reactivity might link the OPRM1 A118G risk allele with an increased relapse risk that was reported in earlier studies. From a clinical perspective, risk-allele carriers might benefit from treatments, such as neuro-feedback or extinction-based therapy that are suggested to reduce mesolimbic reactivity.

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

    PubMed

    Krantz, Mori J; Mehler, Philip S

    2004-02-01

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

  10. Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS

    PubMed Central

    Marrone, Gina F.; Grinnell, Steven G.; Lu, Zhigang; Rossi, Grace C.; Le Rouzic, Valerie; Xu, Jin; Majumdar, Susruta; Pan, Ying-Xian; Pasternak, Gavril W.

    2016-01-01

    The clinical management of severe pain depends heavily on opioids acting through mu opioid receptors encoded by the Oprm1 gene, which undergoes extensive alternative splicing. In addition to generating a series of prototypic seven transmembrane domain (7TM) G protein-coupled receptors (GPCRs), Oprm1 also produces a set of truncated splice variants containing only six transmembrane domains (6TM) through which selected opioids such as IBNtxA (3′-iodobenzoyl-6β-naltrexamide) mediate a potent analgesia without many undesirable effects. Although morphine analgesia is independent of these 6TM mu receptor isoforms, we now show that the selective loss of the 6TM variants in a knockout model eliminates the analgesic actions of delta and kappa opioids and of α2-adrenergic compounds, but not cannabinoid, neurotensin, or muscarinic drugs. These observations were confirmed by using antisense paradigms. Despite their role in analgesia, loss of the 6TM variants were not involved with delta opioid-induced seizure activity, aversion to the kappa drug U50,488H, or α2-mediated hypolocomotion. These observations support the existence of parallel opioid and nonopioid pain modulatory systems and highlight the ability to dissociate unwanted delta, kappa1, and α2 actions from analgesia. PMID:26976581

  11. Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS.

    PubMed

    Marrone, Gina F; Grinnell, Steven G; Lu, Zhigang; Rossi, Grace C; Le Rouzic, Valerie; Xu, Jin; Majumdar, Susruta; Pan, Ying-Xian; Pasternak, Gavril W

    2016-03-29

    The clinical management of severe pain depends heavily on opioids acting through mu opioid receptors encoded by the Oprm1 gene, which undergoes extensive alternative splicing. In addition to generating a series of prototypic seven transmembrane domain (7TM) G protein-coupled receptors (GPCRs), Oprm1 also produces a set of truncated splice variants containing only six transmembrane domains (6TM) through which selected opioids such as IBNtxA (3'-iodobenzoyl-6β-naltrexamide) mediate a potent analgesia without many undesirable effects. Although morphine analgesia is independent of these 6TM mu receptor isoforms, we now show that the selective loss of the 6TM variants in a knockout model eliminates the analgesic actions of delta and kappa opioids and of α2-adrenergic compounds, but not cannabinoid, neurotensin, or muscarinic drugs. These observations were confirmed by using antisense paradigms. Despite their role in analgesia, loss of the 6TM variants were not involved with delta opioid-induced seizure activity, aversion to the kappa drug U50, 488H, or α2-mediated hypolocomotion. These observations support the existence of parallel opioid and nonopioid pain modulatory systems and highlight the ability to dissociate unwanted delta, kappa1, and α2 actions from analgesia. PMID:26976581

  12. Implant Proves Effective At Combating Opioid Dependence

    MedlinePlus

    ... a film dissolved in the mouth. Buprenorphine provides effects that are similar to, but weaker than, opioids ... and Mental Health Services Administration (SAMHSA). But those effects level off at moderate doses, lowering the risk ...

  13. Implementation of a collaborative care management program with buprenorphine in primary care: A comparison between opioid-dependent patients and chronic pain patients using opioids non-medically

    PubMed Central

    Suzuki, Joji; Matthews, Michele L.; Brick, David; Nguyen, Minh-Thuy; Jamison, Robert N.; Ellner, Andrew L.; Tishler, Lori W.; Weiss, Roger D.

    2014-01-01

    Objective To implement a collaborative care management program with buprenorphine in a primary care clinic. Design Prospective observational study. Setting A busy urban academic primary care clinic affiliated with a tertiary care hospital. Participants Opioid dependent patients or chronic pain patients using opioids non-medically were recruited for the study. A total of 45 participants enrolled. Interventions Patients were treated with buprenorphine and managed by a supervising psychiatrist, pharmacist care manager and health coaches. The care manager conducted buprenorphine inductions and all follow-ups visits. Health coaches offered telephonic support. The psychiatrist supervised both the care manager and health coaches. Main outcome measures Primary outcomes were treatment retention at 6 months, and change in the proportion of aberrant toxicology results and opioid craving scores from baseline to 6 months. After data collection, clinical outcomes were compared between opioid dependent patients and chronic pain patients using opioids non-medically. Overall, 55.0% (25/45) of participants remained in treatment at 6 months. PCPs’ attitudes about opioid dependence treatment were surveyed at baseline and at 18-months. Results Forty-three patients (95.6%) accepted treatment and 25 (55.0%) remained in treatment at 6 months. The proportion of aberrant urine toxicology results decreased significantly from baseline to 6 months (p<0.01). Craving scores significantly decreased from baseline to 6 months (p<0.01). Opioid dependent patients, as opposed to chronic pain patients using opioids non-medically, were significantly more likely to complete 6 months of treatment (p<0.05). PCPs’ confidence in treating opioid dependence in primary care increased significantly from baseline to 18-months post-implementation (p<0.01). Conclusion Collaborative care management for opioid dependence with buprenorphine may be feasible in a primary care clinic. More research is needed to

  14. Review of perioperative pain management of opioid-dependent patients.

    PubMed

    Vadivelu, Nalini; Mitra, Sukanya; Kai, Alice M; Kodumudi, Gopal; Gritsenko, Karina

    2016-01-01

    Opioid dependence can occur due to prescription opioid use, recreational opioid use, or as a result of opioid use for the treatment of drug addiction. Pain control in these patients is truly a challenge. It is important to understand the patient's condition such as the phenomenon of drug dependence, drug addiction, and pseudoaddiction to provide effective analgesia. This may be accomplished using appropriate multimodal therapies and by treatment of coexisting diseases such as anxiety. The goal is to provide effective analgesia, prevent cognitive and emotional problems, and produce a positive postoperative rehabilitation process. Multimodal options include pharmacological and nonpharmacological approaches, psychological support, and interventional pain procedures, all focused toward providing optimal pain control while preventing undertreatment, withdrawal symptoms, and other complications. PMID:27575830

  15. Treatment of Opioid Dependent Pregnant Women: Clinical and Research Issues

    PubMed Central

    Jones, H.E.; Martin, P.R.; Heil, S.H.; Stine, S.M.; Kaltenbach, K.; Selby, P.; Coyle, M.G.; O’Grady, K.E.; Arria, A.M.; Fischer, G.

    2008-01-01

    This paper addresses common questions that clinicians face when treating pregnant women with opioid dependence. Guidance is provided to aid clinical decision-making, based on both research evidence and the collective clinical experience of the authors which include investigators in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) project. MOTHER is a double-blind, double-dummy, flexible–dosing, parallel-group clinical trial examining the comparative safety and efficacy of methadone and buprenorphine for the opioid dependence treatment among pregnant women and their neonates. The paper begins with a discussion of appropriate assessment during pregnancy, and then addresses clinical management stages, including maintenance medication selection, induction and stabilization, opioid agonist medication management before, during and after delivery, pain management, breast-feeding, and transfer to aftercare. Lastly, other important clinical issues including managing co-occurring psychiatric disorders and medication interactions are discussed. PMID:18248941

  16. Sexual Dysfunction in Patients with Alcohol and Opioid Dependence

    PubMed Central

    Grover, Sandeep; Mattoo, Surendra K.; Pendharkar, Shreyas; Kandappan, Venkatesh

    2014-01-01

    There are limited numbers of studies which have evaluated the sexual dysfunction (SD) in patients with alcohol and opioids dependence. This article reviews the existing literature. Electronic searches were carried out using the PubMed, Google Scholar, and ScienceDirect to locate the relevant literature. Subjects addicted to heroin or on methadone maintenance treatment (MMT) or buprenorphine maintenance treatment (BMT) show higher rates of SD in comparison to the general population. SD rates have ranged 34-85% for heroin addicts, 14-81% for MMT, 36-83% for BMT, and 90% for naltrexone maintenance. The rates of SD in alcohol-dependent population have ranged 40-95.2%, with rates being consistently much higher in alcohol-dependent population than in the healthy controls or social drinkers. The common SDs reported have been erectile dysfunction followed by premature ejaculation, retarded ejaculation and decreased sexual desire among men, and dyspareunia and vaginal dryness among women. This review suggests that long-term use of alcohol and opioids are associated with SD in almost all domains of sexual functioning. There is a need to increase the awareness of clinicians about this association as many times SD in patients with substance abuse lead to poor treatment compliance and relapse. Further, there is a need to carry out more number of studies to understand the relationship in a better way. PMID:25336765

  17. Alterations in brain structure and functional connectivity in prescription opioid-dependent patients.

    PubMed

    Upadhyay, Jaymin; Maleki, Nasim; Potter, Jennifer; Elman, Igor; Rudrauf, David; Knudsen, Jaime; Wallin, Diana; Pendse, Gautam; McDonald, Leah; Griffin, Margaret; Anderson, Julie; Nutile, Lauren; Renshaw, Perry; Weiss, Roger; Becerra, Lino; Borsook, David

    2010-07-01

    A dramatic increase in the use and dependence of prescription opioids has occurred within the last 10 years. The consequences of long-term prescription opioid use and dependence on the brain are largely unknown, and any speculation is inferred from heroin and methadone studies. Thus, no data have directly demonstrated the effects of prescription opioid use on brain structure and function in humans. To pursue this issue, we used structural magnetic resonance imaging, diffusion tensor imaging and resting-state functional magnetic resonance imaging in a highly enriched group of prescription opioid-dependent patients [(n=10); from a larger study on prescription opioid dependent patients (n=133)] and matched healthy individuals (n=10) to characterize possible brain alterations that may be caused by long-term prescription opioid use. Criteria for patient selection included: (i) no dependence on alcohol or other drugs; (ii) no comorbid psychiatric or neurological disease; and (iii) no medical conditions, including pain. In comparison to control subjects, individuals with opioid dependence displayed bilateral volumetric loss in the amygdala. Prescription opioid-dependent subjects had significantly decreased anisotropy in axonal pathways specific to the amygdala (i.e. stria terminalis, ventral amygdalofugal pathway and uncinate fasciculus) as well as the internal and external capsules. In the patient group, significant decreases in functional connectivity were observed for seed regions that included the anterior insula, nucleus accumbens and amygdala subdivisions. Correlation analyses revealed that longer duration of prescription opioid exposure was associated with greater changes in functional connectivity. Finally, changes in amygdala functional connectivity were observed to have a significant dependence on amygdala volume and white matter anisotropy of efferent and afferent pathways of the amygdala. These findings suggest that prescription opioid dependence is associated

  18. The early maladaptive schemas of an opioid-dependent sample of treatment seeking young adults: a descriptive investigation.

    PubMed

    Shorey, Ryan C; Stuart, Gregory L; Anderson, Scott

    2012-04-01

    Opioid dependence is an increasingly prevalent problem throughout the world, particularly for young adults (e.g., ages 17-25 years). Opioid dependence is associated with a wealth of negative consequences and is often a chronic, relapsing condition. Research on factors that may contribute to the etiology of opioid dependence could result in improved treatment outcomes. Using preexisting patient records, the current study examined early maladaptive schemas among young adult opioid-dependent residential treatment patients (N = 169), as it is theorized that early maladaptive schemas may underlie or maintain substance use. Results showed that all 18 early maladaptive schemas were endorsed at various levels among male and female patients, with insufficient self-control being the most prevalent schema. In addition, females scored significantly higher than males on 11 of the 18 schemas. Findings from the current study are discussed in terms of future research and implications for the treatment of opioid dependence.

  19. Is residential treatment effective for opioid use disorders? A longitudinal comparison of treatment outcomes among opioid dependent, opioid misusing, and non-opioid using emerging adults with substance use disorder

    PubMed Central

    Schuman-Olivier, Zev; Greene, M. Claire; Bergman, Brandon G.; Kelly, John F.

    2014-01-01

    Background Opioid misuse and dependence rates among emerging adults have increased substantially. While office-based opioid treatments (e.g., buprenorphine/naloxone) have shown overall efficacy, discontinuation rates among emerging adults are high. Abstinence-based residential treatment may serve as a viable alternative, but has seldom been investigated in this age group. Methods Emerging adults attending 12-step-oriented residential treatment (N=292; 18–24yrs, 74% Male, 95% White) were classified into opioid dependent (OD; 25%), opioid misuse (OM; 20%), and no opiate use (NO; 55%) groups. Paired t-tests and ANOVAs tested baseline differences and whether groups differed in their during-treatment response. Longitudinal multilevel models tested whether groups differed on substance use outcomes and treatment utilization during the year following the index treatment episode. Results Despite a more severe clinical profile at baseline among OD, all groups experienced similar during-treatment increases on therapeutic targets (e.g., abstinence self-efficacy), while OD showed a greater decline in psychiatric symptoms. During follow-up relative to OM, both NO and OD had significantly greater Percent Days Abstinent, and significantly less cannabis use. OD attended significantly more outpatient treatment sessions than OM or NO; 29% of OD was completely abstinent at 12-month follow-up. Conclusions Findings here suggest residential treatment may be helpful for emerging adults with opioid dependence. This benefit may be less prominent, though, among non-dependent opioid misusers. Randomized trials are needed to compare more directly the relative benefits of outpatient agonist-based treatment to abstinence-based, residential care in this vulnerable age-group, and to examine the feasibility of an integrated model. PMID:25267606

  20. 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.

  1. Community-wide measures of wellness in a remote First Nations community experiencing opioid dependence

    PubMed Central

    Kanate, Dinah; Folk, David; Cirone, Sharon; Gordon, Janet; Kirlew, Mike; Veale, Terri; Bocking, Natalie; Rea, Sara; Kelly, Len

    2015-01-01

    Abstract Objective To document the development of unique opioid-dependence treatment in remote communities that combines First Nations healing strategies and substitution therapy with buprenorphine-naloxone. Design Quantitative measurements of community wellness and response to community-based opioid-dependence treatment. Setting Remote First Nations community in northwestern Ontario. Participants A total of 140 self-referred opioid-dependent community members. Intervention Community-developed program of First Nations healing, addiction treatment, and substitution therapy. Main outcome measures Community-wide measures of wellness: number of criminal charges, addiction-related medical evacuations, child protection agency cases, school attendance, and attendance at community events. Results The age-adjusted adult rate of opioid-dependence treatment was 41%. One year after the development of the in-community healing and substitution therapy program for opioid dependence, police criminal charges had fallen by 61.1%, child protection cases had fallen by 58.3%, school attendance had increased by 33.3%, and seasonal influenza immunizations had dramatically gone up by 350.0%. Attendance at community events is now robust, and sales at the local general store have gone up almost 20%. Conclusion Community-wide wellness measures have undergone dramatic public health changes since the development of a First Nations healing program involving opioid substitution therapy with buprenorphine-naloxone. Funding for such programs is ad hoc and temporary, and this threatens the survival of the described program and other such programs developing in this region, which has been strongly affected by an opioid-dependence epidemic. PMID:25821874

  2. Training HIV Physicians to Prescribe Buprenorphine for Opioid Dependence

    ERIC Educational Resources Information Center

    Sullivan, Lynn E.; Tetrault, Jeanette; Bangalore, Deepa; Fiellin, David A.

    2006-01-01

    Few HIV physicians are trained to provide buprenorphine treatment. We conducted a cross-sectional survey to assess the impact of an eight-hour course on the treatment of opioid dependence on HIV physicians' preparedness to prescribe buprenorphine. One hundred thirteen of 257 trained physicians (44%) provided HIV care. Post-course, the majority of…

  3. Comorbid substance use diagnoses and partner violence among offenders receiving pharmacotherapy for opioid dependence.

    PubMed

    Crane, Cory A; Schlauch, Robert C; Devine, Susan; Easton, Caroline J

    2016-01-01

    While previous studies find mixed evidence of an association between opioid use and intimate partner violence perpetration among community samples, initial evidence has detected increased rates of partner violence among individuals receiving pharmacological intervention for opioid dependence. The current study evaluated the role of current comorbid substance use diagnoses, a robust risk factor for violent behavior, on the likelihood of perpetrating partner violence among a high risk sample of offenders receiving pharmacological intervention for opioid dependence. The authors analyzed self-report data provided by 81 (55 male) opioid dependent offenders during a court-ordered substance use interview. Approximately one-third of the sample evidenced the recent use of intimate partner violence. Findings indicated that cocaine and benzodiazepine use were independently associated with an increased likelihood of reporting physical partner violence. Alcohol and cannabis use were not associated with partner violence. The current results offer further support for the ongoing need to conduct routine partner violence screenings among substance involved offenders and highlight the importance of developing individualized treatment plans that address comorbid substance use and partner-violent behaviors among individuals in treatment for opioid dependence. PMID:26901289

  4. The Need for Psychosocial Interventions to Facilitate the Transition to Extended-Release Naltrexone (XR-NTX) Treatment for Opioid Dependence: A Concise Review of the Literature

    PubMed Central

    Ramsey, Susan E.; Rounsaville, Dan; Hoskinson, Randall; Park, Tae Woo; Ames, Evan G.; Neirinckx, Victor D.; Friedmann, Peter

    2016-01-01

    Given the increase of opioid dependence and opioid-related morbidity and mortality, improving treatment options for individuals with opioid dependence warrants increased attention. This article provides a concise review of work in this area. Remission from opioid dependence can be very difficult to sustain, particularly in the absence of opioid replacement or opioid antagonist therapy. For those who wish to transition from opioid use or opioid replacement therapy to opioid antagonist therapy, a significant challenge can be the period of withdrawal symptoms that must be endured prior to the initiation of opioid antagonist therapy. Studies that have incorporated psychosocial interventions into detoxification protocols have found that they can result in improved treatment outcomes. Interventions based on Acceptance and Commitment Therapy have shown promise in the treatment of clinical disorders that present with symptoms similar to those of opioid withdrawal and have been found to positively impact outcomes among those tapering from methadone. However, the use of an Acceptance and Commitment Therapy-based intervention has yet to be studied among opioid-dependent patients transitioning to XR-NTX, and its value to those transitioning to XR-NTX is currently unknown. PMID:27512336

  5. The Need for Psychosocial Interventions to Facilitate the Transition to Extended-Release Naltrexone (XR-NTX) Treatment for Opioid Dependence: A Concise Review of the Literature.

    PubMed

    Ramsey, Susan E; Rounsaville, Dan; Hoskinson, Randall; Park, Tae Woo; Ames, Evan G; Neirinckx, Victor D; Friedmann, Peter

    2016-01-01

    Given the increase of opioid dependence and opioid-related morbidity and mortality, improving treatment options for individuals with opioid dependence warrants increased attention. This article provides a concise review of work in this area. Remission from opioid dependence can be very difficult to sustain, particularly in the absence of opioid replacement or opioid antagonist therapy. For those who wish to transition from opioid use or opioid replacement therapy to opioid antagonist therapy, a significant challenge can be the period of withdrawal symptoms that must be endured prior to the initiation of opioid antagonist therapy. Studies that have incorporated psychosocial interventions into detoxification protocols have found that they can result in improved treatment outcomes. Interventions based on Acceptance and Commitment Therapy have shown promise in the treatment of clinical disorders that present with symptoms similar to those of opioid withdrawal and have been found to positively impact outcomes among those tapering from methadone. However, the use of an Acceptance and Commitment Therapy-based intervention has yet to be studied among opioid-dependent patients transitioning to XR-NTX, and its value to those transitioning to XR-NTX is currently unknown. PMID:27512336

  6. Determinants of Fentanyl and other Potent μ Opioid Agonist Misuse in Opioid-Dependent Individuals

    PubMed Central

    Cicero, Theodore J.; Ellis, Matthew S.; Paradis, Alethea; Ortbal, Zachary

    2010-01-01

    Purpose Based on preclinical and clinical abuse liability assessments, fentanyl and other potent μ opioid agonists (e.g. hydromorphone and morphine) should be the most misused opioids if accessibility in the real world were not an issue. Since the latter is seldom true, we postulated that there would be a significant mismatch between actual and predicted rates of misuse. Methods We recruited 1,818 prescription-opioid dependent patients entering drug treatment programs to complete an anonymous survey, covering drug use and health related issues. Results Hydrocodone and oxycodone products were the drugs of choice in 75% of patients, whereas potent μ opioid agonists (fentanyl, hydromorphone and morphine), with the greatest predicted abuse potential, were very rarely chosen (<5% each). Most unexpectedly, the rank order of the actual drug of choice and the preferred drug in an ideal world were highly correlated. The reason most commonly given for the failure to endorse fentanyl, for example, as an actual or preferred drug, was fear of toxicity and overdose. We found few differences in drug use patterns between a subset of high-risk, impaired health care professionals (N=196) and all other patients other than source of drug, (forged prescriptions and doctors more common and dealers much less common in the HC sample). Conclusions These results indicate that it should not be assumed- particularly for new drug formulations- that a high potential for abuse will result in actual abuse; and, most importantly, that the hesitancy to use potent opioids because of fears of abuse may be misguided. PMID:20597128

  7. Chronic opioid use is associated with increased DNA methylation correlating with increased clinical pain.

    PubMed

    Doehring, Alexandra; Oertel, Bruno Georg; Sittl, Reinhard; Lötsch, Jörn

    2013-01-01

    Environmentally caused changes in chromosomes that do not alter the DNA sequence but cause phenotypic changes by altering gene transcription are summarized as epigenetics. A major epigenetic mechanism is methylation or demethylation at CpG-rich DNA islands. DNA methylation triggered by drugs has largely unexplored therapeutic consequences. Here we report increased methylation at a CpG rich island in the OPRM1 gene coding for μ-opioid receptors and at a global methylation site (LINE-1) in leukocytes of methadone-substituted former opiate addicts compared with matched healthy controls. Higher DNA methylation associated with chronic opioid exposure was reproduced in an independent cohort of opioid-treated as compared to non-opioid-treated pain patients. This suggests that opioids may stimulate DNA methylation. The OPRM1 methylation had no immediate effect on μ-opioid receptor transcription and was not associated with opioid dosing requirements. However, the global DNA methylation at LINE-1 was significantly correlated with increased chronic pain. This suggests inhibitory effects on the transcription of still unspecified nocifensive gene products. It further implies that opioids may be causally associated with increased genome-wide DNA methylation, although currently there is no direct evidence of this. This has phenotypic consequences for pain and may provide a new, epigenetics-associated mechanism of opioid-induced hyperalgesia. The results indicate a potential influence of opioid analgesics on the patients' epigenome. They emphasize the need for reliable and cost-effective screening tools and may imply that high-throughput screening for lead compounds in artificial expression systems may not provide the best tools for identifying new pain medications.

  8. Medicaid coverage of medications to treat alcohol and opioid dependence.

    PubMed

    Mark, Tami L; Lubran, Robert; McCance-Katz, Elinore F; Chalk, Mady; Richardson, John

    2015-08-01

    Substance use disorders affect 12% of Medicaid beneficiaries. The prescription drug epidemic and growing need for treatment of alcohol and opioid dependence have refocused states' attention on their provision of substance use disorder treatment services, including medications. This study characterized how Medicaid programs cover these treatment medications. Data were from 2013 Medicaid pharmacy documents, 2011 and 2012 Medicaid state drug utilization records, and a 2013 American Society of Addiction Medicine survey. Results showed that only 13 state Medicaid programs included all medications approved for alcohol and opioid dependence on their preferred drug lists. The most commonly excluded were extended-release naltrexone (19 programs), acamprosate (19 programs), and methadone (20 programs). For combined buprenorphine-naloxone, 48 Medicaid programs required prior authorization, and 11 programs used 1- to 3-year lifetime treatment limits. Given the chronic nature of substance use disorders and the overwhelming evidence supporting ongoing coverage for many of these medications, states may want to reexamine substance use disorder benefits.

  9. Hepatitis Infection in the Treatment of Opioid Dependence and Abuse

    PubMed Central

    Kresina, Thomas F; Sylvestre, Diana; Seeff, Leonard; Litwin, Alain H; Hoffman, Kenneth; Lubran, Robert; Clark, H Westley

    2008-01-01

    Many new and existing cases of viral hepatitis infections are related to injection drug use. Transmission of these infections can result directly from the use of injection equipment that is contaminated with blood containing the hepatitis B or C virus or through sexual contact with an infected individual. In the latter case, drug use can indirectly contribute to hepatitis transmission through the dis-inhibited at-risk behavior, that is, unprotected sex with an infected partner. Individuals who inject drugs are at-risk for infection from different hepatitis viruses, hepatitis A, B, or C. Those with chronic hepatitis B virus infection also face additional risk should they become co-infected with hepatitis D virus. Protection from the transmission of hepatitis viruses A and B is best achieved by vaccination. For those with a history of or who currently inject drugs, the medical management of viral hepatitis infection comprising screening, testing, counseling and providing care and treatment is evolving. Components of the medical management of hepatitis infection, for persons considering, initiating, or receiving pharmacologic therapy for opioid addiction include: testing for hepatitis B and C infections; education and counseling regarding at-risk behavior and hepatitis transmission, acute and chronic hepatitis infection, liver disease and its care and treatment; vaccination against hepatitis A and B infection; and integrative primary care as part of the comprehensive treatment approach for recovery from opioid abuse and dependence. In addition, participation in a peer support group as part of integrated medical care enhances treatment outcomes. Liver disease is highly prevalent in patient populations seeking recovery from opioid addiction or who are currently receiving pharmacotherapy for opioid addiction. Pharmacotherapy for opioid addiction is not a contraindication to evaluation, care, or treatment of liver disease due to hepatitis virus infection. Successful

  10. Arguments in favour of compulsory treatment of opioid dependence

    PubMed Central

    2013-01-01

    Abstract Twelve agencies of the United Nations, including the World Health Organization, have issued a joint statement that calls on Member States to replace the compulsory detention of people who use opioids in treatment centres with voluntary, evidence-informed and rights-based health and social services. The arguments in favour of this position fall into three broad categories: Compulsory treatment centres infringe on an individual’s liberty, they put human beings at risk of harm, and evidence of their effectiveness against opioid dependence has not been generated. The United Nations statement underscores that although countries apply different criteria for sending individuals to compulsory treatment centres, detention often takes place without due process, legal safeguards or judicial review. This clearly violates internationally recognized human rights standards. Furthermore, people who are committed to these centres are often exposed to physical and sexual violence, forced labour and sub-standard living conditions. They are often denied health care, despite their heightened vulnerability to HIV infection and tuberculosis. Finally, there is no evidence, according to the statement, that these centres offer an environment that is conducive to recovery from opioid dependence or to the rehabilitation of commercial sex workers or of children who have suffered sexual exploitation, abuse or lack of care and protection. The author of this paper sets forth several arguments that counter the position taken by the United Nations and argues in favour of compulsory treatment within a broader harm reduction strategy aimed at protecting society as well as the individual concerned. PMID:23554527

  11. Arguments in favour of compulsory treatment of opioid dependence.

    PubMed

    Wu, Zunyou

    2013-02-01

    Twelve agencies of the United Nations, including the World Health Organization, have issued a joint statement that calls on Member States to replace the compulsory detention of people who use opioids in treatment centres with voluntary, evidence-informed and rights-based health and social services. The arguments in favour of this position fall into three broad categories: Compulsory treatment centres infringe on an individual's liberty, they put human beings at risk of harm, and evidence of their effectiveness against opioid dependence has not been generated. The United Nations statement underscores that although countries apply different criteria for sending individuals to compulsory treatment centres, detention often takes place without due process, legal safeguards or judicial review. This clearly violates internationally recognized human rights standards. Furthermore, people who are committed to these centres are often exposed to physical and sexual violence, forced labour and sub-standard living conditions. They are often denied health care, despite their heightened vulnerability to HIV infection and tuberculosis. Finally, there is no evidence, according to the statement, that these centres offer an environment that is conducive to recovery from opioid dependence or to the rehabilitation of commercial sex workers or of children who have suffered sexual exploitation, abuse or lack of care and protection. The author of this paper sets forth several arguments that counter the position taken by the United Nations and argues in favour of compulsory treatment within a broader harm reduction strategy aimed at protecting society as well as the individual concerned.

  12. Cannabinoid and opioid interactions: implications for opiate dependence and withdrawal

    PubMed Central

    Scavone, J.L.; Sterling, R.C.; Van Bockstaele, E.J.

    2013-01-01

    Withdrawal from opiates, such as heroin or oral narcotics, is characterized by a host of aversive physical and emotional symptoms. High rates of relapse and limited treatment success rates for opiate addiction have prompted a search for new approaches. For many opiate addicts, achieving abstinence may be further complicated by poly-drug use and co-morbid mental disorders. Research over the past decade has shed light on the influence of endocannabinoids on the opioid system. Evidence from both animal and clinical studies point towards an interaction between these two systems, and suggest that targeting the endocannabinoid system may provide novel interventions for managing opiate dependence and withdrawal. This review will summarize the literature surrounding the molecular effects of cannabinoids and opioids system on the locus coeruleus-norepinephrine system, a key circuit implicated in the negative sequelae of opiate addiction. A consideration of the trends and effects of marijuana use in those seeking treatment to abstain from opiates in the clinical setting will also be presented. In summary, the present review details how cannabinoid-opioid interactions may inform novel interventions in management of opiate dependence and withdrawal. PMID:23624062

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

    PubMed Central

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

    2015-01-01

    Pain management in opioid abusers engenders ethical and practical difficulties for clinicians, often resulting in pain mismanagement. Although chronic opioid administration may alter pain states, the presence of pain itself may alter the propensity to self-administer opioids, and previous history of drug abuse comorbid with chronic pain promotes higher rates of opioid misuse. Here, we tested the hypothesis that inflammatory pain leads to increased heroin self-administration resulting from altered mu opioid receptor (MOR) regulation of mesolimbic dopamine (DA) transmission. To this end, the complete Freund's adjuvant (CFA) model of inflammation was used to assess the neurochemical and functional changes induced by inflammatory pain on MOR-mediated mesolimbic DA transmission and on rat intravenous heroin self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. In the presence of inflammatory pain, heroin intake under an FR schedule was increased for high, but attenuated for low, heroin doses with concomitant alterations in mesolimbic MOR function suggested by DA microdialysis. Consistent with the reduction in low dose FR heroin self-administration, inflammatory pain reduced motivation for a low dose of heroin, as measured by responding under a PR schedule of reinforcement, an effect dissociable from high heroin dose PR responding. Together, these results identify a connection between inflammatory pain and loss of MOR function in the mesolimbic dopaminergic pathway that increases intake of high doses of heroin. These findings suggest that pain-induced loss of MOR function in the mesolimbic pathway may promote opioid dose escalation and contribute to opioid abuse-associated phenotypes. SIGNIFICANCE STATEMENT This study provides critical new insights that show that inflammatory pain alters heroin intake through a desensitization of MORs located within the VTA. These findings expand our knowledge of the interactions between

  14. Contingency management is efficacious in opioid-dependent outpatients not maintained on agonist pharmacotherapy.

    PubMed

    Petry, Nancy M; Carroll, Kathleen M

    2013-12-01

    Contingency management (CM) is an empirically supported intervention for substance dependence, but it has not been evaluated systematically in non maintained opioid-dependent patients. This retrospective analysis examined whether CM was effective in opioid-dependent patients initiating intensive outpatient psychosocial treatment. In the primary trial (Petry, N. M., Weinstock, J., & Alessi, S. M. [2011]. A randomized trial of contingency management delivered in the context of group counseling. Journal of Consulting and Clinical Psychology, 79, 686-696), substance-abusing patients (n = 239) at two community-based clinics were randomized to standard care (SC) or SC with CM for 12 weeks; in the CM condition, patients earned opportunities to win prizes for attending treatment and submitting drug-negative samples. For this analysis, patients were further classified as non-opioid-dependent (n = 159), opioid-dependent and not receiving maintenance therapy (n = 33), or opioid-dependent and on methadone or Suboxone maintenance therapy (n = 47). Main effects of opioid dependence/maintenance status, treatment condition, and their interaction were evaluated with respect to attendance and abstinence outcomes. Opioid-dependent patients receiving maintenance pharmacotherapy attended treatment on fewer days and achieved less abstinence than their opioid-dependent counterparts who were not on opioid agonist therapy, with Cohen's d effect sizes of 0.63 and 0.61 for attendance and abstinence outcomes, respectively. Nonmaintained opioid-dependent patients evidenced similar outcomes as substance abusing patients who were not opioid-dependent. CM also improved retention and abstinence (d = .26 and .40, respectively), with no interaction effects with opioid dependence/maintenance status noted. These data suggest that CM may be an effective psychosocial intervention potentially suitable for the growing population of opioid-dependent patients, including those not receiving maintenance

  15. Cannabis Withdrawal in Patients With and Without Opioid Dependence

    PubMed Central

    Chauchard, Emeline; Goncharov, Oleg; Krupitsky, Evgeny; Gorelick, David A.

    2014-01-01

    Background Cannabis use is common among opioid-dependent individuals, but little is known about cannabis withdrawal in this population. Method Thirty inpatients (57% men) completed the Marijuana Quit Questionnaire (MJQQ) after completing acute heroin detoxification treatment in St. Petersburg, Russia. The MJQQ collected data on motivations for quitting, withdrawal symptoms, and coping strategies used to help maintain abstinence during their most “userious” (self-defined) quit attempt made without formal treatment outside a controlled environment. Results At the start of their quit attempt, 70% of participants smoked cannabis at least weekly (40% daily), averaging [SD] 2.73 [1.95] joints daily; 60% were heroin-dependent. Subjects with heroin dependence were significantly older at the start of their quit attempt (22.9 [3.6] years vs. 19.1 [2.9] years), were significantly less likely to report withdrawal irritability/anger/aggression (22% vs. 58%), restlessness (0% vs. 25%), or physical symptoms (6% vs. 33%), or to meet diagnostic criteria for DSM-5 cannabis withdrawal syndrome (6% vs. 33%), and had shorter duration of abstinence (29.6 [28.7] months vs. 73.7 [44.1] months) than those without heroin dependence. Conclusion Cannabis users with opioid dependence are less likely to experience cannabis withdrawal, suggesting that opiate use may prevent or mask the experience of cannabis withdrawal. Results should be considered preliminary due to small convenience sample and retrospective data. PMID:24745656

  16. Risk-Taking Propensity as a Predictor of Induction onto Naltrexone Treatment for Opioid Dependence

    PubMed Central

    Aklin, Will M.; Severtson, S. Geoffrey; Umbricht, Annie; Fingerhood, Michael; Bigelow, George E.; Lejuez, C. W.; Silverman, Kenneth

    2014-01-01

    Objective Heroin addiction is a chronic relapsing disorder that has devastating social, medical, and economic consequences. Naltrexone is an antagonist that blocks opioid effects and could be an effective medication for the treatment of opioid dependence. However, its clinical utility has been limited partly because of poor adherence and acceptability. Given the importance of compliance to naltrexone treatment for opioid dependence, the goal of the current study was to examine predictors involved in successful induction onto naltrexone treatment. Method Parametric and nonparametric statistical tests were performed on data from a sample of 64 individuals entering treatment who met DSM-IV criteria for opioid dependence. The relationship between naltrexone induction (i.e., inducted- vs. not-inducted onto naltrexone) and risk-taking propensity, as indexed by riskiness on the Balloon Analogue Risk Task (BART) was examined. Participants were recruited from local detoxification programs, inpatient drug treatment, and other Baltimore programs that provided services to opioid dependent adults (e.g., Baltimore Needle Exchange Program) during the period from August 2007 to September 2008. Results Positive association between risk-taking propensity and odds of naltrexone induction. Specifically, each five point increase in the total BART score was associated with a 25% decrease in odds of naltrexone induction (OR=0.76, 95% CI: 0.58–0.99, p = .041). This association remained statistically significant even after adjusting for potential confounds, including injection drug use and cocaine positive urine results (p = .05). After adjusting for the covariates, each five point increase in BART score was associated with 28% decrease in the odds of achieving the maintenance dose (AOR=0.73, 95% CI: 0.54–0.99, p = .046). Conclusions Risk taking propensity was predictive of induction onto naltrexone treatment, above and beyond injection drug use and cocaine-positive urine samples. PMID

  17. Psychiatric comorbidity is associated prospectively with diminished opioid analgesia and increased opioid misuse in patients with chronic low back pain

    PubMed Central

    Wasan, Ajay, D.; Michna, Edward; Edwards, Robert, R.; Katz, Jeff, N.; Nedeljkovic, Srdjan, S.; Dolman, Andrew, J.; Janfaza, David; Isaac, Zach; Jamison, Robert, N.

    2015-01-01

    Background Opioids are frequently prescribed for chronic low back pain (CLBP), but there is little prospective data on which patient subgroups may benefit. Psychiatric comorbidity, such as high levels of depression and anxiety symptoms (termed, comorbid negative affect [NA]) is a common presentation and may predict diminished opioid analgesia and/or increased opioid misuse. Methods We conducted a 6½-month prospective cohort study of oral opioid therapy, with an active drug/placebo run-in period, in 81 CLBP patients with low, moderate, and high levels of NA. Treatment included an opioid titration phase with a prescribing physician blinded to NA group assignment, and a 4-month continuation phase, during which subjects recorded daily pain levels using an electronic diary. The primary outcome was the percent improvement in average daily pain, summarized weekly. Results There was an overall 25% drop out rate. Despite the high NA group being prescribed a higher average daily dose of morphine equivalents, linear mixed model analysis revealed that the 24 study completers in each of the high and low NA groups had an average 21% vs. 39% improvement in pain, respectively (p<.01). The high NA group also had a significantly greater rate of opioid misuse (39% vs. 8%, p<.05), and significantly more and intense opioid side effects (p<.01). Conclusions These results indicate that the benefit and risk considerations in CLBP patients with high vs. low NA are distinctly different. Thus, negative affect is an important phenotypic variable to characterize at baseline, prior to deciding whether to prescribe opioids for CLBP. PMID:26375824

  18. 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

  19. Catastrophic thinking and increased risk for prescription opioid misuse in patients with chronic pain

    PubMed Central

    Martel, MO; Wasan, AD; Jamison, RN; Edwards, RR

    2013-01-01

    Background As a consequence of the substantial rise in the prescription of opioids for the treatment of chronic noncancer pain, greater attention has been paid to the factors that may be associated with an increased risk for prescription opioid misuse. Recently, a growing number of studies have shown that patients with high levels of catastrophizing are at increased risk for prescription opioid misuse. Objective The primary objective of this study was to examine the variables that might underlie the association between catastrophizing and risk for prescription opioid misuse in patients with chronic pain. Methods Patients with chronic musculoskeletal pain (n = 115) were asked to complete the SOAPP-R, a validated self-report questionnaire designed to identify patients at risk for prescription opioid misuse. Patients were also asked to complete self-report measures of pain intensity, catastrophizing, anxiety, and depression. Results Consistent with previous research, we found that catastrophizing was associated with an increased risk for prescription opioid misuse. Results also revealed that the association between catastrophizing and risk for opioid misuse was partially mediated by patients’ levels of anxiety. Follow-up analyses, however, indicated that catastrophizing remained a significant ‘unique’ predictor of risk for opioid misuse even when controlling for patients’ levels of pain severity, anxiety and depressive symptoms. Discussion Discussion addresses the factors that might place patients with high levels of catastrophizing at increased risk for prescription opioid misuse. The implications of our findings for the management of patients considered for opioid therapy are also discussed. PMID:23618767

  20. Mu Opioid Receptor Binding Correlates with Nicotine Dependence and Reward in Smokers

    PubMed Central

    Brasic, James R.; Contoreggi, Carlo; Cascella, Nicola; Mackowick, Kristen M.; Taylor, Richard; Rousset, Olivier; Willis, William; Huestis, Marilyn A.; Concheiro, Marta; Wand, Gary; Wong, Dean F.; Volkow, Nora D.

    2014-01-01

    The rewarding effects of nicotine are associated with activation of nicotine receptors. However, there is increasing evidence that the endogenous opioid system is involved in nicotine's rewarding effects. We employed PET imaging with [11C]carfentanil to test the hypotheses that acute cigarette smoking increases release of endogenous opioids in the human brain and that smokers have an upregulation of mu opioid receptors (MORs) when compared to nonsmokers. We found no significant changes in binding potential (BPND) of [11C]carfentanil between the placebo and the active cigarette sessions, nor did we observe differences in MOR binding between smokers and nonsmokers. Interestingly, we showed that in smokers MOR availability in bilateral superior temporal cortices during the placebo condition was negatively correlated with scores on the Fagerström Test for Nicotine Dependence (FTND). Also in smokers, smoking-induced decreases in [11C]carfentanil binding in frontal cortical regions were associated with self-reports of cigarette liking and wanting. Although we did not show differences between smokers and nonsmokers, the negative correlation with FTND corroborates the role of MORs in superior temporal cortices in nicotine addiction and provides preliminary evidence of a role of endogenous opioid signaling in frontal cortex in nicotine reward. PMID:25493427

  1. Medicaid coverage of medications to treat alcohol and opioid dependence.

    PubMed

    Mark, Tami L; Lubran, Robert; McCance-Katz, Elinore F; Chalk, Mady; Richardson, John

    2015-08-01

    Substance use disorders affect 12% of Medicaid beneficiaries. The prescription drug epidemic and growing need for treatment of alcohol and opioid dependence have refocused states' attention on their provision of substance use disorder treatment services, including medications. This study characterized how Medicaid programs cover these treatment medications. Data were from 2013 Medicaid pharmacy documents, 2011 and 2012 Medicaid state drug utilization records, and a 2013 American Society of Addiction Medicine survey. Results showed that only 13 state Medicaid programs included all medications approved for alcohol and opioid dependence on their preferred drug lists. The most commonly excluded were extended-release naltrexone (19 programs), acamprosate (19 programs), and methadone (20 programs). For combined buprenorphine-naloxone, 48 Medicaid programs required prior authorization, and 11 programs used 1- to 3-year lifetime treatment limits. Given the chronic nature of substance use disorders and the overwhelming evidence supporting ongoing coverage for many of these medications, states may want to reexamine substance use disorder benefits. PMID:25921475

  2. Pharmacologic treatments for opioid dependence: detoxification and maintenance options

    PubMed Central

    Kleber, Herbert D.

    2007-01-01

    While opioid dependence has more treatment agents available than other abused drugs, none are curative. They can, however, markedly diminish withdrawal symptoms and craving, and block opioid effects due to lapses. The most effective withdrawal method is substituting and tapering methadone or buprenorphine, α-2 Adrenergic agents can ameliorate untreated symptoms or substitute for agonists if not available. Shortening withdrawal by precipitating it with narcotic antagonists has been studied, but the methods are plagued by safety issues or persisting symptoms. Neither the withdrawal agents nor the methods are associated with better long-term outcome, which appears mostly related to post-detoxification treatment. Excluding those with short-term habits, the best outcome occurs with long-term maintenance on methadone or buprenorphine accompanied by appropriate psychosocial interventions. Those with strong external motivation may do well on the antagonist naltrexone. Currently, optimum duration of maintenance on either is unclear. Better agents are needed to impact the brain changes related to addiction. PMID:18286804

  3. Increasing Potential Access to Opioid Agonist Treatment in U.S. Treatment Shortage Areas

    PubMed Central

    Dick, Andrew W.; Pacula, Rosalie Liccardo; Gordon, Adam J.; Sorbero, Mark; Burns, Rachel M.; Leslie, Douglas L.; Stein, Bradley D.

    2015-01-01

    Opioid use disorders are a significant public health problem, affecting over 2 million individuals in the US. Although opioid agonist treatment, predominantly offered in licensed methadone clinics, is both effective and cost-effective, many individuals do not receive it. Buprenorphine, approved in 2002 for prescription by waivered physicians, could improve opioid agonist treatment access for individuals unable or unwilling to receive methadone. We examine the extent to which the geographic distribution of waivered physicians has enhanced potential opioid agonist treatment access, particularly in non-metropolitan areas with fewer methadone clinics. We found that while the approximately 90% of counties classified as methadone clinic shortage areas remained constant, buprenorphine shortage areas fell from 99% of counties in 2002 to 51% in 2011, lowering the US population percentage residing in opioid treatment shortage counties to approximately 10%. The increase in buprenorphine-waivered physicians has dramatically increased potential access to opioid agonist treatment, especially in non-metropolitan counties. PMID:26056209

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

    PubMed

    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.

  5. 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

  6. 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

  7. Integrated Psychosocial and Opioid-Antagonist Treatment for Alcohol Dependence: A Systematic Review of Controlled Evaluations

    ERIC Educational Resources Information Center

    Vaughn, Michael G.; Howard, Matthew O.

    2004-01-01

    Methodological characteristics and outcomes of 14 controlled clinical investigations of integrated psychosocial and opioid-antagonist alcohol dependence treatment were evaluated. The 14 studies were identified through computerized bibliographic and manual literature searches. Clients receiving integrated psychosocial and opioid-antagonist…

  8. Long-Term Agonist and Antagonist Therapy for Adolescent Opioid Dependence: A Description of Two Cases

    PubMed Central

    Ranjan, Rajeev; Pattanayak, Raman Deep; Dhawan, Anju

    2014-01-01

    Adolescents constitute only a small percentage of treatment seekers in drug dependence treatment settings. Little research evidence is available for pharmacological treatment of adolescent opioid dependence and no prior case report is available from India. We discuss two adolescent patients with opioid (heroin) dependence visiting a tertiary care center who have been stabilized on agonist (sublingual buprenorphine-naloxone) and antagonist (oral naltrexone) respectively for a substantial period of time. A comprehensive management approach, including intensive psychosocial interventions and family involvement, was followed in addition to pharmacotherapies. More research is needed on the efficacy of pharmacological treatment in adolescent opioid users. PMID:25336782

  9. Sleep Disturbances and Pain among Individuals with Prescription Opioid Dependence

    PubMed Central

    Hartwell, Emily E.; Pfeifer, James G.; McCauley, Jenna L.; Maria, Megan Moran-Santa; Back, Sudie E.

    2014-01-01

    BACKGROUND Poor sleep quality has been observed in individuals with substance use disorders and is often a trigger for relapse. To date, little research has investigated sleep quality among individuals with prescription opioid (PO) dependence. The present study aimed to address this gap in the literature by examining subjective and objective sleep disturbances among PO dependent individuals. METHODS Subjects were 68 non-treatment seeking individuals (33 PO dependent, 35 healthy controls). Subjective sleep was assessed with the Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI). Subjects were admitted for an overnight inpatient hospital stay during which objective sleep data was collected using an actigraphy device. Self-report pain was measured with the Brief Pain Inventory. RESULTS Significant group differences in subjective sleep quality were revealed in the PSQI (p<0.01) and ISI (p<0.01). Poor sleep quality (i.e., PSQI total score > 5) was identified in 80.6% of the PO group, as compared to 8.8% of the control group (p<.001). Significant group differences in sleep quality were identified in five of six actigraphy variables: total time asleep, sleep efficiency, latency of onset of sleep, total time awake and time mobile. Furthermore, significant associations between pain severity and sleep quality were observed. CONCLUSIONS Results indicate high rates of sleep impairment and poor sleep quality among PO dependent individuals. Pain severity was significantly correlated with sleep quality. Although preliminary, the findings highlight the importance of assessing and treating sleep disturbances, as well as pain, among patients with PO dependence. PMID:24999989

  10. Clinical Management of the Breast-Feeding Mother-Infant Dyad in Recovery From Opioid Dependence.

    PubMed

    Busch, Deborah W

    2016-01-01

    Human milk is one of the most health-promoting and cost-effective nutritional substances known to humankind. Breastmilk provides substantial and remarkable physiological and psychological health benefits. Within the last decade, there has been a resurgence of breast-feeding in the United States and worldwide and an increased awareness of the immense health benefits for mothers, infants, and societies that support it. Each mother-baby dyad is a unique pair, with distinct relationships, biases, barriers, and obstacles. This article aims to address clinical management for the opioid-recovering breast-feeding dyad and to translate current evidenced-based practice findings, recommendations, and resources to best support this unique population. The recovering breast-feeding mother and newborn with opioid dependence deserve special consideration and expert care to foster their recovery and breast-feeding efforts. It is our moral and ethical responsibility as healthcare professionals to enable, foster, and promote breast-feeding among all families, especially those who stand to benefit the greatest. Substance recovery cannot be treated in isolation, nor can breast-feeding efforts; an interdisciplinary professional team effort promises the greatest chances for recovery success. With appropriate evidence-based practice support, training, and intervention by knowledgeable professionals, many women can overcome the biases and obstacles associated with opioid recovery to successfully breast-feed their babies.

  11. Clinical Management of the Breast-Feeding Mother-Infant Dyad in Recovery From Opioid Dependence.

    PubMed

    Busch, Deborah W

    2016-01-01

    Human milk is one of the most health-promoting and cost-effective nutritional substances known to humankind. Breastmilk provides substantial and remarkable physiological and psychological health benefits. Within the last decade, there has been a resurgence of breast-feeding in the United States and worldwide and an increased awareness of the immense health benefits for mothers, infants, and societies that support it. Each mother-baby dyad is a unique pair, with distinct relationships, biases, barriers, and obstacles. This article aims to address clinical management for the opioid-recovering breast-feeding dyad and to translate current evidenced-based practice findings, recommendations, and resources to best support this unique population. The recovering breast-feeding mother and newborn with opioid dependence deserve special consideration and expert care to foster their recovery and breast-feeding efforts. It is our moral and ethical responsibility as healthcare professionals to enable, foster, and promote breast-feeding among all families, especially those who stand to benefit the greatest. Substance recovery cannot be treated in isolation, nor can breast-feeding efforts; an interdisciplinary professional team effort promises the greatest chances for recovery success. With appropriate evidence-based practice support, training, and intervention by knowledgeable professionals, many women can overcome the biases and obstacles associated with opioid recovery to successfully breast-feed their babies. PMID:27272990

  12. Risk Factors for Relapse and Higher Costs Among Medicaid Members with Opioid Dependence or Abuse: Opioid Agonists, Comorbidities, and Treatment History.

    PubMed

    Clark, Robin E; Baxter, Jeffrey D; Aweh, Gideon; O'Connell, Elizabeth; Fisher, William H; Barton, Bruce A

    2015-10-01

    Clinical trials show that opioid agonist therapy (OAT) with methadone or buprenorphine is more effective than behavioral treatments, but state policymakers remain ambivalent about covering OAT for long periods. We used Medicaid claims for 52,278 Massachusetts Medicaid beneficiaries with a diagnosis of opioid abuse or dependence between 2004 and 2010 to study associations between use of methadone, buprenorphine or other behavioral health treatment without OAT, and time to relapse and total healthcare expenditures. Cox Proportional Hazards ratios for patients treated with either methadone or buprenorphine showed approximately 50% lower risk of relapse than behavioral treatment without OAT. Expenditures per month were from $153 to $233 lower for OAT episodes compared to other behavioral treatment. Co-occurring alcohol abuse/dependence quadrupled the risk of relapse, other non-opioid abuse/dependence doubled the relapse risk and severe mental illness added 80% greater risk compared to those without each of those disorders. Longer current treatment episodes were associated with lower risk of relapse. Relapse risk increased as prior treatment exposure increased but prior treatment was associated with slightly lower total healthcare expenditures. These findings suggest that the effectiveness of OAT that has been demonstrated in clinical trials persists at the population level in a less controlled setting and that OAT is associated with lower total healthcare expenditures compared to other forms of behavioral treatment for patients with opioid addiction. Co-occurring other substance use and mental illness exert strong influences on cost and risk of relapse, suggesting that individuals with these conditions need more comprehensive treatment.

  13. Risk Factors for Relapse and Higher Costs among Medicaid Members with Opioid Dependence or Abuse: Opioid Agonists, Comorbidities, and Treatment History

    PubMed Central

    Clark, Robin E.; Baxter, Jeffrey D.; Aweh, Gideon; O'Connell, Elizabeth; Fisher, William H.; Barton, Bruce A.

    2015-01-01

    Clinical trials show that opioid agonist therapy (OAT) with methadone or buprenorphine is more effective than behavioral treatments, but state policymakers remain ambivalent about covering OAT for long periods. We used Medicaid claims for 52,278 Massachusetts Medicaid beneficiaries with a diagnosis of opioid abuse or dependence between 2004 and 2010 to study associations between use of methadone, buprenorphine or other behavioral health treatment without OAT, and time to relapse and total healthcare expenditures. Cox Proportional Hazards ratios for patients treated with either methadone or buprenorphine showed approximately 50% lower risk of relapse than behavioral treatment without OAT. Expenditures per month were from $153 to $233 lower for OAT episodes compared to other behavioral treatment. Co-occurring alcohol abuse/dependence quadrupled the risk of relapse, other non-opioid abuse/dependence doubled the relapse risk and severe mental illness added 80% greater risk compared to those without each of those disorders. Longer current treatment episodes were associated with lower risk of relapse. Relapse risk increased as prior treatment exposure increased but prior treatment was associated with slightly lower total healthcare expenditures. These findings suggest that the effectiveness of OAT that has been demonstrated in clinical trials persists at the population level in a less controlled setting and that OAT is associated with lower total healthcare expenditures compared to other forms of behavioral treatment for patients with opioid addiction. Co-occurring other substance use and mental illness exert strong influences on cost and risk of relapse, suggesting that individuals with these conditions need more comprehensive treatment. PMID:25997674

  14. Safety and efficacy of buprenorphine/naloxone in opioid-dependent patients: an Italian observational study.

    PubMed

    Magnelli, Fernanda; Biondi, Lorita; Calabria, Roberto; Fiore, Angelo; Peluso, Eugenio; Vonella, Domenico; Rota, Amerigo Giuseppe

    2010-01-01

    Opioid dependence is a growing problem. Methadone is an established agent for the treatment of opioid dependence, but there is a risk of this agent being abused, a potential for interaction with antiretroviral agents and a risk of cardiac toxicity. Another option is the partial mu-opioid receptor opioid agonist buprenorphine, which has been used successfully to manage opioid dependence. While the risk of abuse is lower than that for methadone, there is still a risk. The sublingual combination formulation of buprenorphine and the opioid receptor antagonist naloxone (buprenorphine/naxolone) is a newer agent with reduced abuse potential, and has been shown to have promising efficacy for opioid dependence. We describe the results of an observational study investigating the safety and efficacy of buprenorphine/naloxone in opioid-dependent patients. A total of 77 patients were included and were switched from buprenorphine to sublingual tables of buprenorphine/naloxone; the buprenorphine dosage was titrated to achieve good control of withdrawal symptoms. The prevalence of withdrawal symptoms, craving, constipation, cramps, insomnia, sexual activity, depression, sweating, distress, bone/joint pain and drowsiness were compared over the first 30 days of treatment (period 1) and the total 120-day study duration (period 2). The average buprenorphine/naloxone dose in period 1 was 7.3 mg/day and 12.7 mg/day in period 2. Most patients did not experience any withdrawal symptoms in either period 1 or period 2. Fewer than 20% of patients experienced any cravings over the 120-day study period. Importantly, the adverse effects observed were usually mild, with very few patients experiencing significant adverse effects. This study shows that buprenorphine/naloxone is an effective and well tolerated treatment for opioid withdrawal when the dosage is titrated to achieve good control of withdrawal symptoms. Switching from buprenorphine alone to buprenorphine/naloxone was possible with very

  15. Characteristics and Correlates of Men and Women with Prescription Opioid Dependence

    PubMed Central

    Back, Sudie E.; Lawson, Katie; Singleton, Lauren; Brady, Kathleen T.

    2011-01-01

    Despite the fact that important gender differences in drug and alcohol use have been previously reported, little research to date has focused on gender differences with regard to nonmedical prescription opioid use. This study preliminarily examined the presenting characteristics and correlates (e.g., age of onset, route of administration, motives for using, method of introduction) of men and women with prescription opioid dependence. Participants were 24 (12 men, 12 women) non-treatment seeking individuals at least 18 years of age with current (i.e., past 12 months) prescription opioid dependence who participated in an in-depth interview. The average age of onset of prescription opioid use was 22.2 years (SD = 8.5). In comparison to men, women were approximately six years older when they initiated prescription opioid use, but were only three years older when they began to use prescription opioids regularly (i.e., weekly), suggesting an accelerated course of disease progression among women. Over half of the sample (61.5%) endorsed chewing and almost half (45.8%) endorsed crushing and snorting prescription opioids. Men were significantly more likely than women to crush and snort prescription opioids (75.0% vs. 16.7%; p = 0.01). Women were significantly more likely than men to be motivated to use prescription opioids in order to cope with interpersonal stress, and to use them first thing in the morning (ps = 0.04). Concomitant alcohol and other drug use were common among both men and women. The findings highlight clinically relevant gender differences and may help enhance the design of gender-sensitive screening and treatment interventions for prescription opioids. PMID:21514061

  16. Psychological and physiological stress negatively impacts early engagement and retention of opioid-dependent individuals on methadone maintenance

    PubMed Central

    Jaremko, Kellie M.; Sterling, Robert C.; Van Bockstaele, Elisabeth J.

    2014-01-01

    The present study investigated whether psychological and/or physiological measures of stress would impede induction onto methadone maintenance and predict early (<6 months) discontinuation. Compared with controls, opioid-dependent subjects displayed increased distress on the perceived stress scale (PSS) and post-traumatic stress disorder checklist (PCLC); 60% exhibited abnormal cortisol. Addiction severity index (ASI), drug-use, and stress indices explained between 17–37% of the variance in engagement including attendance, opioid abstinence, and methadone stabilization. Participants who discontinued treatment displayed poor engagement, abnormal cortisol, elevated withdrawal symptoms, higher distress, and increased ongoing opioid use versus compliant individuals. Discontinuation was initially related to drug-use severity; however, by 6 months, retention depended primarily upon cortisol abnormalities, which increased an individual’s discontinuation risk by 7.7-fold. These findings support admission screening with the ASI/cortisol for drop out, and stress/drug-use indices for engagement that together may enable clinically-relevant early recognition and interventions for prevention of stress-induced relapse in opioid-dependent populations. PMID:25239858

  17. 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

  18. A placebo-controlled trial of memantine as an adjunct to injectable extended-release naltrexone for opioid dependence.

    PubMed

    Bisaga, Adam; Sullivan, Maria A; Glass, Andrew; Mishlen, Kaitlyn; Carpenter, Kenneth M; Mariani, John J; Levin, Frances R; Nunes, Edward V

    2014-01-01

    There is preclinical support for using NMDA receptor glutamatergic antagonists to aid in naltrexone-based treatment of opioid dependence. We hypothesized that adding memantine will improve efficacy of extended-release (XR) naltrexone to prevent relapse. In this double blind study opioid-dependent participants (N=82) underwent inpatient detoxification and naltrexone induction. During naltrexone initiation participants were randomized to receive memantine 40 mg or placebo and continued treatment for 12-weeks with XR naltrexone and relapse-prevention therapy. Sixty eight percent of participants completed detoxification and received the first dose of XR naltrexone. Rates of trial completion were significantly greater in participants receiving placebo than memantine (70% vs. 43%, p<0.05). Severity of opioid withdrawal symptoms during the first 3 weeks of the trial appeared to be lower in the group receiving memantine (p=0.07). Adding memantine does not appear to increase the effectiveness of injectable XR naltrexone as a relapse prevention strategy in opioid dependence and may lead to an increase in treatment drop-out.

  19. Mortality among individuals accessing pharmacological treatment for opioid dependence in California, 2006 - 2010

    PubMed Central

    Evans, Elizabeth; Li, Libo; Min, Jeong; Huang, David; Urada, Darren; Liu, Lei; Hser, Yih-Ing; Nosyk, Bohdan

    2015-01-01

    Aims To estimate mortality rates among treated opioid-dependent individuals by cause and in relation to the general population, and to estimate the instantaneous effects of opioid detoxification and maintenance treatment (MMT) on the hazard of all-cause and cause-specific mortality. Design Population-based treatment cohort study. Setting Linked mortality data on all individuals first enrolled in publicly-funded pharmacological treatment for opioid dependence in California, USA from 2006 to 2010. Participants 32,322 individuals, among whom there were 1,031 deaths (3.2%) over a median follow-up of 2.6 years (interquartile range: 1.4 - 3.7). Measurements The primary outcome was mortality, indicated by time to death, crude mortality rates (CMR), and standardized mortality ratios (SMR). Findings Individuals being treated for opioid dependence had a more than four-fold increase of mortality risk compared with the general population (SMR 4.5 95% CI: 4.2, 4.8). Mortality risk was higher (1) when individuals were out-of-treatment (SMR 6.1, 95% CI: 5.7, 6.5) than in-treatment (SMR 1.8, 95% CI: 1.6, 2.1) and (2) during detoxification (SMR 2.4, 95% CI 1.5, 3.8) than during MMT (SMR 1.8, 95% CI 1.5, 2.1), especially in the two weeks post-treatment entry (SMR 5.5, 95% CI 2.7, 9.8 versus SMR 2.5, 95% CI 1.7, 4.9). Detoxification and MMT both independently reduced the instantaneous hazard of all-cause and drug-related mortality. MMT preceded by detoxification was associated with lower all-cause and other-cause-specific mortality than MMT alone. Conclusions In people with opiate dependence, detoxification and methadone maintenance treatment both independently reduce the instantaneous hazard of all-cause and drug-related mortality. PMID:25644938

  20. Safety and tolerability of slow-release oral morphine versus methadone in the treatment of opioid dependence.

    PubMed

    Hämmig, Robert; Köhler, Wilfried; Bonorden-Kleij, Karin; Weber, Bernd; Lebentrau, Karin; Berthel, Toni; Babic-Hohnjec, Lucija; Vollmert, Christian; Höpner, Doris; Gholami, Najibulah; Verthein, Uwe; Haasen, Christian; Reimer, Jens; Ruckes, Christian

    2014-10-01

    Opioid substitution treatment (OST) for opioid dependence may be limited by adverse events (AEs). Increasing the range of therapeutic options optimizes outcomes and facilitates patient management. An international, multi-center, two-phase study investigated the efficacy and safety of slow-release oral morphine (SROM) versus methadone in patients receiving methadone therapy for opioid dependence. In phase 1 (two way cross-over, 11 weeks each period) patients were randomized to SROM or methadone oral solution. In phase 2 (25 weeks), patients continued treatment with SROM (group A) or switched from methadone to SROM (group B). In total, 211 out of 276 completed phase 1 and 198 entered phase 2 (n=95 group A, n=103 group B). Treatment with both SROM and methadone was well tolerated. However, the mean QTc-interval associated with methadone was significantly longer than that under SROM. Higher treatment satisfaction, fewer cravings for heroin, and lower mental stress were reported with SROM. This study adds a significant further weight of evidence that SROM is an effective and well tolerated long-term maintenance treatment for opioid dependence with a beneficial risk profile compared to methadone regarding cardiac effects and supports its clinical utility.

