Introduction Dependence on opioids is a multifactorial condition involving genetic and psychosocial factors. There are three approaches to treating opioid dependence. Stabilisation is usually by opioid substitution treatments, and aims to ensure that the drug use becomes independent of mental state (such as craving and mood) and independent of circumstances (such as finance and physical location). The next stage is to withdraw (detox) from opioids. The final aim is relapse prevention. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments for stabilisation (maintenance) in people with opioid dependence? What are the effects of drug treatments for withdrawal in people with opioid dependence? What are the effects of drug treatments for relapse prevention in people with opioid dependence? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 23 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review, we present information relating to the effectiveness and safety of the following interventions: buprenorphine; clonidine; lofexidine; methadone; naltrexone; and ultra-rapid withdrawal regimes. PMID:21696648
Introduction Dependence on opioids is a multifactorial condition involving genetic and psychosocial factors. There are three stages to treating opioid dependence. Stabilisation is usually by opioid substitution treatments, and aims to ensure that the drug use becomes independent of mental state (such as craving and mood) and independent of circumstances (such as finance and physical location). The next stage is to withdraw (detox) from opioids. The final stage is relapse prevention. This treatment process contributes to recovery of the individual, which also includes improved overall health and wellbeing, as well as engagement in society. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments for stabilisation (maintenance) in people with opioid dependence? What are the effects of drug treatments for withdrawal in people with opioid dependence? What are the effects of drug treatments for relapse prevention in people with opioid dependence? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 26 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review, we present information relating to the effectiveness and safety of the following interventions: buprenorphine; clonidine; lofexidine; methadone; naltrexone; and ultra-rapid withdrawal regimens. PMID:21929827
Goldberg, L R; Kirkpatrick, S L; Yazdani, N; Luttik, K P; Lacki, O A; Keith Babbs, R; Jenkins, D F; Evan Johnson, W; Bryant, C D
Genetic and pharmacological studies indicate that casein kinase 1 epsilon (Csnk1e) contributes to psychostimulant, opioid, and ethanol motivated behaviors. We previously used pharmacological inhibition to demonstrate that Csnk1e negatively regulates the locomotor stimulant properties of opioids and psychostimulants. Here, we tested the hypothesis that Csnk1e negatively regulates opioid and psychostimulant reward using genetic inhibition and the conditioned place preference assay in Csnk1e knockout mice. Similar to pharmacological inhibition, Csnk1e knockout mice showed enhanced opioid-induced locomotor activity with the mu opioid receptor agonist fentanyl (0.2 mg/kg i.p.) as well as enhanced sensitivity to low-dose fentanyl reward (0.05 mg/kg). Interestingly, female knockout mice also showed a markedly greater escalation in consumption of sweetened palatable food - a behavioral pattern consistent with binge eating that also depends on mu opioid receptor activation. No difference was observed in fentanyl analgesia in the 52.5°C hot plate assay (0-0.4 mg/kg), naloxone conditioned place aversion (4 mg/kg), or methamphetamine conditioned place preference (0-4 mg/kg). To identify molecular adaptations associated with increased drug and food behaviors in knockout mice, we completed transcriptome analysis via mRNA sequencing of the striatum. Enrichment analysis identified terms associated with myelination and axon guidance and pathway analysis identified a differentially expressed gene set predicted to be regulated by the Wnt signaling transcription factor, Tcf7l2. To summarize, Csnk1e deletion increased mu opioid receptor-dependent behaviors, supporting previous studies indicating an endogenous negative regulatory role of Csnk1e in opioid behavior. © 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.
Tolomeo, Serenella; Matthews, Keith; Steele, Douglas; Baldacchino, Alex
This study aimed to investigate the relationship between compulsivity versus impulsivity and structural MRI abnormalities in opioid dependence. We recruited 146 participants: i) patients with a history of opioid dependence due to chronic heroin use (n=24), ii) heroin users stabilised on methadone maintenance treatment (n=48), iii) abstinent participants with a history of opioid dependence due to heroin use (n=24) and iv) healthy controls (n=50). Compulsivity was measured using Intra/Extra-Dimensional (IED) Task and impulsivity was measured using the Cambridge Gambling Task (CGT). Structural Magnetic Resonance Imaging (MRI) data were also obtained. As hypothesised, compulsivity was negatively associated with impulsivity (p<0.02). Testing for the neural substrates of compulsivity versus impulsivity, we found a higher compulsivity/impulsivity ratio associated with significantly decreased white matter adjacent to the nucleus accumbens, bed nucleus of stria terminalis and rostral cingulate in the abstinent group, compared to the other opioid dependent groups. In addition, self-reported duration of opioid exposure correlated negatively with bilateral globus pallidus grey matter reductions. Our findings are consistent with Volkow & Koob's addiction models and underline the important role of compulsivity versus impulsivity in opioid dependence. Our results have implications for the treatment of opioid dependence supporting the assertion of different behavioural and biological phenotypes in the opioid dependence and abstinence syndromes. Copyright © 2017 Elsevier Inc. All rights reserved.
Winklbaur, Bernadette; Jung, Erika; Fischer, Gabriele
The management of opioid dependence during pregnancy has received considerable attention over the past three decades. Recent peer-reviewed literature in the fields of pregnancy and opioid dependence and neonatal abstinence syndrome has been evaluated and discussed. Pregnant opioid-dependent women must be carefully managed to minimize harm to the fetus; therefore, standardized care for maternal health is required. In a multidisciplinary care system opioid maintenance therapy is the recommended treatment approach during pregnancy. Equivalent attention must be given to the treatment of neonatal abstinence syndrome, which occurs in 55-94% of neonates after intrauterine opioid exposure with a 60% likelihood of requiring treatment; heterogeneous rating scales as well as heterogeneous treatment approaches are often responsible for extended hospital stays. Interpretation of available literature is confounded by several methodological flaws. In general, there is still a lack of evidence-based study designs for pharmacological treatment of these patients as well as neonatal abstinence syndrome.
Juurlink, David N; Dhalla, Irfan A
The use of opioids for chronic noncancer pain has increased dramatically over the past 25 years in North America and has been accompanied by a major increase in opioid addiction and overdose deaths. The increase in opioid prescribing is multifactorial and partly reflects concerns about the effectiveness and safety of alternative medications, particularly the nonsteroidal anti-inflammatory drugs. However, much of the rise in opioid prescribing reflects the assertion, widely communicated to physicians in the 1990s, that the risks of dependence and addiction during chronic opioid therapy were low, predictable, and could be minimized by the use of controlled-release opioid formulations. In this narrative review, we offer a critical appraisal of the publications most frequently cited as evidence that the risk of addiction during chronic opioid therapy is low. We conclude that very few well-designed studies support the notion that opioid addiction is rare during chronic opioid therapy and that none can be readily generalized to present-day practice. Despite serious methodological limitations, these studies have been repeatedly mischaracterized as showing that the risk of addiction during chronic opioid therapy is rare. These studies are countered by a larger, more rigorous and contemporary body of evidence demonstrating that dependence and addiction are relatively common consequences of chronic opioid therapy, occurring in up to one-third of patients in some series.
Höflich, Anna S.; Langer, Martin; Jagsch, Reinhold; Bäwert, Andjela; Winklbaur, Bernadette; Fischer, Gabriele; Unger, Annemarie
Increased pain sensitivity and the development of opioid tolerance complicate the treatment of pain experienced by opioid maintained pregnant women during delivery and the perinatal period. The aim of the present study was to investigate differences in pain management of opioid maintained compared to non-dependent pregnant women during delivery and the postpartum period. 40 deliveries of 37 opioid dependent women enrolled in a double-blind, double-dummy randomized controlled trial (RCT) examining the safety and efficacy of methadone (mean dose at the time of delivery = 63.89 mg) and buprenorphine (mean dose at the time of delivery = 14.05 mg) during pregnancy were analyzed and participants were matched to a non-dependent comparison group of 80 pregnant women. Differences in pain management (opioid and non-opioid analgesic medication) during delivery and perinatal period were analyzed. Following cesarean delivery opioid maintained women received significantly less opioid analgesics (day of delivery p = 0.038; day 1: p = 0.02), NSAIDs were administered more frequently to opioid dependent patients than to the comparison group during cesarean section and on the third day postpartum. Significantly higher nicotine consumption in the group of opioid dependent women had a strong influence on the retrieved results, and might be considered as an independent factor of altered pain experience. Differences in pain treatment became evident when comparing opioid maintained women to healthy controls. These differences might be based on psychosocial consequences of opioid addiction along with the lack of an interdisciplinary consensus on pain treatment protocols for opioid dependent patients. PMID:22396085
Hilario, E Yvette; Griffin, Margaret L; McHugh, R Kathryn; McDermott, Katherine A; Connery, Hilary S; Fitzmaurice, Garrett M; Weiss, Roger D
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.
Pihkala, Heljä; Sandlund, Mikael
Many patients in maintenance treatment programs for opioid dependence are parents to underage children. The aim of this study was to explore how parents who are regular patients in maintenance treatment perceive their parenthood. 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. 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. 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.
Loh, Ryan; Collins, Sean; Galvez, Roberto
There are several lines of evidence that indicate a prominent role for the opioid system in the acquisition and consolidation of learned associations. Specifically, kappa opioid receptor (KOR) modulation has been demonstrated to alter various behavioral tasks including whisker trace eyeblink conditioning (WTEB). WTEB is an associative conditioning paradigm in which a neutral conditioned stimulus (CS; Whisker stimulation) is paired following a short stimulus free trace interval with a salient unconditioned stimulus that elicits a blink response (US; Eye shock). Work from our laboratory has shown that WTEB conditioning is dependent upon and induces plasticity in primary somatosensory cortex (S1), a likely site for memory storage. Our subsequent studies have shown that WTEB acquisition or consolidation are impaired when the initial or later phase of KOR activation in S1 is respectively blocked. Interestingly, this mechanism by which KOR is activated in S1 during learning remains unexplored. Dynorphin (DYN), KOR's endogenous ligand, is synthesized from the precursor prodynorphin (PD) that is synthesized from preprodynorphin (PPD). In S1, most PPD is found in inhibitory GABAergic somatostatin interneurons (SOM), suggesting that these SOM interneurons are upstream regulators of learning induced KOR activation. Using immunofluorescence to investigate the expression of PD and SOM, the current study found that PD/SOM expression was transiently increased in S1 during learning. Interestingly, these findings have direct implications towards a time- and learning-dependent role for KOR activation in neocortical mechanisms mediating learning. Copyright © 2017 Elsevier B.V. All rights reserved.
Weiss, Roger D; Potter, Jennifer Sharpe; Griffin, Margaret L; McHugh, R Kathryn; Haller, Deborah; Jacobs, Petra; Gardin, John; Fischer, Dan; Rosen, Kristen D
The number of individuals seeking treatment for prescription opioid dependence has increased dramatically, fostering a need for research on this population. The aim of this study was to examine reasons for prescription opioid use among 653 participants with and without chronic pain, enrolled in the Prescription Opioid Addiction Treatment Study, a randomized controlled trial of treatment for prescription opioid dependence. Participants identified initial and current reasons for opioid use. Participants with chronic pain were more likely to report pain as their primary initial reason for use; avoiding withdrawal was rated as the most important reason for current use in both groups. Participants with chronic pain rated using opioids to cope with physical pain as more important, and using opioids in response to social interactions and craving as less important, than those without chronic pain. Results highlight the importance of physical pain as a reason for opioid use among patients with chronic pain. Copyright © 2014 Elsevier Inc. All rights reserved.
Benningfield, Margaret M; Arria, Amelia M; Kaltenbach, Karol; Heil, Sarah H; Stine, Susan M; Coyle, Mara G; Fischer, Gabriele; Jones, Hendrée E; Martin, Peter R
The interaction of psychiatric symptoms with drug dependence during pregnancy is not well understood. This study examines the relationship of psychiatric symptoms to severity of drug use and drug-related problems among participants in a clinical trial of pharmacologic treatment of opioid dependence during pregnancy (N = 174). A total of 64.6% reported additional psychiatric symptoms (48.6% mood symptoms, 40.0% anxiety symptoms, and 12.6% suicidal thinking). Women who endorsed co-occurring psychiatric symptoms showed more severe impairment on the Addiction Severity Index. Further investigation is warranted to understand the effect of psychiatric symptoms on long-term maternal and neonatal outcomes.
The use of opioids has long been accepted as the standard of care in patients with cancer and acute pain. Opioids can further be used effectively in specific subgroups of patients with chronic nonmalignant pain states. While the development of tolerance and physical dependence are known effects of opioids in cancer and noncancer pain populations, these patients can not be regarded as addicted. However, long-term therapy with short-acting opioids predisposes to tolerance and addiction. Recent research has confirmed the important role of psychopathologic and psychosocial conditions as predictors of failed opioid effectiveness in a significant number of noncancer pain subgroups. The clinical picture of failed therapy may be complicated by noncompliance, concealed consumption of psychotropic substances, and diversion of prescribed opioids for various purposes as, e.g., selling for profit, or sharing excess opioids with others. This article discusses the effects of opioid therapy, including tolerance, physical dependence, drug-aberrant behavior, drug history, psychopathology, and somatization.
Park, Eliza M; Meltzer-Brody, Samantha; Suzuki, Joji
Background Opioid use disorders are a growing public health problem in the United States. Most women who are opioid dependent are of childbearing age and management of opioid dependence during pregnancy poses unique challenges. Assessment includes evaluation for addiction, withdrawal syndromes, and co-morbid psychiatric diagnoses. Consultation-liaison psychiatrists may also be involved in acute pain management, perinatal medication management, buprenorphine induction and stabilization. For the past four decades, the standard of care has included methadone maintenance, but the increasing use of buprenorphine creates new treatment issues and opportunities. Objective To educate consultation-liaison psychiatrists in emergency and obstetrical settings about the appropriate approach toward the evaluation and basic management of women with opioid dependence in pregnancy. Method The authors reviewed the consensus literature and all new treatment options on opioid dependence during pregnancy. Discussion In this review, the authors summarize known and emerging management strategies for opioid dependence in pregnancy pertinent to consultation-liaison psychiatrists. PMID:22902085
Hilario, E. Yvette; Griffin, Margaret L.; McHugh, R. Kathryn; McDermott, Katherine A.; Connery, Hilary S.; Fitzmaurice, Garrett M.; Weiss, Roger D.
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
Murphy, Sean M; Fishman, Paul A; McPherson, Sterling; Dyck, Dennis G; Roll, John R
This study assessed the social, demographic and clinical determinants of whether an opioid-dependent patient received buprenorphine versus an alternative therapy. A retrospective cohort analysis of opioid-dependent adults enrolled in Group Health Cooperative between January 1, 2006 and December 1, 2010 was performed. Increasing the number of physicians with DATA waivers in a region and living in a relatively-populated area increased the likelihood of being treated with buprenorphine, indicating that lack of access is a potential barrier. Comorbidity also appeared to be a factor in receipt of treatment, with the effect varying by diagnosis. Finally, patients with an insurance plan allowing health services to be sought from any provider, with increased cost sharing, were significantly more likely to receive buprenorphine, implying that patient demand is a factor. Programs integrating patient education, physician training, and support from addiction specialists would be likely facilitators of increasing access to this cost-effective treatment. © 2014.
Lobmaier, P; Kornør, H; Kunøe, N; Bjørndal, A
Naltrexone is an opioid antagonist which effectively blocks heroin effects. Since opioid dependence treatment with naltrexone tablets suffers from high dropout rates, several depot injections and implants are under investigation. Sustained-release formulations are claimed to be effective, but a systematic review of the literature is lacking. To evaluate the effectiveness of sustained-release naltrexone for opioid dependence and its adverse effects in different study populations. The following databases were searched from their inception to November 2007: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, LILACS, PsycINFO, ISI Web of Science, trial database at http://clinicaltrials.gov, available NIDA monographs, CPDD and AAAP conference proceedings. The reference lists of identified studies, published reviews and relevant web sides were searched manually. Study authors and drug companies were contacted to obtain any unpublished material or missing data. To evaluate effectiveness only RCTs were included. To evaluate safety, any clinical trial reporting adverse effects was assessed. Treatment condition was extended to include alcohol dependent subjects and healthy volunteers. Reviewers independently evaluated the reports, rated methodological quality and extracted data. Analyses were performed separately for opioid dependent, alcohol dependent and healthy participants. Foe effectiveness, one report met inclusion criteria. Two dosages of naltrexone depot injections (192 and 384 mg) were compared to placebo. High-dose significantly increased days in treatment compared to placebo (WMD 21.00, 95% CI 10.68 to 31.32, p<0.0001). High-dose compared to low-dose significantly increased days in treatment (WMD 12.00, 95% CI 1.69 to 22.31, p=0.02). Number of patients retained in treatment did not show significant differences between groups. For adverse effects, seventeen reports met inclusion criteria analyses, six were RCTs. Side effects were significantly
Young, Jessica L; Martin, Peter R
Opioid dependence in the setting of pregnancy provides a distinct set of challenges for providers. Treatment plans must take into consideration psychiatric and medical comorbidities while balancing risks and benefits for the maternal-fetal dyad. Treatment is best offered through a comprehensive treatment program designed to effectively deliver opioid agonist maintenance treatment along with psychosocial and obstetric care. As misuse of prescription analgesics increases in the United States, identification of the problem in pregnancy will become more important because this misuse is expected to lead to an increased prevalence of opioid dependence in pregnancy. Buprenorphine as maintenance treatment of opioid dependence during pregnancy has promise and may offer some benefits, but more research is needed, especially regarding induction of actively addicted women during pregnancy. For the present, methadone maintenance remains the standard of care for agonist treatment of opioid dependence in pregnancy against which other treatments must be compared.
Kaltenbach, K; Berghella, V; Finnegan, L
This article describes the complex problems associated with opioid dependence during pregnancy. Medical, obstetric, and psychosocial problems are presented. Methadone maintenance for the treatment of opioid dependence is described in this article. Specific issues of appropriate methadone dose during pregnancy, medical withdrawal, and the relationship of methadone dose and the severity of neonatal abstinence also are discussed.
Garland, Eric L; Froeliger, Brett E; Passik, Steven D; Howard, Matthew O
Recurrent use of prescription opioid analgesics by chronic pain patients may result in opioid dependence, which involves implicit neurocognitive operations that organize and impel craving states and compulsive drug taking behavior. Prior studies have identified an attentional bias (AB) towards heroin among heroin dependent individuals. The aim of this study was to determine whether opioid-dependent chronic pain patients exhibit an AB towards prescription opioid-related cues. Opioid-dependent chronic pain patients (n = 32) and a comparison group of non-dependent opioid users with chronic pain (n = 33) completed a dot probe task designed to measure opioid AB. Participants also rated their opioid craving and self-reported arousal associated with opioid-related and neutral images, pain severity, and relief from pain treatments. Repeated-measures ANOVA revealed a significant group (opioid-dependent vs. non-dependent opioid user) × presentation duration (200. vs. 2,000 ms.) interaction, such that opioid-dependent individuals evidenced a significant AB towards opioid cues presented for 200 ms but not for cues presented for 2,000 ms, whereas non-dependent opioid users did not exhibit a significant mean AB at either stimulus duration. Among opioid-dependent individuals, 200 ms opioid AB was significantly associated with opioid craving, while among non-dependent opioid users, 200 ms opioid AB was significantly associated with relief from pain treatments. Furthermore, dependent and non-dependent opioid users experienced opioid cues as significantly more arousing than neutral cues. Opioid dependence among chronic pain patients appears to involve an automatic AB towards opioid-related cues. When coupled with chronic pain, attentional fixation on opioid cues may promote compulsive drug use and addictive behavior.
Garland, Eric L.; Froeliger, Brett; Passik, Steven D.; Howard, Matthew O.
Recurrent use of prescription opioid analgesics by chronic pain patients may result in opioid dependence, which involves implicit neurocognitive operations that organize and impel craving states and compulsive drug taking behavior. Prior studies have identified an attentional bias (AB) towards heroin among heroin dependent individuals. The aim of this study was to determine whether opioid-dependent chronic pain patients exhibit an AB towards prescription opioidrelated cues. Opioid-dependent chronic pain patients (n = 32) and a comparison group of non-dependent opioid users with chronic pain (n = 33) completed a dot probe task designed to measure opioid AB. Participants also rated their opioid craving and self-reported arousal associated with opioid-related and neutral images, pain severity, and relief from pain treatments. Repeated-measures ANOVA revealed a significant group (opioid-dependent vs. non-dependent opioid user) × presentation duration (200 ms. vs. 2000 ms.) interaction, such that opioid-dependent individuals evidenced a significant AB towards opioid cues presented for 200 ms but not for cues presented for 2000 ms, whereas non-dependent opioid users did not exhibit a significant mean AB at either stimulus duration. Among opioid-dependent individuals, 200 ms opioid AB was significantly associated with opioid craving, while among non-dependent opioid users, 200 ms opioid AB was significantly associated with relief from pain treatments. Furthermore, dependent and non-dependent opioid users experienced opioid cues as significantly more arousing than neutral cues. Opioid dependence among chronic pain patients appears to involve an automatic AB towards opioid-related cues. When coupled with chronic pain, attentional fixation on opioid cues may promote compulsive drug use and addictive behavior. PMID:22968666
Stotts, Angela L.; Dodrill, Carrie L.; Kosten, Thomas R.
The development of effective treatments for opioid dependence is of great importance given the devastating consequences of the disease. Pharmacotherapies for opioid addiction include opioid agonists, partial agonists, opioid antagonists, and alpha-2-adrenergic agonists, which are targeted toward either detoxification or long-term agonist maintenance. Agonist maintenance therapy is currently the recommended treatment for opioid dependence due to its superior outcomes relative to detoxification. Detoxification protocols have limited long term efficacy and patient discomfort remains a significant therapy challenge. Buprenorphine’s effectiveness relative to methadone remains a controversy and may be most appropriate for patients in need of low doses of agonist treatment. Buprenorphine appears superior to alpha-2 agonists, however, and office-based treatment with buprenorphine in the US is gaining support. Studies of sustained-release formulations of naltrexone suggest improved effectiveness for retention and sustained abstinence, however, randomized clinical trials are needed. PMID:19538000
Opioid use in pregnancy is not uncommon, and the use of illicit opioids during pregnancy is associated with an increased risk of adverse outcomes. The current standard of care for pregnant women with opioid dependence is referral for opioid-assisted therapy with methadone, but emerging evidence suggests that buprenorphine also should be considered. Medically supervised tapered doses of opioids during pregnancy often result in relapse to former use. Abrupt discontinuation of opioids in an opioid-dependent pregnant woman can result in preterm labor, fetal distress, or fetal demise. During the intrapartum and postpartum period, special considerations are needed for women who are opioid dependent to ensure appropriate pain management, to prevent postpartum relapse and a risk of overdose, and to ensure adequate contraception to prevent unintended pregnancies. Patient stabilization with opioid-assisted therapy is compatible with breastfeeding. Neonatal abstinence syndrome is an expected and treatable condition that follows prenatal exposure to opioid agonists.
Mistry, Chetna J; Bawor, Monica; Desai, Dipika; Marsh, David C; Samaan, Zainab
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
Sander, Stephanie C Eken; Hays, Lon R
Prescription opioids are used medically to treat pain, but their diversion and abuse continues to escalate in the United States. Abuse of OxyContin (Purdue Pharma LP, Stamford, CT), a timed-release form of oxycodone, is a major focus of public health and law enforcement agencies. The rise in opioid abuse may lead to an increase in opioid dependence in pregnancy, which was a focus of this study. Our retrospective chart review examined the demographics and patterns of opioid addiction of pregnant women admitted to an inpatient psychiatric unit in an academic medical center in central Kentucky. Charts of 94 women admitted from January 2001 to May 2004 were reviewed. Information obtained included demographics and details of their opioid use, including the specific opioid(s) used, route of administration, and duration of use. Treatment information included length of hospital stay, stabilizing dose of methadone, comorbid drug use, and concomitant Axis I diagnoses. Most women were in their mid-twenties and in the second trimester of pregnancy when they sought treatment. Benzodiazepines were the most common comorbid drugs of abuse and the most frequent medical complication of their drug use was hepatitis C, newly diagnosed in 11 patients. This study demonstrates the need for further research in prescription opioid dependency in pregnancy, methadone maintenance therapy, the safety of detoxification, and neonatal outcomes.
Sarkar, Siddharth; Varshney, Mohit; Patil, Vaibhav; Lal, Rakesh
Background: Although tramadol has been used in the management of acute withdrawal in patients with opioid dependence, its use for maintenance treatment as a harm reduction approach has not been assessed systematically. This case series describes patients with opioid dependence who were treated with tramadol for long-term maintenance. Methods: Patients with opioid dependence who received treatment at the National Drug Dependence Treatment Centre of All India Institute of Medical Sciences, New Delhi, were included in the study. Patients who received at least 6 months of tramadol and had follow-up adherence of more than 80% were included in the case series. Results: A total of 25 cases were included, all of whom were males. The types of opioids being taken at the time of initiation of tramadol were natural opiates (poppy husk and raw opium), followed by heroin. The median dose of tramadol at initiation and maintenance was 300 mg/day. Nineteen patients were able to achieve complete abstinence to other opiates on tramadol. Conclusion: Tramadol may be an effective option in the long-term management of patients with opioid dependence. Further studies are required for establishing the efficacy of tramadol for agonist management of patients with opioid dependence. PMID:28936080
Sarkar, Siddharth; Varshney, Mohit; Patil, Vaibhav; Lal, Rakesh
Although tramadol has been used in the management of acute withdrawal in patients with opioid dependence, its use for maintenance treatment as a harm reduction approach has not been assessed systematically. This case series describes patients with opioid dependence who were treated with tramadol for long-term maintenance. Patients with opioid dependence who received treatment at the National Drug Dependence Treatment Centre of All India Institute of Medical Sciences, New Delhi, were included in the study. Patients who received at least 6 months of tramadol and had follow-up adherence of more than 80% were included in the case series. A total of 25 cases were included, all of whom were males. The types of opioids being taken at the time of initiation of tramadol were natural opiates (poppy husk and raw opium), followed by heroin. The median dose of tramadol at initiation and maintenance was 300 mg/day. Nineteen patients were able to achieve complete abstinence to other opiates on tramadol. Tramadol may be an effective option in the long-term management of patients with opioid dependence. Further studies are required for establishing the efficacy of tramadol for agonist management of patients with opioid dependence.
The purpose of the study was to investigate a new method for detoxifying opioid-dependent patients. Butorphanol is an opiod with mixed agonist-antagonist properties, and is marketed as a nasal spray. Undiluted, it will cause significant physical withdrawal symptoms in a population dependent on opioids. Forty patients dependent on opioids were detoxified using dilute butorphanol spray. The initial concentration was 40% and gradually reduced. This technique was highly successful in keeping this difficult group of patients engaged in the treatment process for a longer period. This time increased the probability of getting these patients involved with postdetoxification services. There was a subset of patients who had chronic pain and were opioid dependent, who had adequate control of pain with butorphanol spray at 10 to 20% concentration. This unique and unusual approach is worthy of open discussion and further scientific studies.
other symptoms. His medical history was significant for posttraumatic stress disorder, anxiety, chronic pain , phantom limb pain , insomnia, and depression...FEB 2013 2. REPORT TYPE N/A 3. DATES COVERED - 4. TITLE AND SUBTITLE Opioid-induced hyperalgesia--worsening pain in opioid-dependent...Report Opioid-induced hyperalgesia—worsening pain in opioid-dependent patients☆ Abstract Patients with chronic opioid use are commonly treated in the
Mannelli, Paolo; Peindl, Kathleen S; Wu, Li-Tzy
Purpose Opioid dependence (OD) is a serious and growing clinical condition with increasing social costs that requires expanding treatment beyond opioid agonist substitution. The opioid antagonist naltrexone has displayed a remarkable association of theoretical effectiveness and poor clinical utility in treating OD due to noncompliant behavior and low acceptability among patients, only partly modified by psychosocial interventions. We reviewed pharmacological studies, including naltrexone depot formulations and combination treatments. Method We searched PubMed for clinical studies on the use of naltrexone implants and slow-release injections in OD, and investigations using adjunct medications to improve naltrexone maintenance therapy of OD. We discussed the results in view of their application to the clinical practice. Results Significant reduction in opioid use and improved retention in treatment have been found in several studies using depot naltrexone formulations, some of which are controlled clinical trials. Pilot investigations have gathered initial positive results on the use of naltrexone in combination with serotonin reuptake inhibitors, α-2 adrenergic, opioid, and γ-aminobutyric acid agonist medications. Conclusion Current evidence suggests that more research on effectiveness and safety is needed in support of depot naltrexone treatment for OD. Further research comparing slow-release with oral naltrexone and opioid agonist medications will help characterize the role of opioid antagonist-mediated treatment of OD. Preliminary investigations on naltrexone combination treatments suggest the opportunity to continue study of new mixed receptor activities for the treatment of OD and other drug addictions. PMID:21731898
Evans, Christopher J; Cahill, Catherine M
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
Lutfy, K; Parikh, D; Lee, D L; Liu, Y; Ferrini, M G; Hamid, A; Friedman, T C
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
Haasen, Christian; van den Brink, Wim
To provide an overview of published studies on agonist maintenance treatment options for opioid-dependent patients. The recent publication of controlled trials confirms earlier clinical evidence of the efficacy of diamorphine (heroin) in the treatment of opioid dependence. Findings show not only efficacy with respect to improvement of health, reduction of illicit drug use, reduction of criminality and stabilization of social conditions, but also cost effectiveness in the treatment of chronic treatment-resistant heroin addicts. Agonist maintenance treatment has become the first-line treatment for chronic opioid dependence. High-quality studies demonstrate the effectiveness of a growing number of different agonist maintenance treatments for opioid dependence such as methadone and buprenorphine. In addition, there is new evidence for the effectiveness of other agonists, mainly slow-release morphine, intravenous and inhalable diamorphine and possibly oral diamorphine. Maintenance treatment with intravenous or inhalable diamorphine should be implemented into the healthcare system to treat a group of severely dependent treatment-resistant patients. Furthermore, the opioid-dependent patients not under treatment need to be engaged in maintenance treatments through other harm reduction measures. Agonist maintenance treatment is very effective in stabilizing the health condition and social situation, while also reducing harm, thereby increasing life expectancy and quality of life.
Loseth, Guro E; Ellingsen, Dan-Mikael; Leknes, Siri
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.
Loseth, Guro E.; Ellingsen, Dan-Mikael; Leknes, Siri
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
Evans, Christopher J.; Cahill, Catherine M.
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
Arunogiri, Shalini; Foo, Lea; Frei, Matthew; Lubman, Dan I
Managing opioid dependence in pregnant women is a complex and potentially challenging task. Drug-dependent women may be difficult to engage in antenatal care and opioid substitution requires careful dose titration. Pregnancy, however, can be an opportune time to effect behaviour change, and supporting an opioid-dependent woman through pregnancy can be a rewarding clinical experience. This article provides an overview of treatment principles for managing opioid dependence in pregnancy, and reviews current treatment guidelines for use of opioid-substitution therapy in pregnant women. The management of opioid dependence during pregnancy requires holistic and comprehensive assessment and referral to specialist services is often appropriate. Specific issues that may need to be addressed include decision-making regarding the choice of opioid-substitution therapy and the potential for neonatal abstinence syndrome in the newborn. General practitioners are often well placed to support and coordinate care of their opioid-dependent pregnant patients.
Potter, Jennifer S; Prather, Kristi; Kropp, Frankie; Byrne, Mimmie; Sullivan, C Rollynn; Mohamedi, Nadia; Copersino, Marc L; Weiss, Roger D
Treatment research with opioid-dependent populations has not traditionally distinguished between those dependent on prescription opioids versus dependent upon heroin. Evidence suggests there is a substantial subpopulation of individuals with opioid dependence resulting largely or exclusively from prescription opioid use. Because this subpopulation may respond to treatment differently from heroin users, a method for discriminating DSM-IV opioid dependence due to prescription opioid use would provide more precision when examining this population. This paper describes an innovative method using a currently available diagnostic instrument, to diagnose DSM-IV opioid dependence and distinguish between dependence resulting from prescription opioids versus dependence upon heroin.
Rolland, B; Bouhassira, D; Authier, N; Auriacombe, M; Martinez, V; Polomeni, P; Brousse, G; Schwan, R; Lack, P; Bachellier, J; Rostaing, S; Bendimerad, P; Vergne-Salle, P; Dematteis, M; Perrot, S
Since the 1990s, the use of prescription opioids has largely spread, which has brought a real progress in the treatment of pain. The long-term use of prescription opioid is sometimes required, and may lead to pharmacological tolerance and withdrawal symptoms, i.e. pharmacological dependence on prescription opioids. Occasionally, this may also lead to misuse of prescription opioids (MPO). MPO preferentially occurs in vulnerable individuals, i.e., those with a young age, history of other addictive or psychiatric disorders, especially anxious and depressive disorders. MPO is associated with numerous complications, including an increased risk of fatal overdose. Prevention of MPO begins before the opioid prescription, with the identification of potential vulnerability factors. A planned and personalized monitoring should be systematically implemented. In vulnerable patients, contractualizing the prescription is warranted. During follow-up, the relevance of the prescription should be regularly reconsidered, according to the benefit observed on pain and the potential underlying signs of MPO. Patients with suspected MPO should be referred early to pain or addiction centers. The treatment of MPO should be based on multidisciplinary strategies, involving both the addiction and pain aspects: progressive opioid withdrawal, non-pharmacological measures against pain, or switching to medication-assisted treatment of addiction (i.e., buprenorphine or methadone).
Worley, Matthew J; Shoptaw, Steven J; Bickel, Warren K; Ling, Walter
Research grounded in behavioral economics has previously linked addictive behavior to disrupted decision-making and reward-processing, but these principles have not been examined in prescription opioid addiction, which is currently a major public health problem. This study examined whether pre-treatment drug reinforcement value predicted opioid use during outpatient treatment of prescription opioid addiction. Secondary analyses examined participants with prescription opioid dependence who received 12 weeks of buprenorphine-naloxone and counseling in a multi-site clinical trial (N=353). Baseline measures assessed opioid source and indices of drug reinforcement value, including the total amount and proportion of income spent on drugs. Weekly urine drug screens measured opioid use. Obtaining opioids from doctors was associated with lower pre-treatment drug spending, while obtaining opioids from dealers/patients was associated with greater spending. Controlling for demographics, opioid use history, and opioid source frequency, patients who spent a greater total amount (OR=1.30, p<.001) and a greater proportion of their income on drugs (OR=1.31, p<.001) were more likely to use opioids during treatment. 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. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Worley, Matthew J.; Shoptaw, Steven J.; Bickel, Warren K.; Ling, Walter
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
... Opioid Dependence Can Start in Just a Few Days Prescribing narcotic painkillers for 3 days or less may lower chances of addiction, study ... the supply of opioids they prescribe to three days or less may help patients avoid the dangers ...
Weigel, Daniel J.; Donovan, Kimberly A.; Krug, Kevin S.; Dixon, Wayne A.
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…
Weigel, Daniel J.; Donovan, Kimberly A.; Krug, Kevin S.; Dixon, Wayne A.
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…
Wang, Xiao-Fei; Barbier, Elisabeth; Chiu, Yi-Ting; He, Yi; Zhan, Jia; Bi, Guo-Hua; Zhang, Hai-Ying; Feng, Bo; Liu-Chen, Lee-Yuan; Wang, Jia Bei; Xi, Zheng-Xiong
The etiology and pathophysiology underlying opioid tolerance and dependence are still unknown. Because mu opioid receptor (MOR) plays an essential role in opioid action, many vulnerability-related studies have focused on single nucleotide polymorphisms of MOR, particularly on A118G. In this study, we found that a single-point mutation at the MOR T394 phosphorylation site could be another important susceptive factor in the development of opioid tolerance and dependence in mice. T394A mutation, in which a threonine at 394 was replaced by an alanine, did not alter agonist binding to MOR and opioid analgesia, but resulted in loss of etorphine-induced MOR internalization in spinal dorsal horn neurons and opioid analgesic tolerance induced by either morphine or etorphine. In addition, this mutation also caused an increase in intravenous heroin self-administration and in nucleus accumbens dopamine response to heroin. These findings suggest that T394 phosphorylation following MOR activation causes MOR internalization and desensitization, which subsequently contributes to the development of tolerance in both opioid analgesia and opioid reward. Accordingly, T394A mutation blocks opioid tolerance and leads to an increase in brain dopamine response to opioids and in opioid-taking behavior. Thus, the T394 may serve as a new drug target for modulating opioid tolerance and the development of opioid abuse and addiction.
Trigg, Bruce G; Dickman, Samuel L
An acute awareness of the profound social and medical costs associated with heroin and opiate addiction in New Mexico has led a group of advocates from public health, state and local governments, corrections, academia, and community activists to collaborate for the purpose of increasing access to medication-assisted therapy (MAT) with buprenorphine and methadone in New Mexico. This paper describes these collaborations, with a focus on the evolution of harm reduction approaches to substance abuse disorders and successful efforts to make MAT available to incarcerated persons.
Tekieh, E; Zaringhalam, Jalal; Manaheji, H; Maghsoudi, N; Alani, B; Zardooz, H
Interleukin (IL)-6 is known to cause pro- and anti-inflammatory effects during different stages of inflammation. Recent therapeutic investigations have focused on treatment of various inflammatory disorders with anti-cytokine substances. As a result, the aim of this study was to further elucidate the influence of IL-6 in hyperalgesia and edema during different stages of Complete Freund's Adjuvant (CFA)-induced arthritis (AA) in male Wistar rats. AA was induced by a single subcutaneous injection of CFA into the rats' hindpaw. Anti-IL-6 was administered either daily or weekly during the 21 days of study. Spinal mu opioid receptor (mOR) expression was detected by Western blotting. Daily and weekly treatment with an anti-IL-6 antibody significantly decreased paw edema in the AA group compared to the AA control group. Additionally, daily and weekly anti-IL-6 administration significantly reduced hyperalgesia on day 7 in the AA group compared to the AA control group; however, there were significant increases in hyperalgesia in the antibody-treated group on days 14 and 21 compared to the AA control group. IL-6 antibody-induced increases in hyperalgesia on the 14(th) and 21(st) days after CFA injection correlated with a time-dependent, significant reduction in spinal mOR expression during anti-IL-6 treatment. Our study confirmed the important time-dependent relationship between serum IL-6 levels and hyperalgesia during AA. These results suggest that the stages of inflammation in AA must be considered for anti-hyperalgesic and anti-inflammatory interventions via anti-IL-6 antibody treatment.
Hillhouse, Maureen; Donovick, Roger; Cunningham-Rathner, Jerry; Charuvastra, Charlie; Torrington, Matthew; Esagoff, Asher E.; Ling, Walter
Although use of buprenorphine in the treatment of opioid dependence is expected to continue to increase, little is known about the optimal setting for providing the medical and psychosocial care required with buprenorphine pharmacotherapy. OBJECTIVE This study compared buprenorphine therapy delivered in three distinct treatment settings: an opioid-treatment program (OTP) offering individual counseling; a group counseling program utilizing the manualized Matrix Model (MMM) of cognitive-behavioral treatment; and a private clinic setting mirroring standard medical management for buprenorphine treatment provided specifically at a psychiatrist’s private practice (PCS). METHOD Participants were inducted on buprenorphine and provided with treatment over a 52-week study duration. All participants were scheduled for weekly treatment visits for the first 6 study weeks, and two sites reduced treatment to monthly visits for dispensing of medication and psychosocial counseling. Outcomes include opioid use, participant retention in treatment, and treatment participation. RESULTS Participants presenting for treatment at the sites differed only by race/ethnicity, and opioid use did not differ by site. Retention differed by treatment site, with the number of participants who stayed in the study until the end of 20 weeks significantly associated with treatment site. The mean number of minutes spent in each individual counseling session also differed by site. Although no difference in opioid use by treatment site was found, results document a significant association between opioid use and buprenorphine dose. DISCUSSION These results show some differences by treatment site, although the similarity and relative ease in which the sites were able to recruit participants for treatment with buprenorphine, and minor implementation problems reported suggests the feasibility of treatment with buprenorphine across various treatment settings. CONCLUSION Similar rates of continued opioid use
Wickersham, Jeffrey A.; Azar, Marwan M.; Cannon, Christopher M.; Altice, Frederick L.; Springer, Sandra A.
The Rapid Opioid Dependence Screen (RODS) is an 8-item measure of opioid dependence designed for quick, targeted screening in clinical and research settings. Based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition, criteria, the RODS has an average administration of less than 2 minutes and can easily be administered as a stand-alone instrument or as part of a comprehensive interview. This study reports on the initial validation of the RODS among a sample of 97 newly incarcerated, HIV-positive individuals. Using the Mini International Neuropsychiatric Interview as the primary measure of opioid dependence, the RODS showed good-to-strong sensitivity (.97), specificity (.76), positive predictive value (.69), and negative predictive value (.98), while concordance analysis revealed moderate diagnostic agreement (κ = .67). Psychometric properties revealed strong internal consistency (α = .92) and inter-item correlations (.66 to .87). PMID:25559628
Anand, K J; Arnold, J H
To review the definitions and scientific basis for opioid tolerance and dependence in neonates and older children; to assess objective methods for the clinical evaluation of opioid abstinence syndromes in this age group; and to suggest therapeutic strategies for the treatment of opioid abstinence in critically ill neonates and children. The published literature on opioid tolerance and dependence in pediatric patients was reviewed. Data from current clinical practices, nursing procedures, and ongoing clinical research were evaluated. Currently proposed mechanisms of opioid tolerance and dependence are assessed, with particular relevance to the developing human central nervous system. The validity and clinical role of currently available objective methods for the assessment of opioid abstinence in neonates and older infants are defined. The efficacy of various pharmacologic and nonpharmacologic modalities for the treatment of opioid abstinence is evaluated and compared, and a therapeutic approach based on receptor mechanisms, clinical monitoring data, and pharmacologic efficacy is suggested. Important parallels for therapeutically-induced opioid tolerance and withdrawal may be drawn from the assessment and management of neonates born from opioid-addicted mothers. Opioid withdrawal can be prevented with appropriate weaning schedules, diagnosed by objective clinical methods, and treated by a variety of pharmacologic and non-pharmacologic means. Pharmacologic therapy includes the use of opioids, with adjuvant drugs such as diazepam, clonidine, or chlorpromazine. The pathophysiology and assessment of therapeutically induced opioid tolerance and withdrawal merit further research in critically ill pediatric patients.
Koushesh, H R; Afshari, Ramin; Afshari, Reza
Opioid abuse is common in Iran. In 2005, a new version of locally produced illicit opioid vials, so called Norgesic, appeared in the illicit market, which gained popularity rapidly and led to an improvement of stigmatizing the general appearance of dependent cases. Later, some cases suffered Cushing's-like problems. A prospective case series was designed to evaluate 18 Norgesic-dependent subjects who volunteered for abstinence therapy in a rehabilitation clinic from November 1, 2005, to December 30, 2005. In this study, we aimed to describe the clinical and paraclinical findings in detail and define the potential determinants of this Cushing's syndrome outbreak. History, physical examination, plasma cortisol level, and urine screen tests were used to describe the patients. All subjects were male with a mean (SEM) age of 29.8 +/- 1.6 years. The opioid-dependence period was 8.4 +/-0.9 years. In an average of 4.7 +/- 0.3 months, subjects increased their usage to 5.5 +/- 0.5 vials a day. Patients claimed to gain weight. Striae were seen in 38.9%, previously documented psychological problems in 33.3%, weakness in 27.8%, high systolic blood pressure in 22.2%, moon face in 16.7%, hirsutism in 11.1%, extensive dermal infection in 11.1%, gynecomastia in 5.6%, back pain in 5.6%, insomnia in 5.6%, and lack of potency in 5.6%. Their cortisol level, on average, was 4.8 +/- 1.1 microg/dL. Hepatitis C virus was positive in 22.2%. Urine-screening tests were positive for morphine and negative for buprenorphine. In conclusion, these new vials contain steroids as well as opioids. This combination could be more dangerous than opioids themselves.
Berens, Richard J; Meyer, Michael T; Mikhailov, Theresa A; Colpaert, Krista D; Czarnecki, Michelle L; Ghanayem, Nancy S; Hoffman, George M; Soetenga, Deborah J; Nelson, Thomas J; Weisman, Steven J
Critically ill children are treated with opioid medication in an attempt to decrease stress and alleviate pain during prolonged pediatric intensive care. This treatment plan places children at risk for opioid dependency. Once dependent, children need to be weaned or risk development of a withdrawal syndrome on abrupt cessation of medication. We enrolled opioid-dependent children into a prospective, randomized trial of 5- versus 10-day opioid weaning using oral methadone. Children exposed to opioids for an average of 3 wk showed no difference in the number of agitation events requiring opioid rescue (3 consecutive neonatal abstinence scores >8 every 2 h) in either wean group. Most of the events requiring rescue occurred on day 5 and 6 of the wean in both treatment groups. Patients may be able to be weaned successfully in 5 days once converted to oral methadone, with a follow-up period after medication wean to observe for a delayed withdrawal syndrome.
Raisch, Dennis W; Fye, Carol L; Boardman, Kathy D; Sather, Mike R
To review opioid dependence (OD) and its treatment. Pharmacologic treatments, including the use of buprenorphine/naloxone, are presented. Pharmaceutical care functions for outpatient OD treatment are discussed. Primary and review articles were identified by MEDLINE and HEALTHSTAR searches (from 1966 to November 2000) and through secondary sources. Tertiary sources were also reviewed regarding general concepts of OD and its treatment. Relevant articles were reviewed after identification from published abstracts. Articles were selected based on the objectives for this article. Studies of the treatment of OD with buprenorphine were selected based on the topic (pharmacology, pharmacokinetics, adverse reactions) and study design (randomized, controlled clinical trials in patients with OD with active/placebo comparisons and/or comparisons of active OD treatments). Articles regarding pharmacists' activities in the treatment and prevention of OD were reviewed for the pharmaceutical care section. OD is considered a medical disorder with costly adverse health outcomes. Although methadone maintenance treatment (MMT) is cost-effective for OD, only about 12% of individuals with OD receive this treatment. Psychological and pharmacologic modalities are used to treat OD, but patients often relapse. Drug therapy includes alpha 2-agonists for withdrawal symptoms, detoxification regimens with or without opioids, opioid antagonists, and opioid replacement including methadone, levomethadyl acetate, and buprenorphine. The Drug Addiction Treatment Act of 1999 allows for office-based opioid replacement therapies. Sublingual buprenorphine with naloxone can be used in this milieu. Buprenorphine with naloxone is currently under new drug application review with the Food and Drug Administration. Clinical research shows buprenorphine to be equal in effectiveness to methadone, but safer in overdose due to its ceiling effect on respiratory depression. It has lower abuse potential and fewer
Kraus, Mark; Lintzeris, Nicholas; Maier, Christoph; Savage, Seddon
The global consumption of opioids continues to rise, which has led to an increasing rate of diversion, misuse, addiction, and deaths related to prescription opioids. This has been particularly well documented in the USA; however, opioid analgesic dependence (OAD) is an increasing concern in Europe. More guidance is required for European healthcare professionals in the prevention, detection, treatment and management of OAD. The first Opioid Analgesic Dependence Education Nexus (OPEN) Mentor Meeting was held in Berlin in September 2014 to address this. An international Expert Panel, combining expertise in OAD from Australia, USA and Europe, invited 16 European experts in the pain and addiction fields to develop a best-practice approach to OAD that European practitioners can adopt. The outcomes from this meeting are presented here and included are a set of shared strategies that may be universally adopted by all healthcare professionals working with patients who use opioids.
Fiellin, David A; Pantalon, Michael V; Chawarski, Marek C; Moore, Brent A; Sullivan, Lynn E; O'Connor, Patrick G; Schottenfeld, Richard S
The optimal level of counseling and frequency of attendance for medication distribution has not been established for the primary care, office-based buprenorphine-naloxone treatment of opioid dependence. We conducted a 24-week randomized, controlled clinical trial with 166 patients assigned to one of three treatments: standard medical management and either once-weekly or thrice-weekly medication dispensing or enhanced medical management and thrice-weekly medication dispensing. Standard medical management was brief, manual-guided, medically focused counseling; enhanced management was similar, but each session was extended. The primary outcomes were the self-reported frequency of illicit opioid use, the percentage of opioid-negative urine specimens, and the maximum number of consecutive weeks of abstinence from illicit opioids. The three treatments had similar efficacies with respect to the mean percentage of opioid-negative urine specimens (standard medical management and once-weekly medication dispensing, 44 percent; standard medical management and thrice-weekly medication dispensing, 40 percent; and enhanced medical management and thrice-weekly medication dispensing, 40 percent; P=0.82) and the maximum number of consecutive weeks during which patients were abstinent from illicit opioids. All three treatments were associated with significant reductions from baseline in the frequency of illicit opioid use, but there were no significant differences among the treatments. The proportion of patients remaining in the study at 24 weeks did not differ significantly among the patients receiving standard medical management and once-weekly medication dispensing (48 percent) or thrice-weekly medication dispensing (43 percent) or enhanced medical management and thrice-weekly medication dispensing (39 percent) (P=0.64). Adherence to buprenorphine-naloxone treatment varied; increased adherence was associated with improved treatment outcomes. Among patients receiving buprenorphine
Neufeld, Karin J.; Kidorf, Michael S.; Kolodner, Kenneth; King, Van L.; Clark, Michael; Brooner, Robert K.
Antisocial personality disorder (APD) is associated with increased problem severity in treatment seeking opioid dependent patients. Treatment studies have reported mixed results but generally show that APD patients make progress that is often comparable to drug dependent patients without the personality disorder. Much of this work is based on secondary analyses of studies evaluating responses to a variety of drug abuse treatment interventions. The present study reports on a randomized prospective trial evaluating a behavioral approach for managing opioid dependent patients with APD. Subjects (N=100) met DSM criteria for opioid dependence and APD using a structured clinical interview, and were randomly assigned to the experimental condition (n = 51) that used a highly structured contingency management intervention, or control condition (n = 49) that reflected standard methadone treatment. Subjects in the experimental group had significantly better counseling attendance and some indication of lower psychosocial impairment compared to the control group. The experimental intervention increased attendance in subjects with low, as well as high levels of psychopathy, and with and without other psychiatric comorbidity. These findings support the development of interventions more tailored to APD drug-dependent patients. PMID:17574801
McCarthy, John J; Leamon, Martin H; Finnegan, Loretta P; Fassbender, Catherine
Increase in the number of opioid-dependent pregnant women delivering babies at risk for neonatal abstinence syndrome prompted a US Government Accountability Office report documenting deficits in research and provider knowledge about care of the maternal/fetal unit and the neonate. There are 3 general sources of dependence: untreated opioid use disorder, pain management, and medication-assisted treatment with methadone or buprenorphine. A survey of methadone patients' experiences when telling a physician of their pregnancy and opioid dependence demonstrated physician confusion about proper care, frequent negative interactions with the mother, and failures to provide appropriate referral. Patients in pain management were discharged without referral when the physician was told of the pregnancy. Methadone and buprenorphine were frequently seen negatively because they "caused" neonatal abstinence syndrome. Most mothers surveyed had to find opioid treatment on their own. How dependence is managed medically is a critical determinant of the level of stress on both mother and fetus, and therefore another determinant of neonatal health. The effects of both opioid withdrawal stress and maternal emotional stress on neonatal and developmental outcomes are reviewed. Currently, there have been efforts to criminalize maternal opioid dependence and to encourage or coerce pregnant women to undergo withdrawal. This practice poses both acute risks of fetal hypoxia and long-term risks of adverse epigenetic programming related to catecholamine and corticosteroid surges during withdrawal. Contemporary studies of the effects of withdrawal stress on the developing fetal brain are urgently needed to elucidate and quantify the risks of such practices. At birth, inconsistencies in the hospital management of neonates at risk for neonatal abstinence syndrome have been observed. Neglect of the critical role of maternal comforting in neonatal abstinence syndrome management is an iatrogenic and
Scherrer, Jeffrey F; Svrakic, Dragan M; Freedland, Kenneth E; Chrusciel, Timothy; Balasubramanian, Sumitra; Bucholz, Kathleen K; Lawler, Elizabeth V; Lustman, Patrick J
Prescription opioid analgesic use has quintupled recently. Evidence linking opioid use with depression emanates from animal models and studies of persons with co-occurring substance use and major depression. Little is known about depressogenic effects of opioid use in other populations. The purpose of this study was to determine whether prescription opioids are associated with increased risk of diagnosed depression. Retrospective cohort study, new user design. Medical record data from 49,770 US Department of Veterans Affairs (VA) health care system patients with no recent (24-month) history of opioid use or a diagnosis of depression in 1999 and 2000. Propensity scores were used to control for bias by indication, and the data were weighted to balance the distribution of covariates by duration of incident opioid exposure. Cox proportional hazard models with adjustment for painful conditions were used to estimate the association between duration of prescription opioid use and the subsequent risk of development of depression between 2001 and 2007. Of 49,770 patients who were prescribed an opioid analgesic, 91 % had a prescription for < 90 days, 4 % for 90-180 days, and 5 % for > 180 days. Compared to patients whose prescription was for < 90 days, the risk of depression increased significantly as the duration of opioid prescription increased (HR = 1.25; 95 % CI: 1.05-1.46 for 90-180 days, and HR = 1.51; 95 % CI:1.31-1.74 for > 180 days). In this sample of veterans with no recent (24-month) history of depression or opioid analgesic use, the risk of development of depression increased as the duration of opioid analgesic exposure increased. The potential for depressogenic effect should be considered in risk-benefit discussions, and patients initiating opioid treatment should be monitored for development of depression.
Rudd, Rose A; Aleshire, Noah; Zibbell, Jon E; Gladden, R Matthew
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
Campbell, Gabrielle; Nielsen, Suzanne; Larance, Briony; Bruno, Raimondo; Mattick, Richard; Hall, Wayne; Lintzeris, Nicholas; Cohen, Milton; Smith, Kimberley; Degenhardt, Louisa
There is increasing concern about the appropriateness of prescribing pharmaceutical opioids for chronic non-cancer pain (CNCP), given the risks of problematic use and dependence. This article examines pharmaceutical opioid dose and dependence and examines the correlates of each. Baseline data were obtained from a national sample of 1,424 people across Australia (median 58 years, 55% female and experiencing pain for a median of 10 years), who had been prescribed opioids for CNCP. Current opioid consumption was estimated in oral morphine equivalent (OME; mg per day), and ICD-10 pharmaceutical opioid dependence was assessed using the Composite International Diagnostic Interview. Current opioid consumption varied widely: 8.8% were taking <20 mg OME per day, 52.1% were taking 21-90 mg OME, 24.3% were taking 91-199 mg OME, and 14.8% were taking >= 200 mg OME. Greater daily OME consumption was associated with higher odds of multiple physical and mental health issues, aberrant opioid use, problems associated with opioid medication and opioid dependence. A significant minority, 8.5%, met criteria for lifetime ICD-10 pharmaceutical opioid dependence and 4.7% met criteria for past year ICD-10 pharmaceutical opioid dependence. Multivariate analysis found past-year dependence was independently associated with being younger, exhibiting more aberrant behaviors and having a history of benzodiazepine dependence. In this population of people taking opioids for CNCP, consumption of higher doses was associated with increased risk of problematic behaviors, and was more likely among people with a complex profile of physical and mental health problems. Wiley Periodicals, Inc.
Lachman, Herbert M; Fann, Cathy S J; Bartzis, Michael; Evgrafov, Oleg V; Rosenthal, Richard N; Nunes, Edward V; Miner, Christian; Santana, Maria; Gaffney, Jebediah; Riddick, Amy; Hsu, Chia-Lin; Knowles, James A
The genetic predisposition to addiction to opioids and other substances is transmitted as a complex genetic trait, which investigators are attempting to characterize using genetic linkage and association. We now report a high-density genome-wide linkage study of opioid dependence. We ascertained 305 DSM-IV opioid dependent affected sibling pairs from an ethnically mixed population of methadone maintained subjects and genotyped their DNA using Affymetrix 10K v2 arrays. Analysis with MERLIN identified a region on chromosome 14q with a non-parametric lod (NPL) of 3.30. Secondary analyses indicated that this locus was relatively specific to the self-identified Puerto Rican subset, as the NPL increased from 3.30 to 5.00 (NPL(Caucasian) = 0.05 and NPL(African Amer.) = 0.15). The 14q peak encompasses the NRXN3 gene (neurexin 3), which was previously identified as a potential candidate gene for addiction. Secondary analyses also identified several regions with gender-specific NPL scores greater than 2.00. The most significant was a peak on (10q) that increased from 0.90 to 3.22 when only males were considered (NPL(female) = 0.05). Our linkage data suggest specific chromosomal loci for future fine-mapping genetic analysis and support the hypothesis that ethnic and gender specific genes underlie addiction susceptibility.
Todadze, Kh; Mosia, S
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
Zaaijer, Eline R; Bruijel, Jessica; Blanken, Peter; Hendriks, Vincent; Koeter, Maarten W J; Kreek, Mary Jeanne; Booij, Jan; Goudriaan, Anna E; van Ree, Jan M; van den Brink, Wim
Most studies investigating the role of personality as a risk factor for the development of opioid dependence compare dependent opioid users with healthy controls who never used heroin. In order to understand the potential protective role of personality, it is crucial to compare illicit opioid users who never became dependent with dependent opioid users. This study aims to examine the role of personality as a risk factor for opioid use and as a protective factor for the development of opioid dependence. Comparing personality factors between three groups: (1) 161 never-dependent illicit opioid users who have been using illicit opioids but never became opioid dependent; (2) 402 dependent opioid users in methadone maintenance treatment or heroin-assisted treatment; and (3) 135 healthy controls who never used heroin. Personality was assessed with a short version of Cloninger's Temperament and Character Inventory. Never-dependent opioid users reported more Novelty Seeking and Harm Avoidance and less Self-Directedness and Cooperativeness than healthy controls and more Reward Dependence and Self-Directedness, and less Harm Avoidance than dependent opioid users. Furthermore, never-dependent opioid users reported more Self-Transcendence than both dependent opioid users and healthy controls. Never-dependent opioid users may have started to use opioids partly due to their tendency to seek novel and/or spiritual experiences (high Novelty Seeking, high Self-Transcendence) and their tendency to avoid aversive stimuli (high Harm Avoidance), whereas they may have been protected against the development of dependence by their need for social approval (high Reward Dependence) and their self-efficacy (high Self-Directedness). Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Zambelli, Vanessa Olzon; Fernandes, Ana Carolina de Oliveira; Gutierrez, Vanessa Pacciari; Ferreira, Julio Cesar Batista; Parada, Carlos Amilcar; Mochly-Rosen, Daria; Cury, Yara
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
Nelson, Elliot C.; Agrawal, Arpana; Heath, Andrew C.; Bogdan, Ryan; Sherva, Richard; Zhang, Bo; Al-Hasani, Ream; Bruchas, Michael R.; Chou, Yi-Ling; Demers, Catherine H.; Carey, Caitlin E.; Conley, Emily D.; Fakira, Amanda K.; Farrer, Lindsay A.; Goate, Alison; Gordon, Scott; Henders, Anjali K.; Hesselbrock, Victor; Kapoor, Manav; Lynskey, Michael T.; Madden, Pamela A.F.; Moron, Jose A.; Rice, John P.; Saccone, Nancy L.; Schwab, Sibylle G.; Shand, Fiona L.; Todorov, Alexandre A.; Wallace, Leanne; Wang, Ting; Wray, Naomi R.; Zhou, Xin; Degenhardt, Louisa; Martin, Nicholas G.; Hariri, Ahmad R.; Kranzler, Henry R.; Gelernter, Joel; Bierut, Laura J.; Clark, David J.; Montgomery, Grant W.
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 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 5 genome-wide significant CNIH3 SNPs. The A allele of rs10799590, the most highly associated SNP, was robustly protective [p=4.30E-9; OR 0.64 (95%CI 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 AMPA glutamate system. PMID:26239289
Tetrault, Jeanette M.; Fiellin, David A.
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. PMID:22235870
Sinchaisuk, S; Ho, I K; Rockhold, R W
The nucleus paragigantocellularis (PGi) has been hypothesized to play an important role in the development of physical dependence on opioids, including the prototype mu-opioid receptor agonist, morphine, and the mixed agonist/antagonist, butorphanol, which shows selective kappa-opioid receptor agonist activity, in rats. In confirmation of previous work, electrical stimulation of the PGi in opioid-nai;ve rats induced stimulus-intensity-related, withdrawal-like behaviors similar to those observed during naloxone-precipitated withdrawal from dependence upon butorphanol. Novel findings were made in rats surgically implanted with cannulae aimed at the lateral ventricle and the right PGi and made physically dependent by intracerebroventricular infusion of either morphine (26 nmol/microl/h) or butorphanol (26 nmol/microl/h) through an osmotic minipump for 3 days. Two hours following termination of the opioid infusion, microinjections of naloxone (11 nmol/400 nl), a nonselective opioid receptor antagonist, or nor-binaltorphimine (nor-BNI) (3.84 nmol/400 nl), a selective kappa-opioid receptor antagonist, were made into the PGi of morphine-dependent and butorphanol-dependent rats. Discrete PGi injections precipitated withdrawal behaviors, with significant (P<.05) increases noted in the incidence of teeth chattering, wet-dog shakes, and scratching. Composite scores for behavioral withdrawal were significantly higher in nor-BNI-precipitated, butorphanol-dependent rats (score=6.8+/-0.6), in naloxone-precipitated, butorphanol-dependent rats (8.9+/-0.8), and in naloxone-precipitated, morphine-dependent rats (11.5+/-0.9) than in all other groups. Both kappa- and mu-opioid receptor mediated dependence can be demonstrated at the level of a discrete medullary site, the PGi, which further supports a specific role for this nucleus in elicitation of behavioral responses during opioid withdrawal.
Marrone, Gina F.; Grinnell, Steven G.; Lu, Zhigang; Rossi, Grace C.; Le Rouzic, Valerie; Xu, Jin; Majumdar, Susruta; Pan, Ying-Xian; Pasternak, Gavril W.
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
Marrone, Gina F; Grinnell, Steven G; Lu, Zhigang; Rossi, Grace C; Le Rouzic, Valerie; Xu, Jin; Majumdar, Susruta; Pan, Ying-Xian; Pasternak, Gavril W
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.
Heberlein, Annemarie; Leggio, Lorenzo; Stichtenoth, Dirk; Hillemacher, Thomas
This article addresses the question of 'best treatment options', which clinicians face when treating pregnant women with alcohol and opioid dependence. Studies show that alcohol consumption is associated with fetal abnormalities and long-term cognitive problems depending on the amount consumed, drinking pattern, and time of gestation. Screening and evaluation of specific interventions are important to reduce alcohol consumption during pregnancy and associated problems in infants. Opioid detoxification is only recommended beyond the first trimester and only in those pregnant women who refuse opioid maintenance therapy. Methadone is the most established treatment of pregnant opioid-dependent women, though recent results indicate some advantages of buprenorphine, slow-release oral methadone and diamorphine compared with methadone. Benzodiazepines seem to be the most recommendable option for managing alcohol withdrawal, and psychosocial interventions succeed in reducing alcohol consumption or in maintaining abstinence in alcohol-dependent pregnant women. Regarding opioid dependence, current results suggest that factors like the health status of the mother, the need for additional medications (e.g. treatment for HIV), comorbid drug dependence, and concurrent drug use need to be considered in order to find the 'best opioid substitute'.
Aldemir, E; Coskunol, H; Kilic, M; Sert, I
Opioid dependence is an increasing public health problem. One of the complications of intravenous opioid use is hepatitis C virus infection, which, in turn, is one of the most common indications for liver transplantations throughout the world. Therefore, the treatment of opioid dependence in a liver transplant recipient requires special attention in terms of graft function, drug interactions, and patient compliance. Buprenorphine is a semi-synthetic opioid-derived agent with analgesic effects. To prevent buprenorphine abuse, it is combined with the opioid antagonist naloxone. This buprenorphine/naloxone combination is the only drug approved for the treatment of opioid dependence in Turkey. Although the literature includes data about the safe usage of buprenorphine in liver transplantation in animals, there is no such evidence in either case reports or clinical trials for the same in humans. In this article, we present a report of our treatment of 2 opioid-dependent patients with buprenorphine/naloxone after liver transplantation due to hepatitis C virus-induced liver cirrhosis. Copyright © 2016 Elsevier Inc. All rights reserved.
McCauley, Jenna L.; Mercer, Mary Ashley; Barth, Kelly S.; Brady, Kathleen T.; Back, Sudie E.
Background Nearly two-thirds of prescription opioid dependent individuals report chronic pain conditions as both an initial and current motivation for prescription opioid use. However, to date, limited information exists regarding perceptions of the adequacy of pain management and pain management behaviors among prescription opioid dependent individuals with a history of treatment for chronic pain. Methods The current study examined perceptions of the medical management of chronic pain among community-recruited individuals (N=39) who met DSM-IV-TR criteria for current prescription opioid dependence and reported a history of treatment for chronic pain. Prescription opioid dependence, symptoms of depression, and pain management perceptions were assessed using the Structured Clinical Interview for DSM Disorders, Beck Depression Inventory, and the Pain Management Questionnaire, respectively. Results Reports of insufficient pain management were common (46.2%), as was utilization of emergency room services for pain management (56.4%). Nearly half reported a physician as their initial source (46.2%) and pain management as their primary initial reason for prescription opioid use (53.8%), whereas 35.9% reported pain relief as their primary reason for current prescription opioid use. Symptoms of depression were common (51.3%), as was comorbid abuse of other substances and history of treatment for substance abuse. Conclusions Results highlight the complicated clinical presentation and prevalent perception of the under-treatment of pain among this population. Findings underscore the importance of interdisciplinary approaches to managing the complex presentation of chronic pain patients with comorbid prescription opioid dependence. Implications for future research are discussed. PMID:25034899
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.
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
Curtis, Kaylah; Viswanath, Humsini; Velasquez, Kenia M; Molfese, David L; Harding, Mark J; Aramayo, Eduardo; Baldwin, Philip R; Ambrosi, Elisa; Madan, Alok; Patriquin, Michelle; Frueh, B Christopher; Fowler, J Christopher; Kosten, Thomas R; Nielsen, David A; Salas, Ramiro
Opioid use disorder (OUD) is a chronic disorder with relapse based on both desire for reinforcement (craving) and avoidance of withdrawal. The aversive aspect of dependence and relapse has been associated with a small brain structure called the habenula, which expresses large numbers of both opioid and nicotinic receptors. Additionally, opioid withdrawal symptoms can be induced in opioid-treated rodents by blocking not only opioid, but also nicotinic receptors. This receptor co-localization and cross-induction of withdrawal therefore might lead to genetic variation in the nicotinic receptor influencing development of human opioid dependence through its impact on the aversive components of opioid dependence. We studied habenular resting state functional connectivity with related brain structures, specifically the striatum. We compared abstinent psychiatric patients who use opioids (N = 51) to psychiatric patients who do not (N = 254) to identify an endophenotype of opioid use that focused on withdrawal avoidance and aversion rather than the more commonly examined craving aspects of relapse. We found that habenula-striatal connectivity was stronger in opioid-using patients. Increased habenula-striatum connectivity was observed in opioid-using patients with the low risk rs16969968 GG genotype, but not in patients carrying the high risk AG or AA genotypes. We propose that increased habenula-striatum functional connectivity may be modulated by the nicotinic receptor variant rs16969968 and may lead to increased opioid use. Our data uncovered a promising brain target for development of novel anti-addiction therapies and may help the development of personalized therapies against opioid abuse. (Am J Addict 2017;26:751-759). © 2017 American Academy of Addiction Psychiatry.
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
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
Opioid dependence is a chronic relapsing disorder that shows excess mortality and comorbidity with somatic and psychiatric disorders. Methadone and buprenorphine/naloxone are widely accepted and are used as first-line maintenance treatments for opioid dependence. Fatal intoxications with these agents, risk of diversion, and accidental intoxications, especially in children, are apparent risks and are of increasing public concern. Buprenorphine/naloxone sublingual tablet is an established treatment for opioid dependence. A novel buprenorphine/naloxone film has been developed with improved pharmacokinetics and a hopefully lower risk of diversion and accidental intoxications. This review evaluates the available preclinical and clinical data on the novel buprenorphine/naloxone film for the treatment of opioid dependence. Literature was identified though a comprehensive PubMed search and data sources included official FDA information. This is an interesting new formulation of a well-established medication in opioid dependence. However, few data have been published on its safety and efficacy. In an experimental study, the new formulation suppressed symptoms of opioid withdrawal as expected. Results of an unpublished study made public by the FDA suggest a spectrum of adverse events similar to that of the conventional sublingual tablet. Some data show patients may prefer the novel film over the sublingual tablet. The estimated lower risk for diversion and especially for accidental poisoning in children cannot be assessed in clinical studies but requires data from emergency room visits.
Rosenthal, Richard N; Goradia, Viral V
Opioid use disorders (OUDs) have long been a global problem, but the prevalence rates have increased over 20 years to epidemic proportions in the US, with concomitant increases in morbidity and all-cause mortality, but especially opioid overdose. These increases are in part attributable to a several-fold expansion in the prescription of opioid pain medications over the same time period. Opioid detoxification and psychosocial treatments alone have each not yielded sufficient efficacy for OUD, but μ-opioid receptor agonist, partial agonist, and antagonist medications have demonstrated the greatest overall benefit in OUD treatment. Buprenorphine, a μ-opioid receptor partial agonist, has been used successfully on an international basis for several decades in sublingual tablet and film preparations for the treatment of OUD, but the nature of formulation, which is typically self-administered, renders it susceptible to nonadherence, diversion, and accidental exposure. This article reviews the clinical trial data for novel buprenorphine delivery systems in the form of subcutaneous depot injections, transdermal patches, and subdermal implants for the treatment of OUD and discusses both the clinical efficacy of longer-acting formulations through increasing consistent medication exposure and their potential utility in reducing diversion. These new delivery systems also offer new dosing opportunities for buprenorphine and strategies for dosing intervals in the treatment of OUD. PMID:28894357
Fischer, G; Johnson, R E; Eder, H; Jagsch, R; Peternell, A; Weninger, M; Langer, M; Aschauer, H N
To assess the maternal and fetal acceptability of buprenorphine and neonatal abstinence syndrome (NAS) in children born to buprenorphine-maintained mothers. Open-label, flexible dosing, inpatient induction with outpatient maintenance, conducted at the University of Vienna within the existing pregnancy and drug addiction program. Fifteen opioid-dependent pregnant women. Sublingual buprenorphine tablets (1-10 mg/day). Mothers: withdrawal symptoms (Wang Scale), nicotine dependence (Fagerström Scale: FTQ) and urinalysis. Neonates: birth outcome and NAS (Finnegan Scale). All subjects were opioid-, nicotine- and cannabis-dependent. Buprenorphine was well tolerated during induction (Wang Score < or = 4) and illicit opioid use was negligible (91% opioid-negative). All maternal, fetal and neonatal safety laboratory measures were within normal limits or not of clinical significance. Mean birth outcome measures including gestational age at delivery (39.6 +/- 1.5 weeks), Apgar scores (1 min = 8.9; 5 min = 9.9; and 10 min = 10), birth weight (3049 +/- 346 g), length (49.8 +/- 1.9 cm) and head circumference (34.1 +/- 1.8 cm) were within normal limits. The NAS was absent, mild (without treatment) and moderate (with treatment) in eight, four and three neonates, respectively. The mean duration of NAS was 1.1 days. Buprenorphine appears to be well accepted by mother and fetus, and associated with a low incidence of NAS. Further investigation of buprenorphine as a maintenance agent for opioid-dependent pregnant women is needed.