  1. A Stress-Coping Profile of Opioid Dependent Individuals Entering Naltrexone Treatment: A Comparison with Healthy Controls

    PubMed Central

    Hyman, Scott M.; Hong, Kwang-Ik A.; Chaplin, Tara M.; Dabre, Zubaida; Comegys, Allison D.; Kimmerling, Anne; Sinha, Rajita

    2009-01-01

    Background Stress is known to increase addiction vulnerability and risk of relapse to substance use. Purpose & Method We compared opioid dependent individuals entering naltrexone treatment (n = 57) with healthy controls (n = 75) on measures of stress, coping, and social support and examined the relative contribution of group membership, coping and social support to stress within the sample. Analyses of variance (ANOVA) and covariance (ANCOVA), and stepwise multiple regression were conducted. Results Compared with controls, opioid dependent subjects reported greater stress, less use of adaptive coping, but comparable use of maladaptive/avoidant coping. No group differences were found with respect to social support. Perceived stress was predicted by group membership, low social support and greater use of maladaptive/avoidant coping, and the prediction by social support and maladaptive/avoidant coping did not differ by group. Conclusion Opioid dependent individuals entering naltrexone treatment experience higher levels of stress and report less use of adaptive coping strategies when compared with controls. Group membership, maladaptive/avoidant coping and social support independently contribute to perceived stress. Findings suggest that novel treatment approaches that decrease maladaptive/avoidant coping and improve social support are important aspects of decreasing stress during early recovery from opioid addiction. PMID:20025367

  2. Increased Risk of Postthoracotomy Pain Syndrome in Patients with Prolonged Hospitalization and Increased Postoperative Opioid Use

    PubMed Central

    Jacob, Adam K.; Passe, Melissa A.; Mantilla, Carlos B.

    2016-01-01

    Background. Postthoracotomy pain syndrome (PTPS) is unfortunately very common following thoracotomy and results in decreased quality of life. The purpose of this retrospective study was to determine perioperative patient, surgical, and analgesic characteristics associated with the development of PTPS. Methods. Sixty-six patients who presented to the Mayo Clinic Rochester Pain Clinic were diagnosed with PTPS 2 months or more after thoracotomy with postoperative epidural analgesia. These patients were matched with sixty-six control patients who underwent thoracotomy with postoperative epidural analgesia and were never diagnosed with PTPS. Results. Median (IQR) hospital stay was significantly different between control patients (5 days (4, 6)) compared with PTPS patients (6 days (5, 8)), P < 0.02. The total opioid equivalent utilized in oral morphine equivalents in milligrams for the first three days postoperatively was significantly different between control patients and PTPS patients. The median (IQR) total opioid equivalent utilized was 237 (73, 508) for controls and 366 (116, 874) for PTPS patients (P < 0.005). Conclusion. Patients with a prolonged hospital stay after thoracotomy were at an increased risk of developing PTPS, and this is a novel finding. Patients who utilize higher oral morphine equivalents for the first 3 days were also at increased risk for PTPS. PMID:27340565

  3. Prescription Opioid Duration, Dose, and Increased Risk of Depression in 3 Large Patient Populations

    PubMed Central

    Scherrer, Jeffrey F.; Salas, Joanne; Copeland, Laurel A.; Stock, Eileen M.; Ahmedani, Brian K.; Sullivan, Mark D.; Burroughs, Thomas; Schneider, F. David; Bucholz, Kathleen K.; Lustman, Patrick J.

    2016-01-01

    PURPOSE Recent results suggests the risk of a new onset of depression increases with longer duration of opioid analgesic use. It is unclear whether new-onset depression related to opioid analgesic use is a function of the dose prescribed or the duration of use or both. METHODS Using a retrospective cohort design, we collected patient data from 2000 to 2012 from the Veterans Health Administration (VHA), and from 2003 to 2012 from both Baylor Scott & White Health (BSWH) and the Henry Ford Health System (HFHS). Patients (70,997 VHA patients, 13,777 BSWH patients, and 22,981 HFHS patients) were new opioid users, aged 18 to 80 years, without a diagnosis of depression at baseline. Opioid analgesic use duration was defined as 1 to 30, 31 to 90, and more than 90 days, and morphine equivalent dose (MED) was defined as 1 to 50 mg/d, 51 to 100 mg/d, and greater than 100 mg/d of analgesic. Pain and other potential confounders were controlled for by inverse probability of treatment–weighted propensity scores. RESULTS New-onset depression after opioid analgesic use occurred in 12% of the VHA sample, 9% of the BSWH sample, and 11% of the HFHS sample. Compared with 1- to 30-day users, new-onset depression increased in those with longer opioid analgesic use. Risk of new-onset depression with 31 to 90 days of opioid analgesic use ranged from hazard ratio [HR] = 1.18 (95% CI, 1.10–1.25) in VHA to HR = 1.33 (95% CI, 1.16–1.52) in HFHS; in opioid analgesic use of more than 90 days, it ranged from HR = 1.35 (95% CI, 1.26–1.44) in VHA to HR = 2.05 (95% CI, 1.75–2.40) in HFHS. Dose was not significantly associated with a new onset of depression. CONCLUSIONS Opioid-related new onset of depression is associated with longer duration of use but not dose. Patients and practitioners should be aware that opioid analgesic use of longer than 30 days imposes risk of new-onset depression. Opioid analgesic use, not just pain, should be considered a potential source when patients report

  4. An intronic variant in OPRD1 predicts treatment outcome for opioid dependence in African-Americans.

    PubMed

    Crist, Richard C; Clarke, Toni-Kim; Ang, Alfonso; Ambrose-Lanci, Lisa M; Lohoff, Falk W; Saxon, Andrew J; Ling, Walter; Hillhouse, Maureen P; Bruce, R Douglas; Woody, George; Berrettini, Wade H

    2013-09-01

    Although buprenorphine and methadone are both effective treatments for opioid dependence, their efficacy can vary significantly among patients. Genetic differences may explain some of the variability in treatment outcome. Understanding the interactions between genetic background and pharmacotherapy may result in more informed treatment decisions. This study is a pharmacogenetic analysis of the effects of genetic variants in OPRD1, the gene encoding the δ-opioid receptor, on the prevalence of opioid-positive urine tests in African-Americans (n=77) or European-Americans (n=566) undergoing treatment for opioid dependence. Patients were randomly assigned to treatment with either methadone or buprenorphine/naloxone (Suboxone) over a 24-week open-label clinical trial, in which illicit opioid use was measured by weekly urinalysis. In African-Americans, the intronic SNP rs678849 predicted treatment outcome for both medications. Methadone patients with the CC genotype were less likely to have opioid-positive urine tests than those in the combined CT and TT genotypes group (relative risk (RR)=0.52, 95% confidence interval (CI)=0.44-0.60, p=0.001). In the buprenorphine treatment group, however, individuals with the CC genotype were more likely to have positive opioid drug screens than individuals in the combined CT and TT genotypes group (RR=2.17, 95% CI=1.95-2.68, p=0.008). These findings indicate that the genotype at rs678849 predicts African-American patient response to two common treatments for opioid dependence, suggesting that matching patients to treatment type based on the genotype at this locus may improve overall treatment efficacy. This observation requires confirmation in an independent population. PMID:23612435

  5. An Intronic Variant in OPRD1 Predicts Treatment Outcome for Opioid Dependence in African-Americans

    PubMed Central

    Crist, Richard C; Clarke, Toni-Kim; Ang, Alfonso; Ambrose-Lanci, Lisa M; Lohoff, Falk W; Saxon, Andrew J; Ling, Walter; Hillhouse, Maureen P; Bruce, R Douglas; Woody, George; Berrettini, Wade H

    2013-01-01

    Although buprenorphine and methadone are both effective treatments for opioid dependence, their efficacy can vary significantly among patients. Genetic differences may explain some of the variability in treatment outcome. Understanding the interactions between genetic background and pharmacotherapy may result in more informed treatment decisions. This study is a pharmacogenetic analysis of the effects of genetic variants in OPRD1, the gene encoding the δ-opioid receptor, on the prevalence of opioid-positive urine tests in African-Americans (n=77) or European-Americans (n=566) undergoing treatment for opioid dependence. Patients were randomly assigned to treatment with either methadone or buprenorphine/naloxone (Suboxone) over a 24-week open-label clinical trial, in which illicit opioid use was measured by weekly urinalysis. In African-Americans, the intronic SNP rs678849 predicted treatment outcome for both medications. Methadone patients with the CC genotype were less likely to have opioid-positive urine tests than those in the combined CT and TT genotypes group (relative risk (RR)=0.52, 95% confidence interval (CI)=0.44–0.60, p=0.001). In the buprenorphine treatment group, however, individuals with the CC genotype were more likely to have positive opioid drug screens than individuals in the combined CT and TT genotypes group (RR=2.17, 95% CI=1.95–2.68, p=0.008). These findings indicate that the genotype at rs678849 predicts African-American patient response to two common treatments for opioid dependence, suggesting that matching patients to treatment type based on the genotype at this locus may improve overall treatment efficacy. This observation requires confirmation in an independent population. PMID:23612435

  6. Regulation of μ and δ opioid receptor functions: involvement of cyclin-dependent kinase 5

    PubMed Central

    Beaudry, H; Mercier-Blais, A-A; Delaygue, C; Lavoie, C; Parent, J-L; Neugebauer, W; Gendron, L

    2015-01-01

    Background and Purpose Phosphorylation of δ opioid receptors (DOP receptors) by cyclin-dependent kinase 5 (CDK5) was shown to regulate the trafficking of this receptor. Therefore, we aimed to determine the role of CDK5 in regulating DOP receptors in rats treated with morphine or with complete Freund's adjuvant (CFA). As μ (MOP) and DOP receptors are known to be co-regulated, we also sought to determine if CDK5-mediated regulation of DOP receptors also affects MOP receptor functions. Experimental Approach The role of CDK5 in regulating opioid receptors in CFA- and morphine-treated rats was studied using roscovitine as a CDK inhibitor and a cell-penetrant peptide mimicking the second intracellular loop of DOP receptors (C11-DOPri2). Opioid receptor functions were assessed in vivo in a series of behavioural experiments and correlated by measuring ERK1/2 activity in dorsal root ganglia homogenates. Key Results Chronic roscovitine treatment reduced the antinociceptive and antihyperalgesic effects of deltorphin II (Dlt II) in morphine- and CFA-treated rats respectively. Repeated administrations of C11-DOPri2 also robustly decreased Dlt II-induced analgesia. Interestingly, DAMGO-induced analgesia was significantly increased by roscovitine and C11-DOPri2. Concomitantly, in roscovitine-treated rats the Dlt II-induced ERK1/2 activation was decreased, whereas the DAMGO-induced ERK1/2 activation was increased. An acute roscovitine treatment had no effect on Dlt II- or DAMGO-induced analgesia. Conclusions and Implications Together, our results demonstrate that CDK5 is a key player in the regulation of DOP receptors in morphine- and CFA-treated rats and that the regulation of DOP receptors by CDK5 is sufficient to modulate MOP receptor functions through an indirect process. PMID:25598508

  7. Effectiveness of Mindfulness-Based Group Therapy Compared to the Usual Opioid Dependence Treatment

    PubMed Central

    Imani, Saeed; Atef Vahid, Mohammad Kazem; Gharraee, Banafsheh; Noroozi, Alireza; Habibi, Mojtaba; Bowen, Sarah

    2015-01-01

    Objective: This study investigated the effectiveness of mindfulness-based group therapy (MBGT) compared to the usual opioid dependence treatment (TAU).Thirty outpatients meeting the DSM-IV-TR criteria for opioid dependence from Iranian National Center for Addiction Studies (INCAS) were randomly assigned into experimental (Mindfulness-Based Group Therapy) and control groups (the Usual Treatment).The experimental group undertook eight weeks of intervention, but the control group received the usual treatment according to the INCAS program. Methods: The Five Factor Mindfulness Questionnaire (FFMQ) and the Addiction Sevier Index (ASI) were administered at pre-treatment and post-treatment assessment periods. Thirteen patients from the experimental group and 15 from the control group completed post-test assessments. Results: The results of MANCOVA revealed an increase in mean scores in observing, describing, acting with awareness, non-judging, non-reacting, and decrease in mean scores of alcohol and opium in MBGT patient group. Conclusion: The effectiveness of MBGT, compared to the usual treatment, was discussed in this paper as a selective protocol in the health care setting for substance use disorders. PMID:26877751

  8. Relationship between buprenorphine adherence and health service utilization and costs among opioid dependent patients.

    PubMed

    Tkacz, Joseph; Volpicelli, Joseph; Un, Hyong; Ruetsch, Charles

    2014-04-01

    Buprenorphine-medication assisted therapy (B-MAT) is an effective treatment for opioid dependence, but may be considered cost-prohibitive based on ingredient cost alone. The purpose of this study was to use medical and pharmacy claims data to estimate the healthcare service utilization and costs associated with B-MAT adherence among a sample of opioid dependent members. Members were placed into two adherence groups based on 1-year medication possession ratio (≥ 0.80 vs. <0.80). The B-MAT adherent group incurred significantly higher pharmacy charges (adjusted means; $6,156 vs. $3,581), but lower outpatient ($9,288 vs. $14,570), inpatient ($10,982 vs. $26,470), ER ($1,891 vs. $4,439), and total healthcare charges ($28,458 vs. $49,051; p<0.01) compared to non-adherent members. Adherence effects were confirmed in general linear models. Though B-MAT adherence requires increased pharmacy utilization, adherent individuals were shown to use fewer expensive health care services, resulting in overall reduced healthcare expenditure compared to non-adherent patients.

  9. Buprenorphine-naloxone use in pregnancy for treatment of opioid dependence

    PubMed Central

    Dooley, Joe; Gerber-Finn, Lianne; Antone, Irwin; Guilfoyle, John; Blakelock, Brittany; Balfour-Boehm, Jazmyn; Hopman, Wilma M.; Jumah, Naana; Kelly, Len

    2016-01-01

    Abstract Objective To examine the maternal course and neonatal outcomes for women using buprenorphine-naloxone for opioid dependence in pregnancy. Design Retrospective cohort study comparing outcomes for the group of pregnant patients exposed to buprenorphine-naloxone with outcomes for those exposed to other narcotics and those not exposed to narcotics. Setting Northwestern Ontario obstetric program. Participants A total of 640 births in an 18-month period from July 1, 2013, to January 1, 2015. Main outcome measures Maternal outcomes included route and time of delivery, medical and surgical complications, out-of hospital deliveries, change in illicit drug use, and length of stay. Neonatal outcomes included stillbirths, incidence and severity of neonatal abstinence syndrome, birth weight, gestational age, Apgar scores, and incidence of congenital abnormalities. Results Thirty pregnant women used buprenorphine-naloxone for a mean (SD) of 18.8 (11.2) weeks; an additional 134 patients were exposed to other opioids; 476 pregnant women were not exposed to opioids. Maternal and neonatal outcomes were similar among the 3 groups, other than the expected clinically insignificant lower birth weights among those exposed to opioids other than buprenorphine-naloxone. Conclusion Buprenorphine-naloxone appears to be safe for use in pregnancy for opioid-dependence substitution therapy. Transferring a pregnant patient to another opioid agonist that has greater abuse potential might not be necessary.

  10. 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

  11. Agonist-antagonist combinations in opioid dependence: a translational approach

    PubMed Central

    Mannelli, P.

    2011-01-01

    Summary The potential therapeutic benefits of co-administering opiate agonist and antagonist agents remain largely to be investigated. This paper focuses on the mechanisms of very low doses of naltrexone that help modulate the effects of methadone withdrawal and review pharmacological properties of the buprenorphine/naltrexone combination that support its clinical investigation. The bench-to-bedside development of the very low dose naltrexone treatment can serve as a translational paradigm to investigate and treat drug addiction. Further research on putative mechanisms elicited by the use of opioid agonist-antagonist combinations may lead to effective pharmacological alternatives to the gold standard methadone treatment, also useful for the management of the abuse of non opioid drugs and alcohol. PMID:22448305

  12. Use of Pharmacotherapies in the Treatment of Alcohol Use Disorders and Opioid Dependence in Primary Care

    PubMed Central

    Lee, Jinhee; Kresina, Thomas F.; Campopiano, Melinda; Lubran, Robert; Clark, H. Westley

    2015-01-01

    Substance-related and addictive disorders are chronic relapsing conditions that substantially impact public health. Effective treatments for these disorders require addressing substance use/dependence comprehensively as well as other associated comorbidities. Comprehensive addressing of substance use in a medical setting involves screening for substance use, addressing substance use directly with the patient, and formulating an appropriate intervention. For alcohol dependence and opioid dependence, pharmacotherapies are available that are safe and effective when utilized in a comprehensive treatment paradigm, such as medication assisted treatment. In primary care, substance use disorders involving alcohol, illicit opioids, and prescription opioid abuse are common among patients who seek primary care services. Primary care providers report low levels of preparedness and confidence in identifying substance-related and addictive disorders and providing appropriate care and treatment. However, new models of service delivery in primary care for individuals with substance-related and addictive disorders are being developed to promote screening, care and treatment, and relapse prevention. The education and training of primary care providers utilizing approved medications for the treatment of alcohol use disorders and opioid dependence in a primary care setting would have important public health impact and reduce the burden of alcohol abuse and opioid dependence. PMID:25629034

  13. Utilizing buprenorphine–naloxone to treat illicit and prescription-opioid dependence

    PubMed Central

    Mauger, Sofie; Fraser, Ronald; Gill, Kathryn

    2014-01-01

    Objectives To review current evidence on buprenorphine–naloxone (bup/nx) for the treatment of opioid-use disorders, with a focus on strategies for clinical management and office-based patient care. Quality of evidence Medline and the Cochrane Database of Systematic Reviews were searched. Consensus reports, guidelines published, and other authoritative sources were also included in this review. Apart from expert guidelines, data included in this review constitute level 1 evidence. Findings Bup/nx is a partial μ-opioid agonist combined with the opioid antagonist naloxone in a 4:1 ratio. It has a lower abuse potential, carries less stigma, and allows for more flexibility than methadone. Bup/nx is indicated for both inpatient and ambulatory medically assisted withdrawal (acute detoxification) and long-term substitution treatment (maintenance) of patients who have a mild-to-moderate physical dependence. A stepwise long-term substitution treatment with regular monitoring and follow-up assessment is usually preferred, as it has better outcomes in reducing illicit opioid use, minimizing concomitant risks such as human immunodeficiency virus and hepatitis C transmission, retaining patients in treatment and improving global functioning. Conclusion Bup/nx is safe and effective for opioid detoxification and substitution treatment. Its unique pharmaceutical properties make it particularly suitable for office-based maintenance treatment of opioid-use disorder. PMID:24741316

  14. Expanding treatment capacity for opioid dependence with office-based treatment with buprenorphine: National surveys of physicians.

    PubMed

    Arfken, Cynthia L; Johanson, Chris-Ellyn; di Menza, Salvatore; Schuster, Charles Roberts

    2010-09-01

    Office-based treatment of opioid dependence with buprenorphine has the potential to expand treatment capacity in the United States. However, nationally, little is known about the number, characteristics, and experiences of physicians certified to prescribe buprenorphine. Moreover, little is known about the impact of easing federal regulations on the number of patients a physician is allowed to treat concurrently. To address these questions, surveys of national samples of physicians certified to prescribe buprenorphine (2004-2008) were analyzed (N = 6,892). There has been a continual increase in the number of physicians certified to prescribe buprenorphine, increase in the mean number of patients treated by physicians, and decrease in patients turned away, coinciding temporally with easing of federal regulations. In addition, most physicians prescribed buprenorphine outside of traditional treatment settings. The U.S. experiment in expanding Schedule III-V medications for opioid dependence to physicians outside of formal substance abuse treatment facilities appears to have resulted in expanded capacity.

  15. Effects of HCV Seropositive Status on Buprenorphine Pharmacokinetics in Opioid-Dependent Individuals

    PubMed Central

    Masson, Carmen L.; Rainey, Petrie M.; Moody, David E.; McCance-Katz, Elinore F.

    2013-01-01

    Background and Objectives The purpose of this study was to examine the effect of hepatitis C virus (HCV) infection on buprenorphine pharmacokinetics in opioid-dependent, buprenorphine/naloxone-maintained adults. Methods A retrospective analysis of buprenorphine pharmacokinetics in HCV seropositive and seronegative buprenorphine/naloxone-maintained individuals (N = 49) was undertaken. Results Relative to HCV seronegative subjects, HCV seropositive subjects had higher buprenorphine exposure, as demonstrated by elevated buprenorphine AUC and Cmax values (p = .03 and .02, respectively) and corresponding elevations in the metabolites, buprenorphine-3-glucuronide AUC values (p = .03) and norbuprenorphine-3-glucuronide AUC and C24 values (p = .05 and .03, respectively). Discussion and Conclusions HCV infection was associated with higher plasma concentrations of buprenorphine and buprenorphine metabolites. Scientific Significance and Future Directions Findings suggest the potential for opioid toxicity among HCV-infected patients treated with buprenorphine/naloxone, and possible hepatotoxic effects related to increased buprenorphine exposure. HCV-infected patients receiving buprenorphine may need lower doses to maintain therapeutic plasma concentrations. PMID:24313239

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

    PubMed

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

    2013-11-01

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

  17. [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

  18. [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

  19. Impact of treatment for opioid dependence on fatal drug‐related poisoning: a national cohort study in England

    PubMed Central

    Pierce, Matthias; Bird, Sheila M.; Hickman, Matthew; Marsden, John; Dunn, Graham; Jones, Andrew

    2015-01-01

    Abstract Aims To compare the change in illicit opioid users’ risk of fatal drug‐related poisoning (DRP) associated with opioid agonist pharmacotherapy (OAP) and psychological support, and investigate the modifying effect of patient characteristics, criminal justice system (CJS) referral and treatment completion. Design National data linkage cohort study of the English National Drug Treatment Monitoring System and the Office for National Statistics national mortality database. Data were analysed using survival methods. Setting All services in England that provide publicly funded, structured treatment for illicit opioid users. Participants Adults treated for opioid dependence during April 2005 to March 2009: 151 983 individuals; 69% male; median age 32.6 with 442 950 person‐years of observation. Measurements The outcome was fatal DRP occurring during periods in or out of treatment, with adjustment for age, gender, substances used, injecting status and CJS referral. Findings There were 1499 DRP deaths [3.4 per 1000 person‐years, 95% confidence interval (CI) = 3.2–3.6]. DRP risk increased while patients were not enrolled in any treatment [adjusted hazard ratio (aHR) = 1.73, 95% CI = 1.55–1.92]. Risk when enrolled only in a psychological intervention was double that during OAP (aHR = 2.07, 95% CI = 1.75–2.46). The increased risk when out of treatment was greater for men (aHR = 1.88, 95% CI = 1.67–2.12), illicit drug injectors (aHR = 2.27, 95% CI = 1.97–2.62) and those reporting problematic alcohol use (aHR = 2.37, 95% CI = 1.90–2.98). Conclusions Patients who received only psychological support for opioid dependence in England appear to be at greater risk of fatal opioid poisoning than those who received opioid agonist pharmacotherapy. PMID:26452239

  20. Association of Opioids and Sedatives with Increased Risk of In-Hospital Cardiopulmonary Arrest from an Administrative Database

    PubMed Central

    Overdyk, Frank J.; Dowling, Oonagh; Marino, Joseph; Qiu, Jiejing; Chien, Hung-Lun; Erslon, Mary; Morrison, Neil; Harrison, Brooke; Dahan, Albert; Gan, Tong J.

    2016-01-01

    Background While opioid use confers a known risk for respiratory depression, the incremental risk of in-hospital cardiopulmonary arrest, respiratory arrest, or cardiopulmonary resuscitation (CPRA) has not been studied. Our aim was to investigate the prevalence, outcomes, and risk profile of in-hospital CPRA for patients receiving opioids and medications with central nervous system sedating side effects (sedatives). Methods A retrospective analysis of adult inpatient discharges from 2008–2012 reported in the Premier Database. Patients were grouped into four mutually exclusive categories: (1) opioids and sedatives, (2) opioids only, (3) sedatives only, and (4) neither opioids nor sedatives. Results Among 21,276,691 inpatient discharges, 53% received opioids with or without sedatives. A total of 96,554 patients suffered CPRA (0.92 per 1000 hospital bed-days). Patients who received opioids and sedatives had an adjusted odds ratio for CPRA of 3.47 (95% CI: 3.40–3.54; p<0.0001) compared with patients not receiving opioids or sedatives. Opioids alone and sedatives alone were associated with a 1.81-fold and a 1.82-fold (p<0.0001 for both) increase in the odds of CPRA, respectively. In opioid patients, locations of CPRA were intensive care (54%), general care floor (25%), and stepdown units (15%). Only 42% of patients survived CPRA and only 22% were discharged home. Opioid patients with CPRA had mean increased hospital lengths of stay of 7.57 days and mean increased total hospital costs of $27,569. Conclusions Opioids and sedatives are independent and additive risk factors for in-hospital CPRA. The impact of opioid sparing analgesia, reduced sedative use, and better monitoring on CPRA incidence deserves further study. PMID:26913753

  1. Opioid Receptor-Dependent Sex Differences in Synaptic Plasticity in the Hippocampal Mossy Fiber Pathway of the Adult Rat

    PubMed Central

    Harte-Hargrove, Lauren C.; Varga-Wesson, Ada; Duffy, Aine M.; Milner, Teresa A.

    2015-01-01

    The mossy fiber (MF) pathway is critical to hippocampal function and influenced by gonadal hormones. Physiological data are limited, so we asked whether basal transmission and long-term potentiation (LTP) differed in slices of adult male and female rats. The results showed small sex differences in basal transmission but striking sex differences in opioid receptor sensitivity and LTP. When slices were made from females on proestrous morning, when serum levels of 17β-estradiol peak, the nonspecific opioid receptor antagonist naloxone (1 μm) enhanced MF transmission but there was no effect in males, suggesting preferential opioid receptor-dependent inhibition in females when 17β-estradiol levels are elevated. The μ-opioid receptor (MOR) antagonist Cys2,Tyr3,Orn5,Pen7-amide (CTOP; 300 nm) had a similar effect but the δ-opioid receptor (DOR) antagonist naltrindole (NTI; 1 μm) did not, implicating MORs in female MF transmission. The GABAB receptor antagonist saclofen (200 μm) occluded effects of CTOP but the GABAA receptor antagonist bicuculline (10 μm) did not. For LTP, a low-frequency (LF) protocol was used because higher frequencies elicited hyperexcitability in females. Proestrous females exhibited LF-LTP but males did not, suggesting a lower threshold for synaptic plasticity when 17β-estradiol is elevated. NTI blocked LF-LTP in proestrous females, but CTOP did not. Electron microscopy revealed more DOR-labeled spines of pyramidal cells in proestrous females than males. Therefore, we suggest that increased postsynaptic DORs mediate LF-LTP in proestrous females. The results show strong MOR regulation of MF transmission only in females and identify a novel DOR-dependent form of MF LTP specific to proestrus. PMID:25632146

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

    PubMed

    Soyka, Michael

    2015-01-01

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

  4. Possible involvement of endogenous opioid system located downstream of α7 nicotinic acetylcholine receptor in mice with physical dependence on nicotine.

    PubMed

    Ueno, Keiko; Kiguchi, Norikazu; Kobayashi, Yuka; Saika, Fumihiro; Wakida, Naoki; Yamamoto, Chizuko; Maeda, Takehiko; Ozaki, Masanobu; Kishioka, Shiroh

    2014-01-01

    We previously reported that nicotine (NIC)-induced analgesia was elicited in part by activation of the endogenous opioid system. Moreover, it is well known that NIC has physical-dependence liability, but its mechanism is unclear. Therefore, we examined whether physical dependence on NIC was mediated by activation of the endogenous opioid system in ICR mice. We evaluated increased serum corticosterone (SCS) as an indicator of NIC withdrawal, as it is a quantitative indicator of naloxone (opioid receptor antagonist, NLX)-precipitated morphine withdrawal in mice. In this study, NLX precipitated an SCS increase in mice receiving repeated NIC, by a dose-dependent mechanism, and correlated with the dose and number of days of repeated NIC administration. When an opioid receptor antagonist (naltrexone) was concomitantly administered with repeated NIC, the NLX-precipitated SCS increase was not elicited. Concomitant administration of the α7 nicotinic acetylcholine receptor (nAChR) antagonist (methyllycaconitine) with repeated NIC, but not the α4β2 nAChR antagonist (dihydro-β-erythroidine), did not elicit an SCS increase by NLX. Thus, a physical dependence on NIC was in part mediated by the activation of the endogenous opioid system, located downstream of α7 nAChR.

  5. Impact of a Standardized Treatment Guideline for Pediatric Iatrogenic Opioid Dependence: A Quality Improvement Initiative

    PubMed Central

    Reyburn-Orne, Teri; Youssef, Tarek H.; Haddad, Imad Y.; Gerkin, Richard D.

    2016-01-01

    OBJECTIVES: To determine whether utilization of a hospital-based clinical practice guideline for the care of pediatric iatrogenic opioid dependence (IOD) would promote a decrease in opioid exposure and improve management of opioid abstinence syndrome (AS). METHODS: This study is a retrospective chart review of critically ill patients from a tertiary care children's hospital. Inclusion criteria included mechanically ventilated patients up to 18 years of age who received continuous opioid infusions for at least 7 days and any length of methadone administration. Data on IOD patients from January 2005 to June 2010 was divided into 3 periods: baseline, phase 1, and phase 2. Primary outcome was decrease in opioid exposure, measured by methadone duration of use and any additional opioid bolus doses used in AS management. Documentation of additional opioid bolus doses was regarded as a surrogate measure of AS. Secondary outcomes included total cumulative fentanyl dose, continuous fentanyl infusion duration of use, and hospital and pediatric intensive care unit length of stay. RESULTS: There was a significant decrease in methadone duration of use in IOD patients from 15.3 ± 8.7 days at baseline to 9.5 ± 3.7 days during phase 1 (p = 0.002), to 8.1 ± 3.7 days on phase 2 (reduction not significant, p = 0.106) of this evaluation. Additional opioid bolus doses were significantly lower from baseline to phase 1 (5.5 ± 5.1 vs. 1.8 ± 2.3, p = 0.001) and from phase 1 to phase 2 (1.8 ± 2.3 vs. 0.2 ± 1.5, p = 0.003). For the remaining outcomes, differences were not observed among the evaluation periods, except for the total cumulative fentanyl dose, which was reduced from 2.8 ± 3.7 mg/kg at baseline to 1 ± 1 mg/kg only during phase 1 (p = 0.017). CONCLUSIONS: Introduction of a standardized, hospital-based clinical practice guideline for children with IOD reduced the length of exposure to opioids and improved opioid AS management. PMID:26997929

  6. Opioid-dependent regulation of high and low fear responses in two inbred mouse strains.

    PubMed

    Szklarczyk, Klaudia; Korostynski, Michal; Cieslak, Przemyslaw Eligiusz; Wawrzczak-Bargiela, Agnieszka; Przewlocki, Ryszard

    2015-10-01

    The molecular mechanisms underlying the susceptibility or resilience to trauma-related disorders remain incompletely understood. Opioids modulate emotional learning, but the roles of specific receptors are unclear. Here, we aimed to analyze the contribution of the opioid system to fear responses in two inbred mouse strains exhibiting distinct behavioral phenotypes. SWR/J and C57BL/6J mice were subjected to five consecutive electric footshocks (1mA each), and the contextual freezing time was measured. Stress-induced alterations in gene expression were analyzed in the amygdala and the hippocampus. In both strains, the fear response was modulated using pharmacological tools. SWR/J mice did not develop conditioned fear but exhibited increased transcriptional expression of Pdyn and Penk in the amygdala region. Blocking opioid receptors prior to the footshocks using naltrexone (2 mg/kg) or naltrindole (5 mg/kg) increased the freezing responses in these animals. The C57BL/6J strain displayed high conditioned fear, although no alteration in the mRNA abundance of genes encoding opioid precursors was observed. Double-injection of morphine (20 mg/kg) following stress and upon context re-exposure prevented the enhancement of freezing. Moreover, selective delta and kappa agonists caused a reduction in conditioned fear responses. To summarize, the increased expression of the Pdyn and Penk genes corresponded to reduced intensity of fear responses. Blockade of the endogenous opioid system restored freezing behavior in stress-resistant animals. The pharmacological stimulation of the kappa and delta opioid receptors in stress-susceptible individuals may alleviate fear. Thus, subtype-selective opioid receptor agonists may protect against the development of trauma-related disorders.

  7. Central amygdala opioid transmission is necessary for increased high-fat intake following 24-h food deprivation, but not following intra-accumbens opioid administration.

    PubMed

    Parker, Kyle E; Johns, Howard W; Floros, Ted G; Will, Matthew J

    2014-03-01

    Previous research has demonstrated a dissociation of certain neural mediators that contribute to the increased consumption of a high-fat diet that follows intra-accumbens (Acb) administration of μ-opioid receptor agonists vs. 24-h food deprivation. These two models, both which induce rapid consumption of the diet, have been shown to involve a distributed corticolimbic circuitry, including the amygdala. Specifically, the central amygdala (CeA) has been shown to be involved in high-fat feeding within both opioid and food-deprivation driven models. The present experiments were conducted to examine the more specific role of CeA opioid transmission in mediating high-fat feeding driven by either intra-Acb administration of the μ-opioid agonist d-Ala2-NMe-Phe4-Glyol5-enkephalin (DAMGO) or 24-h home cage food deprivation. Injection of DAMGO into the Acb (0.25 μg/0.5 μl/side) increased consumption of the high-fat diet, but this feeding was unaffected by administration of opioid antagonist, naltrexone (5 μg/0.25 μl/side) administered into the CeA. In contrast, intra-CeA naltrexone administration attenuated high-fat intake driven by 24-h food deprivation, demonstrating a specific role for CeA opioid transmission in high-fat consumption. Intra-CeA naltrexone administration alone had no effect on baseline feeding levels within either feeding model. These findings suggest that CeA opioid transmission mediates consumption of a palatable high-fat diet driven by short-term negative-energy balance (24-h food deprivation), but not intra-Acb opioid receptor activation.

  8. 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.

  9. Meperidine (pethidine) versus morphine in acute pain management of opioid-dependent patients

    PubMed Central

    Solhi, Hassan; Sanaei-Zadeh, Hossein; Solhi, Sadra; Azizi Nadian, Mohammad Ali; Gharibi, Morteza; Sadeghi Sedeh, Bahman

    2016-01-01

    The present study aimed to evaluate the effectiveness of morphine and meperidine (pethidine) as pain relief in opioid-dependent patients with acute pain. A total of 122 opioid-dependent patients with acute pain were included in the study. Their pain severity was assessed, using visual analog scale (VAS) scores ranging from 0 to 10. The patients randomly received intravenous morphine (up to 0.15 mg/kg) or meperidine (up to 1.5 mg/kg) for pain control by patient control analgesia (PCA) pump. The clinical opioid withdrawal scale (COWS) was employed for the assessment of withdrawal symptoms. The pain relief and the emergence of withdrawal symptoms were measured at 15, 30, and 60 minutes after drug administration. The patients who received morphine reported a better pain control compared to those who received meperidine (mean ± standard deviation [SD] VAS scores 4.11±1.90 vs 5.85±2.08 at the end of the study; P<0.001). On the other hand, the patients who received meperidine indicated prominent withdrawal symptoms (mean ± SD COWS scores 4.80±2.18 vs. 1.98±0.82 at the end of the study; P<0.001). Our findings revealed that morphine can be recommended in acute pain management of opioid-dependent patients. In addition, emergency physicians should ask their patients about any drug dependence before selecting the appropriate drug for their acute pain management. PMID:27621675

  10. Meperidine (pethidine) versus morphine in acute pain management of opioid-dependent patients

    PubMed Central

    Solhi, Hassan; Sanaei-Zadeh, Hossein; Solhi, Sadra; Azizi Nadian, Mohammad Ali; Gharibi, Morteza; Sadeghi Sedeh, Bahman

    2016-01-01

    The present study aimed to evaluate the effectiveness of morphine and meperidine (pethidine) as pain relief in opioid-dependent patients with acute pain. A total of 122 opioid-dependent patients with acute pain were included in the study. Their pain severity was assessed, using visual analog scale (VAS) scores ranging from 0 to 10. The patients randomly received intravenous morphine (up to 0.15 mg/kg) or meperidine (up to 1.5 mg/kg) for pain control by patient control analgesia (PCA) pump. The clinical opioid withdrawal scale (COWS) was employed for the assessment of withdrawal symptoms. The pain relief and the emergence of withdrawal symptoms were measured at 15, 30, and 60 minutes after drug administration. The patients who received morphine reported a better pain control compared to those who received meperidine (mean ± standard deviation [SD] VAS scores 4.11±1.90 vs 5.85±2.08 at the end of the study; P<0.001). On the other hand, the patients who received meperidine indicated prominent withdrawal symptoms (mean ± SD COWS scores 4.80±2.18 vs. 1.98±0.82 at the end of the study; P<0.001). Our findings revealed that morphine can be recommended in acute pain management of opioid-dependent patients. In addition, emergency physicians should ask their patients about any drug dependence before selecting the appropriate drug for their acute pain management.

  11. Millon Clinical Multiaxial Inventory-III Subtypes of Opioid Dependence: Validity and Matching to Behavioral Therapies

    ERIC Educational Resources Information Center

    Ball, Samuel A.; Nich, Charla; Rounsaville, Bruce J.; Eagan, Dorothy; Carroll, Kathleen M.

    2004-01-01

    The concurrent and predictive validity of 2 different methods of Millon Clinical Multiaxial Inventory-III subtyping (protocol sorting, cluster analysis) was evaluated in 125 recently detoxified opioid-dependent outpatients in a 12-week randomized clinical trial. Participants received naltrexone and relapse prevention group counseling and were…

  12. Long term outcomes of pharmacological treatments for opioid dependence: does methadone still lead the pack?

    PubMed Central

    Garcia-Portilla, Maria Paz; Bobes-Bascaran, Maria Teresa; Bascaran, Maria Teresa; Saiz, Pilar Alejandra; Bobes, Julio

    2014-01-01

    The aim of this review was to update and summarize the scientific knowledge on the long term outcomes of the different pharmacological treatment options for opioid dependence currently available and to provide a critical discussion on the different treatment options based on these results. We performed a literature search using the PubMed databases and the reference lists of the identified articles. Data from research show that the three pharmacological options reviewed are effective treatments for opioid dependence with positive long term outcomes. However, each one has its specific target population and setting. While methadone and buprenorphine are first line options, heroin-assisted treatment is a second line option for those patients refractory to treatment with methadone with concomitant severe physical, mental, social and/or functional problems. Buprenorphine seems to be the best option for use in primary care offices. The field of opioid dependence treatment is poised to undergo a process of reinforcement and transformation. Further efforts from researchers, clinicians and authorities should be made to turn new pharmacological options into clinical reality and to overcome the structural and functional obstacles that maintenance programmes face in combatting opioid dependence. PMID:23145768

  13. Long term outcomes of pharmacological treatments for opioid dependence: does methadone still lead the pack?

    PubMed

    Garcia-Portilla, Maria Paz; Bobes-Bascaran, Maria Teresa; Bascaran, Maria Teresa; Saiz, Pilar Alejandra; Bobes, Julio

    2014-02-01

    The aim of this review was to update and summarize the scientific knowledge on the long term outcomes of the different pharmacological treatment options for opioid dependence currently available and to provide a critical discussion on the different treatment options based on these results. We performed a literature search using the PubMed databases and the reference lists of the identified articles. Data from research show that the three pharmacological options reviewed are effective treatments for opioid dependence with positive long term outcomes. However, each one has its specific target population and setting. While methadone and buprenorphine are first line options, heroin-assisted treatment is a second line option for those patients refractory to treatment with methadone with concomitant severe physical, mental, social and/or functional problems. Buprenorphine seems to be the best option for use in primary care offices. The field of opioid dependence treatment is poised to undergo a process of reinforcement and transformation. Further efforts from researchers, clinicians and authorities should be made to turn new pharmacological options into clinical reality and to overcome the structural and functional obstacles that maintenance programmes face in combatting opioid dependence.

  14. How Does Cognitive Behaviour Therapy Work with Opioid-Dependent Clients? Results of the UKCBTMM Study

    ERIC Educational Resources Information Center

    Kouimtsidis, Christos; Reynolds, Martina; Coulton, Simon; Drummond, Colin

    2012-01-01

    Introduction: Process research in psychotherapy is important to understand how treatment works. The National Institute of Clinical Excellence guidelines suggest that in methadone maintenance treatment (MMT) for opioid dependence, drug key-working should be based on cognitive behavioural therapy (CBT) principles. This article reports the findings…

  15. Meperidine (pethidine) versus morphine in acute pain management of opioid-dependent patients.

    PubMed

    Solhi, Hassan; Sanaei-Zadeh, Hossein; Solhi, Sadra; Azizi Nadian, Mohammad Ali; Gharibi, Morteza; Sadeghi Sedeh, Bahman

    2016-01-01

    The present study aimed to evaluate the effectiveness of morphine and meperidine (pethidine) as pain relief in opioid-dependent patients with acute pain. A total of 122 opioid-dependent patients with acute pain were included in the study. Their pain severity was assessed, using visual analog scale (VAS) scores ranging from 0 to 10. The patients randomly received intravenous morphine (up to 0.15 mg/kg) or meperidine (up to 1.5 mg/kg) for pain control by patient control analgesia (PCA) pump. The clinical opioid withdrawal scale (COWS) was employed for the assessment of withdrawal symptoms. The pain relief and the emergence of withdrawal symptoms were measured at 15, 30, and 60 minutes after drug administration. The patients who received morphine reported a better pain control compared to those who received meperidine (mean ± standard deviation [SD] VAS scores 4.11±1.90 vs 5.85±2.08 at the end of the study; P<0.001). On the other hand, the patients who received meperidine indicated prominent withdrawal symptoms (mean ± SD COWS scores 4.80±2.18 vs. 1.98±0.82 at the end of the study; P<0.001). Our findings revealed that morphine can be recommended in acute pain management of opioid-dependent patients. In addition, emergency physicians should ask their patients about any drug dependence before selecting the appropriate drug for their acute pain management. PMID:27621675

  16. Endogenous opioids regulate glucocorticoid-dependent stress-coping strategies in mice.

    PubMed

    Szklarczyk, Klaudia; Korostynski, Michal; Golda, Slawomir; Piechota, Marcin; Ficek, Joanna; Przewlocki, Ryszard

    2016-08-25

    Coping skills are essential in determining the outcomes of aversive life events. Our research was aimed to elucidate the molecular underpinnings of different coping styles in two inbred mouse strains, C57BL/6J and SWR/J. We compared the influence of a preceding stressor (0.5h of restraint) on behavioral and gene expression profiles between these two strains. The C57BL/6J strain exhibited increased conditioned fear and high immobility (passive coping). Oppositely, the SWR/J mice demonstrated low freezing and immobility, low post-restraint anxiety and considerable struggling during the forced swim test (active coping). Gene profiling in the amygdala revealed transcriptional patterns that were related to the differential stress reactivity, such as the activation of glucocorticoid-dependent genes specifically in the C57BL/6J mice. Post-restraint blood sampling for corticosterone levels confirmed the association of hypothalamic-pituitary-adrenal (HPA) activation with a passive coping style. Pharmacological tools were used to modulate the stress-coping strategies. The blockade of opioid receptors (ORs) before the aversive event caused transcriptional and neuroendocrine changes in the SWR/J mice that were characteristic of the passive coping strategy. We found that treatment with a glucocorticoid receptor (GR) agonist (dexamethasone (DEX), 4mg/kg) impaired the consolidation of fear memory in the C57BL/6J mice and that this effect was reversed by OR blockade (naltrexone (NTX), 2mg/kg). In parallel, a glucocorticoid receptor antagonist (mifepristone (MIF), 20mg/kg) reversed the effect of morphine (20mg/kg) on conditioned fear in the C57BL/6J mice. Our results suggest that in mice, stress-coping strategies are determined by opioid-dependent mechanisms that modulate activity of the HPA axis. PMID:27235740

  17. Comparing Mindfulness-Based Group Therapy With Treatment as Usual for Opioid Dependents: A Pilot Randomized Clinical Trial Study Protocol

    PubMed Central

    Imani, Saeed; Atef Vahid, Mohammad Kazem; Gharraee, Banafsheh; Habibi, Mojtaba; Bowen, Sarah; Noroozi, Alireza

    2015-01-01

    Background: In response to high burden of opioid abuse in Iran, Ministry of Health has launched a large-scale opioid maintenance treatment program, delivered through a network of certified drug treatment centers. To promote opioid pharmacotherapies, there is an urgent need to develop and introduce evidence-based psychosocial interventions into the network. Patients and Methods: This is a randomized clinical trial (RCT) to investigate feasibility and effectiveness of adding mindfulness-based group therapy to opioid pharmacotherapies as compared to opioid pharmacotherapies alone. The primary outcomes were treatment retention and percentage of weekly morphine, methamphetamine, and benzodiazepine negative tests. Discussion: This is the first RCT that explores the effectiveness of mindfulness-based relapse prevention group therapy among opioid dependent clients in Iran. The feasibility of group therapy and comparison of outcomes in intervention and control groups should be discussed in the outcome article. PMID:26251659

  18. Laboratory-induced cue reactivity among individuals with prescription opioid dependence.

    PubMed

    Back, Sudie E; Gros, Daniel F; McCauley, Jenna L; Flanagan, Julianne C; Cox, Elizabeth; Barth, Kelly S; Brady, Kathleen T

    2014-08-01

    Prescription opioid (PO) dependence is a critical health problem. Although examination of drug cue reactivity paradigms has advanced the understanding of risk factors for relapse for a variety of substances (e.g., cocaine, alcohol, nicotine), no PO specific drug cue paradigm has been developed. The current study addressed this gap in the literature and evaluated the ability of a newly developed PO drug cue paradigm to elicit subjective, physiological, and neuroendocrine changes among PO-dependent participants (n = 20) as compared to controls (n = 17). The drug cue paradigm included an induction script, viewing and handling paraphernalia (e.g., bottle of oxycontin pills, pill crusher) and watching a video depicting people using POs as well as places related to POs (e.g., pharmacies). Consistent with hypotheses, the PO group demonstrated significant pre- to post-cue increases on subjective ratings of craving, difficulty resisting POs, stress, and anger. The control group did not demonstrate significant changes on any of the subjective measures. Both the PO group and the control group evidenced significant pre- to post-cue increases in physiological responses (e.g., blood pressure, skin conductance), as expected given the arousing nature of the drug cue stimuli. The PO group, but not the control group, evidenced a significant pre- to post-cue increase in heart rate and salivary cortisol levels. The development and validation of a drug cue paradigm for POs may help inform future research and treatment development efforts for patients with PO dependence. PMID:24813546

  19. Female Sexual Dysfunction Among the Wives of Opioid-Dependent Males in Iran

    PubMed Central

    Anvar Abnavi, Marjan; Ahmadi, Jamshid; Hamidian, Sajedeh; Ghaffarpour, Sara

    2016-01-01

    Background Opiate abuse in males has significant effects on their sexual functions. In contrast, sexuality in females is a multidimensional issue that can strongly be affected by several factors in their partners. However, only a limited number of studies have assessed the role of males’ opioid dependency in their female partners’ sexual function. Objectives The present study aimed to evaluate the effect of males’ opioid dependency on their wives’ sexual function compared to the sexual function of the females whose husbands were not opioid dependent. Patients and Methods This study included 340 women who were selected through convenience sampling and divided into a control (females whose husbands were not opioid dependent) and a case group (women whose husbands were opioid dependent). The data were collected through an interview according to the DSM-IV-R criteria for female sexual dysfunctions by a senior female medical student who was one of the researchers. Finally, the data were entered into the SPSS statistical software (v. 15) and analyzed using the t-test and chi-square test. Results According to the results, the frequency of hypoactive sexual desire disorder and sexual aversion disorder in the control group was significantly higher than that of the case group (P < 0.05). Conclusions The results showed that having an addicted husband could strongly affect some sexual domains in women. It could change the pattern of desire and motivation for sexual contact in females and alter their attitude toward the sexual relationship, thereby causing disturbances in the females’ normal sexual function. PMID:27218067

  20. Failure to identify or effectively manage prescription opioid dependence acted as a gateway to heroin use-buprenorphine/naloxone treatment and recovery in a surgical patient.

    PubMed

    Conroy, Stephen; Hill, Duncan

    2014-12-17

    The prescribing of opioid pain medication has increased markedly in recent years, with strong opioid dispensing increasing 18-fold in Tayside, Scotland since 1995. Despite this, little data is available to quantify the problem of opioid pain medication dependence (OPD) and until recently there was little guidance on best-practice treatment. We report the case of a young mother prescribed dihydrocodeine for postoperative pain relief who became opioid dependent. When her prescription was stopped without support, she briefly used heroin to overcome her withdrawal. After re-exposure to dihydrocodeine following surgery 9 years later and treatment with methadone for dependency, she was transferred to buprenorphine/naloxone. In our clinical experience and in agreement with Department of Health and Royal College of General Practitioner guidance, buprenorphine/naloxone is the preferred opioid substitution treatment for OPD. Our patient remains within her treatment programme and has returned to work on buprenorphine 16 mg/naloxone 4 mg in conjunction with social and psychological support.

  1. Predictors of Abstinence: National Institute of Drug Abuse Multisite Buprenorphine/Naloxone Treatment Trial in Opioid-Dependent Youth

    ERIC Educational Resources Information Center

    Subramaniam, Geetha A.; Warden, Diane; Minhajuddin, Abu; Fishman, Marc J.; Stitzer, Maxine L.; Adinoff, Bryon; Trivedi, Madhukar; Weiss, Roger; Potter, Jennifer; Poole, Sabrina A.; Woody, George E.

    2011-01-01

    Objective: To examine predictors of opioid abstinence in buprenorphine/naloxone (Bup/Nal)-assisted psychosocial treatment for opioid-dependent youth. Method: Secondary analyses were performed of data from 152 youth (15-21 years old) randomly assigned to 12 weeks of extended Bup/Nal therapy or up to 2 weeks of Bup/Nal detoxification with weekly…

  2. Induction of opioid-dependent individuals onto buprenorphine and buprenorphine/naloxone soluble-films.

    PubMed

    Strain, E C; Harrison, J A; Bigelow, G E

    2011-03-01

    A sublingual soluble-film formulation of buprenorphine/naloxone (B/N) has been approved by the US Food and Drug Administration for the treatment of opioid dependency. This preparation provides unit-dose, child-resistant packaging amenable to tracking and accountability, offers more rapid dissolution, and has a potentially preferred taste vs. tablets. This study compared the ability of buprenorphine (B) and B/N films to suppress spontaneous withdrawal in opioid-dependent volunteers. Participants were maintained on morphine and underwent challenge sessions to confirm sensitivity to naloxone-induced opioid withdrawal. Subjects were randomized to receive either B (16 mg, n = 18) or B/N (16/4 mg, n = 16) soluble films for 5 days. The primary outcome measure was the Clinical Opiate Withdrawal Scale (COWS) score. Thirty-four subjects completed induction onto soluble films. There was a significant decrease in COWS scores but no significant differences between the groups. The results support the use of B and B/N soluble films as safe and effective delivery methods for opioid induction. PMID:21270789

  3. Methadone and buprenorphine for the management of opioid dependence in pregnancy.

    PubMed

    Jones, Hendrée E; Finnegan, Loretta P; Kaltenbach, Karol

    2012-04-16

    This article provides an overview and discussion of the collective maternal, fetal and neonatal outcome research on women maintained on methadone or buprenorphine during pregnancy. Its focus is on an assessment of the comparative effectiveness of methadone and buprenorphine pharmacotherapy, with particular attention given to recent findings from the literature. Recommendations for clinical practice are outlined, and directions for future research are presented. Findings from comparative studies of methadone and buprenorphine underscore the efficacy of both medications in preventing relapse to illicit opioid use in the treatment of opioid-dependent pregnant patients, as well as the simplicity of induction onto methadone and patient retention while receiving such therapy. Fetal monitoring suggests that buprenorphine results in less fetal cardiac and movement suppression than does methadone. The clinical implications of these findings need future exploration. For the neonate, evidence from studies using a wide range of designs, including retrospective chart reviews, prospective observational studies, and randomized clinical trials, show consistent results, with prenatal exposure to buprenorphine resulting in less severe neonatal abstinence syndrome relative to methadone. Any medication given to pregnant women should be prescribed only after considering the risk : benefit ratio for the maternal-fetal dyad. Medication choices for each opioid-dependent patient during pregnancy need to be made on a patient-by-patient basis, taking into consideration the patient's opioid dependence history, previous and current treatment experiences, medical circumstances and treatment preferences. Moreover, for a full remission of opioid addiction to be sustainable, both post-partum and across the lifespan, treatment providers must not rely solely on medication to treat their patients but should also utilize women-specific comprehensive treatment models that address the underlying

  4. Alcohol-Induced Changes in Opioid Peptide Levels in Adolescent Rats Are Dependent on Housing Conditions

    PubMed Central

    Palm, Sara; Nylander, Ingrid

    2014-01-01

    Background Endogenous opioids are implicated in the mechanism of action of alcohol and alcohol affects opioids in a number of brain areas, although little is known about alcohol's effects on opioids in the adolescent brain. One concern, in particular when studying young animals, is that alcohol intake models often are based on single housing that may result in alcohol effects confounded by the lack of social interactions. The aim of this study was to investigate short- and long-term alcohol effects on opioids and the influence of housing conditions on these effects. Methods In the first part, opioid peptide levels were measured after one 24-hour session of single housing and 2-hour voluntary alcohol intake in adolescent and adult rats. In the second part, a model with a cage divider inserted during 2-hour drinking sessions was tested and the effects on opioids were examined after 6 weeks of adolescent voluntary intake in single-and pair-housed rats, respectively. Results The effects of single housing were age specific and affected Met-enkephalin-Arg6Phe7 (MEAP) in particular. In adolescent rats, it was difficult to distinguish between effects induced by alcohol and single housing, whereas alcohol-specific effects were seen in dynorphin B (DYNB), beta-endorphin (BEND), and MEAP levels in adults. Voluntary drinking affected several brain areas and the majority of alcohol-induced effects were not dependent on housing. However, alcohol effects on DYNB and BEND in the amygdala were dependent on housing. Housing alone affected MEAP in the cingulate cortex. Conclusions Age-specific housing- and alcohol-induced effects on opioids were found. In addition, prolonged voluntary alcohol intake under different housing conditions produced several alcohol-induced effects independent of housing. However, housing-dependent effects were found in areas implicated in stress, emotionality, and alcohol use disorder. Housing condition and age may therefore affect the reasons and

  5. The hyperinsulinemia produced by concanavalin A in rats is opioid-dependent and hormonally regulated.

    PubMed

    Francisco-DoPrado, J; Zambelli, J E; Melo-Lima, M H; Ribeiro-DaSilva, G

    1998-05-01

    The present study examines the effect of concanavalin A (Con A) on the blood insulin and glucose levels of rats. Male and female rats treated with Con A (62.5-500 micrograms/kg) for three days showed a dose- and time-dependent hyperinsulinemia that lasted more than 48 h. Male rats were more sensitive to Con A. Thus, 6 h after treatment with Con A the circulating insulin levels in male rats had increased by 85% (control: 10.2 +/- 0.9 mU/l and Con A-treated: 18.8 +/- 1 mU/l) compared to only 38% (control: 7.5 +/- 0.2 mU/l; Con A-treated: 10.3 +/- mU/l) in females. An identical response was seen after 12 h. Con A (250 micrograms/kg) produced time-dependent hypoglycemia in both sexes but more pronounced in males. There was no correlation between the hypoglycemia and hyperinsulinemia described above. The Con A-induced hyperinsulinemia in rats of both sexes was abolished in gonadectomized animals (intact males: +101 +/- 17% vs orchiectomized males: -5 +/- 3%; intact females: +86 +/- 23% vs ovariectomized females: -18 +/- 7.2%). Pretreating intact male and female rats with human chorionic gonadotropin also significantly inhibited the Con A-induced hyperinsulinemia. Estradiol (10 micrograms/kg,i.m.) significantly blocked the Con A-induced increase in circulating insulin in male rats (101 +/- 17% for controls vs 32 +/- 5.3% for estradiol-treated animals, P < 0.05) while testosterone (10 mg/kg, i.m.) had no similar effect on intact female rats. Pretreating Con A-injected rats with opioid antagonists such as naloxone (1 mg/kg, s.c.) and naltrexone (5 mg/kg, s.c.) blocked the hyperinsulinemia produced by the lectin in males (control: +101 +/- 17% vs naloxone-treated: +5 +/- 14%, or naltrexone-treated: -23 +/- 4.5%) and females (control: +86 +/- 23% vs naloxone-treated: +21 +/- 20%, or naltrexone-treated: -18 +/- 11%). These results demonstrate that Con A increases the levels of circulating insulin in rats and that this response is opioid-dependent and hormonally regulated

  6. Low-dose add-on memantine treatment may improve cognitive performance and self-reported health conditions in opioid-dependent patients undergoing methadone-maintenance-therapy.

    PubMed

    Chang, Yun-Hsuan; Chen, Shiou-Lan; Lee, Sheng-Yu; Chen, Po See; Wang, Tzu-Yun; Lee, I Hui; Chen, Kao Chin; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band

    2015-01-01

    An important interaction between opioid and dopamine systems has been indicated, and using opioids may negatively affect cognitive functioning. Memantine, a medication for Alzheimer's disease, increasingly is being used for several disorders and maybe important for cognitive improvement. Opioid-dependent patients undergoing methadone-maintenance-therapy (MMT) and healthy controls (HCs) were recruited. Patients randomly assigned to the experimental (5 mg/day memantine (MMT+M) or placebo (MMT+P) group: 57 in MMT+M, 77 in MMT+P. Those completed the cognitive tasks at the baseline and after the 12-week treatment were analyzed. Thirty-seven age- and gender-matched HCs, and 42 MMT+P and 39 MMT+M patients were compared. The dropout rates were 49.4% in the MMT+P and 26.3% in the MMT+M. Both patient groups' cognitive performances were significantly worse than that of the HCs. After the treatment, both patient groups showed improved cognitive performance. We also found an interaction between the patient groups and time which indicated that the MMT+M group's post-treatment improvement was better than that of the MMT+P group. Memantine, previously reported as neuroprotective may attenuate chronic opioid-dependence-induced cognitive decline. Using such low dose of memantine as adjuvant treatment for improving cognitive performance in opioid dependents; the dose of memantine might be a worthy topic in future studies. PMID:25989606

  7. Low-dose add-on memantine treatment may improve cognitive performance and self-reported health conditions in opioid-dependent patients undergoing methadone-maintenance-therapy.

    PubMed

    Chang, Yun-Hsuan; Chen, Shiou-Lan; Lee, Sheng-Yu; Chen, Po See; Wang, Tzu-Yun; Lee, I Hui; Chen, Kao Chin; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band

    2015-05-19

    An important interaction between opioid and dopamine systems has been indicated, and using opioids may negatively affect cognitive functioning. Memantine, a medication for Alzheimer's disease, increasingly is being used for several disorders and maybe important for cognitive improvement. Opioid-dependent patients undergoing methadone-maintenance-therapy (MMT) and healthy controls (HCs) were recruited. Patients randomly assigned to the experimental (5 mg/day memantine (MMT+M) or placebo (MMT+P) group: 57 in MMT+M, 77 in MMT+P. Those completed the cognitive tasks at the baseline and after the 12-week treatment were analyzed. Thirty-seven age- and gender-matched HCs, and 42 MMT+P and 39 MMT+M patients were compared. The dropout rates were 49.4% in the MMT+P and 26.3% in the MMT+M. Both patient groups' cognitive performances were significantly worse than that of the HCs. After the treatment, both patient groups showed improved cognitive performance. We also found an interaction between the patient groups and time which indicated that the MMT+M group's post-treatment improvement was better than that of the MMT+P group. Memantine, previously reported as neuroprotective may attenuate chronic opioid-dependence-induced cognitive decline. Using such low dose of memantine as adjuvant treatment for improving cognitive performance in opioid dependents; the dose of memantine might be a worthy topic in future studies.

  8. Laboratory-Induced Stress and Craving among Individuals with Prescription Opioid Dependence

    PubMed Central

    Back, Sudie E.; Gros, Daniel F.; Price, Matthew; LaRowe, Steve; Flanagan, Julianne; Brady, Kathleen T.; Davis, Charles; Jaconis, Maryanne; McCauley, Jenna L.

    2015-01-01

    Background Stress and conditioned drug cues have been implicated in the initiation, maintenance and relapse to substances of abuse. Although stress and drug cues are often encountered together, little research exists on whether stress potentiates the response to drug cues. Method Participants (N = 75) were 39 community recruited individuals with current prescription opioid (PO) dependence and 36 healthy controls. Participants stayed overnight in the hospital for one night and then completed laboratory testing the following morning. During laboratory testing, participants were randomly assigned to a stress task (Trier Social Stress Task; TSST) or a no-stress condition. Following the stress manipulation, all participants completed a PO cue paradigm. Immediately before and after the stress and cue tasks, the following were assessed: subjective (stress, craving, anger, sadness, happiness), physiological (heart rate, blood pressure, galvanic skin response), and neuroendocrine responses (cortisol and dehydroepiandrosterone). Results Internal validity of the stress task was demonstrated, as evidenced by significantly higher subjective stress, as well as cortisol, heart rate and blood pressure in the TSST compared to the no-stress group. Individuals with PO dependence evidenced significantly greater reactivity to the stress task than controls. Craving increased significantly in response to the drug cue task among PO participants. No stress × cue interaction was observed. Conclusions In this study, heightened stress reactivity was observed among individuals with PO dependence. Exposure to acute stress, however, did not potentiate craving in response to conditioned drug cues. PMID:26342626

  9. [Personality changes in opioid-dependent subjects in a methadone maintenance treatment program].

    PubMed

    Trémeau, F; Darreye, A; Leroy, B; Renckly, V; Ertlé, S; Weibel, H; Khidichian, F; Macher, J-P

    2003-01-01

    Personality disorders and particularly antisocial personality disorders (APD) are quite frequent in opioid-dependent subjects. They show various personality traits: high neuroticism, high impulsivity, higher extraversion than the general population. Previous studies have reported that some but not all personality traits improved with treatment. In a previous study, we found a low rate of APD in a French population of opioid-dependent subjects. For this reason, we evaluated personality traits at intake and during maintenance treatment with methadone. Methods - The form A of the Eysenck Personality Inventory (EPI) was given to opioid addicts at intake and after 6 and 12 months of methadone treatment. Results - 134 subjects (96 males and 38 females) took the test at intake, 60 completed 12 months of treatment. After 12 months, the EPI Neuroticism (N) and the Extraversion-introversion (E) scale scores decreased significantly. The N score improved in the first 6 months, while the E score improved only during the second 6 months of treatment. Compared to a reference group of French normal controls, male and female opioid addicts showed high N and E scores. Demographic data and EPI scores of patients who stayed in treatment for 12 months did not differ significantly from those of dropouts (n=23). Patients with a history of suicide attempts (SA) started to use heroin at an earlier age and they showed a higher E score and a tendency for a higher N score at intake. Discussion - The two personality dimensions of the EPI changed during MMT, and the N score converged towards the score of normal controls. Opioid addicts differ from normal controls mostly in their N score. The EPI did not help to differentiate 12-month completers from dropouts. Higher E scores in patients with an SA history might reflect a higher impulsivity, which has been linked to suicidality in other patient groups.

  10. Employment-based abstinence reinforcement following inpatient detoxification in HIV-positive opioid and/or cocaine-dependent patients.

    PubMed

    Dunn, Kelly E; Fingerhood, Michael; Wong, Conrad J; Svikis, Dace S; Nuzzo, Paul; Silverman, Kenneth

    2014-02-01

    Employment-based reinforcement interventions have been used to promote abstinence from drugs among chronically unemployed injection drug users. The current study used an employment-based reinforcement intervention to promote opioid and cocaine abstinence among opioid and/or cocaine-dependent, HIV-positive participants who had recently completed a brief inpatient detoxification. Participants (n = 46) were randomly assigned to an abstinence and work group that was required to provide negative urine samples in order to enter the workplace and to earn incentives for work (n = 16), a work-only group that was permitted to enter the workplace and to earn incentives independent of drug use (n = 15), and a no-voucher control group that did not receive any incentives for working (n = 15) over a 26-week period. The primary outcome was urinalysis-confirmed opioid, cocaine, and combined opioid/cocaine abstinence. Participants were 78% male and 89% African American. Results showed no significant between-groups differences in urinalysis-verified drug abstinence or HIV risk behaviors during the 6-month intervention. The work-only group had significantly greater workplace attendance, and worked more minutes per day when compared to the no-voucher group. Several features of the study design, including the lack of an induction period, setting the threshold for entering the workplace too high by requiring immediate abstinence from several drugs, and increasing the risk of relapse by providing a brief detoxification that was not supported by any continued pharmacological intervention, likely prevented the workplace from becoming established as a reinforcer that could be used to promote drug abstinence. However, increases in workplace attendance have important implications for adult training programs. PMID:24490712

  11. Employment-based abstinence reinforcement following inpatient detoxification in HIV-positive opioid and/or cocaine-dependent patients.

    PubMed

    Dunn, Kelly E; Fingerhood, Michael; Wong, Conrad J; Svikis, Dace S; Nuzzo, Paul; Silverman, Kenneth

    2014-02-01

    Employment-based reinforcement interventions have been used to promote abstinence from drugs among chronically unemployed injection drug users. The current study used an employment-based reinforcement intervention to promote opioid and cocaine abstinence among opioid and/or cocaine-dependent, HIV-positive participants who had recently completed a brief inpatient detoxification. Participants (n = 46) were randomly assigned to an abstinence and work group that was required to provide negative urine samples in order to enter the workplace and to earn incentives for work (n = 16), a work-only group that was permitted to enter the workplace and to earn incentives independent of drug use (n = 15), and a no-voucher control group that did not receive any incentives for working (n = 15) over a 26-week period. The primary outcome was urinalysis-confirmed opioid, cocaine, and combined opioid/cocaine abstinence. Participants were 78% male and 89% African American. Results showed no significant between-groups differences in urinalysis-verified drug abstinence or HIV risk behaviors during the 6-month intervention. The work-only group had significantly greater workplace attendance, and worked more minutes per day when compared to the no-voucher group. Several features of the study design, including the lack of an induction period, setting the threshold for entering the workplace too high by requiring immediate abstinence from several drugs, and increasing the risk of relapse by providing a brief detoxification that was not supported by any continued pharmacological intervention, likely prevented the workplace from becoming established as a reinforcer that could be used to promote drug abstinence. However, increases in workplace attendance have important implications for adult training programs.

  12. Reduced striatal dopamine transporter density associated with working memory deficits in opioid-dependent male subjects: a SPECT study.

    PubMed

    Liang, Chih-Sung; Ho, Pei-Shen; Yen, Che-Hung; Yeh, Yi-Wei; Kuo, Shin-Chang; Huang, Chang-Chih; Chen, Chun-Yen; Shih, Mei-Chen; Ma, Kuo-Hsing; Huang, San-Yuan

    2016-01-01

    Research on the effects of repeated opioid use on striatal dopamine transporters has yielded inconsistent results, possibly confounded by a history of methamphetamine or methadone exposure in opioid-dependent individuals. Previous studies have shown that striatal dopamine transporter density is positively correlated with the cognitive performance of healthy volunteers. This study aimed to investigate changes in striatal dopamine transporter density and their functional significance in opioid-dependent individuals. Single-photon emission computed tomography with [(99m) Tc]TRODAT-1 as a ligand was used to measure striatal dopamine transporter levels in 20 opioid-dependent individuals and 20 age- and sex-matched healthy controls. Opioid-dependent individuals had no history of methamphetamine or methadone use. The Wisconsin Card Sorting Test (WCST) was performed to assess neurocognitive function. We found that compared with healthy controls, opioid-dependent individuals showed a significant reduction in striatal dopamine transporter density. They also showed poorer performance on the WCST in terms of the trials administered, total errors, perseverative responses, perseverative errors, and non-perseverative errors. Striatal dopamine transporter levels negatively correlated with non-perseverative errors not only in opioid-dependent individuals but also in healthy controls. These findings suggest that in human, repeated opioid exposure reduces striatal dopamine transporter density, which can be associated with non-perseverative errors. Non-perseverative errors may be one of the more sensitive parameters in WCST to identify working memory deficits associated with striatal dopamine transporter reduction. Moreover, we suggest that whether opioid-associated neurotoxicity is reversible depends on the brain region. PMID:25439653

  13. GIRK Channels Modulate Opioid-Induced Motor Activity in a Cell Type- and Subunit-Dependent Manner.

    PubMed

    Kotecki, Lydia; Hearing, Matthew; McCall, Nora M; Marron Fernandez de Velasco, Ezequiel; Pravetoni, Marco; Arora, Devinder; Victoria, Nicole C; Munoz, Michaelanne B; Xia, Zhilian; Slesinger, Paul A; Weaver, C David; Wickman, Kevin

    2015-05-01

    G-protein-gated inwardly rectifying K(+) (GIRK/Kir3) channel activation underlies key physiological effects of opioids, including analgesia and dependence. GIRK channel activation has also been implicated in the opioid-induced inhibition of midbrain GABA neurons and consequent disinhibition of dopamine (DA) neurons in the ventral tegmental area (VTA). Drug-induced disinhibition of VTA DA neurons has been linked to reward-related behaviors and underlies opioid-induced motor activation. Here, we demonstrate that mouse VTA GABA neurons express a GIRK channel formed by GIRK1 and GIRK2 subunits. Nevertheless, neither constitutive genetic ablation of Girk1 or Girk2, nor the selective ablation of GIRK channels in GABA neurons, diminished morphine-induced motor activity in mice. Moreover, direct activation of GIRK channels in midbrain GABA neurons did not enhance motor activity. In contrast, genetic manipulations that selectively enhanced or suppressed GIRK channel function in midbrain DA neurons correlated with decreased and increased sensitivity, respectively, to the motor-stimulatory effect of systemic morphine. Collectively, these data support the contention that the unique GIRK channel subtype in VTA DA neurons, the GIRK2/GIRK3 heteromer, regulates the sensitivity of the mouse mesolimbic DA system to drugs with addictive potential.

  14. GIRK Channels Modulate Opioid-Induced Motor Activity in a Cell Type- and Subunit-Dependent Manner

    PubMed Central

    Kotecki, Lydia; Hearing, Matthew; McCall, Nora M.; Marron Fernandez de Velasco, Ezequiel; Pravetoni, Marco; Arora, Devinder; Victoria, Nicole C.; Munoz, Michaelanne B.; Xia, Zhilian; Slesinger, Paul A.; Weaver, C. David

    2015-01-01

    G-protein-gated inwardly rectifying K+ (GIRK/Kir3) channel activation underlies key physiological effects of opioids, including analgesia and dependence. GIRK channel activation has also been implicated in the opioid-induced inhibition of midbrain GABA neurons and consequent disinhibition of dopamine (DA) neurons in the ventral tegmental area (VTA). Drug-induced disinhibition of VTA DA neurons has been linked to reward-related behaviors and underlies opioid-induced motor activation. Here, we demonstrate that mouse VTA GABA neurons express a GIRK channel formed by GIRK1 and GIRK2 subunits. Nevertheless, neither constitutive genetic ablation of Girk1 or Girk2, nor the selective ablation of GIRK channels in GABA neurons, diminished morphine-induced motor activity in mice. Moreover, direct activation of GIRK channels in midbrain GABA neurons did not enhance motor activity. In contrast, genetic manipulations that selectively enhanced or suppressed GIRK channel function in midbrain DA neurons correlated with decreased and increased sensitivity, respectively, to the motor-stimulatory effect of systemic morphine. Collectively, these data support the contention that the unique GIRK channel subtype in VTA DA neurons, the GIRK2/GIRK3 heteromer, regulates the sensitivity of the mouse mesolimbic DA system to drugs with addictive potential. PMID:25948263

  15. Frequency of Psychiatric Disorders in Children of Opioid or Methamphetamine-Dependent Patients

    PubMed Central

    Parvaresh, Noushin; Mazhari, Shahrzad; Nazari-Noghabi, Maryam

    2015-01-01

    Background Addiction is one of the main problems of human societies, which is more common in developing countries. In addition, it causes to personal and social problems and family problem. The aim of this study was to examine the prevalence of psychiatric disorders in children 5-15 years old of opioid or methamphetamine dependence patients. Methods For this study, three groups including: (1) children of parents addicted to opium, (2) children of parents addicted to methamphetamine, and (3) control group were examined. Child symptom inventory-4 (CSI-4) questionnaires completed by non-hospitalized guardian and control group; then make interviews with the children by the Kiddie-schedule for affective disorders and schizophrenia (K-SADS). Data were analyzed by chi-square test and ANOVA. Findings Survey showed that the frequency of attention deficit hyperactivity disorder (ADHD), major depressive disorder (MDD), generalized anxiety disorder, obsessive-compulsive disorder, specific phobia (SP), and separation anxiety disorder in children of addicted parents were more than a non-addicted parent. However, there was no significant difference between the two groups in the frequency of conduct disorder, social phobia, and oppositional defiant disorders (ODDs). Conclusion Parental addiction can lead to an increase in some psychiatric disorders in the children. Therefore follow-up, early diagnosis, treatment, and prevention of these disorders in children of the drug-dependent parent are necessary to reduce health costs and improve the health system. PMID:26885350

  16. Chronic Pain and Hepatitis C Virus Infection in Opioid Dependent Injection Drug Users

    PubMed Central

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

    2011-01-01

    It is unknown if infection with hepatitis C virus (HCV) is a risk factor for pain among persons who have used injection drugs (IDU). Multivariate regression was used to determine whether HCV was associated with greater likelihood of reporting significant chronic pain and discomfort intolerance in a cohort of 97 opioid dependent IDU. Study results suggest that participants with HCV may be more likely to suffer chronic pain (aOR=1.98; 95% CI: 0.76 to 5.12, p=0.16). Furthermore, HCV was found to be associated with a higher discomfort intolerance scale score, reflecting intolerance to physical discomfort (β=2.34; 95% CI: 0.06 to 4.62, p=0.04). Infection with HCV may be an overlooked cause for chronic pain and discomfort intolerance among opioid dependent IDU. PMID:21491290

  17. Assessment and management of opioid withdrawal symptoms in buprenorphine-dependent subjects.

    PubMed

    San, L; Camí, J; Fernández, T; Ollé, J M; Peri, J M; Torrens, M

    1992-01-01

    The spontaneous physical dependence of buprenorphine was assessed in opioid addicts who switched from heroin to sublingual or intravenous buprenorphine. Twenty-two patients were randomly assigned to double-blind administration of methadone (n = 11) or placebo (n = 11) for 13 days after abrupt withdrawal of buprenorphine. Methadone was administered according to four pre-established dosing schedules depending on the previous amount of daily consumed buprenorphine. No methadone-treated patient required modification of the therapeutic regimen, whereas eight of eleven placebo-treated patients needed treatment with methadone. Buprenorphine withdrawal syndrome was of opioid type, began somewhat more slowly, and showed a peak until day 5. The occurrence, time-course and characteristics of buprenorphine withdrawal syndrome make it necessary to reconsider the abuse potential of this analgesic.

  18. Sex-specificity and estrogen-dependence of kappa opioid receptor-mediated antinociception and antihyperalgesia.

    PubMed

    Lawson, Kera P; Nag, Subodh; Thompson, Analisa D; Mokha, Sukhbir S

    2010-12-01

    This investigation determined whether the activation of the kappa opioid receptor (KOR) in the spinal cord produces estrogen-dependent, sex-specific modulation of acute and inflammation-induced persistent nociception. We demonstrate for the first time that KOR antinociception and gene expression are enhanced by exogenous or endogenous estrogen in the female. The lack of KOR antinociception and KOR gene expression are not altered by the hormonal status (testosterone or estrogen) in males. Cannulae were implanted intrathecally in male, gonadectomized male (GDX), intact and ovariectomized female (OVX) Sprague-Dawley rats. Estradiol was injected subcutaneously, 48h before testing (GDX+E and OVX+E). Intrathecal injection of U50,488H, a selective KOR agonist, dose dependently increased heat-evoked tail flick latencies (TFLs) in proestrous and OVX+E groups, but not in male, GDX, GDX+E, OVX, and diestrous groups. Further, estrogen dose-dependently enhanced the effect of U50,488H in OVX rats. KOR selective antagonist, nor-binaltorphimine (Nor-BNI), blocked the antinociceptive effect of U50,488H. U50,488H reversed the carrageenan-induced thermal hyperalgesia in OVX+E rats, but not in male or OVX rats. However, U50,488H treatment did not alter mechanical thresholds in any group, with or without inflammation. KOR gene expression was enhanced in proestrous and OVX+E groups as compared to any other group. We conclude that selective activation of KOR in the spinal cord produces sex-specific, stimulus- and estrogen-dependent attenuation of acute and inflammatory pain in the rat via estrogen-induced upregulation of the KOR gene expression in the spinal cord. These findings may further implicate estrogen dependence of KOR effects in learning, epilepsy, stress response, addiction etc. PMID:20926192

  19. Rooming-in care for infants of opioid-dependent mothers

    PubMed Central

    Newman, Adam; Davies, Gregory A.; Dow, Kimberly; Holmes, Belinda; Macdonald, Jessica; McKnight, Sarah; Newton, Lynn

    2015-01-01

    Problem addressed Infants born to opioid-dependent women are admitted to intensive care units for management of neonatal abstinence syndrome (NAS), serious morbidity, and prevention of mortality; however, the disadvantages of this approach include infants experiencing more severe NAS and exhibiting a greater need for pharmacotherapy owing to the interference with mother-infant bonding. Objective of program To implement a rooming-in program to support close uninterrupted contact between opioid-dependent women and their infants in order to decrease the severity of NAS scores, lessen the need for pharmacotherapy, and shorten hospital stays. Program description Opioid-dependent pregnant women were assessed antenatally by a multidisciplinary team and provided with education and support. Psychosocial issues were addressed in collaboration with a community program developed to support addicted mothers. The mother-infant dyad was admitted postpartum to a private room and attended by nurses trained in Finnegan scoring. Infants remained with their mothers unless persistently elevated scores made transfer to neonatal intensive care units necessary for initiation of pharmacotherapy. Conclusion With the rooming-in program, the proportion of infants requiring pharmacotherapy decreased from 83.3% to 14.3% (P < .001) and the average length of stay decreased from 25 days to 8 days (P < .001). The rooming-in experience was rated favourably by participating mothers. PMID:27035006

  20. Buprenorphine-based regimens and methadone for the medical management of opioid dependence: selecting the appropriate drug for treatment.

    PubMed

    Maremmani, Icro; Gerra, Gilberto

    2010-01-01

    Maintenance therapy with methadone or buprenorphine-based regimens reduces opioid dependence and associated harms. The perception that methadone is more effective than buprenorphine for maintenance treatment has been based on low buprenorphine doses and excessively slow induction regimens used in early buprenorphine trials. Subsequent studies show that the efficacy of buprenorphine sublingual tablet (Subutex®) or buprenorphine/naloxone sublingual tablet (Suboxone®) is equivalent to that of methadone when sufficient buprenorphine doses, rapid induction, and flexible dosing are used. Although methadone remains an essential maintenance therapy option, buprenorphine-based regimens increase access to care and provide safer, more appropriate treatment than methadone for some patients. PMID:20958853

  1. Methadone Induction in Primary Care for Opioid Dependence: A Pragmatic Randomized Trial (ANRS Methaville)

    PubMed Central

    Carrieri, Patrizia Maria; Michel, Laurent; Lions, Caroline; Cohen, Julien; Vray, Muriel; Mora, Marion; Marcellin, Fabienne; Spire, Bruno; Morel, Alain; Roux, Perrine

    2014-01-01

    Objective Methadone coverage is poor in many countries due in part to methadone induction being possible only in specialized care (SC). This multicenter pragmatic trial compared the effectiveness of methadone treatment between two induction models: primary care (PC) and SC. Methods In this study, registered at ClinicalTrials.Gov (NCT00657397), opioid-dependent individuals not on methadone treatment for at least one month or receiving buprenorphine but needing to switch were randomly assigned to start methadone in PC (N = 155) or in SC (N = 66) in 10 sites in France. Visits were scheduled at months M0, M3, M6 and M12. The primary outcome was self-reported abstinence from street-opioids at 12 months (M12) (with an underlying 15% non-inferiority hypothesis for PC). Secondary outcomes were abstinence during follow-up, engagement in treatment (i.e. completing the induction period), retention and satisfaction with the explanations provided by the physician. Primary analysis used intention to treat (ITT). Mixed models and the log-rank test were used to assess the arm effect (PC vs. SC) on the course of abstinence and retention, respectively. Results In the ITT analysis (n = 155 in PC, 66 in SC), which compared the proportions of street-opioid abstinent participants, 85/155 (55%) and 22/66 (33%) of the participants were classified as street-opioid abstinent at M12 in PC and SC, respectively. This ITT analysis showed the non-inferiority of PC (21.5 [7.7; 35.3]). Engagement in treatment and satisfaction with the explanations provided by the physician were significantly higher in PC than SC. Retention in methadone and abstinence during follow-up were comparable in both arms (p = 0.47, p = 0.39, respectively). Conclusions Under appropriate conditions, methadone induction in primary care is feasible and acceptable to both physicians and patients. It is as effective as induction in specialized care in reducing street-opioid use and ensuring engagement and

  2. Patterns of non-compliant buprenorphine, levomethadone, and methadone use among opioid dependent persons in treatment

    PubMed Central

    2014-01-01

    Background The non-compliant use of opioid substitution treatment (OST) medicines is widespread and well-documented. However, less is known about characteristics of non-compliant OST medicine use and the factors that predict it. The two main goals of this study are to compare characteristics of non-compliant levomethadone, methadone, and buprenorphine use and to explore factors that may differentially predict it among opioid dependent persons in treatment. Methods Data from 595 opioid dependent patients with non-compliant OST medicine use were analyzed. Characteristics of use between substances were compared using chi-squared tests and predictive factors were explored through multinomial logistic regressions. Results Non-compliant levomethadone and methadone use was characterized by more frequent parallel consumption of other psychoactive substances and intravenous use, whereas buprenorphine was more often procured without a prescription. Regarding predictive factors, methadone was perceived to relieve withdrawal symptoms better than buprenorphine and levomethadone was perceived as being better at modulating the effects of other substances and worst at enhancing mood. Conclusions Patterns of non-compliant use differ according to OST medicine. These patterns are considered with the reduction of non-compliant use and the improvement of treatment in mind. PMID:24885218

  3. Increased Burden of Healthcare Utilization and Cost Associated with Opioid-Related Constipation Among Patients with Noncancer Pain

    PubMed Central

    Fernandes, Ancilla W.; Kern, David M.; Datto, Catherine; Chen, Yen-Wen; McLeskey, Charles; Tunceli, Ozgur

    2016-01-01

    Background Opioids are widely accepted as treatment for moderate to severe pain, and opioid-induced constipation is one of the most common side effects of opioids. This side effect negatively affects pain management and patients’ quality of life, which could result in increased healthcare utilization and costs. Objective To assess healthcare utilization and costs (all-cause, constipation-related, and pain-related) for individuals with and without opioid-induced constipation during the 12 months after initiation of opioid therapy for noncancer pain. Methods This retrospective cohort study was conducted using administrative claims data from HealthCore Integrated Research Environment between January 1, 2006, and June 30, 2014. The analysis was limited to patients aged ≥18 years who filled a prescription for continuous opioid treatment (≥28 days) for noncancer pain. Propensity scores were used to match opioid users with constipation (cohort 1) and opioid users without constipation (cohort 2), using a 1:1 ratio. Generalized linear models were used to estimate all-cause, constipation-related, and pain-related healthcare utilization and costs during the 12 months after the initiation of opioid therapy. Results After matching and balancing for all prespecified variables, 17,384 patients were retained in each cohort (mean age, 56 years; 63% female). Opioid users with constipation were twice as likely as those without constipation to have ≥1 inpatient hospitalizations (odds ratio, 2.28; 95% confidence interval [CI], 2.17–2.39) during the 12 months. The total mean adjusted overall costs per patient during the study period were $12,413 higher for patients with constipation versus those without it (95% CI, $11,726–$13,116). The total mean adjusted overall pain-related costs per patient were $6778 (95% CI, $6293–$7279) higher for the patients with constipation than those without. Among patients using opioids for noncancer pain, the annual mean constipation

  4. Dissociating Motivational From Physiological Withdrawal in Alcohol Dependence: Role of Central Amygdala κ-Opioid Receptors.

    PubMed

    Kissler, Jessica L; Walker, Brendan M

    2016-01-01

    Chronic intermittent alcohol vapor exposure leads to increased dynorphin (DYN) A-like peptide expression and heightened kappa-opioid receptor (KOR) signaling in the central nucleus of the amygdala (CeA) and these neuroadaptive responses differentiate alcohol-dependent from non-dependent phenotypes. Important for therapeutic development efforts is understanding the nature of the stimulus that drives dependence-like phenotypes such as escalated alcohol self-administration. Accordingly, the present study examined the impact of intra-CeA KOR antagonism on escalated operant alcohol self-administration and physiological withdrawal symptoms during acute withdrawal and protracted abstinence in rats previously exposed to chronic intermittent alcohol vapor. Following operant training, rats were implanted with intra-CeA guide cannula and exposed to long-term intermittent alcohol vapor exposure that resulted in escalated alcohol self-administration and elevated physiological withdrawal signs during acute withdrawal. Animals received intra-CeA infusions of the KOR antagonist nor-binaltorphimine (nor-BNI; 0, 2, 4, or 6 μg) prior to operant alcohol self-administration sessions and physiological withdrawal assessment during acute withdrawal and protracted abstinence. The results indicated that site-specific KOR antagonism in the CeA ameliorated escalated alcohol self-administration during both acute withdrawal and protracted abstinence test sessions, whereas KOR antagonism had no effect on physiological withdrawal scores at either time point. These results dissociate escalated alcohol self-administration from physiological withdrawal symptoms in relation to KOR signaling in the CeA and help clarify the nature of the stimulus that drives escalated alcohol self-administration during acute withdrawal and protracted abstinence.

  5. Increased agonist affinity at the mu-opioid receptor induced by prolonged agonist exposure

    PubMed Central

    Birdsong, William T.; Arttamangkul, Seksiri; Clark, Mary J.; Cheng, Kejun; Rice, Kenner C.; Traynor, John R.; Williams, John T.

    2013-01-01

    Prolonged exposure to high-efficacy agonists results in desensitization of the mu opioid receptor (MOR). Desensitized receptors are thought to be unable to couple to G-proteins, preventing downstream signaling, however the changes to the receptor itself are not well characterized. In the current study, confocal imaging was used to determine whether desensitizing conditions cause a change in agonist-receptor interactions. Using rapid solution exchange, the binding kinetics of fluorescently labeled opioid agonist, dermorphin Alexa594 (derm A594), to MORs was measured in live cells. The affinity of derm A594 binding increased following prolonged treatment of cells with multiple agonists that are known to cause receptor desensitization. In contrast, binding of a fluorescent antagonist, naltrexamine Alexa 594, was unaffected by similar agonist pre-treatment. The increased affinity of derm A594 for the receptor was long-lived and partially reversed after a 45 min wash. Treatment of the cells with pertussis toxin did not alter the increase in affinity of the derm A594 for MOR. Likewise the affinity of derm A594 for MORs expressed in mouse embryonic fibroblasts derived from arrestin 1 and 2 knockout animals increased following treatment of the cells with the desensitization protocol. Thus, opioid receptors were “imprinted” with a memory of prior agonist exposure that was independent of G-protein activation or arrestin binding that altered subsequent agonist-receptor interactions. The increased affinity suggests that acute desensitization results in a long lasting but reversible conformational change in the receptor. PMID:23447620

  6. Electromagnetic millimeter wave induced hypoalgesia: frequency dependence and involvement of endogenous opioids.

    PubMed

    Radzievsky, A A; Gordiienko, O V; Alekseev, S; Szabo, I; Cowan, A; Ziskin, M C

    2008-05-01

    Millimeter wave treatment (MMWT) is based on the systemic biological effects that develop following local skin exposure to low power electromagnetic waves in the millimeter range. In the present set of experiments, the hypoalgesic effect of this treatment was analyzed in mice. The murine nose area was exposed to MMW of "therapeutic" frequencies: 42.25, 53.57, and 61.22 GHz. MMWT-induced hypoalgesia was shown to be frequency dependent in two experimental models: (1) the cold water tail-flick test (chronic non-neuropathic pain), and (2) the wire surface test (chronic neuropathic pain following unilateral constriction injury to the sciatic nerve). Maximum hypoalgesic effect was obtained when the frequency was 61.22 GHz. Other exposure parameters were: incident power density = 13.3 mW/cm(2), duration of each exposure = 15 min. Involvement of delta and kappa endogenous opioids in the MMWT-induced hypoalgesia was demonstrated using selective blockers of delta- and kappa-opioid receptors and the direct ELISA measurement of endogenous opioids in CNS tissue. Possible mechanisms of the effect and the perspectives of the clinical application of MMWT are discussed.

  7. Traditional Chinese and Indian medicine in the treatment of opioid-dependence: a review

    PubMed Central

    Doosti, Fatemeh; Dashti, Saeedeh; Tabatabai, Seyed Meghdad; Hosseinzadeh, Hossein

    2013-01-01

    Objective: In this study, the current literatures on the use of herbs and herbal preparations of Traditional Chinese and Indian Medicine for the treatment of opioid addiction were reviewed. Matherials and Methods: Search was done in databases such as Pub Med, Science Direct, Scopus, Springer Link, and Google Scholar. Results: Among 18 retrieved studies, 3 studies were about asafetida extract, an approved preparation for ameliorating drug abstinence in China. Chinese preparations including Composite Dong Yuan Gao, Qingjunyin and TJ-97 (a water extract of dai-bofu-to) as well as Indian ones, Mentate and Shilajit, were reported to have positive effects against opioid withdrawal, dependence, and tolerance. Moreover, Levo-tetrahydropalmatine and L-Stepholidine, in addition to extracts of Caulis Sinomenii and Sinomenium acutum showed similar effects. Banxia Houpu Decoction, Fu-Yuan pellet, Jinniu capsules, Qingjunyin, Tai-Kang-Ning capsule, and Xuan Xia Qudu Jiaonang (WeiniCom) from Chinese preparations, showed anti-addiction effects in randomized, double-blind and, in some studies, multicenter clinical trials. Conclusion : Traditional herbal preparations of China and India have anti-addiction effects with less adverse effects than alpha2-adrenergic or opioid agonists. PMID:25050276

  8. A Prolonged NO-Dependent, Opioid-Mediated Antinociceptive Effect of Hyperbaric Oxygen in Mice

    PubMed Central

    Zelinski, Lisa M.; Ohgami, Yusuke; Chung, Eunhee; Shirachi, Donald Y.; Quock, Raymond M.

    2009-01-01

    Hyperbaric oxygen (HBO2) therapy is reported to cause pain relief in several conditions of chronic pain. A single 60-min session of HBO2 treatment produced a prolonged antinociceptive effect in mice that persisted for 90 min after cessation of treatment. The HBO2-induced antinociception was significantly attenuated by pretreatment prior to HBO2 exposure with the opioid antagonist naltrexone, the non-specific nitric oxide synthase (NOS)-inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and the selective neuronal NOS-inhibitor S-methyl-L-thiocitrulline (SMTC) but not the selective endothelial NOS-inhibitor N5-(1-iminoethyl)-L-ornithine (L-NIO). The antinociception was also significantly reduced by central pretreatment with a rabbit antiserum against dynorphin1-13 but not by rabbit antisera against either β-endorphin or methionine-enkephalin. The prolonged antinociceptive effect at 90 min after HBO2-induced treatment was also significantly attenuated by naltrexone but not L-NAME administered 60 min following HBO2 treatment but prior to nociceptive testing. These findings indicate that the antinociception that persists for 90 min after HBO2 exposure is mediated by nitric oxide (NO) and opioid mechanisms but that the NO involvement is critical during the HBO2 treatment and not at the time of nociceptive testing. These results are consistent with the concept that HBO2 may induce an NO-dependent release of opioid peptide to cause a long-acting antinociceptive effect. PMID:18976963

  9. Initial response as a predictor of 12-week buprenorphine-naloxone treatment response in a prescription opioid dependent population

    PubMed Central

    McDermott, Katherine A.; Griffin, Margaret L.; Connery, Hilary S.; Hilario, E. Yvette; Fiellin, David A.; Fitzmaurice, Garrett M.; Weiss, Roger D.

    2015-01-01

    Objective Initial medication response has been shown to predict treatment outcome across a variety of substance use disorders, but no studies have examined the predictive power of initial response to buprenorphine-naloxone in the treatment of prescription opioid dependence. We therefore conducted a secondary analysis of data from the Prescription Opioid Addiction Treatment Study to determine whether initial response to buprenorphine-naloxone predicted 12-week treatment outcome in a prescription opioid-dependent population. Method Using data from a multi-site, randomized controlled trial of buprenorphine-naloxone plus counseling for DSM-IV prescription opioid dependence (June 2006–July 2009), we conducted a secondary analysis to investigate the relationship between initial medication response and 12-week treatment outcome to establish how soon the efficacy of buprenorphine-naloxone could be predicted. Outcomes were determined from the Substance Use Report, a self-report measure of substance use, and confirmatory urinalysis. Predictive values were calculated to determine the importance of abstinence vs. use at various time points within the first month of treatment (week 1, weeks 1–2, 1–3, or 1–4) in predicting successful vs. unsuccessful treatment outcome (based on abstinence or near-abstinence from opioids) in the last 4 weeks of buprenorphine-naloxone treatment (weeks 9–12). Results Outcome was best predicted by medication response after two weeks of treatment. Two weeks of initial abstinence was moderately predictive of treatment success (positive predictive value = 71%), while opioid use in both of the first two weeks was strongly predictive of unsuccessful treatment outcome (negative predictive value (NPV) = 84%), especially when successful outcome was defined as total abstinence from opioids in weeks 9–12 (NPV = 94%). Conclusion Evaluating prescription opioid-dependent patients after two weeks of buprenorphine-naloxone treatment may help determine

  10. Fentanyl Law Enforcement Submissions and Increases in Synthetic Opioid-Involved Overdose Deaths - 27 States, 2013-2014.

    PubMed

    Gladden, R Matthew; Martinez, Pedro; Seth, Puja

    2016-01-01

    In March and October 2015, the Drug Enforcement Administration (DEA) and CDC, respectively, issued nationwide alerts identifying illicitly manufactured fentanyl (IMF) as a threat to public health and safety (1,2). IMF is unlawfully produced fentanyl, obtained through illicit drug markets, includes fentanyl analogs, and is commonly mixed with or sold as heroin (1,3,4). Starting in 2013, the production and distribution of IMF increased to unprecedented levels, fueled by increases in the global supply, processing, and distribution of fentanyl and fentanyl-precursor chemicals by criminal organizations (3). Fentanyl is a synthetic opioid 50-100 times more potent than morphine (2).* Multiple states have reported increases in fentanyl-involved overdose (poisoning) deaths (fentanyl deaths) (2). This report examined the number of drug products obtained by law enforcement that tested positive for fentanyl (fentanyl submissions) and synthetic opioid-involved deaths other than methadone (synthetic opioid deaths), which include fentanyl deaths and deaths involving other synthetic opioids (e.g., tramadol). Fentanyl deaths are not reported separately in national data. Analyses also were conducted on data from 27 states(†) with consistent death certificate reporting of the drugs involved in overdoses. Nationally, the number of fentanyl submissions and synthetic opioid deaths increased by 426% and 79%, respectively, during 2013-2014; among the 27 analyzed states, fentanyl submission increases were strongly correlated with increases in synthetic opioid deaths. Changes in fentanyl submissions and synthetic opioid deaths were not correlated with changes in fentanyl prescribing rates, and increases in fentanyl submissions and synthetic opioid deaths were primarily concentrated in eight states (high-burden states). Reports from six of the eight high-burden states indicated that fentanyl-involved overdose deaths were primarily driving increases in synthetic opioid deaths. Increases in

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

    PubMed

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

    2011-10-01

    On the basis of efficacy, opioid antagonists are classified as inverse opioid agonists (e.g. naltrexone) or neutral opioid antagonists (e.g. 6β-naltrexol). This study examined the interaction between naltrexone and 6β-naltrexol in the precipitated opioid withdrawal syndrome in morphine dependent mice. Furthermore, the possible contribution of constitutive opioid receptor activity to precipitated withdrawal was evaluated using increasing levels of morphine dependence. In the first experiment, low doses of 6β-naltrexol antagonized naltrexone precipitated withdrawal while high doses acted additively. All doses of naltrexone increased 6β-naltrexol's potency to precipitate withdrawal. The next experiment examined changes in antagonist potency to precipitate withdrawal with increasing morphine dependence. Mice were exposed to morphine for 1-6 days and then withdrawal was precipitated. Naltrexone was more potent than 6β-naltrexol at all the time points. The ED(50) of both drugs decreased at the same rate suggesting that increased dependence produced no change in constitutive opioid receptor activity. Taken together these results indicate that the functional efficacy of 6β-naltrexol is dose-dependent and that constitutive opioid receptor activity did not change as opioid dependence increased from 1 to 6 days. PMID:21736895

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

    PubMed

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

    2011-10-01

    On the basis of efficacy, opioid antagonists are classified as inverse opioid agonists (e.g. naltrexone) or neutral opioid antagonists (e.g. 6β-naltrexol). This study examined the interaction between naltrexone and 6β-naltrexol in the precipitated opioid withdrawal syndrome in morphine dependent mice. Furthermore, the possible contribution of constitutive opioid receptor activity to precipitated withdrawal was evaluated using increasing levels of morphine dependence. In the first experiment, low doses of 6β-naltrexol antagonized naltrexone precipitated withdrawal while high doses acted additively. All doses of naltrexone increased 6β-naltrexol's potency to precipitate withdrawal. The next experiment examined changes in antagonist potency to precipitate withdrawal with increasing morphine dependence. Mice were exposed to morphine for 1-6 days and then withdrawal was precipitated. Naltrexone was more potent than 6β-naltrexol at all the time points. The ED(50) of both drugs decreased at the same rate suggesting that increased dependence produced no change in constitutive opioid receptor activity. Taken together these results indicate that the functional efficacy of 6β-naltrexol is dose-dependent and that constitutive opioid receptor activity did not change as opioid dependence increased from 1 to 6 days.

  13. Management of opioid painkiller dependence in primary care: ongoing recovery with buprenorphine/naloxone.

    PubMed

    Hard, Bernadette

    2014-11-28

    Opioid painkiller dependence is a growing problem and best-practice management is not well defined. We report a case of a young woman exhibiting dependence on codeine, originally prescribed for myalgic encephalopathy, after escalating use over a 10-year period. In 2012, a consultation with a new general practitioner, who had extensive experience of patients with substance abuse, revealed the underlying dependence. After building trust for 6 months, she was able to admit to medication abuse, and was referred to the community drug and alcohol team. On presentation to the team, the patient had no pain issues and the dihydrocodeine use--600 tablets/week--solely reflected her dependence. The patient successfully underwent rapid induction with buprenorphine/naloxone as opioid substitution treatment over 2 days. She is currently stable, engaged with recovery support services and psychosocial counselling, and has just returned to work. She is maintained on a therapeutic dose of buprenorphine 10 mg/naloxone 2.5 mg.

  14. Cost Effectiveness of Injectable Extended Release Naltrexone Compared to Methadone Maintenance and Buprenorphine Maintenance Treatment for Opioid Dependence

    PubMed Central

    Jackson, Heide; Mandell, Kara; Johnson, Kimberly; Chatterjee, Debanjana; Vanness, David J.

    2015-01-01

    Background The aim of this study was to estimate the cost-effectiveness of injectable extended release naltrexone (XR-NTX) compared to methadone maintenance and buprenorphine maintenance treatment (MMT and BMT respectively) for adult males enrolled in treatment for opioid dependence in the United States from the perspective of state-level addiction treatment payers. Methods We used a Markov model with daily time cycles to estimate the incremental cost per opioid-free day in a simulated cohort of adult males ages 18–65 over a six-month period from the state health program perspective. Results XR-NTX is predicted to be more effective and more costly than methadone or buprenorphine in our target population, with an incremental cost per opioid-free day gained relative to the next-most effective treatment (MMT) of $72. The cost-effectiveness of XR-NTX relative to MMT was driven by its effectiveness in deterring opioid use while receiving treatment. Conclusions XR-NTX is a cost-effective medication for treating opioid dependence if state addiction treatment payers are willing to pay at least $72 per opioid-free day. PMID:25775099

  15. mu and delta opioid agonists at low concentrations decrease voltage-dependent K+ currents in F11 neuroblastoma x DRG neuron hybrid cells via cholera toxin-sensitive receptors.

    PubMed

    Fan, S F; Shen, K F; Crain, S M

    1993-03-12

    In a previous study, we showed that microM concentrations of mu or delta opioid agonists increase voltage-dependent outward K+ currents in neuroblastoma x DRG neuron hybrid F11 cells via pertussis toxin-sensitive receptors. The present study demonstrates that much lower concentrations (fM to nM) of these opioids (DAGO and DPDPE) decreased voltage-dependent outward K+ currents during step depolarization. The opioid antagonist, naloxone (3 nM) prevented these decreases in K+ current as did the cholera toxin subunits A or B (ca. 1 nM). Furthermore, the specific mu opioid receptor antagonist, beta-funaltrexamine (5 nM) blocked the decrease by DAGO and the specific delta antagonist, naltrindole (1 nM) blocked that by DPDPE. Acute GM1 ganglioside (1 microM) treatment markedly enhanced the efficacy of opioid-induced decrease in K+ current. After treating the cells with pertussis toxin (1 microgram/ml) for 2 days or more, these opioids decreased the K+ current even when tested at concentrations as high as 1 microM. These results indicate that the decrease in K+ current elicited in F11 cells by low concentrations of mu and delta opioid agonists resembles the opioid-induced prolongation of the action potential duration and decrease in voltage-dependent K+ conductance that occur in DRG neurons in primary cultures. The F11 cell line provides therefore a valuable model system for correlative pharmacologic, electrophysiologic and biochemical analyses of Gs-coupled, GM1 ganglioside-regulated excitatory opioid receptor functions, in addition to G(i)/G(o)-coupled inhibitory receptor functions, in sensory neurons.

  16. Contribution of Endogenous Spinal Endomorphin 2 to Intrathecal Opioid Antinociception in Rats Is Agonist-Dependent and Sexually Dimorphic

    PubMed Central

    Kumar, Arjun; Liu, Nai-Jiang; Madia, Priyanka A.; Gintzler, Alan R.

    2016-01-01

    Interactions between exogenous and endogenous opioids are not commonly investigated as a basis for sexually dimorphic opioid analgesia. We investigated the influence of spinal endomorphin 2 (EM2), an endogenous mu-opioid receptor (MOR) ligand, on the spinal antinociception produced by intrathecally administered opioids. Activation of spinal MORs facilitated spinal EM2 release. This effect was sexually dimorphic, occurring in males but not females. Although activational effects of testosterone were required for opioid facilitation of spinal EM2 release in males, the absence of this facilitation in females resulted from neither insufficient levels of testosterone nor mitigating effects of estrogens. Strikingly, in males, the contribution of spinal EM2 to the analgesia produced by intrathecally applied MOR agonists depended on their analgesic efficacy relative to that of EM2. Spinal EM2 released by the higher efficacy MOR agonist sufentanil diminished sufentanil’s analgesic effect, whereas EM2 released by the lower efficacy morphine had the opposite effect on spinal morphine antinociception. Understanding antithetical contributions of endogenous EM2 to intrathecal opioid antinociception not only enlightens the selection of opioid medications for pain management, but also helps explain variable sex-dependence of the antinociception produced by different opioids, facilitating the acceptance of sexually dimorphic antinociception as a basic tenet. Perspective The male-specific MOR-coupled enhancement of spinal EM2 release implies a parallel ability to harness endogenous EM2 antinociception. The inferred diminished ability of females to utilize the spinal EM2 antinociceptive system could contribute to their greater frequency and severity of chronic pain syndromes. PMID:26342648

  17. Ca2+/calmodulin-dependent protein kinase II alpha is required for the initiation and maintenance of opioid-induced hyperalgesia.

    PubMed

    Chen, Yan; Yang, Cheng; Wang, Zaijie Jim

    2010-01-01

    Repeated administration of opioids not only leads to tolerance and dependence, but also results in nociceptive enhancement called opioid-induced hyperalgesia (OIH). Nociceptive mediators involved in OIH generation remain poorly understood. In the present study, we tested the hypothesis that Ca(2+)/calmodulin-depent protein kinase II (CaMKIIalpha) is critical for OIH. Opioid-induced hyperalgesia was produced by repeated morphine administration or pellet implantation in mice. Correlating with the development of tactile allodynia and thermal hyperalgesia, spinal CaMKIIalpha activity was significantly increased in OIH. KN93, a CaMKII inhibitor, dose- and time-dependently reversed OIH and CaMKII activation without impairing locomotor coordination. To elucidate the specific CaMKII isoform involved, we targeted CaMKIIalpha by using small interfering RNA and demonstrated that knockdown of spinal CaMKIIalpha attenuated OIH. Furthermore, morphine failed to induce OIH in CaMKIIalpha(T286A) point mutant mice, although wild-type littermate mice developed robust OIH after repeated treatments with morphine. These data implicate, for the first time, an essential role of CaMKIIalpha as a cellular mechanism leading to and maintaining opioid-induced hyperalgesia.

  18. Massage Impact on Pain in Opioid-dependent Patients in Substance Use Treatment

    PubMed Central

    Wiest, Katharina L.; Asphaug, Victoria J.; Carr, Kathryn E.; Gowen, Emily A.; Hartnett, Timothy T.

    2015-01-01

    Background: Chronic pain is a common cause of health care utilization and high levels of pain are pronounced in individuals engaged in methadone maintenance treatment. Although massage has been demonstrated to alleviate chronic pain symptoms, its use as an adjunctive therapy to modify pain during opioid-replacement treatment is absent from the literature. Purpose: To consider the efficacy of Swedish massage in reducing pain in opioid-dependent patients with chronic pain receiving methadone treatment. Setting: Trial was conducted at a nonprofit methadone treatment center serving low-income patients. Research Design: A randomized clinical trial with randomized to either 1) massage plus treatment-as-usual (TAU) (n = 27) or 2) TAU (n = 24). Durability of treatment effect was evaluated at Week 12. Intervention: Eight weekly 50-minute Swedish massage sessions plus TAU or TAU alone. Main Outcome Measures: Pain, anxiety, depression, physical functioning, decreased substance use, and improvement in treatment engagement. Results: Randomized participants were comparable at Baseline for demographic, pain, physical, and emotional variables. Massage group reported improved pain scores; worst pain had a clinically significant 2-point improvement while the other pain scores did not. Overall improvements were not observed in treatment engagement or levels of anxiety, depression, or physical functioning. A subgroup of the participants, who felt they could be pain-free, consistently reported improvements in pain from Baseline to Week 8, and this was most pronounced and clinically significant in the massage group. Conclusions: These preliminary findings do not support an overall clinically significant positive effect of Swedish massage on reduction in pain ratings or improvement in anxiety, depression, or treatment engagement in a substance-using, opioid-dependent population with chronic pain. Future nonpharmacologic pain research in marginalized substance-using populations may wish

  19. Comparing adaptive stepped care and monetary-based voucher interventions for opioid dependence.

    PubMed

    Brooner, Robert K; Kidorf, Michael S; King, Van L; Stoller, Kenneth B; Neufeld, Karin J; Kolodner, Ken

    2007-05-01

    This 6-month randomized clinical trial (with 3-month follow-up) used a 2x2 design to compare the independent and combined effectiveness of two interventions designed to improve outcomes in treatment-seeking opioid dependent patients (n=236): motivated stepped care (MSC) and contingent voucher incentives (CVI). MSC is an adaptive treatment strategy that uses principles of negative reinforcement and avoidance to motivate both attendance to varying levels of counseling services and brief periods of abstinence [Brooner, R.K., Kidorf, M., 2002. Using behavioral reinforcement to improve methadone treatment participation. Sci. Pract. Perspect. 1, 38-46; Brooner, R.K., Kidorf, M.S., King, V.L., Peirce, J.M., Bigelow, G.E., Kolodner, K., 2004. A modified "stepped care" approach to improve attendance behavior in treatment seeking opioid abusers. J. Subst. Abuse Treat. 27, 223-232]. In contrast, CVI [Higgins, S., Delaney, D.D., Budney, A.J., Bickel, W.K., Hughes, J.R., Foerg, B.A., Fenwick, J.W., 1991. A behavioral approach to achieving initial cocaine abstinence. Am. Psychiatr. 148, 1218-1224] relies on positive reinforcement to motivate drug abstinence. The results showed that the combined approach (MSC+CVI) was associated with the highest proportion of drug-negative urine samples during both the randomized and 3-month follow-up arms of the evaluation. The CVI-only and the MSC-only conditions evidenced similar proportions of drug-negative urine samples that were both significantly greater than the standard care (SC) comparison group. Voucher-based reinforcement was associated with better retention, while adaptive stepped-based care was associated with better adherence to scheduled counseling sessions. These results suggest that both CVI and MSC are more effective than routine care for reducing drug use in opioid dependent outpatients, and that the overall benefits of MSC are enhanced further by adding positive reinforcement.

  20. Psychiatric comorbidities in opioid-dependent patients undergoing a replacement therapy programme in Spain: The PROTEUS study.

    PubMed

    Roncero, Carlos; Barral, Carmen; Rodríguez-Cintas, Laia; Pérez-Pazos, Jesús; Martinez-Luna, Nieves; Casas, Miguel; Torrens, Marta; Grau-López, Lara

    2016-09-30

    Opioid-dependent patients show a high rate of psychiatric comorbidities. The prevalence and characteristics of patients with dual diagnosis have not been well established in Spanish opioid agonist treatment (OAT) programmes. Thus, 621 opioid-dependent patients enrolled in OAT programmes were assessed, using the EuropASI questionnaire, for psychiatric comorbidities, which were detected in 67% of patients (anxiety 53%, mood disorders 48%, sleep disorders 41%, substance-related disorders 36%). In addition, compared with patients without a dual diagnosis, patients with dual pathology were significantly older, used benzodiazepines and cannabis in significantly greater percentages, and showed significantly more frequent infectious and non-infectious comorbidities, worse overall working status, a lower proportion of drivers and higher levels of severity regarding medical, employment, alcohol, legal, family and psychological issues. Therefore, the data showed a very high prevalence of psychiatric comorbidity in opioid-dependent patients receiving OAT in Spain and several problems frequently associated with patients with dual diagnosis. Physicians treating opioid-dependent patients should be aware of these facts to correctly identify and manage patients with a dual diagnosis. PMID:27416536

  1. How to design an opioid drug that causes reduced tolerance and dependence.

    PubMed

    Berger, Amy Chang; Whistler, Jennifer L

    2010-05-01

    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.

  2. Looking for the uninsured in Massachusetts? Check opioid dependent persons seeking detoxification

    PubMed Central

    Stein, MD; Bailey, GL; Thurmond, P; Paull, N

    2014-01-01

    Background We examined the rate of uninsurance among persons seeking detoxification at a large drug treatment program in Massachusetts in 2013, five years after insurance mandates. Methods We interviewed three hundred and forty opioid dependent persons admitted for inpatient detoxification in Fall River, Massachusetts. Potential predictors of self-reported insurance status included age, gender, ethnicity, employment, homelessness, years of education, current legal status, and self-perceived health status. Results Participants mean age was 32 years, 71% were male, and 87% were non-Hispanic Caucasian. Twenty-three percent were uninsured. In the multivariate model, the odds of being uninsured was positively associated with years of education (OR = 1.22, 95%CI 1.03; 1.46, p < .05), higher among males than females (OR = 2.63, 95%CI 1.33; 5.20, p < .01), and inversely associated with age (OR = 0.94, 95%CI 0.90; 0.98, p < .01). Conclusion Opioid dependent persons recruited from a detoxification program in Massachusetts are uninsured at rates far above the state average. With the arrival of the Affordable Care Act, drug treatment programs in Massachusetts and nationally will be important sites to target to expand health coverage. PMID:24438841

  3. [Is the availability of buprenorphine/naloxone therapy for opioid-dependent inmates a necessity? ].

    PubMed

    Marco, A; López-Burgos, A; García-Marcos, L; Gallego, C; Antón, J J; Errasti, A

    2013-02-01

    Agonist therapy (OAT) programs in combination with a psychosocial approach are the most effective way to prevent relapse in opioid-dependent patients. These programs reduce morbidity and risk behaviours for HIV transmission and other infections, improve quality of life and retention in treatment, and have a positive impact on antisocial behaviour. They are therefore very useful for prisoners with a history of opiate use. OATs based on buprenorphine/naloxone (B/N), along with others using methadone, are currently available in Spain. Diversified treatment offers an alternative treatment for opioid dependence that is more personalized and tailored to the patient's characteristics. As regards effectiveness, both drugs are very similar, but B/N shows a better safety profile and fewer drug-drug interactions and can be dispensed in pharmacies once the patient is released, which can assist with the patient' social reintegration. B/N treatment is more expensive than methadone. It is advisable to have different modes of OAT. These should be prescribed according to the characteristics and needs of each case, without incarceration impeding the right to drug treatment, which should be similar to that performed outside prison. PMID:24270319

  4. Increased gabaergic input to ventral tegmental area dopaminergic neurons associated with decreased cocaine reinforcement in mu-opioid receptor knockout mice.

    PubMed

    Mathon, D S; Lesscher, H M B; Gerrits, M A F M; Kamal, A; Pintar, J E; Schuller, A G P; Spruijt, B M; Burbach, J P H; Smidt, M P; van Ree, J M; Ramakers, G M J

    2005-01-01

    There is general agreement that dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens and prefrontal cortex play a key role in drug reinforcement. The activity of these neurons is strongly modulated by the inhibitory and excitatory input they receive. Activation of mu-opioid receptors, located on GABAergic neurons in the VTA, causes hyperpolarization of these GABAergic neurons, thereby causing a disinhibition of VTA dopaminergic neurons. This effect of mu-opioid receptors upon GABA neurotransmission is a likely mechanism for mu-opioid receptor modulation of drug reinforcement. We studied mu-opioid receptor signaling in relation to cocaine reinforcement in wild-type and mu-opioid receptor knockout mice using a cocaine self-administration paradigm and in vitro electrophysiology. Cocaine self-administration was reduced in mu-opioid receptor knockout mice, suggesting a critical role of mu-opioid receptors in cocaine reinforcement. The frequency of spontaneous inhibitory post-synaptic currents onto dopaminergic neurons in the ventral tegmental area was increased in mu-opioid receptor knockout mice compared with wild-type controls, while the frequency of spontaneous excitatory post-synaptic currents was unaltered. The reduced cocaine self-administration and increased GABAergic input to VTA dopaminergic neurons in mu-opioid receptor knockout mice supports the notion that suppression of GABAergic input onto dopaminergic neurons in the VTA contributes to mu-opioid receptor modulation of cocaine reinforcement. PMID:15664692

  5. Brief versus extended counseling along with buprenorphine/naloxone for HIV-infected opioid dependent patients.

    PubMed

    Tetrault, Jeanette M; Moore, Brent A; Barry, Declan T; O'Connor, Patrick G; Schottenfeld, Richard; Fiellin, David A; Fiellin, Lynn E

    2012-12-01

    Untreated opioid dependence adversely affects HIV outcomes. Integrating buprenorphine/naloxone into HIV treatment settings is feasible; however, the optimal level of counseling has not been established. We conducted a 12-week randomized clinical trial of physician management (PM) versus PM plus enhanced medical management (EMM) in 47 subjects. At 12 weeks, there were no differences between the two groups in percentage of opioid negative urines (63.6% PM vs. 69.0% PM+EMM, p=.5), maximum duration of continuous abstinence (4.9 weeks PM vs. 5.2 weeks PM+EMM, p=.8) or retention (80% PM vs. 59% PM+EMM, p=.1). The percentage of subjects with detectable HIV viral loads decreased from 58% at baseline to 40% at 12 weeks across both groups (p=.02 for time) with no between group differences (p=.84 and p=.27 for the interaction). Providing more extensive counseling beyond PM is feasible in an HIV clinic, but we are unable to detect an improvement in outcomes associated with these services. PMID:22938914

  6. Determinants of Increased Opioid-Related Mortality in the United States and Canada, 1990–2013: A Systematic Review

    PubMed Central

    Fraser, Veronique; Boikos, Constantina; Richardson, Robin; Harper, Sam

    2014-01-01

    We review evidence of determinants contributing to increased opioid-related mortality in the United States and Canada between 1990 and 2013. We identified 17 determinants of opioid-related mortality and mortality increases that we classified into 3 categories: prescriber behavior, user behavior and characteristics, and environmental and systemic determinants. These determinants operate independently but interact in complex ways that vary according to geography and population, making generalization from single studies inadvisable. Researchers in this area face significant methodological difficulties; most of the studies in our review were ecological or observational and lacked control groups or adjustment for confounding factors; thus, causal inferences are difficult. Preventing additional opioid-related mortality will likely require interventions that address multiple determinants and are tailored to specific locations and populations. PMID:24922138

  7. Featured Article: Nuclear export of opioid growth factor receptor is CRM1 dependent.

    PubMed

    Kren, Nancy P; Zagon, Ian S; McLaughlin, Patricia J

    2016-02-01

    Opioid growth factor receptor (OGFr) facilitates growth inhibition in the presence of its specific ligand opioid growth factor (OGF), chemically termed [Met(5)]-enkephalin. The function of the OGF-OGFr axis requires the receptor to translocate to the nucleus. However, the mechanism of nuclear export of OGFr is unknown. In this study, endogenous OGFr, as well as exogenously expressed OGFr-EGFP, demonstrated significant nuclear accumulation in response to leptomycin B (LMB), an inhibitor of CRM1-dependent nuclear export, suggesting that OGFr is exported in a CRM1-dependent manner. One consensus sequence for a nuclear export signal (NES) was identified. Mutation of the associated leucines, L217 L220 L223 and L225, to alanine resulted in decreased nuclear accumulation. NES-EGFP responded to LMB, indicating that this sequence is capable of functioning as an export signal in isolation. To determine why the sequence functions differently in isolation than as a full length protein, the localization of subNES was evaluated in the presence and absence of MG132, a potent inhibitor of proteosomal degradation. MG132 had no effect of subNES localization. The role of tandem repeats located at the C-terminus of OGFr was examined for their role in nuclear trafficking. Six of seven tandem repeats were removed to form deltaTR. DeltaTR localized exclusively to the nucleus indicating that the tandem repeats may contribute to the localization of the receptor. Similar to the loss of cellular proliferation activity (i.e. inhibition) recorded with subNES, deltaTR also demonstrated a significant loss of inhibitory activity indicating that the repeats may be integral to receptor function. These experiments reveal that OGFr contains one functional NES, L217 L220 L223 and L225 and can be exported from the nucleus in a CRM1-dependent manner.

  8. Featured Article: Nuclear export of opioid growth factor receptor is CRM1 dependent

    PubMed Central

    Kren, Nancy P; Zagon, Ian S

    2015-01-01

    Opioid growth factor receptor (OGFr) facilitates growth inhibition in the presence of its specific ligand opioid growth factor (OGF), chemically termed [Met5]-enkephalin. The function of the OGF-OGFr axis requires the receptor to translocate to the nucleus. However, the mechanism of nuclear export of OGFr is unknown. In this study, endogenous OGFr, as well as exogenously expressed OGFr-EGFP, demonstrated significant nuclear accumulation in response to leptomycin B (LMB), an inhibitor of CRM1-dependent nuclear export, suggesting that OGFr is exported in a CRM1-dependent manner. One consensus sequence for a nuclear export signal (NES) was identified. Mutation of the associated leucines, L217 L220 L223 and L225, to alanine resulted in decreased nuclear accumulation. NES-EGFP responded to LMB, indicating that this sequence is capable of functioning as an export signal in isolation. To determine why the sequence functions differently in isolation than as a full length protein, the localization of subNES was evaluated in the presence and absence of MG132, a potent inhibitor of proteosomal degradation. MG132 had no effect of subNES localization. The role of tandem repeats located at the C-terminus of OGFr was examined for their role in nuclear trafficking. Six of seven tandem repeats were removed to form deltaTR. DeltaTR localized exclusively to the nucleus indicating that the tandem repeats may contribute to the localization of the receptor. Similar to the loss of cellular proliferation activity (i.e. inhibition) recorded with subNES, deltaTR also demonstrated a significant loss of inhibitory activity indicating that the repeats may be integral to receptor function. These experiments reveal that OGFr contains one functional NES, L217 L220 L223 and L225 and can be exported from the nucleus in a CRM1-dependent manner. PMID:26429201

  9. Experiencing neonatal maternal separation increased the seizure threshold in adult male mice: Involvement of the opioid system.

    PubMed

    Amini-Khoei, Hossein; Amiri, Shayan; Shirzadian, Armin; Haj-Mirzaian, Arya; Alijanpour, Sakineh; Rahimi-Balaei, Maryam; Mohammadi-Asl, Ali; Hassanipour, Mahsa; Mehr, Shahram Ejtemaie; Dehpour, Ahmad Reza

    2015-11-01

    Experiencing early-life stress has been considered as a potent risk factor for the development of many of brain disorders, including seizures. Intervening mechanisms through which neonatal maternal separation (MS) alters the seizure susceptibility in adulthood have not been well studied. In the current study, by applying 180 min of MS stress (PND 2-14), we determined the seizure susceptibility and considered the role of the opioid system. Maternal separation increased the seizure threshold, and administration of anticonvulsant/proconvulsant doses of morphine (1 and 30 mg/kg, respectively) reversed the impact of MS. Using tail flick and hot plate tests, we exposed animals to 30 min Restraint stress (RS) and found that MS decreased the pain threshold, suggesting the hyporesponsiveness of the opioid system. These results supported the abnormal seizure activity observed in the MS mice and suggested that abnormalities in the opioid system following MS alter seizure susceptibility in later life. PMID:26409126

  10. Delta-opioid receptor blockade in the ventral pallidum increases perceived palatability and consumption of saccharin solution in rats.

    PubMed

    Inui, Tadashi; Shimura, Tsuyoshi

    2014-08-01

    The ventral pallidum (VP) is involved in ingestive behaviour. It receives dense GABAergic projections from the nucleus accumbens. GABAergic terminals in the VP co-express enkephalin, an endogenous ligand of delta-opioid receptors. The role of the delta-opioid receptors in the VP in the context of ingestive behaviour remains unclear, in contrast to the well-understood involvement of the mu-opioid receptors. We used the single-bottle test to examine the effects of VP microinjections of the delta-opioid receptor antagonist naltrindole on consumption of a saccharin solution. Naltrindole injections significantly increased the intake of saccharin, but not water, during a 2-h test session. We also investigated perceived palatability of saccharin using a taste reactivity test. The drug treatments increased ingestive responses to intraorally infused saccharin. Further experimentation explored the role of VP delta-opioid receptors in behavioural responses to saccharin that were previously paired with malaise upon the retrieval of conditioned taste aversion (CTA). Naltrindole-injected rats exhibited longer latency for the first occurrence of aversive responses than vehicle-injected control rats. However, there was no between-group difference in total aversive responses. These results suggest that naltrindole injections into the VP induce an enhancement of perceived palatability of a normally preferred saccharin solution, and thereby facilitate consumption of the solution. On the other hand, delayed aversive responses to the conditioned aversive saccharin suggest that the delta-opioid receptors in the VP mediate the initiation of aversive taste reactivity responses to the conditioned stimulus upon CTA retrieval.