Shorey, Ryan C.; Stuart, Gregory L.; Anderson, Scott
Opioid dependence is an increasingly prevalent problem throughout the world, particularly for young adults (e.g., ages 17–25). 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 pre-existing patient records, the current study examined the 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. PMID:22014405
Background Opioids are psychoactive analgesic drugs prescribed for pain relief and palliative care. Due to their addictive potential, effort and vigilance in controlling prescriptions is needed to avoid misuse and dependence. Despite the effort, the prevalence of opioid use disorder continues to rise. Opioid substitution therapies are commonly used to treat opioid dependence; however, there is minimal consensus as to which therapy is most effective. Available treatments include methadone, heroin, buprenorphine, as well as naltrexone. This systematic review aims to assess and compare the effect of all available opioid substitution therapies on the treatment of opioid dependence. Methods/Design The authors will search Medline, EMBASE, PubMed, PsycINFO, Web of Science, Cochrane Library, Cochrane Clinical Trials Registry, World Health Organization International Clinical Trials Registry Platform Search Portal, and the National Institutes for Health Clinical Trials Registry. The title, abstract, and full-text screening will be completed in duplicate. When appropriate, multiple treatment comparison Bayesian meta-analytic methods will be performed to deduce summary statistics estimating the effectiveness of all opioid substitution therapies in terms of retention and response to treatment (as measured through continued opioid abuse). Discussion Using evidence gained from this systematic review, we anticipate disseminating an objective review of the current available literature on the effectiveness of all opioid substitution therapies for the treatment of opioid use disorder. The results of this systematic review are imperative to the further enhancement of clinical practice in addiction medicine. Systematic review registration PROSPERO CRD42013006507. PMID:25239213
Kunøe, Nikolaj; Lobmaier, Philipp; Vederhus, John Kåre; Hjerkinn, Bjørg; Hegstad, Solfrid; Gossop, Michael; Kristensen, Oistein; Waal, Helge
Naltrexone's usefulness in the treatment of opioid dependence stems from its ability to block the action of heroin and other opioids. However, many patients are ambivalent towards naltrexone and often drop out of treatment with orally administered naltrexone. Sustained release naltrexone seems promising in reducing opioid use, but the extent to which patients remain in treatment beyond the first dosage of naltrexone is not clear. Patients (n=61) receving treatment with sustained release naltrexone implants were offered a second naltrexone implant after 6 months. Patients who remained in treatment were compared to those who did not, on drug use, mental health, and social problems before and during naltrexone implant treatment. Information was obtained on other treatments sought by patients who discontinued naltrexone. Blood samples were used to verify naltrexone release, and hair samples to confirm opioid intake. Of the patients who received the first naltrexone implant, 51% (n=31) remained in naltrexone implant treatment. Among those who discontinued treatment, 21% expressed a wish to reimplant but failed to attend for reimplantation and 28% declined reimplantation: 6 non-retained patients initiated maintenance or residential treatment. Remaining in naltrexone treatment was related to pre-study length of employment, illicit drug use, and concern for family problems. Higher levels of substance misuse and criminal activity during naltrexone treatment were negatively related to subsequent retention. Rates of retention among opioid-dependent patients receiving naltrexone implant treatment are encouraging and support this as a feasible long-term treatment option. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.
Bandawar, Mrunal; Kandasamy, Arun; Chand, Prabhat; Murthy, Pratima; Benegal, Vivek
Background: Opioid Use disorders are emerging as a serious public health concern in India. Opioid substitution treatment is one of the emerging forms of treatment in this population which needs more evidence to increase its availability and address prejudices towards the same. Materials and Methods: This is a case control study with retrospective design reviewing the charts of patients with opioid dependence syndrome registered between January 2005 to December 2012. Adherence to treatment was the outcome variable assessed in this study. Results: The odds of the Buprenorphine Maintenance Treatment (BMT) group remaining in treatment is 4.5 (P < 0.005) times more than Naltrexone Maintenance Treatment (NMT) group and 7 times (P < 0.001) more than Psychosocial intervention (PST) alone group. Discussion: We believe that these study findings will help in reducing the prejudice towards BMT and encourage further research in this field. Conclusion: BMT has a better adherence rate than other treatments in opioid use disorders. PMID:26664083
Jones, Hendrée E; Chisolm, Margaret S; Jansson, Lauren M; Terplan, Mishka
The present paper considers naltrexone to treat opioid dependence during pregnancy. The public health problem of opioid dependence and its treatment during pregnancy is reviewed first. Next, the naltrexone and opioid dependence treatment literature is summarized, with overviews of the pre-clinical and clinical research on prenatal naltrexone exposure. Finally, considerations and recommendations for future medication research for the treatment of opioid dependence in pregnant women are provided. The efficacy of long-acting injectable naltrexone relative to placebo, its blockade of opioid agonist euphoric effects, its lack of abuse and tolerance development and its modest adverse effect profile make it a potential medication for opioid-dependent pregnant women. However, it is not without seriously concerning potential drawbacks, including the difficulty surrounding medication induction that may lead to vulnerability with regard to relapse, physical dependence re-establishment, increased risk behaviors, treatment dropout and resulting opioid overdose. Before embarking on future research with this medication, the benefits and risks for the mother-embryo/fetus/child dyad should be weighed carefully. Should future research be conducted, a multi-level commitment to proactive ethical research is needed to reach the ultimate goal of improving the lives of women and children affected by opioid dependence. © 2012 The Authors, Addiction © 2012 Society for the Study of Addiction.
The age-dependency of opioid analgesia and tolerance has been noticed in both clinical observation and laboratory studies. Evidence shows that many molecular and cellular events that play essential roles in opioid analgesia and tolerance are actually age-dependent. For example, the expression and functions of endogenous opioid peptides, multiple types of opioid receptors, G protein subunits that couple to opioid receptors, and regulators of G protein signaling (RGS proteins) change with development and age. Other signaling systems that are critical to opioid tolerance development, such as N-methyl-D-aspartic acid (NMDA) receptors, also undergo age-related changes. It is plausible that the age-dependent expression and functions of molecules within and related to the opioid signaling pathways, as well as age-dependent cellular activity such as agonist-induced opioid receptor internalization and desensitization, eventually lead to significant age-dependent changes in opioid analgesia and tolerance development. PMID:22612909
Kanate, Dinah; Folk, David; Cirone, Sharon; Gordon, Janet; Kirlew, Mike; Veale, Terri; Bocking, Natalie; Rea, Sara; Kelly, Len
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
McHugh, R Kathryn; Park, Sara; Weiss, Roger D
Cues associated with heroin use (eg, needles, powder) elicit robust craving responses in individuals dependent upon heroin. Elevated cue-induced craving may be a risk factor for relapse and can persist after periods of drug abstinence. Despite the growing prevalence of opioid dependence involving prescription opioids, published studies have yet to examine whether cue-induced craving is also present in prescription opioid dependence. A sample of 50 adults diagnosed with opioid dependence (20 prescription opioid users, 25 heroin users, and 5 mixed opioid users) completed a cue reactivity assessment. Participants were administered a series of 90 pictures, including heroin-specific, prescription opioid-specific, and neutral images, and were asked to rate craving and cue salience after each image. Both the prescription opioid and heroin groups experienced significantly more craving to drug than to neutral stimuli. The prescription opioid group reported significantly less craving to prescription opioid stimuli than the heroin group to heroin stimuli; however, this effect was smaller and non-significant when controlling for group differences in cue salience. This study found evidence for cue-induced craving in individuals dependent upon prescription opioids. Further research is needed to better understand the role of cue reactivity in the course and treatment of opioid dependence involving prescription opioid use. As elevated craving reactivity to drug cues may reflect a risk factor for relapse, understanding the nature of cue-induced craving in individuals with opioid dependence is important to improving treatments for this population. © American Academy of Addiction Psychiatry.
Sullivan, Lynn E.; Tetrault, Jeanette; Bangalore, Deepa; Fiellin, David A.
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…
Sullivan, Lynn E.; Tetrault, Jeanette; Bangalore, Deepa; Fiellin, David A.
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…
Budney, A J; Bickel, W K; Amass, L
Information concerning the association between marijuana use and opioid dependence and its treatment is needed to determine effective clinical guidelines for addressing marijuana use among opioid abusers. Marijuana use was assessed in 107 people enrolled in treatment for opioid dependence. Univariate comparisons of marijuana users and non-users and multivariate regression analyses were performed to examine associations between marijuana use and socio-demographic, psychosocial, medical and substance-use variables. The relationship between marijuana use and treatment outcome was also explored in a subset of this sample who received treatment that included buprenorphine detoxification and behavior therapy (N = 79). Sixty-six per cent of participants were current marijuana users and almost all (94%) continued to use during treatment. Users were less likely to be married than non-users, and more likely to report financial difficulties, be involved in drug dealing and engage in sharing of needles (p < 0.05). A unique effect of marijuana use on drug dealing and sharing needles was retained after statistically controlling for the influence of heroin and alcohol use and other socio-demographic variables. No significant adverse relations were observed between marijuana use and treatment outcome. Pending a more comprehensive understanding of the function and consequences of marijuana use on psychosocial functioning, it appears that progress in treatment for opioid dependence can be made without mandating that patients abstain from marijuana use.
Ramsey, Susan E.; Rounsaville, Dan; Hoskinson, Randall; Park, Tae Woo; Ames, Evan G.; Neirinckx, Victor D.; Friedmann, Peter
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
Vo, Hoa T; Schacht, Rebecca; Mintzer, Miriam; Fishman, Marc
Cannabis and opioid use are associated with cognitive impairment, whether preexisting or substance-induced, but there have been few substance-specific assessments of cognitive functioning in adolescent substance users. Working memory impairment may be particularly important, as it has been linked to poorer performance in substance abuse treatment. Working memory (Wechsler Intelligence Scale for Children-IV or Adult Intelligence Scale-IV) and baseline substance use were assessed in 42 youth (mean age = 17.9 years, SD = 1.3, range: 16-20; 65% Caucasian, 30% female) 1-2 weeks after admission to residential treatment with supervised abstinence, 19 for primary cannabis dependence and 23 for primary opioid dependence. There were substantial deficits in working memory in both groups, with significant differences (P < .001) between the opioid (M = 39.1th%ile, SD = 25.6) and cannabis (M = 16.3th%ile, SD = 13.6) groups. The primary opioid group had high rates of cannabis use, with no significant difference in past-month days of cannabis use from the primary cannabis group. The opioid group was older and had completed more years of formal education. Seventy-nine percent of the cannabis group had public health care coverage (mostly Medicaid), compared with 24% of the opioid sample. Working memory impairment was substantial in treatment-seeking youth with primary cannabis and opioid dependence (the latter actually having comparable rates of cannabis use), and significantly more pronounced in the primary cannabis-dependent group. Without an assessment of working memory prior to substance exposure, the differential contributions of substance-induced vs. preexisting impairment are unclear. Lower scores in the cannabis group may reflect lower socioeconomic status (SES), which is typically correlated with cognitive performance. These findings highlight underrecognized cognitive impairment in youth with SUDs, especially inner-city cannabis-dependent youth. Modification of treatments
Wollman, Scott C; Alhassoon, Omar M; Hall, Matthew G; Stern, Mark J; Connors, Eric J; Kimmel, Christine L; Allen, Kenneth E; Stephan, Rick A; Radua, Joaquim
Prior research utilizing whole-brain neuroimaging techniques has identified structural differences in gray matter in opioid-dependent individuals. However, the results have been inconsistent. The current study meta-analytically examines the neuroimaging findings of studies published before 2016 comparing opioid-dependent individuals to drug-naïve controls. Exhaustive search of five databases yielded 12 studies that met inclusion criteria. Anisotropic Effect-Size Seed-Based d Mapping (AES-SDM) was used to analyze the data extracted by three independent researchers. Voxel-based AES-SDM distinguishes increases and decreases in brain matter significant at the whole-brain level. AES-SDM identified the fronto-temporal region, bilaterally, as being the primary site of gray matter deficits associated with opioid use. Moderator analysis revealed that length of opioid use was negatively associated with gray matter in the left cerebellar vermis and the right Rolandic operculum, including the insula. Meta-regression revealed no remaining significant areas of gray matter reductions, except in the precuneus, following longer abstinence from opioids. Opioid-dependent individuals had significantly less gray matter in several regions that play a key role in cognitive and affective processing. The findings provide evidence that opioid dependence may result in the breakdown of two distinct yet highly overlapping structural and functional systems. These are the fronto-cerebellar system that might be more responsible for impulsivity, compulsive behaviors, and affective disturbances and the fronto-insular system that might account more for the cognitive and decision-making impairments.
Opioids are extremely effective in managing cancer pain, and now are utilized for longer periods of time in cancer patients as the treatment for malignancies has become more successful. The goals in cancer pain treatment includes maintaining function in patients with cancer pain (especially in earlier stage disease), and palliation in advanced disease. The perception of the lay public and inexperienced clinicians that addiction is inevitable, often leads to an inappropriate fear to utilize opioids to appropriately manage pain; resulting in persistent under-treatment of cancer pain internationally. There is much confusion about the phenomenon of physical dependence and how this can be differentiated from the maladaptive behaviors that constitute a diagnosis of substance abuse. The burden of cancer and associated cancer pain is projected to continue to rise, and is often at an advanced stage at diagnosis in less developed countries. To be able to provide quality care for this patient population availability of opioids and skilled clinicians in pain management is paramount. In the majority of cases, the main concern is to abate concerns about risks of opioid addiction; to allow adequate pain relief. To understand the infrequent phenomenon of substance abuse in the setting of cancer pain management clear definitions are needed, and review of the epidemiology of occurrence in cancer populations is needed. It is also important to clearly separate the issues of substance abuse at the patient level and diversion of prescribed opioids. There are principles of managing cancer pain in the rare clinical scenario when the risk of substance abuse is high, which can still allow safe management of cancer pain with opioids.
Krebs, Emanuel; Thomas, Kerr; Julio, Montaner; Evan, Wood; Bohdan, Nosyk
Background Research into the avoided crime-related costs associated with methadone maintenance treatment (MMT) is sparse. Our objective was to characterize the dynamics in crime-related costs associated with MMT effectiveness among opioid dependent individuals in Vancouver, Canada. Methods We considered individuals enrolled in a prospective study between December, 2011 and May, 2013. Monthly crime-related costs (2013 CAD) were derived from self-reported criminal activity. On the basis of MMT receipt and illicit opioid use, individuals were classified in mutually exclusive health states: (i) MMT high effectiveness; (ii) MMT low effectiveness; (iii) opioid abstinence; or (iv) relapse. We classified individuals as daily, non-daily or non-stimulant users and controlled for demographic and socio-economic characteristics. A two-part multiple regression model was constructed; the first part modeled non-zero cost probability, the second estimated the level of costs. Avoided costs were estimated for each health state and stratified by stimulant use intensity. Results Our study included 982 individuals (median age 47, 38% female) for 2232 observations. Individuals on MMT with high effectiveness incurred lower monthly costs of criminality (avoided costs of $6298; 95% C.I. ($1578, $11,017)), as did opioid abstinent individuals ($6563 ($1564, $11,561)). Avoided costs for daily stimulant users were greater than for non-daily users, both for individuals on MMT with high effectiveness ($12,975 vs. $4125) and opioid abstinent ($12,640 vs. $4814). Conclusion Using longitudinal data on individuals with a history of MMT, we found substantially lower costs of criminality associated with high effect to MMT. Avoided costs were highest among daily stimulant users that were on MMT with high effectiveness or those opioid abstinent. PMID:25282307
Doehring, Alexandra; Oertel, Bruno Georg; Sittl, Reinhard; Lötsch, Jörn
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. Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
Zahari, Zalina; Lee, Chee Siong; Ibrahim, Muslih Abdulkarim; Musa, Nurfadhlina; Mohd Yasin, Mohd Azhar; Lee, Yeong Yeh; Tan, Soo Choon; Mohamad, Nasir; Ismail, Rusli
This study compared pain sensitivity among opioid dependent patients on methadone maintenance therapy (MMT) and opioid naive subjects. The three hundred participants comprised 152 opioid naive subjects and 148 opioid dependent patients. Opioid naive subjects had not taken any opioids including morphine and methadone to their best knowledge and were presumed so after two consecutive negative urine screenings for drugs. All opioid dependent patients were stabilized in treatment, defined as having been enrolled in the program for more than one month with no change of methadone dosage over the past one month. Excluded from the study were individuals with chronic or ongoing acute pain and individuals with a history of analgesics ingestion within 3 d before the cold pressor test (CPT). Pain tolerance to CPT was evaluated at 0 h, and at 2, 4, 8, 12, and 24 h post-methadone dose. Patients exhibited a significantly shorter mean pain tolerance time of 34.17 s (95% CI 24.86, 43.49) versus 61.36 (52.23, 70.48) [p < 0.001] compared with opioid naive subjects. Time-dependent mean pain tolerance was also significantly different when naive subjects were compared to patients (p = 0.016). This study revealed hyperalgesia amongst patients on MMT, as manifested by their quicker hand withdrawal. The complaints of pain in this population should not be underestimated and the pain should be evaluated seriously and managed aggressively.
Saleh, M I
The present analysis describes the longitudinal change in buprenorphine treatment outcome. It also examines several participant characteristics to predict response to buprenorphine. Participants (n=501, age>15 years) received buprenorphine/naloxone treatment for 4 weeks, and then were randomly assigned to undergo dose tapering over either 7 days or 28 days. An empirical model was developed to describe the longitudinal changes in treatment outcome. Several patient characteristics were also examined as possible factors influencing treatment outcome. We have developed a model that captures the general behavior of the longitudinal change in the probability of having an opioid-negative urine sample following buprenorphine treatment. The model captures both the initial increase (i. e., initial response) and the subsequent decrease (i. e., relapse to opioid) in the likelihood of providing an opioid-negative urine sample. Characteristics associated with successful buprenorphine treatment outcome include: having a negative urine test for drugs, having alcohol problems [assessed using alcohol domain of addiction severity index (ASI-alcohol)] at screening, being older, and receiving low cumulative buprenorphine dose. However, ASI-alcohol values were generally low which make the application of the proposed alcohol effect for patients with more severe alcohol problems questionable. A novel approach for analyzing buprenorphine treatment outcome is presented in this manuscript. This approach describes the longitudinal change in the probability of providing an opioid-free urine sample instead of considering opioid use outcome at a single time point. Additionally, this model successfully describes relapse to opioid. Finally, several patient characteristics are identified as predictors of treatment outcome. © Georg Thieme Verlag KG Stuttgart · New York.
Epstein, Richard A.; Bobo, William V.; Martin, Peter R.; Morrow, James A.; Wang, Wei; Chandrasekhar, Rameela; Cooper, William O.
Purpose To quantify the prevalence of prescribed opioid analgesics among pregnant women enrolled in Tennessee Medicaid from 1995 to 2009. Methods Retrospective cohort study of 277,555 pregnancies identified from birth and fetal death certificates, and linked to previously-validated computerized pharmacy records. Poisson regression was used to estimate trends over time, rate ratios and 95% confidence intervals. Results During the study period, 29% of pregnant women filled a prescription for an opioid analgesic. From 1995 to 2009, any pregnancy-related use increased 1.90-fold (95% CI = 1.83, 1.98), first trimester use increased 2.27-fold (95% CI = 2.14, 2.41), and second or third trimester use increased 2.02-fold (95% CI = 1.93, 2.12), after adjusting for maternal characteristics. Any pregnancy-related, first trimester, and second or third trimester use were each more likely among mothers who were at least 21 years old, white, non-Hispanic, prima gravid, resided in non-urban areas, enrolled in Medicaid due to disability, and who had less than a high school education. Conclusions Opioid analgesic use by Tennessee Medicaid-insured pregnant women increased nearly 2-fold from 1995 to 2009. Additional study is warranted in order to understand the implications of this increased use. PMID:23889859
Weiss, Roger D.; Potter, Jennifer Sharpe; Fiellin, David A.; Byrne, Marilyn; Connery, Hilary S.; Dickinson, William; Gardin, John; Griffin, Margaret L.; Gourevitch, Marc N.; Haller, Deborah L.; Hasson, Albert L.; Huang, Zhen; Jacobs, Petra; Kosinski, Andrzej S.; Lindblad, Robert; McCance-Katz, Elinore F.; Provost, Scott E.; Selzer, Jeffrey; Somoza, Eugene C.; Sonne, Susan C.; Ling, Walter
Context No randomized trials have examined treatments for prescription opioid dependence, despite its increasing prevalence. Objective To evaluate the efficacy of brief and extended buprenorphine-naloxone treatment, with different counseling intensities, for patients dependent upon prescription opioids. Setting, Participants 653 treatment-seeking outpatients dependent on prescription opioids, at 10 U.S. sites from June 2006-July 2009. Design Multi-site, randomized clinical trial, using a two-phase adaptive treatment research design. Brief treatment (Phase 1) included 2-week buprenorphine-naloxone stabilization, 2-week taper, and 8-week post-medication follow-up. Patients with successful opioid use outcomes exited the study; unsuccessful patients entered Phase 2: extended (12-week) buprenorphine-naloxone treatment, 4-week taper, and 8-week post-medication follow-up. Main outcome measures Pre-defined “successful outcome” in each phase: composite measures indicating minimal or no opioid use, based on urine-confirmed self-reports. Interventions In both phases, patients were randomized to Standard Medical Management (SMM) or SMM+Opioid Drug Counseling (ODC); all received buprenorphine-naloxone. Results During Phase 1, only 6.6% (43/653) of patients had successful outcomes, with no difference between the SMM and SMM+ODC. In contrast, 49.2% (177/360) attained successful outcomes in Phase 2 during extended buprenorphine-naloxone treatment (week 12), with no difference between counseling conditions. Success rates 8 weeks after completing the buprenorphine-naloxone taper (Phase 2, week 24) dropped sharply to 8.6% (31/360), again with no counseling difference. In secondary analyses, successful Phase 2 outcomes were far more common while taking buprenorphine-naloxone than 8 weeks post-taper (49.2% (177/360) vs. 8.6% (31/360), p<0.001). Chronic pain did not affect opioid use outcomes; a history of ever using heroin was associated with lower Phase 2 success rates while
Kresina, Thomas F; Sylvestre, Diana; Seeff, Leonard; Litwin, Alain H; Hoffman, Kenneth; Lubran, Robert; Clark, H Westley
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
McGlone, Laura; Mactier, Helen
The aim of this study is to describe infant neurodevelopment in 81 infants of methadone-prescribed opioid-dependent mothers. Griffith MD scores at six months. Scores were lower in all domains compared to controls (p<0.001). Poly-drug exposed infants and those treated for neonatal abstinence syndrome performed significantly poorer (p=0.002 and p=0.008 respectively). Infants of methadone-maintained opioid-dependent mothers show poorer neurodevelopment at six months of age than non-drug exposed comparison infants. Developmental difficulties are confounded by delayed visual development. These highly vulnerable children merit close surveillance throughout infancy. Griffith MD scores at six months in 81 infants born to methadone-prescribed opioid-dependent mothers were lower in all domains compared to controls (p<0.001). Poly-drug exposed infants and those treated for neonatal abstinence syndrome performed significantly poorer (p=0.002 and p=0.008 respectively). Co-existing visual problems were common. Copyright © 2014 Elsevier Ltd. All rights reserved.
Opioid dependence during pregnancy is associated with significant health risks for both the mother and her fetus. Opioid maintenance therapy with methadone (Dolophine) is the current standard of care, reduces medical and social risks associated with illicit drug use, and decreases rates of prematurity and low birth weight. However, treatment with methadone is frequently associated with neonatal abstinence syndrome. Buprenorphine is an alternative to methadone that preliminary data indicates is equivalent in safety and efficacy to methadone and significantly increases access to treatment. The pharmacology of buprenorphine and its implications for the care of pregnant women with opioid dependence are described. © 2011 by the American College of Nurse-Midwives.
Background Opioid dependent patients have legal problems, driving violations and accidents more frequently than the general population. We have hypothesized that those patients currently driving may have better legal outcomes than those who do not possess a valid driving license. With this aim we have analyzed the information gathered in the PROTEUS study regarding the legal and driving statuses and assessed the possible association between them. The PROTEUS study was an observational, cross-sectional, descriptive, multicenter nationwide representative study, conducted in Spanish healthcare centers for opioid dependent patients. Findings The driving and legal statuses of a population of opioid dependent patients ≥18 years and enrolled in Opioid Agonist Therapy treatment centers in Spain, were assessed using a short specific questionnaire and the EuropASI questionnaire to highlight distinct individual clinical needs. 621 patients were evaluable (84% men, 24.5% active workers). 321 patients (52%) drove on a regular basis. Nineteen percent of patients had some problem with the criminal justice system. There was a significant difference (p = 0.0433) in status, according to the criminal justice system, between patients who drove on a regular basis and those who did not, with a higher percentage of patients with non-pending charges among usual drivers. Conclusions Regular drivers showed fewer legal problems than non-regular drivers, with the exception of those related to driving (driving violations and drunk driving). Driving is a good prognostic factor for the social integration of the patients and policies should be implemented to enable these patients to drive safely under medical authorization. The legal description will be useful to assess treatment efficacy. PMID:23731546
Roncero, Carlos; Álvarez, F Javier; Barral, Carmen; Gómez-Baeza, Susana; Gonzalvo, Begoña; Rodríguez-Cintas, Laia; Brugal, M Teresa; Jacas, Carlos; Romaguera, Anna; Casas, Miguel
Opioid dependent patients have legal problems, driving violations and accidents more frequently than the general population. We have hypothesized that those patients currently driving may have better legal outcomes than those who do not possess a valid driving license. With this aim we have analyzed the information gathered in the PROTEUS study regarding the legal and driving statuses and assessed the possible association between them. The PROTEUS study was an observational, cross-sectional, descriptive, multicenter nationwide representative study, conducted in Spanish healthcare centers for opioid dependent patients. The driving and legal statuses of a population of opioid dependent patients ≥ 18 years and enrolled in Opioid Agonist Therapy treatment centers in Spain, were assessed using a short specific questionnaire and the EuropASI questionnaire to highlight distinct individual clinical needs. 621 patients were evaluable (84% men, 24.5% active workers). 321 patients (52%) drove on a regular basis. Nineteen percent of patients had some problem with the criminal justice system. There was a significant difference (p = 0.0433) in status, according to the criminal justice system, between patients who drove on a regular basis and those who did not, with a higher percentage of patients with non-pending charges among usual drivers. Regular drivers showed fewer legal problems than non-regular drivers, with the exception of those related to driving (driving violations and drunk driving). Driving is a good prognostic factor for the social integration of the patients and policies should be implemented to enable these patients to drive safely under medical authorization. The legal description will be useful to assess treatment efficacy.
Birnbaum, Howard G; White, Alan G; Schiller, Matt; Waldman, Tracy; Cleveland, Jody M; Roland, Carl L
The objective of this study was to estimate the societal costs of prescription opioid abuse, dependence, and misuse in the United States. Costs were grouped into three categories: health care, workplace, and criminal justice. Costs were estimated by 1) quantity method, which multiplies the number of opioid abuse patients by cost per opioid abuse patient; and 2) apportionment method, which begins with overall costs of drug abuse per component and apportions the share associated with prescription opioid abuse based on relative prevalence of prescription opioid to overall drug abuse. Excess health care costs per patient were based on claims data analysis of privately insured and Medicaid beneficiaries. Other data/information were derived from publicly available survey and other secondary sources. Total US societal costs of prescription opioid abuse were estimated at $55.7 billion in 2007 (USD in 2009). Workplace costs accounted for $25.6 billion (46%), health care costs accounted for $25.0 billion (45%), and criminal justice costs accounted for $5.1 billion (9%). Workplace costs were driven by lost earnings from premature death ($11.2 billion) and reduced compensation/lost employment ($7.9 billion). Health care costs consisted primarily of excess medical and prescription costs ($23.7 billion). Criminal justice costs were largely comprised of correctional facility ($2.3 billion) and police costs ($1.5 billion). The costs of prescription opioid abuse represent a substantial and growing economic burden for the society. The increasing prevalence of abuse suggests an even greater societal burden in the future. Wiley Periodicals, Inc.
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.
Scavone, J.L.; Sterling, R.C.; Van Bockstaele, E.J.
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
Chen, Dingyan; Liu, Fang; Shang, Qinggang; Song, Xiaoqin; Miao, Xiaoping; Wang, Zengzhen
Several studies have assessed the association between genetic polymorphisms of DRD2 and DRD4 genes and opioid dependence risk, while the results were inconsistent. We performed a meta-analysis, including 6,846 opioid dependence cases and 4,187 controls from 22 individual studies, to evaluate the roles of four variants (DRD2 -141ins/delC, rs1799732; DRD2 311 Ser > Cys, rs1801028; DRD2-related TaqI A, rs1800497 and DRD4 exon III VNTR) in opioid dependence for the first time. We found that the -141delC polymorphism was significantly associated with increased risk of opioid dependence (homozygote comparison: odds ratios [OR], 2.71; 95% confidence interval [CI], 1.74-4.22; dominant comparison: OR, 1.27; 95% CI, 1.09-1.48). Similarly, the TaqI A1 polymorphism was also significantly increased opioid dependence risk (homozygote comparison: OR, 2.06; 95% CI, 1.25-3.42; dominant comparison: OR, 1.34; 95% CI, 1.08-1.67). Moreover, long allele (≥5-repeat) and 7-repeat allele of DRD4 exon III VNTR were found to be associated with significantly increased opioid dependence risk (OR, 1.50; 95% CI, 1.24-1.80 and OR, 1.57; 95%, 1.18-2.09, respectively). However, no association was detected between the DRD2 311 Ser > Cys polymorphism and opioid dependence. In conclusion, our results suggested that DRD2 -141ins/delC, DRD2-related TaqI A and DRD4 exon III VNTR polymorphisms might play important roles in the development of opioid dependence.
Carlson, Robert G; Nahhas, Ramzi W; Martins, Silvia S; Daniulaityte, Raminta
Increases in illicit pharmaceutical opioid (PO) use have been associated with risk for transition to heroin use. We identify predictors of transition to heroin use among young, illicit PO users with no history of opioid dependence or heroin use at baseline. Respondent-driven sampling recruited 383 participants; 362 returned for at least one biannual structured interview over 36 months. Cox regression was used to test for associations between lagged predictors and hazard of transition to heroin use. Potential predictors were based on those suggested in the literature. We also computed population attributable risk (PAR) and the rate of heroin transition. Over 36 months, 27 (7.5%) participants initiated heroin use; all were white, and the rate of heroin initiation was 2.8% per year (95% CI=1.9%-4.1%). Mean length of PO at first reported heroin use was 6.2 years (SD=1.9). Lifetime PO dependence (AHR=2.39, 95% CI=1.07-5.48; PAR=32%, 95% CI=-2% to 64%), early age of PO initiation (AHR=3.08, 95%; CI=1.26-7.47; PAR=30%, 95% CI=2%-59%), using illicit POs to get high but not to self-medicate a health problem (AHR=4.83, 95% CI=2.11-11.0; PAR=38%, 95% CI=12%-65%), and ever using PO non-orally most often (AHR=6.57, 95% CI=2.81-17.2; PAR=63%, 95% CI=31%-86%) were significant predictors. This is one of the first prospective studies to test observations from previous cross-sectional and retrospective research on the relationship between illicit PO use and heroin initiation among young, initially non-opioid dependent PO users. The results provide insights into targets for the design of urgently needed prevention interventions. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Carlson, Robert G.; Nahhas, Ramzi W.; Martins, Silvia S.; Daniulaityte, Raminta
Background Increases in illicit pharmaceutical opioid (PO) use have been associated with risk for transition to heroin use. We identify predictors of transition to heroin use among young, illicit PO users with no history of opioid dependence or heroin use at baseline. Methods Respondent-driven sampling recruited 383 participants; 362 returned for at least one biannual structured interview over 36 months. Cox regression was used to test for associations between lagged predictors and hazard of transition to heroin use. Potential predictors were based on those suggested in the literature. We also computed population attributable risk (PAR) and the rate of heroin transition. Results Over 36 months, 27 (7.5%) participants initiated heroin use; all were white, and the rate of heroin initiation was 2.8% per year (95% CI=1.9%–4.1%). Mean length of PO at first reported heroin use was 6.2 years (SD=1.9). Lifetime PO dependence (AHR=2.39, 95% CI= 1.07–5.48; PAR=32%, 95% CI=−2%–64%), early age of PO initiation (AHR=3.08, 95%; CI= 1.26–7.47; PAR=30%, 95% CI=2%–59%), using illicit POs to get high but not to self-medicate a health problem (AHR=4.83, 95% CI= 2.11–11.0; PAR=38%, 95% CI=12%–65%), and ever using PO non-orally most often (AHR=6.57, 95% CI=2.81–17.2; PAR=63%, 95% CI=31%–86%) were significant predictors. Conclusion This is one of the first prospective studies to test observations from previous cross-sectional and retrospective research on the relationship between illicit PO use and heroin initiation among young, initially non-opioid dependent PO users. The results provide insights into targets for the design of urgently needed prevention interventions. PMID:26785634
Soyka, Michael; Rösner, Susanne
Alcohol dependence is a widespread psychiatric disorder. While relapse prevention therapy in alcoholism was exclusively dominated by social and psychological treatments for many years, in the last decades the benefits of pharmacological agents for the rehabilitation treatment in alcoholism have become increasingly evident. Naltrexone, an opiate receptor antagonist, blocks the pleasant and reinforcing effects of alcohol by preventing the stimulation of opioid receptors and the reduction of dopamine release in the ventral tegmental area (VTA). Clinical evidence about the effectiveness of the substance is not always consistent, but meta-analyses confirm naltrexone's effect on the risk of heavy drinking. Evidence about the abstinence-maintaining effects of the substance comes from a relatively small database and needs further investigation. The evaluation of differential effects of naltrexone depending on biological or psychological profiles, which could further enhance the effectiveness of treatments for alcohol dependence, remains a challenge. Nalmefene, another opioid antagonist, as well as naltrexone depot, a sustained release formulation of naltrexone, are further promising strategies for the treatment of alcohol dependence. The review at hand gives on overview of the current evidence on opioid antagonists for the treatment of alcohol dependence regarding the possible mechanism of action, the substances' safety profiles and their effectiveness. The corresponding evidence is critically reviewed taking into consideration the influence of the study design on the magnitude and consistency of effect sizes as well the impact of patient characteristics on the response to the treatment with opioid antagonists. Future studies on the role of different subtypes of alcoholics according to their genetic or psychological profile to explain or even predict the effects of opioid antagonists in the treatment of alcohol dependence are needed.
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; Morón, Jose A
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. 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 inflammatory pain and opioid
Negus, S. Stevens; Banks, Matthew L.