  11. Mu opioid receptor expression is increased in inflammatory bowel diseases: implications for homeostatic intestinal inflammation

    PubMed Central

    Philippe, D; Chakass, D; Thuru, X; Zerbib, P; Tsicopoulos, A; Geboes, K; Bulois, P; Breisse, M; Vorng, H; Gay, J; Colombel, J‐F; Desreumaux, P; Chamaillard, M

    2006-01-01

    Background and aims Recent studies with μ opioid receptor (MOR) deficient mice support a physiological anti‐inflammatory effect of MOR at the colon interface. To better understand the potential pharmacological effect of certain opiates in inflammatory bowel diseases (IBD), we (1) evaluated the regulation in vivo and in vitro of human MOR expression by inflammation; and (2) tested the potential anti‐inflammatory function of a specific opiate (DALDA) in inflamed and resting human mucosa. Patients and methods Expression of MOR mRNA and protein was evaluated in healthy and inflamed small bowel and colonic tissues, isolated peripheral blood mononuclear cells and purified monocytes, and CD4+ and CD8+ T cells from healthy donors and IBD patients. The effect of cytokines and nuclear factor κB (NFκB) activation on MOR expression in lymphocyte T and monocytic human cell lines was assessed. Finally, DALDA induced anti‐inflammatory effect was investigated in mucosal explants from controls and IBD patients. Results MOR was expressed in ileal and colonic enteric neurones as well as in immunocytes such as myeloid cells and CD4+ and CD8+ T cells. Overexpressed in active IBD mucosa, MOR was significantly enhanced by cytokines and repressed by NFκB inhibitor in myeloid and lymphocytic cell lines. Furthermore, ex vivo DALDA treatment dampened tumour necrosis factor α mRNA expression in the colon of active IBD patients. Conclusions Given the increased expression of MOR and the ex vivo beneficial effect of DALDA in active IBD, natural and/or synthetic opioid agonists could help to prevent overt pathological intestinal inflammation. PMID:16299031

  12. Quality of life and health of opioid-dependent subjects in India

    PubMed Central

    Giri, Om Prakash; Srivastava, Mona; Shankar, Ravi

    2014-01-01

    Background and Objectives: The quality of life (QoL) of substance abusers is known to be severely impaired. This study was carried out to assess the impact of opioid dependence on the QoL of subjects and compared it with the normal subjects. Materials and Methods: Based on specified inclusion criteria a total of 47 subjects were recruited from a tertiary care center from India. The WHOQoL-BREF scale domain scores obtained at baseline were compared to that of normal subjects. An assessment of dysfunction and reasons for continuing and other parameters were assessed. Results: WHOQoL-BREF domains (Physical, Psychological, Social relationships and Environment) showed significantly lower scores and the difference was statistically significant. Interpretation and Conclusions: The results showed that QoL is an important parameter in assessment of substance abusers and can be used for long-term prognosis of these individuals. PMID:25288838

  13. Millon Clinical Multiaxial Inventory–III Subtypes of Opioid Dependence: Validity and Matching to Behavioral Therapies

    PubMed Central

    Ball, Samuel A.; Nich, Charla; Rounsaville, Bruce J.; Eagan, Dorothy; Carroll, Kathleen M.

    2013-01-01

    The concurrent and predictive validity of 2 different methods of Millon Clinical Multiaxial Inventory–III subtyping (protocol sorting, cluster analysis) was evaluated in 125 recently detoxified opioid-dependent outpatients in a 12-week randomized clinical trial. Participants received naltrexone and relapse prevention group counseling and were assigned to 1 of 3 intervention conditions: (a) no-incentive vouchers, (b) incentive vouchers alone, or (c) incentive vouchers plus relationship counseling. Affective disturbance was the most common Axis I protocol-sorted subtype (66%), antisocial–narcissistic was the most common Axis II subtype (46%), and cluster analysis suggested that a 2-cluster solution (high vs. low psychiatric severity) was optimal. Predictive validity analyses indicated less symptom improvement for the higher problem subtypes, and patient treatment matching analyses indicated that some subtypes had better outcomes in the no-incentive voucher conditions. PMID:15301655

  14. Repeated experience with naloxone facilitates acute morphine withdrawal: potential role for conditioning processes in acute opioid dependence.

    PubMed

    Schulteis, Gery; Morse, Andrew C; Liu, Jian

    2003-12-01

    Single injections with morphine can induce a state of acute opioid dependence in humans and animals, typically measured as precipitated withdrawal when an antagonist such as naloxone is administered 4-24 h after morphine. Repeated treatment with morphine at 24-h intervals can result in a progressive shift in potency of naloxone to produce such acute withdrawal signs, including suppression of operant responding for food reward. The current study characterized fully both morphine and naloxone dose-effect functions in an effort to establish the relative contributions of repeated morphine vs. repeated naloxone (Nal) experience to these potency shifts. Rats trained on an FR15 schedule for food received four vehicle or morphine injections (0.56-5.6 mg/kg sc), spaced 24 h apart. Four hours after each morphine pretreatment (Repeat Nal), or 4 h after the fourth and final morphine pretreatment only (Single Nal), a cumulative dose-effect function for naloxone-induced suppression of responding was determined. Vehicle-pretreated (Morphine Naive) rats showed little change in the naloxone dose effect function even after four cumulative dose-effect determinations. By contrast, a progressive increase in naloxone potency was observed following successive pretreatments with morphine under Repeat Nal conditions, and the magnitude of naloxone potency shift was morphine dose dependent. At a morphine dose of 5.6 mg/kg, repeated naloxone experience in the presence of morphine was not an absolute requirement to produce an increase in naloxone potency across days, but repeated naloxone could potentiate the magnitude of the observed shift, indicating both experience-independent and experience-dependent processes at work. At lower doses of morphine (1.0 and 3.3 mg/kg) no shift in naloxone potency was observed across days of morphine treatment in the absence of repeated naloxone experience (Single Nal conditions), indicating an increasing contribution of naloxone experience-dependent processes

  15. Investigating the Co-Occurrence of Self-Mutilation and Suicide Attempts among Opioid-Dependent Individuals

    ERIC Educational Resources Information Center

    Maloney, Elizabeth; Degenhardt, Louisa; Darke, Shane; Nelson, Elliot C.

    2010-01-01

    The prevalence and risk factors associated with self-mutilation among opioid dependent cases and controls were determined, and the co-occurrence of self-mutilation and attempted suicide was examined. The prevalence of self-mutilation among cases and controls did not differ significantly (25% vs. 23%, respectively), with gender differences…

  16. The role of mu opioid receptor desensitization and endocytosis in morphine tolerance and dependence.

    PubMed

    Martini, Lene; Whistler, Jennifer L

    2007-10-01

    Following activation, most G protein coupled receptors undergo regulation by a cascade of events that promote receptor desensitization and endocytosis. Following endocytosis, receptors can then be recycled to the plasma membrane, retained in an intracellular compartment, or targeted for degradation. For receptors that are recycled, like the mu opioid receptor (MOR), endocytosis serves as the first step toward resensitizing receptors. For receptors that are degraded, endocytosis serves as the first step toward receptor downregulation. Thus, for receptors like the MOR, the desensitization-endocytosis-resensitization cycle serves as a rapid and dynamic means to titrate signaling through the receptor. However, not all agonist ligands at the MOR promote the same degree of receptor desensitization and endocytosis. For example, the endogenous peptide ligands at the MOR induce rapid desensitization, endocytosis, and recycling. By contrast, morphine induces only weak or partial desensitization and little to no endocytosis. As a consequence, signal transduction promoted by morphine is less dynamic than that induced by endogenous ligands as well as other opioid agonists that promote endocytosis. The resulting imbalance of desensitization-endocytosis-resensitization has at least two consequences: (1) in cell types where morphine induces desensitization but not endocytosis and/or resensitization, desensitization is protracted; (2) in cell types where morphine induces neither desensitization nor endocytosis, prolonged signaling through the receptor leads to multiple cellular adaptations downstream of receptor-G protein coupling. Both protracted desensitization and adaptive cellular changes probably contribute to the pronounced in vivo tolerance and dependence that occur with chronic morphine treatment. As a consequence, facilitating receptor endocytosis, using either genetic or pharmacological approaches, can restore the balance of signaling through the receptor and affect the

  17. Genomewide association study of opioid dependence: multiple associations mapped to calcium and potassium pathways

    PubMed Central

    Gelernter, Joel; Kranzler, Henry R.; Sherva, Richard; Koesterer, Ryan; Almasy, Laura; Zhao, Hongyu; Farrer, Lindsay A.

    2013-01-01

    Background We report a GWAS of two populations, African- and European-American (AA, EA) for opioid dependence (OD) in three sets of subjects, to identify pathways, genes, and alleles important in OD risk. Methods Design employed three phases (based on separate sample collections). Phase 1 included our discovery GWAS dataset consisting of 5,697 subjects (58% AA) diagnosed with opioid and/or other substance dependence (SD), and controls. Subjects were genotyped using the Illumina OmniQuad microarray, yielding 890,000 SNPs suitable for analysis. Additional genotypes were imputed using the 1000 Genomes reference panel. Top-ranked findings were further evaluated in Phase 2 by incorporating information from the publicly available SAGE dataset, with GWAS data from 4,063 subjects (32% AA). In Phase 3, the most significant SNPs from Phase 2 were genotyped in 2,549 independent subjects (32% AA). Analyses were performed using case-control and ordinal trait designs. Results Most significant results emerged from the AA subgroup. Genomewide-significant associations (p<5.0×10−8) were observed with SNPs from multiple loci - KCNC1*rs60349741 most significant after combining results from datasets in every phase of the study. The most compelling results were obtained with genes involved in potassium signaling pathways (e.g., KCNC1, KCNG2, and KCNA4). Pathway analysis also implicated genes involved in calcium signaling and long-term potentiation. Conclusions This is the first study to identify risk variants for OD using GWAS. Our results strongly implicate risk pathways, provide insights into novel therapeutic and prevention strategies, and may provide biologically bridge OD and other non-SD psychiatric traits where similar pathways have been implicated. PMID:24143882

  18. Patterns of opioid and cocaine co-use: a descriptive study in a Canadian sample of untreated opioid-dependent individuals.

    PubMed

    Leri, Francesco; Stewart, Jane; Fischer, Benedikt; Jürgen, Rehm; Marsh, David C; Brissette, Suzanne; Bruneau, Julie; El-Guebaly, Nady; Noël, Lina; Tyndall, Mark W; Wild, T Cameron

    2005-11-01

    This study examined prevalence and patterns of co-use of opioids and cocaine in regular users of illicit opioids (N = 729) recruited from 5 Canadian cities. Fifty-seven percent (n = 417) reported having used both opioids and cocaine in the month and week preceding the interview; of these, 73% (n = 304) were able to identify a typical pattern of daily co-use. In a typical day, injectors of opioids and cocaine (n = 119) and injectors of opioids who inhaled cocaine (n = 111) showed stable opioid use but variable cocaine use, which peaked at 21 hr. Overall, 30% of the individuals used both drugs exclusively in a sequential fashion, 35% reported taking opioids and cocaine within the same hour, and 35% reported taking them together at the same time or mixing them. These findings indicate that different individuals display different patterns of opioids and cocaine co-use.

  19. Cell death sensitization of leukemia cells by opioid receptor activation

    PubMed Central

    Friesen, Claudia; Roscher, Mareike; Hormann, Inis; Fichtner, Iduna; Alt, Andreas; Hilger, Ralf A.; Debatin, Klaus-Michael; Miltner, Erich

    2013-01-01

    Cyclic AMP (cAMP) regulates a number of cellular processes and modulates cell death induction. cAMP levels are altered upon stimulation of specific G-protein-coupled receptors inhibiting or activating adenylyl cyclases. Opioid receptor stimulation can activate inhibitory Gi-proteins which in turn block adenylyl cyclase activity reducing cAMP. Opioids such as D,L-methadone induce cell death in leukemia cells. However, the mechanism how opioids trigger apoptosis and activate caspases in leukemia cells is not understood. In this study, we demonstrate that downregulation of cAMP induced by opioid receptor activation using the opioid D,L-methadone kills and sensitizes leukemia cells for doxorubicin treatment. Enhancing cAMP levels by blocking opioid-receptor signaling strongly reduced D,L-methadone-induced apoptosis, caspase activation and doxorubicin-sensitivity. Induction of cell death in leukemia cells by activation of opioid receptors using the opioid D,L-methadone depends on critical levels of opioid receptor expression on the cell surface. Doxorubicin increased opioid receptor expression in leukemia cells. In addition, the opioid D,L-methadone increased doxorubicin uptake and decreased doxorubicin efflux in leukemia cells, suggesting that the opioid D,L-methadone as well as doxorubicin mutually increase their cytotoxic potential. Furthermore, we found that opioid receptor activation using D,L-methadone alone or in addition to doxorubicin inhibits tumor growth significantly in vivo. These results demonstrate that opioid receptor activation via triggering the downregulation of cAMP induces apoptosis, activates caspases and sensitizes leukemia cells for doxorubicin treatment. Hence, opioid receptor activation seems to be a promising strategy to improve anticancer therapies. PMID:23633472

  20. Child Maltreatment as a Risk Factor for Opioid Dependence: Comparison of Family Characteristics and Type and Severity of Child Maltreatment with a Matched Control Group

    ERIC Educational Resources Information Center

    Conroy, Elizabeth; Degenhardt, Louisa; Mattick, Richard P.; Nelson, Elliot C.

    2009-01-01

    Objective: To examine the prevalence, characteristics and risk factors for child maltreatment among opioid-dependent persons compared to a community sample of similar social disadvantage. Method: The study employed a case-control design. Cases had a history of opioid pharmacotherapy. Controls were frequency matched to cases with regard to age, sex…

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

    ERIC Educational Resources Information Center

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

    2005-01-01

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

  2. Methadone maintenance in the treatment of opioid dependence. A current perspective.

    PubMed

    Zweben, J E; Payte, J T

    1990-05-01

    We describe the historical underpinnings of negative attitudes towards methadone and how these affect medical decisions. Current developments have increased the understanding of the origins of opioid addiction, such as how receptor system dysfunction may affect the ability to remain abstinent once out of treatment. Specialized topics include the pregnant addict, the role of methadone maintenance in limiting the spread of the acquired immunodeficiency syndrome, and patients with a dual diagnosis. We also describe issues that arise when methadone is used in conjunction with prescribed or abused drugs, noting pharmacologic alternatives and adjuncts to methadone treatment. Finally, we comment on treatment issues such as methadone patients in 12-step programs and the growing legitimacy of this treatment method.

  3. Genetic variation in OPRD1 and the response to treatment for opioid dependence with buprenorphine in European-American females.

    PubMed

    Clarke, T-K; Crist, R C; Ang, A; Ambrose-Lanci, L M; Lohoff, F W; Saxon, A J; Ling, W; Hillhouse, M P; Bruce, R D; Woody, G; Berrettini, W H

    2014-06-01

    Two commonly prescribed treatments for opioid addiction are methadone and buprenorphine. Although these drugs show some efficacy in treating opioid dependence, treatment response varies among individuals. It is likely that genetic factors have a role in determining treatment outcome. This study analyses the pharmacogenetic association of six polymorphisms in OPRD1, the gene encoding the delta-opioid receptor, on treatment outcome in 582 opioid addicted European Americans randomized to either methadone or buprenorphine/naloxone (Suboxone) over the course of a 24-week open-label clinical trial. Treatment outcome was assessed as the number of missed or opioid-positive urine drug screens over the 24 weeks. In the total sample, no single-nucleotide polymorphisms (SNPs) in OPRD1 were significantly associated with treatment outcome in either treatment arm. However, sex-specific analyses revealed two intronic SNPs (rs581111 and rs529520) that predicted treatment outcome in females treated with buprenorphine. Females with the AA or AG genotypes at rs581111 had significantly worse outcomes than those with the GG genotype when treated with buprenorphine (P=0.03, relative risk (RR)=1.67, 95% confidence interval (CI) 1.06-2.1). For rs529520, females with the AA genotype had a significantly worse outcome than those with the CC genotype when (P=0.006, RR=2.15, 95% CI 1.3-2.29). No significant associations were detected in males. These findings suggest that rs581111 and rs52920 may be useful when considering treatment options for female opioid addicts, however, confirmation in an independent sample is warranted. PMID:24126707

  4. Genetic variation in OPRD1 and the response to treatment for opioid dependence with buprenorphine in European American females

    PubMed Central

    Clarke, Toni-Kim; Crist, Richard C.; Ang, Alfonso; Ambrose-Lanci, Lisa M.; Lohoff, Falk W.; Saxon, Andrew J.; Ling, Walter; Hillhouse, Maureen P.; Bruce, R. Douglas; Woody, George; Berrettini, Wade H.

    2013-01-01

    Two commonly prescribed treatments for opioid addiction are methadone and buprenorphine. While these drugs show some efficacy in treating opioid dependence, treatment response varies among individuals. It is likely that genetic factors play a role in determining treatment outcome. This study analyses the pharmacogenetic association of 6 polymorphisms in OPRD1, the gene encoding the delta-opioid receptor, on treatment outcome in 582 opioid addicted European Americans randomized to either methadone or buprenorphine/naloxone ((Suboxone®) over the course of a 24 week open-label clinical trial. Treatment outcome was assessed as the number of missed or opioid positive urine drug screens over the 24 weeks. In the total sample, no SNPs in OPRD1 were significantly associated with treatment outcome in either treatment arm. However, sex-specific analyses revealed 2 intronic SNPs (rs581111 and rs529520) that predicted treatment outcome in females treated with buprenorphine. Females with the AA or AG genotypes at rs581111 had significantly worse outcomes than those with the GG genotype when treated with buprenorphine (p=0.03, RR=1.67, 95% C.I.[1.06-2.1]). For rs529520, females with the AA genotype had a significantly worse outcome than those with the CC genotype when (p=0.006, RR=2.15, 95%C.I.[1.3-2.29]). No significant associations were detected in males. These findings suggest that rs581111 and rs52920 may be useful when considering treatment options for female opioid addicts, however confirmation in an independent sample is warranted. PMID:24126707

  5. Opioid agonist and antagonist treatment differentially regulates immunoreactive mu-opioid receptors and dynamin-2 in vivo.

    PubMed

    Yoburn, Byron C; Purohit, Vishal; Patel, Kaushal; Zhang, Qiuyu

    2004-09-13

    density, determined in radioligand binding assays, and immunoreactive dynamin-2 abundance are regulated by continuous, but not intermittent, opioid ligand treatment. Furthermore, the differential regulation of mu-opioid receptor abundance by agonists and antagonists in immunoblotting assays contrasts with changes in [3H] DAMGO binding. Taken together, these results suggest that etorphine-induced down-regulation may depend upon mu-opioid receptor degradation and changes in dynamin-2-mediated receptor trafficking. Conversely, antagonist-induced up-regulation does not require an increase in mu-opioid receptor synthesis and may entail conversion of receptors to an appropriate conformation to bind ligand, as well as changes in receptor trafficking.

  6. Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System.

    PubMed

    Karkhanis, Anushree N; Rose, Jamie H; Weiner, Jeffrey L; Jones, Sara R

    2016-08-01

    Chronic early-life stress increases vulnerability to alcoholism and anxiety disorders during adulthood. Similarly, rats reared in social isolation (SI) during adolescence exhibit augmented ethanol intake and anxiety-like behaviors compared with group housed (GH) rats. Prior studies suggest that disruption of dopamine (DA) signaling contributes to SI-associated behaviors, although the mechanisms underlying these alterations are not fully understood. Kappa opioid receptors (KORs) have an important role in regulating mesolimbic DA signaling, and other kinds of stressors have been shown to augment KOR function. Therefore, we tested the hypothesis that SI-induced increases in KOR function contribute to the dysregulation of NAc DA and the escalation in ethanol intake associated with SI. Our ex vivo voltammetry experiments showed that the inhibitory effects of the kappa agonist U50,488 on DA release were significantly enhanced in the NAc core and shell of SI rats. Dynorphin levels in NAc tissue were observed to be lower in SI rats. Microdialysis in freely moving rats revealed that SI was also associated with reduced baseline DA levels, and pretreatment with the KOR antagonist nor-binaltorphimine (nor-BNI) increased DA levels selectively in SI subjects. Acute ethanol elevated DA in SI and GH rats and nor-BNI pretreatment augmented this effect in SI subjects, while having no effect on ethanol-stimulated DA release in GH rats. Together, these data suggest that KORs may have increased responsiveness following SI, which could lead to hypodopaminergia and contribute to an increased drive to consume ethanol. Indeed, SI rats exhibited greater ethanol intake and preference and KOR blockade selectively attenuated ethanol intake in SI rats. Collectively, the findings that nor-BNI reversed SI-mediated hypodopaminergic state and escalated ethanol intake suggest that KOR antagonists may represent a promising therapeutic strategy for the treatment of alcohol use disorders, particularly

  7. Genome-Wide Association Study of Copy Number Variations (CNVs) with Opioid Dependence

    PubMed Central

    Li, Dawei; Zhao, Hongyu; Kranzler, Henry R; Li, Ming D; Jensen, Kevin P; Zayats, Tetyana; Farrer, Lindsay A; Gelernter, Joel

    2015-01-01

    Single-nucleotide polymorphisms that have been associated with opioid dependence (OD) altogether account for only a small proportion of the known heritability. Most of the genetic risk factors are unknown. Some of the ‘missing heritability' might be explained by copy number variations (CNVs) in the human genome. We used Illumina HumanOmni1 arrays to genotype 5152 African-American and European-American OD cases and screened controls and implemented combined CNV calling methods. After quality control measures were applied, a genome-wide association study (GWAS) of CNVs with OD was performed. For common CNVs, two deletions and one duplication were significantly associated with OD genome-wide (eg, P=2 × 10−8 and OR (95% CI)=0.64 (0.54–0.74) for a chromosome 18q12.3 deletion). Several rare or unique CNVs showed suggestive or marginal significance with large effect sizes. This study is the first GWAS of OD using CNVs. Some identified CNVs harbor genes newly identified here to be of biological importance in addiction, whereas others affect genes previously known to contribute to substance dependence risk. Our findings augment our specific knowledge of the importance of genomic variation in addictive disorders, and provide an addiction CNV pool for further research. These findings require replication. PMID:25345593

  8. Survey Criteria for Fibromyalgia Independently Predict Increased Postoperative Opioid Consumption after Lower Extremity Joint Arthroplasty: A Prospective, Observational Cohort Study

    PubMed Central

    Brummett, Chad M.; Janda, Allison M.; Schueller, Christa M.; Tsodikov, Alex; Morris, Michelle; Williams, David A.; Clauw, Daniel J.

    2013-01-01

    Background Variance in pain following total knee and hip arthroplasty may be due to a number of procedural and peripheral factors but also, in some individuals, to aberrant central pain processing as is described in conditions like fibromyalgia. To test this hypothesis, we conducted a prospective, observational cohort study of patients undergoing lower extremity joint arthroplasty. Methods 519 patients were preoperatively phenotyped using validated self-reported pain questionnaires, psychological measures, and health information. In addition to assessing factors previously found to be associated with poor outcomes in arthroplasty, participants also completed the American College of Rheumatology survey criteria for fibromyalgia. Previous studies have suggested that rather than being “present” or “absent,” features of fibromyalgia as measured by this instrument, occur over a wide continuum. Postoperative pain control was assessed by total postoperative opioid consumption. Results Preoperatively, patients with higher fibromyalgia survey scores were younger, more likely to be female, taking more opioids, reported higher pain severity, and had a more negative psychological profile. In the multivariate analysis, the fibromyalgia survey score, younger age, preoperative opioid use, knee (vs. hip), pain severity at baseline, and the anesthetic technique were all predictive of increased postoperative opioid consumption. Conclusions Using the survey criteria for fibromyalgia distinct phenotypic differences were found, and the measure was independently predictive of opioid consumption. This self-report measure may provide an additional simple means of predicting postoperative pain outcomes and analgesic requirements. Future studies are needed to determine whether tailored therapies can improve postoperative pain control in this population. PMID:24343289

  9. Design and methods of a double blind randomized placebo-controlled trial of extended-release naltrexone for HIV-infected, opioid dependent prisoners and jail detainees who are transitioning to the community

    PubMed Central

    Di Paola, Angela; Lincoln, Thomas; Skiest, Daniel J.; Desabrais, Maureen; Altice, Frederick L.; Springer, Sandra A.

    2014-01-01

    Background People with opioid dependence and HIV are concentrated within criminal justice settings (CJS). Upon release, however, drug relapse is common and contributes to poor HIV treatment outcomes, increased HIV transmission risk, reincarceration and mortality. Extended-release naltrexone (XR-NTX) is an evidence-based treatment for opioid dependence, yet is not routinely available for CJS populations. Methods A randomized, double-blind, placebo-controlled trial of XR-NTX for HIV-infected inmates transitioning from correctional to community settings is underway to assess its impact on HIV and opioid-relapse outcomes. Results We describe the methods and early acceptability of this trial. In addition we provide protocol details to safely administer XR-NTX near community release and describe logistical implementation issues identified. Study acceptability was modest, with 132 (66%) persons who consented to participate from 199 total referrals. Overall, 79% of the participants had previously received opioid agonist treatment before this incarceration. Thus far, 65 (49%) of those agreeing to participate in the trial have initiated XR-NTX or placebo. Of the 134 referred patients who ultimately did not receive a first injection, the main reasons included a preference for an alternative opioid agonist treatment (37%), being ineligible (32%), not yet released (10%), and lost upon release before an receiving their injection (14%). Conclusions Study findings should provide high internal validity about HIV and opioid treatment outcomes for HIV-infected prisoners transitioning to the community. The large number of patients who ultimately did not receive the study medication may raise external validity concerns due to XR-NTX acceptability and interest in opioid agonist treatments. PMID:25240704

  10. Mu opioid receptor (OPRM1) as a predictor of treatment outcome in opiate-dependent individuals of Arab descent

    PubMed Central

    AL-Eitan, Laith N; Jaradat, Saied A; Su, Steve YS; Tay, Guan K; Hulse, Gary K

    2012-01-01

    Background: A number of research studies on the genetics of opiate dependence have focused on the μ-opioid receptor (OPRM1), which is a primary target for opiates. This study aims to identify genetic polymorphisms within the OPRM1 gene involved in response to the biopsychosocial treatment in opiate-dependent individuals of Arab descent. Methods: Unrelated Jordanian Nationals of Arab descent (N = 183) with opiate dependence were selected for this study. These individuals, all males, met the DSM-IV criteria for opiate dependence and were undergoing a voluntary 8-week treatment program at a Jordanian Drug Rehabilitation Centre. All individuals were genotyped for 22 single nucleotide polymorphisms (SNPs) within the OPRM1 gene using the Sequenom MassARRAY® system (iPLEX GOLD). Statistical analyses were carried out using the R package. Results: Patients receiving biopsychosocial treatment showed that there was a significant difference in their OPRM1 SNPs’ genotyping distribution between good, moderate, and poor responders to the treatment at two sites (rs6912029 [G-172T], and rs12205732 [G-1510A], P < 0.05, Fisher’s exact test). Conclusion: This study is the first report of an association between the OPRM1 G-172T and G-1510A polymorphisms and treatment response for opiate dependence. Specifically, this study demonstrated that the OPRM1 GG-172 and GG-1510 genotypes were more frequent among patients who were nonresponders to the biopsychosocial treatment. However, further pharmacogenetic studies in a larger cohort of opiate-dependent patients of Arab descent are needed to confirm these findings and identify individuals with increased chance of relapse. PMID:23226066

  11. A Comparison of Trauma Profiles among Individuals with Prescription Opioid, Nicotine or Cocaine Dependence

    PubMed Central

    Lawson, Katie M.; Back, Sudie E.; Hartwell, Karen J.; Maria, Megan Moran-Santa; Brady, Kathleen T.

    2013-01-01

    Exposure to traumatic events is common among individuals with substance use disorders. Little is known, however, about the trauma histories among individuals with various types of addiction. The present study compared the trauma histories (general, sexual, physical and emotional) of non-treatment seeking outpatients dependent on prescription opioids (n=41), nicotine (n=87) or cocaine (n=73). The Life Stressor Checklist-Revised (LSC-R) was completed by participants to assess childhood and adult trauma. The findings revealed that all three groups endorsed high levels of trauma exposure, with 96.5% of the entire sample experiencing at least one traumatic event in their lifetime. The prescription opiate group experienced a greater number of general and total traumas than the nicotine group. However, no group differences in the number of emotional, physical, or sexual traumas were revealed. The prescription opiate group reported a younger age of first traumatic event than the cocaine group, and was significantly more likely to report childhood traumatic events than both the cocaine and nicotine groups. The findings provide clinically relevant information that may help improve screening, interventions, and preventative efforts. PMID:23414497

  12. Oral heroin in opioid-dependent patients: pharmacokinetic comparison of immediate and extended release tablets

    PubMed Central

    Perger, Ludwig; Rentsch, Katharina M.; Kullak-Ublick, Gerd A.; Verotta, Davide; Fattinger, Karin

    2009-01-01

    In diacetylmorphine prescription programs for heavily dependent addicts, diacetylmorphine is usually administered intravenously, but this may not be possible due to venosclerosis or when heroin abuse had occurred via non-intravenous routes. Since up to 25% of patients administer diacetylmorphine orally, we characterised morphine absorption after single oral doses of immediate and extended release diacetylmorphine in 8 opioid addicts. Plasma concentrations were determined by liquid chromatography-mass spectrometry. Non-compartmental methods and deconvolution were applied for data analysis. Mean (±SD) immediate and extended release doses were 719 ± 297 mg and 956 ± 404 mg, with high absolute morphine bioavailabilities of 56% to 61%, respectively. Immediate release diacetylmorphine caused rapid morphine absorption, peaking at 10 to 15 min. Morphine absorption was considerably slower and more sustained for extended release diacetylmorphine, with only ~30% of maximal immediate release absorption being reached after 10 min and maintained for 3 to 4 h, with no relevant food interaction. The relative extended to immediate release bioavailability was calculated to be 86% by non-compartmental analysis and 93% by deconvolution analysis. Thus, immediate and extended release diacetylmorphine produce the intended morphine exposures. Both are suitable for substitution treatments. Similar doses can be applied if used in combination or sequentially. PMID:19084595

  13. Buprenorphine Treatment of Opioid-Dependent Pregnant Women: A Comprehensive Review

    PubMed Central

    Jones, Hendrée E.; Arria, Amelia M.; Baewert, Andjela; Heil, Sarah H.; Kaltenbach, Karol; Martin, Peter R.; Coyle, Mara G.; Selby, Peter; Stine, Susan M.; Fischer, Gabriele

    2015-01-01

    Aims This paper reviews the published literature regarding outcomes following maternal treatment with buprenorphine in five areas: maternal efficacy, fetal effects, neonatal effects, effects on breast milk, and longer-term developmental effects. Methods Within each outcome area, findings are summarized first for the 3 randomized controlled trials and then for the 44 non-randomized studies (i.e., prospective studies, case reports and series, and retrospective chart reviews), only 28 of which involve independent samples. Results Results indicate that maternal treatment with buprenorphine has comparable efficacy to methadone, although difficulties may exist with current buprenorphine induction methods. The available fetal data suggest buprenorphine results in less physiologic suppression of fetal heart rate and movements than methadone. Regarding neonatal effects, perhaps the single definitive conclusion is that prenatal buprenorphine treatment results in a clinically significant less severe neonatal abstinence syndrome (NAS) than treatment with methadone. The limited research suggests that, like methadone, buprenorphine is compatible with breastfeeding. Data available thus far suggest that there are no deleterious effects of in utero buprenorphine exposure on infant development. Conclusions Buprenorphine produces a less severe neonatal abstinence syndrome than methadone, but there is still a role for methadone in the treatment of opioid dependence during pregnancy. PMID:23106923

  14. The role of perceived belongingness to a drug subculture among opioid-dependent patients.

    PubMed

    Moshier, Samantha J; McHugh, R Kathryn; Calkins, Amanda W; Hearon, Bridget A; Rosellini, Anthony J; Weitzman, Meara L; Otto, Michael W

    2012-12-01

    Illicit drug use frequently occurs in a context of a drug subculture characterized by social ties with other drug users, feelings of excitement and effectiveness deriving from illicit activities, and alienation from mainstream society. Identification with this subculture is recognized anecdotally as a barrier to recovery, but clear quantification of individual differences in perceived belongingness to the drug subculture has been absent from the literature. The purpose of this study was to describe the development and psychometric properties of a brief self-report measure designed to assess this construct, the Belongingness to Drug Culture Questionnaire (BDCQ). Ninety-six opioid-dependent, methadone-maintained participants completed the BDCQ, related self-report measures, and assessment of drug use patterns. The BDCQ demonstrated high internal consistency (α = .88) and was significantly associated with self-reported days of drug use in the past 30 days, desire to quit, impulsivity, psychopathy, and social, enhancement, and coping drug use motives. These findings encourage continued psychometric evaluation of the BDCQ and study of the role of belongingness in the development and maintenance of substance use disorders.

  15. Increased survival of tumor-bearing mice by the delta opioid SNC 80.

    PubMed

    Gomez-Flores, Ricardo; Caballero-Hernández, Diana; Tamez-Guerra, Reyes; Rodríguez-Padilla, Cristina; Tamez-Guerra, Patricia; Rice, Kenner C; Hicks, Mary E; Weber, Richard J

    2005-01-01

    Opioids represent a major source of relief from pain. However, opioid abuse may cause immunosuppression and cancer. We have recently reported results on novel non-peptidic delta- and mu-selective opioids that induced immunopotentiation of T cell and macrophage functions in vitro and ex vivo. In the present study, the effects of the delta-opioid receptor agonist and potent analgesic (+)-4-((alpha R)-alpha-((2S, 5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N, N-diethyl-benzamide (SNC80) on in vitro and in vivo tumor cell growth were investigated using the L5178Y-R murine model. SNC80 marginally, but significantly (p < 0.05), inhibited (up to 14%) the in vitro growth of L5178Y-R tumor cells. However, in vivo intratumor administration of SNC80 (2 and 4 mg/kg) reduced up to 60% L5178Y-R tumor-bearing Balb/c mice death, and significantly (p < 0.05) reduced tumor weights (up to 73% reduction) in these animals. This study may support the evaluation of SNC80 in preclinical and clinical studies.

  16. A Multi-Site Pilot Study of Extended-Release Injectable Naltrexone Treatment for Previously Opioid-Dependent Parolees and Probationers

    PubMed Central

    Coviello, D.M.; Cornish, J.W.; Lynch, K.G.; Boney, T.Y.; Clark, C.A.; Lee, J.D.; Friedmann, P.D.; Nunes, E.V.; Kinlock, T.W.; Gordon, M.S.; Schwartz, R.P.; Nuwayser, E.S.; O’Brien, C.P.

    2012-01-01

    A feasibility study was conducted to pilot test the ability of five sites to recruit, treat, and retain opioid-dependent offenders in a trial of extended-release injectable naltrexone (XR-NTX). The participants, 61 previously opioid-dependent individuals under legal supervision in the community, received up to six monthly injections of Depotrex® brand naltrexone and completed a six-month follow-up interview. Six-month outcomes showed that those who completed treatment had significantly fewer opioid-positive urines and were less likely to have been incarcerated than those who had not completed treatment. The findings indicate that XR-NTX holds promise as a feasible, effective treatment option for opioid-dependent offenders. PMID:22263713

  17. The δ-Opioid Receptor Affects Epidermal Homeostasis via ERK-Dependent Inhibition of Transcription Factor POU2F3

    PubMed Central

    Neumann, Christine; Bigliardi-Qi, Mei; Widmann, Christian; Bigliardi, Paul L

    2015-01-01

    Neuropeptides and their receptors are present in human skin, and their importance for cutaneous homeostasis and during wound healing is increasingly appreciated. However, there is currently a lack of understanding of the molecular mechanisms by which their signaling modulates keratinocyte function. Here, we show that δ-opioid receptor (DOPr) activation inhibits proliferation of human keratinocytes, resulting in decreased epidermal thickness in an organotypic skin model. DOPr signaling markedly delayed induction of keratin intermediate filament (KRT10) during in vitro differentiation and abolished its induction in the organotypic skin model. This was accompanied by deregulation of involucrin (IVL), loricrin, and filaggrin. Analysis of the transcription factor POU2F3, which is involved in regulation of KRT10, IVL, and profilaggrin expression, revealed a DOPr-mediated extracellular signal-regulated kinase (ERK)-dependent downregulation of this factor. We propose that DOPr signaling specifically activates the ERK 1/2 mitogen-activated protein kinase pathway to regulate keratinocyte functions. Complementing our earlier studies in DOPr-deficient mice, these data suggest that DOPr activation in human keratinocytes profoundly influences epidermal morphogenesis and homeostasis. PMID:25178105

  18. Monoglyceride lipase deficiency causes desensitization of intestinal cannabinoid receptor type 1 and increased colonic μ-opioid receptor sensitivity

    PubMed Central

    Taschler, U; Eichmann, T O; Radner, F P W; Grabner, G F; Wolinski, H; Storr, M; Lass, A; Schicho, R; Zimmermann, R

    2015-01-01

    Background and Purpose Monoglyceride lipase (MGL) degrades 2-arachidonoyl glycerol (2-AG), an endogenous agonist of cannabinoid receptors (CB1/2). Because the CB1 receptor is involved in the control of gut function, we investigated the effects of pharmacological inhibition and genetic deletion of MGL on intestinal motility. Furthermore, we determined whether defective 2-AG degradation affects μ-opioid receptor (μ receptor) signalling, a parallel pathway regulating gut motility. Experimental Approach Gut motility was investigated by monitoring Evans Blue transit and colonic bead propulsion in response to MGL inhibition and CB1 receptor or μ receptor stimulation. Ileal contractility was investigated by electrical field stimulation. CB1 receptor expression in ileum and colon was assessed by immunohistochemical analyses. Key Results Pharmacological inhibition of MGL slowed down whole gut transit in a CB1 receptor-dependent manner. Conversely, genetic deletion of MGL did not affect gut transit despite increased 2-AG levels. Notably, MGL deficiency caused complete insensitivity to CB1 receptor agonist-mediated inhibition of whole gut transit and ileal contractility suggesting local desensitization of CB1 receptors. Accordingly, immunohistochemical analyses of myenteric ganglia of MGL-deficient mice revealed that CB1 receptors were trapped in endocytic vesicles. Finally, MGL-deficient mice displayed accelerated colonic propulsion and were hypersensitive to μ receptor agonist-mediated inhibition of colonic motility. This phenotype was reproduced by chronic pharmacological inhibition of MGL. Conclusion and Implications Constantly elevated 2-AG levels induce severe desensitization of intestinal CB1 receptors and increased sensitivity to μ receptor-mediated inhibition of colonic motility. These changes should be considered when cannabinoid-based drugs are used in the therapy of gastrointestinal diseases. PMID:26075589

  19. Kappa Opioid Receptor Activation of p38 MAPK Is GRK3- and Arrestin-dependent in Neurons and Astrocytes*

    PubMed Central

    Bruchas, Michael R.; Macey, Tara A.; Lowe, Janet D.; Chavkin, Charles

    2007-01-01

    AtT-20 cells expressing the wild-type kappa opioid receptor (KOR) increased phospho-p38 MAPK following treatment with the kappa agonist U50,488. The increase was blocked by the kappa antagonist norbinaltorphimine and not evident in untransfected cells. In contrast, U50,488 treatment of AtT-20 cells expressing KOR having alanine substituted for serine-369 (KSA) did not increase phospho-p38. Phosphorylation of serine 369 in the KOR carboxyl terminus by G-protein receptor kinase 3 (GRK3) was previously shown to be required for receptor desensitization, and the results suggest that p38 MAPK activation by KOR may require arrestin recruitment. This hypothesis was tested by transfecting arrestin3-(R170E), a dominant positive form of arrestin that does not require receptor phosphorylation for activation. AtT-20 cells expressing both KSA and arrestin3-(R170E) responded to U50,488 treatment with an increase in phospho-p38 consistent with the hypothesis. Primary cultured astrocytes (glial fibrillary acidic protein-positive) and neurons (γ-aminobutyric acid-positive) isolated from mouse striata also responded to U50,488 by increasing phospho-p38 immunolabeling. p38 activation was not evident in either striatal astrocytes or neurons isolated from KOR knock-out mice or GRK3 knock-out mice. Astrocytes pretreated with small interfering RNA for arrestin3 were also unable to activate p38 in response to U50,488 treatment. Furthermore, in striatal neurons, the kappa-mediated phospho-p38 labeling was colocalized with arrestin3. These findings suggest that KOR may activate p38 MAPK in brain by a GRK3 and arrestin-dependent mechanism. PMID:16648139

  20. 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.

  1. Medium Increased Risk for Central Sleep Apnea but Not Obstructive Sleep Apnea in Long-Term Opioid Users: A Systematic Review and Meta-Analysis

    PubMed Central

    Filiatrault, Marie-Lou; Chauny, Jean-Marc; Daoust, Raoul; Roy, Marie-Pier; Denis, Ronald; Lavigne, Gilles

    2016-01-01

    Study Objective: Opioids are associated with higher risk for ataxic breathing and sleep apnea. We conducted a systematic literature review and meta-analysis to assess the influence of long-term opioid use on the apnea-hypopnea and central apnea indices (AHI and CAI, respectively). Methods: A systematic review protocol (Cochrane Handbook guidelines) was developed for the search and analysis. We searched Embase, Medline, ACP Journal Club, and Cochrane Database up to November 2014 for three topics: (1) narcotics, (2) sleep apnea, and (3) apnea-hypopnea index. The outcome of interest was the variation in AHI and CAI in opioid users versus non-users. Two reviewers performed the data search and extraction, and disagreements were resolved by discussion. Results were combined by standardized mean difference using a random effect model, and heterogeneity was tested by χ2 and presented as I2 statistics. Results: Seven studies met the inclusion criteria, for a total of 803 patients with obstructive sleep apnea (OSA). We compared 2 outcomes: AHI (320 opioid users and 483 non-users) and 790 patients with CAI (315 opioid users and 475 non-users). The absolute effect size for opioid use was a small increased in apnea measured by AHI = 0.25 (95% CI: 0.02–0.49) and a medium for CAI = 0.45 (95% CI: 0.27–0.63). Effect consistency across studies was calculated, showing moderate heterogeneity at I2 = 59% and 29% for AHI and CAI, respectively. Conclusions: The meta-analysis results suggest that long-term opioid use in OSA patients has a medium effect on central sleep apnea. Citation: Filiatrault ML, Chauny JM, Daoust R, Roy MP, Denis R, Lavigne G. Medium increased risk for central sleep apnea but not obstructive sleep apnea in long-term opioid users: a systematic review and meta-analysis. J Clin Sleep Med 2016;12(4):617–625. PMID:26943709

  2. Escitalopram is associated with reductions in pain severity and pain interference in opioid dependent patients with depressive symptoms.

    PubMed

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

    2011-11-01

    Pain is common among opioid-dependent patients, yet pharmacologic strategies are limited. The aim of this study was to explore whether escitalopram, a selective serotonin reuptake inhibitor, was associated with reductions in pain. The study used longitudinal data from a randomized, controlled trial that evaluated the effects of escitalopram on treatment retention in patients with depressive symptoms who were initiating buprenorphine/naloxone for treatment of opioid dependence. Participants were randomized to receive escitalopram 10 mg or placebo daily. Changes in pain severity, pain interference, and depression were assessed at 1-, 2-, and 3-month visits with the visual analog scale, Brief Pain Inventory, and the Beck Depression Inventory II, respectively. Fixed-effects estimators for panel regression models were used to assess the effects of intervention on changes in outcomes over time. Additional models were estimated to explore whether the intervention effect was mediated by within-person changes in depression. In this sample of 147 adults, we found that participants randomized to escitalopram had significantly larger reductions on both pain severity (b=-14.34, t=-2.66, P<.01) and pain interference (b=-1.20, t=-2.23, P<.05) between baseline and follow-up. After adjusting for within-subject changes in depression, the estimated effects of escitalopram on pain severity and pain interference were virtually identical to the unadjusted effects. This study of opioid-dependent patients with depressive symptoms found that treatment with escitalopram was associated with clinically meaningful reductions in pain severity and pain interference during the first 3 months of therapy.

  3. 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 in Toronto, Ontario. Over 12 weeks, patients were prospectively identified for the study, and charts were later reviewed to characterize opioid use during the hospital stay and upon discharge. The primary outcomes were the proportions of opioid-naive patients for whom opioids were prescribed in hospital and upon discharge. Data on serious adverse events related to opioid use (e.g., need for naloxone or occurrence of falls) were also collected through chart review. Results: From July 4 to September 22, 2011, a total of 721 patients were admitted to the study unit, of whom 381 (53%) were classified as opioid-naive. Opioids were prescribed for 82 (22%) of these opioid-naive patients while they were in hospital. Among the opioid-naive patients, there were a total of 247 opioid prescriptions, with hydromorphone (110 prescriptions) and morphine (92 prescriptions) being the drugs most commonly prescribed. For 23 (28%) of the patients with a prescription for opioids in hospital (6% of all opioid-naive patients), an opioid was also prescribed upon discharge. The indication for opioids was documented in 16 (70%) of the 23 discharge prescriptions. No adverse events or deaths related to opioid use were identified during the hospital stays. Conclusions: Among opioid-naive patients admitted to the internal medicine unit, opioids were prescribed for about 1 in 5 patients, and

  4. Opioid-induced endocrinopathy.

    PubMed

    Colameco, Stephen; Coren, Joshua S

    2009-01-01

    Debilitating chronic nonmalignant pain is often managed using opioid medications. However, with increased use of this drug class comes concern about adverse effects on patients' endocrine function. In the present review, the authors discuss opioid-induced interference with the hypothalamic-pituitary-gonadal axis, effects on adrenal androgen production, and endocrine deficiency. In addition, the authors describe symptomology for opioid-induced endocrinopathy as well as diagnostic testing options. Treatment modalities for those afflicted with this condition are also described.

  5. Combating an Epidemic of Prescription Opioid Abuse.

    PubMed

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

    2015-11-01

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

  6. Combating an Epidemic of Prescription Opioid Abuse.

    PubMed

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

    2015-11-01

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

  7. Classically conditioned responses in opioid and cocaine dependence: a role in relapse?

    PubMed

    Childress, A R; McLellan, A T; Ehrman, R; O'Brien, C P

    1988-01-01

    We have shown that conditioned phenomena occur in a number of drug-related settings and that they can be reliably elicited and studied. Our recent work suggests that conditioned craving is an extremely prevalent, if poorly understood, response to drug-related stimuli and that it can occur independent of conditioned withdrawal responses. Our current extinction protocols are effective in reducing the conditioned responses to both opioid and cocaine-related test stimuli. How well this extinction training generalizes to the "real world," is, of course, the crucial clinical question. We are trying to maximize the generalization of extinction through use of realistic, individualized drug "reminders." The final clinical impact of these extinction procedures awaits completion of our ongoing treatment/outcome studies in abstinent opioid and cocaine abusers.

  8. Activation of μ-opioid receptors inhibits calcium-currents in the vestibular afferent neurons of the rat through a cAMP dependent mechanism

    PubMed Central

    Seseña, Emmanuel; Vega, Rosario; Soto, Enrique

    2014-01-01

    Opioid receptors are expressed in the vestibular endorgans (afferent neurons and hair cells) and are activated by the efferent system, which modulates the discharge of action potentials in vestibular afferent neurons (VANs). In mammals, VANs mainly express the μ opioid-receptor, but the function of this receptors activation and the cellular mechanisms by which they exert their actions in these neurons are poorly studied. To determine the actions of μ opioid receptor (MOR) and cell signaling mechanisms in VANs, we made perforated patch-clamp recordings of VANs that were obtained from postnatal days 7 to 10 (P7–10) rats and then maintained in primary culture. The MOR agonist [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) inhibited the total voltage-gated outward current; this effect was prevented by the perfusion of a Ca2+-free extracellular solution. We then studied the voltage-gated calcium current (Ica) and found that DAMGO Met-enkephalin or endomorphin-1 inhibited the ICa in a dose-response fashion. The effects of DAMGO were prevented by the MOR antagonist (CTAP) or by pertussis toxin (PTX). The use of specific calcium channel blockers showed that MOR activation inhibited T-, L- and N-type ICa. The use of various enzyme activators and inhibitors and of cAMP analogs allowed us to demonstrate that the MOR acts through a cAMP dependent signaling mechanism. In current clamp experiments, MOR activation increased the duration and decreased the amplitude of the action potentials and modulated the discharge produced by current injection. Pre-incubation with PTX occluded MOR activation effect. We conclude that MOR activation inhibits the T-, L- and N-type ICa through activation of a Gαi/o protein that involves a decrease in AC-cAMP-PKA activity. The modulation of ICa may have an impact on the synaptic integration, excitability, and neurotransmitter release from VANs. PMID:24734002

  9. Pharmacotherapy for opioid dependence in jails and prisons: research review update and future directions

    PubMed Central

    Sharma, Anjalee; O’Grady, Kevin E; Kelly, Sharon M; Gryczynski, Jan; Mitchell, Shannon Gwin; Schwartz, Robert P

    2016-01-01

    Purpose The World Health Organization recommends the initiation of opioid agonists prior to release from incarceration to prevent relapse or overdose. Many countries in the world employ these strategies. This paper considers the evidence to support these recommendations and the factors that have slowed their adoption in the US. Methods We reviewed randomized controlled trials (RCTs) and longitudinal/observational studies that examine participant outcomes associated with the initiation or continuation of opioid agonists (methadone, buprenorphine) or antagonists (naltrexone) during incarceration. Papers were identified through a literature search of PubMed with an examination of their references and were included if they reported outcomes for methadone, buprenorphine, or naltrexone continued during incarceration or initiated prior to release in a correctional institution. Results Fourteen studies were identified, including eight RCTs and six observational studies. One RCT found that patients treated with methadone who were continued on versus tapered off methadone during brief incarceration were more likely to return to treatment upon release. A second RCT found that the group starting methadone treatment in prison versus a waiting list was less likely to report using heroin and sharing syringes during incarceration. A third RCT found no differences in postrelease heroin use or reincarceration between individuals initiating treatment with methadone versus those initiating treatment with buprenorphine during relatively brief incarcerations. Findings from four additional RCTs indicate that starting opioid agonist treatment during incarceration versus after release was associated with higher rates of entry into community treatment and reduced heroin use. Finally, one pilot RCT showed that providing extended-release naltrexone prior to discharge resulted in significantly lower rates of opioid relapse compared to no medication. Conclusion Reasons why uptake of these

  10. Association of Smoking with Mu- Opioid Receptor Availability Before and During Naltrexone Blockade in Alcohol-Dependent Subjects

    PubMed Central

    Weerts, Elise M.; Wand, Gary S.; Kuwabara, Hiroto; Xu, Xiaoqiang; Frost, J.James; Wong, Dean F.; McCaul, Mary E.

    2012-01-01

    Persons with a history of alcohol dependence are more likely to use tobacco and to meet criteria for nicotine dependence compared to social drinkers or nondrinkers. The high levels of comorbidity of nicotine and alcohol use and dependence are thought to be related to interactions between nicotinic, opioid and dopamine receptors in mesolimbic regions. The current study examined whether individual differences in regional mu-opioid receptor (MOR) availability were associated with tobacco use, nicotine dependence, and level of nicotine craving in 25 alcohol dependent (AD) subjects. AD subjects completed an inpatient protocol, which included medically supervised alcohol withdrawal, monitored alcohol abstinence, transdermal nicotine maintenance (21 mg/day), and Positron Emission Tomography (PET) imaging using the MOR agonist [11C]-carfentanil (CFN) before (basal scan) and during treatment with 50 mg/day naltrexone (naltrexone scan). Subjects who had higher scores on the Fagerström Nicotine Dependence Test had significantly lower basal scan binding potential (BPND) across mesolimbic regions including the amygdala, cingulate, globus pallidus, thalamus and insula. Likewise, the number of cigarettes per day was negatively associated with basal scan BPND in mesolimbic regions Higher nicotine craving was significantly associated with lower BPND in amygdala, globus pallidus, putamen, thalamus and ventral striatum. Although blunted during naltrexone treatment, the negative association was maintained for nicotine dependence and cigarettes per day, but not for nicotine craving. These findings suggest that intensity of cigarette smoking and severity of nicotine dependence symptoms are systematically related to reduced BPND across multiple brain regions in AD subjects. PMID:23252742

  11. Extended-Release Naltrexone To Prevent Relapse Among Opioid Dependent, Criminal Justice System Involved Adults: Rationale and Design of a Randomized Controlled Effectiveness Trial

    PubMed Central

    Lee, Joshua D.; Friedmann, Peter D.; Boney, Tamara Y.; Hoskinson, Randall A.; McDonald, Ryan; Gordon, Michael; Fishman, Marc; Chen, Donna T.; Bonnie, Richard J.; Kinlock, Timothy W.; Nunes, Edward V.; Cornish, James W.; O’Brien, Charles P.

    2015-01-01

    Background Extended-release naltrexone (XR-NTX, Vivitrol® Alkermes Inc.) is an injectable monthly sustained-release mu opioid receptor antagonist. XR-NTX is a potentially effective intervention for opioid use disorders and as relapse prevention among criminal justice system (CJS) populations. Methods This 5-site open-label randomized controlled effectiveness trial examines whether XR-NTX reduces opioid relapse compared with treatment as usual (TAU) among community dwelling, non-incarcerated volunteers with current or recent CJS involvement. The XR-NTX arm receives 6 monthly XR-NTX injections at Medical Management visits; the TAU group receives referrals to available community treatment options. Assessments occur every 2 weeks during a 24-week treatment phase and at 12- and 18-month follow-ups. The primary outcome is a relapse event, defined as either self-report or urine toxicology evidence of ≥10 days of opioid use in a 28-day (4 week) period, with a positive or missing urine test counted as 5 days of opioid use. Results We describe the rationale, specific aims, and design of the study. Alternative design considerations and extensive secondary aims and outcomes are discussed. Conclusions XR-NTX is a potentially important treatment and relapse prevention option among persons with opioid dependence and CJS involvement. PMID:25602580

  12. Preliminary buprenorphine sublingual tablet pharmacokinetic data in plasma, oral fluid and sweat during treatment of opioid-dependent pregnant women

    PubMed Central

    Concheiro, Marta; Jones, Hendreé E.; Johnson, Rolley E.; Choo, Robin; Huestis, Marilyn A.

    2011-01-01

    Background Buprenorphine is currently under investigation as a pharmacotherapy to treat pregnant women for opioid dependence. This research evaluates buprenorphine (BUP), norbuprenophine (NBUP), buprenorphine-glucuronide (BUP-Gluc) and norbuprenorphine-glucuronide (NBUP-Gluc) pharmacokinetics after high dose (14–20 mg) BUP sublingual tablet administration in three opioid-dependent pregnant women. Methods Oral fluid and sweat specimens were collected in addition to plasma specimens for 24 h during gestation weeks 28 or 29 and 34, and 2 months after delivery. Tmax was not affected by pregnancy; however, BUP and NBUP Cmax and AUC0–24h tended to be lower during pregnancy compared to postpartum levels. Results Statistically significant but weak positive correlations were found for BUP plasma and OF concentrations, and BUP/NBUP ratios in plasma and OF. Conclusion Statistically significant negative correlations were observed for times of specimen collection and BUP and NBUP OF/plasma ratios. BUP-Gluc and NBUP-Gluc were detected in only 5% of OF specimens. In sweat, BUP and NBUP were detected in only 4 of 25 (12 or 24 h) specimens in low concentrations (<2.4 ng/patch). These preliminary data describe BUP and metabolite pharmacokinetics in pregnant women and suggest that, like methadone, upward dose adjustments may be needed with advancing gestation. PMID:21860340

  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. A comparison of independent depression and substance-induced depression in cannabis-, cocaine-, and opioid-dependent treatment seekers.

    PubMed

    Dakwar, Elias; Nunes, Edward V; Bisaga, Adam; Carpenter, Kenneth C; Mariani, John P; Sullivan, Maria A; Raby, Wilfrid N; Levin, Frances R

    2011-01-01

    Depressive symptoms often coexist with substance use disorders (SUDs). The DSM-IV has identified two distinct categories for depression coexisting with SUDs-independent depression and substance-induced depression. While this distinction has important therapeutic and prognostic implications, it remains difficult to make in clinical practice; the differentiation is often guided by chronological and symptom severity criteria that patients may be unable to precisely provide. Furthermore, it is unclear whether the various substances commonly abused-cannabis, cocaine, and opioids-are equally associated with the two types of depression. Predictors, associations, and other markers may be helpful in guiding the diagnostic process. We, therefore, examined the differences between cannabis-, cocaine-, and opioid-dependent individuals contending with independent depression and those contending with substance-induced depression in regard to several variables, hypothesizing that independent depression is more commonly found in females, and that it is associated with higher symptom severity and psychiatric comorbidity. Cocaine-, cannabis-, and/or opioid-dependent, treatment-seeking individuals underwent a structured clinical interview for DSM-IV-TR disorders after providing consent at our clinical research site; those with co-existing primary depression or substance-induced depression diagnoses were provided with further questionnaires and were entered into this analysis (n= 242). Pair-wise comparisons were conducted between the groups classified as independent versus substance-induced depression with 2-by-2 tables and chi-square tests for dichotomous independent variables, and t-tests for continuous variables. Binomial logistic regression was performed in order to ascertain which of the variables were significant predictors. Women were more likely than men to have independent depression (p< .005). Cannabis dependence was highly associated with independent depression (p< .001

  15. A Comparison of Independent Depression and Substance-Induced Depression in Cannabis, Cocaine, and Opioid Dependent Treatment Seekers

    PubMed Central

    Dakwar, Elias; Nunes, Edward V.; Bisaga, Adam; Carpenter, Kenneth C.; Mariani, John P.; Sullivan, Maria A.; Raby, Wilfrid N.; Levin, Frances R.

    2012-01-01

    Depressive symptoms often co-exist with substance use disorders (SUDs). The DSM-IV has identified two distinct categories for depression coexisting with SUDs – independent depression and substance-induced depression. While this distinction has important therapeutic and prognostic implications, it remains difficult to make in clinical practice; the differentiation is often guided by chronological and symptom severity criteria that patients may be unable to precisely provide. Furthermore, it is unclear whether the various substances commonly abused – cannabis, cocaine, and opioids – are equally associated with the two types of depression. Predictors, associations, and other markers may be helpful in guiding the diagnostic process. We therefore examined the differences between cannabis, cocaine, and opioid dependent individuals contending with independent depression and those contending with substance-induced depression in regards to several variables, hypothesizing that independent depression is more commonly found in females, and that it is associated with higher symptom severity and psychiatric comorbidity. Cocaine, cannabis, and/or opioid dependent, treatment-seeking individuals underwent a SCID after providing consent at our clinical research site; those with coexisting primary depression or substance-induced depression diagnoses were provided with further questionnaires and were entered into this analysis (n=242). Pair-wise comparisons were conducted between the groups classified as independent versus substance induced depression with 2 by 2 tables and chi-square tests for dichotomous independent variables, and t-tests for continuous variables. Binomial logistic regression was performed in order to ascertain which of the variables were significant predictors. Women were more likely than men to have independent depression (p<0.005). Cannabis dependence was highly associated with independent depression (p<0.001), while cocaine dependence was highly

  16. Benzodiazepine use during buprenorphine treatment for opioid dependence: Clinical and safety outcomes

    PubMed Central

    Schuman-Olivier, Zev; Hoeppner, Bettina B.; Weiss, Roger D.; Borodovsky, Jacob; Shaffer, Howard J.; Albanese, Mark J.

    2013-01-01

    Background Prescribing benzodiazepines during buprenorphine treatment is a topic of active discussion. Clinical benefit is unclear. Overdose, accidental injury, and benzodiazepine misuse remain concerns. We examine the relationship between benzodiazepine misuse history, benzodiazepine prescription, and both clinical and safety outcomes during buprenorphine treatment. Methods We retrospectively examined outpatient buprenorphine treatment records, classifying patients by past-year benzodiazepine misuse history and approved benzodiazepine prescription at intake. Primary clinical outcomes included 12-month treatment retention and urine toxicology for illicit opioids. Primary safety outcomes included total emergency department (ED) visits and odds of an ED visit related to overdose or accidental injury during treatment. Results The 12-month treatment retention rate for the sample (N = 328) was 40%. Neither benzodiazepine misuse history nor benzodiazepine prescription was associated with treatment retention or illicit opioid use. Poisson regressions of ED visits during buprenorphine treatment revealed more ED visits among those with a benzodiazepine prescription versus those without (p < 0.001); benzodiazepine misuse history had no effect. The odds of an accidental injury-related ED visit during treatment were greater among those with a benzodiazepine prescription (OR: 3.7, p < 0.01), with an enhanced effect among females (OR: 4.7, p < 0.01). Overdose was not associated with benzodiazepine misuse history or prescription. Conclusions We found no effect of benzodiazepine prescriptions on opioid treatment outcomes; however, benzodiazepine prescription was associated with more frequent ED visits and accidental injuries, especially among females. When prescribing benzodiazepines during buprenorphine treatment, patients need more education about accidental injury risk. Alternative treatments for anxiety should be considered when possible, especially among females. PMID

  17. Striatal opioid receptor availability is related to acute and chronic pain perception in arthritis: does opioid adaptation increase resilience to chronic pain?

    PubMed

    Brown, Christopher A; Matthews, Julian; Fairclough, Michael; McMahon, Adam; Barnett, Elizabeth; Al-Kaysi, Ali; El-Deredy, Wael; Jones, Anthony K P

    2015-11-01

    The experience of pain in humans is modulated by endogenous opioids, but it is largely unknown how the opioid system adapts to chronic pain states. Animal models of chronic pain point to upregulation of opioid receptors (OpR) in the brain, with unknown functional significance. We sought evidence for a similar relationship between chronic pain and OpR availability in humans. Using positron emission tomography and the radiotracer (11)C-diprenorphine, patients with arthritis pain (n = 17) and healthy controls (n = 9) underwent whole-brain positron emission tomography scanning to calculate parametric maps of OpR availability. Consistent with the upregulation hypothesis, within the arthritis group, greater OpR availability was found in the striatum (including the caudate) of patients reporting higher levels of recent chronic pain, as well as regions of interest in the descending opioidergic pathway including the anterior cingulate cortex, thalamus, and periaqueductal gray. The functional significance of striatal changes were clarified with respect to acute pain thresholds: data across patients and controls revealed that striatal OpR availability was related to reduced pain perception. These findings are consistent with the view that chronic pain may upregulate OpR availability to dampen pain. Finally, patients with arthritis pain, compared with healthy controls, had overall less OpR availability within the striatum specifically, consistent with the greater endogenous opioid binding that would be expected in chronic pain states. Our observational evidence points to the need for further studies to establish the causal relationship between chronic pain states and OpR adaptation.

  18. A ghrelin receptor (GHS-R1A) antagonist attenuates the rewarding properties of morphine and increases opioid peptide levels in reward areas in mice.

    PubMed

    Engel, Jörgen A; Nylander, Ingrid; Jerlhag, Elisabet

    2015-12-01

    Gut-brain hormones such as ghrelin have recently been suggested to have a role in reward regulation. Ghrelin was traditionally known to regulate food intake and body weight homoeostasis. In addition, recent work has pin-pointed that this peptide has a novel role in drug-induced reward, including morphine-induced increase in the extracellular levels of accumbal dopamine in rats. Herein the effect of the ghrelin receptor (GHS-R1A) antagonist, JMV2959, on morphine-induced activation of the mesolimbic dopamine system was investigated in mice. In addition, the effects of JMV2959 administration on opioid peptide levels in reward related areas were investigated. In the present series of experiment we showed that peripheral JMV2959 administration, at a dose with no effect per se, attenuates the ability of morphine to cause locomotor stimulation, increase the extracellular levels of accumbal dopamine and to condition a place preference in mice. JMV2959 administration significantly increased tissue levels of Met-enkephalin-Arg(6)Phe(7) in the ventral tegmental area, dynorphin B in hippocampus and Leu-enkephalin-Arg(6) in striatum. We therefore hypothesise that JMV2959 prevents morphine-induced reward via stimulation of delta receptor active peptides in striatum and ventral tegmental areas. In addition, hippocampal peptides that activate kappa receptor may be involved in JMV2959׳s ability to regulate memory formation of reward. Given that development of drug addiction depends, at least in part, of the effects of addictive drugs on the mesolimbic dopamine system the present data suggest that GHS-R1A antagonists deserve to be elucidated as novel treatment strategies of opioid addiction.