Here we describe methods for preclinical evaluation of candidate medications to treat opioid abuse and dependence. Our perspective is founded on the propositions that (1) drug self-administration procedures provide the most direct method for assessment of medication effects, (2) procedures that assess choice between opioid and nondrug reinforcers are especially useful, and (3) the states of opioid dependence and withdrawal profoundly influence both opioid reinforcement and the effects of candidate medications. Effects of opioid medications on opioid choice in nondependent and opioid-dependent subjects are reviewed. Various nonopioid medications have also been examined, but none yet have been identified that safely and reliably reduce opioid choice. Future research will focus on (1) strategies for increasing safety and/or effectiveness of opioid medications, and (2) continued development of nonopioids such as inhibitors of endocannabinoid catabolic enzymes or inhibitors of opioid-induced glial activation. PMID:23125072
Karow, A; Reimer, J; Schäfer, I; Krausz, M; Haasen, C; Verthein, U
There is increasing evidence that health-related quality of life (HRQOL) is associated with a successful treatment and better outcome in opioid addiction. The aim of the present study was the longitudinal investigation of HRQOL in patients with severe opioid dependence, who were randomly assigned to four groups of medical and psychosocial treatment: heroin (diacetylmorphine) versus methadone and case management (CM) versus psychoeducation (PSE) respectively. HRQOL (MSQoL) and physical health (OTI) were investigated in 938 subjects, who participated in the German multi-centre study examining the effects of heroin-assisted treatment in patients with severe opioid dependence. Data for the present analysis were taken from baseline and 12-month follow up. Under both forms of maintenance and psychosocial treatment HRQOL improved significantly during the observation period. HRQOL improvement under maintenance with heroin exceeded improvement under methadone, especially with regard to subjective physical health. HRQOL improvement was significantly associated with better expert-rated physical health. Further analyses showed significant better improvement of HRQOL in subjects treated with PSE compared with CM. The advantage of heroin with regard to the improvement of HRQOL may be partially explained by a better improvement of physical health under maintenance with heroin compared with methadone, which highlights the importance of a comprehensive model of health care for patients with severe opioid dependence. Future studies need to investigate the benefits of PSE for patients in maintenance therapy. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
Aklin, Will M.; Severtson, S. Geoffrey; Umbricht, Annie; Fingerhood, Michael; Bigelow, George E.; Lejuez, C. W.; Silverman, Kenneth
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
Florence, Curtis S; Zhou, Chao; Luo, Feijun; Xu, Likang
It is important to understand the magnitude and distribution of the economic burden of prescription opioid overdose, abuse, and dependence to inform clinical practice, research, and other decision makers. Decision makers choosing approaches to address this epidemic need cost information to evaluate the cost effectiveness of their choices. To estimate the economic burden of prescription opioid overdose, abuse, and dependence from a societal perspective. Incidence of fatal prescription opioid overdose from the National Vital Statistics System, prevalence of abuse and dependence from the National Survey of Drug Use and Health. Fatal data are for the US population, nonfatal data are a nationally representative sample of the US civilian noninstitutionalized population ages 12 and older. Cost data are from various sources including health care claims data from the Truven Health MarketScan Research Databases, and cost of fatal cases from the WISQARS (Web-based Injury Statistics Query and Reporting System) cost module. Criminal justice costs were derived from the Justice Expenditure and Employment Extracts published by the Department of Justice. Estimates of lost productivity were based on a previously published study. Calendar year 2013. Monetized burden of fatal overdose and abuse and dependence of prescription opioids. The total economic burden is estimated to be $78.5 billion. Over one third of this amount is due to increased health care and substance abuse treatment costs ($28.9 billion). Approximately one quarter of the cost is borne by the public sector in health care, substance abuse treatment, and criminal justice costs. These estimates can assist decision makers in understanding the magnitude of adverse health outcomes associated with prescription opioid use such as overdose, abuse, and dependence.
The prevalence of prescription opioid abuse has increased nationally in the last decade with increased incidence rates reported among pregnant women. This was a qualitative study designed to understand the role of pregnant women with an opioid use disorder participating in medical decision making regarding their prenatal care while addressing their addiction. Group interviews were conducted with postpartum women who self-identified as opioid dependent during their pregnancy, and the data were analyzed using Interpretative Phenomenological Analysis. Social workers in the health care setting are an integral part of the interdisciplinary team in caring for pregnant and postpartum opioid-dependent women. Social workers are ideal in creating stigma reduction strategies, peer and professional supports, and comprehensive coordinated care. A social justice-based practice may be a framework to utilize when caring for this unique population.
Shand, Fiona L; Degenhardt, Louisa; Nelson, Elliot C; Mattick, Richard P
Compared to other mental health problems, social anxiety is under-acknowledged amongst opioid dependent populations. This study aimed to assess levels of social anxiety and identify its predictors in an opioid dependent sample and a matched control group. Opioid dependent participants (n=1385) and controls (n=417) completed the Social Interaction Anxiety Scale (SIAS), the Social Phobia Scale (SPS) and a diagnostic interview. Regression analyses were used to test a range of predictors of social anxiety. Opioid dependent cases had higher mean scores on both scales compared to controls. Predictors of social anxiety centred on emotional rejection in childhood, either by parents or peers. For opioid dependent cases, but not controls, lifetime non-opioid substance dependence (cannabis, sedatives, and tobacco) was associated with higher levels of social anxiety. However, much of the variance in social anxiety remains unexplained for this population.
Bie, Bihua; Wang, Yan; Cai, You-Qing; Zhang, Zhi; Hou, Yuan-Yuan; Pan, Zhizhong Z
The rewarding properties of opioids are essential driving force for compulsive drug-seeking and drug-taking behaviors in the development of opioid-mediated drug addiction. Prior drug use enhances sensitivity to the rewarding effects of subsequently used drugs, increasing vulnerability to relapse. The molecular mechanisms underlying this reward sensitization are still unclear. We report here that morphine that induced reward sensitization, as demonstrated by reinstatement of the behavior of conditioned place preference (CPP) with sub-threshold priming morphine, epigenetically upregulated the output activity of Ngf encoding the nerve growth factor (NGF) by increasing histone H4 acetylation in the rat central nucleus of the amygdala (CeA). NGF locally infused into the CeA mimicked the morphine effect in inducing new functional delta-opioid receptor (DOR) that was required for the reward sensitization, and morphine-induced reward sensitization was inhibited by blocking NGF receptor signaling in the CeA. Histone deacetylase inhibitors that increased the acetylation level at the Ngf promoter and NGF expression in the CeA also induced reward sensitization in a CeA NGF signaling- and DOR-dependent manner. Furthermore, CeA-applied NGF substituted prior morphine to induce reward sensitization in naive rats and also substituted priming morphine to reinstate the CPP induced by prior morphine. Thus, epigenetic upregulation of NGF activity in the CeA may promote the behavior of opioid reward and increase the sensitivity to the rewarding effect of subsequent opioids, a potentially important mechanism in drug addiction. PMID:22871918
Tabatabai, Seyed Meghdad; Dashti, Saeedeh; Doosti, Fatemeh; Hosseinzadeh, Hossein
Development of tolerance and dependence is a major problem associated with opioid treatment. Withdrawal syndrome is common between medical and illicit users of these agents. Phytomedicine has shown promise in the treatment of this complicated psychosomatic condition. In this study, the effects of plant extracts and active components on morphine dependence and withdrawal syndrome are discussed. Proper keywords were used to search through PubMed, Google Scholar, and SciVerse, as well as two local scientific databases, www.iranmedex.com and www.SID.com. All relevant results (original articles, meeting abstracts, patents, etc.) published from 2000 to 2013 were chosen for final review. A total of 35 plant species were studied on this subject. Plants from Lamiaceae, Ranunculaceae, and Apiaceae families were especially effective. A few studies were carried out on human subjects and the rest in animal models. Opioid dependence and withdrawal syndrome remain an intimidating challenge. Nonetheless, plants and their derivatives are suitable sources for their treatment. Although there are several plants shown to be effective in animal models, few clinical studies are available.
Pan, Aileen; Zakowski, Mark
Opioid abuse and dependence continues to rise in both the general population and pregnancy, with opioid overdose deaths having quadrupled in the last 15 years. Illicit drug use in last 30 days of pregnancy was over 4% with almost 0.6% documented maternal opiate use at time of birth. The management of the opioid-tolerant, buprenorphine-dependent or methadone-dependent patient in the peripartum period is reviewed. Options for treatment of opioid dependence, acute pain management, and perioperative multimodal analgesia are discussed. The effects of maternal management on neonatal abstinence syndrome are also reviewed.
Al-Hasani, Ream; Bruchas, Michael R.
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
Kuwabara, Hiroto; Heishman, Stephen J; 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
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.
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.
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
Brogly, Susan B; Turner, Suzanne; Lajkosz, Katherine; Davies, Greg; Newman, Adam; Johnson, Ana; Dow, Kimberly
There is a paucity of data characterizing mother-infant pairs with prenatal opioid dependence in Canada. We therefore conducted a study of relevant births in Ontario from 2002 to 2014. We used data from the Institute for Clinical Evaluative Sciences, the linked databases of coded population-based Ontario health services records. Differences in characteristics of opioid-dependent mother-neonate pairs and infant hospital costs by year were assessed using linear regression, and we calculated rates of preterm birth, low birth weight, birth defects, mortality, and neonatal abstinence syndrome. The number of infants born to opioid-dependent women in Ontario rose from 46 in 2002 to almost 800 in 2014. Methadone was most frequently used for prenatal opioid dependence; there was little buprenorphine or buprenorphine + naloxone use. Rates of preterm birth and low birth weight were high. The proportion of neonates with neonatal abstinence syndrome (58%) was stable over the study period. The mean length of neonatal hospital stay was 13.96 days. Infant hospital costs increased from $724 774 in 2003 to $10 539 988 in 2013, and the mean cost per infant grew from $9928 to $12 917. Birth defect prevalence was 75.84/1000 live births (95% CI 68.12/1000 to 84.10/1000). The stillbirth rate was 11.39/1000 births (95% CI 8.47/1000 to 14.99/1000), and the infant mortality rate was 12.21/1000 live births (95% CI 9.16/1000 to 15.95/1000). We observed a 16-fold increase in the number of mother-infant pairs affected by opioid dependence in Ontario over the past decade. Adverse birth outcome rates were high. Expanded services for opioid-dependent women and their children are needed. Copyright © 2017 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.
Wasan, Ajay, D.; Michna, Edward; Edwards, Robert, R.; Katz, Jeff, N.; Nedeljkovic, Srdjan, S.; Dolman, Andrew, J.; Janfaza, David; Isaac, Zach; Jamison, Robert, N.
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
Van den Berg, C L; Kitchen, I; Gerrits, M A; Spruijt, B M; Van Ree, J M
The consequences of juvenile isolation and morphine treatment on general activity, social activity and endogenous opioid release during a social interaction test were investigated in the adult rat. Rats were either isolated or socially housed during weeks 4 and 5 of age and treated daily during this isolation period subcutaneously with either saline or morphine. Directly after a social interaction test at 10 weeks of age, rats were injected with [3H]-diprenorphine and subsequently prepared for in vivo autoradiography. The autoradiographic technique was used to visualise neuroanatomical changes in opioid receptor occupancy, probably reflecting changes in opioid peptide release, as a result of social activity. Juvenile isolation increased general activity during the social interaction test, an effect which was accompanied by a reduction of opioid receptor occupancy in many brain areas, suggesting an increased opioid peptide release as a consequence of socially-induced general activity. Morphine treatment in isolated rats caused an increase in adult social activity and enhanced opioid peptide release in some cortical regions and the ventral tegmental area as compared to saline treated rats. Both social activity and opioid receptor occupancy were unaffected by morphine treatment in non-isolated rats. The present study underscores the role of opioid systems in adult social behaviors as a consequence of juvenile isolation. The results suggest a relationship between social activity and opioid peptide release during social contact. Increased social activity seems to be accompanied by elevated opioid peptide release in distinct brain areas after morphine treatment during juvenile isolation.
Pradhan, Amynah; Smith, Monique; McGuire, Brenna; Evans, Christopher; Walwyn, Wendy
Opioid receptors regulate a diverse array of physiological functions. Mu opioid receptor agonists are well-known analgesics for treating acute pain. In contrast, animal models suggest that chronic pain is more effectively relieved by delta opioid receptor agonists. A number of studies have shown that chronic pain results in increased function of delta opioid receptors. This is proposed to result from enhanced trafficking of the delta opioid receptor to the cell membrane induced by persistent tissue injury. However, recent studies have questioned this mechanism, which has resulted in some uncertainty as to whether delta opioid receptors are indeed upregulated in chronic pain states. To clarify this question, we have examined the effect of chronic inflammatory pain over time using both an ex vivo measure of delta function: receptor-Ca2+ channel coupling, and an in vivo measure; the relief of chronic pain by a delta opioid receptor agonist. In addition, as beta-arrestin 2 can regulate delta opioid receptor trafficking and signaling, we have further examined whether deleting this scaffolding and signal transduction molecule alters delta opioid receptor function. We used the Complete Freund's Adjuvant model of inflammatory pain, and examined the effectiveness of the delta agonist, SNC80, to both inhibit Ca2+ channels in primary afferent neurons and to attenuate mechanical allodynia. In naïve beta-arrestin 2 wildtype and knockout mice, SNC80 neither significantly inhibited voltage-dependent Ca2+ currents nor produced antinociception. However, following inflammatory pain, both measures showed a significant and long-lasting enhancement of delta opioid receptor function that persisted for up to 14 days post-injury regardless of genotype. Furthermore, although this pain model did not alter Ca2+ current density, the contribution of N-type Ca2+ channels to the total current appeared to be regulated by the presence of beta-arrestin 2. Our results indicate that there is an
Middleton, L.S.; Lofwall, M.R.; Nuzzo, P.A.; Siegel, A.; Walsh, S.L.
Oxycodone, an opioid with known abuse liability, is misused by the intranasal route. Our objective was to develop a model of intranasal oxycodone self-administration useful for assessing the relative reinforcing effects of opioids and potential pharmacotherapies for opioid use disorders. Healthy, sporadic intranasal opioid abusers (n=8; 7 M, 1 F) completed this inpatient 2.5-week, randomized, double blind, placebo-controlled, crossover study. Each intranasal oxycodone dose (0, 14 & 28 mg) was tested in a separate 3-day block of sessions. The first day of each block was a sample session in which the test dose was given. Two randomized progressive ratio sessions were conducted on the next 2 days: 1) subjects could work for the test dose over 7 trials (1/7th of total dose/trial), and 2) subjects could work for either a portion of the dose (1/7th) or money ($3) over 7 trials. Physiological and subjective measures were collected before and after drug administration for all sessions. Subjects never worked to self-administer placebo regardless of whether money was available. In both self-administration sessions, oxycodone self-administration was dose-dependent. Subjects worked less for drug (28 mg oxycodone) when money was available, but only modestly so. Oxycodone dose-dependently increased VAS ratings of positive drug effects (e.g., ‘like’) during sample sessions (p<0.05). These reports were positively correlated with self-administration behavior (e.g., ‘like’, r=0.65). These data suggest that both procedures are sensitive for detecting the reinforcing properties of intranasal oxycodone and may be employed to further explore the characteristics of opioid compounds and potential pharmacotherapies for treatment. PMID:22686495
Middleton, Lisa S; Lofwall, Michelle R; Nuzzo, Paul A; Siegel, Anthony J; Walsh, Sharon L
Oxycodone, an opioid with known abuse liability, is misused by the intranasal route. Our objective was to develop a model of intranasal oxycodone self-administration useful for assessing the relative reinforcing effects of opioids and potential pharmacotherapies for opioid use disorders. Healthy, sporadic intranasal opioid abusers (n = 8; 7 M, 1 F) completed this inpatient 2.5-week, randomized, double-blind, placebo-controlled, crossover study. Each intranasal oxycodone dose (0, 14 & 28 mg) was tested in a separate 3-day block of sessions. The first day of each block was a sample session in which the test dose was given. Two randomized progressive ratio sessions were conducted on the next 2 days: (1) subjects could work for the test dose over 7 trials (1/7th of total dose/trial), and (2) subjects could work for either a portion of the dose (1/7th) or money ($3) over 7 trials. Physiological and subjective measures were collected before and after drug administration for all sessions. Subjects never worked to self-administer placebo regardless of whether money was available. In both self-administration sessions, oxycodone self-administration was dose-dependent. Subjects worked less for drug (28 mg oxycodone) when money was available but only modestly so. Oxycodone dose-dependently increased VAS ratings of positive drug effects (e.g., "like") during sample sessions (p < .05). These reports were positively correlated with self-administration behavior (e.g., "like," r = .65). These data suggest that both procedures are sensitive for detecting the reinforcing properties of intranasal oxycodone and may be used to further explore the characteristics of opioid compounds and potential pharmacotherapies for treatment.
Cooper, Z D; Johnson, K W; Vosburg, S K; Sullivan, M A; Manubay, J; Martinez, D; Jones, J D; Saccone, P A; Comer, S D
Opioid-induced glial activation is hypothesized to contribute to the development of tolerance to opioid-induced analgesia. This inpatient, double-blind, placebo-controlled, within-subject and between-groups pilot study investigated the dose-dependent effects of ibudilast, a glial cell modulator, on oxycodone-induced analgesia. Opioid-dependent volunteers were maintained on morphine (30mg, PO, QID) for two weeks and received placebo ibudilast (0mg, PO, BID) during the 1st week (days 1-7). On day 8, participants (N=10/group) were randomized to receive ibudilast (20 or 40mg, PO, BID) or placebo for the remainder of the study. On days 4 (week 1) and 11 (week 2), the analgesic, subjective, and physiological effects of oxycodone (0, 25, 50mg/70kg, PO) were determined. Analgesia was measured using the cold pressor test; participants immersed their hand in cold water (4°C) and pain threshold and pain tolerability were recorded. Oxycodone decreased pain threshold and tolerability in all groups during week 1. During week 2, the placebo group exhibited a blunted analgesic response to oxycodone for pain threshold and subjective pain ratings, whereas the 40mg BID ibudilast group exhibited greater analgesia as measured by subjective pain ratings (p≤0.05). Oxycodone also increased subjective drug effect ratings associated with abuse liability in all groups during week 1 (p≤0.05); ibudilast did not consistently affect these ratings. These findings suggest that ibudilast may enhance opioid-induced analgesia. Investigating higher ibudilast doses may establish the utility of pharmacological modulation of glial activity to maximize the clinical use of opioids. Copyright © 2017. Published by Elsevier B.V.
Kleber, Herbert D.
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
Trafton, Jodie A; Minkel, Jared; Humphreys, Keith
Background Randomized clinical trials of methadone maintenance have found that on average high daily doses are more effective for reducing heroin use, and clinical practice guidelines recommend 60 mg/d as a minimum dosage. Nevertheless, many clinicians report that some patients can be stably maintained on lower methadone dosages to optimal effect, and clinic dosing practices vary substantially. Studies of individual responses to methadone treatment may be more easily translated into clinical practice. Methods and Findings A volunteer sample of 222 opioid-dependent US veterans initiating methadone treatment was prospectively observed over the year after treatment entry. In the 168 who achieved at least 1 mo of heroin abstinence, methadone dosages on which patients maintained heroin-free urine samples ranged from 1.5 mg to 191.2 mg (median = 69 mg). Among patients who achieved heroin abstinence, higher methadone dosages were predicted by having a diagnosis of posttraumatic stress disorder or depression, having a greater number of previous opioid detoxifications, living in a region with lower average heroin purity, attending a clinic where counselors discourage dosage reductions, and staying in treatment longer. These factors predicted 42% of the variance in dosage associated with heroin abstinence. Conclusions Effective and ineffective methadone dosages overlap substantially. Dosing guidelines should focus more heavily on appropriate processes of dosage determination rather than solely specifying recommended dosages. To optimize therapy, methadone dosages must be titrated until heroin abstinence is achieved. PMID:16448216
D’Onofrio, Gail; O’Connor, Patrick G.; Pantalon, Michael V.; Chawarski, Marek C.; Busch, Susan H.; Owens, Patricia H.; Bernstein, Steven L.; Fiellin, David A.
statistically across groups, with 53.8% (95% CI, 42%-65%) in the referral group, 42.9% (95% CI, 31%-55%) in the brief intervention group, and 57.6% (95% CI, 47%-68%) in the buprenorphine group (P = .17). There were no statistically significant differences in HIV risk across groups (P = .66). Eleven percent of patients in the buprenorphine group (95% CI, 6%-19%) used inpatient addiction treatment services, whereas 37% in the referral group (95% CI, 27%-48%) and 35% in the brief intervention group (95% CI, 25%-37%) used inpatient addiction treatment services (P < .001). CONCLUSIONS AND RELEVANCE Among opioid-dependent patients, ED-initiated buprenorphine treatment vs brief intervention and referral significantly increased engagement in addiction treatment, reduced self-reported illicit opioid use, and decreased use of inpatient addiction treatment services but did not significantly decrease the rates of urine samples that tested positive for opioids or of HIV risk. These findings require replication in other centers before widespread adoption. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00913770 PMID:25919527
Abramoff, Benjamin A.; Lange, Hannah L. H.; Matson, Steven C.; Cottrill, Casey B.; Bridge, Jeffrey A.; Abdel-Rasoul, Mahmoud; Bonny, Andrea E.
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
The treatment of opioid dependence during pregnancy has historically consisted of either medication-assisted withdrawal or maintenance treatment with methadone. Buprenorphine maintenance treatment is emerging as a treatment during pregnancy with distinct benefits for the neonate and the pregnant woman. Buprenorphine is effective in decreasing the risk of relapse in pregnant women. In addition, prenatal use of buprenorphine appears to decrease the severity and duration of neonatal abstinence syndrome as compared with methadone maintenance. Management of buprenorphine includes initiation and maintenance treatment as well as careful planning for pain control during and after delivery and prevention of postpartum relapse risk. Only very small amounts of buprenorphine enter breast milk, making it a good option for those who elect to breast-feed. There is evidence that emerging collaborative care models are effective ways to deliver buprenorphine maintenance treatment, although more investigation is needed to generalize this to the obstetric setting.
Williams, John T
Desensitization of µ-opioid receptors (MORs) develops over 5-15 minutes after the application of some, but not all, opioid agonists and lasts for tens of minutes after agonist removal. The decrease in function is receptor selective (homologous) and could result from 1) a reduction in receptor number or 2) a decrease in receptor coupling. The present investigation used photolysis of two caged opioid ligands to examine the kinetics of MOR-induced potassium conductance before and after MOR desensitization. Photolysis of a caged antagonist, carboxynitroveratryl-naloxone (caged naloxone), blocked the current induced by a series of agonists, and the time constant of decline was significantly decreased after desensitization. The increase in the rate of current decay was not observed after partial blockade of receptors with the irreversible antagonist, β-chlornaltrexamine (β-CNA). The time constant of current decay after desensitization was never more rapid than 1 second, suggesting an increased agonist off-rate rather than an increase in the rate of channel closure downstream of the receptor. The rate of G protein-coupled K(+) channel (GIRK) current activation was examined using photolysis of a caged agonist, carboxynitrobenzyl-tyrosine-[Leu(5)]-enkephalin. After acute desensitization or partial irreversible block of MORs with β-CNA, there was an increase in the time it took to reach a peak current. The decrease in the rate of agonist-induced GIRK conductance was receptor selective and dependent on receptor number. The results indicate that opioid receptor desensitization reduced the number of functional receptor and that the remaining active receptors have a reduced agonist affinity.
Liao, Dezhi; Grigoriants, Olga O.; Loh, Horace H.; Law, Ping-Yee
Although chronic treatment with morphine is known to alter the function and morphology of excitatory synapses, the effects of other opioids on these synapses are not clear. Here we report distinct effects of several opioids (morphine, DAMGO and etorphine) on miniature excitatory postsynaptic currents (mEPSCs) in cultured hippocampal neurons: (1) Chronic treatment with morphine for > 3 days decreased the amplitude, frequency, rise time and decay time of mEPSCs. In contrast, “internalizing” opioids such as etorphine and DAMGO increased the frequency of mEPSCs and had no significant effect on the amplitude and kinetics of mEPSCs. These results demonstrate that different opioids can have distinct effects on the function of excitatory synapses. (2) MOR-GFP is clustered in dendritic spines in most hippocampal neurons but is concentrated in axon-like processes in striatal and corticostriatal non-spiny neurons. It suggests that MORs might mediate pre- or post-synaptic effects depending upon cell types. (3) Neurons were cultured from MOR knock-out mice and were exogenously transfected with GFP-tagged MORs (MOR-GFP). Chronic treatment with morphine suppressed mEPSCs only in neurons that contained postsynaptic MOR-GFP, indicating thatopioids can modulate excitatory synaptic transmission postsynaptically. (4) Morphine acutely decreased mEPSC amplitude in neurons expressing exogenous MOR-GFP, but had no effect on neurons expressing GFP. It indicates that the low level of endogenous MORs could only allow slow opioid-induced plasticity of excitatory synapses under normal conditions. (5) A theoretical model suggests that morphine might affect the function of spines by decreasing the electrotonic distance from synaptic inputs to the soma. PMID:17122315
Scharnagel, R; Kaiser, U; Schütze, A; Heineck, R; Gossrau, G; Sabatowski, R
Annually published data show a continual increase in the volume of opioid prescriptions in Germany, thus indicating an intensification of opioid therapy. The majority of opioids are prescribed to treat chronic non-cancer-related pain. On the basis of current guidelines, as well as in terms of the lack of data regarding long-term use of opioids and their effectiveness beyond a period of 3 months, this development must be viewed critically. With reference to four case reports, we discuss and evaluate opioid therapy in relation to medication misuse and the development of drug dependency. Particular emphasis is placed on the administration of rapid-release and short-acting opioid preparations, which we consider to be particularly problematic.
Cooper, Ziva D; Johnson, Kirk W; Pavlicova, Martina; Glass, Andrew; Vosburg, Suzanne K; Sullivan, Maria A; Manubay, Jeanne M; Martinez, Diana M; Jones, Jermaine D; Saccone, Phillip A; Comer, Sandra D
Glial activation is hypothesized to contribute directly to opioid withdrawal. This study investigated the dose-dependent effects of a glial cell modulator, ibudilast, on withdrawal symptoms in opioid-dependent volunteers after abrupt discontinuation of morphine administration. Non-treatment-seeking heroin-dependent volunteers (n = 31) completed the in-patient, double-blind, placebo-controlled, within-subject and between-group study. Volunteers were maintained on morphine (30 mg, QID) for 14 days and placebo (0 mg, QID) for the last 7 days of the 3-week study. Volunteers also received placebo (0 mg, PO, BID) capsules on days 1-7. On days 8-21, volunteers were randomized to receive ibudilast (20 or 40 mg, PO, BID) or placebo capsules. Subjective and clinical ratings of withdrawal symptoms were completed daily using daily using the Subjective Opioid Withdrawal Scale (SOWS) and Clinical Opioid Withdrawal Scale (COWS). Medication side effects were also monitored. Relative to the first 2 weeks, all groups exhibited withdrawal during the third week as assessed by the SOWS and COWS (P ≤ 0.0001). Although overall SOWS scores did not differ between groups, exploratory analyses pooling the two ibudilast groups demonstrated that they had lower ratings of withdrawal symptoms on SOWS items ('anxious,' 'perspiring,' 'restless,' 'stomach cramps') during detoxification relative to the placebo group. Ibudilast was well tolerated; no serious adverse events occurred during the study. Pharmacological modulation of glial activity with ibudilast decreased some subjective ratings of opioid withdrawal symptoms. These exploratory findings are the first to demonstrate the potential clinical utility of glial modulators for treating opioid withdrawal in humans.
Scherrer, Jeffrey F.; Salas, Joanne; Copeland, Laurel A.; Stock, Eileen M.; Schneider, F. David; Sullivan, Mark; Bucholz, Kathleen K.; Burroughs, Thomas; Lustman, Patrick J.
Several studies have demonstrated chronic opioid analgesic use is associated with increased risk of new onset depression. It is not known if patients with remitted depression are at increased risk of relapse following exposure to opioid analgesics. A retrospective cohort design using patient data from the Veterans Health Administration (VHA; n=5,400), and Baylor Scott & White Health (BSWH; n=842) was performed with an observation period 2002–2012 in VHA and 2003–2012 in BSWH. Eligible patients had a diagnosis of depression at baseline and experienced a period of remission. Risk of depression recurrence was modeled in patients that either started an opioid or remained without opioid prescriptions before or during remission. Cox-proportional hazard models measured the association between opioid use and depression recurrence controlling for pain, and other confounders. Patients exposed to an opioid compared to those unexposed had a significantly greater risk of depression recurrence in both patient populations (VHA: HR=2.17; 95% CI:2.01–2.34; BSWH: HR=1.77; 95% CI:1.42–2.21). These results suggest opioid use doubles the risk of depression recurrence even after controlling for pain, psychiatric disorders and opioid misuse. Further work is needed to determine if risk increases with duration of use. Repeated screening for depression after opioid initiation may be warranted. PMID:26884282
Berrendero, Fernando; Robledo, Patricia; Trigo, José Manuel; Martín-García, Elena; Maldonado, Rafael
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
Walsh, Sharon L; Nuzzo, Paul A; Babalonis, Shanna; Casselton, Victoria; Lofwall, Michelle R
Buprenorphine can be abused by the intranasal route. This study sought to examine the relative abuse liability and reinforcing efficacy of intranasal buprenorphine compared to intranasal buprenorphine/naloxone in opioid-dependent individuals. Eleven healthy male and female volunteers physically dependent on short-acting opioids resided as inpatients during participation in this double blind, within subject, placebo-controlled study. Participants were maintained on oxycodone (30 mg/q.i.d., p.o.) throughout the 6-week study. Eight pairs of experimental sessions were conducted at ≥48 h intervals to examine the pharmacodynamic profile (Sample) and reinforcing efficacy (Self-administration the following day) of intranasal placebo, oxycodone (60 mg), buprenorphine (2, 8 & 16 mg) and buprenorphine/naloxone (2/0.5, 8/2 & 16/4 mg). Subjective, observer-rated and physiological measures were collected to assess the magnitude of opioid agonist and antagonist effects. A progressive ratio self-administration procedure assessed choices for drug versus money. All active doses produced opioid agonist-like effects (e.g., increased ratings of "liking," and miosis) compared to placebo. The effects of buprenorphine and buprenorphine/naloxone were not reliably dose-dependent. Intranasal buprenorphine/naloxone elicited modest and transient opioid withdrawal-like effects in the first hour post-drug administration, while simultaneously blunting or blocking the early onset of agonist effects seen with buprenorphine alone. All active doses of buprenorphine were self-administered more than placebo, but buprenorphine/naloxone doses were not. These data confirm that intranasal buprenorphine/naloxone has deterrent properties related to transient withdrawal effects that likely decrease its desirability for misuse compared to buprenorphine in opioid-dependent individuals maintained on short-acting opioids. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Walsh, Sharon L.; Nuzzo, Paul A.; Babalonis, Shanna; Casselton, Victoria; Lofwall, Michelle R.
Background Buprenorphine can be abused by the intranasal route. This study sought to examine the relative abuse liability and reinforcing efficacy of intranasal buprenorphine compared to intranasal buprenorphine/naloxone in opioid-dependent individuals. Methods Eleven healthy male and female volunteers physically dependent on short-acting opioids resided as inpatients during participation in this double blind, within subject, placebo-controlled study. Participants were maintained on oxycodone (30 mg/q.i.d., p.o.) throughout the 6-week study. Eight pairs of experimental sessions were conducted at ≥48 hour intervals to examine the pharmacodynamic profile (Sample) and reinforcing efficacy (Self-administration the following day) of intranasal placebo, oxycodone (60 mg), buprenorphine (2, 8 & 16 mg) and buprenorphine/naloxone (2/0.5, 8/2 & 16/4 mg). Subjective, observer-rated and physiological measures were collected to assess the magnitude of opioid agonist and antagonist effects. A progressive ratio self-administration procedure assessed choices for drug versus money. Results All active doses produced opioid agonist-like effects (e.g., increased ratings of “liking,” and miosis) compared to placebo. The effects of buprenorphine and buprenorphine/naloxone were not reliably dose-dependent. Intranasal buprenorphine/naloxone elicited modest and transient opioid withdrawal-like effects in the first hour post-drug administration, while simultaneously blunting or blocking the early onset of agonist effects seen with buprenorphine alone. All active doses of buprenorphine were self-administered more than placebo, but buprenorphine/naloxone doses were not. Conclusions These data confirm that intranasal buprenorphine/naloxone has deterrent properties related to transient withdrawal effects that likely decrease its desirability for misuse compared to buprenorphine in opioid-dependent individuals maintained on short-acting opioids. PMID:27012435
Cooper, Sasha; Campbell, Gabrielle; Larance, Briony; Murnion, Bridin; Nielsen, Suzanne
The dramatic increase in pharmaceutical opioid (PO) use in high-income countries is a growing public health concern. Stigma and social support are important as they may influence treatment uptake and outcomes, yet few studies exist regarding perceived stigma and social support among people with PO dependence. The aims of the study are to: (i) compare characteristics of those with PO dependence from iatrogenic and non-iatrogenic causes; (ii) document perceived stigma and its correlates in people in treatment for PO dependence; and (iii) examine correlates of social support in people in treatment for PO dependence. This prospective cohort study included (n = 108) PO-dependent people referred from treatment services. Telephone interviews were conducted at baseline, 3, 12 and 24 months. Multivariate linear regression was used to examine correlations. Mean age was 41 (SD = 10.5). Half (n = 56, 52%) were female. Two in five met the criteria for iatrogenic dependence (n = 41, 38%), with iatrogenic dependence associated with chronic pain, and no history of injection or heroin use. One quarter of study subjects reported past month unsanctioned opioid use (n = 25, 23%). Being married/de facto or female was associated with higher levels of perceived stigma. Unsanctioned opioid use, iatrogenic dependence and mental health conditions were associated with lower social support. Stigma affects all people in treatment. Those who are married/de facto and female may benefit from interventions to address stigma. The association of low social support with poorer mental health and ongoing substance use indicate that treatment could focus more on this area. © 2017 Australasian Professional Society on Alcohol and other Drugs.
Zhang, Guo-Fu; Ren, Yan-Ping; Sheng, Li-Xia; Chi, Yong; Du, Wan-Jun; Guo, Song; Jiang, Zuo-Ning; Xiao, Le; Luo, Xiao-Nian; Tang, Yi-Lang; Smith, Alicia K; Liu, Zhen-Qi; Zhang, Hong-Xi
The function of the Hypothalamic-Pituitary-Adrenal (HPA) axis during opioid dependence has been inconsistent. We compared HPA axis measures between subjects during methadone stabilization and drug-free detoxification with healthy controls. Sixty heroin dependent patients received either non-opiate treatment (NOT) with benzodiazepines and clonidine (n = 30) or methadone stabilization treatment (MT, n = 30), and their serum levels of corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol (COR) were measured and compared to those of healthy, nondependent controls. Compared with healthy controls, CRH was significantly lower (p < .001) while COR was higher (p < .001) during acute withdrawal in the NOT group. CRH and COR was lower (p < .001), while ACTH was normal in the MT group compared to healthy controls. Our findings suggest that chronic opioid dependence may cause reduced function of the HPA axis, while opioid withdrawal may decrease the response of the pituitary to CRH and increase the adrenal response to ACTH.