  19. Correlates of Nine-Month Retention following Interim Buprenorphine-Naloxone Treatment in Opioid Dependence: A Pilot Study

    PubMed Central

    Håkansson, A.; Widinghoff, C.; Abrahamsson, T.; Gedeon, C.

    2016-01-01

    Interim medication-only treatment has been suggested for the initiation of opioid maintenance treatment (OMT) in opioid-dependent subjects, but this rarely has been studied using buprenorphine instead of methadone. Following a pilot trial assessing interim buprenorphine-naloxone treatment in order to facilitate transfer into OMT, we here aimed to study retention, and potential correlates of retention, in full-scale treatment. Thirty-six patients successfully referred from a waiting list through an interim treatment phase were followed for nine months in OMT. Baseline characteristics, as well as urine analyses during the interim phase and during full-scale OMT, were studied as potential correlates of retention. The nine-month retention in OMT was 83 percent (n = 30). While interim-phase urine samples positive for benzodiazepines did not significantly predict dropout from full-scale OMT (p = 0.09), urine samples positive for benzodiazepines within full-scale OMT were significantly associated with dropout (p < 0.01), in contrast to other substances and baseline characteristics. Retention remained high through nine months in this pilot study sample of patients referred through buprenorphine-naloxone interim treatment, but use of benzodiazepines is problematic, and the present data suggest that it may be associated with treatment dropout. PMID:26904355

  20. Opioid-dependent growth of glial cultures: Suppression of astrocyte DNA synthesis by met-enkephalin

    SciTech Connect

    Stiene-Martin, A.; Hauser, K.F. )

    1990-01-01

    The action of met-enkephalin on the growth of astrocytes in mixed-glial cultures was examined. Primary, mixed-glial cultures were isolated from 1 day-old mouse cerebral hemispheres and continuously treated with either basal growth media, 1 {mu}M met-enkephalin, 1 {mu}M met-enkephalin plus the opioid antagonist naloxone, or naloxone alone. Absolute numbers of neural cells were counted in unstained preparations, while combined ({sup 3}H)-thymidine autoradiography and glial fibrillary acid protein (GFAP) immunocytochemistry was performed to identify specific changes in astrocytes. When compared to control and naloxone treated cultures, met-enkephalin caused a significant decrease in both total cell numbers, and in ({sup 3}H)-thymidine incorporation by GFAP-positive cells with flat morphology. These results indicate that met-enkephalin suppresses astrocyte growth in culture.

  1. 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

  2. Cost-effectiveness of Extended Buprenorphine-Naloxone Treatment for Opioid-Dependent Youth: Data from a Randomized Trial

    PubMed Central

    Polsky, Daniel; Glick, Henry A.; Yang, Jianing; Subramaniam, Geetha A.; Poole, Sabrina A.; Woody, George E.

    2010-01-01

    Introduction The objective is to estimate cost, net social cost, and cost-effectiveness in a clinical trial of extended buprenorphine-naloxone treatment versus brief detoxification treatment in opioid-dependent youth. Methods Economic evaluation of a clinical trial conducted at 6 community outpatient treatment programs from July 2003 to December 2006 including 152 patients aged 15 to 21 years who were randomized to 12 weeks of buprenorphine-naloxone (BUP) or a 14-day taper (DETOX). BUP patients were prescribed up to 24 mg per day for 9 weeks and then tapered to zero at the end of week 12. DETOX patients were prescribed up to 14 mg per day and then tapered to zero on day 14. All were offered twice weekly drug counseling. Data were collected prospectively during the 12-week treatment and at follow-up interviews at months 6, 9, and 12. Results The 12-week outpatient study treatment cost was $1514 (p<0.001) higher for BUP relative to DETOX. One-year total direct medical cost was only $83 higher for BUP (p=0.97). The cost-effectiveness ratio of BUP relative to DETOX was $1,376 in terms of 1-year direct medical cost per quality-adjusted life year (QALY) and $25,049 in terms of outpatient treatment program cost per QALY. The acceptability curve suggests that the cost-effectiveness ratio of BUP relative to DETOX has an 86% chance of being accepted as cost-effective for a threshold of $100,000 per QALY. Conclusions Extended buprenorphine-naloxone treatment relative to brief detoxification is cost effective in the U.S. health care system for the outpatient treatment of opioid-dependent youth. PMID:20626379

  3. mu-Opioid receptor downregulation contributes to opioid tolerance in vivo.

    PubMed

    Stafford, K; Gomes, A B; Shen, J; Yoburn, B C

    2001-01-01

    The present study examined the contribution of downregulation of mu-opioid receptors to opioid tolerance in an intact animal model. Mice were implanted subcutaneously with osmotic minipumps that infused etorphine (50-250 microg/kg/day) for 7 days. Other mice were implanted subcutaneously with a morphine pellet (25 mg) or a morphine pellet plus an osmotic minipump that infused morphine (5-40 mg/kg/day) for 7 days. Controls were implanted with an inert placebo pellet. At the end of treatment, pumps and pellets were removed, and saturation binding studies were conducted in whole brain ([3H]DAMGO) or morphine and etorphine analgesic ED(50)s were determined (tail-flick). Morphine tolerance increased linearly with the infusion dose of morphine (ED(50) shift at highest infusion dose, 4.76). No significant downregulation of mu-receptors in whole brain was observed at the highest morphine treatment dose. Etorphine produced dose-dependent downregulation of mu-opioid receptor density and tolerance (ED(50) shift at highest infusion dose, 6.97). Downregulation of mu-receptors only occurred at the higher etorphine infusion doses (> or =150 microg/kg/day). Unlike morphine tolerance, the magnitude of etorphine tolerance was a nonlinear function of the dose and increased markedly at infusion doses that produced downregulation. These results suggest that mu-opioid receptor downregulation contributes to opioid tolerance in vivo. Therefore, opioid tolerance appears to rely upon both "receptor density-dependent" and " receptor density-independent" mechanisms.

  4. Evaluation of opioid modulation in major depressive disorder.

    PubMed

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

    2015-05-01

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

  5. Evaluation of opioid modulation in major depressive disorder.

    PubMed

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

    2015-05-01

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

  6. Prescription Opioids in Adolescence and Future Opioid Misuse

    PubMed Central

    Johnston, Lloyd; O’Malley, Patrick M.; Keyes, Katherine M.; Heard, Kennon

    2015-01-01

    BACKGROUND AND OBJECTIVE: Legitimate opioid use is associated with an increased risk of long-term opioid use and possibly misuse in adults. The objective of this study was to estimate the risk of future opioid misuse among adolescents who have not yet graduated from high school. METHODS: Prospective, panel data come from the Monitoring the Future study. The analysis uses a nationally representative sample of 6220 individuals surveyed in school in 12th grade and then followed up through age 23. Analyses are stratified by predicted future opioid misuse as measured in 12th grade on the basis of known risk factors. The main outcome is nonmedical use of a prescription opioid at ages 19 to 23. Predictors include use of a legitimate prescription by 12th grade, as well as baseline history of drug use and baseline attitudes toward illegal drug use. RESULTS: Legitimate opioid use before high school graduation is independently associated with a 33% increase in the risk of future opioid misuse after high school. This association is concentrated among individuals who have little to no history of drug use and, as well, strong disapproval of illegal drug use at baseline. CONCLUSIONS: Use of prescribed opioids before the 12th grade is independently associated with future opioid misuse among patients with little drug experience and who disapprove of illegal drug use. Clinic-based education and prevention efforts have substantial potential to reduce future opioid misuse among these individuals, who begin opioid use with strong attitudes against illegal drug use. PMID:26504126

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

    PubMed

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

    2009-12-01

    Growing evidence shows that trafficking of the mu-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.

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

    PubMed Central

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

    2015-01-01

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

  9. Recent advances in opioid prescription for chronic non-cancer pain.

    PubMed

    Snidvongs, Saowarat; Mehta, Vivek

    2012-02-01

    Chronic pain is pain that persists past the normal time of healing, and is seen as a common problem with a significant socioeconomic impact. Pharmacological management for chronic non-cancer pain also involves the prescription of opioids, with the aim of an improved quality of life for the patient. New guidelines have been published to aid prescribing clinicians improve opioid safety and patient care, and include recommendations on when to refer patients to a pain specialist. In recent years there has been a rapid increase in opioid prescription in the UK and USA, prompting further concern regarding opioid abuse and side effects. Opioid use may also result in physical dependence and tolerance. Earlier recognition and diagnosis of unwanted effects of long-term opioid use is needed, such as opioid induced suppression of the hypothalamic-pituitary-gonadal axis, and opioid induced immunosuppression. Patients may themselves discontinue opioids, however, due to minor side effects. Recent advances in opioid prescription include the increasing use of transdermal preparations and extended release, oral, once daily preparations. New formulations of existing drugs have been developed, as well as a new chemical entity. Abuse deterrent formulations and delivery systems may prevent the artificial acceleration of drug delivery and reduce the potential for opioid addiction. Overdose concerns and the potential for fatal overdose may necessitate mandatory training for all clinicians who prescribe opioids. Despite the widespread use of opioids in the management of chronic non-cancer pain, significant research gaps remain. An improvement in the evidence base for its prescription is required.

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

    PubMed

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

    2016-01-01

    Beginning in the late 1990s, a movement began within the pain management field focused upon the underutilization of opioids, thought to be a potentially safe and effective class of pain medication. Concern for addiction and misuse were present at the start of this shift within pain medicine, and an emphasis was placed on developing reliable and valid methods and measures of identifying those at risk for opioid misuse. Since that time, the evidence for the safety and effectiveness of chronic opioid therapy (COT) has not been established. Rather, the harmful, dose-dependent deleterious effects have become clearer, including addiction, increased risk of injuries, respiratory depression, opioid induced hyperalgesia, and death. Still, many individuals on low doses of opioids for long periods of time appear to have good pain control and retain social and occupational functioning. Therefore, we propose that the question, "Who is at risk of opioid misuse?" should evolve to, "Who may benefit from COT?" in light of the current evidence. PMID:27417617

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

    PubMed Central

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

    2016-01-01

    Beginning in the late 1990s, a movement began within the pain management field focused upon the underutilization of opioids, thought to be a potentially safe and effective class of pain medication. Concern for addiction and misuse were present at the start of this shift within pain medicine, and an emphasis was placed on developing reliable and valid methods and measures of identifying those at risk for opioid misuse. Since that time, the evidence for the safety and effectiveness of chronic opioid therapy (COT) has not been established. Rather, the harmful, dose-dependent deleterious effects have become clearer, including addiction, increased risk of injuries, respiratory depression, opioid induced hyperalgesia, and death. Still, many individuals on low doses of opioids for long periods of time appear to have good pain control and retain social and occupational functioning. Therefore, we propose that the question, “Who is at risk of opioid misuse?” should evolve to, “Who may benefit from COT?” in light of the current evidence. PMID:27417617

  12. Clinical interpretation of opioid tolerance versus opioid-induced hyperalgesia.

    PubMed

    Chen, Lucy; Sein, Michael; Vo, Trang; Amhmed, Shihab; Zhang, Yi; Hilaire, Kristin St; Houghton, Mary; Mao, Jianren

    2014-01-01

    Opioid analgesics are commonly used to manage moderate to severe pain. However, the long-term use of opioids could lead to opioid tolerance (OT) and opioid-induced hyperalgesia (OIH). Distinguishing OIH from OT would impact the practice of opioid therapy because opioid dose adjustment may differentially influence OT and OIH. Currently, there are no standard criteria of OT versus OIH causing considerable ambiguity in clinical interpretation and management of these conditions. The authors designed a practitioner-based survey consisting of 20 targeted questions. Answering these questions would require responders' actual clinical experiences with opioid therapy. The survey was conducted between 2011 and 2012 through direct mails or e-mails to 1,408 physicians who are currently practicing in the United States. The authors find that certain clinical characteristics (eg, increased pain despite opioid dose escalation) are often used by practitioners to make differential diagnosis of OT and OIH despite some overlap in their clinical presentation. A key difference in clinical outcome is that OT and OIH could be improved and exacerbated by opioid dose escalation, respectively. Our survey results revealed a significant knowledge gap in some responders regarding differential diagnosis and management of OT and OIH. The results also identified several issues, such as opioid dose adjustment and clinical comorbidities related to OT and OIH, which require future patient-based studies.

  13. Mu-opioid receptor down-regulation and tolerance are not equally dependent upon G-protein signaling.

    PubMed

    Gomes, Benedict A; Shen, Ji; Stafford, Kristi; Patel, Minesh; Yoburn, Byron C

    2002-05-01

    In the present study, the contribution of pertussis toxin (PTX)-sensitive G(i/o)-proteins to opioid tolerance and mu-opioid receptor down-regulation in the mouse were examined. Mice were injected once intracerebroventricularly and intrathecally with PTX (0.1 microg/site). Controls were treated with saline. On the 10th day following PTX treatment, continuous subcutaneous infusion of etorphine (150 or 200 microg/kg/day) or morphine (40 mg/kg/day+25 mg slow-release pellet) was begun. Control mice were implanted with inert placebo pellets. Pumps and pellets were removed 3 days later, and mice were tested for morphine analgesia or mu-opioid receptor density was determined in the whole brain, spinal cord, and midbrain. Both infusion doses of etorphine produced significant tolerance (ED50 shift=approximately 4-6-fold) and down-regulation of mu-opioid receptors (approximately 20-35%). Morphine treatment also produced significant tolerance (ED50 shift= approximately 5-8-fold), but no mu-opioid receptor down-regulation. PTX dramatically reduced the acute potency of morphine and blocked the further development of tolerance by both etorphine and morphine treatments. However, PTX had no effect on etorphine-induced mu-opioid receptor down-regulation in brain, cord, or midbrain. These results suggest that PTX-sensitive G-proteins have a minimal role in agonist-induced mu-opioid receptor density regulation in vivo, but are critical in mediating acute and chronic functional effects of opioids such as analgesia and tolerance.

  14. Dopamine and opioid gene variants are associated with increased smoking reward and reinforcement owing to negative mood.

    PubMed

    Perkins, Kenneth A; Lerman, Caryn; Grottenthaler, Amy; Ciccocioppo, Melinda M; Milanak, Melissa; Conklin, Cynthia A; Bergen, Andrew W; Benowitz, Neal L

    2008-09-01

    Negative mood increases smoking reinforcement and risk of relapse. We explored associations of gene variants in the dopamine, opioid, and serotonin pathways with smoking reward ('liking') and reinforcement (latency to first puff and total puffs) as a function of negative mood and expected versus actual nicotine content of the cigarette. Smokers of European ancestry (n=72) were randomized to one of four groups in a 2x2 balanced placebo design, corresponding with manipulation of actual (0.6 vs. 0.05 mg) and expected (told nicotine and told denicotinized) nicotine 'dose' in cigarettes during each of two sessions (negative vs. positive mood induction). Following mood induction and expectancy instructions, they sampled and rated the assigned cigarette, and then smoked additional cigarettes ad lib during continued mood induction. The increase in smoking amount owing to negative mood was associated with: dopamine D2 receptor (DRD2) C957T (CC>TT or CT), SLC6A3 (presence of 9 repeat>absence of 9), and among those given a nicotine cigarette, DRD4 (presence of 7 repeat>absence of 7) and DRD2/ANKK1 TaqIA (TT or CT>CC). SLC6A3, and DRD2/ANKK1 TaqIA were also associated with smoking reward and smoking latency. OPRM1 (AA>AG or GG) was associated with smoking reward, but SLC6A4 variable number tandem repeat was unrelated to any of these measures. These results warrant replication but provide the first evidence for genetic associations with the acute increase in smoking reward and reinforcement owing to negative mood.

  15. Dopamine and opioid gene variants are associated with increased smoking reward and reinforcement owing to negative mood.

    PubMed

    Perkins, Kenneth A; Lerman, Caryn; Grottenthaler, Amy; Ciccocioppo, Melinda M; Milanak, Melissa; Conklin, Cynthia A; Bergen, Andrew W; Benowitz, Neal L

    2008-09-01

    Negative mood increases smoking reinforcement and risk of relapse. We explored associations of gene variants in the dopamine, opioid, and serotonin pathways with smoking reward ('liking') and reinforcement (latency to first puff and total puffs) as a function of negative mood and expected versus actual nicotine content of the cigarette. Smokers of European ancestry (n=72) were randomized to one of four groups in a 2x2 balanced placebo design, corresponding with manipulation of actual (0.6 vs. 0.05 mg) and expected (told nicotine and told denicotinized) nicotine 'dose' in cigarettes during each of two sessions (negative vs. positive mood induction). Following mood induction and expectancy instructions, they sampled and rated the assigned cigarette, and then smoked additional cigarettes ad lib during continued mood induction. The increase in smoking amount owing to negative mood was associated with: dopamine D2 receptor (DRD2) C957T (CC>TT or CT), SLC6A3 (presence of 9 repeat>absence of 9), and among those given a nicotine cigarette, DRD4 (presence of 7 repeat>absence of 7) and DRD2/ANKK1 TaqIA (TT or CT>CC). SLC6A3, and DRD2/ANKK1 TaqIA were also associated with smoking reward and smoking latency. OPRM1 (AA>AG or GG) was associated with smoking reward, but SLC6A4 variable number tandem repeat was unrelated to any of these measures. These results warrant replication but provide the first evidence for genetic associations with the acute increase in smoking reward and reinforcement owing to negative mood. PMID:18690118

  16. A randomized, controlled trial of the efficacy of an interoceptive exposure-based CBT for treatment-refractory outpatients with opioid dependence.

    PubMed

    Otto, Michael W; Hearon, Bridget A; McHugh, R Kathryn; Calkins, Amanda W; Pratt, Elizabeth; Murray, Heather W; Safren, Steven A; Pollack, Mark H

    2014-01-01

    Many patients diagnosed with opioid dependence do not adequately respond to pharmacologic, psychosocial, or combination treatment, highlighting the importance of novel treatment strategies for this population. The current study examined the efficacy of a novel behavioral treatment focusing on internal cues for drug use (Cognitive Behavioral Therapy for Interoceptive Cues; CBT-IC) relative to an active comparison condition, Individual Drug Counseling (IDC), when added to methadone maintenance treatment (MMT) among those who had not responded to MMT. Participants (N=78) were randomly assigned to receive 15 sessions of CBT-IC or IDC as an adjunct to ongoing MMT and counseling. Oral toxicology screens were the primary outcome. Results indicated no treatment differences between CBT-IC and IDC and a small, significant reduction of self-reported drug use, but no change on toxicology screens. Tests of potential moderators, including sex, anxiety sensitivity, and coping motives for drug use, did not yield significant interactions. Among opioid-dependent outpatients who have not responded to MMT and counseling, the addition of IDC or CBT-IC did not result in additive outcome benefits. These results highlight the need for more potent treatment strategies for opioid dependence, particularly among those who do not fully respond to frontline treatment.

  17. Pain Raises Risk of Opioid Addiction

    MedlinePlus

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

  18. 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

  19. Naloxone-induced anorexia increases neuropeptide Y concentrations in the dorsomedial hypothalamus: evidence for neuropeptide Y-opioid interactions in the control of food intake.

    PubMed

    Lambert, P D; Wilding, J P; al-Dokhayel, A A; Gilbey, S G; Ghatei, M A; Bloom, S R

    1994-01-01

    We measured neuropeptide Y (NPY) concentration in microdissected hypothalamic nuclei, by radioimmunoassay, and NPY mRNA in the hypothalamus in rats treated systemically with the nonspecific opioid antagonist, naloxone, to produce mild anorexia. Twenty rats were treated with daily SC injections of naloxone (7.5 mg/kg); 20 were treated with vehicle alone. Naloxone produced a 7% reduction in food intake (p < 0.01) and a reduction in weight gain (p < 0.002). Neuropeptide Y concentrations were increased specifically in the dorsomedial nucleus of the hypothalamus (DMN) in rats treated with naloxone (6.8 +/- 0.7 fmol/micrograms protein vs. 3.1 +/- 1.0 fmol/micrograms protein, p < 0.05, n = 10 per group). Total hypothalamic NPY mRNA was unchanged. Neuropeptide Y-opioid interactions may be important in the control of food intake.

  20. Pain and Associated Substance Use among Opioid Dependent Individuals Seeking Office-Based Treatment with Buprenorphine-Naloxone: A Needs Assessment Study

    PubMed Central

    Barry, Declan T.; Savant, Jonathan D.; Beitel, Mark; Cutter, Christopher J.; Moore, Brent A.; Schottenfeld, Richard S.; Fiellin, David A.

    2012-01-01

    Background and Objectives A paucity of studies has examined the pain experiences of opioid dependent individuals seeking office-based buprenorphine-naloxone treatment (BNT). We set out to examine, among those seeking BNT: (a) the prevalence of pain types (i.e., recent pain, chronic pain), (b) the characteristics of pain (intensity, frequency, duration, interference, location, and genesis), and (c) substance use to alleviate pain. Methods We surveyed 244 consecutive individuals seeking office-based buprenorphine-naloxone treatment (BNT) for opioid dependence about physical pain and associated substance use. Results Thirty-six percent of respondents reported chronic pain (CP) (i.e., pain lasting at least 3 months) and 36% reported “some pain” (SP) (i.e., past week pain not meeting the threshold for CP). In comparison to SP respondents, those with CP were, on average, older; reported greater current pain intensity, pain frequency, typical pain duration, typical pain intensity, and typical pain interference; were more likely to report shoulder or pelvis and less likely to report stomach or arms as their most bothersome pain location; and were more likely to report accident or nerve damage and less likely to report opioid withdrawal as the genesis of their pain. Both pain subgroups reported similarly high rates of past-week substance use to alleviate pain. Conclusions and Scientific Significance The high rates of pain and self-reported substance use to manage pain suggest the importance of assessing and addressing pain in BNT patients. PMID:23617861

  1. Opioid intoxication

    MedlinePlus

    ... develop. This is from the talc, cornstarch, or cellulose that is used to dilute or bind the ... McGraw-Hill; 2004:chap 167. Lank PM, Kusin S. Ethanol and opioid intoxication and withdrawal. In: Adams JG, ...

  2. Hepatic resection is associated with reduced postoperative opioid requirement

    PubMed Central

    Moss, Caitlyn Rose; Caldwell, Julia Christine; Afilaka, Babatunde; Iskandarani, Khaled; Chinchilli, Vernon Michael; McQuillan, Patrick; Cooper, Amanda Beth; Gusani, Niraj; Bezinover, Dmitri

    2016-01-01

    Background and Aims: Postoperative pain can significantly affect surgical outcomes. As opioid metabolism is liver-dependent, any reduction in hepatic volume can lead to increased opioid concentrations in the blood. The hypothesis of this retrospective study was that patients undergoing open hepatic resection would require less opioid for pain management than those undergoing open pancreaticoduodenectomy. Material and Methods: Data from 79 adult patients who underwent open liver resection and eighty patients who underwent open pancreaticoduodenectomy at our medical center between January 01, 2010 and June 30, 2013 were analyzed. All patients received both general and neuraxial anesthesia. Postoperatively, patients were managed with a combination of epidural and patient-controlled analgesia. Pain scores and amount of opioids administered (morphine equivalents) were compared. A multivariate lineal regression was performed to determine predictors of opioid requirement. Results: No significant differences in pain scores were found at any time point between groups. Significantly more opioid was administered to patients having pancreaticoduodenectomy than those having a hepatic resection at time points: Intraoperative (P = 0.006), first 48 h postoperatively (P = 0.001), and the entire length of stay (LOS) (P = 0.002). Statistical significance was confirmed after controlling for age, sex, body mass index, and American Society of Anesthesiologists physical status classification (adjusted P = 0.006). Total hospital LOS was significantly longer after pancreaticoduodenectomy (P = 0.03). A multivariate lineal regression demonstrated a lower opioid consumption in the hepatic resection group (P = 0.03), but there was no difference in opioid use based on the type of hepatic resection. Conclusion: Patients undergoing open hepatic resection had a significantly lower opioid requirement in comparison with patients undergoing open pancreaticoduodenectomy. A multicenter prospective

  3. Hepatic resection is associated with reduced postoperative opioid requirement

    PubMed Central

    Moss, Caitlyn Rose; Caldwell, Julia Christine; Afilaka, Babatunde; Iskandarani, Khaled; Chinchilli, Vernon Michael; McQuillan, Patrick; Cooper, Amanda Beth; Gusani, Niraj; Bezinover, Dmitri

    2016-01-01

    Background and Aims: Postoperative pain can significantly affect surgical outcomes. As opioid metabolism is liver-dependent, any reduction in hepatic volume can lead to increased opioid concentrations in the blood. The hypothesis of this retrospective study was that patients undergoing open hepatic resection would require less opioid for pain management than those undergoing open pancreaticoduodenectomy. Material and Methods: Data from 79 adult patients who underwent open liver resection and eighty patients who underwent open pancreaticoduodenectomy at our medical center between January 01, 2010 and June 30, 2013 were analyzed. All patients received both general and neuraxial anesthesia. Postoperatively, patients were managed with a combination of epidural and patient-controlled analgesia. Pain scores and amount of opioids administered (morphine equivalents) were compared. A multivariate lineal regression was performed to determine predictors of opioid requirement. Results: No significant differences in pain scores were found at any time point between groups. Significantly more opioid was administered to patients having pancreaticoduodenectomy than those having a hepatic resection at time points: Intraoperative (P = 0.006), first 48 h postoperatively (P = 0.001), and the entire length of stay (LOS) (P = 0.002). Statistical significance was confirmed after controlling for age, sex, body mass index, and American Society of Anesthesiologists physical status classification (adjusted P = 0.006). Total hospital LOS was significantly longer after pancreaticoduodenectomy (P = 0.03). A multivariate lineal regression demonstrated a lower opioid consumption in the hepatic resection group (P = 0.03), but there was no difference in opioid use based on the type of hepatic resection. Conclusion: Patients undergoing open hepatic resection had a significantly lower opioid requirement in comparison with patients undergoing open pancreaticoduodenectomy. A multicenter prospective

  4. Context-Dependent Links between Song Production and Opioid-Mediated Analgesia in Male European Starlings (Sturnus vulgaris)

    PubMed Central

    Kelm-Nelson, Cynthia A.; Stevenson, Sharon A.; Riters, Lauren V.

    2012-01-01

    Little is known about the neural mechanisms that ensure appropriate vocal behaviors within specific social contexts. Male songbirds produce spontaneous (undirected) songs as well as female-directed courtship songs. Opioid neuropeptide activity in specific brain regions is rewarding, at least in mammals, and past studies suggest that the opioid met-enkephalin in such areas is more tightly linked to undirected than female-directed song. Recent data using a song-associated place preference paradigm further suggest that production of undirected but not directed song is tightly linked to intrinsic reward. Opioids have analgesic properties. Therefore, if production of undirected song is closely linked to opioid-mediated reward, the production of undirected but not directed song should be associated with analgesia. Consistent with this prediction, in male starlings we identified a positive correlation between analgesia (decreased reactivity to a hot water bath) and undirected song (in non-breeding season condition males in affiliative flocks) but not female-directed song (in breeding season condition males presented with females). When breeding condition males were divided according to social status, a negative correlation was found in subordinate males (i.e. males that failed to acquire a nest box). These data are consistent with the hypotheses 1) that the production of undirected song is facilitated or maintained by opioids (and/or other neuromodulators that also induce analgesia) and 2) that production of female-directed song is not linked in the same way to release of the same neuromodulators. Results also demonstrate a link between analgesia and song in subordinate individuals lacking a nesting territory within the breeding season. Overall, the findings indicate that distinct neural mechanisms regulate communication in different social contexts and support the working hypothesis that undirected but not directed song is tightly linked to opioid release. PMID:23056422

  5. Context-dependent links between song production and opioid-mediated analgesia in male European starlings (Sturnus vulgaris).

    PubMed

    Kelm-Nelson, Cynthia A; Stevenson, Sharon A; Riters, Lauren V

    2012-01-01

    Little is known about the neural mechanisms that ensure appropriate vocal behaviors within specific social contexts. Male songbirds produce spontaneous (undirected) songs as well as female-directed courtship songs. Opioid neuropeptide activity in specific brain regions is rewarding, at least in mammals, and past studies suggest that the opioid met-enkephalin in such areas is more tightly linked to undirected than female-directed song. Recent data using a song-associated place preference paradigm further suggest that production of undirected but not directed song is tightly linked to intrinsic reward. Opioids have analgesic properties. Therefore, if production of undirected song is closely linked to opioid-mediated reward, the production of undirected but not directed song should be associated with analgesia. Consistent with this prediction, in male starlings we identified a positive correlation between analgesia (decreased reactivity to a hot water bath) and undirected song (in non-breeding season condition males in affiliative flocks) but not female-directed song (in breeding season condition males presented with females). When breeding condition males were divided according to social status, a negative correlation was found in subordinate males (i.e. males that failed to acquire a nest box). These data are consistent with the hypotheses 1) that the production of undirected song is facilitated or maintained by opioids (and/or other neuromodulators that also induce analgesia) and 2) that production of female-directed song is not linked in the same way to release of the same neuromodulators. Results also demonstrate a link between analgesia and song in subordinate individuals lacking a nesting territory within the breeding season. Overall, the findings indicate that distinct neural mechanisms regulate communication in different social contexts and support the working hypothesis that undirected but not directed song is tightly linked to opioid release. PMID:23056422

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

    PubMed Central

    Dinarvand, Amin; Goodarzi, Ali; Vousooghi, Nasim; Hashemi, Mehrdad; Dinarvand, Rasoul; Ostadzadeh, Fahimeh; Khoshzaban, Ahad; Zarrindast, Mohammad-Reza

    2014-01-01

    Introduction Association between single-nucleotide polymorphisms (SNPs) in mu opioid receptor gene and drug addiction has been shown in various studies. Here, we have evaluated the existence of polymorphisms in exon 3 of this gene in Iranian population and investigated the possible association between these mutations and opioid addiction. Methods 79 opioid-dependent subjects (55 males, 24 females) and 134 non-addict or control individuals (74 males, 60 females) participated in the study. Genomic DNA was extracted from volunteers’ peripheral blood and exon 3 of the mu opioid receptor gene was amplified by polymerase chain reaction (PCR) whose products were then sequenced. Results Three different heterozygote polymorphisms were observed in 3 male individuals: 759T > C and 877G > A mutations were found in 2 control volunteers and 1043G > C substitution was observed in an opioid-addicted subject. Association between genotype and opioid addiction for each mutation was not statistically significant. Discussion It seems that the sample size used in our study is not enough to confirm or reject any association between 759T > C, 877G > A and 1043G > C substitutions in exon 3 of the mu opioid receptor gene and opioid addiction susceptibility in Iranian population. PMID:25436079

  7. Real-time assessment of alcohol drinking and drug use in opioid-dependent polydrug users.

    PubMed

    Preston, Kenzie L; Jobes, Michelle L; Phillips, Karran A; Epstein, David H

    2016-10-01

    We investigated relationships between drinking, other drug use, and drug craving, using ecological momentary assessment (EMA), in a sample of polydrug users who were not heavy drinkers. In a prospective longitudinal cohort study, 114 heroin and cocaine users on methadone-maintenance treatment carried handheld electronic diaries during waking hours and were screened for drug and alcohol use for up to 25 weeks. Individuals who fulfilled the Diagnostic and Statistical Manual of Mental Disorders criteria for alcohol abuse or dependence were excluded. Participants responded to 2-5 random prompts per day to report on their moods, cravings, and activities and initiated entries when they used or acutely craved heroin or cocaine. Drinking alcohol was assessed in both types of entries. Breath alcohol was measured three times weekly. Participants reported drinking alcohol in 1.6% of random-prompt entries, 3.7% of event-contingent entries when craving cocaine and/or heroin, and 11.6% of event-contingent entries when using cocaine and/or heroin. Alcohol drinking was also associated with higher craving ratings and prestudy alcohol use. More drinking was detected by ambulatory self-report than by in-clinic breath testing. Even though we had screened out heavy drinkers from our sample of polydrug users, drinking was associated with heroin and cocaine craving and actual use. PMID:27579810

  8. Discounting of delayed rewards in opioid-dependent outpatients: exponential or hyperbolic discounting functions?

    PubMed

    Madden, G J; Bickel, W K; Jacobs, E A

    1999-08-01

    Recent theories of substance abuse have used value discounting of delayed rewards to partly explain the decision to take drugs. Normative-economic theory holds that an exponential function describes the effects of delay on discounting, whereas the matching law posits a hyperbolic discounting function. The ability of these functions to describe 18 human heroin-dependent individuals' monetary- and heroin-reward delay-discounting functions was assessed. In the 1st condition, participants chose between immediate and delayed hypothetical monetary rewards. Delayed rewards were $1,000, and the immediate reward amount was adjusted until choices reflected indifference. In the 2nd condition, participants chose between immediate and delayed heroin (the delayed amount was that which each participant reported he or she could purchase with $1,000). The hyperbolic function produced significantly higher R2 values and significantly lower sums of squared error values. Consistent with previous findings, delayed heroin rewards were discounted at a significantly higher rate than were delayed monetary rewards.

  9. Women in treatment: within-gender differences in the clinical presentation of opioid-dependent women.

    PubMed

    McMahon, T J; Luthar, S S

    2000-10-01

    Despite consistent evidence of gender differences in the nature of drug dependence, there has been little consideration of within-gender differences in the clinical presentation of drug-abusing women. In this study, cluster analysis and standardized ratings obtained from 153 women seeking methadone maintenance treatment were used to define four groups of women with different profiles of problem severity. The four clusters were characterized as Unemployed, Medically Ill, Psychiatrically Distressed, and Higher Functioning. When the validity of this four-cluster solution was examined, there were significant differences in the ethnic composition of the four groups, and the four clusters differed in terms of a) psychiatric status, b) medical status, c) vocational-educational history, d) lifetime history of maltreatment, and e) perception of social support available from friends and family. The findings suggest that, although understanding of gender differences cannot be ignored, understanding of ways women differ from one another may be as important in the development of gender-sensitive treatment programs.

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

    PubMed Central

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

    2015-01-01

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

  11. 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].

  12. Kappa Opioid Receptor Activation Potentiates the Cocaine-Induced Increase in Evoked Dopamine Release Recorded In Vivo in the Mouse Nucleus Accumbens

    PubMed Central

    Ehrich, Jonathan M; Phillips, Paul E M; Chavkin, Charles

    2014-01-01

    Behavioral stressors increase addiction risk in humans and increase the rewarding valence of drugs of abuse including cocaine, nicotine and ethanol in animal models. Prior studies have established that this potentiation of drug reward was mediated by stress-induced release of the endogenous dynorphin opioids and subsequent kappa opioid receptor (KOR) activation. In this study, we used in vivo fast scan cyclic voltammetry to test the hypothesis that KOR activation before cocaine administration might potentiate the evoked release of dopamine from ventral tegmental (VTA) synaptic inputs to the nucleus accumbens (NAc) and thereby increase the rewarding valence of cocaine. The KOR agonist U50488 inhibited dopamine release evoked by either medial forebrain bundle (MFB) or pedunculopontine tegmental nucleus (PPTg) activation of VTA inputs to the shell or core of the mouse NAc. Cocaine administration increased the dopamine response recorded in either the shell or core evoked by either MFB or PPTg stimulation. Administration of U50488 15 min before cocaine blocked the conditioned place preference (CPP) to cocaine, but only significantly reduced the effect of cocaine on the dopamine response evoked by PPTg stimulation to NAc core. In contrast, administration of U50488 60 min before cocaine significantly potentiated cocaine CPP and significantly increased the effects of cocaine on the dopamine response evoked by either MFB or PPTg stimulation, recorded in either NAc shell or core. Results of this study support the concept that stress-induced activation of KOR by endogenous dynorphin opioids may enhance the rewarding valence of drugs of abuse by potentiating the evoked dopamine response. PMID:24971603

  13. Kappa opioid receptor activation potentiates the cocaine-induced increase in evoked dopamine release recorded in vivo in the mouse nucleus accumbens.

    PubMed

    Ehrich, Jonathan M; Phillips, Paul E M; Chavkin, Charles

    2014-12-01

    Behavioral stressors increase addiction risk in humans and increase the rewarding valence of drugs of abuse including cocaine, nicotine and ethanol in animal models. Prior studies have established that this potentiation of drug reward was mediated by stress-induced release of the endogenous dynorphin opioids and subsequent kappa opioid receptor (KOR) activation. In this study, we used in vivo fast scan cyclic voltammetry to test the hypothesis that KOR activation before cocaine administration might potentiate the evoked release of dopamine from ventral tegmental (VTA) synaptic inputs to the nucleus accumbens (NAc) and thereby increase the rewarding valence of cocaine. The KOR agonist U50488 inhibited dopamine release evoked by either medial forebrain bundle (MFB) or pedunculopontine tegmental nucleus (PPTg) activation of VTA inputs to the shell or core of the mouse NAc. Cocaine administration increased the dopamine response recorded in either the shell or core evoked by either MFB or PPTg stimulation. Administration of U50488 15 min before cocaine blocked the conditioned place preference (CPP) to cocaine, but only significantly reduced the effect of cocaine on the dopamine response evoked by PPTg stimulation to NAc core. In contrast, administration of U50488 60 min before cocaine significantly potentiated cocaine CPP and significantly increased the effects of cocaine on the dopamine response evoked by either MFB or PPTg stimulation, recorded in either NAc shell or core. Results of this study support the concept that stress-induced activation of KOR by endogenous dynorphin opioids may enhance the rewarding valence of drugs of abuse by potentiating the evoked dopamine response. PMID:24971603

  14. Role of opioid receptors in the reinstatement of opioid-seeking behavior: an overview.

    PubMed

    Fattore, Liana; Fadda, Paola; Antinori, Silvia; Fratta, Walter

    2015-01-01

    Opioid abuse in humans is characterized by discontinuous periods of drug use and abstinence. With time, the probability of falling into renewed drug consumption becomes particularly high and constitutes a considerable problem in the management of heroin addicts. The major problem in the treatment of opioid dependence still remains the occurrence of relapse, to which stressful life events, renewed use of heroin, and exposure to drug-associated environmental cues are all positively correlated. To study the neurobiology of relapse, many research groups currently use the reinstatement animal model, which greatly contributed to disentangle the mechanisms underlying relapse to drug-seeking in laboratory animals. The use of this model is becoming increasingly popular worldwide, and new versions have been recently developed to better appreciate the differential contribution of each opioid receptor subtype to the relapse phenomenon. In this chapter we review the state of the art of our knowledge on the specific role of the opioid receptors as unrevealed by the reinstatement animal model of opioid-seeking behavior.

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

    PubMed

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

    2012-01-01

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

  16. Molecular mechanism for opioid dichotomy: bidirectional effect of μ-opioid receptors on P2X₃ receptor currents in rat sensory neurones.

    PubMed

    Chizhmakov, Igor; Kulyk, Vyacheslav; Khasabova, Iryna; Khasabov, Sergey; Simone, Donald; Bakalkin, Georgy; Gordienko, Dmitri; Verkhratsky, Alexei; Krishtal, Oleg

    2015-06-01

    Here, we describe a molecular switch associated with opioid receptors-linked signalling cascades that provides a dual opioid control over P2X3 purinoceptor in sensory neurones. Leu-enkephalin inhibited P2X3-mediated currents with IC50 ~10 nM in ~25% of small nociceptive rat dorsal root ganglion (DRG) neurones. In contrast, in neurones pretreated with pertussis toxin leu-enkephalin produced stable and significant increase of P2X3 currents. All effects of opioid were abolished by selective μ-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), nonselective inhibitor naloxone, and by PLC inhibitor U73122. Thus, we discovered a dual link between purinoceptors and μ-opioid receptors: the latter exert both inhibitory (pertussis toxin-sensitive) and stimulatory (pertussis toxin-insensitive) actions on P2X3 receptors through phospholipase C (PLC)-dependent pathways. This dual opioid control of P2X3 receptors may provide a molecular explanation for dichotomy of opioid therapy. Pharmacological control of this newly identified facilitation/inhibition switch may open new perspectives for the adequate medical use of opioids, the most powerful pain-killing agents known today.

  17. Opioid Drug Abuse and Modulation of Immune Function: Consequences in the Susceptibility to Opportunistic Infections

    PubMed Central

    Roy, Sabita; Ninkovic, Jana; Banerjee, Santanu; Charboneau, Richard; Das, Subhas; Dutta, Raini; Kirchner, Varvara; Koodie, Lisa; Ma, Jing; Meng, Jingjing

    2013-01-01

    Infection rate among intravenous drug users (IDU) is higher than the general public, and is the major cause of morbidity and hospitalization in the IDU population. Epidemiologic studies provide data on increased prevalence of opportunistic bacterial infections such as TB and pneumonia, and viral infections such as HIV-1 and hepatitis in the IDU population. An important component in the intravenous drug abuse population and in patients receiving medically indicated chronic opioid treatment is opioid withdrawal. Data on bacterial virulence in the context of opioid withdrawal suggest that mice undergoing withdrawal had shortened survival and increased bacterial load in response to Salmonella infection. As the body of evidence in support of opioid dependency and its immunosuppressive effects is growing, it is imperative to understand the mechanisms by which opioids exert these effects and identify the populations at risk that would benefit the most from the interventions to counteract opioid immunosuppressive effects. Thus, it is important to refine the existing animal model to closely match human conditions and to cross-validate these findings through carefully controlled human studies. Better understanding of the mechanisms will facilitate the search for new therapeutic modalities to counteract adverse effects including increased infection rates. This review will summarize the effects of morphine on innate and adaptive immunity, identify the role of the mu opioid receptor in these functions and the signal transduction activated in the process. The role of opioid withdrawal in immunosuppression and the clinical relevance of these findings will also be discussed. PMID:21789507

  18. Rational use of opioids.

    PubMed

    Mastronardi, P; Cafiero, T

    2001-04-01

    The role of analgesia and sedation in intensive care units (ICU) is ancillary to other intensive care strategies, nevertheless they permit that every other diagnostic and therapeutic procedure is safely performed by keeping the patient pain-free, anxiety-free and cooperative. Commonly used opioids in ICU include morphine, fentanyl, sufentanil and remifentanil. The choice among opioid drugs relies on their pharmacokinetics and their pharmacodynamic effects. Cardiovascular stability observed with fentanyl and sufentanil indicates their use in hemodynamically compromised patients. Short-acting remifentanil offers several advantages in patients requiring prolonged infusions. The organ-independent metabolism of this newer molecule may be valuable in patients with multiple organ failure. The main indications for opioid analgesia and sedation in ICU include: 1) Anxiety, pain and agitation: in turn, they can increase cardiac workload, myocardial oxygen consumption and rate of dysarrhythmias; 2) immediate postoperative period after major surgery; 3) short-term invasive procedures. Potential advantages offered by opioids in the ICU setting also include: a) Cardiac protection: in animal models, it has been observed that delta-opiate receptor stimulation confers a preconditioning-like protective effects against myocardial ischemia; b) Neuroprotection: recent studies suggest that mu- and kappa-opiate receptors are involved in ischemic preconditioning against seizures in the brain. During opioid therapy in the ICU, drug tolerance and withdrawal symptoms should be anticipated and the dose adjusted accordingly.

  19. Sex and age-dependent effects of a maternal junk food diet on the mu-opioid receptor in rat offspring.

    PubMed

    Gugusheff, Jessica R; Bae, Sung Eun; Rao, Alexandra; Clarke, Iain J; Poston, Lucilla; Taylor, Paul D; Coen, Clive W; Muhlhausler, Beverly S

    2016-03-15

    Perinatal junk food exposure increases the preference for palatable diets in juvenile and adult rat offspring. Previous studies have implicated reduced sensitivity of the opioid pathway in the programming of food preferences; however it is not known when during development these changes in opioid signalling first emerge. This study aimed to determine the impact of a maternal junk food (JF) diet on mu-opioid receptor (MuR) expression and ligand binding in two key regions of the reward pathway, the nucleus accumbens (NAc) and the ventral tegmental area (VTA) in rats during the early suckling (postnatal day (PND) 1 and 7) and late suckling/early post-weaning (PND 21 and 28) periods. Female rats were fed either a JF or a control diet for two weeks prior to mating and throughout pregnancy and lactation. MuR expression in the VTA was significantly reduced in female JF offspring on PND 21 and 28 (by 32% and 57% respectively, P<0.05), but not at earlier time points (PND 1 and 7). MuR ligand binding was also reduced (by 22%, P<0.05) in the VTA of female JF offspring on PND 28. No effects of perinatal junk food exposure on MuR mRNA expression or binding were detected at these time points in male offspring. These findings provide evidence that the opioid signalling system is a target of developmental programming by the end of the third postnatal week in females, but not in males. PMID:26718219

  20. Highly Selective Dopamine D3 Receptor (D3R) Antagonists and Partial Agonists Based on Eticlopride and the D3R Crystal Structure: New Leads for Opioid Dependence Treatment.

    PubMed

    Kumar, Vivek; Bonifazi, Alessandro; Ellenberger, Michael P; Keck, Thomas M; Pommier, Elie; Rais, Rana; Slusher, Barbara S; Gardner, Eliot; You, Zhi-Bing; Xi, Zheng-Xiong; Newman, Amy Hauck

    2016-08-25

    The recent and precipitous increase in opioid analgesic abuse and overdose has inspired investigation of the dopamine D3 receptor (D3R) as a target for therapeutic intervention. Metabolic instability or predicted toxicity has precluded successful translation of previously reported D3R-selective antagonists to clinical use for cocaine abuse. Herein, we report a series of novel and D3R crystal structure-guided 4-phenylpiperazines with exceptionally high D3R affinities and/or selectivities with varying efficacies. Lead compound 19 was selected based on its in vitro profile: D3R Ki = 6.84 nM, 1700-fold D3R versus D2R binding selectivity, and its metabolic stability in mouse microsomes. Compound 19 inhibited oxycodone-induced hyperlocomotion in mice and reduced oxycodone-induced locomotor sensitization. In addition, pretreatment with 19 also dose-dependently inhibited the acquisition of oxycodone-induced conditioned place preference (CPP) in rats. These findings support the D3R as a target for opioid dependence treatment and compound 19 as a new lead molecule for development. PMID:27508895

  1. Berberine Improves Intestinal Motility and Visceral Pain in the Mouse Models Mimicking Diarrhea-Predominant Irritable Bowel Syndrome (IBS-D) Symptoms in an Opioid-Receptor Dependent Manner

    PubMed Central

    Pan, Qiuhui; Fichna, Jakub; Zheng, Lijun; Wang, Kesheng; Yu, Zhen; Li, Yongyu; Li, Kun; Song, Aihong; Liu, Zhongchen; Song, Zhenshun; Kreis, Martin

    2015-01-01

    Background and Aims Berberine and its derivatives display potent analgesic, anti-inflammatory and anticancer activity. Here we aimed at characterizing the mechanism of action of berberine in the gastrointestinal (GI) tract and cortical neurons using animal models and in vitro tests. Methods The effect of berberine was characterized in murine models mimicking diarrhea-predominant irritable bowel syndrome (IBS-D) symptoms. Then the opioidantagonists were used to identify the receptors involved. Furthermore, the effect of berberineon opioid receptors expression was established in the mouse intestine and rat fetal cortical neurons. Results In mouse models, berberine prolonged GI transit and time to diarrhea in a dose-dependent manner, and significantly reduced visceral pain. In physiological conditions the effects of berberine were mediated by mu- (MOR) and delta- (DOR) opioidreceptors; hypermotility, excessive secretion and nociception were reversed by berberine through MOR and DOR-dependent action. We also found that berberine increased the expression of MOR and DOR in the mouse bowel and rat fetal cortical neurons. Conclusion Berberine significantly improved IBS-D symptoms in animal models, possibly through mu- and delta- opioid receptors. Berberine may become a new drug candidate for the successful treatment of IBS-D in clinical conditions. PMID:26700862

  2. Increased methylation of the MOR gene proximal promoter in primary sensory neurons plays a crucial role in the decreased analgesic effect of opioids in neuropathic pain

    PubMed Central

    2014-01-01

    Background The analgesic potency of opioids is reduced in neuropathic pain. However, the molecular mechanism is not well understood. Results The present study demonstrated that increased methylation of the Mu opioid receptor (MOR) gene proximal promoter (PP) in dorsal root ganglion (DRG) plays a crucial role in the decreased morphine analgesia. Subcutaneous (s.c.), intrathecal (i.t.) and intraplantar (i.pl.), not intracerebroventricular (i.c.v.) injection of morphine, the potency of morphine analgesia was significantly reduced in nerve-injured mice compared with control sham-operated mice. After peripheral nerve injury, we observed a decreased expression of MOR protein and mRNA, accompanied by an increased methylation status of MOR gene PP, in DRG. However, peripheral nerve injury could not induce a decreased expression of MOR mRNA in the spinal cord. Treatment with 5-aza-2′-deoxycytidine (5-aza-dC), inhibited the increased methylation of MOR gene PP and prevented the decreased expression of MOR in DRG, thereby improved systemic, spinal and periphery morphine analgesia. Conclusions Altogether, our results demonstrate that increased methylation of the MOR gene PP in DRG is required for the decreased morphine analgesia in neuropathic pain. PMID:25118039

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

    PubMed

    Taha, Sharif A

    2010-07-14

    It is well established that opioid signaling in the central nervous system constitutes a powerful stimulus for food intake. The role of opioids in determining food preference, however, is less well defined. Opioids have been proposed to promote intake of preferred foods, or, alternatively, to preferentially increase consumption of fat. In the present manuscript, I comprehensively review results from previous studies investigating this issue. Data from these studies suggests a mechanism for opioid action that may reconcile the previously proposed hypotheses: opioid effects on food intake do appear to be largely specific for fat consumption, but individual animals' sensitivity to this effect may be dependent on baseline food preferences. In addition, I highlight the possibility that the selectivity of endogenous opioid effects may importantly differ from that of exogenous agonists in the degree to which baseline preferences, rather than macronutrient intake, are altered. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009. PMID:20211638

  4. 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

  5. Micro-opioid receptor activation in the basolateral amygdala mediates the learning of increases but not decreases in the incentive value of a food reward.

    PubMed

    Wassum, Kate M; Cely, Ingrid C; Balleine, Bernard W; Maidment, Nigel T

    2011-02-01

    The decision to perform, or not perform, actions known to lead to a rewarding outcome is strongly influenced by the current incentive value of the reward. Incentive value is largely determined by the affective experience derived during previous consumption of the reward-the process of incentive learning. We trained rats on a two-lever, seeking-taking chain paradigm for sucrose reward, in which responding on the initial seeking lever of the chain was demonstrably controlled by the incentive value of the reward. We found that infusion of the μ-opioid receptor antagonist, CTOP (d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH(2)), into the basolateral amygdala (BLA) during posttraining, noncontingent consumption of sucrose in a novel elevated-hunger state (a positive incentive learning opportunity) blocked the encoding of incentive value information normally used to increase subsequent sucrose-seeking responses. Similar treatment with δ [N, N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174,864)] or κ [5'-guanidinonaltrindole (GNTI)] antagonists was without effect. Interestingly, none of these drugs affected the ability of the rats to encode a decrease in incentive value resulting from experiencing the sucrose in a novel reduced-hunger state. However, the μ agonist, DAMGO ([d-Ala2, NMe-Phe4, Gly5-ol]-enkephalin), appeared to attenuate this negative incentive learning. These data suggest that upshifts and downshifts in endogenous opioid transmission in the BLA mediate the encoding of positive and negative shifts in incentive value, respectively, through actions at μ-opioid receptors, and provide insight into a mechanism through which opiates may elicit inappropriate desire resulting in their continued intake in the face of diminishing affective experience. PMID:21289167

  6. Behavioral Economic Analysis of Opioid Consumption In Heroin-Dependent Individuals: Effects of Alternative Reinforcer Magnitude and Post-Session Drug Supply

    PubMed Central

    Greenwald, Mark K; Steinmiller, Caren L

    2009-01-01

    This study investigated the extent to which hydromorphone (HYD) choice and behavioral economic demand were influenced by HYD unit price (UP), alternative money reinforcement magnitude and post-session HYD supply. Heroin dependent research volunteers (n=13) stabilized on buprenorphine 8 mg/day first sampled two HYD doses (12 and 24 mg IM, labeled Drug A [session 1] and Drug B [session 2]). In each of the final six sessions, volunteers were given access to a 12-trial choice progressive ratio (PR) task and could earn a HYD unit dose (2 mg, fixed) or money ($2 or $4, varied across sessions), administered immediately after the work session. Before the PR task, volunteers were told which HYD supplemental dose (none, Drug A or B) would be available 3 hr after receiving the PR-contingent dose. PR-contingent HYD choice significantly decreased when $4 relative to $2 was concurrently available. Information about the post-session HYD supplement moderated this effect: when subjects were told a supplemental dose was available, HYD-seeking behavior decreased when the money alternative was smaller ($2), but this information did not further attenuate HYD choice, which was already low, when the money alternative was higher ($4). HYD demand elasticity was only increased by the $4 relative to $2 alternative without the HYD supplement. In summary, opioid-seeking behavior is influenced by the availability of concurrent non-drug and drug alternatives. These findings show that drug availability and non-drug alternatives interact to modulate drug-seeking behavior. PMID:19464125

  7. Icilin evokes a dose- and time-dependent increase in glutamate within the dorsal striatum of rats.

    PubMed

    Werkheiser, J L; Rawls, S M; Cowan, A

    2006-05-01

    Icilin, the peripheral cold channel agonist, activates TRPM8 and TRPA1, localized on dorsal root ganglia and trigeminal neurons in rats. Icilin precipitates immediate wet-dog shakes in this species, which are antagonized by centrally acting mu and kappa opioid agonists, implicating the central nervous system in the behavioral response. We studied the effect icilin has on glutamate levels in the dorsal striatum, a brain region involved in movement. Icilin (0.25, 0.5 and 0.75 mg/kg, i.p.) elicited a dose- and time-dependent increase in glutamate within the striatum, indicative of icilin's neurochemical effect in rats.

  8. Opioids and differentiation in human cancer cells.

    PubMed

    Zagon, Ian S; McLaughlin, Patricia J

    2005-10-01

    This study was designed to examine the role of opioids on cell differentiation, with an emphasis on the mechanism of opioid growth factor (OGF, [Met5]-enkephalin)-dependent growth inhibition. Three human cancer cell lines (SK-N-SH neuroblastoma and SCC-1 and CAL-27 squamous cell carcinoma of the head and neck), along with OGF and the opioid antagonist naltrexone (NTX) at a dosage (10(-6) M) known to repress or increase, respectively, cell replication, were utilized. The effects on differentiation (neurite formation, process lengths, betaIII-tubulin, involucrin) were investigated in cells exposed to OGF or NTX for up to 6 days. In addition, the influence of a variety of other natural and synthetic opioids on differentiation was examined. OGF, NTX, naloxone, [D-Pen2,5]-enkephalin, dynorphin A1-8, beta-endorphin, endomorphin-1 and -2, [D-Ala2, MePhe4, Glycol5]-enkephalin (DAMGO), morphine, and U69,593 at concentrations of 10(-6) M did not alter cell differentiation of any cancer cell line. In NTX-treated SK-N-SH cells, cellular area was increased 23%, and nuclear area was decreased 17%, from control levels; no changes in cell or nuclear area were recorded in OGF-exposed cells. F-actin concentration was increased 40% from control values in SK-N-SH cells subjected to NTX, whereas alpha-tubulin was decreased 53% in OGF-treated cells. These results indicate that the inhibitory or stimulatory actions of OGF and NTX, respectively, on cell growth in tissue culture are not due to alterations in differentiation pathways. However, exposure to OGF and NTX modified some aspects of cell structure, but this was independent of differentiation. The absence of effects on cancer cell differentiation by a variety of other opioids supports the previously reported lack of growth effects of these compounds.

  9. Patterns of opioid analgesic prescription among patients with osteoarthritis.

    PubMed

    Dominick, Kelli L; Bosworth, Hayden B; Dudley, Tara K; Waters, Sandra J; Campbell, Lisa C; Keefe, Francis J

    2004-01-01

    This study describes patterns of opioid analgesic prescription during a one-year period among a sample of patients with osteoarthritis (OA). The study sample included 3,061 patients with prior ICD-9 codes indicating a diagnosis of OA who were treated at a federal Veterans Affairs Medical Center. Specific opioid variables included: any opioid prescription, number of specific opioid drugs prescribed, total number of opioid prescriptions, total number of days supply of opioids, and daily opioid doses. We also examined relationships of demographic characteristics to opioid variables. Results revealed that 41% of patients received at least one opioid prescription. Opioids were prescribed significantly less frequently among African-Americans than Caucasians and the number of opioid prescriptions declined with increasing age. The mean annual supply of opioids was 104 days. Days' supply of opioids was also lower for African Americans and older patients. Daily opioid doses were, on average, below recommended daily doses for the treatment of OA. Findings of this study suggest that opioids are frequently prescribed to individuals with OA and that these drugs may be gaining acceptability for the treatment of chronic musculoskeletal pain. Additional research is needed to examine reasons for racial differences in opioid prescribing, as well as the prescription of these medications at fairly low doses.

  10. Low-dose memantine attenuated methadone dose in opioid-dependent patients: a 12-week double-blind randomized controlled trial.

    PubMed

    Lee, Sheng-Yu; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chen, Po See; Huang, San-Yuan; Tzeng, Nian-Sheng; Wang, Liang-Jen; Lee, I Hui; Wang, Tzu-Yun; Chen, Kao Chin; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band

    2015-05-19

    Low-dose memantine might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. We investigated whether add-on memantine reduced cytokine levels and benefitted patients with opioid dependence undergoing methadone maintenance therapy (MMT) in a randomized, double-blind, controlled 12-week study. Patients were randomly assigned to a group: Memantine (5 mg/day) (n = 53) or Placebo (n = 75). The methadone dose required and retention in treatment were monitored. Plasma tumor necrosis factor (TNF)-α, C-reactive protein (CRP), interleukin (IL)-6, IL-8, transforming growth factor (TGF)-β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. General linear mixed models were used to examine therapeutic effect. After 12 weeks, Memantine-group required a somewhat lower methadone dose than did Placebo-group (P = 0.039). They also had significantly lower plasma TNF-α and significantly higher TGF-β1 levels. We provide evidence of the benefit of add-on memantine in opioid dependent patients undergoing MMT.

  11. HIV risk behavior in treatment-seeking opioid-dependent youth: Results from a NIDA Clinical Trials Network multi-site study

    PubMed Central

    Meade, Christina S.; Weiss, Roger D.; Fitzmaurice, Garrett M.; Poole, Sabrina A.; Subramaniam, Geetha A.; Patkar, Ashwin A.; Connery, Hilary S.; Woody, George E.

    2011-01-01

    Objective To assess baseline rates of and changes in HIV drug and sexual risk behavior as a function of gender and treatment in opioid-dependent youth. Methods 150 participants were randomly assigned to extended buprenorphine/naloxone therapy for 12 weeks (BUP) or detoxification for 2 weeks (DETOX); all received drug counseling for 12 weeks. HIV risk was assessed at baseline and 4-, 8-, and 12-week follow-ups. Behavioral change was examined using generalized estimating equations. Results Baseline rates of past-month HIV risk for females/males were 51%/45% for injection drug use (IDU) (ns), 77%/35% for injection risk (p<.001), 82%/74% for sexual activity (ns), 14%/24% for multiple partners (ns), and 68%/65% for unprotected intercourse (ns). IDU decreased over time (p<.001), with greater decreases in BUP versus DETOX (p<.001) and females versus males in BUP (p<.05). Injection risk did not change for persistent injectors. Sexual activity decreased in both genders and conditions (p<.01), but sexual risk did not. Conclusions Overall IDU and sexual activity decreased markedly, particularly in BUP patients and females, but injection and sexual risk behaviors persisted. While extended buprenorphine/naloxone therapy appears to have favorable effects on HIV risk behavior in opioid-dependent youth, risk reduction counseling may be necessary to extend its benefits. PMID:20393347

  12. 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

    Whistler, Jennifer L

    2012-03-01

    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.

  13. 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

    Whistler, Jennifer L

    2012-03-01

    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

  14. Acute and chronic mu opioids differentially regulate thrombospondins 1 and 2 isoforms in astrocytes.

    PubMed

    Phamduong, Ellen; Rathore, Maanjot K; Crews, Nicholas R; D'Angelo, Alexander S; Leinweber, Andrew L; Kappera, Pranay; Krenning, Thomas M; Rendell, Victoria R; Belcheva, Mariana M; Coscia, Carmine J

    2014-02-19

    Chronic opioids induce synaptic plasticity, a major neuronal adaptation. Astrocyte activation in synaptogenesis may play a critical role in opioid tolerance, withdrawal, and dependence. Thrombospondins 1 and 2 (TSP1/2) are astrocyte-secreted matricellular glycoproteins that promote neurite outgrowth as well as dendritic spine and synapse formation, all of which are inhibited by chronic μ opioids. In prior studies, we discovered that the mechanism of TSP1 regulation by μ opioids in astrocytes involves crosstalk between three different classes of receptors, μ opioid receptor, EGFR and TGFβR. Moreover, TGFβ1 stimulated TSP1 expression via EGFR and ERK/MAPK activation, indicating that EGFR is a signaling hub for opioid and TGFβ1 actions. Using various selective antagonists, and inhibitors, here we compared the mechanisms of chronic opioid regulation of TSP1/2 isoform expression in vivo and in immortalized rat cortical astrocytes. TSP1/2 release from astrocytes was also monitored. Acute and chronic μ opioids, morphine, and the prototypic μ ligand, DAMGO, modulated TSP2 protein levels. TSP2 but not TSP1 protein content was up-regulated by acute (3 h) morphine or DAMGO by an ERK/MAPK dependent mechanism. Paradoxically, TSP2 protein levels were altered neither by TGFβ1 nor by astrocytic neurotrophic factors, EGF, CNTF, and BMP4. TSP1/2 immunofluorescence was increased in astrocytes subjected to scratch-wounding, suggesting TSPs may be useful markers for the "reactive" state of these cells and potentially for different types of injury. Previously, we determined that chronic morphine attenuated both neurite outgrowth and synapse formation in cocultures of primary astrocytes and neurons under similar temporal conditions that μ opioids reduced TSP1 protein levels in astrocytes. Here we found that, after the same 8 day treatment, morphine or DAMGO diminished TSP2 protein levels in astrocytes. Therefore, μ opioids may deter synaptogenesis via both TSP1/2 isoforms, but

  15. 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

  16. Prescription Opioid Use Among Seriously Mentally Ill Veterans Nationally in the Veterans Health Administration.

    PubMed

    Mathew, Nickie; Rosenheck, Robert A

    2016-02-01

    Frequent prescription opioid use has been recognized as a growing problem but there have been no studies specifically among veterans with serious mental illness (SMI). National data from the Veterans Health Administration (VHA) during Fiscal Year 2012 show that VHA patients with SMI receive more opioid prescriptions than other veterans. Additionally, high numbers of opioid prescriptions is associated with greater use of anxiolytics/sedative-hypnotics, drug dependence and COPD-all of which pose an increased risk of respiratory depression and falls and warrant substantial caution and improved coordination between mental health and non-mental health prescribers to evaluate risk-benefit tradeoffs. PMID:26374435

  17. Opioid Abstinence Reinforcement Delays Heroin Lapse during Buprenorphine Dose Tapering

    ERIC Educational Resources Information Center

    Greenwald, Mark K.

    2008-01-01

    A positive reinforcement contingency increased opioid abstinence during outpatient dose tapering (4, 2, then 0 mg/day during Weeks 1 through 3) in non-treatment-seeking heroin-dependent volunteers who had been maintained on buprenorphine (8 mg/day) during an inpatient research protocol. The control group (n = 12) received $4.00 for completing…

  18. Opioid and non-opioid mechanisms of footshock-induced analgesia: role of the spinal dorsolateral funiculus.

    PubMed

    Lewis, J W; Terman, G W; Watkins, L R; Mayer, D J; Liebeskind, J C

    1983-05-01

    Exposure to inescapable footshock causes either an opioid or non-opioid mediated analgesia in the rat depending on the temporal parameters of its administration. Lesions of the spinal dorsolateral funiculus significantly reduce both the opioid and non-opioid forms of this footshock-induced analgesia. Thus, these two neurochemically discrete pain-inhibitory systems appear to depend on the integrity of the same descending path, one known to be activated by morphine and by analgesic brain stimulation.

  19. Involvement of opioid peptides in the regulation of reproduction in the prawn Penaeus indicus

    NASA Astrophysics Data System (ADS)

    Sreenivasula Reddy, P.

    The possible involvement of an endogenous opioid system in the regulation of ovarian development in the prawn Penaeus indicus was investigated. Injection of leucine-enkephalin significantly increased the ovarian index and oocyte diameter in a dose-dependent manner. In contrast, injection of methionine-enkephalin significantly decreased the ovarian index and oocyte diameters. These results provide evidence to support the hypothesis that an opioid system is involved in the regulation of reproduction in crustaceans.

  20. Investigating expectation and reward in human opioid addiction with [(11) C]raclopride PET.

    PubMed

    Watson, Ben J; Taylor, Lindsay G; Reid, Alastair G; Wilson, Sue J; Stokes, Paul R; Brooks, David J; Myers, James F; Turkheimer, Federico E; Nutt, David J; Lingford-Hughes, Anne R

    2014-11-01

    The rewarding properties of some abused drugs are thought to reside in their ability to increase striatal dopamine levels. Similar increases have been shown in response to expectation of a positive drug effect. The actions of opioid drugs on striatal dopamine release are less well characterized. We examined whether heroin and the expectation of heroin reward increases striatal dopamine levels in human opioid addiction. Ten opioid-dependent participants maintained on either methadone or buprenorphine underwent [(11) C]raclopride positron emission tomography imaging. Opioid-dependent participants were scanned three times, receiving reward from 50-mg intravenous heroin (diamorphine; pharmaceutical heroin) during the first scan to generate expectation of the same reward at the second scan, during which they only received 0.1-mg intravenous heroin. There was no heroin injection during the third scan. Intravenous 50-mg heroin during the first scan induced pronounced effects leading to high levels of expectation at the second scan. There was no detectable increase in striatal dopamine levels to either heroin reward or expectation of reward. We believe this is the first human study to examine whether expectation of heroin reward increases striatal dopamine levels in opioid addiction. The absence of detectable increased dopamine levels to both the expectation and delivery of a heroin-related reward may have been due to the impact of substitute medication. It does however contrast with the changes seen in abstinent stimulant users, suggesting that striatal dopamine release alone may not play such a pivotal role in opioid-maintained individuals.

  1. Cohort protocol paper: The Pain and Opioids In Treatment (POINT) study

    PubMed Central

    2014-01-01

    Background Internationally, there is concern about the increased prescribing of pharmaceutical opioids for chronic non-cancer pain (CNCP). In part, this is related to limited knowledge about the long-term benefits and outcomes of opioid use for CNCP. There has also been increased injection of some pharmaceutical opioids by people who inject drugs, and for some patients, the development of problematic and/or dependent use. To date, much of the research on the use of pharmaceutical opioids among people with CNCP, have been clinical trials that have excluded patients with complex needs, and have been of limited duration (i.e. fewer than 12 weeks). The Pain and Opioids In Treatment (POINT) study is unique study that aims to: 1) examine patterns of opioid use in a cohort of patients prescribed opioids for CNCP; 2) examine demographic and clinical predictors of adverse events, including opioid abuse or dependence, medication diversion, other drug use, and overdose; and 3) identify factors predicting poor pain relief and other outcomes. Methods/Design The POINT cohort comprises around 1,500 people across Australia prescribed pharmaceutical opioids for CNCP. Participants will be followed-up at four time points over a two year period. POINT will collect information on demographics, physical and medication use history, pain, mental health, drug and alcohol use, non-adherence, medication diversion, sleep, and quality of life. Data linkage will provide information on medications and services from Medicare (Australia’s national health care scheme). Data on those who receive opioid substitution therapy, and on mortality, will be linked. Discussion This study will rigorously examine prescription opioid use among CNCP patients, and examine its relationship to important health outcomes. The extent to which opioids for chronic pain is associated with pain reduction, quality of life, mental and physical health, aberrant medication behavior and substance use disorders will be

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

    PubMed

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

    2007-06-01

    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 mu-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 tau estimated. Mice were injected with the irreversible mu-opioid receptor antagonist clocinnamox (0.32-25.6 mg/kg, i.p), and 24 h 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 (50-250 microg/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 mu-opioid receptors, while etorphine produced approximately 40% reduction in mu-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

  3. Nalmefene induced elevation in serum prolactin in normal human volunteers: partial kappa opioid agonist activity?

    PubMed

    Bart, Gavin; Schluger, James H; Borg, Lisa; Ho, Ann; Bidlack, Jean M; Kreek, Mary Jeanne

    2005-12-01

    In humans, mu- and kappa-opioid receptor agonists lower tuberoinfundibular dopamine, which tonically inhibits prolactin release. Serum prolactin is, therefore, a useful biomarker for tuberoinfundibular dopamine. The current study evaluated the unexpected finding that the relative mu- and kappa-opioid receptor selective antagonist nalmefene increases serum prolactin, indicating possible kappa-opioid receptor agonist activity. In all, 33 healthy human volunteers (14 female) with no history of psychiatric or substance use disorders received placebo, nalmefene 3 mg, and nalmefene 10 mg in a double-blind manner. Drugs were administered between 0900 and 1000 on separate days via 2-min intravenous infusion. Serial blood specimens were analyzed for serum levels of prolactin. Additional in vitro studies of nalmefene binding to cloned human kappa-opioid receptors transfected into Chinese hamster ovary cells were performed. Compared to placebo, both doses of nalmefene caused significant elevations in serum prolactin (p<0.002 for nalmefene 3 mg and p<0.0005 for nalmefene 10 mg). There was no difference in prolactin response between the 3 and 10 mg doses. Binding assays confirmed nalmefene's affinity at kappa-opioid receptors and antagonism of mu-opioid receptors. [(35)S]GTPgammaS binding studies demonstrated that nalmefene is a full antagonist at mu-opioid receptors and has partial agonist properties at kappa-opioid receptors. Elevations in serum prolactin following nalmefene are consistent with this partial agonist effect at kappa-opioid receptors. As kappa-opioid receptor activation can lower dopamine in brain regions important to the persistence of alcohol and cocaine dependence, the partial kappa agonist effect of nalmefene may enhance its therapeutic efficacy in selected addictive diseases.

  4. Problem Drinking and Low-Dose Naltrexone-Assisted Opioid Detoxification*

    PubMed Central

    Mannelli, Paolo; Peindl, Kathleen; Patkar, Ashwin A.; Wu, Li-Tzy; Tharwani, Haresh M.; Gorelick, David A.

    2011-01-01

    Objective: The influence of alcohol use on opioid dependence is a major problem that warrants a search for more effective treatment strategies. The addition of very-low-dose naltrexone (VLNTX) to methadone taper was recently associated with reduced withdrawal intensity during detoxification. In a secondary analysis of these data, we sought to determine whether problem drinking affects detoxification outcomes and whether symptoms are influenced by VLNTX use. Method: Opioid-dependent patients (N = 174) received naltrexone (0.125 or 0.250 mg/day) or placebo in a double-blind, randomized design during methadone-based, 6-day inpatient detoxification. Alcohol consumption was assessed at admission using the Addiction Severity Index and self-report. Outcome measures were opioid withdrawal intensity, craving, and retention in treatment. Results: Problem drinking—opioid dependent patients (n = 79) showed episodic heavy alcohol use and reported increased subjective opioid withdrawal intensity (p = .001), craving (p = .001), and significantly lower rate of retention in treatment (p = .02). Individuals with problem drinking and opioid dependence who were treated with VLNTX (n = 55) showed reduced withdrawal (p = .05) and a lower rate of treatment discontinuation (p = .03), resuming alcohol intake in smaller numbers the day following discharge (p = .03). Treatment effects were more pronounced on anxiety, perspiration, shakiness, nausea, stomach cramps, and craving. There were no group differences in use of adjuvant medications and no treatment-related adverse events. Conclusions: Heavy drinking is associated with worse opioid detoxification outcomes. The addition of VLNTX is safe and is associated with reduced withdrawal symptoms and better completion rate in these patients. Further studies should explore the use of VLNTX in detoxification and long-term treatment of combined alcohol—opioid dependence and alcohol dependence alone. PMID:21513688

  5. Intravenous Oxycodone, Hydrocodone and Morphine in Recreational Opioid Users: Abuse Potential and Relative Potencies

    PubMed Central

    Stoops, William W.; Hatton, Kevin W.; Lofwall, Michelle R.; Nuzzo, Paul A.; Walsh, Sharon L.

    2010-01-01

    Rationale Nonmedical use and abuse of prescription opioids is an increasing public health problem. Intravenous (IV) administration of opioid analgesics intended for oral use is not uncommon, yet little is known about the relative abuse potential of these drugs when administered intravenously to recreational opioid abusers without physical dependence. Methods This inpatient study employed a double-blind, randomized, within-subject, placebo-controlled design to examine the relative abuse potential of IV doses of oxycodone, hydrocodone and morphine. Nine healthy adult participants reporting recreational opioid use and histories of IV opioid use completed 11 experimental sessions, including one active-dose practice session. IV doses were infused over 5-min and included three identical doses of each opioid (5, 10 and 20 mg/10 ml) and saline placebo. Physiological, subjective and performance effects were collected before and for 6 h after drug administration. Results All three opioids produced prototypical mu agonist effects (e.g., miosis; increased ratings of liking) that were generally dose-related. Pharmacodynamic effects were observed within 5 min of IV administration. Physiological effects were more prolonged than subjective effects for all three drugs. While the magnitude of effects was generally comparable across drugs and qualitatively similar, valid potency assays indicated the following potency relationship: oxycodone > morphine > hydrocodone. Conclusions There were modest potency differences between oxycodone, hydrocodone and morphine, but their overall profile of effects was similar, indicating significant abuse potential when administered intravenously. PMID:20665209

  6. Compulsive-like responding for opioid analgesics in rats with extended access.

    PubMed

    Wade, Carrie L; Vendruscolo, Leandro F; Schlosburg, Joel E; Hernandez, Daniel O; Koob, George F

    2015-01-01

    The abuse of prescription opioids that are used for the treatment of chronic pain is a major public health concern, costing ∼$53.4 billion annually in lost wages, health-care costs, and criminal costs. Although opioids remain a first-line therapy for the treatment of severe chronic pain, practitioners remain cautious because of the potential for abuse and addiction. Opioids such as heroin are considered very rewarding and reinforcing, but direct and systematic comparisons of compulsive intake between commonly prescribed opioids and heroin in animal models have not yet been performed. In the present study, we evaluated the potential for compulsive-like drug seeking and taking, using intravenous self-administration of oxycodone, fentanyl, and buprenorphine in rats allowed long access sessions (12 h). We measured compulsive-like intake using an established escalation model and responding on a progressive ratio schedule of reinforcement. We compared the potential for compulsive-like self-administration of these prescription opioids and heroin, which has been previously established to induce increasing intake that models the transition to addiction in humans. We found that animals that self-administered oxycodone, fentanyl, or heroin, but not buprenorphine had similar profiles of escalation and increases in breakpoints. The use of extended access models of prescription opioid intake will help better understand the biological factors that underlie opioid dependence.

  7. Compulsive-Like Responding for Opioid Analgesics in Rats with Extended Access

    PubMed Central

    Wade, Carrie L; Vendruscolo, Leandro F; Schlosburg, Joel E; Hernandez, Daniel O; Koob, George F

    2015-01-01

    The abuse of prescription opioids that are used for the treatment of chronic pain is a major public health concern, costing ∼$53.4 billion annually in lost wages, health-care costs, and criminal costs. Although opioids remain a first-line therapy for the treatment of severe chronic pain, practitioners remain cautious because of the potential for abuse and addiction. Opioids such as heroin are considered very rewarding and reinforcing, but direct and systematic comparisons of compulsive intake between commonly prescribed opioids and heroin in animal models have not yet been performed. In the present study, we evaluated the potential for compulsive-like drug seeking and taking, using intravenous self-administration of oxycodone, fentanyl, and buprenorphine in rats allowed long access sessions (12 h). We measured compulsive-like intake using an established escalation model and responding on a progressive ratio schedule of reinforcement. We compared the potential for compulsive-like self-administration of these prescription opioids and heroin, which has been previously established to induce increasing intake that models the transition to addiction in humans. We found that animals that self-administered oxycodone, fentanyl, or heroin, but not buprenorphine had similar profiles of escalation and increases in breakpoints. The use of extended access models of prescription opioid intake will help better understand the biological factors that underlie opioid dependence. PMID:25060491

  8. Opioid receptors in the gastrointestinal tract

    PubMed Central

    Holzer, Peter

    2011-01-01

    Opium is arguably one of the oldest herbal medicines, being used as analgesic, sedative and antidiarrheal drug for thousands of years. These effects mirror the actions of the endogenous opioid system and are mediated by the principal μ-, κ- and δ-opioid receptors. In the gut, met-enkephalin, leu-enkephalin, β-endorphin and dynorphin occur in both neurons and endocrine cells. When released, opioid peptides activate opioid receptors on the enteric circuitry controlling motility and secretion. As a result, inhibition of gastric emptying, increase in sphincter tone, induction of stationary motor patterns and blockade of peristalsis ensue. Together with inhibition of ion and fluid secretion, these effects cause constipation, one of the most frequent and troublesome adverse reactions of opioid analgesic therapy. Although laxatives are most frequently used to ameliorate opioid-induced bowel dysfunction, their efficacy is unsatisfactory. Specific antagonism of peripheral opioid receptors is a more rational approach. This goal is addressed by the use of opioid receptor antagonists with limited absorption such as oral prolonged-release naloxone and opioid receptor antagonists that do not penetrate the blood-brain barrier such as methylnaltrexone and alvimopan. Preliminary evidence indicates that peripherally restricted opioid receptor antagonists may act as prokinetic drugs in their own right. PMID:19345246

  9. 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

  10. Prescription Opioids during Pregnancy

    MedlinePlus

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

  11. Supersensitive Kappa Opioid Receptors Promotes Ethanol Withdrawal-Related Behaviors and Reduce Dopamine Signaling in the Nucleus Accumbens

    PubMed Central

    Rose, Jamie H.; Karkhanis, Anushree N.; Chen, Rong; Gioia, Dominic; Lopez, Marcelo F.; Becker, Howard C.; McCool, Brian A.

    2016-01-01

    Background: Chronic ethanol exposure reduces dopamine transmission in the nucleus accumbens, which may contribute to the negative affective symptoms associated with ethanol withdrawal. Kappa opioid receptors have been implicated in withdrawal-induced excessive drinking and anxiety-like behaviors and are known to inhibit dopamine release in the nucleus accumbens. The effects of chronic ethanol exposure on kappa opioid receptor-mediated changes in dopamine transmission at the level of the dopamine terminal and withdrawal-related behaviors were examined. Methods: Five weeks of chronic intermittent ethanol exposure in male C57BL/6 mice were used to examine the role of kappa opioid receptors in chronic ethanol-induced increases in ethanol intake and marble burying, a measure of anxiety/compulsive-like behavior. Drinking and marble burying were evaluated before and after chronic intermittent ethanol exposure, with and without kappa opioid receptor blockade by nor-binaltorphimine (10mg/kg i.p.). Functional alterations in kappa opioid receptors were assessed using fast scan cyclic voltammetry in brain slices containing the nucleus accumbens. Results: Chronic intermittent ethanol-exposed mice showed increased ethanol drinking and marble burying compared with controls, which was attenuated with kappa opioid receptor blockade. Chronic intermittent ethanol-induced increases in behavior were replicated with kappa opioid receptor activation in naïve mice. Fast scan cyclic voltammetry revealed that chronic intermittent ethanol reduced accumbal dopamine release and increased uptake rates, promoting a hypodopaminergic state of this region. Kappa opioid receptor activation with U50,488H concentration-dependently decreased dopamine release in both groups; however, this effect was greater in chronic intermittent ethanol-treated mice, indicating kappa opioid receptor supersensitivity in this group. Conclusions: These data suggest that the chronic intermittent ethanol-induced increase

  12. Strategies to Reduce the Tampering and Subsequent Abuse of Long-acting Opioids: Potential Risks and Benefits of Formulations With Physical or Pharmacologic Deterrents to Tampering

    PubMed Central

    Stanos, Steven P.; Bruckenthal, Patricia; Barkin, Robert L.

    2012-01-01

    Increased prescribing of opioid analgesics for chronic noncancer pain may reflect acceptance that opioid benefits outweigh risks of adverse events for a broadening array of indications and patient populations; however, a parallel increase in the abuse, misuse, and diversion of prescription opioids has resulted. There is an urgent need to reduce opioid tampering and subsequent abuse without creating barriers to safe, effective analgesia. Similar to the “magic bullet” concept of antibiotic development (kill the bacteria without harming the patient), the idea behind reformulating opioid analgesics is to make them more difficult to tamper with and abuse by drug abusers but innocuous to the compliant patient. As antibiotics exploit differences in bacterial and human physiology, tamper-resistant formulations depend on differences in the way drug abusers and compliant patients consume opioids. Most opioid abusers tamper with tablets to facilitate oral, intranasal, or intravenous administration, whereas compliant patients usually take intact tablets. Pharmaceutical strategies to deter opioid abuse predominantly focus on tablet tampering, incorporating physical barriers (eg, crush resistance) or embedded chemicals that render tampered tablets inert, unusable, or noxious. Deterring tampering and abuse of intact tablets is more challenging. At present, only a few formulations with characteristics designed to oppose tampering for abuse have received approval by the US Food and Drug Administration, and none has been permitted to include claims of abuse deterrence or tamper resistance in their labeling. This review discusses the potential benefits, risks, and limitations associated with available tamper-resistant opioids and those in development. PMID:22766088

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

    PubMed

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

    2016-05-01

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

  14. Peripherally acting opioids and clinical implications for pain control.

    PubMed

    Sehgal, Nalini; Smith, Howard S; Manchikanti, Laxmaiah

    2011-01-01

    Opioid receptors are widely expressed in the central and peripheral nervous system and in the non-neuronal tissues. Data from animal and human clinical studies support the involvement of peripheral opioid receptors in analgesia, especially in the presence of inflammation. Inflammation has been shown to increase the synthesis of opioid receptors in the dorsal root ganglion neurons and enhance transport and accumulation of opioid receptors in the peripheral terminals of sensory neurons. Under the influence of chemokines and adhesion molecules, opioid peptide-containing immune cells extravasate and accumulate in the injured tissues. Stress, chemokines, cytokines, and other releasing factors in inflamed tissues stimulate these granulocytes to release opioid peptides. Once secreted, opioid peptides bind to and activate peripheral opioid receptors on sensory nerve fibers and produce analgesia by decreasing the excitability of sensory nerves and/or inhibiting release of pro-inflammatory neuropeptides. Research has revealed that local application of exogenous opioid agonists produces a potent analgesic effect by activating peripheral opioid receptors in inflamed tissues. The analgesic activity occurs without activation of opioid receptors in the central nervous system (CNS), and therefore centrally mediated side effects, such as respiratory depression, mental clouding, altered consciousness, or addiction, are not associated with peripheral opioid activity. This discovery has stimulated research on developing peripherally restricted opioid agonists that lack CNS effects. In addition, it has been recognized that opioid receptors modulate inflammation, and that opioids have anti-inflammatory effects. The anti-inflammatory actions of opioids are not well known or understood. Conflicting reports on mu-opioids suggest both anti-inflammatory and pro-inflammatory effects. This article will present the basis for peripheral opioid analgesia and describe current research directed at

  15. Bi- or multifunctional opioid peptide drugs.

    PubMed

    Schiller, Peter W

    2010-04-10

    Strategies for the design of bi- or multifunctional drugs are reviewed. A distinction is made between bifunctional drugs interacting in a monovalent fashion with two targets and ligands containing two distinct pharmacophores binding in a bivalent mode to the two binding sites in a receptor heterodimer. Arguments are presented to indicate that some of the so-called "bivalent" ligands reported in the literature are unlikely to simultaneously interact with two binding sites. Aspects related to the development of bi- or multifunctional drugs are illustrated with examples from the field of opioid analgesics. The drug-like properties of the tetrapeptide Dmt(1)[DALDA] with triple action as a micro opioid agonist, norepinephrine uptake inhibitor and releaser of endogenous opioid peptides to produce potent spinal analgesia are reviewed. Rationales for the development of opioid peptides with mixed agonist/antagonist profiles as analgesics with reduced side effects are presented. Progress in the development of mixed micro opioid agonist/delta opioid antagonists with low propensity to produce tolerance and physical dependence is reviewed. Efforts to develop bifunctional peptides containing a micro opioid agonist and a cholecystokinin antagonist or an NK1 receptor antagonist as analgesics expected to produce less tolerance and dependence are also reviewed. A strategy to improve the drug-like properties of bifunctional opioid peptide analgesics is presented.

  16. Morphine withdrawal precipitated by specific mu, delta or kappa opioid receptor antagonists: a c-Fos protein study in the rat central nervous system.

    PubMed

    Le Guen, Stéphanie; Gestreau, Christian; Besson, Jean-Marie

    2003-06-01

    We have recently shown concurrent changes in behavioural responses and c-Fos protein expression in the central nervous system in both naive and morphine-dependent rats after systemic administration of the opioid antagonist naloxone. However, because naloxone acts on the three major types of opioid receptors, the present study aimed at determining, in the same animals, both changes in behaviour and c-Fos-like immunoreactivity after intravenous injection of selective opioid antagonists, such as mu (beta-funaltrexamine, 10 mg/kg), delta (naltrindole, 4 mg/kg) or kappa (nor-binaltorphimine, 5 mg/kg) opioid receptor antagonists, in naive or morphine-dependent rats. In a first experimental series, only beta-funaltrexamine increased c-Fos expression in the eight central nervous system structures examined, whereas no effect was seen after naltrindole or nor-binaltorphimine administration in naive rats. These results suggest a tonic activity in the endogenous opioid peptides acting on mu opioid receptors in normal rats. A second experimental series in morphine-dependent rats showed that beta-funaltrexamine had the highest potency in the induction of classical signs of morphine withdrawal syndrome, as well as the increase in c-Fos expression in the 22 central nervous system structures studied, suggesting a major role of mu opioid receptors in opioid dependence. However, our results also demonstrated that naltrindole and, to a lesser extent, nor-binaltorphimine were able to induce moderate signs of morphine withdrawal and relatively weak c-Fos protein expression in restricted central nervous system structures. Therefore, delta and kappa opioid receptors may also contribute slightly to opioid dependence.

  17. Review of naloxone safety for opioid overdose: practical considerations for new technology and expanded public access

    PubMed Central

    2015-01-01

    Opioid overdose and mortality have increased at an alarming rate prompting new public health initiatives to reduce drug poisoning. One initiative is to expand access to the opioid antidote naloxone. Naloxone has a long history of safe and effective use by organized healthcare systems and providers in the treatment of opioid overdose by paramedics/emergency medicine technicians, emergency medicine physicians and anesthesiologists. The safety of naloxone in a prehospital setting administered by nonhealthcare professionals has not been formally established but will likely parallel medically supervised experiences. Naloxone dose and route of administration can produce variable intensity of potential adverse reactions and opioid withdrawal symptoms: intravenous administration and higher doses produce more adverse events and more severe withdrawal symptoms in those individuals who are opioid dependent. More serious adverse reactions after naloxone administration occur rarely and may be confounded by the effects of other co-intoxicants and the effects of prolonged hypoxia. One component of the new opioid harm reduction initiative is to expand naloxone access to high-risk individuals (addicts, abusers, or patients taking high-dose or extended-release opioids for pain) and their close family or household contacts. Patients or their close contacts receive a naloxone prescription to have the medication on their person or in the home for use during an emergency. Contacts are trained on overdose recognition, rescue breathing and administration of naloxone by intramuscular injection or nasal spraying of the injection prior to the arrival of emergency medical personnel. The safety profile of naloxone in traditional medical use must be considered in this new context of outpatient prescribing, dispensing and treatment of overdose prior to paramedic arrival. New naloxone delivery products are being developed for this prehospital application of naloxone in treatment of opioid

  18. Opioid partial agonist buprenorphine dampens responses to psychosocial stress in humans

    PubMed Central

    Bershad, Anya K.; Jaffe, Jerome H.; Childs, Emma; de Wit, Harriet

    2014-01-01

    Preclinical and clinical evidence indicates that opioid drugs have stress-dampening effects. In animal models, opioid analgesics attenuate responses to isolation distress, and in humans, opioids reduce stress related to anticipation of physical pain. The stress-reducing effects of opioid drugs may contribute to their abuse potential. Despite this evidence in laboratory animals, the effects of opioids on responses to psychosocial stress have not been determined in humans. Here we examined the effects of buprenorphine, a μ-opioid partial agonist used to treat opioid dependence and pain, on subjective and physiological responses to a stressful public speaking task in healthy adults. We hypothesized that buprenorphine would reduce subjective and physiological stress responses. Healthy adult volunteers (N = 48) were randomly assigned to receive placebo, 0.2mg sublingual buprenorphine, or 0.4mg sublingual buprenorphine in a two-session study with a stressful speaking task (Trier Social Stress Test; TSST) and a non-stressful control task. During the sessions, the participants reported on their mood states, provided subjective appraisals of the task, and measures of salivary cortisol, heart rate, and blood pressure at regular intervals. Stress produced its expected effects, increasing heart rate, blood pressure, salivary cortisol, and subjective ratings of anxiety and negative mood. In line with our hypothesis, both doses of buprenorphine significantly dampened salivary cortisol responses to stress. On self-report ratings, buprenorphine reduced how threatening participants found the tasks. These results suggest that enhanced opioid signaling dampens responses to social stress in humans, as it does in laboratory animals. This stress-dampening effect of buprenorphine may contribute to the non-medical use of opioid drugs. PMID:25544740

  19. 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.

  20. Prescription of Opioid and Non-opioid Analgesics for Dental Care in Emergency Departments: Findings from the National Hospital Ambulatory Medical Care Survey

    PubMed Central

    Okunseri, Christopher; Okunseri, Elaye; Xiang, Qun; Thorpe, Joshua M.; Szabo, Aniko

    2014-01-01

    Objective The aim of this study was to examine trends and associated factors in the prescription of opioid analgesics, non-opioid analgesics, opioid and non-opioid analgesic combinations and no analgesics by emergency physicians for nontraumatic dental condition (NTDC)-related visits. Our secondary aim was to investigate whether race/ethnicity is a possible predictor of receiving a prescription for either type of medication for NTDC visits in emergency departments (EDs) after adjustment for potential covariates. Methods We analyzed data from the National Hospital Ambulatory Medical Care Survey for 1997–2000 and 2003–2007, and used multinomial multivariate logistic regression to estimate the probability of receiving a prescription for opioid analgesics, non-opioid analgesics, or a combination of both compared to receiving no analgesics for NTDC-related visits. Results During 1997–2000 and 2003–2007, prescription of opioid analgesics and combinations of opioid and non-opioid analgesics increased and that of no analgesics decreased over time. The prescription rates for opioid analgesics, non-opioid analgesics, opioid and non-opioid analgesic combinations and no analgesics for NTDC-related visits in EDs were 43%, 20%, 12% and 25% respectively. Majority of patients categorized as having severe pain received prescriptions for opioids for NTDC-related visits in EDs. After adjusting for covariates, patients with self-reported dental reasons for visit and severe pain had a significantly higher probability of receiving prescriptions for opioid analgesics and opioid and non-opioid analgesic combinations. Conclusion Prescription of opioid analgesics increased over time. ED physicians were more likely to prescribe opioid analgesics and opioid and non-opioid analgesic combinations for NTDC-related visits with reported severe pain. PMID:24863407

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

    PubMed

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

    2015-09-01

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

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

    PubMed

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

    2015-09-01

    Practitioners are highly likely to encounter patients with concurrent use of nicotine products and opioid analgesics. Smokers present with more severe and extended chronic pain outcomes and have a higher frequency of prescription opioid use. Current tobacco smoking is a strong predictor of risk for nonmedical use of prescription opioids. Opioid and nicotinic-cholinergic neurotransmitter systems interact in important ways to modulate opioid and nicotine effects: dopamine release induced by nicotine is dependent on facilitation by the opioid system, and the nicotinic-acetylcholine system modulates self-administration of several classes of abused drugs-including opioids. Nicotine can serve as a prime for the use of other drugs, which in the case of the opioid system may be bidirectional. Opioids and compounds in tobacco, including nicotine, are metabolized by the cytochrome P450 enzyme system, but the metabolism of opioids and tobacco products can be complicated. Accordingly, drug interactions are possible but not always clear. Because of these issues, asking about nicotine use in patients taking opioids for pain is recommended. When assessing patient tobacco use, practitioners should also obtain information on products other than cigarettes, such as cigars, pipes, smokeless tobacco, and electronic nicotine delivery systems (ENDS, or e-cigarettes). There are multiple forms of behavioral therapy and pharmacotherapy available to assist patients with smoking cessation, and opioid agonist maintenance and pain clinics represent underutilized opportunities for nicotine intervention programs. PMID:26375198

  3. Opioid addiction and abuse in primary care practice: a comparison of methadone and buprenorphine as treatment options.

    PubMed

    Bonhomme, Jean; Shim, Ruth S; Gooden, Richard; Tyus, Dawn; Rust, George

    2012-01-01

    Opioid abuse and addiction have increased in frequency in the United States over the past 20 years. In 2009, an estimated 5.3 million persons used opioid medications nonmedically within the past month, 200000 used heroin, and approximately 9.6% of African Americans used an illicit drug. Racial and ethnic minorities experience disparities in availability and access to mental health care, including substance use disorders. Primary care practitioners are often called upon to differentiate between appropriate, medically indicated opioid use in pain management vs inappropriate abuse or addiction. Racial and ethnic minority populations tend to favor primary care treatment settings over specialty mental health settings. Recent therapeutic advances allow patients requiring specialized treatment for opioid abuse and addiction to be managed in primary care settings. The Drug Addiction Treatment Act of 2000 enables qualified physicians with readily available short-term training to treat opioid-dependent patients with buprenorphine in an office-based setting, potentially making primary care physicians active partners in the diagnosis and treatment of opioid use disorders. Methadone and buprenorphine are effective opioid replacement agents for maintenance and/or detoxification of opioid-addicted individuals. However, restrictive federal regulations and stigmatization of opioid addiction and treatment have limited the availability of methadone. The opioid partial agonist-antagonist buprenorphine/naloxone combination has proven an effective alternative. This article reviews the literature on differences between buprenorphine and methadone regarding availability, efficacy, safety, side-effects, and dosing, identifying resources for enhancing the effectiveness of medication-assisted recovery through coordination with behavioral/psychological counseling, embedded in the context of recovery-oriented systems of care. PMID:23092049

  4. 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

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

    PubMed Central

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

    2015-01-01

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

  6. Effects of experimental Unemployment, Employment and Punishment analogs on opioid seeking and consumption in heroin-dependent volunteers.

    PubMed

    Greenwald, Mark K

    2010-09-01

    This study investigated the extent to which hydromorphone (HYD) choice and behavioral economic demand differed during experimental analogs of Unemployment (Drug Only: HYD and no money alternative), Employment (Drug or Money: HYD and $4 alternative), and Punishment (Drug Only+Money Loss: HYD only and $4 subtracted for each HYD choice), in the context of anticipated high vs. low post-session drug availability (HYD 24 mg vs. placebo). Eleven heroin-dependent, buprenorphine-stabilized (8 mg/day) volunteers first sampled two HYD doses (0 and 24 mg IM in randomized, counterbalanced order, labeled Drug A [session 1] and Drug B [session 2]). In each of the final six sessions, volunteers were given access to a 12-trial choice progressive ratio (PR) task and could work to receive HYD unit doses (2mg each); cumulative dose units earned were administered in a bolus injection after the work session. Before the PR task, volunteers were told which HYD dose (Drug A or B) would be available 3h after the PR-contingent injection. Relative to Unemployment (Drug Only), Employment (Drug or Money) and Punishment (Drug Only+Money Loss) each significantly suppressed HYD seeking (e.g., breakpoints). Employment and Punishment also reduced HYD behavioral economic demand, but via different mechanisms: Employment increased HYD price-elasticity, whereas Punishment decreased HYD demand intensity. Adjusting for the initial level difference (i.e., normalized demand), Employment significantly decreased P(max) (i.e., lower "essential value" of HYD) and O(max) (maximum HYD responding) compared to Punishment or Unemployment. These effects were not significantly altered by post-session drug availability.

  7. Effects of Experimental Unemployment, Employment and Punishment Analogs on Opioid Seeking and Consumption in Heroin-Dependent Volunteers

    PubMed Central

    Greenwald, Mark K.

    2010-01-01

    This study investigated the extent to which hydromorphone (HYD) choice and behavioral economic demand differed during experimental analogs of Unemployment (Drug Only: HYD and no money alternative), Employment (Drug or Money: HYD and $4 alternative), and Punishment (Drug Only + Money Loss: HYD only and $4 subtracted for each HYD choice), in the context of anticipated high vs. low post-session drug availability (HYD 24 mg vs. placebo). Eleven heroin-dependent, buprenorphine-stabilized (8-mg/day) volunteers first sampled two HYD doses (0 and 24 mg IM in randomized, counterbalanced order, labeled Drug A [session 1] and Drug B [session 2]). In each of the final six sessions, volunteers were given access to a 12-trial choice progressive ratio (PR) task and could work to receive HYD unit doses (2 mg each); cumulative dose units earned were administered in a bolus injection after the work session. Before the PR task, volunteers were told which HYD dose (Drug A or B) would be available 3 hr after the PR-contingent injection. Relative to Unemployment (Drug Only), Employment (Drug or Money) and Punishment (Drug Only + Money Loss) each significantly suppressed HYD seeking (e.g., breakpoints). Employment and Punishment also reduced HYD behavioral economic demand, but via different mechanisms: Employment increased HYD price-elasticity, whereas Punishment decreased HYD demand intensity. Adjusting for the initial level difference (i.e., normalized demand), Employment significantly decreased Pmax (i.e., lower “essential value” of HYD) and Omax (maximum HYD responding) compared to Punishment or Unemployment. These effects were not significantly altered by post-session drug availability. PMID:20537815

  8. Effects of experimental Unemployment, Employment and Punishment analogs on opioid seeking and consumption in heroin-dependent volunteers.

    PubMed

    Greenwald, Mark K

    2010-09-01

    This study investigated the extent to which hydromorphone (HYD) choice and behavioral economic demand differed during experimental analogs of Unemployment (Drug Only: HYD and no money alternative), Employment (Drug or Money: HYD and $4 alternative), and Punishment (Drug Only+Money Loss: HYD only and $4 subtracted for each HYD choice), in the context of anticipated high vs. low post-session drug availability (HYD 24 mg vs. placebo). Eleven heroin-dependent, buprenorphine-stabilized (8 mg/day) volunteers first sampled two HYD doses (0 and 24 mg IM in randomized, counterbalanced order, labeled Drug A [session 1] and Drug B [session 2]). In each of the final six sessions, volunteers were given access to a 12-trial choice progressive ratio (PR) task and could work to receive HYD unit doses (2mg each); cumulative dose units earned were administered in a bolus injection after the work session. Before the PR task, volunteers were told which HYD dose (Drug A or B) would be available 3h after the PR-contingent injection. Relative to Unemployment (Drug Only), Employment (Drug or Money) and Punishment (Drug Only+Money Loss) each significantly suppressed HYD seeking (e.g., breakpoints). Employment and Punishment also reduced HYD behavioral economic demand, but via different mechanisms: Employment increased HYD price-elasticity, whereas Punishment decreased HYD demand intensity. Adjusting for the initial level difference (i.e., normalized demand), Employment significantly decreased P(max) (i.e., lower "essential value" of HYD) and O(max) (maximum HYD responding) compared to Punishment or Unemployment. These effects were not significantly altered by post-session drug availability. PMID:20537815

  9. Too much or never enough: a response to Treatment of opioid disorders in Canada: looking at the 'other epidemic'.

    PubMed

    Eibl, Joseph K; Morin-Taus, Kristen A; Marsh, David C

    2016-01-01

    Prescription opioid (PO) misuse is a major health concern across North America, and it is the primary cause of preventable death for the 18-35 year old demographic. Medication assisted therapy including methadone and buprenorphine, is the standard of care for patients with opioid-dependence. Moreover, both of these medications are recognized as essential medicines by World Health Organization. In Ontario Canada, the availability of medication assisted therapy has expanded substantially, with almost a ten-fold increase number of patients accessing methadone in Ontario in the past decade. In their manuscript, Fischer et. al. (2016), present a view that expansion of opioid maintenance therapy (OMT) has outpaced true patient need and alternate strategies should be considered as first-line treatments. Here, we present a countering perspective-that medication assisted therapy, along with other harm reduction strategies, should be widely available to all opioid-dependent people as first-line treatments. PMID:27646674

  10. Increased distensibility in dependent veins following prolonged bedrest.

    PubMed

    Kölegård, Roger; Mekjavic, Igor B; Eiken, Ola

    2009-07-01

    Displacement of blood to the lower portion of the body that follows a postural transition from recumbent to erect is augmented by a prolonged period of recumbency (bedrest). Information is scarce as to what extent this augmented blood-volume shift to dependent veins is attributable to increased distensibility of the veins. Accordingly, we studied the effect of 5 weeks of horizontal bedrest on the pressure-distension relationship in limb veins. Elevation of venous distending pressure was induced by exposure of the body except the tested limb to supra-atmospheric pressure with the subject seated in a pressure chamber with one arm, or supine with a lower leg, protruding through a hole in the chamber door. Diameter changes in response to an increase of intravenous pressure (distensibility) from 60 to about 140 mmHg were measured in the brachial and posterior tibial veins using ultrasonographic techniques. Prior to bedrest, the distensibility was substantially less in the tibial than in the brachial vein. Bedrest increased (P < 0.01) pressure distension in the tibial vein by 86% from 7 +/- 3% before to 13 +/- 3% after bedrest. In the brachial vein, bedrest increased (P < 0.05) pressure distension by 36% from 14 +/- 5% before to 19 +/- 5% after bedrest. Thus, removal of the gravity-dependent pressure components that act along the blood vessels in erect posture increases the distensibility of dependent veins.

  11. The Changing Use of Intravenous Opioids in an Emergency Department

    PubMed Central

    Sutter, Mark E.; Wintemute, Garen J.; Clarke, Samuel O.; Roche, Bailey M.; Chenoweth, James A.; Gutierrez, Rory; Albertson, Timothy E.

    2015-01-01

    Introduction Government agencies are increasingly emphasizing opioid safety in hospitals. In 2012, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) started a sentinel event program, the “Safe Use of Opioids in Hospitals.” We sought to determine if opioid use patterns in our emergency department (ED) changed from 2011, before the program began, to 2013, after start of the program. Methods This was a retrospective study of all adult ED patients who received an intravenous opioid and had a serum creatinine measured. We recorded opioids used, dose prescribed, and serum creatinine. As an index of the safety of opioids, uses of naloxone after administration of an opioid was recorded. Results Morphine is still the most commonly used opioid by doses given, but its percentage of opioids used decreased from 68.9% in 2011 to 52.8% in 2013. During the same period, use of hydromorphone increased from 27.5% to 42.9%, while the use of fentanyl changed little (3.6% to 4.3%). Naloxone administration was rare after an opioid had been given. Opioids were not dosed in an equipotent manner. Conclusion The use of hydromorphone in our ED increased by 56% (absolute increase of 15.4%), while the use of morphine decreased by 30.5% (absolute decrease 16.1%) of total opioid use from 2011 to 2013. The JCAHO program likely was at least indirectly responsible for this change in relative dosing of the opioids. Based on frequency of naloxone administered after administration of an opioid, the use of opioids was safe. PMID:26759658

  12. Criminal convictions among dependent heroin users during a 3-year period prior to opioid maintenance treatment: a longitudinal national cohort study.

    PubMed

    Bukten, Anne; Skurtveit, Svetlana; Stangeland, Per; Gossop, Michael; Willersrud, Astrid B; Waal, Helge; Havnes, Ingrid; Clausen, Thomas

    2011-12-01

    This study investigates frequency and types of criminal convictions among a national sample of heroin users during a 3-year period prior to opioid maintenance treatment (OMT). All heroin users (N = 3,789) in Norway who applied for and were eligible for OMT (1997-2003) were included. The OMT records were cross-linked to Norwegian crime statistics. During observation, 24,478 convictions were recorded among 60.9% of the sample. Differences of criminal convictions were found within the group; a large proportion (39.1%) had no convictions, whereas 10% of the sample was responsible for 37.8% of all convictions. Convictions for acquisitive crimes and drug crimes were the most common. Variations in the cohort's individual crime sequences were found. The heavy involvement of heroin users with the criminal justice system provides an opportunity to intervene with dependent offenders. Coordination between treatment providers and police or courts can play an important role in improving outcomes through better access to treatment.

  13. Comment on "a comparison of buprenorphine + naloxone to buprenorphine and methadone in the treatment of opioid dependence during pregnancy: maternal and neonatal outcomes".

    PubMed

    Newman, Robert G; Gevertz, Susan G

    2013-01-01

    In a recent article, Lund et al sought to compare maternal and neonatal outcomes of various treatment regimens for opioid dependence during pregnancy.1 In their background, discussion the authors state that "In the United States buprenorphine plus naloxone [Suboxone(®)] … has been the preferred form of prescribed buprenorphine due to its reduced abuse liability relative to buprenorphine alone [Subutex(®)]." This claim is certainly consistent with the view of the firm that has manufactured and sold both products, Reckitt Benckiser. In September of 2011, the company announced that it was "… discontinuing distribution and sale of Subutex(®) tablets as we believe that mono product (product containing buprenorphine alone with no naloxone) creates a greater risk of misuse, abuse and diversion …".2 Supporting evidence for the alleged "reduced abuse liability" appears to be lacking, however, and evidence cannot be located in the two references cited by Dr. Lund and his co-authors, which in fact are silent on the subject of abuse potential.3,4 In contrast, it has been reported that the transition to buprenorphine/naloxone from the mono formulation has been associated with "… no reduction in injection risk behaviors among IDUs."5. PMID:23772177

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

    PubMed

    Smith, Mark A; Lyle, Megan A

    2006-09-01

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

  15. Opioid risk assessment in palliative medicine.

    PubMed

    Dale, Rebecca; Edwards, Jeremy; Ballantyne, Jane

    2016-03-01

    Pain management with opioids is an integral part of palliative medicine. As the doses and durations of opioid therapy increase, the inherent risks of opioid therapy rise. Although opioids are effective analgesics, they bring with them complex medical and psychological side effects. Aberrant behavior is dangerous and can be difficult to identify as it results in a splitting in the goals of treatment between the patient and providers. One effective strategy in preventing that situation is through the early identification of at-risk patients. There are several tools that can help identify patients at higher risk of addiction and aberrant behaviors during opioid therapy. Structured use of these tools in conjunction with the clinic exam, regular follow-up visits, and lab testing can further reduce patient risk and improve success in opioid therapy. This article will review the background behind a structured strategy for opioid risk assessment using the Opioid Risk Tool, SOAPP-R, and DIRE tools. In addition, example aberrant behaviors and follow-up strategies will be reviewed. It will be demonstrated that careful screening and follow-up allow risk factors to be recognized and addressed early. PMID:27058865

  16. Long-term Use of Opioids for Complex Chronic Pain

    PubMed Central

    Von Korff, Michael R.

    2014-01-01

    Increased opioid prescribing for back pain and other chronic musculoskeletal pain conditions has been accompanied by dramatic increases in prescription opioid addiction and fatal overdose. Opioid-related risks appear to increase with dose. While short-term randomized trials of opioids for chronic pain have found modest analgesic benefits (a one-third reduction in pain intensity on average), the long-term safety and effectiveness of opioids for chronic musculoskeletal pain is unknown. Given the lack of large, long-term randomized trials, recent epidemiologic data suggests the need for caution when considering long-term use of opioids to manage chronic musculoskeletal pain, particularly at higher dosage levels. Principles for achieving more selective and cautious use of opioids for chronic musculoskeletal pain are proposed. PMID:24315147

  17. Endothelial-dependent vasodilators preferentially increase subendocardial blood flow

    SciTech Connect

    Pelc, L.R.; Gross, G.J.; Warltier, D.C.

    1986-03-05

    Interference with arachidonic acid metabolism on the effect of acetylcholine (Ach) or arachidonic acid (AA) to preferentially increase subendocardial perfusion was investigated in anesthetized dogs. Hemodynamics, regional myocardial blood flow (MBF (ml/min/g):radioactive microspheres) and the left ventricular transmural distribution of flow (endo/epi) were measured. Intracoronary infusion of Ach (10 ..mu..g/min) and AA (585 ..mu..g/min) significantly (P < .05*) increased myocardial perfusion and selectively redistributed flow to the subendocardium (increased endo/epi) without changes in systemic hemodynamics. Inhibition of phospholipase A/sub 2/ by quinacrine (Q; 600 ..mu..g/min, ic) attenuated the increase in myocardial perfusion produced by Ach but not by AA and inhibited the redistribution of flow to the subendocardium. The present results suggest that endothelium-dependent vasodilators produce a preferential increase in subendocardial perfusion via a product of AA metabolism.

  18. Psychotherapeutic benefits of opioid agonist therapy.

    PubMed

    Tenore, Peter L

    2008-01-01

    Opioids have been used for centuries to treat a variety of psychiatric conditions with much success. The so-called "opium cure" lost popularity in the early 1950s with the development of non-addictive tricyclic antidepressants and monoamine oxidase inhibitors. Nonetheless, recent literature supports the potent role of methadone, buprenorphine, tramadol, morphine, and other opioids as effective, durable, and rapid therapeutic agents for anxiety and depression. This article reviews the medical literature on the treatment of psychiatric disorders with opioids (notably, methadone and buprenorphine) in both the non-opioid-dependent population and in the opioid-dependent methadone maintenance population. The most recent neurotransmitter theories on the origin of depression and anxiety will be reviewed, including current information on the role of serotonin, N-Methyl d-Aspartate, glutamate, cortisol, catecholamine, and dopamine in psychiatric disorders. The observation that methadone maintenance patients with co-existing psychiatric morbidity (so called dual diagnosis patients) require substantially higher methadone dosages by between 20% and 50% will be explored and qualified. The role of methadone and other opioids as beneficial psychiatric medications that are independent of their drug abuse mitigating properties will be discussed. The mechanisms by which methadone and other opioids can favorably modulate the neurotransmitter systems controlling mood will also be discussed.

  19. Announcing the CDC guideline for prescribing opioids for chronic pain.

    PubMed

    Houry, Debra; Baldwin, Grant

    2016-06-01

    This guideline provides recommendations for primary care providers who are prescribing opioids for chronic pain outside of active cancer treatment, palliative care, and end-of-life care. The guideline addresses: (a) when to initiate or continue opioids for chronic pain; (b) opioid selection, dosage, duration, follow-up, and discontinuation; and (c) assessing risk and addressing harms of opioid use. This guideline is intended to improve communication between providers and patients about the risks and benefits of opioid therapy for chronic pain, improve the safety and effectiveness of pain treatment, and reduce the risks associated with long-term opioid therapy, including abuse, dependence, overdose, and death (Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016. MMWR Recomm Rep 2016;65:1-49. DOI: http://dx.doi.org/10.15585/mmwr.rr6501e1.). PMID:27178083

  20. Prescribing opioid analgesics for chronic non-malignant pain in general practice – a survey of attitudes and practice

    PubMed Central

    Blake, Holly; Leighton, Paul; van der Walt, Gerrie; Ravenscroft, Andrew

    2015-01-01

    Background: This study replicates a previous postal survey of general practitioners (GPs) to explore whether attitudes to opioid prescribing have changed at a time when the number of opioid prescriptions issued in primary care has increased. Methods: With permission, a 57-item survey instrument previously utilised with GPs in the South-west of England was circulated to 214 GPs in city-centre practices in the East Midlands. The survey instrument included items relating to practice context, prescribing patterns and attitudes about analgesic medication, perceived prescribing frequency and reluctance to prescribe. Results: Responses were received from 94 GPs (45%). Almost three-quarters (72.7%) of GPs reported that they sometimes or frequently prescribed strong opioids for chronic non-cancer pain. Over two-thirds (67.8%) reported that they were sometimes or frequently reluctant to prescribe strong opioids for chronic non-cancer pain. No significant relationships were observed between perceived frequency of prescribing and a range of demographic factors; however, concerns about ‘physical dependence’, ‘long-term commitment to prescribing’ and ‘media reports’ were associated with less frequent reported prescribing of, and greater reluctance to prescribe, strong opioids. Discussion: Given the national trend for increased opioid prescriptions, it is unsurprising that more frequent self-reported prescribing is reported here; however, increased frequency does not translate into less reluctance about prescribing. The effectiveness of strong opioids for chronic pain is recognised, but concerns about addiction, dependence and misuse inform a reluctance to use strong opioids. These juxtapositions highlight a continued need for clearer understanding of GPs’ perceptions of strong opioids and point to the potential benefit of dedicated guidelines or specialist education and training to address their uncertainties. PMID:26526705

  1. Targeted Opioid Receptor Antagonists in the Treatment of Alcohol Use Disorders

    PubMed Central

    Niciu, Mark J.

    2015-01-01

    In 1994, the US Food and Drug Administration approved the μ-opioid receptor antagonist naltrexone to treat alcohol dependence. However, treatments requiring daily administration, such as naltrexone, are inconsistently adhered to in substance abusing populations, and constant medication exposure can increase risk of adverse outcomes, e.g., hepatotoxicity. This has fostered a ‘targeted’ or ‘as needed’ approach to opioid receptor antagonist treatment, in which medications are used only in anticipation of or during high-risk situations, including times of intense cravings. Initial studies of the ability of targeted naltrexone to reduce drinking-related outcomes were conducted in problem drinkers and have been extended into larger, multi-site, placebo-controlled investigations with positive results. Another μ-opioid receptor antagonist, nalmefene, has been studied on an ‘as-needed’ basis to reduce heavy drinking in alcohol-dependent individuals. These studies include three large multi-site trials in Europe of up to 1 year in duration, and serve as the basis for the recent approval of nalmefene by the European Medicines Agency as an ‘as-needed’ adjunctive treatment for alcohol dependence. We review potential moderators of opioid receptor antagonist treatment response including subjective assessments, objective clinical measures and genetic variants. In sum, the targeted or ‘as-needed’ approach to treatment with opioid antagonists is an efficacious harmreduction strategy for problem drinking and alcohol dependence. PMID:23881605

  2. 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

  3. Pain volatility and prescription opioid addiction treatment outcomes in patients with chronic pain.

    PubMed

    Worley, Matthew J; Heinzerling, Keith G; Shoptaw, Steven; Ling, Walter

    2015-12-01

    The combination of prescription opioid dependence and chronic pain is increasingly prevalent and hazardous to public health. Variability in pain may explain poor prescription opioid addiction treatment outcomes in persons with chronic pain. This study examined pain trajectories and pain volatility in patients with chronic pain receiving treatment for prescription opioid addiction. We conducted secondary analyses of adults with chronic pain (n = 149) who received buprenorphine/naloxone (BUP/NLX) and counseling for 12 weeks in an outpatient, multisite clinical trial. Good treatment outcome was defined as urine-verified abstinence from opioids at treatment endpoint (Week 12) and during at least 2 of the previous 3 weeks. Pain severity significantly declined over time during treatment (b = -0.36, p < .001). Patients with greater pain volatility were less likely to have a good treatment outcome (odds ratio = 0.55, p < .05), controlling for baseline pain severity and rate of change in pain over time. A 1 standard deviation increase in pain volatility was associated with a 44% reduction in the probability of endpoint abstinence. The significant reduction in subjective pain during treatment provides observational support for the analgesic effects of BUP/NLX in patients with chronic pain and opioid dependence. Patients with greater volatility in subjective pain during treatment have increased risk of returning to opioid use by the conclusion of an intensive treatment with BUP/NLX and counseling. Future research should examine underlying mechanisms of pain volatility and identify related therapeutic targets to optimize interventions for prescription opioid addiction and co-occurring chronic pain.

  4. Pain volatility and prescription opioid addiction treatment outcomes in patients with chronic pain.

    PubMed

    Worley, Matthew J; Heinzerling, Keith G; Shoptaw, Steven; Ling, Walter

    2015-12-01

    The combination of prescription opioid dependence and chronic pain is increasingly prevalent and hazardous to public health. Variability in pain may explain poor prescription opioid addiction treatment outcomes in persons with chronic pain. This study examined pain trajectories and pain volatility in patients with chronic pain receiving treatment for prescription opioid addiction. We conducted secondary analyses of adults with chronic pain (n = 149) who received buprenorphine/naloxone (BUP/NLX) and counseling for 12 weeks in an outpatient, multisite clinical trial. Good treatment outcome was defined as urine-verified abstinence from opioids at treatment endpoint (Week 12) and during at least 2 of the previous 3 weeks. Pain severity significantly declined over time during treatment (b = -0.36, p < .001). Patients with greater pain volatility were less likely to have a good treatment outcome (odds ratio = 0.55, p < .05), controlling for baseline pain severity and rate of change in pain over time. A 1 standard deviation increase in pain volatility was associated with a 44% reduction in the probability of endpoint abstinence. The significant reduction in subjective pain during treatment provides observational support for the analgesic effects of BUP/NLX in patients with chronic pain and opioid dependence. Patients with greater volatility in subjective pain during treatment have increased risk of returning to opioid use by the conclusion of an intensive treatment with BUP/NLX and counseling. Future research should examine underlying mechanisms of pain volatility and identify related therapeutic targets to optimize interventions for prescription opioid addiction and co-occurring chronic pain. PMID:26302337

  5. Smoking tobacco along with marijuana increases symptoms of cannabis dependence

    PubMed Central

    Ream, Geoffrey L.; Benoit, Ellen; Johnson, Bruce D.; Dunlap, Eloise

    2008-01-01

    Aim User practices/rituals that involve concurrent use of tobacco and marijuana – smoking blunts and “chasing” marijuana with tobacco – are hypothesized to increase cannabis dependence symptoms. Design Ethnographers administered group surveys to a diverse, purposive sample of marijuana users who appeared to be 17–35 years old. Setting New York City, including non-impoverished areas of Manhattan, the transitional area of East Village/Lower East Side, low-income areas of northern Manhattan and South Bronx, and diverse areas of Brooklyn and Queens. Participants 481 marijuana users ages 14–35, 57% male, 43% female; 27% White, 30% Black, 19% Latino, 5% Asian, 20% of other/multiple race. Measurements Among many other topics, group surveys measured cannabis dependence symptoms; frequencies of chasing, blunt smoking, joint/pipe smoking, using marijuana while alone, and general tobacco use; and demographic factors. Findings Blunt smoking and chasing marijuana with tobacco were each uniquely associated with five of the seven cannabis dependence symptoms. Across symptoms, predicted odds were 2.4–4.1 times greater for participants who smoked blunts on all 30 of the past 30 days than for participants who did not smoke blunts in the past 30 days. Significant increases in odds over the whole range of the five-point chasing frequency measure (from never to always) ranged from 3.4 times to 5.1 times. Conclusions Using tobacco with marijuana – smoking blunts and “chasing” marijuana with tobacco – contributes to cannabis dependence symptoms. Treatment for cannabis dependence may be more effective it addresses the issue of concurrent tobacco use. PMID:18339491

  6. Increased Dependence of Humans on Ecosystem Services and Biodiversity

    PubMed Central

    Guo, Zhongwei; Zhang, Lin; Li, Yiming

    2010-01-01

    Humans have altered ecosystems more rapidly and extensively than ever, largely to meet rapidly growing demands for resources along with economic development. These demands have been considered important drivers of ecosystem degradation and biodiversity loss. Are humans becoming less dependent on ecosystem services and biodiversity following economic development? Here, we used roundwood production, hydroelectricity generation and tourism investment in 92 biodiversity hotspot and 60 non-hotspot countries as cases to seek the answer. In 1980–2005, annual growth rates of roundwood production, hydroelectricity generation and tourism investment were higher in hotspot countries (5.2, 9.1 and 7.5%) than in non-hotspot countries (3.4, 5.9 and 5.6%), when GDP grew more rapidly in hotspot countries than non-hotspot countries. Annual growth rates of per capita hydropower and per capita tourism investment were higher in hotspot countries (5.3% and 6.1%) than in non-hotspot countries (3.5% and 4.3%); however, the annual growth rate of per capita roundwood production in hotspot countries (1%) was lower than in non-hotspot countries (1.4%). The dependence of humans on cultural services has increased more rapidly than on regulating services, while the dependence on provisioning services has reduced. This pattern is projected to continue during 2005–2020. Our preliminary results show that economic growth has actually made humans more dependent upon ecosystem services and biodiversity. As a consequence, the policies and implementations of both economic development and ecosystems/biodiversity conservation should be formulated and carried out in the context of the increased dependence of humans on ecosystem services along with economic development. PMID:20957042

  7. National study of discontinuation of long-term opioid therapy among veterans.

    PubMed

    Vanderlip, Erik R; Sullivan, Mark D; Edlund, Mark J; Martin, Bradley C; Fortney, John; Austen, Mark; Williams, James S; Hudson, Teresa

    2014-12-01

    Veterans have high rates of chronic pain and long-term opioid therapy (LTOT). Understanding predictors of discontinuation from LTOT will clarify the risks for prolonged opioid use and dependence among this population. All veterans with at least 90 days of opioid use within a 180-day period were identified using national Veteran's Health Affairs (VHA) data between 2009 and 2011. Discontinuation was defined as 6 months with no opioid prescriptions. We used Cox proportional hazards analysis to determine clinical and demographic correlates for discontinuation. A total of 550,616 veterans met criteria for LTOT. The sample was primarily male (93%) and white (74%), with a mean age of 57.8 years. The median daily morphine equivalent dose was 26 mg, and 7% received high-dose (>100mg MED) therapy. At 1 year after initiation, 7.5% (n=41,197) of the LTOT sample had discontinued opioids. Among those who discontinued (20%, n=108,601), the median time to discontinuation was 317 days. Factors significantly associated with discontinuation included both younger and older age, lower average dosage, and having received less than 90 days of opioids in the previous year. Although tobacco use disorders decreased the likelihood of discontinuation, co-morbid mental illness and substance use disorders increased the likelihood of discontinuation. LTOT is common in the VHA system and is marked by extended duration of use at relatively low daily doses with few discontinuation events. Opioid discontinuation is more likely in veterans with mental health and substance use disorders. Further research is needed to delineate causes and consequences of opioid discontinuation.

  8. Synergistic activity between the delta-opioid agonist SNC80 and amphetamine occurs via a glutamatergic NMDA-receptor dependent mechanism

    PubMed Central

    Bosse, Kelly E.; Jutkiewicz, Emily M.; Schultz, Kristin N.; Mabrouk, Omar S.; Kennedy, Robert T.; Gnegy, Margaret E.; Traynor, John R.