Fudalej, Sylwia; Jakubczyk, Andrzej; Kopera, Maciej; Piwoński, Jerzy; Bielecki, Wojciech; Drygas, Wojciech; Wasilewska, Krystyna; Ilgen, Mark; Bohnert, Amy; Barry, Kristen; Płoski, Rafał; Blow, Frederic C.; Wojnar, Marcin
Objective: Disrupted-in-schizophrenia 1 (DISC1) has been linked to vulnerability to a variety of psychiatric disorders and neuropsychiatric phenotypes. However, DISC1 has not been frequently examined as a potential risk factor for substance dependence. An association between opioid dependence and DISC1 rs2738888 polymorphism has been recently reported. In addition, opioid dependence was associated with rs6419156 located close to the protein phosphatase 3 catalytic subunit alpha isoform (PPP3CA) gene. The aim of the present study was to examine the associations between opioid dependence with rs2738888 and rs6419156 in an independent sample. Method: The selected polymorphisms were genotyped in a sample of 392 individuals (69.9% male) diagnosed as alcohol- and/or opioid-dependent. A control group (n = 257; 67.7% male) was derived from the Polish National Health Survey (N = 14,350). Results: The frequency of rs2738888 C allele was higher in controls than in opioid-dependent cases (OR = 0.65, p = .045). Phenotypic-oriented analyses performed within opioid-dependent individuals revealed the association between lifetime suicide attempt and rs2738888. The C allele of rs2738888 had a protective effect on lifetime suicide attempt in opioid-dependent patients (OR = 0.25, p = .003). Rs6419156 was not associated with substance dependence in the examined sample. Conclusions: The DISC1 may play an important role in vulnerability to opioid dependence. In addition, DISC1 may also be a genetic risk factor for suicide attempt in opioid-dependent individuals. PMID:26997180
Vaughn, Michael G.; Howard, Matthew O.
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…
Hefner, Kathryn; Sofuoglu, Mehmet; Rosenheck, Robert
Cannabis use is common among patients taking prescription opioids, although rates of concomitant cannabis use disorder (CUD) have been largely unexamined. CUD may increase safety risks in those taking opioid pain medications but it is unknown whether cannabis and opioids function as substitutes (cannabis use is associated with less prescription opioid use), or rather as complements (cannabis is associated with increased use of prescription opioids). We examined rates of CUD in a national sample of Veterans Health Administration (VHA) patients (n = 1,316,464) with non-cancer pain diagnoses receiving opioid medications in fiscal year 2012. Using bivariate analysis to identify potentially confounding variables associated with CUD (e.g., psychotropic medication, other substance use disorders) in this population, we then utilized logistic regression to examine rates of cannabis use disorder among individuals receiving different numbers of opioid prescriptions (0, 1-2, 3-10, 11-19, 20+). Descriptive analysis, largely confirmed by logistic regression, demonstrated that greater numbers of prescription opioid fills were associated with greater likelihood of CUD. This relationship was reduced somewhat for those receiving the most opioid prescriptions (20+) in the logistic regression, which controlled for potentially confounding variables. These results warrant increased attention to CUDs among patients receiving numerous opioid prescriptions. Increasing legalization of cannabis is likely to further increase use and abuse of cannabis in patients prescribed opioids. These findings suggest that clinicians should be alert to concomitant CUD and prescription opioid use, as these substances appear to complement each other. © American Academy of Addiction Psychiatry.
Garcia-Orjuela, Maria G; Alarcon-Franco, Lineth; Sanchez-Fernandez, Juan C; Agudelo, Yuli; Zuluaga, Andres F
In some countries the misuse and diversion of prescribed opioid analgesic is increasing considerably, but there is no official data regarding the situation in Colombia. The aim of this study was to identify all dependent to opioid analgesics legally prescribed patients that were treated in a University Hospital in Medellin, Colombia during 4 years and to characterize this population. Observational study in a University Hospital in Medellin, Colombia, searching for patients with ICD-10 codes related with opioid related disorders, adverse events or pain and treated between January 2011 and December 2014. Sixty patients with opioid dependence according to DSM-IV criteria were found from 3332 clinical charts reviewed. The median age was 43 years. Although all patients met the DSM-IV criteria, 33 % of patients were wrongly diagnosed by other ICD-10 codes. Almost all patient (88 %) initiated opioids after medical prescription although the adherence to pain scale was low (25 %). The median time of consumption was 48 months. Tramadol was the opioid more frequently used by patients, followed by morphine and oxycodone. A statistically significant higher consumption of other psychotropic substances was observed in male than female (P = 0.005 by Fisher's test). After be diagnosed, 55 % of patients gone a methadone-based replacement therapy. Legally prescribed opioid dependence was belatedly diagnosed in 60 patients in a University hospital, after prolonged use of drugs to treat chronic pain and with low adherence to pain scale or guidelines. This is the first report in Colombia.
Chetty, Mersha; Kenworthy, James J; Langham, Sue; Walker, Andrew; Dunlop, William C N
Opioid dependence is a chronic condition with substantial health, economic and social costs. The study objective was to conduct a systematic review of published health-economic models of opioid agonist therapy for non-prescription opioid dependence, to review the different modelling approaches identified, and to inform future modelling studies. Literature searches were conducted in March 2015 in eight electronic databases, supplemented by hand-searching reference lists and searches on six National Health Technology Assessment Agency websites. Studies were included if they: investigated populations that were dependent on non-prescription opioids and were receiving opioid agonist or maintenance therapy; compared any pharmacological maintenance intervention with any other maintenance regimen (including placebo or no treatment); and were health-economic models of any type. A total of 18 unique models were included. These used a range of modelling approaches, including Markov models (n = 4), decision tree with Monte Carlo simulations (n = 3), decision analysis (n = 3), dynamic transmission models (n = 3), decision tree (n = 1), cohort simulation (n = 1), Bayesian (n = 1), and Monte Carlo simulations (n = 2). Time horizons ranged from 6 months to lifetime. The most common evaluation was cost-utility analysis reporting cost per quality-adjusted life-year (n = 11), followed by cost-effectiveness analysis (n = 4), budget-impact analysis/cost comparison (n = 2) and cost-benefit analysis (n = 1). Most studies took the healthcare provider's perspective. Only a few models included some wider societal costs, such as productivity loss or costs of drug-related crime, disorder and antisocial behaviour. Costs to individuals and impacts on family and social networks were not included in any model. A relatively small number of studies of varying quality were found. Strengths and weaknesses relating to model structure, inputs and approach were identified across
Hartwell, Emily E.; Pfeifer, James G.; McCauley, Jenna L.; Maria, Megan Moran-Santa; Back, Sudie E.
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
Despite decades of experience treating heroin or prescription opioid dependence with methadone or buprenorphine— two forms of opioid substitution therapy—gaps remain between current practices and evidence-based standards in both Canada and the United States. This is largely because of regulatory constraints and pervasive suboptimal clinical practices. Less than 10 percent of all people dependent on opioids in the United States are receiving substitution treatment, although the proportion may increase with expanded health insurance coverage as a result of the Affordable Care Act. In light of the accumulated evidence, we recommend eliminating restrictions on office-based methadone prescribing in the United States; reducing financial barriers to treatment, such as varying levels of copayment in Canada and the United States; reducing reliance on less effective and potentially unsafe opioid detoxification; and evaluating and creating mechanisms to integrate emerging treatments. Taking these steps can greatly reduce the consequent harms of opioid dependence by maximizing the individual and public health benefits of treatment. PMID:23918492
Zhu, Feng; Yan, Chun-xia; Wen, Yi-chong; Wang, Jiayin; Bi, Jinbo; Zhao, Ya-ling; Wei, Lai; Gao, Cheng-ge; Jia, Wei; Li, Sheng-bin
Dopamine D1 receptor (DRD1) modulates opioid reinforcement, reward, and opioid-induced neuroadaptation. We propose that DRD1 polymorphism affects susceptibility to opioid dependence (OD), the efficiency of transition to OD, and opioid-induced pleasure response. We analyzed potential association between seven DRD1 polymorphisms with the following traits: duration of transition from the first use to dependence (DTFUD), subjective pleasure responses to opioid on first use and post-dependence use, and OD risk in 425 Chinese with OD and 514 healthy controls. DTFUD and level of pleasure responses were examined using a semi-structured interview. The DTFUD of opioid addicts ranged from 5 days to 11 years. Most addicts (64.0%) reported non-comfortable response upon first opioid use, while after dependence, most addicts (53.0%) felt strong opioid-induced pleasure. Survival analysis revealed a correlation of prolonged DTFUD with the minor allele-carrying genotypes of DRD1 rs4532 (hazard ratios (HR) = 0.694; p = 0.001) and rs686 (HR = 0.681, p = 0.0003). Binary logistic regression indicated that rs10063995 GT genotype (vs. GG+TT, OR = 0.261) could predict decreased pleasure response to first-time use and the minor alleles of rs686 (OR = 0.535) and rs4532 (OR = 0.537) could predict decreased post-dependence pleasure. Moreover, rs686 minor allele was associated with a decreased risk for rapid transition from initial use to dependence (DTFUD≤30 days; OR = 0.603) or post-dependence euphoria (OR = 0.603) relative to major allele. In conclusion, DRD1 rs686 minor allele decreases the OD risk by prolonging the transition to dependence and attenuating opioid-induced pleasure in Chinese.
Meyer, Marjorie; Benvenuto, Anna; Howard, Diantha; Johnston, Anne; Plante, Dawn; Metayer, Jerilyn; Mandell, Todd
The goal of this study was to determine whether improved access to medication assisted therapy in the general population, with improved coordination of ancillary services for pregnant women, improved perinatal outcomes in a nonurban area. The cohort of women treated for opioid dependence during pregnancy with medication-assisted therapy and delivered at a single institution between 2000 and 2006 were retrospectively identified (n = 149 women; n = 151 neonates). Access to opioid agonist therapy for the general population was determined as the combined number of available treatment positions for medication-assisted therapy. Treatment during pregnancy (interim substitution therapy vs opioid treatment program) and pregnancy outcomes were noted from chart review. The primary outcome of trend of prenatal care indices and newborn birth weight over time was determined by Kendall's tau. As access to treatment in the general population expanded from 2000 to 2006, the number of women receiving treatment increased, the proportion of women receiving interim substitution therapy decreased (P < 0.001), gestational age at the initiation of treatment decreased (P < 0.001), and the proportion of women receiving treatment before pregnancy increased (P < 0.001). Infants delivered to mothers in a treatment program had improved birth weight z score compared with those receiving interim substitution therapy (P = 0.007). The proportion of infants discharged to the care of the mother and remaining in maternal care at 1 year improved both over time (P = 0.03; P = 0.004) and with treatment within a treatment program (P < 0.001; P = 0.004). Improved access to opioid agonist treatment programs for the general population in nonurban areas improves perinatal outcome and retention of maternal guardianship.
Stein, Michael D; Herman, Debra S; Moitra, Ethan; Hecht, Jacki; Lopez, Rosalie; Anderson, Bradley J; Brown, Richard A
Buprenorphine opioid agonist treatment (OAT) has established efficacy for treating opioid dependency but early relapse rates are high and are often associated with withdrawal-related or emotional distress. To determine whether a novel distress tolerance (DT) intervention during buprenorphine initiation decreases opioid relapse, we conducted a preliminary randomized controlled trial with opioid-dependent outpatients. Participants received buprenorphine-naloxone induction and 3-months of maintenance buprenorphine plus seven, 50-min manualized, individual sessions (DT vs. health education (HE) control) over a 28-day period, linked to clinician medication dosing visits, and beginning 2 days prior to buprenorphine induction. Primary outcomes included use of illicit opioids (positive defined as any self-reported use in the prior 28 days or detected by urine toxicology) and treatment drop out. Among 49 participants, the mean age was 41 years, 65.3% were male. Persons randomized to DT had lower rates of opioid use at all three monthly assessments, and at 3-months, 72% of HE participants were opioid positive compared with 62.5% of DT participants. Rates of dropout were 24% and 25% in the HE and DT arms, respectively. This distress tolerance treatment produced a small, but not statistically significant reduction in opioid use during the first three months of treatment although no differences were found in drop-out rates between conditions. If replicated in a larger study, DT could offer clinicians a useful behavioral treatment to complement the effects of buprenorphine. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
De, Biswajit; Mattoo, Surendra K.; Basu, Debasish
This study attempted to apply age at onset typology in ICD-10 diagnosed opioid dependence. The sample comprised 80 men seeking treatment at an addiction clinic. The measures included socio-demographic and clinical profile, Severity of Opioid Dependence Questionnaire, Modified Sensation Seeking Scale, Multiphasic Personality Questionnaire (MPQ) and Family History Assessment Module. A cut-off age of 20/21 years for an early-onset late-onset typology of opioid dependence was obtained using two methods - the modal age at onset method and one-third sample by age at onset method. The early onset group showed significant differences in terms of it being more often younger, urban, unmarried, wage earning or students, using oral opioids (not heroin or injectables), showing higher lifetime use and dependence of sedatives, earlier onset of use and dependence of sedatives and tobacco, and higher global psychopathology in terms of MPQ. The early onset group also showed statistically insignificant trends for lesser use and dependence of alcohol, higher severity of opioid dependence, more legal and less social complications, higher sensation seeking (except boredom susceptibility), and more frequent substance dependence in first degree relatives. The age at onset typology in opioid dependence appears to be feasible and having some similarities to similar typology in alcoholism. PMID:21206561
Busch, Deborah W
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.
DiPaula, Bethany A; Menachery, Elizabeth
To develop a physician-pharmacist collaborative practice for opioid-dependent patients designed to increase access to treatment, optimize patient care, reduce cost, minimize physician burden, and prevent diversion. Suburban health department. Physician-pharmacist buprenorphine/naloxone maintenance practice. Traditionally, health department buprenorphine/naloxone patients have been referred to community physicians at considerable cost with varying outcomes. In this pilot project, patients were managed using a drug therapy management model. Intake assessments and follow-up appointments were conducted by the pharmacist. The pharmacist debriefed with the physician and documented each interaction, allowing for efficient assessment completion. The physician appended notes, when applicable, and cosigned each patient's record. The pharmacist prevented diversion by gathering data from outside providers, pharmacies, and laboratories. This health department program improved care by producing structure and expanding treatment options. A total of 12 patients completed full intakes with 135 follow-up appointments equating to an estimated savings of $22,000. The program demonstrated a 91% attendance rate, 100% 6-month retention rate, and 73% 12-month retention rate. Overall, 127 (98%) urine toxicology screens were positive for buprenorphine and 114 (88%) were positive for buprenorphine and negative for opioids. Physician and pharmacist collaboration optimized care of buprenorphine-maintained patients. Data from this pilot were used to develop a permanent physician-pharmacist program and to obtain approval for the first state-approved opioid use disorder drug therapy management protocol.
Poole, Sabrina A.; Pecoraro, Anna; Subramaniam, Geetha; Woody, George; Vetter, Victoria L
Objective To evaluate buprenorphine-naloxone effects on the QTc in youth with opioid dependence. Buprenorphine is a partial agonist that is an effective treatment for opioid dependence. Compared to methadone it has a lower risk of QTc prolongation in adults but is less well studied in youth. It may also reduce the risk for torsades de pointes (TdP) an uncommon variant of polymorphic ventricular tachycardia, that can result in syncope, ventricular fibrillation, and sudden death. Methods Secondary analysis of ECG data from 95 subjects who participated in a multi-site trial for youth with opioid dependence. Subjects were randomized to a 2-week (DETOX), or a 12-week course of buprenorphine-naloxone (BUP). 12-lead ECGs were done at baseline, weeks 4 and 12, and QTc intervals were hand measured and calculated using Bazett's formula. Increases > 60 milliseconds (ms) were considered clinically significant, and readings > 450 ms (males) and 470 ms (females) indicated a prolonged QTc. Results Mean QTc intervals were higher for BUP than DETOX participants at baseline, week 4, and week 12 (p = 0.045), and females had longer mean QTc intervals than males (p < 0.0005). Variations in QTc intervals were observed in some, however none were above 500 ms, the level at which risk for TdP becomes more significant. Conclusion In this randomized trial, the mean QTc at baseline, before randomization, was higher in BUP than DETOX patients. Minimal changes in the QTc were seen at 4 and 12-weeks in a few patients in both groups. There was no evidence that buprenorphine-naloxone alone increased the QTc to a level that increased the risk for TdP. PMID:26690291
Poole, Sabrina A; Pecoraro, Anna; Subramaniam, Geetha; Woody, George; Vetter, Victoria L
The aim of the study was to evaluate buprenorphine-naloxone effects on the QTc in youth with opioid dependence. Buprenorphine is a partial agonist that is an effective treatment for opioid dependence. Compared with methadone, it has a lower risk of QTc prolongation in adults, but is less studied in the youth. It may also reduce the risk of torsades de pointes (TdP)--an uncommon variant of polymorphic ventricular tachycardia--that can result in syncope, ventricular fibrillation, and sudden death. Secondary analysis of the electrocardiogram data from 95 individuals who participated in a multisite trial for youth with opioid dependence. The participants were randomized to a 2-week (DETOX) or a 12-week course of buprenorphine-naloxone (BUP). At baseline, 12-lead electrocardiograms were done at weeks 4 and 12, and QTc intervals were hand-measured and calculated using Bazett formula. Increases above 60 milliseconds were considered clinically significant, and readings above 450 milliseconds (in men) and 470 milliseconds (in women) indicated a prolonged QTc. Mean QTc intervals were higher for BUP than for DETOX participants at baseline, week 4, and week 12 (P = 0.045), and women had longer mean QTc intervals than men (P < 0.0005). Variations in the QTc intervals were observed in some; however, none were above 500 milliseconds--the level at which risk for TdP becomes more significant. In this randomized trial, the mean QTc at baseline, before randomization, was higher in BUP than in DETOX patients. Minimal changes in the QTc were seen at 4 and 12 weeks in a few patients in both groups. There was no evidence that buprenorphine-naloxone alone increased the QTc to a level that increased the risk for TdP.
Chu, Larry F; Sun, John; Clemenson, Anna; Erlendson, Matthew J; Rico, Tom; Cornell, Erika; Obasi, Hannah; Sayyid, Zahra N; Encisco, Ellen M; Yu, Jeff; Gamble, Jamison G; Carroll, Ian; Clark, J David
Individuals taking opioids for an extended period of time may become physically dependent, and will therefore experience opioid withdrawal should they stop taking the medication. Previous work in animal and human models has shown that the serotonin (5-HT3) receptor may be implicated in opioid withdrawal. In this study, we investigated if ondansetron, a 5-HT3-receptor antagonist, could reduce the symptoms of opioid withdrawal after chronic opioid exposure in humans. In this double-blinded, randomized, crossover study, 33 chronic back pain patients (N = 33) were titrated onto sustained-release oral morphine for 30 days. After titration, participants attended 2 study sessions, 1 week apart, in which opioid withdrawal was induced with intravenous naloxone, with or without 8 mg intravenous ondansetron pretreatment. Opioid withdrawal symptoms were assessed by a blinded research assistant (objective opioid withdrawal score [OOWS]) and by the research participant (subjective opioid withdrawal score [SOWS]). Clinically significant signs of withdrawal were observed during both the ondansetron (ΔOOWS = 3.58 ± 2.22, P < 0.0001; ΔSOWS = 12.48 ± 11.18, P < 0.0001) and placebo sessions (ΔOOWS = 3.55 ± 2.39, P < 0.0001; ΔSOWS = 12.21 ± 10.72, P < 0.0001), but no significant differences were seen between the treatment sessions in either the OOWS or SOWS scores. We hypothesized that ondansetron would reduce opioid withdrawal symptoms in human subjects, but found no difference in withdrawal severity between ondansetron and placebo sessions. These findings suggest that more investigation may be necessary to determine if 5-HT3-receptor antagonists are suitable treatment options for opioid withdrawal.
Winklbaur, Bernadette; Kopf, Nina; Ebner, Nina; Jung, Erika; Thau, Kenneth; Fischer, Gabriele
Through a novel synthesis of the literature and our own clinical experience, we have derived a set of evidence-based recommendations for consideration as guidance in the management of opioid-dependent pregnant women and infants. PubMed literature searches were carried out to identify recent key publications in the areas of pregnancy and opioid dependence, neonatal abstinence syndrome (NAS) prevention and treatment, multiple substance abuse and psychiatric comorbidity. Pregnant women dependent on opioids require careful treatment to minimize harm to the fetus and neonate and improve maternal health. Applying multi-disciplinary treatment as early as possible, allowing medication maintenance and regular monitoring, benefits mother and child both in the short and the long term. However, there is a need for randomized clinical trials with sufficient sample sizes. Opioid maintenance therapy is the recommended treatment approach during pregnancy. Treatment decisions must encompass the full clinical picture, with respect to frequent complications arising from psychiatric comorbidities and the concomitant consumption of other drugs. In addition to standardized approaches to pregnancy, equivalent attention must be given to the treatment of NAS, which occurs frequently after opioid medication. Methodological flaws and inconsistencies confound interpretation of today's literature. Based on this synthesis of available evidence and our clinical experience, we propose recommendations for further discussion.
Krans, Elizabeth E.; Cochran, Gerald; Bogen, Debra L.
Pregnancy is an opportune time to identify opioid dependence, facilitate conversion to opioid maintenance treatment, and coordinate care with specialists in addiction medicine, behavioral health and social services. Comprehensive prenatal care for opioid dependent women involves the evaluation and management of co-occurring psychiatric disorders, polysubstance use, infectious diseases, social stressors and counseling regarding the importance of breastfeeding, contraception and neonatal abstinence syndrome. While the complex psychiatric, social and environmental factors faced by this population pose significant challenges to obstetric care providers, the development of strong patient-provider relationships can facilitate the ability to deliver efficient and effective health care during pregnancy. PMID:25775440
Krans, Elizabeth E; Cochran, Gerald; Bogen, Debra L
Pregnancy is an opportune time to identify opioid dependence, facilitate conversion to opioid maintenance treatment, and coordinate care with specialists in addiction medicine, behavioral health, and social services. Comprehensive prenatal care for opioid-dependent women involves the evaluation and the management of co-occurring psychiatric disorders, polysubstance use, infectious diseases, social stressors, and counseling regarding the importance of breastfeeding, contraception, and neonatal abstinence syndrome. Although the complex psychiatric, social, and environmental factors faced by this population pose significant challenges to obstetric care providers, the development of strong patient-provider relationships can facilitate the ability to deliver efficient and effective health care during pregnancy.
Clark, Robin E.; Baxter, Jeffrey D.; Aweh, Gideon; O'Connell, Elizabeth; Fisher, William H.; Barton, Bruce A.
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
Clark, Robin E; Baxter, Jeffrey D; Aweh, Gideon; O'Connell, Elizabeth; Fisher, William H; Barton, Bruce A
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. Copyright © 2015 Elsevier Inc. All rights reserved.
Meyer, Marjorie C.; Johnston, Anne M.; Crocker, Abigail M.; Heil, Sarah H.
Objective To compare maternal characteristics, prenatal care and newborn outcomes in a cohort of opioid-dependent pregnant women treated with methadone vs. buprenorphine. Methods Retrospective cohort study. 609 pregnant, opioid-dependent women were treated with methadone (n=248) or buprenorphine (n=361) between 2000–2012 at a single institution. Results Mothers treated with buprenorphine were more likely to start medication prior to or earlier in pregnancy, had longer gestation and larger infants. Newborns of buprenorphine- vs. methadone-maintained mothers required treatment for neonatal abstinence significantly less often and for a shorter duration. Conclusions These data suggest pregnancy outcomes following buprenorphine to treat opioid dependence during pregnancy in clinical practice are as good and often better than outcomes with methadone. These results are consistent with efficacy data from randomized clinical trials and further support the use of buprenorphine for the treatment of opioid-dependence during pregnancy. PMID:25622120
Meyer, Marjorie C; Johnston, Anne M; Crocker, Abigail M; Heil, Sarah H
To compare maternal characteristics, prenatal care, and newborn outcomes in a cohort of opioid-dependent pregnant women treated with methadone versus buprenorphine. In a retrospective cohort study, 609 pregnant, opioid-dependent women were treated with methadone (n = 248) or buprenorphine (n = 361) between 2000 and 2012 at a single institution. Mothers treated with buprenorphine were more likely to start medication before or earlier in pregnancy, had longer gestation, and gave birth to larger infants. Newborns of buprenorphine- versus methadone-maintained mothers required treatment for neonatal abstinence significantly less often and for a shorter duration. These data suggest pregnancy outcomes with buprenorphine to treat opioid dependence during pregnancy in clinical practice are as good and often better than outcomes with methadone. These results are consistent with efficacy data from randomized clinical trials and further support the use of buprenorphine for the treatment of opioid dependence during pregnancy.
Han, Huijun; Kass, Philip H.; Wilsey, Barth L.; Li, Chin-Shang
Purpose To examine the age and gender-specific trends of schedule II opioid use among California residents, with special reference to multiple provider users (“doctor shoppers”). Methods Utilizing data from the California Prescription Drug Monitoring Program, we examined age and gender-specific trends of Schedule II opioid use during calendar years 1999–2007. Specifically, we analyzed: 1) the prevalence of Schedule II opioid users among California’s population, and 2) the proportion of these opioid users who were doctor shoppers (defined as an individual who used more than five different prescribers for all schedule II opioids he/she obtained in a calendar year). Results Among all age and gender groups, the prevalence of Schedule II opioid users in California increased by 150%–280% and the prevalence of doctor shoppers among users increased by 111%–213% over nine years. The prevalence of opioid users was lowest among 18–44 year-old males (1.25%) and highest among 65 years and older females (5.31%) by 2007. The prevalence of doctor shoppers was approximately 1.4% among those up to age 64 and 0.5% among those 65 years and older. The gender difference in doctor shoppers among all age groups was negligible. On average, the cumulative morphine-equivalent amount of Schedule II opioid per individual obtained per year was three- to six-fold higher for doctor shoppers than for the general population across different age and gender groups. Conclusions Age and gender differences in opioid use were relatively small, while the trends for use of opioids and multiple providers grew at a disquieting rate. PMID:23956137
Orman, Jennifer S; Keating, Gillian M
Buprenorphine/naloxone (Suboxone) comprises the partial micro-opioid receptor agonist buprenorphine in combination with the opioid antagonist naloxone in a 4 : 1 ratio. When buprenorphine/naloxone is taken sublingually as prescribed, the naloxone exerts no clinically significant effect, leaving the opioid agonist effects of buprenorphine to predominate. However, when buprenorphine/naloxone is parenterally administered in patients physically dependent on full agonist opioids, the opioid antagonism of naloxone causes withdrawal effects, thus reducing the abuse potential of the drug combination. Buprenorphine/naloxone is an effective maintenance therapy for opioid dependence and has generally similar efficacy to methadone, although more data are needed. Less frequent dispensing of buprenorphine/naloxone (e.g. thrice weekly) does not appear to compromise efficacy and can improve patient satisfaction. Buprenorphine/naloxone is more effective than clonidine as a medically supervised withdrawal therapy. Moreover, buprenorphine/naloxone is a generally well tolerated medically supervised withdrawal and maintenance treatment. Thus, sublingual buprenorphine/naloxone is a valuable pharmacotherapy for the treatment of opioid dependence.
Racz, Ildiko; Schürmann, Britta; Karpushova, Anna; Reuter, Martin; Cichon, Sven; Montag, Christian; Fürst, Robert; Schütz, Christian; Franke, Petra E; Strohmaier, Jana; Wienker, Thomas F; Terenius, Lars; Osby, Urban; Gunnar, Agneta; Maier, Wolfgang; Bilkei-Gorzó, Andras; Nöthen, Markus; Zimmer, Andreas
Experimental evidence indicates that the endogenous opioid system influences stress responses as well as reinforces effects of addictive drugs. Because stress is an important factor contributing to drug dependence and relapse, we have now studied ethanol preference in enkephalin- and beta-endorphin-deficient mice under baseline conditions and after stress exposure. In the present study we used a two-bottle choice paradigm to study ethanol consumption and stress-induced ethanol preference. To examine alcohol withdrawal symptoms the forced drinking procedure was employed. We performed an association analysis in two case-control samples of alcohol addicts to determine whether these opioid peptides also contribute to ethanol dependence in humans. Ethanol consumption was significantly reduced in the absence of beta-endorphins, particularly in female knockout animals. Stress exposure results in an increased ethanol consumption in wild-type mice but did not influence ethanol-drinking in beta-endorphin knockouts. Enkephalin-deficient mice showed no difference from wild-type mice in baseline ethanol preference but also showed no stress-induced elevation of ethanol consumption. Interestingly, we found a two-marker haplotype in the POMC gene that was associated with alcohol dependence in females in both cohorts. Together these results indicate a contribution of beta-endorphin to ethanol consumption and dependence.
Hu, Xiaoyu; Huang, Fang; Szymusiak, Magdalena
Chronic use of opioid analgesics has been hindered by the development of opioid addiction and tolerance. We have reported that curcumin, a natural flavonoid from the rhizome of Curcuma longa, attenuated opioid tolerance, although the underlying mechanism remains unclear. In this study, we tested the hypothesis that curcumin may inhibit Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα), a protein kinase that has been previously proposed to be critical for opioid tolerance and dependence. In this study, we used state-of-the-art polymeric formulation technology to produce poly(lactic-co-glycolic acid) (PLGA)-curcumin nanoparticles (nanocurcumin) to overcome the drug’s poor solubility and bioavailability, which has made it extremely difficult for studying in vivo pharmacological actions of curcumin. We found that PLGA-curcumin nanoparticles reduced the dose requirement by 11- to 33-fold. Pretreatment with PLGA-curcumin (by mouth) prevented the development of opioid tolerance and dependence in a dose-dependent manner, with ED50 values of 3.9 and 3.2 mg/kg, respectively. PLGA-curcumin dose-dependently attenuated already-established opioid tolerance (ED50 = 12.6 mg/kg p.o.) and dependence (ED50 = 3.1 mg/kg p.o.). Curcumin or PLGA-curcumin did not produce antinociception by itself or affect morphine (1–10 mg/kg) antinociception. Moreover, we found that the behavioral effects of curcumin on opioid tolerance and dependence correlated with its inhibition of morphine-induced CaMKIIα activation in the brain. These results suggest that curcumin may attenuate opioid tolerance and dependence by suppressing CaMKIIα activity. PMID:25515789
Jaremko, Kellie M.; Sterling, Robert C.; Van Bockstaele, Elisabeth J.
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
Jaremko, Kellie M; Sterling, Robert C; Van Bockstaele, Elisabeth J
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 and 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.
Morgan, Michael M; Christie, MacDonald J
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
Morgan, Michael M; Christie, MacDonald J
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.
Cousins, Sarah J; Radfar, Seyed Ramin; Crèvecoeur-MacPhail, Desirée; Ang, Alfonso; Darfler, Kendall; Rawson, Richard A
Extended-release naltrexone (XR-NTX) is associated with an increased number of opioid-free days, improved adherence rates in substance use disorder treatment programs, and reduced cravings and drug-seeking behaviors. There is little evidence on the predictive associations between baseline characteristics of opioid-dependent patients and XR-NTX utilization. Some studies have demonstrated better pharmacotherapy adherence and/or retention rates among non-heroin opioid users compared to heroin users. This study examines predictive associations between characteristics of patients and XR-NTX utilization, as well as participants' urge to use opiates. Our findings suggest that XR-NTX may contribute to decreases in urges to use among both heroin and non-heroin opioid users. Non-heroin opioid users and heroin users were retained in XR-NTX treatment for comparable periods of time. However, those who identified as homeless, injected opioids (regardless of opioid-type), or were diagnosed with a mental illness were less likely to be retained in treatment with XR-NTX.
McHugh, R. Kathryn; Fulciniti, Francesca; Mashhoon, Yasmin; Weiss, Roger D.
Background and Objectives Stimuli that are repeatedly paired with substance use, such as drug paraphernalia, can themselves elicit drug craving. The aim of this study was to examine whether particular cue types elicit greater craving responses than others among individuals with opioid dependence. Methods Participants seeking inpatient treatment for opioid dependence were recruited for a study of cue-induced craving. This sample (N=50), included 25 primary heroin users, 20 primary prescription opioid users, and 5 users of heroin and prescription opioids equally. Participants completed a cue reactivity task, in which images of drug-related stimuli were presented on a computer screen, each followed by a question assessing state drug craving. Results Overall, participants reported higher craving following paraphernalia stimuli relative to drug stimuli. However, this was moderated by opioid type; there was significantly higher craving in response to images of paraphernalia cues in the heroin group, and higher craving in response to drug cues in the prescription opioid group. Discussion and Conclusions These findings highlight potential differences in cue reactivity to opioid paraphernalia and drug cues, which appears to be moderated by drug type. Scientific Significance Cue-induced craving is an important factor in relapse. This study adds further to the literature on cue-induced craving in opioid dependence, suggesting that craving may vary based on both cue type and opioid type. Future studies designed to discriminate the impact of substance of abuse, route of administration, and cue type will help to further understand cue-induced craving in this population. PMID:26848719
Lobmaier, Philipp P; Kunøe, Nikolaj; Gossop, Michael; Waal, Helge
Naltrexone is an opioid receptor antagonist that blocks the reinforcing effects of opioids and reduces alcohol consumption and craving. It has no abuse potential, mild and transient side effects, and thus appears an ideal pharmacotherapy for opioid dependence. Its effectiveness in alcohol dependence is less evident, but compliance with naltrexone combined with psychosocial support has been repeatedly shown to improve drinking outcomes. Limited compliance with oral naltrexone treatment is a known drawback. Several naltrexone implant and injectable depot formulations are being investigated and provide naltrexone release for at least 1 month. Studies among opioid-dependent patients indicate significant reductions in heroin use, but sample sizes are usually small. In alcohol dependence, two large multicenter trials report alcohol and craving reductions for naltrexone and placebo groups, indicating a significant but moderate effect. The pharmacokinetic profile of the injectable formulation indicates reliable naltrexone release over 1 month at therapeutic levels. Implant formulations releasing naltrexone up to 7 months are reported. Findings on safety and tolerability confirm the generally mild adverse effects described for naltrexone tablets. However, further research on therapeutic levels (i.e., opioid blocking) is warranted. The majority of naltrexone implants lacks approval for regular clinical use and larger longitudinal studies are needed. The available naltrexone depot formulations have the potential to significantly improve medication compliance in opioid and alcohol dependence. In certain circumstances, they may constitute a promising new treatment option. © 2010 Blackwell Publishing Ltd.
Bisaga, Adam; Sullivan, Maria A; Glass, Andrew; Mishlen, Kaitlyn; Carpenter, Kenneth M; Mariani, John J; Levin, Frances R; Nunes, Edward V
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.
Marchand, Kirsten; Oviedo-Joekes, Eugenia; Guh, Daphne; Marsh, David C; Brissette, Suzanne; Schechter, Martin T
Substitution with opioid-agonists (e.g., methadone) has shown to be an effective treatment for chronic long-term opioid dependency. Survival sex work, very common among injection drug users, has been associated with poor Opioid Agonist Treatment (OAT) engagement, retention and response. Therefore, this study was undertaken to determine factors associated with engaging in sex work among long-term opioid dependent women receiving OAT. Data from a randomized controlled trial, the North American Opiate Medication Initiative (NAOMI), conducted in Vancouver and Montreal (Canada) between 2005-2008, was analyzed. The NAOMI study compared the effectiveness of oral methadone to injectable diacetylmorphine or injectable hydromorphone, the last two on a double blind basis, over 12 months. A research team, independent of the clinic services, obtained outcome evaluations at baseline and follow-up (3, 6, 9, 12, 18 and 24 months). A total 53.6% of women reported engaging in sex work in at least one of the research visits. At treatment initiation, women who were younger and had fewer years of education were more likely to be engaged in sex work. The multivariate logistic generalized estimating equation regression analysis determined that psychological symptoms, and high illicit heroin and cocaine use correlated with women's involvement in sex work during the study period. After entering OAT, women using injection drugs and engaging in sex work represent a particularly vulnerable group showing poorer psychological health and a higher use of heroin and cocaine compared to women not engaging in sex work. These factors must be taken into consideration in the planning and provision of OAT in order to improve treatment outcomes. NCT00175357.
Evans, Elizabeth; Li, Libo; Min, Jeong; Huang, David; Urada, Darren; Liu, Lei; Hser, Yih-Ing; Nosyk, Bohdan
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
McCall Jones, Christopher; Baldwin, Grant T; Compton, Wilson M
To assess trends in cocaine overdose deaths and examine the role opioids play in these deaths. We used data on drug overdose deaths in the United States from 2000 to 2015 collected in the National Vital Statistics System to calculate annual rates and numbers of cocaine-related overdose deaths overall and deaths both involving and not involving opioids. We assessed statistically significant changes in trends with joinpoint regression. Rates of cocaine-related overdose deaths increased significantly from 1.26 to 2.50 per 100 000 population from 2000 to 2006, declined to 1.35 in 2010, and increased to 2.13 in 2015. Cocaine-related overdose deaths involving opioids increased from 0.37 to 0.91 from 2000 to 2006, declined to 0.57 in 2010, and then increased to 1.36 in 2015. Cocaine-related overdose deaths not involving opioids increased from 0.89 to 1.59 from 2000 to 2006 and then declined to 0.78 in 2015. Opioids, primarily heroin and synthetic opioids, have been driving the recent increase in cocaine-related overdose deaths. This corresponds to the growing supply and use of heroin and illicitly manufactured fentanyl in the United States.
Minozzi, Silvia; Amato, Laura; Davoli, Marina
To assess the incidence or prevalence of opioid dependence syndrome in adults (with and without previous history of substance abuse) following treatment with opioid analgesics for pain relief. Medline, Embase, CINHAL and the Cochrane Library were searched up to January 2011. Systematic reviews and primary studies were included if they reported data about incidence or prevalence of opioid dependence syndrome (as defined by DSM-IV or ICD-10) in patients receiving strong opioids (or opioid-type analgesics) for treatment of acute or chronic pain due to any physical condition. The data were abstracted, and the methodological quality was assessed using validated checklists. Data were extracted from 17 studies involving a total of 88 235 participants. The studies included three systematic reviews, one randomized controlled trial, eight cross-sectional studies and four uncontrolled case series. Most studies included adult patients with chronic non-malignant pain; two also included patients with cancer pain; only one included patients with a previous history of dependence. Incidence ranged from 0 to 24% (median 0.5%); prevalence ranged from 0 to 31% (median 4.5%). The available evidence suggests that opioid analgesics for chronic pain conditions are not associated with a major risk for developing dependence. © 2012 The Authors, Addiction © 2012 Society for the Study of Addiction.
Jones, Hendree E; Martin, Peter R; Heil, Sarah H; Kaltenbach, Karol; Selby, Peter; Coyle, Mara G; Stine, Susan M; O'Grady, Kevin E; Arria, Amelia M; Fischer, Gabriele
This article addresses common questions that clinicians face when treating pregnant women with opioid dependence. Guidance, 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, is provided to aid clinical decision making. The MOTHER project is a double-blind, double-dummy, flexible-dosing, parallel-group clinical trial examining the comparative safety and efficacy of methadone and buprenorphine for the treatment of opioid dependence in pregnant women and their neonates. The article 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.
Yang, Bao-Zhu; Han, Shizhong; Kranzler, Henry R; Palmer, Abraham A; Gelernter, Joel
Sex influences risk for opioid dependence (OD). We hypothesized that sex might interact with genetic loci that influence the risk for OD. Therefore we performed an analysis to identify sex-specific genomic susceptibility regions for OD using linkage. Over 6,000 single nucleotide polymorphism (SNP) markers were genotyped for 1,758 African- and European-American (AA and EA) individuals from 739 families, ascertained via affected sib-pairs with OD and/or cocaine dependence. Autosomewide non-parametric linkage scans, stratified by sex and population, were performed. We identified one significant linkage region, segregating with OD in EA men, at 71.1 cM on chromosome 4 (LOD = 3.29; point-wise P = 0.00005; empirical autosome-wide P = 0.042), which significantly differed from the linkage signal at the same location in EA women (empirical P = 0.002). Three suggestive linkage signals were identified at 181.3 cM on chromosome 7 (LOD = 2.18), 104 cM on chromosome 11 (LOD = 1.85), and 60.9 cM on chromosome 16 (LOD = 1.93) in EA women. In AA men, four suggestive linkage signals were detected at 201.1 cM on chromosome 3 (LOD = 2.32), 152.9 cM on chromosome 6 (LOD = 1.86), 16.8 cM on chromosome 7 (LOD = 1.95), and 36.1 cM on chromosome 17 (LOD = 1.99). The significant region, mapping to 4q12-4q13.1, harbors several OD candidate genes with interconnected functionality, including VEGFR, CLOCK, PDCL2, NMU, NRSF, and IGFBP7. In conclusion, these results provide an evidence for the existence of sex-specific and population-specific differences in OD. Furthermore, these results provide positional information that will facilitate the use of targeted next-generation sequencing to search for genes that contribute to sex-specific differences in OD. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.
Dorn, Spencer D; Meek, Patrick D; Shah, Nilay D
Opioids are sometimes used to treat chronic abdominal pain. However, opioid analgesics have not been proven to be an effective treatment for chronic abdominal pain and have been associated with drug misuse, constipation, and worsening abdominal pain. We sought to estimate the national prescribing trends and factors associated with opioid prescribing for chronic abdominal pain. Chronic abdominal pain-related visits by adults to US outpatient clinics were identified using reason-for-visit codes from the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey (1997-2008). Data were weighted to produce national estimates of opioid prescriptions over time. Logistic regression analyses, adjusted for complex survey design, were performed to identify factors associated with opioid use. The number of outpatient visits for chronic abdominal pain consistently decreased over time from 14.8 million visits (95% confidence interval [CI], 11.6-18.0 visits) in 1997 through 1999 to 12.2 million visits (95% CI, 9.0-15.6 visits) or 1863 visits per 100,000 population in 2006 through 2008 (P for trend = 0.04). Conversely, the adjusted prevalence of visits for which an opioid was prescribed increased from 5.9% (95% CI, 3.5%-8.3%) in 1997 through 1999 to 12.2% (95% CI, 7.5%-17.0%) in 2006 through 2008 (P = 0.03 for trend). Opioid prescriptions were most common among patients aged 25 to 40 years old (odds ratio [OR] 4.6; 95% CI, 1.2-18.4). Opioid prescriptions were less common among uninsured (OR 0.1; 95% CI, 0.04-0.40) and African American (OR 0.3; 95% CI, 0.1-0.9) patients. From 1997 to 2008 opioid prescriptions for chronic abdominal pain more than doubled. Further studies are needed to better understand the reasons for and consequences of this trend. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
Rice, J Bradford; White, Alan G; Birnbaum, Howard G; Schiller, Matt; Brown, David A; Roland, Carl L
The objective of this study was to use administrative claims data to identify and analyze patient characteristics and behavior associated with diagnosed opioid abuse. Patients, aged 12-64 years, with at least one prescription opioid claim during 2007-2009 (n = 821,916) were selected from a de-identified administrative claims database of privately insured members (n = 8,316,665). Patients were divided into two mutually exclusive groups: those diagnosed with opioid abuse during 1999-2009 (n = 6,380) and those without a diagnosis for opioid abuse (n = 815,536). A logistic regression model was developed to estimate the association between an opioid abuse diagnosis and patient characteristics, including patient demographics, prescription drug use and filling behavior, comorbidities, medical resource use, and family member characteristics. Sensitivity analyses were conducted on the model's predictive power. In addition to demographic factors associated with abuse (e.g., male gender), the following were identified as "key characteristics" (i.e., odds ratio [OR] > 2): prior opioid prescriptions (OR = 2.23 for 1-5 prior Rxs; OR = 6.85 for 6+ prior Rxs); at least one prior prescription of buprenorphine (OR = 51.75) or methadone (OR = 2.97); at least one diagnosis of non-opioid drug abuse (OR = 9.89), mental illness (OR = 2.45), or hepatitis (OR = 2.36); and having a family member diagnosed with opioid abuse (OR = 3.01). Using medical as well as drug claims data, it is feasible to develop models that could assist payers in identifying patients who exhibit characteristics associated with increased risk for opioid abuse. These models incorporate medical information beyond that available to prescription drug monitoring programs that are reliant on drug claims data and can be an important tool to identify potentially inappropriate opioid use. Wiley Periodicals, Inc.
Mannelli, Paolo; Patkar, Ashwin A; Peindl, Kathleen; Murray, Heather W; Wu, Li-Tzy; Hubbard, Robert
The clinical use of naltrexone (NTX) in the treatment of opioid dependence has been limited because of poor compliance and inconsistent outcomes. In particular, the therapeutic benefit of extended treatment with NTX after opioid detoxification is unclear. The present study evaluated whether the augmentation with low-dose NTX during the post-detoxification treatment of opioid dependence would improve outcomes. In an open-label naturalistic design, 435 opioid-dependent patients who had completed inpatient detoxification were offered the choice of entering 1 of the 2 outpatient treatment arms: clonidine extended treatment (CET) (clonidine + psychosocial treatment), or enhanced extended treatment (EET) (oral NTX [1-10 mg/d] + CET) for 21 days. The primary outcome measure was retention in treatment. Secondary outcomes included abstinence from opioids, dropouts, and adherence to postdischarge care. One hundred sixty-two patients (37.2%) accepted EET. Subjects receiving EET stayed longer in the program (F = 64.4; P = 0.000), were less likely to drop out, used less opioids, and followed through with referral to long-term outpatient treatment in a higher number, compared with patients in the CET arm (P = 0.000 in each case). The NTX + clonidine combination was safe and well tolerated. This preliminary study indicates the potential benefit of augmentation with low-dose NTX to improve outcomes after opioid detoxification for a preferred group of patients. Randomized controlled trials are necessary to further evaluate the role of low-dose NTX in the outpatient treatment of opioid dependence.
Dreifuss, Jessica A; Griffin, Margaret L; Frost, Katherine; Fitzmaurice, Garrett M; Potter, Jennifer Sharpe; Fiellin, David A; Selzer, Jeffrey; Hatch-Maillette, Mary; Sonne, Susan C; Weiss, Roger D
Prescription opioid dependence is a growing problem, but little research exists on its treatment, including patient characteristics that predict treatment outcome. A secondary analysis of data from a large multisite, randomized clinical trial, the National Drug Abuse Treatment Clinical Trials Network Prescription Opioid Addiction Treatment Study (POATS) was undertaken to examine baseline patient characteristics (N=360) associated with success during 12-week buprenorphine/naloxone treatment for prescription opioid dependence. Baseline predictor variables included self-reported demographic and opioid use history information, diagnoses assessed via the Composite International Diagnostic Interview, and historical opioid use and related information from the Pain And Opiate Analgesic Use History. In bivariate analyses, pre-treatment characteristics associated with successful opioid use outcome included older age, past-year or lifetime diagnosis of major depressive disorder, initially obtaining opioids with a medical prescription to relieve pain, having only used opioids by swallowing or sublingual administration, never having used heroin, using an opioid other than extended-release oxycodone most frequently, and no prior opioid dependence treatment. In multivariate analysis, age, lifetime major depressive disorder, having only used opioids by swallowing or sublingual administration, and receiving no prior opioid dependence treatment remained as significant predictors of successful outcome. This is the first study to examine characteristics associated with treatment outcome in patients dependent exclusively on prescription opioids. Characteristics associated with successful outcome after 12 weeks of buprenorphine/naloxone treatment include some that have previously been found to predict heroin-dependent patients' response to methadone treatment and some specific to prescription opioid-dependent patients receiving buprenorphine/naloxone. Copyright © 2012 Elsevier Ireland
Chu, Larry F.; Liang, De-Yong; Li, Xiangqi; Sahbaie, Peyman; D'Arcy, Nicole; Liao, Guochun; Peltz, Gary; Clark, J. David
Objectives Addiction to opioid narcotics represents a major public health challenge. Animal models of one component of addiction, physical dependence, show this trait to be highly heritable. The analysis of opioid dependence using contemporary in-silico techniques offers an approach to discover novel treatments for dependence and addiction. Methods In these experiments, opioid withdrawal behavior in 18 inbred strains of mice was assessed. Mice were treated for 4 days with escalating doses of morphine before the administration of naloxone allowing the quantification of opioid dependence. After haplotypic analysis, experiments were designed to evaluate the top gene candidate as a modulator of physical dependence. Behavioral studies as well as measurements of gene expression on the mRNA and protein levels were completed. Finally, a human model of opioid dependence was used to quantify the effects of the 5-HT3 antagonist ondansetron on signs and symptoms of withdrawal. Results The Htr3a gene corresponding to the 5-HT3 receptor emerged as the leading candidate. Pharmacological studies using the selective 5-HT3 antagonist ondansetron supported the link in mice. Morphine strongly regulated the expression of the Htr3a gene in various central nervous system regions including the amygdala, dorsal raphe, and periaqueductal gray nuclei, which have been linked to opioid dependence in previous studies. Using an acute morphine administration model, the role of 5-HT3 in controlling the objective signs of withdrawal in humans was confirmed. Conclusion These studies show the power of in-silico genetic mapping, and reveal a novel target for treating an important component of opioid addiction. PMID:19214139
Chu, Larry F; Liang, De-Yong; Li, Xiangqi; Sahbaie, Peyman; D'arcy, Nicole; Liao, Guochun; Peltz, Gary; David Clark, J
Addiction to opioid narcotics represents a major public health challenge. Animal models of one component of addiction, physical dependence, show this trait to be highly heritable. The analysis of opioid dependence using contemporary in-silico techniques offers an approach to discover novel treatments for dependence and addiction. In these experiments, opioid withdrawal behavior in 18 inbred strains of mice was assessed. Mice were treated for 4 days with escalating doses of morphine before the administration of naloxone allowing the quantification of opioid dependence. After haplotypic analysis, experiments were designed to evaluate the top gene candidate as a modulator of physical dependence. Behavioral studies as well as measurements of gene expression on the mRNA and protein levels were completed. Finally, a human model of opioid dependence was used to quantify the effects of the 5-HT3 antagonist ondansetron on signs and symptoms of withdrawal. The Htr3a gene corresponding to the 5-HT3 receptor emerged as the leading candidate. Pharmacological studies using the selective 5-HT3 antagonist ondansetron supported the link in mice. Morphine strongly regulated the expression of the Htr3a gene in various central nervous system regions including the amygdala, dorsal raphe, and periaqueductal gray nuclei, which have been linked to opioid dependence in previous studies. Using an acute morphine administration model, the role of 5-HT3 in controlling the objective signs of withdrawal in humans was confirmed. These studies show the power of in-silico genetic mapping, and reveal a novel target for treating an important component of opioid addiction.
Opioid dependence is a severe medical disorder with a high psychiatric and somatic comorbidity and mortality rate. The opioid agonist methadone, mixed agonist-antagonist buprenorphine and the combination of buprenorphine with the opioid antagonist naloxone are the first-line maintenance treatments for opioid dependence. Risk of diversion and accidental intoxications, especially in children, are of great concern. To lower these risks, a novel buprenorphine-naloxone film has been developed and introduced in the USA and Australia. This review evaluates the available preclinical and clinical data on the novel buprenorphine-naloxone film for treatment of opioid dependence. Literature was identified through a comprehensive PubMed search. Data sources also included official FDA information and material made public by the manufacturer. Few preclinical and clinical data on safety and efficacy have been published. The pharmacological differences between the novel film and the conventional buprenorphine/naloxone are small. In an experimental study, the new formulation suppressed symptoms of opioid withdrawal. The spectrum of adverse events seems to be similar to that of the conventional sublingual tablet. Recent data show that patients prefer the novel film over the conventional sublingual tablet. Emerging surveillance data indicate a lower risk of accidental poisoning in children compared with the conventional formulation. Further clinical and preclinical data are needed to explore additional possible advantages of the new formulation.
Jacob, Adam K.; Passe, Melissa A.; Mantilla, Carlos B.
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
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
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.
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
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
Beaudry, H; Mercier-Blais, A-A; Delaygue, C; Lavoie, C; Parent, J-L; Neugebauer, W; Gendron, L
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
Compton, Peggy; Canamar, Catherine P.; Hillhouse, Maureen; Ling, Walter
Evidence suggests that patients on opiate maintenance therapy for the treatment of addiction present with opioid-induced hyperalgesia (OIH). This study compared the experimental (cold-pressor, electrical stimulation) pain responses of 82 treatment-seeking heroin-dependent adults randomized to methadone (METH, n = 11) or buprenorphine (BUP, n = 64) therapy, with matched drug free controls (n = 21). Heroin-dependent participants were evaluated at baseline (treatment entry), medication (METH or BUP) stabilization (4-8 weeks), and chronic administration (12-18 weeks), at trough (just prior to dosing) and peak (3 hours after dosing) plasma levels. Collection of the control group’s pain responses occurred twice during a single session, three hours apart. Baseline comparisons indicate that heroin-dependent individuals demonstrate significantly shorter latencies to threshold and tolerance for cold-pressor pain than the control group. Across pain stimuli and time points, little change in pain responses were found over time, the exception being cold pressor pain tolerance, for which hyperalgesia significantly increased at trough METH/BUP levels in both groups as they stabilized in treatment. We conclude that heroin-dependent individuals are hyperalgesic, and that once stabilized in treatment, are not different in pain responses regardless of treatment agent. The effects of non-pharmacologic therapy and previous heroin use may explain increased hyperalgesia found with treatment. Perspective To better understand the clinical phenomenon of OIH, this article describes experimental pain responses of heroin-dependent participants both prior to and over the course of maintenance therapy with methadone or buprenorphine. Hyperalgesia is present with illicit and treatment opioid use, and does not appear to appreciably improve over the course of treatment. PMID:22424799
Dooley, Joe; Gerber-Finn, Lianne; Antone, Irwin; Guilfoyle, John; Blakelock, Brittany; Balfour-Boehm, Jazmyn; Hopman, Wilma M.; Jumah, Naana; Kelly, Len
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.
Borkowski, K. R.
1. The dependence of kappa-opioid agonist-induced diuresis, upon an intact and functional adrenal medulla in conscious rats, was investigated in order to test the hypothesis that the diuresis is mediated by a blood-borne 'diuretic factor', of adrenomedullary origin, released by kappa-opioid receptor stimulation. 2. Confirming previous observations, adrenal demedullation significantly attenuated diuretic responses to the kappa-opioid agonists U50488H, ethylketocyclazocine (EKC) and tifluadom, but did not affect basal urine output, furosemide-induced diuresis or the antidiuretic response to the mu-opioid agonist, buprenorphine. Naloxone abolished U50488H-induced diuresis, confirming an involvement of opioid receptors. 3. Transfusion studies established that blood, from intact rats treated with U50488H, induced diuresis in intact and demedullated recipient rats, whether or not the recipients had been pretreated with naloxone. However, blood from demedullated rats treated with U50448H was unable to induce diuresis when administered to intact or demedullated recipients. 4. It is concluded that kappa-opioid agonist-induced diuresis is dependent upon an intact and functional adrenal medulla and appears to be mediated by a blood-borne 'diuretic factor' of adrenomedullary origin. PMID:2558758
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
Hayek, Salim M; Veizi, I Elias; Narouze, Samer N; Mekhail, Nagy
Age and gender may exert important influences on opioid responsiveness and chronic pain. These effects have not been explored in the setting of chronic intrathecal (IT) opioid therapy. The objective of this study was to evaluate the effect of age and sex on IT opioid requirements during the first year after implantation of an intrathecal drug delivery system (IDDS) in chronic noncancer pain patients. Retrospective study. METHODS AND PATIENT POPULATION: In this retrospective study, 135 chronic noncancer pain patients consecutively implanted with IDDSs for opioid therapy had their first year postimplant records examined. Similar pain relief was achieved at 12 months after implant in both age groups. Relative to the dose at implant, younger patients had significantly higher rates of IT opioid dose escalation compared with older patients at 12 months (750 ± 450% in patients ≤50 years old vs 195 ± 120% in patients >50 years old, P < 0.001). Oral opioid consumption was significantly decreased at 12 months in the older patient population (140 ± 89 to 62 ± 35 mg/day at 12 months, P < 0.001, n = 85), while in the younger patient group, there was no change in oral opioid consumption (128 ± 81 mg/day to 105 ± 140 mg/day at 12 months, P = 0.65, n = 50). Gender-based analysis (55% males and 45% females) revealed similar reductions in pain scores during the first year postimplant. Oral opioid consumption was significantly higher in females (126 ± 138 mg) vs males (79 ± 89 mg) at 12 months postimplant; however, IT opioid dose escalation at 12 months postimplant was not statistically different between males and females. IT opioid dose escalation occurs more steeply in the younger (under 50 years old) IDDS patient population without a concomitant significant decrease in oral consumption of opioids. Age-dependent changes may have important clinical implications on the effectiveness of IT opioid therapy in
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.
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
Gonzalez, Gerardo; DiGirolamo, Gregory; Romero-Gonzalez, Mauricio; Smelson, David; Ziedonis, Douglas; Kolodziej, Monika
Background Opioid use disorders are considered a serious public health problem among young adults. Current treatment is limited to long-term opioid substitution therapy, with high relapse rates after discontinuation. This study evaluated the co-administration of memantine to brief buprenorphine pharmacotherapy as a treatment alternative. Methods 13-week double-blind placebo-controlled trial evaluating 80 young adult opioid dependent participants treated with buprenorphine/naloxone 16-4 mg/day and randomized to memantine (15mg or 30mg) or placebo. Primary outcomes were a change in the weekly mean proportion of opioid use, and cumulative abstinence rates after rapid buprenorphine discontinuation on week 9. Results Treatment retention was not significantly different between groups. The memantine 30mg group was significantly less likely to relapse and to use opioids after buprenorphine discontinuation. Among participants abstinent on week 8, those in the memantine 30mg group (81.9%) were significantly less likely to relapse after buprenorphine was discontinued compared to the placebo group (30%) (p < 0.025). Also, the memantine 30mg group had significantly reduced opioid use (mean = 0, SEM ± 0.00) compared to the placebo group (mean = 0.33, SEM ± 0.35; p < 0.004) during the last 2 weeks of study participation. Conclusions Memantine 30mg significantly improved short-term treatment with buprenorphine/naloxone for opioid dependent young adults by reducing relapse and opioid use after buprenorphine discontinuation. Combined short-term treatment with buprenorphine/naloxone may be an effective alternative treatment to long-term methadone or buprenorphine maintenance in young adults. PMID:26454835
Stein, Michael D.; Herman, Debra S.; Moitra, Ethan; Hecht, Jacki; Lopez, Rosalie; Anderson, Bradley J; Brown, Richard A.
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
Gonzalez, Gerardo; DiGirolamo, Gregory; Romero-Gonzalez, Mauricio; Smelson, David; Ziedonis, Douglas; Kolodziej, Monika
Opioid use disorders are considered a serious public health problem among young adults. Current treatment is limited to long-term opioid substitution therapy, with high relapse rates after discontinuation. This study evaluated the co-administration of memantine to brief buprenorphine pharmacotherapy as a treatment alternative. 13-week double-blind placebo-controlled trial evaluating 80 young adult opioid dependent participants treated with buprenorphine/naloxone 16-4mg/day and randomized to memantine (15mg or 30mg) or placebo. Primary outcomes were a change in the weekly mean proportion of opioid use, and cumulative abstinence rates after rapid buprenorphine discontinuation on week 9. Treatment retention was not significantly different between groups. The memantine 30mg group was significantly less likely to relapse and to use opioids after buprenorphine discontinuation. Among participants abstinent on week 8, those in the memantine 30mg group (81.9%) were significantly less likely to relapse after buprenorphine was discontinued compared to the placebo group (30%) (p<0.025). Also, the memantine 30mg group had significantly reduced opioid use (mean=0, SEM±0.00) compared to the placebo group (mean=0.33, SEM±0.35; p<0.004) during the last 2 weeks of study participation. Memantine 30mg significantly improved short-term treatment with buprenorphine/naloxone for opioid dependent young adults by reducing relapse and opioid use after buprenorphine discontinuation. Combined short-term treatment with buprenorphine/naloxone may be an effective alternative treatment to long-term methadone or buprenorphine maintenance in young adults. Published by Elsevier Ireland Ltd.
Lee, Jinhee; Kresina, Thomas F.; Campopiano, Melinda; Lubran, Robert; Clark, H. Westley
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
Beer, Beate; Erb, Robert; Pavlic, Marion; Ulmer, Hanno; Giacomuzzi, Salvatore; Riemer, Yvonne; Oberacher, Herbert
It is becoming increasingly evident that genetic variants contribute to the development of opioid addiction. An elucidation of these genetic factors is crucial for a better understanding of this chronic disease and may help to develop novel therapeutic strategies. In recent years, several candidate genes were implicated in opioid dependence. However, most study findings have not been replicated and additional studies are required before reported associations can be considered robust. Thus, the major objective of this study was to replicate earlier findings and to identify new genetic polymorphisms contributing to the individual susceptibility to opioid addiction, respectively. Therefore, a candidate gene association study was conducted including 142 well-phenotyped long-term opioid addicts undergoing opioid maintenance therapy and 142 well-matched healthy controls. In both study groups, 24 single nucleotide polymorphisms predominantly located in pharmacogenetic candidate genes have been genotyped using an accurate mass spectrometry based method. The most significant associations with opioid addiction (remaining significant after adjustment for multiple testing) were observed for the rs948854 SNP in the galanin gene (GAL, p = 0.001) and the rs2236861 SNP in the delta opioid receptor gene (OPRD1, p = 0.001). Moreover, an association of the ATP binding cassette transporter 1 (ABCB1) variant rs1045642 and the Mu Opioid receptor (OPRM1) variant rs9479757 with opioid addiction was observed. The present study provides further support for a contribution of GAL and OPRD1 variants to the development of opioid addiction. Furthermore, our results indicate a potential contribution of OPRM1 and ABCB1 SNPs to the development of this chronic relapsing disease. Therefore it seems important that these genes are addressed in further addiction related studies. PMID:24086514
Chisolm, Margaret S; Fitzsimons, Heather; Leoutsakos, Jeannie-Marie S; Acquavita, Shauna P; Heil, Sarah H; Wilson-Murphy, Molly; Tuten, Michelle; Kaltenbach, Karol; Martin, Peter R; Winklbaur, Bernadette; Jansson, Lauren M; Jones, Hendrée E
Little is known about the relationship between cigarette smoking and agonist treatment in opioid-dependent pregnant patients. The objective of this study is to examine the extent to which cigarette smoking profiles differentially changed during the course of pregnancy in opioid-dependent patients receiving either double-blind methadone or buprenorphine. Patients were participants in the international, randomized controlled Maternal Opioid Treatment: Human Experimental Research (MOTHER) study. A sample of opioid-maintained pregnant patients (18-41 years old) with available smoking data who completed a multisite, double-blind, double-dummy, randomized controlled trial of methadone (n = 67) and buprenorphine (n = 57) between 2005 and 2008. Participants were compared on smoking variables based on opioid agonist treatment condition. Overall, 95% of the sample reported cigarette smoking at treatment entry. Participants in the two medication conditions were similar on pretreatment characteristics including smoking rates and daily cigarette amounts. Over the course of the pregnancy, no meaningful changes in cigarette smoking were observed for either medication condition. The fitted difference in change in adjusted cigarettes per day between the two conditions was small and nonsignificant (β = -0.08, SE = 0.05, p = .132). Results support high rates of smoking with little change during pregnancy among opioid-dependent patients, regardless of the type of agonist medication received. These findings are consistent with evidence that suggests nicotine effects, and interactions may be similar for buprenorphine compared with methadone. The outcomes further highlight that aggressive efforts are needed to reduce/eliminate smoking in opioid-dependent pregnant women.
Introduction: Little is known about the relationship between cigarette smoking and agonist treatment in opioid-dependent pregnant patients. The objective of this study is to examine the extent to which cigarette smoking profiles differentially changed during the course of pregnancy in opioid-dependent patients receiving either double-blind methadone or buprenorphine. Patients were participants in the international, randomized controlled Maternal Opioid Treatment: Human Experimental Research (MOTHER) study. Methods: A sample of opioid-maintained pregnant patients (18–41 years old) with available smoking data who completed a multisite, double-blind, double-dummy, randomized controlled trial of methadone (n = 67) and buprenorphine (n = 57) between 2005 and 2008. Participants were compared on smoking variables based on opioid agonist treatment condition. Results: Overall, 95% of the sample reported cigarette smoking at treatment entry. Participants in the two medication conditions were similar on pretreatment characteristics including smoking rates and daily cigarette amounts. Over the course of the pregnancy, no meaningful changes in cigarette smoking were observed for either medication condition. The fitted difference in change in adjusted cigarettes per day between the two conditions was small and nonsignificant (β = −0.08, SE = 0.05, p = .132). Conclusions: Results support high rates of smoking with little change during pregnancy among opioid-dependent patients, regardless of the type of agonist medication received. These findings are consistent with evidence that suggests nicotine effects, and interactions may be similar for buprenorphine compared with methadone. The outcomes further highlight that aggressive efforts are needed to reduce/eliminate smoking in opioid-dependent pregnant women. PMID:23288871
Makarenko, Iuliia; Mazhnaya, Alyona; Polonsky, Maxim; Marcus, Ruthanne; Bojko, Martha J.; Filippovich, Sergii; Springer, Sandra; Dvoriak, Sergii; Altice, Frederick L.
Background Coverage with opioid agonist treatments (OAT) is low (N=8,400, 2.7%) for the 310,000 people who inject drugs (PWID) in Ukraine. In the context of widespread negative attitudes toward OAT in the region, patient-level interventions targeting the barriers and willingness to initiate OAT are urgently needed. Methods A sample of 1,179 opioid dependent PWID not currently on OAT from five regions in Ukraine was assessed using multivariable logistic regression for independent factors related to willingness to initiate OAT, stratified by their past OAT experience. Results Overall, 421 (36%) PWID were willing to initiate OAT. Significant adjusted odds ratios (aOR) for covariates associated with the willingness to initiate OAT common for both groups included: higher injection frequency (previously on OAT: aOR=2.7; never on OAT: aOR=1.8), social and family support (previously on OAT: aOR=2.0; never on OAT: aOR=2.0), positive attitude towards OAT (previously on OAT: aOR=1.3; never on OAT: aOR=1.4). Among participants previously on OAT, significant correlates also included: HIV-negative status (aOR=2.6) and depression (aOR=2.7). Among participants never on OAT, however, living in Kyiv (aOR=4.8) or Lviv (aOR=2.7), previous imprisonment (aOR=1.5), registration at a Narcology service (aOR=1.5) and recent overdose (aOR=2.6) were significantly correlated with willingness to initiate OAT. Conclusions These findings emphasize the need for developing interventions aimed to eliminate existing negative preconceptions regarding OAT among opioid dependent PWID in Ukraine, which should be tailored to the needs of specific characteristics of PWID in geographically distinct setting, higher injection frequency, prior incarceration, and psychiatric and HIV status. PMID:27370527
Calabria, Bianca; Degenhardt, Louisa; Briegleb, Christina; Vos, Theo; Hall, Wayne; Lynskey, Michael; Callaghan, Bridget; Rana, Umer; McLaren, Jennifer
To review and summarize existing prospective studies reporting on remission from dependence upon amphetamines, cannabis, cocaine or opioids. Systematic searches of the peer-reviewed literature were conducted to identify prospective studies reporting on remission from amphetamines, cannabis, cocaine or opioid dependence. Searches were limited to publication between 1990 and 2009. Reference lists of review articles and important studies were searched to identify additional studies. Remission was defined as no longer meeting diagnostic criteria for drug dependence or abstinence from drug use; follow-up periods of at least three years were investigated. The remission rate was estimated for each drug type, allowing pooling across studies with varying follow-up times. There were few studies examining the course of psychostimulant dependence that met inclusion criteria (one for amphetamines and four for cocaine). There were ten studies of opioid and three for cannabis dependence. Definitions of remission varied and most did not clearly assess remission from dependence. Amphetamine dependence had the highest remission rate (0.4477; 95%CI 0.3991, 0.4945), followed by opioid (0.2235; 95%CI 0.2091, 0.2408) and cocaine dependence (0.1366; 95%CI 0.1244, 0.1498). Conservative estimates of remission rates followed the same pattern with cannabis dependence (0.1734; 95%CI 0.1430, 0.2078) followed by amphetamine (0.1637; 95%CI 0.1475, 0.1797), opioid (0.0917; 95%CI 0.0842, 0.0979) and cocaine dependence (0.0532; 95%CI 0.0502, 0.0597). The limited prospective evidence suggests that "remission" from dependence may occur relatively frequently but rates may differ across drugs. There is very little research on remission from drug dependence; definitions used are often imprecise and inconsistent across studies and there remains considerable uncertainty about the longitudinal course of dependence upon these most commonly used illicit drugs. Copyright 2010 Elsevier Ltd. All rights reserved.
Reingardiene, Dagmara; Vilcinskaite, Jolita
The dangers of opioid overdose have been recognized for as long as the use of opium itself. When used correctly for medical purposes, opioids are remarkably safe and effective agents. However, excessive dosing, whether with therapeutic, suicidal, or euphoric intent, may results in significant toxicity. In a number of countries the use of heroin and other opioids in nonmedical contexts in associated with on increasing rate of overdose and often of fatal opioid overdose. This review article discusses opioid-receptor pharmacology, which is necessary for understanding of the signs and symptoms of opioid ingestion and management principles, clinical and toxic effects mediated with the opioids, the diagnosis and management guidelines in opioid intoxication, a clinical prediction rule to identify patients who can be safely discharge from hospital, the problems of the significant morbidity and mortality associated with opioid overdose.
Assadi, Seyed Mohammad; Radgoodarzi, Reza; Ahmadi-Abhari, Seyed Ali
Background Results of preclinical studies suggest that the GABAB receptor agonist baclofen may be useful in treatment of opioid dependence. This study was aimed at assessing the possible efficacy of baclofen for maintenance treatment of opioid dependence. Methods A total of 40 opioid-dependent patients were detoxified and randomly assigned to receive baclofen (60 mg/day) or placebo in a 12-week, double blind, parallel-group trial. Primary outcome measure was retention in treatment. Secondary outcome measures included opioids and alcohol use according to urinalysis and self-report ratings, intensity of opioid craving assessed with a visual analogue scale, opioid withdrawal symptoms as measured by the Short Opiate Withdrawal Scale and depression scores on the Hamilton inventory. Results Treatment retention was significantly higher in the baclofen group. Baclofen also showed a significant superiority over placebo in terms of opiate withdrawal syndrome and depressive symptoms. Non-significant, but generally favorable responses were seen in the baclofen group with other outcome measures including intensity of opioid craving and self-reported opioid and alcohol use. However, no significant difference was seen in the rates of opioid-positive urine tests. Additionally, the drug side effects of the two groups were not significantly different. Conclusion The results support further study of baclofen in the maintenance treatment of opioid dependence. PMID:14624703
Plesner, K; Jensen, H I; Højsted, J
Previous studies have demonstrated a positive association between smoking and addiction to opioids in patients with chronic non-malignant pain. This could be explained by a susceptibility in some patients to develop addiction. Another explanation could be that nicotine influences both pain and the opioid system. The objective of the study was to investigate whether smoking, former smoking ± nicotine use and nicotine dependence in patients with chronic non-malignant pain were associated with opioid use and addiction to opioids. The study was a cross-sectional study carried out at a multidisciplinary Danish pain centre. All patients aged 18 or more in treatment at the pain centre on the 1st of September 2013 were invited to participate in the study. A total of 98 patients (65%) participated in the study. The prevalence of current smokers was twice as high as in the general population. The prevalence of patients using opioids was 54% and the prevalence of addiction to opioids was 6%. No significant differences in addiction were found between the different smoking groups, but smokers and former smokers using nicotine tended to use opioids more frequently and at higher doses than never smokers and former smokers not using nicotine. The study supports previous evidence that smoking is associated with chronic pain. Our data suggest that information about use of nicotine substitution in chronic non-malignant patients are relevant both in a clinical setting, but also in future studies of the association between smoking habits, pain and opioid use. © 2016 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.