    2014-01-01

    Glutamate is known to cause the release of dopamine through a Ca2+-sensitive mechanism that involves activation of NMDA ionotropic glutamate receptors. In the current study, we tested the hypothesis that the delta opioid agonist SNC80 acts indirectly, via the glutamatergic system, to enhance both amphetamine-stimulated dopamine efflux from striatal preparations and amphetamine-stimulated locomotor activity. SNC80 increased extracellular glutamate content, which was accompanied by a concurrent decrease in GABA levels. Inhibition of NMDA signaling with the selective antagonist MK801 blocked the enhancement of both amphetamine-induced dopamine efflux and hyperlocomotion observed with SNC80 pretreatment. Addition of exogenous glutamate also potentiated amphetamine-stimulated dopamine efflux in a Mg2+- and MK801-sensitive manner. After removal of Mg2+ to relieve the ion conductance inhibition of NMDA receptors, SNC80 both elicited dopamine release alone and produced a greater enhancement of amphetamine-evoked dopamine efflux. The action of SNC80 to enhance amphetamine-evoked dopamine efflux was mimicked by the GABAB antagonist 2-hydroxysaclofen. These cumulative findings suggest SNC80 modulates amphetamine-stimulated dopamine efflux through an intra-striatal mechanism involving inhibition of GABA transmission leading to the local release of glutamate followed by subsequent activation of NMDA receptors. PMID:24035916

  9. Preferential Delivery of an Opioid Antagonist to the Fetal Brain in Pregnant Mice.

    PubMed

    Oberdick, John; Ling, Yonghua; Phelps, Mitch A; Yudovich, Max S; Schilling, Karl; Sadee, Wolfgang

    2016-07-01

    Prolonged fetal exposure to opioids results in neonatal abstinence syndrome (NAS), a major medical problem requiring intensive care and increased hospitalization times for newborns with NAS. Multiple strategies are currently available to alleviate withdrawal in infants with NAS. To prevent NAS caused by opioid maintenance programs in pregnant women, blocking fetal dependence without compromising the mother's opiate therapy is desirable. Here we tested in pregnant mice whether a peripherally selective opioid antagonist can preferentially enter the fetal brain and, thereby, in principle, selectively protect the fetus. We show using mass spectrometry that 6β-naltrexol, a neutral opioid antagonist with very limited ability to cross the blood-brain barrier (BBB), readily crosses the placental barrier and enters the fetal brain at high levels, although it is relatively excluded from the maternal brain. Furthermore, owing to the late development of the BBB in postnatal mice, we show that 6β-naltrexol can readily enter the juvenile mouse brain until at least postnatal day 14. Taking advantage of this observation, we show that long-term exposure to morphine starting in the second postnatal week causes robust and quantifiable dependence behaviors that are suppressed by concomitant administration of 6β-naltrexol with much greater potency (ID50 0.022-0.044 mg/kg, or 1/500 the applied dose of morphine) than previously demonstrated for either the suppression of central nervous system opioid effects or the induction of withdrawal in adults. These results indicate that peripherally selective opioid antagonists capable of penetrating the placenta may be beneficial for preventing or reducing neonatal dependence and NAS in a dose range that should not interfere with maternal opioid maintenance. PMID:27189967

  10. Opioid-induced hyperalgesia and burn pain.

    PubMed

    Holtman, Joseph R; Jellish, W Scott

    2012-01-01

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

  11. National and State Treatment Need and Capacity for Opioid Agonist Medication-Assisted Treatment

    PubMed Central

    Campopiano, Melinda; Baldwin, Grant; McCance-Katz, Elinore

    2015-01-01

    Objectives. We estimated national and state trends in opioid agonist medication-assisted treatment (OA-MAT) need and capacity to identify gaps and inform policy decisions. Methods. We generated national and state rates of past-year opioid abuse or dependence, maximum potential buprenorphine treatment capacity, number of patients receiving methadone from opioid treatment programs (OTPs), and the percentage of OTPs operating at 80% capacity or more using Substance Abuse and Mental Health Services Administration data. Results. Nationally, in 2012, the rate of opioid abuse or dependence was 891.8 per 100 000 people aged 12 years or older compared with national rates of maximum potential buprenorphine treatment capacity and patients receiving methadone in OTPs of, respectively, 420.3 and 119.9. Among states and the District of Columbia, 96% had opioid abuse or dependence rates higher than their buprenorphine treatment capacity rates; 37% had a gap of at least 5 per 1000 people. Thirty-eight states (77.6%) reported at least 75% of their OTPs were operating at 80% capacity or more. Conclusions. Significant gaps between treatment need and capacity exist at the state and national levels. Strategies to increase the number of OA-MAT providers are needed. PMID:26066931

  12. Endocrine effects of chronic opioid therapy: implications for clinical management.

    PubMed

    Elliott, Jennifer A; Fibuch, Eugene E

    2013-05-01

    SUMMARY Over the past few decades, the use of opioids in the management of chronic pain conditions has greatly increased. As opioid utilization has expanded, so has the recognition of associated hormonal derangements. These hormonal disturbances involve disruption, predominantly of the hypothalamic-pituitary-gonadal axis, and can affect both men and women treated with opioids. The best recognized of these hormonal disorders is opioid-associated androgen deficiency. Opioid-associated androgen deficiency is most likely to occur with prolonged, high-dose opioid therapy and may be associated with the development of other conditions such as depression, osteoporosis and possible hyperalgesia. Once identified, opioid-associated androgen deficiency should be managed with appropriate hormonal replacement therapy and patients should be closely monitored for adequacy of treatment and treatment-associated adverse events.

  13. Alcohol Screening among Opioid Agonist Patients in a Primary Care Clinic and an Opioid Treatment Program

    PubMed Central

    Klimas, Jan; Muench, John; Wiest, Katharina; Croff, Raina; Rieckmann, Traci; McCarty, Dennis

    2016-01-01

    Problem alcohol use is associated with adverse health and economic outcomes, especially among people in opioid agonist treatment. Screening, brief intervention and referral to treatment (SBIRT) are effective in reducing alcohol use; however, issues involved in SBIRT implementation among opioid agonist patients are unknown. To assess identification and treatment of alcohol use disorders, we reviewed clinical records of opioid agonist patients screened for an alcohol use disorder in a primary care clinic (n =208) and in an opioid treatment program (n = 204) over a two year period. In the primary care clinic, 193 (93%) buprenorphine patients completed an annual alcohol screening and six (3%) had elevated AUDIT scores. Among the patients treated in the opioid treatment program, an alcohol abuse or dependence diagnosis was recorded for 54 (27%) methadone patients. Practitioner focus groups were completed in the primary care (n = 4 physicians) and the opioid treatment program (n = 11 counsellors) to assess experience with and attitudes towards screening opioid agonist patients for alcohol use disorders. Focus groups suggested organizational, structural, provider, patient and community variables hindered or fostered alcohol screening. Alcohol screening is feasible among opioid agonist patients. Effective implementation, however, requires physician training and systematic changes in workflow. PMID:25715074

  14. Effectiveness of Relapse Prevention Cognitive-Behavioral Model in Opioid-Dependent Patients Participating in the Methadone Maintenance Treatment in Iran

    PubMed Central

    PASHAEI, Tahereh; SHOJAEIZADEH, Davoud; RAHIMI FOROUSHANI, Abbas; GHAZITABATABAE, Mahmoud; MOEENI, Maryam; RAJATI, Fatemeh; M RAZZAGHI, Emran

    2013-01-01

    Background: To evaluate the effectiveness of a relapse prevention cognitive-behavioral model, based on Marlatt treatment approach, in Opioid-dependent patients participating in the Methadone Maintenance Treatment (MMT) in Iran. Methods: The study consisted of 92 individuals treated with methadone in Iranian National Center of Addiction Studies (INCAS). Participants were randomized into two groups: educational intervention group (N=46) and control group (N=46). The intervention was comprised of 10 weekly 90 minute sessions, done during a period of 2.5 months based on the most high risk situations determined using Inventory Drug Taking Situation instrument. Relapse was defined as not showing up for MMT, drug use for at least 5 continuous days, and a positive urinary morphine test. Results: While, only 36.4% of the intervention group relapsed into drug use, 63.6% of the control group relapsed. The result of the logistic regressions showed that the odd ratio of the variable of intervention program for the entire follow up period was 0.43 (P<0.01). Further, the odd ratio of this variable in one month, three months, and 195 days after the therapy were 0.48 (P<.03), 0.31 (P<.02), and 0.13 (P<.02) respectively that revealed that on average, the probability of relapse among individuals in the intervention group was lower than patients in control group Conclusion: Relapse prevention model based on Marlatt treatment approach has an effective role in decreasing relapse rate. This model can be introduced as a complementary therapy in patients treated with methadone maintenance. PMID:26056645

  15. Kappa-Opioid Receptor Signaling in the Striatum as a Potential Modulator of Dopamine Transmission in Cocaine Dependence

    PubMed Central

    Trifilieff, Pierre; Martinez, Diana

    2013-01-01

    Cocaine addiction is accompanied by a decrease in striatal dopamine signaling, measured as a decrease in dopamine D2 receptor binding as well as blunted dopamine release in the striatum. These alterations in dopamine transmission have clinical relevance, and have been shown to correlate with cocaine-seeking behavior and response to treatment for cocaine dependence. However, the mechanisms contributing to the hypodopaminergic state in cocaine addiction remain unknown. Here we review the positron emission tomography (PET) imaging studies showing alterations in D2 receptor binding potential and dopamine transmission in cocaine abusers and their significance in cocaine-seeking behavior. Based on animal and human studies, we propose that the kappa receptor/dynorphin system, because of its impact on dopamine transmission and upregulation following cocaine exposure, could contribute to the hypodopaminergic state reported in cocaine addiction, and could thus be a relevant target for treatment development. PMID:23760592

  16. College Students Using More Pot, Fewer Opioids

    MedlinePlus

    ... More Pot, Fewer Opioids Nearly 5 percent use marijuana daily, survey finds To use the sharing features ... 2016 (HealthDay News) -- American college students' use of marijuana continues to increase, but the appeal of other ...

  17. Effects of environmental enrichment on sensitivity to mu, kappa, and mixed-action opioids in female rats.

    PubMed

    Smith, Mark A; Cole, Kathryn T; Gergans, Samantha R; Iordanou, Jordan C; Lyle, Megan A; Schmidt, Karl T

    2008-07-01

    Several studies report that environmental enrichment enhances sensitivity to opioid receptor agonists in male rats. Very few studies have examined the effects of enrichment in female rats, and thus it is not clear whether females are similarly sensitive to these effects. Consequently, the purpose of the present study was to examine the effects of environmental enrichment on sensitivity to representative mu, kappa, and mixed-action opioids in female rats. Following a protocol established in males, females were obtained at weaning and randomly assigned to two groups immediately upon arrival: isolated rats were housed individually with no visual or tactile contact with other rats; enriched rats were housed in groups of four in large cages and given various novel objects on a regular basis. After 6 weeks under these conditions, the antinociceptive effects of mu (morphine, levorphanol), kappa (spiradoline, U69,593), and mixed-action (buprenorphine, butorphanol) opioids were examined in a warm-water, tail-withdrawal procedure. All the opioids examined produced dose-dependent increases in antinociception; however, no differences in opioid sensitivity were observed between the two groups. To determine whether these findings were consistent across behavioral endpoints, the antidiuretic effects of representative mu opioids, and the diuretic effects of representative kappa opioids, were examined in female rats reared under isolated or enriched conditions for 10 weeks. Similar to that seen in the antinociceptive experiment, no significant differences in opioid sensitivity were observed between groups. These data indicate that environmental enrichment does not alter sensitivity to the effects of opioid receptor agonists in female rats, and suggest that females may respond differently to environmental enrichment than males. PMID:18456292

  18. Confounding of the Comparative Safety of Prenatal Opioid Agonist Therapy

    PubMed Central

    Brogly, Susan B; Hahn, Kristen A; Diaz, Sonia Hernandez; Werler, Martha

    2016-01-01

    Prenatal opioid agonist therapy with methadone or buprenorphine prevents maternal illicit opioid use and withdrawal and improves pregnancy outcomes compared to heroin use alone. Historically, methadone has been the first-line opioid agonist therapy for pregnant opioid dependent women; in recent years buprenorphine has become first-line treatment for some opioid dependent pregnant women. While there is some evidence of better outcomes in neonates exposed to buprenorphine vs. methadone, the effect of confounding from differences in women who use buprenorphine and methadone has not been carefully examined in most studies. This review explores mechanisms by which confounding can arise in measuring associations between prenatal buprenorphine vs. methadone exposure on neonatal outcomes using a graphical approach, directed acyclic graphs. The goal of this paper is to facilitate better understanding of the factors influencing neonatal abstinence syndrome and accurate assessment of the comparative safety of opioid agonist therapies on the neonate. PMID:27547489

  19. Avoiding Opioids and Their Harmful Side Effects in the Postoperative Patient: Exogenous Opioids, Endogenous Endorphins, Wellness, Mood, and Their Relation to Postoperative Pain.

    PubMed

    Stephan, Bradley C; Parsa, Fereydoun D

    2016-03-01

    Prescribed opioids are routinely used for many postoperative patients. However, these medications have daunting adverse effects on the body's innate pain management system--the action of the beta-endorphins. The prescribed opioids not only severely impair the function of the mu-opioid receptors, but also inhibit the release of beta-endorphin. This is unfortunate, because beta-endorphin appears to be a much more potent agonist of the mu-opioid receptor than opioids. In addition, beta-endorphin indirectly elevates dopamine, a neurotransmitter related to feelings of euphoria. Therefore, by prescribing opioids, practitioners may inadvertently prolong and increase the overall intensity of the postoperative patients' pain as well as herald anhedonia. This article highlights the relationships between prescribed (exogenous) opioids, beta-endorphins, mu-opioid receptors, wellness, mood, and postoperative pain. The role of patient education, opioid alternatives, and additional recommendations regarding pain control in the postoperative patient are also discussed. PMID:27011886

  20. Avoiding Opioids and Their Harmful Side Effects in the Postoperative Patient: Exogenous Opioids, Endogenous Endorphins, Wellness, Mood, and Their Relation to Postoperative Pain

    PubMed Central

    Parsa, Fereydoun D

    2016-01-01

    Prescribed opioids are routinely used for many postoperative patients. However, these medications have daunting adverse effects on the body's innate pain management system - the action of the beta-endorphins. The prescribed opioids not only severely impair the function of the mu-opioid receptors, but also inhibit the release of beta-endorphin. This is unfortunate, because beta-endorphin appears to be a much more potent agonist of the mu-opioid receptor than opioids. In addition, beta-endorphin indirectly elevates dopamine, a neurotransmitter related to feelings of euphoria. Therefore, by prescribing opioids, practitioners may inadvertently prolong and increase the overall intensity of the postoperative patients' pain as well as herald anhedonia. This article highlights the relationships between prescribed (exogenous) opioids, beta-endorphins, mu-opioid receptors, wellness, mood, and postoperative pain. The role of patient education, opioid alternatives, and additional recommendations regarding pain control in the postoperative patient are also discussed. PMID:27011886

  1. Development and validation of the opioid prescription medication motives questionnaire: a four-factor model of reasons for use.

    PubMed

    Jones, Rachel E; Spradlin, Alexander; Robinson, R Joe; Tragesser, Sarah L

    2014-12-01

    There is considerable evidence that understanding reasons for using substances is important for understanding patterns of use and related consequences as well as for developing assessment and intervention strategies. Despite increases in prescription opioid use and related problems (e.g., overdose deaths), a comprehensive measure of prescription opioid motives has yet to be developed. As such, the current study sought to develop and provide validation evidence for a measure of prescription opioid motives. One hundred eleven male and 226 female undergraduate students completed an initial pool of motive items based on the current literature and measures of prescription opioid use and related problems. Confirmatory factor analysis results demonstrated that the predicted 4-factor model provided a good fit to the data. The 4 motives-pain, social, enhancement, and coping-each showed differential patterns of associations with prescription opioid-related contextual and use variables. Enhancement motives were associated with quantity of use (past 3 months and maximum use in 1 day), frequency of use, in multiple contexts, misuse, and related problems. Coping motives demonstrated relations with maximum pills (in 1 day), frequency of use, and prescription opioid misuse, consequences, and dependence features. For social motives, significant associations were found with frequency of use (in past 3 months), typical number of pills (in 1 day), dependence features, and use both on weekdays and on weekends; this motive had a negative association with maximum number of pills taken in 1 day. Pain motives were largely related to frequency of use (in past 3 months), consequencess, and dependence features. The present study is the first to present an empirical measure of prescription opioid motives and demonstrates how these motives have important implications for understanding patterns of prescription opioid use and related problems. PMID:25180561

  2. 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

  3. Opioids and endocrine dysfunction.

    PubMed

    Seyfried, Oliver; Hester, Joan

    2012-02-01

    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.

  4. The Opioid Epidemic in the United States.

    PubMed

    Wilkerson, Richard Gentry; Kim, Hong K; Windsor, Thomas Andrew; Mareiniss, Darren P

    2016-05-01

    There is an epidemic of opioid abuse. This article discusses the history of opioid use. Abusers of opioids are at great risk of harm. There have been increasing legislative efforts to curb this abuse and we present a review of the current state of these laws. Naloxone has made a profound impact in the care of these patients if they present for medical care early enough. This paper discusses naloxone pharmacodynamics, its use in the medical setting, and how its use is now being expanded to include nontraditional providers with take home naloxone programs. PMID:27133253

  5. Interactions between cannabinoid receptor agonists and mu opioid receptor agonists in rhesus monkeys discriminating fentanyl.

    PubMed

    Maguire, David R; France, Charles P

    2016-08-01

    Cannabinoid receptor agonists such as delta-9-tetrahydrocannabinol (Δ(9)-THC) enhance some (antinociceptive) but not other (positive reinforcing) effects of mu opioid receptor agonists, suggesting that cannabinoids might be combined with opioids to treat pain without increasing, and possibly decreasing, abuse. The degree to which cannabinoids enhance antinociceptive effects of opioids varies across drugs insofar as Δ(9)-THC and the synthetic cannabinoid receptor agonist CP55940 increase the potency of some mu opioid receptor agonists (e.g., fentanyl) more than others (e.g., nalbuphine). It is not known whether interactions between cannabinoids and opioids vary similarly for other (abuse-related) effects. This study examined whether Δ(9)-THC and CP55940 differentially impact the discriminative stimulus effects of fentanyl and nalbuphine in monkeys (n=4) discriminating 0.01mg/kg of fentanyl (s.c.) from saline. Fentanyl (0.00178-0.0178mg/kg) and nalbuphine (0.01-0.32mg/kg) dose-dependently increased drug-lever responding. Neither Δ(9)-THC (0.032-1.0mg/kg) nor CP55940 (0.0032-0.032mg/kg) enhanced the discriminative stimulus effects of fentanyl or nalbuphine; however, doses of Δ(9)-THC and CP55940 that shifted the nalbuphine dose-effect curve markedly to the right and/or down were less effective or ineffective in shifting the fentanyl dose-effect curve. The mu opioid receptor antagonist naltrexone (0.032mg/kg) attenuated the discriminative stimulus effects of fentanyl and nalbuphine similarly. These data indicate that the discriminative stimulus effects of nalbuphine are more sensitive to attenuation by cannabinoids than those of fentanyl. That the discriminative stimulus effects of some opioids are more susceptible to modification by drugs from other classes has implications for developing maximally effective therapeutic drug mixtures with reduced abuse liability. PMID:27184925

  6. The antinociceptive effect of mirtazapine in mice is mediated through serotonergic, noradrenergic and opioid mechanisms.

    PubMed

    Schreiber, Shaul; Rigai, Tova; Katz, Yeshayahu; Pick, Chaim G

    2002-09-30

    The antinociceptive effects of the noradrenergic and specific serotonergic antidepressant (NaSSA) drug mirtazapine and its interaction with various opioid receptor subtypes were evaluated in mice with a hotplate analgesicmeter. Mirtazapine elicited an antinociceptive effect in a dose-dependent manner following doses from 1 to 7.5mg/kg. As the mirtazapine dose increased beyond 10mg/kg latencies returned to baseline, yielding a biphasic dose-response curve. The effect of opioid, adrenergic, and serotonergic receptor antagonists was examined as to their ability to block mirtazapine antinociception. Mirtazapine (at 10mg/kg)-induced antinociception was significantly inhibited by naloxone, nor-BNI, and naltrindole, but neither by beta-FNA nor by naloxonazine, implying the involvement of kappa(1)- and delta-opioid mechanisms. When adrenergic and serotonergic antagonists were used, both metergoline and yohimbine, decreased antinociception elicited by mirtazapine, implying a combined serotonergic and noradrenergic mechanism of antinociception. When mirtazapine was administered together with various agonists of the opioid receptor subtypes, it significantly potentiated antinociception mediated only by kappa(3)-opioid receptor subtypes. Summing up these results we conclude that the antinociceptive effect of mirtazapine is mainly influenced by the kappa(3)-opioid receptor subtype combined with both serotonergic and noradrenergic receptors. These results suggest a potential use of mirtazapine in the management of some pain syndromes, and raise questions regarding a possible indirect opioid-dependence induced by mirtazapine. However, further research is needed in order to establish both the exact clinical indications and the effective doses of mirtazapine when prescribed for pain. PMID:12372565

  7. Berberine induces pacemaker potential inhibition via cGMP-dependent ATP-sensitive K+ channels by stimulating mu/delta opioid receptors in cultured interstitial cells of Cajal from mouse small intestine.

    PubMed

    Kim, Hyun Jung; Kim, Hyungwoo; Jung, Myeong Ho; Kwon, Young Kyu; Kim, Byung Joo

    2016-10-01

    Berberine is traditionally used to treat gastrointestinal (GI) motility disorders. The interstitial cells of Cajal (ICCs) are the pacemaker cells of the gastrointestinal tract, which are responsible for the production of gut movements. The present study aimed to investigate the effects of berberine on pacemaker potentials (PPs) in cultured ICC clusters from the mouse small intestine, and sought to identify the receptors involved and the underlying mechanisms of action. All experiments were performed on cultured ICCs, and a whole‑cell patch‑clamp configuration was used to record PPs from ICC clusters (current clamp mode). Under current clamp mode, berberine was shown to decrease the amplitude and frequency of PPs. However, these effects were suppressed by treatment with glibenclamide, a specific ATP‑sensitive K+ channel blocker. Nor‑binaltorphimine dihydrochloride (a kappa opioid receptor antagonist) did not suppress berberine‑induced PP inhibition, whereas ICI 174,864 (a delta opioid receptor antagonist) and CTOP (a mu opioid receptor antagonist) did suppress the inhibitory effects of berberine. Pretreatment with SQ‑22536 (an adenylate cyclase inhibitor) or with KT‑5720 (a protein kinase A inhibitor) did not suppress the effects of berberine; however, pretreatment with 1H‑[1,2,4] oxadiazolo [4,3‑a] quinoxalin‑1‑one (a guanylate cyclase inhibitor) or KT‑5823 [a protein kinase G (PKG) inhibitor] did. In addition, berberine stimulated cyclic guanosine monophosphate (cGMP) production in ICCs. These observations indicate that berberine may inhibit the pacemaker activity of ICC clusters via ATP‑sensitive K+ channels and the cGMP‑PKG‑dependent pathway by stimulating mu and delta opioid receptors. Therefore, berberine may provide a basis for the development of novel agents for the treatment of GI motility dysfunction. PMID:27601272

  8. 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.

  9. 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. PMID:24882143

  10. In silico substrate dependence increases community productivity but threatens biodiversity

    NASA Astrophysics Data System (ADS)

    Daly, Aisling J.; Baetens, Jan M.; De Baets, Bernard

    2016-04-01

    The critical role that biodiversity plays in ecosystem functioning has motivated many studies of the mechanisms that sustain biodiversity, a notable example being cyclic competition. We extend existing models of communities with cyclic competition by incorporating variable community evenness and resource dependence in demographic processes, two features that have generally been neglected. In this way, we align previous approaches more closely with real-world microbial ecosystems. We demonstrate the existence of a trade-off between increasing biomass production and maintaining biodiversity. This supports experimental observations of a net negative biodiversity effect on biomass productivity, due to competition effects suffered by highly productive species in diverse communities. Our results also support the important role assigned by microbial ecologists to evenness in maintaining ecosystem stability, thus far largely overlooked in in silico approaches.

  11. 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

  12. Predictors of dropout from inpatient opioid detoxification with buprenorphine: a chart review.

    PubMed

    Hakansson, Anders; Hallén, Emma

    2014-01-01

    Inpatient withdrawal treatment (detoxification) is common in opioid dependence, although dropout against medical advice often limits its outcome. This study aimed to assess baseline predictors of dropout from inpatient opioid detoxification with buprenorphine, including age, gender, current substance use, and type of postdetoxification planning. A retrospective hospital chart review was carried out for inpatient standard opioid detoxifications using buprenorphine taper, in a detoxification ward in Malmö, Sweden (N = 122). Thirty-four percent of patients (n = 42) dropped out against medical advice. In multivariate logistic regression, dropout was significantly associated with younger age (OR 0.93 [0.89-0.97]) and negatively predicted by inpatient postdetoxification plan (OR 0.41 [0.18-0.94]), thus favouring an inpatient plan as opposed to outpatient treatment while residing at home. Dropout was unrelated to baseline urine toxicology. In opioid detoxification, patients may benefit from a higher degree of postdetoxification planning, including transition to residential treatment, in order to increase the likelihood of a successful detoxification and treatment entry. Young opioid-dependent patients may need particular attention in the planning of detoxification. PMID:25530903

  13. Long-term course of opioid addiction.

    PubMed

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

    2015-01-01

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

  14. Opioid-induced hyperalgesia: is it clinically relevant for the treatment of pain patients?

    PubMed

    Raffa, Robert B; Pergolizzi, Joseph V

    2013-09-01

    There is a curious and paradoxic phenomenon, reliably demonstrated in animal models, that consists of an increased sensitivity to pain that is apparently induced by the very opioid drugs used to ameliorate the pain. This phenomenon is termed "opioid-induced hyperalgesia." Whether opioid-induced hyperalgesia occurs in humans, and, if so, to what extent and consequence, is far less established. This is a critical question for attempting to treat pain. If opioid-induced hyperalgesia develops in a patient, it would masquerade as tolerance (because the clinical effectiveness of the opioid would be diminished), yet the appropriate clinical adjustment would be precisely the opposite to that of tolerance. It would be to decrease, rather than increase, the dose of opioid. We review the evidence, particularly the clinical evidence, about opioid-induced hyperalgesia and the postulated mechanisms. We conclude that given the clinical ramifications, opioid-induced hyperalgesia is one of the most understudied important aspects of opioid research.

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

    PubMed

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

    2016-05-01

    The use of opioids for chronic pain has increased significantly due to a combination of the high patient burden of pain and the more widespread availability of a range of long-acting opioid preparations. This increased opioid use has translated into the care of many patients with fibromyalgia. The pain mechanism in fibromyalgia is complex but does not seem to involve disturbance of opioid analgesic functions. Hence, there is general concern about the harms in the absence of benefits of opioids in this setting. There is no evidence that pure opioids are effective in fibromyalgia but there is some evidence that opioids with additional actions on the norepinephrine-related pain modulatory pathways, such as tramadol, can be clinically useful in some patients. Novel actions of low-dose opioid antagonists may lead to better understanding of the role of opioid function in fibromyalgia. PMID:27296831

  16. 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

  17. Defining opioid tolerance and dependency.

    PubMed

    Ferri, César Margarit

    2013-12-01

    This report is adapted from paineurope 2013; Issue 2, ©Haymarket Medical Publications Ltd., and is presented with permission. paineurope is provided as a service to pain management by Mundipharma International, LTD. and is distributed free of charge to healthcare professionals in Europe. Archival issues can be accessed via the website: http://www.paineurope.com at which European health professionals can register online to receive copies of the quarterly publication.

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

    PubMed

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

    2016-08-01

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

  19. Association of time-dependent changes in mu opioid receptor mRNA, but not BDNF, TrkB, or MeCP2 mRNA and protein expression in the rat nucleus accumbens with incubation of heroin craving

    PubMed Central

    Theberge, Florence R. M.; Pickens, Charles L.; Goldart, Evan; Fanous, Sanya; Hope, Bruce T.; Liu, Qing-Rong

    2013-01-01

    Rationale and objectives Responding to heroin cues progressively increases after cessation of heroin self-administration (incubation of heroin craving). We investigated whether this incubation is associated with time-dependent changes in brain-derived neurotrophic factor (BDNF) and methyl-CpG binding protein 2 (MeCP2) signaling and mu opioid receptor (MOR) expression in nucleus accumbens (NAc), dorsal striatum (DS), and medial pre-frontal cortex (mPFC). We also investigated the effect of the preferential MOR antagonist naloxone on cue-induced heroin seeking during abstinence. Methods We trained rats to self-administer heroin or saline for 9–10 days and then dissected the NAc, DS, and mPFC at different abstinence days and measured mRNA and protein levels of BDNF, TrkB, and MeCP2, as well as MOR mRNA (Oprm1). In other groups, we assessed cue-induced heroin seeking in extinction tests after 1, 11, and 30 abstinence days, and naloxone’s (0–1.0 mg/kg) effect on extinction responding after 1 and 15 days. Results Cue-induced heroin seeking progressively increased or incubated during abstinence. This incubation was not associated with changes in BDNF, TrkB, or MeCP2 mRNA or protein levels in NAc, DS, or mPFC; additionally, no molecular changes were observed after extinction tests on day 11. In NAc, but not DS or mPFC, MOR mRNA decreased on abstinence day 1 and returned to basal levels over time. Naloxone significantly decreased cue-induced heroin seeking after 15 abstinence days but not 1 day. Conclusions Results suggest a role of MOR in incubation of heroin craving. As previous studies implicated NAc BDNF in incubation of cocaine craving, our data suggest that different mechanisms contribute to incubation of heroin versus cocaine craving. PMID:22790874

  20. Opioid-induced androgen deficiency (OPIAD).

    PubMed

    Smith, Howard S; Elliott, Jennifer A

    2012-07-01

    Opioid therapy is one of the most effective forms of analgesia currently in use. In the past few decades, the use of opioids as a long-term treatment for chronic pain has increased dramatically. Accompanying this upsurge in the use of long-term opioid therapy has been an increase in the occurrence of opioid associated endocrinopathy, most commonly manifested as an androgen deficiency and therefore referred to as opioid associated androgen deficiency (OPIAD). This syndrome is characterized by the presence of inappropriately low levels of gonadotropins (follicle stimulating hormone and luteinizing hormone) leading to inadequate production of sex hormones, particularly testosterone. Symptoms that may manifest in patients with OPIAD include reduced libido, erectile dysfunction, fatigue, hot flashes, and depression. Physical findings may include reduced facial and body hair, anemia, decreased muscle mass, weight gain, and osteopenia or osteoporosis. Additionally, both men and women with OPIAD may suffer from infertility. While the literature regarding OPIAD remains limited, it is apparent that OPIAD is becoming increasingly prevalent among chronic opioid consumers but often goes unrecognized. OPIAD can have a significant negative impact on the the quality of life of opioid users, and clinicians should anticipate the potential for its occurrence whenever long-term opioid prescribing is undertaken. Once diagnosed, treatment for OPIAD may be offered utilizing a number of androgen replacement therapy options including a variety of testosterone preparations and, for female patients with OPIAD, dehydroepiandrosterone (DHEA) supplementation. Follow-up evaluation of patients receiving androgen replacement therapy should include a review of any unresolved symptoms of hypogonadism, laboratory evaluation, and surveillance for potential adverse effects of androgen replacement therapy including prostate disease in males.: PMID:22786453

  1. Mu Opioid Receptor Actions in the Lateral Habenula

    PubMed Central

    Margolis, Elyssa B.; Fields, Howard L.

    2016-01-01

    Increased activity of lateral habenula (LHb) neurons is correlated with aversive states including pain, opioid abstinence, rodent models of depression, and failure to receive a predicted reward. Agonists at the mu opioid receptor (MOR) are among the most powerful rewarding and pain relieving drugs. Injection of the MOR agonist morphine directly into the habenula produces analgesia, raising the possibility that MOR acts locally within the LHb. Consequently, we examined the synaptic actions of MOR agonists in the LHb using whole cell patch clamp recording. We found that the MOR selective agonist DAMGO inhibits a subset of LHb neurons both directly and by inhibiting glutamate release onto these cells. Paradoxically, DAMGO also presynaptically inhibited GABA release onto most LHb neurons. The behavioral effect of MOR activation will thus depend upon both the level of intrinsic neuronal activity in the LHb and the balance of activity in glutamate and GABA inputs to different LHb neuronal populations. PMID:27427945

  2. Mu Opioid Receptor Actions in the Lateral Habenula.

    PubMed

    Margolis, Elyssa B; Fields, Howard L

    2016-01-01

    Increased activity of lateral habenula (LHb) neurons is correlated with aversive states including pain, opioid abstinence, rodent models of depression, and failure to receive a predicted reward. Agonists at the mu opioid receptor (MOR) are among the most powerful rewarding and pain relieving drugs. Injection of the MOR agonist morphine directly into the habenula produces analgesia, raising the possibility that MOR acts locally within the LHb. Consequently, we examined the synaptic actions of MOR agonists in the LHb using whole cell patch clamp recording. We found that the MOR selective agonist DAMGO inhibits a subset of LHb neurons both directly and by inhibiting glutamate release onto these cells. Paradoxically, DAMGO also presynaptically inhibited GABA release onto most LHb neurons. The behavioral effect of MOR activation will thus depend upon both the level of intrinsic neuronal activity in the LHb and the balance of activity in glutamate and GABA inputs to different LHb neuronal populations. PMID:27427945

  3. Pain and Poppies: The Good, the Bad, and the Ugly of Opioid Analgesics

    PubMed Central

    Al-Hasani, Ream; Salvemini, Daniela; Salter, Michael W.; Gutstein, Howard

    2015-01-01

    Treating pain is one of the most difficult challenges in medicine and a key facet of disease management. The isolation of morphine by Friedrich Sertürner in 1804 added an essential pharmacological tool in the treatment of pain and spawned the discovery of a new class of drugs known collectively as opioid analgesics. Revered for their potent pain-relieving effects, even Morpheus the god of dreams could not have dreamt that his opium tincture would be both a gift and a burden to humankind. To date, morphine and other opioids remain essential analgesics for alleviating pain. However, their use is plagued by major side effects, such as analgesic tolerance (diminished pain-relieving effects), hyperalgesia (increased pain sensitivity), and drug dependence. This review highlights recent advances in understanding the key causes of these adverse effects and explores the effect of chronic pain on opioid reward. SIGNIFICANCE STATEMENT Chronic pain is pervasive and afflicts >100 million Americans. Treating pain in these individuals is notoriously difficult and often requires opioids, one of the most powerful and effective classes of drugs used for controlling pain. However, their use is plagued by major side effects, such as a loss of pain-relieving effects (analgesic tolerance), paradoxical pain (hyperalgesia), and addiction. Despite the potential side effects, opioids remain the pharmacological cornerstone of modern pain therapy. This review highlights recent breakthroughs in understanding the key causes of these adverse effects and explores the cellular control of opioid systems in reward and aversion. The findings will challenge traditional views of the good, the bad, and the ugly of opioids. PMID:26468188

  4. Supraspinal peroxynitrite modulates pain signaling by suppressing the endogenous opioid pathway

    PubMed Central

    Little, Joshua W.; Chen, Zhoumou; Doyle, Tim; Porreca, Frank; Ghaffari, Mahsa; Neumann, William L.; Salvemini, Daniela

    2012-01-01

    Peroxynitrite (PN, ONOO−) is a potent oxidant and nitrating agent that contributes to pain through peripheral and spinal mechanisms, but its supraspinal role is unknown. We present evidence here that PN in the rostral ventromedial medulla (RVM) is essential for descending nociceptive modulation in rats during inflammatory and neuropathic pain through PN-mediated suppression of opioid signaling. Carrageenan-induced thermal hyperalgesia was associated with increased 3-nitrotyrosine (NT), a PN biomarker, in the RVM. Furthermore, intra-RVM microinjections of the PN decomposition catalyst (PNDC), Fe(III)-5,10,15,20-tetrakis(N-methyl-pyridinium-4-yl)porphyrin (FeTMPyP5+) dose-dependently reversed this thermal hyperalgesia. These effects of FeTMPyP5+ were abrogated by intra-RVM naloxone, implicating potential interplay between PN and opioids. In support, we identified NT co-localization with the endogenous opioid, enkephalin (ENK), in the RVM during thermal hyperalgesia, suggesting potential in situ interactions. To address the functional significance of such interactions, we exposed methionine-enkephalin (MENK) to PN and identified the major metabolite, 3-nitrotyrosine-methionine-sulfoxide (NSO-MENK), using liquid chromatography-mass spectrometry (LCMS). Next, we isolated, purified, and tested NSO-MENK for opioid receptor binding affinity and analgesic effects. Compared to MENK, this NSO-MENK metabolite lacked appreciable binding affinity for δ, µ, and κ opioid receptors. Intrathecal injection of NSO-MENK in rats did not evoke antinociception suggesting that PN-mediated chemical modifications of ENK suppress opioid signaling. When extended to chronic pain, intra-RVM FeTMPyP5+ produced naloxone-sensitive reversal of mechanical allodynia in rats following chronic constriction injury (CCI) of the sciatic nerve. Collectively, our data reveal the central role of PN in RVM descending facilitation during inflammatory and neuropathic pain potentially through anti-opioid

  5. Opioid requirement, opioid receptor expression, and clinical outcomes in patients with advanced prostate cancer

    PubMed Central

    Zylla, Dylan; Gourley, Brett L.; Vang, Derek; Jackson, Scott; Boatman, Sonja; Lindgren, Bruce; Kuskowski, Michael A.; Le, Chap; Gupta, Kalpna; Gupta, Pankaj

    2013-01-01

    Background Preclinical studies show that opioids stimulate angiogenesis and tumor progression through the mu opioid receptor (MOR). Although MOR is over-expressed in several human malignancies, the effect of chronic opioid requirement on cancer progression or survival has not been examined in humans. Methods We performed a retrospective analysis on 113 patients identified in the Minneapolis VA Tumor Registry (test cohort) and 480 patients from the national VA Central Cancer Registry (validation cohort) diagnosed with stage IV prostate cancer between 1995 and 2010, to examine whether MOR expression or opioid requirement is associated with disease progression and survival. All opioids were converted to oral morphine equivalents (OME) for comparison. Laser scanning confocal microscopy was used to analyze MOR-immunoreactivity in prostate cancer biopsies. The effects of variables on outcomes were analyzed in univariable and multivariable models. Results In patients with metastatic prostate cancer, MOR expression and opioid requirement were independently associated with inferior progression-free survival (PFS) (HR 1.65, 1.33–2.07; p<0.001 and HR 1.08, 1.03–1.13; p<0.001, respectively) and overall survival (OS; HR 1.55, 1.20–1.99; p<0.001 and HR 1.05, 1.00–1.10; p=0.031, respectively). The validation cohort confirmed that increasing opioid requirement was associated with worse OS (HR 1.005, 1.002–1.008, p=0.001). Conclusion Higher MOR expression and greater opioid requirement are associated with shorter PFS and OS in patients with metastatic prostate cancer. Nevertheless, clinical practice should not be changed until prospective randomized trials show that opioid use is associated with inferior clinical outcomes, and that abrogation of the peripheral activities of opioids ameliorates this effect. PMID:24104703

  6. Opioid induced hyperalgesia in anesthetic settings.

    PubMed

    Lee, Hyeon Jeong; Yeomans, David C

    2014-11-01

    Pain is difficult to investigate and difficult to treat, in part, because of problems in quantification and assessment. The use of opioids, combined with classic anesthetics to maintain hemodynamic stability by controlling responses to intraoperative painful events has gained significant popularity in the anesthetic field. However, several side effects profiles concerning perioperative use of opioid have been published. Over the past two decades, many concerns have arisen with respect to opioid-induced hyperalgesia (OIH), which is the paradoxical effect wherein opioid usage may decrease pain thresholds and increase atypical pain unrelated to the original, preexisting pain. This brief review focuses on the evidence, mechanisms, and modulatory and pharmacologic management of OIH in order to elaborate on the clinical implication of OIH.

  7. Prescription practices involving opioid analgesics among Americans with Medicaid, 2010.

    PubMed

    Mack, Karin A; Zhang, Kun; Paulozzi, Leonard; Jones, Christopher

    2015-02-01

    Recent state-based studies have shown an increased risk of opioid overdose death in Medicaid populations. To explore one side of risk, this study examines indicators of potential opioid inappropriate use or prescribing among Medicaid enrollees. We examined claims from enrollees aged 18-64 years in the 2010 Truven Health MarketScan® Multi-State Medicaid database, which consisted of weighted and nationally representative data from 12 states. Pharmaceutical claims were used to identify enrollees (n=359,368) with opioid prescriptions. Indicators of potential inappropriate use or prescribing included overlapping opioid prescriptions, overlapping opioid and benzodiazepine prescriptions, long acting/extended release opioids for acute pain, and high daily doses. In 2010, Medicaid enrollees with opioid prescriptions obtained an average 6.3 opioid prescriptions, and 40% had at least one indicator of potential inappropriate use or prescribing. These indicators have been linked to opioid-related adverse health outcomes, and methods exist to detect and deter inappropriate use and prescribing of opioids.

  8. Continuous opioid therapy (COT) is rarely advisable for refractory chronic daily headache: limited efficacy, risks, and proposed guidelines.

    PubMed

    Saper, Joel R; Lake, Alvin E

    2008-06-01

    Intractable pain, headache or otherwise, is a devastating and life-controlling experience. The need to effectively and aggressively control pain is a fundamental tenet of clinical care. In the past several years, increasing advocacy for continuous opioid therapy has become an important, if not controversial, theme in the development of treatment guidelines and teaching programs. Ironically, the increasing willingness of physicians to prescribe scheduled opioids for their headache and pain patients has occurred in the absence of compelling data demonstrating efficacy or long-term safety. To the contrary, two meta-analyses on chronic noncancer pain (CNCP) and one long-term uncontrolled study on headache patients demonstrate a relatively small number of patients benefiting from the treatment. Recent neuroscience data on the effects of opioids on the brain raise serious concern for long-term safety and also provide the basis for the mechanism by which chronic opioid use might induce progression of headache frequency and severity. Significant adverse effects, including influence on sexual hormonal balances, physical and psychological dependence, the development of opioid-induced hyperalgesia, and cardiac arrhythmia and sudden death that can be seen with standard dosages of methadone, make a strong argument against widespread use of continuous opioid therapy (COT) in otherwise healthy young and middle-aged headache patients. We believe that COT should be used in rare circumstances for chronic headache patients, and propose initial guidelines for selecting patients and monitoring treatment. The physician should be well versed in the details of opioid prescribing, administration, and monitoring, and should be prepared to discontinue opioids when clinical justification, patient behavior, or failure to achieve therapeutic goals make discontinuance necessary.

  9. Opioid-induced hyperalgesia: when pain killers make pain worse.

    PubMed

    Kaneria, Anshuni

    2014-06-04

    A 44-year-old woman had a temporal glioma and was admitted to the hospice with pain that was not controlled despite escalating opioids. Her pain levels rose after every dose increase resulting now in continuous pain, making her very low in mood. Her short-term memory had also declined in a stepwise fashion with each increase in opioids. Additionally, her poor health had had a detrimental effect on family life. Physical examination was difficult due to allodynia but no major abnormality was found. The team suspected opioid-induced hyperalgesia and decided to cut the patient's opioids by one-third initially. This immediately improved the overall pain. The opioids continued to be decreased incrementally every 1-2 days until the pain had disappeared completely. She was stabilised on a dose almost one-seventh of her original regime. Mood and memory also improved as opioids decreased and she was discharged home after 8 days.

  10. Suspected opioid-induced hyperalgesia in an infant.

    PubMed

    Hallett, B R; Chalkiadis, G A

    2012-01-01

    One explanation for diminished opioid analgesic efficacy is opioid-induced hyperalgesia (OIH). We report a case of OIH in an infant with gastroschisis, requiring multiple surgical interventions and prolonged sedation for ventilation. This is the first report of OIH in an infant. On day 41 of life after nine separate surgical interventions, the patient's pain scores increased and remained elevated, despite increasing opioid administration. The patient also developed hyperalgesia, allodynia, and photophobia and became extremely irritable upon handling. Other possible causes were excluded, including interruption to opioid delivery, sepsis, acid-base and electrolyte disturbance, and ongoing surgical pathology. An opioid rotation to hydromorphone was initiated and ketamine was commenced. Sedation for ventilation was achieved with dexmedetomidine and midazolam infusions. Over a period of 24 h after opioid de-escalation, pain scores reduced rapidly and the patient became significantly less irritable with handling. All infusions were gradually weaned and eventually ceased.

  11. [Opioid-induced hyperalgesia. Pathophysiology and clinical relevance].

    PubMed

    Koppert, W

    2004-05-01

    Opioids are the drugs of choice for the treatment of moderate to severe acute and chronic pain. However, clinical evidence suggests that opioids can elicit increased sensitivity to noxious stimuli suggesting that administration of opioids can activate both pain inhibitory and pain facilitatory systems. Acute receptor desensitization via uncoupling of the receptor from G-proteins, up-regulation of the cAMP pathway, activation of the N-methyl-D-aspartate (NMDA) receptor system, as well as descending facilitation, have been proposed as potential mechanisms underlying opioid-induced hyperalgesia. Numerous reports exist demonstrating that opioid-induced hyperalgesia is observed both in animal and human experimental models. Brief exposures to micro-receptor agonists induce long-lasting hyperalgesic effects for days, which might by reflected by clinical observations that large doses of intraoperative micro-receptor agonists increased postoperative pain and morphine consumption. Furthermore, the prolonged use of opioids in patients often requires increasing doses and may be accompanied by the development of abnormal pain. Successful strategies that may decrease or prevent opioid-induced hyperalgesia include the concomitant administration of drugs like NMDA-antagonists, alpha(2)-agonists, or non-steroidal anti-inflammatory drugs (NSAIDs), opioid rotation or combinations of opioids with different receptor selectivity.

  12. Impact of Internet Pharmacy Regulation on Opioid Analgesic Availability*

    PubMed Central

    Boyer, Edward W.; Wines, James D.

    2008-01-01

    Objective: Access to prescription opioid analgesics has made Internet pharmacies the object of increased regulatory scrutiny, but the effectiveness of regulatory changes in curtailing availability of opioid analgesics from online sources has been not assessed. As part of an ongoing investigation into the relationship between the Internet and substance abuse, we examined the availability of prescription opioid analgesics from online pharmacies. Method: From a pharmacy watch Web site, we constructed a data set of postings entered every 3 months beginning November 1, 2005, that were related to the purchase of prescription opioid analgesics. Trained examiners assessed whether the final post described accessibility of pain medications that was increasing or decreasing. Results: We identified 45 threads related to the availability of opioid analgesics from Internet pharmacies. Of the 41 (91%) threads describing the declining availability of opioid analgesic agents from Internet pharmacies, 34 (82%) received posts on November 1, 2007. Despite the subjective nature of the research question, there was high interobserver agreement between coders (κ = .845) that availability of opioid analgesics from online pharmacies had decreased. This finding was supported by a dramatic rise in the number of pageviews (an accepted measure of Web site visitor interest in a page's content) of Web pages describing decreased availability of opioid analgesics. Conclusions: These data suggest striking decreases in the availability of prescription opioid analgesic pharmaceuticals. This self-reported change in drug availability may be related to increased regulation of and law enforcement operations directed against Internet pharmacies. PMID:18781245

  13. 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

  14. Pharmacogenomic considerations in opioid analgesia

    PubMed Central

    Vuilleumier, Pascal H; Stamer, Ulrike M; Landau, Ruth

    2012-01-01

    Translating pharmacogenetics to clinical practice has been particularly challenging in the context of pain, due to the complexity of this multifaceted phenotype and the overall subjective nature of pain perception and response to analgesia. Overall, numerous genes involved with the pharmacokinetics and dynamics of opioids response are candidate genes in the context of opioid analgesia. The clinical relevance of CYP2D6 genotyping to predict analgesic outcomes is still relatively unknown; the two extremes in CYP2D6 genotype (ultrarapid and poor metabolism) seem to predict pain response and/or adverse effects. Overall, the level of evidence linking genetic variability (CYP2D6 and CYP3A4) to oxycodone response and phenotype (altered biotransformation of oxycodone into oxymorphone and overall clearance of oxycodone and oxymorphone) is strong; however, there has been no randomized clinical trial on the benefits of genetic testing prior to oxycodone therapy. On the other hand, predicting the analgesic response to morphine based on pharmacogenetic testing is more complex; though there was hope that simple genetic testing would allow tailoring morphine doses to provide optimal analgesia, this is unlikely to occur. A variety of polymorphisms clearly influence pain perception and behavior in response to pain. However, the response to analgesics also differs depending on the pain modality and the potential for repeated noxious stimuli, the opioid prescribed, and even its route of administration. PMID:23226064

  15. X Chromosome Inactivation in Opioid Addicted Women

    PubMed Central

    Vousooghi, Nasim; Shirazi, Mitra-Sadat Sadat; Goodarzi, Ali; Abharian, Peyman Hassani; Zarrindast, Mohammad-Reza

    2015-01-01

    Introduction: X chromosome inactivation (XCI) is a process during which one of the two X chromosomes in female human is silenced leading to equal gene expression with males who have only one X chromosome. Here we have investigated XCI ratio in females with opioid addiction to see whether XCI skewness in women could be a risk factor for opioid addiction. Methods: 30 adult females meeting DSM IV criteria for opioid addiction and 30 control females with no known history of addiction were included in the study. Digested and undigested DNA samples which were extracted from blood were analyzed after amplification of the polymorphic androgen receptor (AR) gene located on the X chromosome. XCI skewness was studied in 3 ranges: 50:50–64:36 (random inactivation), 65:35–80:20 (moderately skewed) and >80:20 (highly skewed). Results: XCI from informative females in control group was 63% (N=19) random, 27% (N=8) moderately skewed and 10% (N=3) highly skewed. Addicted women showed 57%, 23% and 20%, respectively. The distribution and frequency of XCI status in women with opioid addiction was not significantly different from control group (P=0.55). Discussion: Our data did not approve our hypothesis of increased XCI skewness among women with opioid addiction or unbalanced (non-random) expression of genes associated with X chromosome in female opioid addicted subjects. PMID:26904175

  16. [Misuse of opioid analgesics. An internet analysis].

    PubMed

    Krüger, R; Meißner, W; Zimmer, A

    2014-10-01

    Apart from the prescribed administration and indications for pain relief, opioids are also used for unintended purposes. Information for misuse is circulated on the internet. In order to analyze the abuse of opioids and opiates,which are only available by prescription, defined search keywords were entered into the search engine of a German language internet forum on drugs in 2010 and 2013 and the results were evaluated. Items to be assessed and analyzed were the frequency of naming various substances and (in the first analysis only) aspects of their incorporation as well as user reports on various aspects of use (e.g. drug procurement, administration, effects and side effects). Tramadol was the most frequently quoted opioid followed by codeine, tilidine, morphine and oxycodone. Other opioids were named in only 10 % of the entries. Oral intake was the most frequently mentioned mode of administration followed by parenteral and nasal routes. These findings can support caregivers to identify unintended use of opioids and to increase awareness of the most frequently used opioids and modes of administration.

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

    PubMed

    2016-05-01

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

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

    PubMed Central

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

    2016-01-01

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

  19. Exposure to prescription opioid analgesics in utero and risk of neonatal abstinence syndrome: population based cohort study

    PubMed Central

    Huybrechts, Krista F; Hernandez-Diaz, Sonia; Mogun, Helen; Patorno, Elisabetta; Kaltenbach, Karol; Kerzner, Leslie S; Bateman, Brian T

    2015-01-01

    Objective To provide absolute and relative risk estimates of neonatal abstinence syndrome (NAS) based on duration and timing of prescription opioid use during pregnancy in the presence or absence of additional NAS risk factors of history of opioid misuse or dependence, misuse of other substances, non-opioid psychotropic drug use, and smoking. Design Observational cohort study. Setting Medicaid data from 46 US states. Participants Pregnant women filling at least one prescription for an opioid analgesic at any time during pregnancy for whom opioid exposure characteristics including duration of therapy: short term (<30 days) or long term (≥30 days); timing of use: early use (only in the first two trimesters) or late use (extending into the third trimester); and cumulative dose (in morphine equivalent milligrams) were assessed. Main outcome measure Diagnosis of NAS in liveborn infants. Results 1705 cases of NAS were identified among 290 605 pregnant women filling opioid prescriptions, corresponding to an absolute risk of 5.9 per 1000 deliveries (95% confidence interval 5.6 to 6.2). Long term opioid use during pregnancy resulted in higher absolute risk of NAS per 1000 deliveries in the presence of additional risk factors of known opioid misuse (220.2 (200.8 to 241.0)), alcohol or other drug misuse (30.8 (26.1 to 36.0)), exposure to other psychotropic medications (13.1 (10.6 to 16.1)), and smoking (6.6 (4.3 to 9.6)) than in the absence of any of these risk factors (4.2 (3.3 to 5.4)). The corresponding risk estimates for short term use were 192.0 (175.8 to 209.3), 7.0 (6.0 to 8.2), 2.0 (1.5 to 2.6), 1.5 (1.0 to 2.0), and 0.7 (0.6 to 0.8) per 1000 deliveries, respectively. In propensity score matched analyses, long term prescription opioid use compared with short term use and late use compared with early use in pregnancy demonstrated greater risk of NAS (risk ratios 2.05 (95% confidence interval 1.81 to 2.33) and 1.24 (1.12 to 1.38), respectively). Conclusions Use of

  20. Opioids for chronic noncancer pain

    PubMed Central

    2015-01-01

    The recent American Academy of Neurology position paper by Franklin, “Opioids for chronic noncancer pain,” suggests that the benefits of opioid treatment are very likely to be substantially outweighed by the risks and recommends avoidance of doses above 80–120 mg/day morphine equivalent. However, close reading of the primary literature supports a different conclusion: opioids have been shown in randomized controlled trials (RCTs) to be highly effective in the treatment of chronic nonmalignant pain; long-term follow-up studies have shown that this effectiveness can be maintained; and effectiveness has been limited in many clinical trials by failure to take into account high variability in dose requirements, failure to adequately treat depression, and use of suboptimal outcome measures. Frequency of side effects in many RCTs has been inflated by overly rapid dose titration and failure to appreciate the high interindividual variability in side effect profiles. The recent marked increase in incidence of opioid overdose is of grave concern, but there is good reason to believe that it has been somewhat exaggerated. Potential causes of overdose include inadequately treated depression; inadequately treated pain, particularly when compounded by hopelessness; inadvertent overdose; concurrent use of alcohol; and insufficient practitioner expertise. Effective treatment of pain can enable large numbers of patients to lead productive lives and improve quality of life. Effective alleviation of suffering associated with pain falls squarely within the physician's professional obligation. Existing scientific studies provide the basis for many improvements in pain management that can increase effectiveness and reduce risk. Many potentially useful areas of further research can be identified. PMID:26138946

  1. Opioids induce while nicotine suppresses apoptosis in human lung cancer cells.

    PubMed

    Maneckjee, R; Minna, J D

    1994-10-01

    Previously, we have shown that opioids acting via specific receptors inhibit the growth of human lung cancer cells while nicotine, acting through nicotinic acetylcholine receptors, reverses this inhibition. Therefore, we studied the role of apoptosis in these processes. Treatment of human lung cancer cells with 0.1-1 microM morphine or methadone resulted in morphological changes and cleavage of DNA into nucleosome-sized fragments characteristic of apoptosis. Quantitation of DNA fragmentation showed that a dose-dependent increase occurred within 2 h of opioid treatment and was blocked by the antagonist naloxone. The apoptotic effect of opioids was suppressed by nicotine, while the nicotinic acetylcholine receptor antagonists, hexamethonium and decamethonium, reversed this suppression. In contrast, sphingosine, a protein kinase C inhibitor, caused significant DNA fragmentation which was not suppressed by nicotine. Unexpectedly, the combination of hexamethonium and opioids or hexamethonium and nicotine stimulated apoptosis. We found that nicotine, like phorbol 12-myristate 13-acetate, increased total protein kinase C (PKC) activity, while morphine and sphingosine decreased PKC activity, and nicotine reversed morphine inhibition of PKC activity. In contrast, methadone unexpectedly increased PKC activity. These results indicate that engagement of opioid receptors in human lung cancer cells induces apoptosis, while engagement of nicotine receptors suppresses apoptosis, which in some cases appear to be working through a PKC pathway. They also suggest complexities in the system where blockade of C6 or C10 nicotinic receptors can lead to facilitation of apoptosis. These findings suggest new strategies for treatment and prevention of cancer using opioids or nicotine receptors antagonists and are consistent with the idea that nicotine functions as a tumor promoter. PMID:7848904

  2. Opioids, Pain, the Brain, and Hyperkatifeia: A Framework for the Rational Use of Opioids for Pain

    PubMed Central

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

    2010-01-01

    Objective 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. Results 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). Conclusions 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. PMID:20545871

  3. Opioids and hypogonadism.

    PubMed

    2012-04-01

    Detailed reports of hypogonadotropic hypogonadism in patients receiving morphine analgesia were published in 2010. Symptoms included flushing and sweating, amenorrhoea, impotence and decreased libido. Epidemiological studies have examined a possible link between hypogonadism and opioid use, in both patients and drug addicts. Statistically significant decreases in plasma hormone concentrations were found, with lower testosterone and LH levels in men, and lower oestradiol, progesterone, LH and FSH levels in women. Animal studies have provided consistent results. It is suspected that opioids affect the hypothalamic-pituitary axis, inhibiting LH secretion. Patients should be warned of this risk. If signs of hypogonadism occur in a patient taking an opioid, the benefits and harms of treatment should be reassessed. If possible, the dose should be reduced or the opioid withdrawn.

  4. Clinical correlates of prescription opioid analgesic use in pregnancy.

    PubMed

    Smith, Megan V; Costello, Darce; Yonkers, Kimberly A

    2015-03-01

    A 2012 committee opinion from the American College of Obstetricians and Gynecologists highlights the considerable increase in opioid addiction in recent years, yet little is known about clinical correlates of prescribed opioids among pregnant women. This study examines clinical and demographic factors associated with the use of opioid analgesics in pregnancy. Data were derived from a prospective cohort study of pregnant women. Participants were administered the Composite International Diagnostic Interview to identify depressive and anxiety disorders and data on medication use were gathered at three assessment points and classified according to the Anatomical Therapeutic Chemical Code (ATC) classification system ATC group N02A. Participants included 2,748 English or Spanish speaking pregnant women. Six percent (n = 165) of women used opioid analgesics at any point in pregnancy. More pregnant women using opioids met diagnostic criteria for major depressive disorder (16 vs. 8 % for non users), generalized anxiety disorder (18 vs. 9 % for non users), post-traumatic stress disorder (11 vs. 4 % for non users) and panic disorder (6 vs. 4 % for non users). Women who reported opioid use were also significantly more likely than non users to report using illicit drugs and almost three times as likely to report smoking cigarettes in the second or third trimester of pregnancy (4 and 23 %, respectively) as compared to non-opioid users (0.5 and 8 %). The use of opioids in pregnancy was associated with higher levels of psychiatric comorbidity and use of other substances as compared to non-opioid users.

  5. Opioid ligands having delayed long-term antagonist activity: potential pharmacotherapies for opioid abuse.

    PubMed

    Husbands, Stephen M; Lewis, John W

    2003-03-01

    Buprenorphine is a partial agonist at the micro -opioid receptor with long duration of action and also exhibits delayed antagonist activity. Buprenorphine is finding increasing use as a treatment agent for opioid abuse, though its low efficacy is not well tolerated by all addicts. There is interest in developing a higher efficacy version of buprenorphine and in this mini-review some of the ligands recently discovered, that share with buprenorphine a profile of agonism followed by delayed antagonism, are discussed.

  6. Data on calcium increases depending on stretch in dystrophic cardiomyocytes.

    PubMed

    Aguettaz, E; Lopez, J J; Krzesiak, A; Constantin, B; Cognard, C; Sebille, S

    2016-09-01

    In this data article, intracellular Ca(2+) concentration ([Ca(2+)]i) was measured in isolated ventricular Wild Type (WT) and mdx cardiomyocytes in two different conditions: at rest and during the application of an axial stretch. Using a carbon microfibers technique, axial stretch was applied to mimic effects of physiological conditions of ventricular filling. A study of cation entry with the same experimental model and the manganese quenching method reported (i) a constitutive cation entry in mdx cardiomyocytes and (ii) the involvement of TRPV2 channels in axial-stretch dependant cation entry, "Axial stretch-dependent cation entry in dystrophic cardiomyopathy: involvement of several TRPs channels" (Aguettaz et al., 2016) [1]. Here, the Ca(2+) dye fluo-8 was used for [Ca(2+)]i measurement, in both resting and stretching conditions, using a perfusion protocol starting initially with a calcium free Tyrode solution followed by the perfusion of 1.8 mM Ca(2+) Tyrode solution. The variation of [Ca(2+)]i was found higher in mdx cardiomyocytes. PMID:27617280

  7. Chronic exposure to morphine decreases the expression of EAAT3 via opioid receptors in hippocampal neurons.

    PubMed

    Guo, Mingyan; Cao, Dexiong; Zhu, Siyu; Fu, Ganglan; Wu, Qiang; Liang, Jianjun; Cao, Minghui

    2015-12-01

    Alterations in glutamate transporter expression are closely related to opiate addition behavior, but the role of opioid receptors is unclear. In this study, we used primary cultures of hippocampal neurons from neonatal rats to study the effects of chronic exposure to morphine on excitatory amino acid transporter 3 (EAAT3) expression and the roles of µ opioid receptor (MOR), δ opioid receptor (DOR), and κ opioid receptor (KOR) in the morphine-dependent alterations in EAAT3 expression. The results showed that the EAAT3 protein and mRNA expression levels decreased significantly after chronic exposure to morphine (10μmol/L) for 48h, whereas the concentration of extracellular glutamate increased. In addition, we found that both the MOR inhibitor CTOP and the DOR inhibitor naltrindole could reverse the decreased expression of EAAT3 after exposure to morphine, whereas the MOR activator DAMGO and the DOR activator DPDPE significantly decreased EAAT3 expression. The KOR inhibitor had no effect on the expression of EAAT3, whereas its activator increased EAAT3 expression. These results suggest that the down-regulation of morphine-dependent EAAT3 expression in primary rat hippocampal cultures may be mediated by MOR and DOR and that KOR may not contribute significantly to this effect.

  8. Effect of opioid prescribing guidelines in primary care.

    PubMed

    Chen, Jonathan H; Hom, Jason; Richman, Ilana; Asch, Steven M; Podchiyska, Tanya; Johansen, Nawal Atwan

    2016-08-01

    Long-term opioid use for noncancer pain is increasingly prevalent yet controversial given the risks of addiction, diversion, and overdose. Prior literature has identified the problem and proposed management guidelines, but limited evidence exists on the actual effectiveness of implementing such guidelines in a primary care setting.A multidisciplinary working group of institutional experts assembled comprehensive guidelines for chronic opioid prescribing, including monitoring and referral recommendations. The guidelines were disseminated in September 2013 to our medical center's primary care clinics via in person and electronic education.We extracted electronic medical records for patients with noncancer pain receiving opioid prescriptions (Rxs) in seasonally matched preintervention (11/1/2012-6/1/2013) and postintervention (11/1/2013-6/1/2014) periods. For patients receiving chronic (3 or more) opioid Rxs, we assessed the rates of drug screening, specialty referrals, clinic visits, emergency room visits, and quantity of opioids prescribed.After disseminating guidelines, the percentage of noncancer clinic patients receiving any opioid Rxs dropped from 3.9% to 3.4% (P = 0.02). The percentage of noncancer patients receiving chronic opioid Rxs decreased from 2.0% to 1.6% (P = 0.03). The rate of urine drug screening increased from 9.2% to 17.3% (P = 0.005) amongst noncancer chronic opioid patients. No significant differences were detected for other metrics or demographics assessed.An educational intervention for primary care opioid prescribing is feasible and was temporally associated with a modest reduction in overall opioid Rx rates. Provider use of routine drug screening increased, but overall rates of screening and specialty referral remained low despite the intervention. Despite national pressures to introduce opioid prescribing guidelines for chronic pain, doing so alone does not necessarily yield substantial changes in clinical practice. PMID:27583928

  9. Effect of opioid prescribing guidelines in primary care.

    PubMed

    Chen, Jonathan H; Hom, Jason; Richman, Ilana; Asch, Steven M; Podchiyska, Tanya; Johansen, Nawal Atwan

    2016-08-01

    Long-term opioid use for noncancer pain is increasingly prevalent yet controversial given the risks of addiction, diversion, and overdose. Prior literature has identified the problem and proposed management guidelines, but limited evidence exists on the actual effectiveness of implementing such guidelines in a primary care setting.A multidisciplinary working group of institutional experts assembled comprehensive guidelines for chronic opioid prescribing, including monitoring and referral recommendations. The guidelines were disseminated in September 2013 to our medical center's primary care clinics via in person and electronic education.We extracted electronic medical records for patients with noncancer pain receiving opioid prescriptions (Rxs) in seasonally matched preintervention (11/1/2012-6/1/2013) and postintervention (11/1/2013-6/1/2014) periods. For patients receiving chronic (3 or more) opioid Rxs, we assessed the rates of drug screening, specialty referrals, clinic visits, emergency room visits, and quantity of opioids prescribed.After disseminating guidelines, the percentage of noncancer clinic patients receiving any opioid Rxs dropped from 3.9% to 3.4% (P = 0.02). The percentage of noncancer patients receiving chronic opioid Rxs decreased from 2.0% to 1.6% (P = 0.03). The rate of urine drug screening increased from 9.2% to 17.3% (P = 0.005) amongst noncancer chronic opioid patients. No significant differences were detected for other metrics or demographics assessed.An educational intervention for primary care opioid prescribing is feasible and was temporally associated with a modest reduction in overall opioid Rx rates. Provider use of routine drug screening increased, but overall rates of screening and specialty referral remained low despite the intervention. Despite national pressures to introduce opioid prescribing guidelines for chronic pain, doing so alone does not necessarily yield substantial changes in clinical practice.