Garcia del Pozo, Javier; Carvajal, Alfonso; Viloria, Jose Maria; Velasco, Alfonso; Garcia del Pozo, Victorina
During the past few years there have been changes in the availability of opioids in Spain, and new policies on palliative care have been implemented. The aim of this study was to describe the new pattern of opioid consumption in Spain and the associated economic impact. A search in the ECOM (Especialidades Consumo de Medicamentos) database of the Ministry of Health and Consumer Affairs for the 1992-2006 period was carried out. This database contains information on prescriptions of primary care medicines that are covered by the National Health System in Spain. Since 1992, overall opioid consumption has increased 14-fold, from 0.3 DDD/1000 inhabitants per day to 4.4 DDD/1000 inhabitants per day. For the six drugs that require a special prescription form--morphine, methadone, oxycodone pethidine, tilidine and fentanyl--consumption increased from 0.1 DDD/1000 inhabitants per day in 1992 to 1.2 in 2006. During this same period, the total costs of these prescriptions increased by 36.8-fold, and the cost per day and per patient doubled. A huge increase in opioid consumption has occurred during the time period covered by this study, with fentanyl consumption accounting for most of that increase. Although oral morphine is the first-choice drug among strong opioids, fentanyl is currently the most consumed.
Crain, Stanley M; Shen, Ke-Fei
Low-dose naloxone-precipitated withdrawal hyperalgesia is a reliable indicator of physical dependence after chronic morphine treatment. A remarkably similar long-lasting (>3-4 h) hyperalgesia is evoked by injection of a low dose of naloxone (10 microg/kg, s.c.) in naïve mice after acute pretreatment with the glycolipid, GM1 ganglioside (1 mg/kg) (measured by warm-water-immersion tail-flick assays). GM1 treatment markedly increases the efficacy of excitatory Gs-coupled opioid receptor signaling in nociceptive neurons. Co-treatment with an ultra-low-dose (0.1 ng/kg, s.c.) of the broad-spectrum opioid receptor antagonist, naltrexone or the selective kappa opioid receptor antagonist, nor-binaltorphimine, blocks naloxone-evoked hyperalgesia in GM1-pretreated naïve mice and unmasks prominent, long-lasting (>4 h) inhibitory opioid receptor-mediated analgesia. This unmasked analgesia can be rapidly blocked by injection after 1-2 h of a high dose of naltrexone (10 mg/kg) or nor-binaltorphimine (0.1 mg/kg). Because no exogenous opioid is administered to GM1-treated mice, we suggest that naloxone may evoke hyperalgesia by inducing release of endogenous bimodally acting opioid agonists from neurons in nociceptive networks by antagonizing putative presynaptic inhibitory opioid autoreceptors that "gate" the release of endogenous opioids. In the absence of exogenous opioids, the specific pharmacological manipulations utilized in our tail-flick assays on GM1-treated mice provide a novel bioassay to detect the release of endogenous bimodally acting (excitatory/inhibitory) opioid agonists. Because mu excitatory opioid receptor signaling is blocked by ultra-low doses of naloxone, the higher doses of naloxone that evoke hyperalgesia in GM1-treated mice cannot be mediated by activation of mu opioid receptors. Co-treatment with ultra-low-dose naltrexone or nor-binaltorphimine may selectively block signaling by endogenous GM1-sensitized excitatory kappa opioid receptors, unmasking
Abrahamsson, Tove; Kral, Alex H.
Background. Nonmedical prescription drug use (NMPDU) is an increasing problem, insufficiently studied among people in opioid maintenance treatment (OMT). This study investigates the prevalence of and factors associated with NMPDU for drug classes insufficiently described in opioid-dependent populations, including antihistaminergic anxiolytics and central stimulants. Methods. Study participants were recruited at two OMT clinics in Malmo, Sweden, between October 2014 and December 2015 (N = 73) and interviewed about their use, motivations for use, and acquisition and administration of prescription drugs. Results. The majority of the sample reported lifetime NMPDU: 60% for benzodiazepine-like hypnotics (z-drugs), 21% for pregabalin, 19% for stimulants, and 12%–15% for antihistaminergic anxiolytics. Lower age was associated with nonmedical benzodiazepine use (Adjusted Odds Ratio = 0.89; 95% Confidence Interval = 0.82–0.97). Illicit acquisition was reported by 61% of people using z-drugs, 46% of people using pregabalin, and 38% of people using prescription stimulants, but only by 6–10% of people using antihistaminergic anxiolytics. Conclusions. The substantial nonmedical use of pregabalin, z-drugs, and prescription stimulants found in this study suggests that clinicians should prescribe these drugs with great caution. Nonmedical use of antihistaminergic anxiolytics does not seem to be a clinical issue among people in OMT in a Swedish setting, but we propose future studies to monitor their use. PMID:28097037
Dahlman, Disa; Abrahamsson, Tove; Kral, Alex H; Hakansson, Anders
Background. Nonmedical prescription drug use (NMPDU) is an increasing problem, insufficiently studied among people in opioid maintenance treatment (OMT). This study investigates the prevalence of and factors associated with NMPDU for drug classes insufficiently described in opioid-dependent populations, including antihistaminergic anxiolytics and central stimulants. Methods. Study participants were recruited at two OMT clinics in Malmo, Sweden, between October 2014 and December 2015 (N = 73) and interviewed about their use, motivations for use, and acquisition and administration of prescription drugs. Results. The majority of the sample reported lifetime NMPDU: 60% for benzodiazepine-like hypnotics (z-drugs), 21% for pregabalin, 19% for stimulants, and 12%-15% for antihistaminergic anxiolytics. Lower age was associated with nonmedical benzodiazepine use (Adjusted Odds Ratio = 0.89; 95% Confidence Interval = 0.82-0.97). Illicit acquisition was reported by 61% of people using z-drugs, 46% of people using pregabalin, and 38% of people using prescription stimulants, but only by 6-10% of people using antihistaminergic anxiolytics. Conclusions. The substantial nonmedical use of pregabalin, z-drugs, and prescription stimulants found in this study suggests that clinicians should prescribe these drugs with great caution. Nonmedical use of antihistaminergic anxiolytics does not seem to be a clinical issue among people in OMT in a Swedish setting, but we propose future studies to monitor their use.
McHugh, R Kathryn; Weitzman, Meara; Safren, Steven A; Murray, Heather W; Pollack, Mark H; Otto, Michael W
The propensity to engage in risk behaviors confers an elevated risk of HIV and other infectious disease transmission in opioid-dependent populations. Although drug abuse treatment may decrease drug-related risk behaviors such as needle-sharing, additional intervention may be needed to reduce HIV risk behavior. In this investigation, we assessed sexual HIV risk behaviors in opioid-dependent patients who were engaging in regular drug use despite ongoing counseling and methadone maintenance therapy. Potential risk and protective factors for engaging in sexual HIV risk behavior were examined. Taking into account demographic, psychiatric, substance use, and psychological variables, the only significant predictor of risk behavior was age. Specifically, younger patients were more likely to engage in sexual HIV risk behavior. The implications of these results for reducing sexual HIV risk behavior and for HIV prevention in methadone-maintained, treatment-refractory opioid-dependent patients are discussed.
Watkins, Linda R.; Hutchinson, Mark R.; Milligan, Erin D.; Maier, Steven F.
It is recently become clear that activated immune cells and immune-like glial cells can dramatically alter neuronal function. By increasing neuronal excitability, these non-neuronal cells are now implicated in the creation and maintenance of pathological pain, such as occurs in response to peripheral nerve injury. Such effects are exerted at multiple sites along the pain pathway, including at peripheral nerves, dorsal root ganglia, and spinal cord. In addition, activated glial cells are now recognized as disrupting the pain suppressive effects of opioid drugs and contributing to opioid tolerance and opioid dependence/withdrawal. While this review focuses on regulation of pain and opioid actions, such immune-neuronal interactions are broad in their implications. Such changes in neuronal function would be expected to occur wherever immune-derived substances come in close contact with neurons. PMID:17706291
Opioids are the oldest and most potent drugs for the treatment of severe pain. Their clinical application is undisputed in acute (e.g., postoperative) and cancer pain, but their long-term use in chronic pain has met increasing scrutiny. This article reviews mechanisms underlying opioid analgesia and other opioid actions. It discusses the structure, function, and plasticity of opioid receptors; the central and peripheral sites of analgesic actions and side effects; endogenous and exogenous opioid receptor ligands; and conventional and novel opioid compounds. Challenging clinical situations, such as the tension between chronic pain and addiction, are also illustrated.
Baltieri, Danilo Antonio; Strain, Eric C; Dias, João Carlos; Scivoletto, Sandra; Malbergier, André; Nicastri, Sérgio; Jerônimo, Cláudio; Andrade, Arthur Guerra de
There is a relatively low prevalence of opioid use in Brazil, particularly involving the non-medical use of codeine and opiate-containing syrups. However, opioid dependence syndrome shows a significant total impact on mortality and morbidity. Over the past 20 years, scientific progress has changed our understanding of the nature of opioid addiction and its various possible treatments. Addiction is a chronic illness treatable if the treatment is well-delivered and tailored to the needs of the particular patient. There is indeed an array of treatments that can effectively reduce drug use, help manage drug cravings, prevent relapses and restore people to productive social functioning. The treatment of drug addiction will be part of long-term, medical, psychological, and social perspectives. This guideline aims at providing guidance to psychiatrists and other mental health professionals who care for patients with opioid dependence syndrome. It comments on the somatic and psychosocial treatment that is used for such patients, and reviews scientific evidences and their strength. Also, the essential historical, epidemiological and neurobiological aspects of opioid dependence are reviewed.
Kishioka, Shiroh; Kiguchi, Norikazu; Kobayashi, Yuka; Saika, Fumihiro; Yamamoto, Chizuko
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
Pierce, Matthias; Bird, Sheila M.; Hickman, Matthew; Marsden, John; Dunn, Graham; Jones, Andrew
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
Pritham, U.A.; Paul, J.A.; Hayes, M.J.
Objective To examine opioid replacement therapy in pregnancy and maternal effects on neonatal outcomes including length of hospital stay for neonatal abstinence syndrome. Design Retrospective descriptive study. Setting Labor and Delivery Unit and Neonatal Intensive Care Unit (NICU), Eastern Maine Medical Center, Bangor, Maine. Participants One hundred fifty two opioid dependent pregnant women on methadone maintenance therapy (MMT) (n = 136) or buprenorphine maintenance therapy (BMT) (n =16) during pregnancy and their neonates. The neonates were born between January 1, 2005 and December 31, 2007. Methods A review of the electronic medical records (EMR) was conducted of all opioid dependent women who were maintained on MMT or BMT at the time of admission for labor and delivery and their neonates. Results Maternal methadone dose and concomitant in-utero exposure to benzodiazepines prolonged the length of hospital stay for neonates. Length of stay was shorter in breastfed neonates as compared to formula fed neonates or neonates who received formula and breast milk. Neonates with a prenatal exposure to MMT as compared to BMT spent more days in the hospital (21 vs. 14 days) for treatment of neonatal abstinence syndrome (NAS). Conclusion These findings are consistent with previous research on the simultaneous use of methadone and benzodiazepines during pregnancy and provide further direction for the treatment of opioid dependency during pregnancy. Harm reduction strategies for opioid dependent pregnant women in substance abuse treatment with MMT may one day include guidance on daily treatment doses and recommendations to avoid the concomitant use of benzodiazepines to lessen NAS. Breastfeeding should be recommended to shorten LOS. Understanding perinatal and neonatal outcomes of pregnant women on methadone or buprenorphine will help to identify optimal treatment for opioid dependency in pregnancy. PMID:22375882
Pritham, Ursula A; Paul, Jonathan A; Hayes, Marie J
To examine opioid replacement therapy in pregnancy and effect on neonatal outcomes, including length of hospital stay for neonatal abstinence syndrome. Retrospective descriptive study. Labor and delivery unit and neonatal intensive care unit (NICU), Eastern Maine Medical Center, Bangor, Maine. One hundred fifty-two opioid-dependent pregnant women on methadone maintenance therapy (MMT) (n = 136) or buprenorphine maintenance therapy (BMT) (n = 16) during pregnancy and their neonates. The neonates were born between January 1, 2005 and December 31, 2007. A review of the electronic medical record (EMR) was conducted of all opioid-dependent women who were maintained on MMT or BMT at the time of admission for labor and delivery and their neonates. Maternal methadone dose and concomitant in-utero exposure to benzodiazepines prolonged the length of hospital stay for neonates. Length of stay was shorter in breastfed neonates than formula-fed neonates or neonates who received formula and breast milk. Neonates with prenatal exposure to MMT spent more days in the hospital (21 vs. 14 days) for treatment of neonatal abstinence syndrome (NAS) than infants with prenatal exposure to BMT. These findings are consistent with previous research on the simultaneous use of methadone and benzodiazepines during pregnancy and provide further direction for the treatment of opioid dependency during pregnancy. Harm reduction strategies for opioid-dependent pregnant women in substance abuse treatment with MMT may one day include guidance on daily treatment doses and recommendations to avoid the concomitant use of benzodiazepines to lessen NAS. Breastfeeding should be recommended to shorten length of stay. Understanding perinatal and neonatal outcomes of pregnant women on methadone or buprenorphine will help to identify optimal treatment for opioid dependency in pregnancy. © 2012 AWHONN, the Association of Women's Health, Obsteric and Neonatal Nurses.
Harte-Hargrove, Lauren C.; Varga-Wesson, Ada; Duffy, Aine M.; Milner, Teresa A.
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
Panneerselvam, Mathivadhani; Tsutsumi, Yasuo M.; Bonds, Jacqueline A.; Horikawa, Yousuke T.; Saldana, Michelle; Dalton, Nancy D.; Head, Brian P.; Patel, Piyush M.; Roth, David M.
Epicatechin, a flavonoid, is a well-known antioxidant linked to a variety of protective effects in both humans and animals. In particular, its role in protection against cardiovascular disease has been demonstrated by epidemiologic studies. Low-dose epicatechin, which does not have significant antioxidant activity, is also protective; however, the mechanism by which low-dose epicatechin induces this effect is unknown. Our laboratory tested the hypothesis that low-dose epicatechin mediates cardiac protection via opioid receptor activation. C57BL/6 mice were randomly assigned to 1 of 10 groups: control, epicatechin, naloxone (nonselective opioid receptor antagonist), epicatechin + naloxone, naltrindole (δ-specific opioid receptor antagonist), epicatechin + naltrindole, norbinaltorphimine (nor-BNI, κ-specific opioid receptor antagonist), epicatechin + nor-BNI, 5-hydroxydecanoic acid [5-HD, ATP-sensitive potassium channel antagonist], and epicatechin + 5-HD. Epicatechin (1 mg/kg) or other inhibitors (5 mg/kg) were administered by oral gavage or intraperitoneal injection, respectively, daily for 10 days. Mice were subjected to 30 min coronary artery occlusion followed by 2 h of reperfusion, and infarct size was determined via planimetry. Whole heart homogenates were assayed for downstream opioid receptor signaling targets. Infarct size was significantly reduced in epicatechin- and epicatechin + nor-BNI-treated mice compared with control mice. This protection was blocked by naloxone, naltrindole, and 5-HD. Epicatechin and epicatechin + nor-BNI increased the phosphorylation of Src, Akt, and IκBα, while simultaneously decreasing the expression of c-Jun NH2-terminal kinase and caspase-activated DNase. All signaling effects are consistent with opioid receptor stimulation and subsequent cardiac protection. Naloxone, naltrindole, and 5-HD attenuated these effects. In conclusion, epicatechin acts via opioid receptors and more specifically through the δ-opioid receptor to
Soyka, Michael; Backmund, Markus; Schmidt, Peggy; Apelt, Sabine
Some case series mention possible liver toxicity in opioid-dependent patients under buprenorphine treatment. This 12-month prospective observational follow-up study in opioid-dependent patients under buprenorphine-naloxone treatment assessed outcome and safety issues. At baseline, 337 eligible datasets were available; 181 patients completed the 12-month study. Liver enzymes were tested at baseline and after 12, 24, and 52 weeks' treatment. One to two percent of patients showed mostly discrete elevations of liver enzymes, but no patient met the criteria for drug-induced liver injury. No serious liver-related adverse events occurred, but two non-serious cases of liver enzyme increase were recorded. No patient dropped out of treatment for liver-related disorders. This study is in line with some recent studies and provides further evidence that buprenorphine-naloxone is relatively safe with respect to liver injury. © American Academy of Addiction Psychiatry.
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
Fiellin, David A; Weiss, Linda; Botsko, Michael; Egan, James E; Altice, Frederick L; Bazerman, Lauri B; Chaudhry, Amina; Cunningham, Chinazo O; Gourevitch, Marc N; Lum, Paula J; Sullivan, Lynn E; Schottenfeld, Richard S; O'Connor, Patrick G
Buprenorphine/naloxone allows the integration of opioid dependence and HIV treatment. We conducted a prospective study in HIV-infected opioid-dependent patients to investigate the impact of buprenorphine/naloxone treatment on drug use. Self-report and chart review assessments were conducted every 3 months (quarters 1-4) for 1 year. Outcomes were buprenorphine/naloxone treatment retention, drug use, and addiction treatment processes. Among 303 patients enrolled between July 2005 and December 2007, retention in buprenorphine/naloxone treatment was 74%, 67%, 59%, and 49% during Quarters 1, 2, 3, and 4, respectively. Past 30-day illicit opioid use decreased from 84% of patients at baseline to 42% in retained patients over the year. Patients were 52% less likely to use illicit opioids for each quarter in treatment (Odds ratio = 0.66; 95% CI: 0.61 to 0.72). Buprenorphine/naloxone doses and office visits approximated guidelines published by the United States Department of Health and Human Services. Urine toxicology monitoring was less frequent than recommended. Buprenorphine/naloxone provided in HIV treatment settings can decrease opioid use. Strategies are needed to improve retention and address ongoing drug use in this treatment population.
Fiellin, David A.; Weiss, Linda; Botsko, Michael; Egan, James E; Altice, Frederick L.; Bazerman, Lauri B.; Chaudhry, Amina; Cunningham, Chinazo O.; Gourevitch, Marc N.; Lum, Paula J.; Sullivan, Lynn E.; Schottenfeld, Richard S.; O'Connor, Patrick G.
Background Buprenorphine/naloxone allows the integration of opioid dependence and HIV treatment. Methods We conducted a prospective study in HIV-infected opioid dependent patients to investigate the impact of buprenorphine/naloxone treatment on drug use. Self-report and chart review assessments were conducted every 3 months (Quarters 1 through 4) for one year. Outcomes were buprenorphine/naloxone treatment retention, drug use, and addiction treatment processes. Results Among 303 patients enrolled between July 2005 and December 2007, retention in buprenorphine/naloxone treatment was 74%, 67%, 59% and 49% during Quarters 1,2 3, and 4, respectively. Past 30 day illicit opioid use decreased from 84% of patients at baseline to 42% in retained patients over the year. Patients were 52% less likely to use illicit opioids for each quarter in treatment (OR = .66; 95% CI 0.61–0.72). Buprenorphine/naloxone doses and office visits approximated guidelines published by the United States Department of Health and Human Services. Urine toxicology monitoring was less frequent than recommended. Conclusions Buprenorphine/naloxone provided in HIV treatment settings can decrease opioid use. Strategies are needed to improve retention and address ongoing drug use in this treatment population. PMID:21317592
Ueno, Keiko; Kiguchi, Norikazu; Kobayashi, Yuka; Saika, Fumihiro; Wakida, Naoki; Yamamoto, Chizuko; Maeda, Takehiko; Ozaki, Masanobu; Kishioka, Shiroh
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.
Conroy, Elizabeth; Degenhardt, Louisa; Mattick, Richard P; Nelson, Elliot C
To examine the prevalence, characteristics and risk factors for child maltreatment among opioid-dependent persons compared to a community sample of similar social disadvantage. 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 and unemployment and were restricted to those with a lifetime opioid use of less than five times. The interview covered child maltreatment, family environment, drug use and psychiatric history. This study found a high prevalence of child maltreatment among both cases and controls. Despite the elevated prevalence among controls, opioid-dependent males had a higher prevalence of physical and emotional abuse; female cases had a higher prevalence and greater severity of sexual abuse. The prevalence of neglect was similar for both groups. Early parental separation was more prevalent among female cases compared to female controls; otherwise the prevalence of the risk factors was comparable for both groups. The risk factors significantly associated with child maltreatment were also similar for both cases and controls. Given the documented association between child maltreatment and adult mental disorder, child maltreatment may be an important antecedent of current psychological distress in persons presenting to treatment for opioid dependence. Apart from a possible association between early parental separation and sexual abuse among female cases, the increased prevalence of child maltreatment associated with opioid dependence did not appear to be related to differences in early childhood risk factors considered in this paper. Other risk factors may be more pertinent for those with opioid dependence. The high prevalence of child maltreatment among the opioid-dependent sample has implications for the assessment and treatment of clients presenting with opioid dependence. Assessment of child maltreatment history could help inform the development of
Dennis, B B; Bawor, M; Paul, J; Plater, C; Pare, G; Worster, A; Varenbut, M; Daiter, J; Marsh, D C; Desai, D; Thabane, L; Samaan, Z
While chronic pain has been said to impact patient's response to methadone maintenance treatment for opioid dependence, the reported findings are inconsistent. These discrepancies may be a direct result of variations in the measurement of chronic pain or definitions of response to methadone treatment. The goal of this study is to evaluate the association between pain and substance use behaviour to determine the real impact of comorbid pain in the methadone population. We also aim to examine sources of variation across the literature with a specific focus on the measurement of pain. We performed a systematic review using an electronic search strategy across CINAHL, MEDLINE, Web of Science, PsychINFO, EMBASE, and the Cochrane Library including Cochrane Reviews and the Cochrane Central Register of Controlled Trials databases. Title, abstract, as well as full text screening and extraction were performed in duplicate. Studies evaluating the association between chronic pain and methadone maintenance treatment response were eligible for inclusion in this review. Using a sample of 297 methadone patients from the Genetics of Opioid Addiction (GENOA) research collaborative, we assessed the reliability of patient self-reported pain and the validated Brief Pain Inventory (BPI) assessment tool. After screening 826 articles we identified five studies eligible for full text extraction, of which three showed a significant relationship between the presence of pain and the increase in substance abuse among patients on methadone for the treatment of opioid dependence. Studies varied largely in the definitions and measurement of both pain and response to treatment. Results from our validation of pain measurement in the GENOA sample (n=297) showed the use of a simple self-reported pain question is highly correlated to the use of the BPI. Simply asking patients whether they have pain showed a 44.2% sensitivity, 88.8% specificity, 84.4% PPV and 53.6% NPV to the BPI. The area under the
Jacobs, Petra; Ang, Alfonso; Hillhouse, Maureen P; Saxon, Andrew J; Nielsen, Suzanne; Wakim, Paul G; Mai, Barbara E; Mooney, Larissa J; S Potter, Jennifer; Blaine, Jack D
Induction is a crucial period of opioid addiction treatment. This study aimed to identify buprenorphine/naloxone (BUP) induction patterns and examine their association with outcomes (opioid use, retention, and related adverse events [AEs]). The secondary analysis of a study of opioid-dependent adults seeking treatment in eight treatment settings included 740 participants inducted on BUP with flexible dosing. Latent class analysis models detected six distinctive induction trajectories: bup1-started and remained on low; bup2-started low, shifted slowly to moderate; bup3-started low, shifted quickly to moderate; bup4-started high, shifted to low; bup5-started and remained on moderate; bup6-started moderate, shifted to high dose (Fig. 1). Baseline characteristics, including Clinical Opioid Withdrawal Scale (COWS), were important predictors of retention. When controlled for the baseline characteristics, bup6 participants were three times less likely to drop out the first 7 days than bup1 participants (adjusted hazard ratio (aHR) = .28, p = .03). Opioid use and AEs were similar across trajectories. Participants on ≥16 mg BUP compared to those on <16 mg at Day 28 were less likely to drop out (aHR = .013, p = .001) and less likely to have AEs during the first 28 days (aOR = .57, p = .03). BUP induction dosing was guided by an objective measure of opioid withdrawal. Participants with higher baseline COWS whose BUP doses were raised more quickly were less likely to drop out in the first 7 days than those whose doses were raised slower. This study supports the use of an objective measure of opioid withdrawal (COWS) during BUP induction to improve retention early in treatment. © American Academy of Addiction Psychiatry.
Szklarczyk, Klaudia; Korostynski, Michal; Cieslak, Przemyslaw Eligiusz; Wawrzczak-Bargiela, Agnieszka; Przewlocki, Ryszard
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. Copyright © 2015 Elsevier B.V. All rights reserved.
Noormohammadi, Arezo; Forinash, Alicia; Yancey, Abigail; Crannage, Erica; Campbell, Kristin; Shyken, Jaye
To evaluate maternal and neonatal safety outcomes for methadone and buprenorphine in the obstetric population. A literature search of PubMed (1966 to March 2016) and EMBASE (1973 to March 2016) was completed using the search terms buprenorphine, methadone, pregnancy, opioid, and neonatal abstinence syndrome Priority was given to randomized controlled trials and trials directly comparing buprenorphine and methadone during pregnancy. The bibliographies were reviewed for other relevant articles. All human studies published in English, that compared methadone and buprenorphine use in pregnancy were evaluated. Because of the limited number of obstetric studies, only 5 critical studies were found. Buprenorphine significantly improved or had similar outcomes to methadone for development of neonatal abstinence syndrome (NAS), percentage of infants requiring treatment for NAS (20%-47% vs 45.5%-57%, respectively), total amount of morphine used to treat NAS (0.472-3.4 vs 1.862-10.4 mg, respectively), duration of NAS (4.1-5.6 vs 5.3-9.9 days, respectively), peak NAS (3.9-11 vs 4.9-12.8 score, respectively), infant hospital stay (6.8-10.6 vs 8.1-17.5 days, respectively), and gestational age at delivery (38.8-39.7 vs 37.9-38.8 weeks, respectively). No difference was found with other neonatal or maternal outcomes. Both methadone and buprenorphine are effective agents, with improved safety compared with continued nonmedical opioid use during pregnancy. There is evidence to suggest that buprenorphine should be considered as an equivalent option to methadone for use in pregnancy; however, larger studies are still needed to fully evaluate buprenorphine safety and advantages over methadone in the obstetric population. © The Author(s) 2016.
Schlosburg, Joel E; Whitfield, Timothy W; Park, Paula E; Crawford, Elena F; George, Olivier; Vendruscolo, Leandro F; Koob, George F
The abuse of opioid drugs, both illicit and prescription, is a persistent problem in the United States, accounting for >1.2 million users who require treatment each year. Current treatments rely on suppressing immediate withdrawal symptoms and replacing illicit drug use with long-acting opiate drugs. However, the mechanisms that lead to preventing opiate dependence are still poorly understood. We hypothesized that κ opioid receptor (KOR) activation during chronic opioid intake contributes to negative affective states associated with withdrawal and the motivation to take increasing amounts of heroin. Using a 12 h long-access model of heroin self-administration, rats showed escalation of heroin intake over several weeks. This was prevented by a single high dose (30 mg/kg) of the long-acting KOR antagonist norbinaltorphimine (nor-BNI), paralleled by reduced motivation to respond for heroin on a progressive-ratio schedule of reinforcement, a measure of compulsive-like responding. Systemic nor-BNI also significantly decreased heroin withdrawal-associated anxiety-like behavior. Immunohistochemical analysis showed prodynorphin content increased in the nucleus accumbens core in all heroin-exposed rats, but selectively increased in the nucleus accumbens shell in long-access rats. Local infusion of nor-BNI (4 μg/side) into accumbens core altered the initial intake of heroin but not the rate of escalation, while local injection into accumbens shell selectively suppressed increases in heroin intake over time without altering initial intake. These data suggest that dynorphin activity in the nucleus accumbens mediates the increasing motivation for heroin taking and compulsive-like responding for heroin, suggesting that KOR antagonists may be promising targets for the treatment of opioid addiction.
Warden, Diane; Subramaniam, Geetha A; Carmody, Thomas; Woody, George E; Minhajuddin, Abu; Poole, Sabrina A; Potter, Jennifer; Fishman, Marc; Bogenschutz, Michael; Patkar, Ashwin; Trivedi, Madhukar H
In opioid dependent youth there is substantial attrition from medication-assisted treatment. If youth at risk for attrition can be identified at treatment entry or early in treatment, they can be targeted for interventions to help retain them in treatment. Opioid dependent adolescents and young adults (n=152), aged 15-21, were randomized to 12 weeks (BUP, n=74) or 2 weeks of detoxification (DETOX, n=78) with buprenorphine/naloxone (Bup/Nal), both in combination with 12 weeks of psychosocial treatment. Baseline and early treatment related predictors of treatment attrition were identified in each group using bivariate and multivariate logistic regression. In the DETOX group 36% left between weeks 2 and 4, at the end of the dose taper, while in the BUP group only 8% left by week 4. In the BUP group, early adherence to Bup/Nal, early opioid negative urines, use of any medications in the month prior to treatment entry, and lifetime non-heroin opioid use were associated with retention while prior 30-day hallucinogen use was associated with attrition. In the DETOX group, only use of sleep medications was associated with retention although not an independent predictor. A broad range of other pre-treatment characteristics was unrelated to attrition. Prompt attention to those with early non-adherence to medication or an early opioid positive urine, markers available in the first 2 weeks of treatment, may improve treatment retention. Extended Bup/Nal treatment appeared effective in improving treatment retention for youth with opioid dependence across a wide range of demographics, and pre-treatment clinical characteristics. Copyright © 2012 Elsevier Ltd. All rights reserved.
Warden, Diane; Subramaniam, Geetha A.; Carmody, Thomas; Woody, George E.; Minhajuddin, Abu; Poole, Sabrina A.; Potter, Jennifer; Fishman, Marc; Bogenschutz, Michael; Patkar, Ashwin; Trivedi, Madhukar H.
Background In opioid dependent youth there is substantial attrition from medication-assisted treatment. If youth at risk for attrition can be identified at treatment entry or early in treatment, they can be targeted for interventions to help retain them in treatment. Methods Opioid dependent adolescents and young adults (n=152), aged 15–21, were randomized to 12 weeks (BUP, n=74) or 2 weeks of detoxification (DETOX, n=78) with buprenorphine/naloxone (Bup/Nal), both in combination with 12 weeks of psychosocial treatment. Baseline and early treatment related predictors of treatment attrition were identified in each group using bivariate and multivariate logistic regression. Results In the DETOX group 36% left between weeks 2 and 4, at the end of the dose taper, while in the BUP group only 8% left by week 4. In the BUP group, early adherence to Bup/Nal, early opioid negative urines, use of any medications in the month prior to treatment entry, and lifetime non-heroin opioid use were associated with retention while prior 30-day hallucinogen use was associated with attrition. In the DETOX group, only use of sleep medications was associated with retention although not an independent predictor. A broad range of other pre-treatment characteristics was unrelated to attrition. Conclusions Prompt attention to those with early non-adherence to medication or an early opioid positive urine, markers available in the first 2 weeks of treatment, may improve treatment retention. Extended Bup/ Nal treatment appeared effective in improving treatment retention for youth with opioid dependence across a wide range of demographics, and pre-treatment clinical characteristics. PMID:22626890
Demaria, Peter A; Sterling, Robert C; Risler, Robin; Frank, Jeremy
: The objective of this study was to characterize a population of opioid-dependent university students who were treated with buprenorphine, describe their treatment outcome, and discuss challenges the authors faced in working with this population in the setting of a university counseling center. : We conducted a retrospective chart review of 27 opioid-dependent university students treated with buprenorphine at the university's counseling center. : Students were predominantly white (85%, n = 23), male (63%, n = 17), average age of 22 years with an average of 33.4 ± 28.79 months (range = 4 to 132) opioid use before presentation. By self-report, 17 (63.0%) students reported heroin use, 9 (33.3%) students reported prescription opioid use, and 1 (3.7%) student reported use of both. Fifteen (56%) reported intravenous use. Treatment retention was high with students receiving an average of 12.00 + 11.49 months treatment (range = 1 to 36). During the course of treatment, 81% of all submitted urine drug screens were negative for opioids, 83.1% were negative for cocaine, 90.7% were negative for illicit (nonprescribed) benzodiazepines, and 59.1% were negative for marijuana. The average buprenorphine dose was 13.8 ± 5.69 mg (range = 4 to 24 mg). No serious adverse effects occurred. In working with this population, we found that continued marijuana use, engagement in treatment, financial concerns, and decision making around family involvement were ongoing challenges. : Opioid-dependent university students are a unique group of substance users. Our results indicate that they can be safely and effectively treated with buprenorphine in a university counseling center.
Comer, Sandra D.; Sullivan, Maria A.; Yu, Elmer; Rothenberg, Jami L.; Kleber, Herbert D.; Kampman, Kyle; Dackis, Charles; O'Brien, Charles P.; Chiang, C. Nora; Hawks, Richard L.
recalculated without the assumption that missing urine samples were positive, however, a main effect of group was not found for any of the drugs tested with the exception of cocaine, where the percentage of cocaine-negative urines was lower in the placebo group. Adverse events were minimal and generally mild in severity. This sustained-release formulation of naltrexone was well tolerated and produced a robust and dose-related increase in treatment retention. Conclusion The present data provide exciting new evidence for the feasibility, efficacy, and tolerability of long-lasting antagonist treatments for opioid dependence. PMID:16461865
Arttamangkul, Seksiri; Birdsong, William; Williams, John T
This study examined the role of agents known to activate PKC on morphine-induced desensitization of μ-opioid receptors (MOP receptors) in brain slices containing locus coeruleus neurons. Intracellular recordings were obtained from rat locus coeruleus neurons. Two measurements were used to characterize desensitization, the decline in hyperpolarization induced by application of a saturating concentration of agonist (acute desensitization) and the decrease in hyperpolarization induced by a subsaturating concentration of [Met](5) enkephalin (ME) following washout of the saturating concentration (sustained desensitization). Internalization of MOP receptors was studied in brain slices prepared from transgenic mice expressing Flag-MOP receptors. The subcellular distribution of activated PKC was examined using a novel fluorescent sensor of PKC in HEK293 cells. The phorbol esters (PMA and PDBu) and muscarine increased acute desensitization induced by a saturating concentration of morphine and ME. These effects were not sensitive to staurosporine. Staurosporine did not block the decline in hyperpolarization induced by muscarine. PDBu and muscarine did not affect sustained desensitization induced by ME nor did phorbol esters or muscarine change the trafficking of MOP receptors induced by morphine or ME. The distribution of activated PKC measured in HEK293 cells differed depending on which phorbol ester was applied. This study demonstrates a distinct difference in two measurements that are often used to evaluate desensitization. The measure of decline correlated well with the reduction in peak amplitudes caused by PKC activators implicating the modification of other factors rather than MOP receptors. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. © 2014 The British Pharmacological Society.