  10. Effect of opioid prescribing guidelines in primary care

    PubMed Central

    Chen, Jonathan H.; Hom, Jason; Richman, Ilana; Asch, Steven M.; Podchiyska, Tanya; Johansen, Nawal Atwan

    2016-01-01

    Abstract Long-term opioid use for noncancer pain is increasingly prevalent yet controversial given the risks of addiction, diversion, and overdose. Prior literature has identified the problem and proposed management guidelines, but limited evidence exists on the actual effectiveness of implementing such guidelines in a primary care setting. A multidisciplinary working group of institutional experts assembled comprehensive guidelines for chronic opioid prescribing, including monitoring and referral recommendations. The guidelines were disseminated in September 2013 to our medical center's primary care clinics via in person and electronic education. We extracted electronic medical records for patients with noncancer pain receiving opioid prescriptions (Rxs) in seasonally matched preintervention (11/1/2012–6/1/2013) and postintervention (11/1/2013–6/1/2014) periods. For patients receiving chronic (3 or more) opioid Rxs, we assessed the rates of drug screening, specialty referrals, clinic visits, emergency room visits, and quantity of opioids prescribed. After disseminating guidelines, the percentage of noncancer clinic patients receiving any opioid Rxs dropped from 3.9% to 3.4% (P = 0.02). The percentage of noncancer patients receiving chronic opioid Rxs decreased from 2.0% to 1.6% (P = 0.03). The rate of urine drug screening increased from 9.2% to 17.3% (P = 0.005) amongst noncancer chronic opioid patients. No significant differences were detected for other metrics or demographics assessed. An educational intervention for primary care opioid prescribing is feasible and was temporally associated with a modest reduction in overall opioid Rx rates. Provider use of routine drug screening increased, but overall rates of screening and specialty referral remained low despite the intervention. Despite national pressures to introduce opioid prescribing guidelines for chronic pain, doing so alone does not necessarily yield substantial changes in clinical

  11. Opioids for cancer pain: the challenge of optimizing treatment.

    PubMed

    Plante, Gérard E; VanItallie, Theodore B

    2010-10-01

    During 2007, 11.7 million US men and women of all ages suffered from some form of invasive cancer. During their illness, at least 70% (8.2 million) will experience pain sufficiently severe to require chronic opioid treatment. Cancer-induced pain is usually described under 3 headings: acute pain, chronic pain, and breakthrough pain. Among patients with chronic, persistent cancer pain controlled by around-the-clock analgesics, there is a high prevalence of breakthrough pain-often precipitated by some form of physical activity. Breakthrough pain seems best treated by a powerful, fast-acting opioid such as intravenous morphine or transmucosal fentanyl. At present, opioids are virtually the only analgesics capable of controlling moderate and severe cancer pain. In recent years, a veritable arsenal of opioids with a wide range of pharmacologic properties has become available for use in different pain situations. The World Health Organization has developed a 3-step "analgesic ladder" to guide management of cancer pain, based on the pain's severity, estimated by means of a 1 to 10 numeric rating scale. As the severity of the pain escalates, more potent (World Health Organization Step III) opioids are used. When faced with a difficult case of cancer pain, the physician must choose-from an array of options-the safest and most effective opioid analgesic and the most appropriate delivery system. Such decisions require an adequate understanding of the available opioids and experience with their use. The pharmacodynamic response to a given opioid depends on the nature of the receptor to which the opioid binds and its affinity for the receptor. Morphine activates the μ-opioid receptors, resulting in not only analgesia and sedation, but also euphoria, respiratory depression, constipation, and pruritus. The existence of a number of opioid receptor subtypes, each with its own repertoire of responses, has given rise to the hope (as yet unrealized) that an opioid can be found (or

  12. Opioid analgesics: does potency matter?

    PubMed

    Passik, Steven D; Webster, Lynn

    2014-01-01

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

  13. Exposure to morphine-associated cues increases mu opioid receptor mRNA expression in the nucleus accumbens of Wistar Kyoto rats.

    PubMed

    Dennis, Torry S; Beck, Kevin D; Cominski, Tara P; Bobzean, Samara A M; Kuzhikandathil, Eldo V; Servatius, Richard J; Perrotti, Linda I

    2016-10-15

    The Wistar-Kyoto (WKY) rat has been proposed as a model of anxiety vulnerability as it exhibits pronounced behavioral inhibition, passive avoidance, exaggerated startle response, enhanced HPA-axis activation, and active avoidance that is resistant to extinction. Accumulating evidence suggests that WKY rats respond differently to rewarding stimuli when compared to outbred strains of rat. Conditioned responding to drug-associated cues is linked with alterations in the activation of mu opioid receptors (MOR) and kappa opioid receptors (KOR) in the nucleus accumbens (NAc). Furthermore, alterations in KOR expression/activation in the NAc of WKY rats are implicated in the regulation of some of the components that make up the unique behavioral phenotype of this strain. The purpose of this study was to extend upon previous work from our laboratory by investigating conditioned morphine reward in adult male WKY and SD rats, and to examine levels of KOR mRNA and MOR mRNA in the NAc at baseline and after acquisition of morphine CPP. Our results demonstrate that SD rats displayed morphine-induced CPP to each of the six doses of morphine tested (0.5, 1.25, 2.5, 5, 7.5, or 10mg/kg). Interestingly, WKY rats demonstrated CPP for only the 1.25, 2.5, and 5mg/kg doses, yet no preference at the lowest (0.5mg/kg) or highest (7.5 and 10mg/kg) doses. qPCR analysis of MOR and KOR in the NAc revealed no strain differences in basal levels of MOR, but higher levels of KOR in WKY rats compared to those of SD rats. Interestingly, after completion of the CPP task, WKY rats had overall higher levels of NAc MOR mRNA compared to SD rats; the initial basal differences in NAc KOR levels persisted without change due to CPP in either strain. These results demonstrate that the WKY rat exhibits a unique pattern of behavioral responding to morphine and implicates differences in NAc KOR signaling as a potential source of aversion to higher doses of morphine. Additionally, the CPP-induced upregulation of

  14. Exposure to morphine-associated cues increases mu opioid receptor mRNA expression in the nucleus accumbens of Wistar Kyoto rats.

    PubMed

    Dennis, Torry S; Beck, Kevin D; Cominski, Tara P; Bobzean, Samara A M; Kuzhikandathil, Eldo V; Servatius, Richard J; Perrotti, Linda I

    2016-10-15

    The Wistar-Kyoto (WKY) rat has been proposed as a model of anxiety vulnerability as it exhibits pronounced behavioral inhibition, passive avoidance, exaggerated startle response, enhanced HPA-axis activation, and active avoidance that is resistant to extinction. Accumulating evidence suggests that WKY rats respond differently to rewarding stimuli when compared to outbred strains of rat. Conditioned responding to drug-associated cues is linked with alterations in the activation of mu opioid receptors (MOR) and kappa opioid receptors (KOR) in the nucleus accumbens (NAc). Furthermore, alterations in KOR expression/activation in the NAc of WKY rats are implicated in the regulation of some of the components that make up the unique behavioral phenotype of this strain. The purpose of this study was to extend upon previous work from our laboratory by investigating conditioned morphine reward in adult male WKY and SD rats, and to examine levels of KOR mRNA and MOR mRNA in the NAc at baseline and after acquisition of morphine CPP. Our results demonstrate that SD rats displayed morphine-induced CPP to each of the six doses of morphine tested (0.5, 1.25, 2.5, 5, 7.5, or 10mg/kg). Interestingly, WKY rats demonstrated CPP for only the 1.25, 2.5, and 5mg/kg doses, yet no preference at the lowest (0.5mg/kg) or highest (7.5 and 10mg/kg) doses. qPCR analysis of MOR and KOR in the NAc revealed no strain differences in basal levels of MOR, but higher levels of KOR in WKY rats compared to those of SD rats. Interestingly, after completion of the CPP task, WKY rats had overall higher levels of NAc MOR mRNA compared to SD rats; the initial basal differences in NAc KOR levels persisted without change due to CPP in either strain. These results demonstrate that the WKY rat exhibits a unique pattern of behavioral responding to morphine and implicates differences in NAc KOR signaling as a potential source of aversion to higher doses of morphine. Additionally, the CPP-induced upregulation of

  15. The impact of opioid-induced hyperalgesia for postoperative pain.

    PubMed

    Koppert, Wolfgang; Schmelz, Martin

    2007-03-01

    Clinical evidence suggests that--besides their well known analgesic activity - opioids can increase rather than decrease sensitivity to noxious stimuli. Based on the observation that opioids can activate pain inhibitory and pain facilitatory systems, this pain hypersensitivity has been attributed to a relative predominance of pronociceptive mechanisms. Acute receptor desensitization via uncoupling of the receptor from G-proteins, upregulation of the cAMP pathway, activation of the N-methyl-D-aspartate (NMDA)-receptor system, as well as descending facilitation, have been proposed as potential mechanisms underlying opioid-induced hyperalgesia. Numerous reports exist demonstrating that opioid-induced hyperalgesia is observed both in animal and human experimental models. Brief exposures to micro-receptor agonists induce long-lasting hyperalgesic effects for days in rodents, and also in humans large-doses of intraoperative micro-receptor agonists were found to increase postoperative pain and morphine consumption. Furthermore, the prolonged use of opioids in patients is often associated with a requirement for increasing doses and the development of abnormal pain. Successful strategies that may decrease or prevent opioid-induced hyperalgesia include the concomitant administration of drugs like NMDA-antagonists, alpha2-agonists, or non-steroidal anti-inflammatory drugs (NSAIDs), opioid rotation or combinations of opioids with different receptor/selectivity.

  16. Effects of opioid peptides on thermoregulation

    SciTech Connect

    Clark, W.G.

    1981-11-01

    In a given species, injected opioid peptides usually cause changes in temperature similar to those caused by nonpeptide opioids. The main effect in those species most studied, the cat, rat, and mouse, is an increase in the level about which body temperature is regulated; there is a coordinated change in the activity of thermoregulatory effectors such that hyperthermia is produced in both hot and cold environments. Larger doses may depress thermoregulation, thereby causing body temperature to decrease in the cold. Elicitation of different patterns of response over a range of environmental temperatures and studies with naloxone and naltrexone indicate that stimulation of a number of different receptors by both peptide and nonpeptide opioids can evoke thermoregulatory responses. ..beta..-Endorphin is readily antagonized by naloxone whereas methionine-enkephalin can act on naloxone-insensitive receptors. Moreover, synthetic peptide analogs do not necessarily evoke the same response as does the related endogenous peptide. The lack of effect of naloxone on body temperature of subjects housed at usual laboratory temperature or on pyrogen-induced increases in body temperature indicates that an action of endogenous peptides on naloxone-sensitive receptors plays little, if any, role in normal thermoregulation or in fever. However, there is some evidence that such an action may be involved in responses to restraint or ambient temperature-induced stress. Further evaluation of possible physiological roles of endogenous opioid peptides will be facilitated when specific antagonists at other types of opioid receptors become available.

  17. Blunted Endogenous Opioid Release Following an Oral Amphetamine Challenge in Pathological Gamblers.

    PubMed

    Mick, Inge; Myers, Jim; Ramos, Anna C; Stokes, Paul R A; Erritzoe, David; Colasanti, Alessandro; Gunn, Roger N; Rabiner, Eugenii A; Searle, Graham E; Waldman, Adam D; Parkin, Mark C; Brailsford, Alan D; Galduróz, José C F; Bowden-Jones, Henrietta; Clark, Luke; Nutt, David J; Lingford-Hughes, Anne R

    2016-06-01

    Pathological gambling is a psychiatric disorder and the first recognized behavioral addiction, with similarities to substance use disorders but without the confounding effects of drug-related brain changes. Pathophysiology within the opioid receptor system is increasingly recognized in substance dependence, with higher mu-opioid receptor (MOR) availability reported in alcohol, cocaine and opiate addiction. Impulsivity, a risk factor across the addictions, has also been found to be associated with higher MOR availability. The aim of this study was to characterize baseline MOR availability and endogenous opioid release in pathological gamblers (PG) using [(11)C]carfentanil PET with an oral amphetamine challenge. Fourteen PG and 15 healthy volunteers (HV) underwent two [(11)C]carfentanil PET scans, before and after an oral administration of 0.5 mg/kg of d-amphetamine. The change in [(11)C]carfentanil binding between baseline and post-amphetamine scans (ΔBPND) was assessed in 10 regions of interest (ROI). MOR availability did not differ between PG and HV groups. As seen previously, oral amphetamine challenge led to significant reductions in [(11)C]carfentanil BPND in 8/10 ROI in HV. PG demonstrated significant blunting of opioid release compared with HV. PG also showed blunted amphetamine-induced euphoria and alertness compared with HV. Exploratory analysis revealed that impulsivity positively correlated with caudate baseline BPND in PG only. This study provides the first evidence of blunted endogenous opioid release in PG. Our findings are consistent with growing evidence that dysregulation of endogenous opioids may have an important role in the pathophysiology of addictions. PMID:26552847

  18. Blunted Endogenous Opioid Release Following an Oral Amphetamine Challenge in Pathological Gamblers

    PubMed Central

    Mick, Inge; Myers, Jim; Ramos, Anna C; Stokes, Paul R A; Erritzoe, David; Colasanti, Alessandro; Gunn, Roger N; Rabiner, Eugenii A; Searle, Graham E; Waldman, Adam D; Parkin, Mark C; Brailsford, Alan D; Galduróz, José C F; Bowden-Jones, Henrietta; Clark, Luke; Nutt, David J; Lingford-Hughes, Anne R

    2016-01-01

    Pathological gambling is a psychiatric disorder and the first recognized behavioral addiction, with similarities to substance use disorders but without the confounding effects of drug-related brain changes. Pathophysiology within the opioid receptor system is increasingly recognized in substance dependence, with higher mu-opioid receptor (MOR) availability reported in alcohol, cocaine and opiate addiction. Impulsivity, a risk factor across the addictions, has also been found to be associated with higher MOR availability. The aim of this study was to characterize baseline MOR availability and endogenous opioid release in pathological gamblers (PG) using [11C]carfentanil PET with an oral amphetamine challenge. Fourteen PG and 15 healthy volunteers (HV) underwent two [11C]carfentanil PET scans, before and after an oral administration of 0.5 mg/kg of d-amphetamine. The change in [11C]carfentanil binding between baseline and post-amphetamine scans (ΔBPND) was assessed in 10 regions of interest (ROI). MOR availability did not differ between PG and HV groups. As seen previously, oral amphetamine challenge led to significant reductions in [11C]carfentanil BPND in 8/10 ROI in HV. PG demonstrated significant blunting of opioid release compared with HV. PG also showed blunted amphetamine-induced euphoria and alertness compared with HV. Exploratory analysis revealed that impulsivity positively correlated with caudate baseline BPND in PG only. This study provides the first evidence of blunted endogenous opioid release in PG. Our findings are consistent with growing evidence that dysregulation of endogenous opioids may have an important role in the pathophysiology of addictions. PMID:26552847

  19. Opioid-mediated regulation of A11 diencephalospinal dopamine neurons: pharmacological evidence of activation by morphine

    PubMed Central

    Pappas, Samuel S.; Kennedy, Tom; Goudreau, John L.; Lookingland, Keith J.

    2011-01-01

    Dopamine (DA) neurons of the A11 diencephalospinal system represent the sole source of DA innervation to the spinal cord in mice, serving neuromodulatory roles in the processing of nociceptive input and movement. These neurons originate in the dorsocaudal diencephalon and project axons unilaterally throughout the rostrocaudal extent of the spinal cord, terminating predominantly in the dorsal horn. The density of A11 DA axon terminals in the lumbar region is greater in males compared to females, while in both sexes the activity of neurons terminating in the thoracic spinal cord is greater than those terminating in the lumbar region. The present study was designed to test the hypothesis that A11 DA neurons are activated by opioids. To test this hypothesis, male and female mice were systemically treated with agonists or antagonists acting at the μ-opioid receptor, and spinal cord concentrations of DA and its metabolite DOPAC were determined in the thoracic and lumbar spinal cord using high performance liquid chromatography coupled with electrochemical detection. Systemic administration of the μ-opioid agonist morphine led to a dose- and time-dependent increase in spinal cord DOPAC/DA ratio (an estimate of DA neuronal activity) in both male and female mice, with greater changes occurring in the lumbar segment. Blockade of opioid receptors with the opioid antagonist naloxone reversed the stimulatory effects of morphine on A11 DA neurons in both male and female mice, but had little to no effect on the activity of these neurons when administered alone. Present findings are consistent with the conclusion that spinal cord- projecting axon terminals of A11 DA neurons are activated by opioids in both male and female mice, most likely through a disinhibitory mechanism. PMID:21605572

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

    PubMed

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

    2014-09-01

    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'.

  1. The epidemic of prescription opioid abuse, the subsequent rising prevalence of heroin use, and the federal response.

    PubMed

    Kanouse, Andrew B; Compton, Peggy

    2015-06-01

    Opioids are a mainstay in the treatment of pain both chronically and acutely. In the past 20 years, the prescribing of opioids has increased exponentially. As the population for whom opioids are indicated has grown, with the number of opioid prescriptions written increased, so have indicators of opioid misuse, abuse, morbidity, and mortality. The purpose of this article is to review and explore the combination of factors of events that led to the current "epidemic" of prescription opioid abuse and overdose deaths, as well as the subsequent resurgence of heroin use among opioid addicts. Federal initiatives to mount war on prescription opioid abuse are reviewed, including responses from the White House, Drug Enforcement Agency (DEA), Food and Drug Administration (FDA), and interagency initiatives. Many initiatives are currently in place to combat the rising rates of morbidity and mortality associated with opioids, and those involved are hopeful in their efforts to curb the epidemic of this deadly phenomenon.

  2. Effects of Competing Narratives on Public Perceptions of Opioid Pain Reliever Addiction during Pregnancy.

    PubMed

    Kennedy-Hendricks, Alene; McGinty, Emma E; Barry, Colleen L

    2016-10-01

    Opioid pain reliever addiction has increased among women of reproductive age over the last fifteen years. News media and public attention have focused on the implications of this trend for infants exposed to opioids prenatally, with state policy responses varying in the extent to which they are punitive or public health oriented. We fielded a six-group randomized experiment among a nationally representative sample of US adults to test the effects of narratives portraying a woman with opioid pain reliever addiction during pregnancy on beliefs about people addicted to opioid pain relievers, perceptions of treatment effectiveness, policy attitudes, and emotional responses. Portraying a high socioeconomic status (SES) woman in the narrative lowered perceptions of individual blame for addiction and reduced public support for punitive policies. Depicting the barriers to treatment faced by a low SES woman lowered support for punitive policies and increased support for expanded insurance coverage for treatment. The extent to which narratives portraying successfully treated addiction affected public attitudes depended on the SES of the woman portrayed. These findings can inform the development of communication strategies to reduce stigma toward this population, reduce support for punitive policies, and increase support for more public health-oriented approaches to addressing this problem. PMID:27256811

  3. Endogenous opioid-dopamine neurotransmission underlie negative CBV fMRI signals.

    PubMed

    Shih, Yen-Yu I; Chiang, Yun-Chen; Shyu, Bai-Chuang; Jaw, Fu-Shan; Duong, Timothy Q; Chang, Chen

    2012-04-01

    Previous studies showed noxious unilateral forepaw electrical stimulation surprisingly evoked negative blood-oxygenation-level-dependent (BOLD), cerebral blood flow (CBF), and cerebral blood volume (CBV) fMRI responses in the bilateral striatum whereas the local neuronal spike and c-Fos activities increased. These negative responses are associated with vasoconstriction and appeared to override the increased hemodynamic responses that typically accompanied with increased neural activity. The current study aimed to investigate the role of μ-opioid system in modulating vasoconstriction in the striatum associated with noxious stimulation on a 4.7-Tesla MRI scanner. Specifically, we investigated: i) how morphine (a μ-opioid receptor agonist) affects the vasoconstriction in the bilateral striatum associated with noxious electrical forepaw stimulation in rats, and ii) how naloxone (an opioid receptor antagonist) and eticlopride (a dopamine D(2)/D(3) receptor antagonist) modulates the morphine effects onwards. Injection of morphine enhanced the negative striatal CBV responses to noxious stimulation. Sequential injection of naloxone in the same animals abolished the stimulus-evoked vasoconstriction. In a separate group of animals, injection of eticlopride following morphine also reduced the vasoconstriction. Our findings suggested that noxious stimulation endogenously activated opioid and dopamine receptors in the striatum and thus leading to vasoconstriction.

  4. Effects of Competing Narratives on Public Perceptions of Opioid Pain Reliever Addiction during Pregnancy.

    PubMed

    Kennedy-Hendricks, Alene; McGinty, Emma E; Barry, Colleen L

    2016-10-01

    Opioid pain reliever addiction has increased among women of reproductive age over the last fifteen years. News media and public attention have focused on the implications of this trend for infants exposed to opioids prenatally, with state policy responses varying in the extent to which they are punitive or public health oriented. We fielded a six-group randomized experiment among a nationally representative sample of US adults to test the effects of narratives portraying a woman with opioid pain reliever addiction during pregnancy on beliefs about people addicted to opioid pain relievers, perceptions of treatment effectiveness, policy attitudes, and emotional responses. Portraying a high socioeconomic status (SES) woman in the narrative lowered perceptions of individual blame for addiction and reduced public support for punitive policies. Depicting the barriers to treatment faced by a low SES woman lowered support for punitive policies and increased support for expanded insurance coverage for treatment. The extent to which narratives portraying successfully treated addiction affected public attitudes depended on the SES of the woman portrayed. These findings can inform the development of communication strategies to reduce stigma toward this population, reduce support for punitive policies, and increase support for more public health-oriented approaches to addressing this problem.

  5. Agonist treatment in opioid use: advances and controversy.

    PubMed

    Viswanath, Biju; Chand, Prabhat; Benegal, Vivek; Murthy, Pratima

    2012-06-01

    Opioid dependence is a chronic relapsing condition which requires comprehensive care; pharmacological agents form the mainstay of its long term treatment. The two most popular approaches are the harm reduction method using agonists and the complete abstinence method using antagonists. Currently, particularly from the harm minimization perspective and the low feasibility of an abstinence based approach, there is an increasing trend toward agonist treatment. The use of buprenorphine has gained popularity in view of its safety profile and the availability of the buprenorphine-naloxone combination has made it popular as a take-home treatment. This review outlines the pharmacological advances and controversies in this area. PMID:22813654

  6. Opioid epidemic in the United States.

    PubMed

    Manchikanti, Laxmaiah; Helm, Standiford; Fellows, Bert; Janata, Jeffrey W; Pampati, Vidyasagar; Grider, Jay S; Boswell, Mark V

    2012-07-01

    Over the past two decades, as the prevalence of chronic pain and health care costs have exploded, an opioid epidemic with adverse consequences has escalated. Efforts to increase opioid use and a campaign touting the alleged undertreatment of pain continue to be significant factors in the escalation. Many arguments in favor of opioids are based solely on traditions, expert opinion, practical experience and uncontrolled anecdotal observations. Over the past 20 years, the liberalization of laws governing the prescribing of opioids for the treatment of chronic non-cancer pain by the state medical boards has led to dramatic increases in opioid use. This has evolved into the present stage, with the introduction of new pain management standards by the Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) in 2000, an increased awareness of the right to pain relief, the support of various organizations supporting the use of opioids in large doses, and finally, aggressive marketing by the pharmaceutical industry. These positions are based on unsound science and blatant misinformation, and accompanied by the dangerous assumptions that opioids are highly effective and safe, and devoid of adverse events when prescribed by physicians. Results of the 2010 National Survey on Drug Use and Health (NSDUH) showed that an estimated 22.6 million, or 8.9% of Americans, aged 12 or older, were current or past month illicit drug users, The survey showed that just behind the 7 million people who had used marijuana, 5.1 million had used pain relievers. It has also been shown that only one in 6 or 17.3% of users of non-therapeutic opioids indicated that they received the drugs through a prescription from one doctor. The escalating use of therapeutic opioids shows hydrocodone topping all prescriptions with 136.7 million prescriptions in 2011, with all narcotic analgesics exceeding 238 million prescriptions. It has also been illustrated that opioid analgesics are now

  7. Opioid-induced hyperalgesia: clinically relevant or extraneous research phenomenon?

    PubMed

    Tompkins, D Andrew; Campbell, Claudia M

    2011-04-01

    Opioids have become the unequivocal therapy of choice in treating many varieties of chronic pain. With the increased prescription of opioids, some unintended consequences have occurred. After prolonged opioid exposure, opioid-induced hyperalgesia (OIH), the paradoxical effect that opioid therapy may in fact enhance or aggravate preexisting pain, may occur. Over the past several decades, an increasing number of laboratory and clinical reports have suggested lowered pain thresholds and heightened atypical pain unrelated to the original perceived pain sensations as hallmarks of OIH. However, not all evidence supports the clinical importance of OIH, and some question whether the phenomenon exists at all. Here, we present a nonexhaustive, brief review of the recent literature. OIH will be reviewed in terms of preclinical and clinical evidence for and against its existence; recommendations for clinical evaluation and intervention also will be discussed.

  8. 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

  9. The “Toll” of Opioid-Induced Glial Activation: Improving the Clinical Efficacy of Opioids by Targeting Glia

    PubMed Central

    Watkins, Linda R.; Hutchinson, Mark R.; Rice, Kenner C.; Maier, Steven F.

    2009-01-01

    Glial activation participates in the mediation of pain including neuropathic pain, due to release of neuroexcitatory, proinflammatory products. Glial activation is now known to occur in response to opioids as well. Opioid-induced glial activation opposes opioid analgesia and enhances opioid tolerance, dependence, reward and respiratory depression. Such effects can occur, not via classical opioid receptors, but rather via non-stereoselective activation of toll-like receptor 4 (TLR4), a recently recognized key glial receptor participating in neuropathic pain as well. This discovery identifies a means for separating the beneficial actions of opioids (opioid receptor mediated) from the unwanted side-effects (TLR4/glial mediated) by pharmacologically targeting TLR4. Such a drug should be a stand-alone therapeutic for treating neuropathic pain as well. Excitingly, with newly-established clinical trials of two glial modulators for treating neuropathic pain and improving the utility of opioids, translation from rats-to-humans now begins with the promise of improved clinical pain control. PMID:19762094

  10. Opioid Pharmacotherapy for Chronic Noncancer Pain: The American Experience

    PubMed Central

    2013-01-01

    Chronic noncancer pain is a significant and growing public health challenge in the United States. Lacking effective alternative interventions for effective chronic noncancer pain management, many physicians have turned to opioid pharmacotherapy. Increased opioid prescribing brings not only gains in therapeutic benefit but also a higher incidence of adverse drug events including increased medication misuse and opioid related mortality. Currently the United States must confront the dual problems of widespread undertreated chronic noncancer pain and a prescription opioid abuse crisis. Withholding pain relieving drugs from patients in need is unjustifiable, yet drug diversion, abuse and adverse drug events have become major social as well as medical problems. At the heart of this crisis is the lack of definitive evidence about the risk to benefit ratio of opioid pharmacotherapy for chronic noncancer pain both on an individual case and on a population basis. This article describes the extent and severity of the American chronic noncancer pain problem and the history of opioid pharmacotherapy for chronic noncancer pain in the United States. It then discusses the concept of evidence based practice and reviews current evidence supporting opioid pharmacotherapy for chronic noncancer pain as well as adverse drug events related to opioid pharmacotherapy including misuse and abuse. Finally, it considers the conflict of providing pain relief versus protecting society and reviews steps that governmental agencies, industry and others are taking to contain and ultimately resolve the problems of excessive prescribing and conflicting priorities. PMID:23342201

  11. The pharmacological basis of opioids.

    PubMed

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

    2015-01-01

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

  12. The prevalence of problem opioid use in patients receiving chronic opioid therapy: computer-assisted review of electronic health record clinical notes.

    PubMed

    Palmer, Roy E; Carrell, David S; Cronkite, David; Saunders, Kathleen; Gross, David E; Masters, Elizabeth; Donevan, Sean; Hylan, Timothy R; Von Kroff, Michael

    2015-07-01

    To estimate the prevalence of problem opioid use, we used natural language processing (NLP) techniques to identify clinical notes containing text indicating problem opioid use from over 8 million electronic health records (EHRs) of 22,142 adult patients receiving chronic opioid therapy (COT) within Group Health clinics from 2006 to 2012. Computer-assisted manual review of NLP-identified clinical notes was then used to identify patients with problem opioid use (overuse, misuse, or abuse) according to the study criteria. These methods identified 9.4% of patients receiving COT as having problem opioid use documented during the study period. An additional 4.1% of COT patients had an International Classification of Disease, version 9 (ICD-9) diagnosis without NLP-identified problem opioid use. Agreement between the NLP methods and ICD-9 coding was moderate (kappa = 0.61). Over one-third of the NLP-positive patients did not have an ICD-9 diagnostic code for opioid abuse or dependence. We used structured EHR data to identify 14 risk indicators for problem opioid use. Forty-seven percent of the COT patients had 3 or more risk indicators. The prevalence of problem opioid use was 9.6% among patients with 3 to 4 risk indicators, 26.6% among those with 5 to 6 risk indicators, and 55.04% among those with 7 or more risk indicators. Higher rates of problem opioid use were observed among young COT patients, patients who sustained opioid use for more than 4 quarters, and patients who received higher opioid doses. Methods used in this study provide a promising approach to efficiently identify clinically recognized problem opioid use documented in EHRs of large patient populations. Computer-assisted manual review of EHR clinical notes found a rate of problem opioid use of 9.4% among 22,142 COT patients over 7 years.

  13. Touch Perception Altered by Chronic Pain and by Opioid Blockade.

    PubMed

    Case, Laura K; Čeko, Marta; Gracely, John L; Richards, Emily A; Olausson, Håkan; Bushnell, M Catherine

    2016-01-01

    Touch plays a significant role in human social behavior and social communication, and its rewarding nature has been suggested to involve opioids. Opioid blockade in monkeys leads to increased solicitation and receipt of grooming, suggesting heightened enjoyment of touch. We sought to study the role of endogenous opioids in perception of affective touch in healthy adults and in patients with fibromyalgia, a chronic pain condition shown to involve reduced opioid receptor availability. The pleasantness of touch has been linked to the activation of C-tactile fibers, which respond maximally to slow gentle touch and correlate with ratings of pleasantness. We administered naloxone to patients and healthy controls to directly observe the consequences of µ-opioid blockade on the perceived pleasantness and intensity of touch. We found that at baseline chronic pain patients showed a blunted distinction between slow and fast brushing for both intensity and pleasantness, suggesting reduced C-tactile touch processing. In addition, we found a differential effect of opioid blockade on touch perception in healthy subjects and pain patients. In healthy individuals, opioid blockade showed a trend toward increased ratings of touch pleasantness, while in chronic pain patients it significantly decreased ratings of touch intensity. Further, in healthy individuals, naloxone-induced increase in touch pleasantness was associated with naloxone-induced decreased preference for slow touch, suggesting a possible effect of opioid levels on processing of C-tactile fiber input. These findings suggest a role for endogenous opioids in touch processing, and provide further evidence for altered opioid functioning in chronic pain patients. PMID:27022625

  14. Post-Craniotomy Pain Management: Beyond Opioids.

    PubMed

    Dunn, Lauren K; Naik, Bhiken I; Nemergut, Edward C; Durieux, Marcel E

    2016-10-01

    Craniotomy pain may be severe and is often undertreated. Pain management following craniotomy is a balancing act of achieving adequate analgesia but avoiding sedation, respiratory depression, hypercapnia, nausea and vomiting, and hypertension. Opioids are a first-line analgesic therapy; however, concern that opioid-related adverse effects (sedation, respiratory depression) may interfere with neurologic assessment and increase intracranial pressure has limited use of these drugs for intracranial surgery. Non-opioid analgesics avoid these effects and may be useful as part of a multimodal regimen for post-craniotomy pain. Regional scalp blocks, paracetamol, and non-steroidal anti-inflammatory drugs are beneficial in the early post-operative period. Recent studies suggest a role for novel analgesics: dexmedetomidine, gabapentinoids, and ketamine, though additional studies are necessary. PMID:27604271

  15. Opioid receptors and legal highs: Salvia divinorum and Kratom.

    PubMed

    Babu, Kavita M; McCurdy, Christopher R; Boyer, Edward W

    2008-02-01

    Salvia divinorum and Mitragyna speciosa ("Kratom"), two unscheduled dietary supplements whose active agents are opioid receptor agonists, have discrete psychoactive effects that have contributed to their increasing popularity. Salvia divinorum contains the highly selective kappa- opioid receptor agonist salvinorin A; this compound produces visual hallucinations and synesthesia. Mitragynine, the major alkaloid identified from Kratom, has been reported as a partial opioid agonist producing similar effects to morphine. An interesting minor alkaloid of Kratom, 7-hydroxymitragynine, has been reported to be more potent than morphine. Both Kratom alkaloids are reported to activate supraspinal mu- and delta- opioid receptors, explaining their use by chronic narcotics users to ameliorate opioid withdrawal symptoms. Despite their widespread Internet availability, use of Salvia divinorum and Kratom represents an emerging trend that escapes traditional methods of toxicologic monitoring. The purpose of this article is to familiarize toxicologists and poison control specialists with these emerging psychoactive dietary supplements. PMID:18259963

  16. Opioid Use Disorders.

    PubMed

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

    2016-07-01

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

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

    PubMed

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

    2010-01-01

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

  18. Opioids inhibit visceral afferent activation of catecholamine neurons in the solitary tract nucleus

    PubMed Central

    Cui, Ran Ji; Roberts, Brandon L.; Zhao, Huan; Andresen, Michael C.; Appleyard, Suzanne M.

    2014-01-01

    Brainstem A2/C2 catecholamine (CA) neurons within the solitary tract nucleus (NTS) influence many homeostatic functions, including food intake, stress, respiratory and cardiovascular reflexes. They also play a role in both opioid reward and withdrawal. Injections of opioids into the NTS modulate many autonomic functions influenced by catecholamine neurons including food intake and cardiac function. We recently showed that NTS-CA neurons are directly activated by incoming visceral afferent inputs. Here we determined whether opioid agonists modulate afferent activation of NTS-CA neurons using transgenic mice with EGFP expressed under the control of the tyrosine hydroxylase promoter (TH-EGFP) to identify catecholamine neurons. The opioid agonist Met-enkephalin (Met-Enk) significantly attenuated solitary tract evoked EPSCs (ST-EPSCs) in NTS TH-EGFP neurons by 80%, an effect reversed by wash or the mu opioid receptor specific antagonist, CTOP. Met-Enk had a significantly greater effect to inhibit afferent inputs onto TH-EGFP positive neurons than EGFP negative neurons, which were only inhibited by 50%. The mu agonist, DAMGO, also inhibited the ST-EPSC in TH-EGFP neurons in a dose-dependent manner. In contrast, neither the delta agonist DPDPE, nor the kappa agonist, U69,593, consistently inhibited the ST-EPSC amplitude. Met-Enk and DAMGO increased the paired pulse ratio, decreased the frequency, but not amplitude, of mini-EPSCs and had no effect on holding current, input resistance or current-voltage relationships in TH-EGFP neurons, suggesting a presynaptic mechanism of action on afferent terminals. Met-Enk significantly reduced both the basal firing rate of NTS TH-EGFP neurons and the ability of afferent stimulation to evoke an action potential. These results suggest that opioids inhibit NTS-CA neurons by reducing an excitatory afferent drive onto these neurons through presynaptic inhibition of glutamate release and elucidate one potential mechanism by which opioids

  19. The effect of various morphine weaning regimens on the sequelae of opioid tolerance involving physical dependency, anxiety and hippocampus cell neurodegeneration in rats.

    PubMed

    Motaghinejad, Majid; Karimian, Seyed Morteza; Motaghinejad, Ozra; Shabab, Behnaz; Asadighaleni, Majid; Fatima, Sulail

    2015-06-01

    Chronic consumption of morphine induces physical dependency, anxiety, and neurodegeneration. In this study, morphine on its own has been used for the management of morphine-induced dependency, oxidative stress, and apoptosis. Forty-eight male rats were randomly divided into six groups. Rats in groups 1-5 were made morphine dependent by an increasing manner of morphine for 7 days (15-45 mg/kg). For the next 14 days, morphine was administered using the following regimen: (i) once daily 45 mg/kg (positive controls), (ii) the same dose at additional intervals (6 h longer than the previous intervals each time), (iii) 45 mg/kg of morphine at irregular intervals like of 12, 24, 36 h, (iv) decreasing dose once daily (every time 2.5 mg/kg less than the former dosage). Group 5 received 45 mg/kg of morphine and 10 mg/kg of SOD mimetic agent (M40401) injection per day. Group 6 (negative control) received saline solution only. On day 22, all animals received naloxone (3 mg/kg) and their Total Withdrawal Index (TWI) and blood cortisol levels were measured. After drug treatment, hippocampus cells were isolated, and oxidative, antioxidative, and apoptotic factors were evaluated. Various regimens of morphine reduced TWI, cortisol levels, Bax activity, caspase-3, caspase-9, TNF-α, and IL-1β and lipid peroxidation. In all treatment groups, GSH level, superoxide dismutase, glutathione peroxidase, and Bcl-2 activity were significantly increased. Furthermore, SOD mimetic agent c diminished morphine effect on SOD activity. Thus, varying the dosage regimen of morphine can reduce the severity of morphine-induced dependency and neurodegeneration.

  20. Impact of Medication-Assisted Treatment for Opioid Addiction on Medicaid Expenditures and Health Services Utilization Rates in Vermont.

    PubMed

    Mohlman, Mary Kate; Tanzman, Beth; Finison, Karl; Pinette, Melanie; Jones, Craig

    2016-08-01

    In the face of increasing rates of overdose deaths, escalating health care costs, and the tremendous social costs of opioid addiction, policy makers are asked to address the questions of whether and how to expand access to treatment services. In response to an upward trend in opioid abuse and adverse outcomes, Vermont is investing in statewide expansion of a medication-assisted therapy program delivered in a network of community practices and specialized treatment centers (Hub & Spoke Program). This study was conducted to test the rationale for these investments and to establish a pre-Hub & Spoke baseline for evaluating the additive impact of the program. Using a serial cross-sectional design from 2008 to 2013 to evaluate medical claims for Vermont Medicaid beneficiaries with opioid dependence or addiction (6158 in the intervention group, 2494 in the control group), this study assesses the treatment and medical service expenditures for those receiving medication-assisted treatment compared to those receiving substance abuse treatment without medication. Results suggest that medication-assisted therapy is associated with reduced general health care expenditures and utilization, such as inpatient hospital admissions and outpatient emergency department visits, for Medicaid beneficiaries with opioid addiction. For state Medicaid leaders facing similar decisions on approaches to opioid addiction, these results provide early support for expanding medication-assisted treatment services rather than relying only on psychosocial, abstinence, or detoxification interventions. PMID:27296656

  1. A first comparison between the consumption of and the need for opioid analgesics at country, regional, and global levels.

    PubMed

    Seya, Marie-Josephine; Gelders, Susanne F A M; Achara, Obianuju Uzoma; Milani, Barbara; Scholten, Willem Karel

    2011-01-01

    The objective of this study was to propose a rough but simple method for estimating the total population need for opioids for treating all various types of moderate and severe pain at the country, regional, and global levels. We determined per capita need of strong opioids for pain related to three important pain causes for 188 countries. These needs were extrapolated to the needs for all the various types of pain by using an adequacy level derived from the top 20 countries in the Human Development Index. By comparing with the actual consumption levels for relevant strong opioid analgesics, we were able to estimate the level of adequacy of opioid consumption for each country. Good access to pain management is rather the exception than the rule: 5.5 billion people (83% of the world's population) live in countries with low to nonexistent access, 250 million (4%) have moderate access, and only 460 million people (7%) have adequate access. Insufficient data are available for 430 million (7%). The consumption of opioid analgesics is inadequate to provide sufficient pain relief around the world. Only the populations of some industrialized countries have good access. Policies should seek a balance between maximizing access for medical use and minimizing abuse and dependence. Countries should aim to increase the medical consumption to the magnitude needed to address the totality of moderate and severe pain.

  2. Self-treatment of opioid withdrawal with a dietary supplement, Kratom.

    PubMed

    Boyer, Edward W; Babu, Kavita M; Macalino, Grace E; Compton, Wilson

    2007-01-01

    We examined the use of Kratom (Mitragyna sp.), a dietary supplement with mu-opioid agonist activity, by members of a cybercommunity who self-treat chronic pain with opioid analgesics from Internet pharmacies. Within one year, an increase in the number of mentions on Drugbuyers.com, a Web site that facilitates the online purchase of opioid analgesics, suggested that members began managing opioid withdrawal with Kratom. This study demonstrates the rapidity with which information on psychoactive substances disseminates through online communities and suggests that online surveillance may be important to the generation of effective opioid analgesic abuse prevention strategies. PMID:17882605

  3. Management of opioid-dependent patients: comparison of the cost associated with use of buprenorphine/naloxone or methadone, and their interactions with concomitant treatments for infectious or psychiatric comorbidities.

    PubMed

    Roncero, Carlos; Domínguez-Hernández, Raquel; Díaz, Tomás; Fernández, José Manuel; Forcada, Rafael; Martínez, José Manuel; Seijo, Pedro; Terán, Antonio; Oyagüez, Itziar

    2015-09-15

    The objective was to estimate the annual interaction management cost of agonist opioid treatment (AOT) for opioid-dependent (OD) patients with buprenorphine-naloxone (Suboxone®) (B/N) or methadone associated with concomitant treatments for infectious (HIV) or psychiatric comorbidities. A costs analysis model was developed to calculate the associated cost of AOT and interaction management. The AOT cost included pharmaceutical costs, drug preparation, distribution and dispensing, based on intake regimen (healthcare center or take-home) and type and frequency of dispensing (healthcare center or pharmacy), and medical visits. The cost of methadone also included single-dose bottles, monthly costs of custody at pharmacy, urine toxicology drug screenings and nursing visits. Potential interactions between AOT and concomitant treatments (antivirals, antibacterials/antifungals, antipsychotics, anxiolytics, antidepressant and anticonvulsants), were identified to determine the additional use of healthcare resources for each interaction management. The annual cost per patient of AOT was €1,525.97 for B/N and €1,467.29 for methadone. The average annual cost per patient of interaction management was €257.07 (infectious comorbidities), €114.03 (psychiatric comorbidities) and €185.55 (double comorbidity) with methadone and €7.90 with B/N in psychiatric comorbidities. Total annual costs of B/N were €1,525.97, €1,533.87 and €1,533.87 compared to €1,724.35, €1,581.32 and €1,652.84 for methadone per patient with infectious, psychiatric or double comorbidity respectively.Compared to methadone, the total cost per patient with OD was lower with B/N (€47.45-€198.38 per year). This is due to the differences in interaction management costs associated with the concomitant treatment of infectious and/or psychiatric comorbidities.

  4. Management of opioid-dependent patients: comparison of the cost associated with use of buprenorphine/naloxone or methadone, and their interactions with concomitant treatments for infectious or psychiatric comorbidities.

    PubMed

    Roncero, Carlos; Domínguez-Hernández, Raquel; Díaz, Tomás; Fernández, José Manuel; Forcada, Rafael; Martínez, José Manuel; Seijo, Pedro; Terán, Antonio; Oyagüez, Itziar

    2015-01-01

    The objective was to estimate the annual interaction management cost of agonist opioid treatment (AOT) for opioid-dependent (OD) patients with buprenorphine-naloxone (Suboxone®) (B/N) or methadone associated with concomitant treatments for infectious (HIV) or psychiatric comorbidities. A costs analysis model was developed to calculate the associated cost of AOT and interaction management. The AOT cost included pharmaceutical costs, drug preparation, distribution and dispensing, based on intake regimen (healthcare center or take-home) and type and frequency of dispensing (healthcare center or pharmacy), and medical visits. The cost of methadone also included single-dose bottles, monthly costs of custody at pharmacy, urine toxicology drug screenings and nursing visits. Potential interactions between AOT and concomitant treatments (antivirals, antibacterials/antifungals, antipsychotics, anxiolytics, antidepressant and anticonvulsants), were identified to determine the additional use of healthcare resources for each interaction management. The annual cost per patient of AOT was €1,525.97 for B/N and €1,467.29 for methadone. The average annual cost per patient of interaction management was €257.07 (infectious comorbidities), €114.03 (psychiatric comorbidities) and €185.55 (double comorbidity) with methadone and €7.90 with B/N in psychiatric comorbidities. Total annual costs of B/N were €1,525.97, €1,533.87 and €1,533.87 compared to €1,724.35, €1,581.32 and €1,652.84 for methadone per patient with infectious, psychiatric or double comorbidity respectively.Compared to methadone, the total cost per patient with OD was lower with B/N (€47.45-€198.38 per year). This is due to the differences in interaction management costs associated with the concomitant treatment of infectious and/or psychiatric comorbidities. PMID:26437312

  5. Treating Pain with Opioids

    MedlinePlus

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

  6. Opioid Antagonist Impedes Exposure.

    ERIC Educational Resources Information Center

    Merluzzi, Thomas V.; And Others

    1991-01-01

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

  7. Blocking opioids attenuates physical warmth-induced feelings of social connection.

    PubMed

    Inagaki, Tristen K; Irwin, Michael R; Eisenberger, Naomi I

    2015-08-01

    "Heartwarming" social experiences, when one feels interpersonally connected to others, have recently been linked with physical warmth. According to one theory (Panksepp, 1998), "social warmth" and physical warmth may be closely linked because both experiences are supported by similar neurobiological mechanisms; however, the neurochemical substrates underlying this overlap have not been explored. Here, an opioid antagonist, naltrexone, was administered in order to examine the role of opioids, previously shown to alter temperature and social bonding behavior, on perceived thermal intensity, general positive affect, and feelings of social connection from physical warmth. Thirty-one participants took both naltrexone and a placebo and completed a temperature manipulation task (held a warm pack, cold pack, and neutral object) while on each drug. Replicating previous research, holding a warm (vs. a cold or neutral) object increased feelings of social connection. Moreover, blocking opioids reduced this effect. Hence, naltrexone specifically reduced feelings of social connection to holding a warm (vs. neutral) object but not to holding a cold (vs. neutral) object. These results lend further support to the theory that social and physical warmth share neurobiological, opioid receptor dependent mechanisms. PMID:26098729

  8. Blocking opioids attenuates physical warmth-induced feelings of social connection

    PubMed Central

    Inagaki, Tristen K.; Irwin, Michael R.; Eisenberger, Naomi I.

    2015-01-01

    “Heartwarming” social experiences, when one feels interpersonally connected to others, have recently been linked with physical warmth. According to one theory (Panksepp, 1998), “social warmth” and physical warmth may be closely linked because both experiences are supported by similar neurobiological mechanisms, however, the neurochemical substrates underlying this overlap have not been explored. Here, an opioid antagonist, naltrexone, was administered in order to examine the role of opioids, previously shown to alter temperature and social bonding behavior, on perceived thermal intensity, general positive affect, and feelings of social connection from physical warmth. Thirty-one participants took both naltrexone and placebo and completed a temperature manipulation task (held a warm pack, cold pack, and neutral object) while on each drug. Replicating previous research, holding a warm (vs. a cold or neutral) object increased feelings of social connection. Moreover, blocking opioids reduced this effect. Hence, naltrexone specifically reduced feelings of social connection to holding a warm (vs. neutral) object but not to holding a cold (vs. neutral) object. These results lend further support to the theory that social and physical warmth share neurobiological, opioid receptor dependent mechanisms. PMID:26098729

  9. The Effect of Opioid Receptor Blockade on the Neural Processing of Thermal Stimuli

    PubMed Central

    Schoell, Eszter D.; Bingel, Ulrike; Eippert, Falk; Yacubian, Juliana; Christiansen, Kerrin; Andresen, Hilke; May, Arne; Buechel, Christian

    2010-01-01

    The endogenous opioid system represents one of the principal systems in the modulation of pain. This has been demonstrated in studies of placebo analgesia and stress-induced analgesia, where anti-nociceptive activity triggered by pain itself or by cognitive states is blocked by opioid antagonists. The aim of this study was to characterize the effect of opioid receptor blockade on the physiological processing of painful thermal stimulation in the absence of cognitive manipulation. We therefore measured BOLD (blood oxygen level dependent) signal responses and intensity ratings to non-painful and painful thermal stimuli in a double-blind, cross-over design using the opioid receptor antagonist naloxone. On the behavioral level, we observed an increase in intensity ratings under naloxone due mainly to a difference in the non-painful stimuli. On the neural level, painful thermal stimulation was associated with a negative BOLD signal within the pregenual anterior cingulate cortex, and this deactivation was abolished by naloxone. PMID:20811582

  10. Blocking opioids attenuates physical warmth-induced feelings of social connection.

    PubMed

    Inagaki, Tristen K; Irwin, Michael R; Eisenberger, Naomi I

    2015-08-01

    "Heartwarming" social experiences, when one feels interpersonally connected to others, have recently been linked with physical warmth. According to one theory (Panksepp, 1998), "social warmth" and physical warmth may be closely linked because both experiences are supported by similar neurobiological mechanisms; however, the neurochemical substrates underlying this overlap have not been explored. Here, an opioid antagonist, naltrexone, was administered in order to examine the role of opioids, previously shown to alter temperature and social bonding behavior, on perceived thermal intensity, general positive affect, and feelings of social connection from physical warmth. Thirty-one participants took both naltrexone and a placebo and completed a temperature manipulation task (held a warm pack, cold pack, and neutral object) while on each drug. Replicating previous research, holding a warm (vs. a cold or neutral) object increased feelings of social connection. Moreover, blocking opioids reduced this effect. Hence, naltrexone specifically reduced feelings of social connection to holding a warm (vs. neutral) object but not to holding a cold (vs. neutral) object. These results lend further support to the theory that social and physical warmth share neurobiological, opioid receptor dependent mechanisms.

  11. Opioid induced hyperalgesia altered with propofol infusion.

    PubMed

    Kaye, Alan D; Chung, Keun Sam; Vadivelu, Nalini; Cantemir, Catalin; Urman, Richard D; Manchikanti, Laxmaiah

    2014-01-01

    Propofol is a common induction agent that is utilized worldwide in the field of anesthesiology. In recent years, its potential therapeutic role in a variety of patient states has been demonstrated. Controversy exists regarding Propofol mediated analgesic and antihyperalgesic properties. Recent studies have suggested a variety of different mechanisms of action, including modulation of N-Methyl-D- Aspartate receptors and the endocannabinoid system. The N-Methyl-D- Aspartate receptor is part of a larger family of glutamate receptors and is an important mediator of excitatory neurotransmission. In the case presented, the pain experienced by the patient was not well-controlled, in spite of increasing doses of opioids, potentially due to superimposed opioid induced hyperalgesia. In the present case, we demonstrate a cycle of opioid induced hyperalgesia which was successfully affected with a Propofol infusion. Controversial reports exist in animal studies on the analgesic properties of Propofol. Randomized controlled studies in animal models studying the effect of Propofol on pain sensation have shown that Propofol possesses an analgesic effect. This clinical case demonstrates that Propofol could possibly have antihyperalgesic effects on opioid induced hyperalgesia caused by high-doses of chronic opioids and worsened by fentanyl. We postulate that a probable mechanism of complete pain relief after the procedure could be the inhibition of activity of the N-Methyl-D- Aspartate receptor by Propofol because it was the only agent the patient received during the procedure, causing a break of the cycle of opioid induced hyperalgesia. Additional research is required to clarify Propofol mediated or modulated analgesic properties in humans.

  12. The burden of the nonmedical use of prescription opioid analgesics.

    PubMed

    Gilson, Aaron M; Kreis, Paul G

    2009-07-01

    An increase in the prescribing of opioids over the past several years often has been perceived as the primary reason for the increase in the nonmedical use of prescription opioids. Determining the prevalence of this illicit use has been difficult, because of varied methodologies and terminologies that are used to estimate the number of people directly contributing to or affected by this burden. Despite these discrepancies, the findings from several nationally recognized surveys have demonstrated that the prevalence of nonmedical prescription opioid use is indeed significant and has been increasing in recent years. The considerable burden on society imposed by misuse and abuse of these drugs is largely due to the monetary costs associated with nonmedical use (e.g., strategies implemented to prevent or deter abuse, treatment programs for misusers, etc.), decreased economic productivity, and the indirect effect on access to appropriate health care. However, using various nonpharmacologic and pharmacologic approaches to treat patients who use prescription opioids illicitly can decrease its overall prevalence and associated impact, with the development of novel opioid formulations designed to reduce nonmedical use providing valuable clinical tools as part of an overall risk management program. In addition, prescription monitoring programs are a prevalent drug control system designed to identify and address abuse and diversion of prescription medications, including opioids. Such resources, along with an accurate understanding of the problem, extend greater hope that the public health challenge of nonmedical prescription opioid use can be effectively mitigated. PMID:19691688

  13. Prevalence of narcotic bowel syndrome in opioid abusers in iran.

    PubMed

    Ahmadi, Bizhan; Arab, Peyman; Zahedi, Mohammad Javad; Shafieipour, Sara; Drossman, Douglas A; Banivaheb, Ghodseyeh

    2014-10-01

    BACKGROUND In spite of the increasing trend in opioid abusers worldwide, the prevalence of narcotic bowel syndrome (NBS) is undetermined. We aimed to estimate the prevalence of NBS and other opioid bowel dysfunction (OBD) in opioid abusers in Kerman, southeast Iran. According to the best of our knowledge, this is the first study to assess the prevalence of NBS in opioid abusers. METHODS By referring to addiction treatment centers in Kerman city and in a cross-sectional study, 577 subjects with opium or opioid subtracts abuse were included in our study. A validated questionnaire was used for OBD assessment and diagnosis of NBS was made according to both the presence of chronic abdominal pain despite increasing the opioid dose and ruling out other causes of abdominal pain. SPSS software version 16 was used for data analysis. p value<0.05 was considered as statistically significant. RESULTS Constipation, regurgitation, and heartburn were the most gastrointestinal complaints that were found in 132(22.9%), 123(21.3%) and 91(15.8%) subjects, respectively. Only 16(2.8%) participants fulfilled all the NBS criteria. Simultaneous use of non-narcotic sedative drugs increased the risk of NBS significantly (the odds ratio 3:1 and p=0.049). CONCLUSION NBS is not rare among opioid abusers and should be considered as a cause of chronic abdominal pain in this group. PMID:25349684

  14. The unsolved case of “bone-impairing analgesics”: the endocrine effects of opioids on bone metabolism

    PubMed Central

    Coluzzi, Flaminia; Pergolizzi, Joseph; Raffa, Robert B; Mattia, Consalvo

    2015-01-01

    The current literature describes the possible risks for bone fracture in chronic analgesics users. There are three main hypotheses that could explain the increased risk of fracture associated with central analgesics, such as opioids: 1) the increased risk of falls caused by central nervous system effects, including sedation and dizziness; 2) reduced bone mass density caused by the direct opioid effect on osteoblasts; and 3) chronic opioid-induced hypogonadism. The impact of opioids varies by sex and among the type of opioid used (less, for example, for tapentadol and buprenorphine). Opioid-associated androgen deficiency is correlated with an increased risk of osteoporosis; thus, despite that standards have not been established for monitoring and treating opioid-induced hypogonadism or hypoadrenalism, all patients chronically taking opioids (particularly at doses ≥100 mg morphine daily) should be monitored for the early detection of hormonal impairment and low bone mass density. PMID:25848298

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

    PubMed Central

    Binswanger, Ingrid A.; Glanz, Jason M.

    2015-01-01

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

  16. Opioid regulation of Pavlovian overshadowing in fear conditioning.

    PubMed

    Zelikowsky, Moriel; Fanselow, Michael S

    2010-08-01

    In Pavlovian overshadowing, a stimulus that predicts a biologically important event reduces conditioning to another, equally predictive stimulus. We tested the effects of an opioid antagonist and dopamine agonist on the ability of a salient white noise to overshadow a less salient light. Rats were conditioned to fear a light or a noise-light compound using a mild footshock. Compound-conditioned rats trained under the saline vehicle revealed significant overshadowing of the light by the noise. This overshadowing effect was significantly attenuated in rats trained under the opioid antagonist naltrexone, consistent with an opioid-mediated negative feedback model of conditioning. In line with predictions made by negative feedback-type models, we failed to obtain overshadowing with few trials, suggesting that the processes underlying conditioning during initial trials do not contribute to the opioid-dependent Pavlovian overshadowing obtained in our preparation. Lastly, we compared the involvement of dopamine-mediated and opioid-mediated processes in overshadowing by conditioning rats under the partial dopamine D1 receptor agonist SKF 38393 or the opioid antagonist naltrexone. Both naltrexone and SKF 38393 were found to attenuate overshadowing; however, the behavioral profiles produced by each pharmacological manipulation were distinct. Collectively, these studies demonstrate an important role for both opioid- and dopamine-mediated processes in multiple-trial overshadowing.

  17. Opioids and immune modulation: more questions than answers.

    PubMed

    Al-Hashimi, M; Scott, S W M; Thompson, J P; Lambert, D G

    2013-07-01

    Opioid addicts are more likely to present with infections suggesting opioids are immune modulators. The potential sites/mechanism(s) for this modulation are controversial and on close inspection not well supported by the current literature. It has long been assumed that opioid-induced immune modulation occurs via a combination of direct actions on the immune cell itself, via the hypothalamic-pituitary-adrenal (HPA) axis, or both. Opioid receptors are classified as MOP (μ, mu), DOP (δ, delta), and KOP (κ, kappa)--classical naloxone sensitive receptors--or NOP (the receptor for nociceptin/orphanin FQ), which is naloxone insensitive. Opioids currently used in clinical practice predominantly target the MOP receptor. There do not appear to be classical opioid receptors present on immune cells. The evidence for HPA activation is also poor and shows some species dependence. Most opioids used clinically or as drugs of abuse do not target the NOP receptor. Other possible target sites for immune modulation include the sympathetic nervous system and central sites. We are currently unable to accurately define the cellular target for immune modulation and suggest further investigation is required. Based on the differences observed when comparing studies in laboratory animals and those performed in humans we suggest that further studies in the clinical setting are needed.

  18. Imaging of opioid receptors in the central nervous system

    PubMed Central

    Henriksen, Gjermund

    2008-01-01

    In vivo functional imaging by means of positron emission tomography (PET) is the sole method for providing a quantitative measurement of μ-, κ and δ-opioid receptor-mediated signalling in the central nervous system. During the last two decades, measurements of changes to the regional brain opioidergic neuronal activation—mediated by endogenously produced opioid peptides, or exogenously administered opioid drugs—have been conducted in numerous chronic pain conditions, in epilepsy, as well as by stimulant- and opioidergic drugs. Although several PET-tracers have been used clinically for depiction and quantification of the opioid receptors changes, the underlying mechanisms for regulation of changes to the availability of opioid receptors are still unclear. After a presentation of the general signalling mechanisms of the opioid receptor system relevant for PET, a critical survey of the pharmacological properties of some currently available PET-tracers is presented. Clinical studies performed with different PET ligands are also reviewed and the compound-dependent findings are summarized. An outlook is given concluding with the tailoring of tracer properties, in order to facilitate for a selective addressment of dynamic changes to the availability of a single subclass, in combination with an optimization of the quantification framework are essentials for further progress in the field of in vivo opioid receptor imaging. PMID:18048446

  19. Screening and Treatment for Alcohol, Tobacco and Opioid Use Disorders: A Survey of Family Physicians across Ontario

    PubMed Central

    Loheswaran, Genane; Soklaridis, Sophie; Selby, Peter; Le Foll, Bernard

    2015-01-01

    Introduction As a primary point of contact within the health care system, family physicians are able to play a vital role in identifying individuals with substance use disorders and connecting them to the appropriate treatment. However, there is very little data available on whether family physicians are actively screening for and treating substance use disorders. The objective of the current survey was to assess whether family physicians in Ontario are screening for alcohol, opioid and tobacco use disorders, using validated tools and providing treatment. Methods An online survey consisting of a series of 38 primarily close-ended questions was circulated to family physicians in Ontario. Rates of screening for alcohol, opioid and tobacco dependence, use of validated tools for screening, providing treatment for dependent individuals and the current barriers to the prescription of pharmacotherapies for these drug dependences were assessed. Results The use of validated screening tools was limited for all three substances. Screening by family physicians for the substance use disorders among adolescents was much lower than screening among adults. Pharmacotherapy was more commonly used as an intervention for tobacco dependence than for alcohol and opioid dependence. This was explained by the lack of knowledge among family physicians on the pharmacotherapies for alcohol and opioid dependence. Conclusions Findings from the current study suggest there is a need for family physicians to integrate screening for substance use disorders using validated tools into their standard medical practice. Furthermore, there is a need for increased knowledge on pharmacotherapies for alcohol and opioid use disorders. It is important to note that the low response rate is a major limitation to this study. One possible reason for this low response rate may be a lack of interest and awareness among family physicians on the importance of screening and treatment of substance use disorders in

  20. Spatiotemporal control of opioid signaling and behavior

    PubMed Central

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

    2015-01-01

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