Khan, Md Sakirul Islam; Ohkubo, Takeshi; Masuda, Naoto; Tachibana, Tetsuya; Ueda, Hiroshi
Metastin, an RFamide peptide, has been isolated from human placenta and possesses several physiological actions in mammals. However, little is known about this bioactive peptide in avian species. This study was conducted to assess the effect of metastin on feeding behavior of chicks (Gallus gallus). The food intake of chicks is significantly increased by the intracerebroventricular injection of metastin. Beta-funaltrexamine, a mu-opioid receptor antagonist, significantly attenuates metastin-induced food intake in chicks. In contrast, delta- and kappa-opioid receptor antagonists did not show any influence on metastin-induced food intake in chicks. In addition, administration of N(G)-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, did not influence metastin-induced food intake. Taken together, this study shows the orexigenic effect of metastin in chicks and suggests that this effect is mediated by mu-opioid receptor.
Fisher, William H; Clark, Robin; Baxter, Jeffrey; Barton, Bruce; O'Connell, Elizabeth; Aweh, Gideon
Persons who abuse or are dependent on opioids are at elevated risk for arrest. Co-occurring behavioral health problems may exacerbate that risk, although the extent of any such increase has not been described. This study examines such risk factors among 40,238 individuals with a diagnosis of opioid abuse or dependence who were enrolled in the Massachusetts Medicaid program in 2010. Medicaid data were merged with statewide arrest data to assess the effects of co-existing mental illness, substance abuse, and previous arrests on arrest during 2010. Persons with serious mental illnesses (psychotic and bipolar disorders) and those with two or more pre-2010 arrests had significantly increased greater odds of arrest. We believe this to be the first study examining effects of co-occurring risk factors on arrest in a large population with opioid dependency/abuse. These findings identify predictors of arrest that could be used to design interventions targeting specific co-occurring risk factors.
Kouimtsidis, Christos; Reynolds, Martina; Coulton, Simon; Drummond, Colin
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…
Garcia-Portilla, Maria Paz; Bobes-Bascaran, Maria Teresa; Bascaran, Maria Teresa; Saiz, Pilar Alejandra; Bobes, Julio
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.
Senay, E C; Shick, J F
Diagnostic pupillography, under blind conditions, produced constrictions greater than 0.75 mm in 25 opiod addicts and no change or dilation in 82 others. Placebo use produced no constrictions in 99 subjects. Methadone test dose pupillography provides significant information useful in diagnosing opioid dependence and is more acceptable to addicts than naloxone testing.
Garcia-Portilla, Maria Paz; Bobes-Bascaran, Maria Teresa; Bascaran, Maria Teresa; Saiz, Pilar Alejandra; Bobes, Julio
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
Ball, Samuel A.; Nich, Charla; Rounsaville, Bruce J.; Eagan, Dorothy; Carroll, Kathleen M.
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…
Stein, Michael D; Caviness, Celeste M; Grimone, Kristin; Audet, Daniel; Borges, Allison; Anderson, Bradley J
Individuals in treatment for opioid dependence have smoking rates 3-5 times greater than the U.S. prevalence rate. Traditional smoking cessation strategies have been ineffective in this population. Novel approaches are needed as well as harm reduction avenues. E-cigarettes (e-cigs) may provide such a novel harm reduction and cessation opportunity, but little is known about the knowledge of, attitudes about, and usage of e-cigs in opioid dependent smokers. The current study enrolled 315 opioid dependent smokers (164 methadone, 151 buprenorphine), treated in the same health system in Fall River, Massachusetts. The sample was 49.7% male and 85.1% non-Latino White. Overall 98.7% had heard of e-cigs, 73.0% had ever tried e-cigs, and 33.8% had used e-cigs in the past 30 days. The most common reasons for use were curiosity (41.4%) and to quit all nicotine (26.0%). The proportion of opioid dependent smokers that had ever tried e-cigs and used them in the past month was substantially greater than that found in recent general population surveys. While e-cigs have been used to quit smoking, how to optimize their utility as a cessation tool remains undefined. E-cigs should be a part of smoking cessation discussions with this vulnerable, difficult-to-treat population. Copyright © 2015 Elsevier Inc. All rights reserved.
Kouimtsidis, Christos; Reynolds, Martina; Coulton, Simon; Drummond, Colin
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…
Solhi, Hassan; Sanaei-Zadeh, Hossein; Solhi, Sadra; Azizi Nadian, Mohammad Ali; Gharibi, Morteza; Sadeghi Sedeh, Bahman
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
Ball, Samuel A.; Nich, Charla; Rounsaville, Bruce J.; Eagan, Dorothy; Carroll, Kathleen M.
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…
Back, Sudie E; Gros, Daniel F; McCauley, Jenna L; Flanagan, Julianne C; Cox, Elizabeth; Barth, Kelly S; Brady, Kathleen T
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.
Anvar Abnavi, Marjan; Ahmadi, Jamshid; Hamidian, Sajedeh; Ghaffarpour, Sara
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
Barnwal, Preeti; Das, Saibal; Mondal, Somnath; Ramasamy, Anand; Maiti, Tanay; Saha, Arunava
Opioid dependence leads to physical dependence and addiction which finally results in profound medical, psychological and social dysfunction. One of the useful medications for opioid dependence is buprenorphine, the partial opioid agonist, which is used alone or in combination with naloxone. However, buprenorphine is the victim of its own success due to its illicit use and accidental poisoning in children. Also, buprenorphine typically requires daily self-administration and its effectiveness heavily depends on patient adherence. So, poor treatment adherence results in ineffective treatment manifesting as craving and withdrawal symptoms. Short-term use of buprenorphine in opioid dependence is also often followed by relapse. Buprenorphine when used sublingually often results in inadequate or fluctuating blood concentrations and poorer treatment retention compared with methadone. All of these led to the development of Probuphine®, a polymeric matrix composed of ethylene vinyl acetate and buprenorphine in the form of implants, that are implanted subdermally in office practice and deliver the active drug over 6 months. Buprenorphine release from such implant is fairly consistent, avoiding plasma peaks and troughs, and the implant is also reported to be safe. In this review article, we have highlighted these aspects of treatment of opioid addiction, stressing on the pharmacology of buprenorphine and Probuphine®, and relevant clinical trials addressing the efficacy and safety of Probuphine®. This sustained-release implantable formulation of buprenorphine has the potential to be a suitable alternative to daily or alternate day sublingual buprenorphine which can thereby eliminate the need for daily supervision, minimizing fluctuations in plasma concentrations, and allowing these patients to reduce clinic or pharmacy visits. PMID:28348732
Holbrook, Amber M.; Baxter, Jason K.; Jones, Hendrée E.; Heil, Sarah H.; Coyle, Mara G.; Martin, Peter R.; Stine, Susan M.; Kaltenbach, Karol
Aims To characterize infections and compare obstetrical outcomes in opioid-dependent pregnant women who participated in a randomized controlled trial comparing agonist medications, methadone and buprenorphine. Design Incidence of infections was identified as part of the screening medical assessment. As part of a planned secondary analysis, ANOVA and polytomous logistic regressions were conducted on obstetrical outcome variables using treatment randomization condition (maternal maintenance with either methadone or buprenorphine) as the predictor variable, controlling for differences between study sites. Setting Six United States sites and one European site that provided comprehensive treatment to opioid-dependent pregnant women. Participants Pregnant opioid-dependent women (n = 131) who delivered while participating in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study. Measurements Obstetrical, infectious, and other maternal medical complications captured by medical records, physical exam, blood tests, and self-report. Neonatal medical complications captured by medical records. Findings Hepatitis C (HCV) was the most common infection (32.3%), followed by hepatitis B (7.6%) and Chlamydia (6.1%) among participants at study enrollment. Maternal methadone versus buprenorphine maintenance was associated with a higher incidence of preterm labor (P = 0.04) and a significantly higher percentage of signs of respiratory distress in neonates at delivery (P = 0.05). Other medical and obstetrical complications were infrequent in the total sample, as well as in both methadone and buprenorphine conditions. Conclusions Buprenorphine appears to have an acceptable safety profile for use during pregnancy. PMID:23106930
Modestin, J; Matutat, B; Würmle, O
Both attention-deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) were explored as possible antecedents of opioid dependence and personality disorder. One hundred adult opioid-dependent, treatment-seeking male inpatients were explored; an extended clinical semistructured interview to collect sociodemographic, drug use related, and clinical data and the Structured Clinical Interview for DSM-IV personality disorders SCID-II were carried out. Four groups of patients, namely ADHD alone (4 patients), ADHD + CD (7 patients), CD alone (47 patients) and no ADHD/no CD (42 patients) were identified and compared with each other. The results indicate that ADHD alone does not predispose to the development of opioid dependence in male inpatients. Childhood ADHD may nevertheless be found more frequently in male opioid addicts due to its comorbidity with CD, which was identified in more than half of our sample. Patients with ADHD history seemed to go through the drug abuse career earlier and to develop more frequently histrionic and obsessive-compulsive personality disorder. Over half of the CD patients developed borderline and/or antisocial personality disorder; both ADHD and CD predispose significantly to the PD development. Early substance use preventive measures are necessary in children and adolescents suffering from CD and from ADHD comorbid with CD.
Kunøe, Nikolaj; Lobmaier, Philipp; Vederhus, John Kåre; Hjerkinn, Bjørg; Hegstad, Solfrid; Gossop, Michael; Kristensen, Øistein; Waal, Helge
Naltrexone has considerable potential in helping to prevent relapse in heroin dependency. A longer-lasting formulation for naltrexone treatment is desirable to further reduce non-adherence and relapse during treatment of opiate dependence. To evaluate the safety and effectiveness of a 6-month naltrexone implant in reducing opioid use after in-patient treatment. A group of 56 abstinence-oriented patients who completed in-patient treatment for opioid dependence were randomly and openly assigned to receive either a 6-month naltrexone implant or their usual aftercare. Drug use and other outcomes were assessed at 6-month follow-up. Patients receiving naltrexone had on average 45 days less heroin use and 60 days less opioid use than controls in the 180-day period (both P<0.05). Blood tests showed naltrexone levels above 1 ng/ml for the duration of 6 months. Two patients died, neither of whom had received an implant. Naltrexone implant treatment safely and significantly reduces opioid use in a motivated population of patients.
Holbrook, Amber M; Baxter, Jason K; Jones, Hendrée E; Heil, Sarah H; Coyle, Mara G; Martin, Peter R; Stine, Susan M; Kaltenbach, Karol
To characterize infections and compare obstetric outcomes in opioid-dependent pregnant women who participated in a randomized clinical trial comparing agonist medications, methadone and buprenorphine. Incidence of infections was identified as part of the screening medical assessment. As part of a planned secondary analysis, analysis of variance and polytomous logistic regressions were conducted on obstetric outcome variables using treatment randomization condition (maternal maintenance with either methadone or buprenorphine) as the predictor variable, controlling for differences between study sites. Six United States sites and one European site that provided comprehensive treatment to opioid-dependent pregnant women. Pregnant opioid-dependent women (n = 131) who delivered while participating in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study. Obstetric, infectious and other maternal medical complications captured by medical records, physical examination, blood tests and self-report. Neonatal medical complications captured by medical records. Hepatitis C was the most common infection (32.3%), followed by hepatitis B (7.6%) and chlamydia (6.1%) among participants at study enrollment. Maternal methadone versus buprenorphine maintenance was associated with a higher incidence of preterm labor (P = 0.04) and a significantly higher percentage of signs of respiratory distress in neonates at delivery (P = 0.05). Other medical and obstetric complications were infrequent in the total sample, as well as in both methadone and buprenorphine conditions. Buprenorphine appears to have an acceptable safety profile for use during pregnancy. © 2012 The Authors, Addiction © 2012 Society for the Study of Addiction.
Lawson, Kera P.; Nag, Subodh; Thompson, Analisa D.; Mokha, Sukhbir S.
This investigation determined whether 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 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, 48 h 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. Selective activation of the kappa opioid receptor by intrathecal U50,488H produces antinociception and antihyperalgesia which are sex-specific, stimulus dependent and require the presence of estrogen. PMID
Conroy, Elizabeth; Degenhardt, Louisa; Mattick, Richard P.; Nelson, Elliot C.
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 and unemployment and were restricted to those with a lifetime opioid use of less than five times. The interview covered child maltreatment, family environment, drug use and psychiatric history. Results This study found a high prevalence of child maltreatment among both cases and controls. Despite the elevated prevalence among controls, opioid-dependent males had a higher prevalence of physical and emotional abuse; female cases had a higher prevalence and greater severity of sexual abuse. The prevalence of neglect was similar for both groups. Early parental separation was more prevalent among female cases compared to female controls; otherwise the prevalence of the risk factors was comparable for both groups. The risk factors significantly associated with child maltreatment were also similar for both cases and controls. Conclusions Given the documented association between child maltreatment and adult mental disorder, child maltreatment may be an important antecedent of current psychological distress in persons presenting to treatment for opioid dependence. Apart from a possible association between early parental separation and sexual abuse among female cases, the increased prevalence of child maltreatment associated with opioid-dependence did not appear to be related to differences in early childhood risk factors considered in this paper. Other risk factors may be more pertinent for those with opioid dependence. Practice Implications The high prevalence of child maltreatment among the opioid-dependent sample has implications for the assessment and treatment of clients presenting with opioid dependence. Assessment of child
Vuong, Cassidy; Van Uum, Stan H M; O'Dell, Laura E; Lutfy, Kabirullah; Friedman, Theodore C
Opioid abuse has increased in the last decade, primarily as a result of increased access to prescription opioids. Physicians are also increasingly administering opioid analgesics for noncancer chronic pain. Thus, knowledge of the long-term consequences of opioid use/abuse has important implications for fully evaluating the clinical usefulness of opioid medications. Many studies have examined the effect of opioids on the endocrine system; however, a systematic review of the endocrine actions of opioids in both humans and animals has, to our knowledge, not been published since 1984. Thus, we reviewed the literature on the effect of opioids on the endocrine system. We included both acute and chronic effects of opioids, with the majority of the studies done on the acute effects although chronic effects are more physiologically relevant. In humans and laboratory animals, opioids generally increase GH and prolactin and decrease LH, testosterone, estradiol, and oxytocin. In humans, opioids increase TSH, whereas in rodents, TSH is decreased. In both rodents and humans, the reports of effects of opioids on arginine vasopressin and ACTH are conflicting. Opioids act preferentially at different receptor sites leading to stimulatory or inhibitory effects on hormone release. Increasing opioid abuse primarily leads to hypogonadism but may also affect the secretion of other pituitary hormones. The potential consequences of hypogonadism include decreased libido and erectile dysfunction in men, oligomenorrhea or amenorrhea in women, and bone loss or infertility in both sexes. Opioids may increase or decrease food intake, depending on the type of opioid and the duration of action. Additionally, opioids may act through the sympathetic nervous system to cause hyperglycemia and impaired insulin secretion. In this review, recent information regarding endocrine disorders among opioid abusers is presented.
Vuong, Cassidy; Van Uum, Stan H. M.; O'Dell, Laura E.; Lutfy, Kabirullah; Friedman, Theodore C.
Opioid abuse has increased in the last decade, primarily as a result of increased access to prescription opioids. Physicians are also increasingly administering opioid analgesics for noncancer chronic pain. Thus, knowledge of the long-term consequences of opioid use/abuse has important implications for fully evaluating the clinical usefulness of opioid medications. Many studies have examined the effect of opioids on the endocrine system; however, a systematic review of the endocrine actions of opioids in both humans and animals has, to our knowledge, not been published since 1984. Thus, we reviewed the literature on the effect of opioids on the endocrine system. We included both acute and chronic effects of opioids, with the majority of the studies done on the acute effects although chronic effects are more physiologically relevant. In humans and laboratory animals, opioids generally increase GH and prolactin and decrease LH, testosterone, estradiol, and oxytocin. In humans, opioids increase TSH, whereas in rodents, TSH is decreased. In both rodents and humans, the reports of effects of opioids on arginine vasopressin and ACTH are conflicting. Opioids act preferentially at different receptor sites leading to stimulatory or inhibitory effects on hormone release. Increasing opioid abuse primarily leads to hypogonadism but may also affect the secretion of other pituitary hormones. The potential consequences of hypogonadism include decreased libido and erectile dysfunction in men, oligomenorrhea or amenorrhea in women, and bone loss or infertility in both sexes. Opioids may increase or decrease food intake, depending on the type of opioid and the duration of action. Additionally, opioids may act through the sympathetic nervous system to cause hyperglycemia and impaired insulin secretion. In this review, recent information regarding endocrine disorders among opioid abusers is presented. PMID:19903933
Conroy, Stephen; Hill, Duncan
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. 2014 BMJ Publishing Group Ltd.
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.
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…
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.
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…
Sites, Brian D.; Beach, Michael L.; Davis, Matthew
Background and Objectives In the United States, use of oral opioid analgesics has been associated with increasing rates of addiction, abuse, and diversion. However, little is known about recent national use of non-illicit prescription opioid analgesics (those prescribed in a doctor-patient relationship), the primary source of these drugs for the general US population. Our primary objective was to examine trends in the use of prescription opioid analgesics in the United States and to identify defining characteristics of patient users of prescribed opioids from 2000 to 2010. Methods We used the nationally representative Medical Expenditure Panel Survey to examine trends in prescription oral opioid analgesic use from 2000 to 2010. We used survey design methods to make national estimates of adults (18 years and older) who reported receiving an opioid analgesic prescription (referred to as opioid users) and used logistic regression to examine predictors of opioid analgesic use. Our primary outcome measures were national estimates of total users of prescription opioid analgesics and total number of prescriptions. Our secondary outcome was that of observing changes in the disability and health of the users. Results The estimated total number of opioid analgesic prescriptions in the United States increased by 104%, from 43.8 million in 2000 to 89.2 million in 2010. In 2000, an estimated 7.4% (95% CI, 6.9–7.9) of adult Americans were prescription opioid users compared with 11.8% (95% CI, 11.2–12.4) in 2010. Based on estimates adjusted for changes in the general population, each year was associated with a 6% increase in the likelihood of receiving an opioid prescription from 2000 to 2010. Despite the apparent increase in use, there were no demonstrable improvements in the age- or sex-adjusted disability and health status measures of opioid users. Conclusions The use of prescription opioid analgesics among adult Americans has increased in recent years, and this increase
Sites, Brian D; Beach, Michael L; Davis, Matthew A
In the United States, use of oral opioid analgesics has been associated with increasing rates of addiction, abuse, and diversion. However, little is known about the recent national use of non-illicit prescription opioid analgesics (those prescribed in a physician-patient relationship), the primary source of these drugs for the general US population. Our primary objective was to examine trends in the use of prescription opioid analgesics in the United States and to identify defining characteristics of patient users of prescribed opioids from 2000 to 2010. We used the nationally representative Medical Expenditure Panel Survey to examine trends in prescription oral opioid analgesic use from 2000 to 2010. We used survey design methods to make national estimates of adults (18 years and older) who reported receiving an opioid analgesic prescription (referred to as opioid users) and used logistic regression to examine predictors of opioid analgesic use. Our primary outcome measures were national estimates of total users of prescription opioid analgesics and total number of prescriptions. Our secondary outcome was that of observing changes in the disability and health of the users. The estimated total number of opioid analgesic prescriptions in the United States increased by 104%, from 43.8 million in 2000 to 89.2 million in 2010. In 2000, an estimated 7.4% (95% confidence interval, 6.9-7.9) of adult Americans were prescription opioid users compared with 11.8% (95% confidence interval, 11.2-12.4) in 2010. On the basis of estimates adjusted for changes in the general population, each year was associated with a 6% increase in the likelihood of receiving an opioid prescription from 2000 to 2010. Despite the apparent increase in use, there were no demonstrable improvements in the age- or sex-adjusted disability and health status measures of opioid users. The use of prescription opioid analgesics among adult Americans has increased in recent years, and this increase does not
Coviello, Donna M; Cornish, James W; Lynch, Kevin G; Alterman, Arthur I; O'Brien, Charles P
Offenders with a history of opioid dependence are a particularly difficult group to treat. A large proportion of offenders typically relapse shortly after release from prison, commit drug-related crimes, and then are arrested and eventually re-incarcerated. Previous research demonstrated that oral naltrexone was effective in reducing opioid use and preventing recidivism among offenders under federal supervision. The 111 opioid-dependent offenders in this study were under various levels of supervision that included county and federal probation/parole, a treatment court, an alternative disposition program, and an intermediate punishment program. Subjects were randomly assigned to receive 6 months of either 300 mg per week of oral naltrexone plus standard psychosocial treatment as usual (n = 56) or standard psychosocial treatment as usual (TAU) without naltrexone (n = 55). While the TAU subjects who remained in treatment used more opioids than the naltrexone subjects who remained, the high dropout rate for both groups made it difficult to assess the effectiveness of naltrexone. The study provides limited support for the use of oral naltrexone for offenders who are not closely monitored by the criminal justice system.
Strain, E C; Harrison, J A; Bigelow, G E
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.
Shorey, Ryan C.; Stuart, Gregory L.; Anderson, Scott
Research suggests that there may be differences between individuals diagnosed with alcohol dependence and individuals diagnosed with opioid dependence on co-morbid mental health problems (e.g., personality disorders, mood disorders, etc.). The current study examined whether there were differences in early maladaptive schemas, which are theorized to underlie mental health problems, among women diagnosed with alcohol dependence or opioid dependence who were seeking treatment for their substance use (N = 420). Results showed that opioid dependent women scored higher on 2 of the 18 early maladaptive schemas, particularly the schemas of dependence and punitiveness. Overall, these findings suggest that early maladaptive schemas may be largely consistent across women diagnosed with alcohol or opioid dependence. Implications of these findings for future research and treatment are discussed. PMID:23494129
Jamison, Robert N; Mao, Jianren
Chronic pain is an international health issue of immense importance that is influenced by both physical and psychological factors. Opioids are useful in treating chronic pain but have accompanying complications. It is important for clinicians to understand the basics of opioid pharmacology, the benefits and adverse effects of opioids, and related problematic issues of tolerance, dependence, and opioid-induced hyperalgesia. In this article, the role of psychiatric comorbidity and the use of validated assessment tools to identify individuals who are at the greatest risk for opioid misuse are discussed. Additionally, interventional treatment strategies for patients with chronic pain who are at risk for opioid misuse are presented. Specific behavioral interventions designed to improve adherence with prescription opioids among persons treated for chronic pain, such as frequent monitoring, periodic urine screens, opioid therapy agreements, opioid checklists, and motivational counseling, are also reviewed. Use of state-sponsored prescription drug monitoring programs is also encouraged. Areas requiring additional investigation are identified, and the future role of abuse-deterrent opioids and innovative technology in addressing issues of opioid therapy and pain are presented. Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.
Jones, Hendrée E; Finnegan, Loretta P; Kaltenbach, Karol
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
Barrio, Pablo; Ezzeldin, Mohamed; Bruguera, Pol; Pérez, Ana; Mansilla, Sara; Fàbrega, Marina; Lligoña, Anna; Mondón, Sílvia; Balcells, Mercè
Prescription opioids (PO) addiction is increasing to an epidemic level. Few studies exist regarding its treatment. Although buprenorphine has been the mainstay so far, other treatment options might be considered, such as methadone. We conducted a retrospective assessment of all patients admitted to a psychiatry ward for PO detoxification using methadone between 2010 and 2013. The assessment and description was carried out during a 3-month follow-up period after their discharge. Although this is a retrospective chart review, our exploration included sociodemographic and treatment variables in addition to the abstinence rates for the whole sample. Eleven patients were included, mostly women (81.8%), with a median age of 50 years. The median duration of dependence was 8 years. Dependence on other substances and psychiatric comorbidities were high. Eight patients were monitored during three months. Of these, 7 (87.5%) were abstinent after that period. The results suggest that methadone deserves further exploration as a potentially efficacious treatment option for PO dependence.
Walker, Brendan M; Valdez, Glenn R; McLaughlin, Jay P; Bakalkin, Georgy
This review represents the focus of a symposium that was presented at the "Alcoholism and Stress: A Framework for Future Treatment Strategies" conference in Volterra, Italy on May 3-6, 2011 and organized/chaired by Dr. Brendan M. Walker. The primary goal of the symposium was to evaluate and disseminate contemporary findings regarding the emerging role of kappa-opioid receptors (KORs) and their endogenous ligands dynorphins (DYNs) in the regulation of escalated alcohol consumption, negative affect and cognitive dysfunction associated with alcohol dependence, as well as DYN/KOR mediation of the effects of chronic stress on alcohol reward and seeking behaviors. Dr. Glenn Valdez described a role for KORs in the anxiogenic effects of alcohol withdrawal. Dr. Jay McLaughlin focused on the role of KORs in repeated stress-induced potentiation of alcohol reward and increased alcohol consumption. Dr. Brendan Walker presented data characterizing the effects of KOR antagonism within the extended amygdala on withdrawal-induced escalation of alcohol self-administration in dependent animals. Dr. Georgy Bakalkin concluded with data indicative of altered DYNs and KORs in the prefrontal cortex of alcohol dependent humans that could underlie diminished cognitive performance. Collectively, the data presented within this symposium identified the multifaceted contribution of KORs to the characteristics of acute and chronic alcohol-induced behavioral dysregulation and provided a foundation for the development of pharmacotherapeutic strategies to treat certain aspects of alcohol use disorders.
Back, Sudie E.; Gros, Daniel F.; Price, Matthew; LaRowe, Steve; Flanagan, Julianne; Brady, Kathleen T.; Davis, Charles; Jaconis, Maryanne; McCauley, Jenna L.
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
Walker, Brendan M.; Valdez, Glenn R.; McLaughlin, Jay P.; Bakalkin, Georgy
This review represents the focus of a symposium that was presented at the “Alcoholism and Stress: A Framework for Future Treatment Strategies” conference in Volterra, Italy on May 3–6, 2011 and organized / chaired by Dr. Brendan M. Walker. The primary goal of the symposium was to evaluate and disseminate contemporary findings regarding the emerging role of kappa-opioid receptors (KORs) and their endogenous ligands dynorphins (DYNs) in the regulation of escalated alcohol consumption, negative affect and cognitive dysfunction associated with alcohol dependence, as well as DYN / KOR mediation of the effects of chronic stress on alcohol reward and seeking behaviors. Dr. Glenn Valdez described a role for KORs in the anxiogenic effects of alcohol withdrawal. Dr. Jay McLaughlin focused on the role of KORs in repeated stress-induced potentiation of alcohol reward and increased alcohol consumption. Dr. Brendan Walker presented data characterizing the effects of KOR antagonism within the extended amygdala on withdrawal-induced escalation of alcohol self-administration in dependent animals. Dr. Georgy Bakalkin concluded with data indicative of altered DYNs and KORs in the prefrontal cortex of alcohol dependent humans that could underlie diminished cognitive performance. Collectively, the data presented within this symposium identified the multifaceted contribution of KORs to the characteristics of acute and chronic alcohol-induced behavioral dysregulation and provided a foundation for the development of pharmacotherapeutic strategies to treat certain aspects of alcohol use disorders. PMID:22459870
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
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.
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
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
Alizadeh, Shaabanali; Mahmoudi, Ghafar Ali; Solhi, Hassan; Sadeghi-Sedeh, Bahman; Behzadi, Reza; Kazemifar, Amir Mohammad
Background Acute and chronic pain is prevalent in patients with opioid dependence. Lack of knowledge concerning the complex relationship between pain, opioid use, and withdrawal syndrome can account for the barriers encountered for pain management. This study was designed to evaluate the efficacy of sublingual (SL) buprenorphine for post-operative analgesia, compared with intravenous (IV) morphine. Methods A total of 68 patients, aged 20-60 years were randomly selected from whom had been underwent laparotomy due to acute abdomen in a University Teaching Hospital in Arak, Iran, and were also opioid (opium or heroin) abuser according to their history. After end of the surgery and patients’ arousal, the patients were evaluated for abdominal pain and withdrawal syndrome by visual analog scale (VAS) and clinical opioid withdrawal score (COWS), respectively 1, 6, and 24 h after the surgery. They received either morphine 5 mg IV or buprenorphine 2 mg SL, 1 h after end of the surgery, and then every 6 h for 24 h. Findings VAS was 4.47 ± 0.73 and 2.67 ± 0.53 at h 6 and 24 in buprenorphine group, respectively. The corresponding score was 5.88 ± 0.69 and 4.59 ± 0.74 in morphine group. At the same time, patients in buprenorphine experienced less severe withdrawal syndrome. Conclusion The present study confirmed the efficacy of SL buprenorphine as a non-invasive, but effective method for management of post-operative pain in opioid dependent patients. Result of this study showed that physicians can rely on SL buprenorphine for post-operative analgesia. PMID:26322212
Trémeau, F; Darreye, A; Leroy, B; Renckly, V; Ertlé, S; Weibel, H; Khidichian, F; Macher, J-P
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.
Haghpanah, Tahereh; Afarinesh, Mohammadreza; Divsalar, Kouros
Background: Long-term use of opioids has acute effects on homeostasis of the body. Discovering the impacts of opioids on hematological parameters of narcotics withdrawal and dependents blood may be helpful in recognizing the homeostasis condition of their body for the useful treatment. Methods: In this study a cross-sectional method was applied. The abusers of opium and heroin for more than two consecutive years were considered as opium and heroin dependent groups, respectively. The dependent people, who passed the 1-month withdrawal period, entered the study as opium and heroin withdrawal groups. In this study, hematological factors of heroin and opium dependent and withdrawal groups were investigated. Findings: The RBC count remained unchanged in all groups. The WBC count had a significant increase in opium dependent group but in heroin dependent group and withdrawal group there was no significant difference. HGB level had a significant increase only in opium and heroin withdrawal groups. The percentage of HCT had a significant increase in all groups. The MCV increased in heroin and opium dependent groups. MCH level increased significantly in heroin and opium withdrawal groups. MCHC level had a significant increase in all groups. Neutrophil and lymphocyte counts in heroin and opium addicted groups significantly decreased. Platelet, neutrophil and monocyte counts significantly increased in opium dependent group. Monocyte countshowed a significant reduction in heroin withdrawal group. Eosinophil count showed no difference in any of the groups. Conclusion: The current study indicated that not only the chronic and long-term use of opium and heroin, also withdrawal of addicted people could change hematological parameters related to human serum. PMID:24494095
Dunn, Kelly E; Fingerhood, Michael; Wong, Conrad J; Svikis, Dace S; Nuzzo, Paul; Silverman, Kenneth
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.
Coloma-Carmona, A; Carballo, J L; Rodríguez-Marín, J; Pérez-Carbonell, A
To analyse the prevalence in the use and dependence on opioid drugs in the Spanish population with chronic pain and evaluate the differences according to sex. The demographic variables, opioid treatment characteristics and use of other substances were assessed in 229 users of opioid drugs. A descriptive bivariate analysis of the data was performed. Forty-six percent of the patients met the criteria of dependence on opioid drugs (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition [DSM-IV-TR]). Alcohol and cannabis consumption was greater in the men. The rates of dependence on the use of opioid drugs were significantly higher in the extended treatments. Planning for treatments with opioids and strategies for preventing inappropriate use should not depend on the patient's sex. We need further studies on the medical and psychological variables related to the use of and dependence on opioids. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.
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
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
Sullivan, Maria A; Bisaga, Adam; Mariani, John J; Glass, Andrew; Levin, Frances R; Comer, Sandra D; Nunes, Edward V
FDA approval of long-acting injectable naltrexone (Vivitrol) for opioid dependence highlights the relevance of understanding mechanisms of antagonist treatment. Principles of learning suggest an antagonist works through extinguishing drug-seeking behavior, as episodes of drug use ("testing the blockade") fail to produce reinforcement. We hypothesized that opiate use would moderate the effect of naltrexone, specifically, that opiate-positive urines precede dropout in the placebo group, but not in the active-medication groups. An 8-week, double-blind, placebo-controlled trial (N=57), compared the efficacy of low (192 mg) and high (384 mg) doses of a long-acting injectable naltrexone (Depotrex) with placebo (Comer et al., 2006). A Cox proportional hazard model was fit, modeling time-to-dropout as a function of treatment assignment and urine toxicology during treatment. Interaction of opiate urines with treatment group was significant. Opiate-positive urines predicted dropout on placebo and low-dose, but less so on high-dose naltrexone, where positive urines were more likely followed by sustained abstinence. Among patients with no opiate-positive urines, retention was higher in both low- and high-dose naltrexone conditions, compared to placebo. Findings confirm that injection naltrexone produces extinction of drug-seeking behavior after episodes of opiate use. Adequate dosage appears important, as low-dose naltrexone resembled the placebo group; opiate positive urines were likely to be followed by dropout from treatment. The observation of high treatment retention among naltrexone-treated patients who do not test the blockade, suggests naltrexone may also exert direct effects on opiate-taking behavior that do not depend on extinction, perhaps by attenuating craving or normalizing dysregulated hedonic or neuroendocrine systems. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Sullivan, Maria A.; Bisaga, Adam; Mariani, John J.; Glass, Andrew; Levin, Frances R.; Comer, Sandra D.; Nunes, Edward V.
Background FDA approval of long-acting injectable naltrexone (Vivitrol) for opioid dependence highlights the relevance of understanding mechanisms of antagonist treatment. Principles of learning suggest an antagonist works through extinguishing drug-seeking behavior, as episodes of drug use (“testing the blockade”) fail to produce reinforcement. We hypothesized that opiate use would moderate the effect of naltrexone, specifically, that opiate-positive urines precede dropout in the placebo group, but not in the active-medication groups. Methods An 8-week, double-blind, placebo-controlled trial (N=57), compared the efficacy of low (192-mg) and high (384-mg) doses of a long-acting injectable naltrexone (Depotrex) with placebo (Comer et al., 2006). A Cox proportional hazard model was fit, modeling time-to-dropout as a function of treatment assignment and urine toxicology during treatment. Results Interaction of opiate urines with treatment group was significant. Opiate-positive urines predicted dropout on placebo and low-dose, but less so on high-dose naltrexone, where positive urines were more likely followed by sustained abstinence. Among patients with no opiate-positive urines, retention was higher in both low- and high-dose naltrexone conditions, compared to placebo. Conclusions Findings confirm that injection naltrexone produces extinction of drug-seeking behavior after episodes of opiate use. Adequate dosage appears important, as low-dose naltrexone resembled the placebo group; opiate positive urines were likely to be followed by dropout from treatment. The observation of high treatment retention among naltrexone-treated patients who do not test the blockade, suggests naltrexone may also exert direct effects on opiate-taking behavior that do not depend on extinction, perhaps by attenuating craving or normalizing dysregulated hedonic or neuroendocrine systems. PMID:23827259
Parvaresh, Noushin; Mazhari, Shahrzad; Nazari-Noghabi, Maryam
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. 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. 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). 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.
Biscaia, Miguel; Fernández, Beatriz; Higuera-Matas, Alejandro; Miguéns, Miguel; Viveros, Maria-Paz; García-Lecumberri, Carmen; Ambrosio, Emilio
Early cannabinoid consumption may predispose individuals to the misuse of addictive drugs later in life. However, there is a lack of experimental evidence as to whether cannabinoid exposure during adolescence might differently affect opiate reinforcing efficacy and the opioid system in adults of both sexes. Our aim was to examine whether periadolescent chronic exposure to the cannabinoid agonist CP-55,940 could exert sex-dependent effects on morphine reinforcing and the opioid system in adulthood. Morphine reinforcing was studied under a progressive ratio (PR) reinforcement schedule in adult male and female rats that previously acquired morphine self-administration under a fixed ratio 1 (FR1) schedule. Binding levels and functionality of mu-opioid receptors were also evaluated. Periadolescent cannabinoid exposure altered morphine self-administration and the opioid system in adult rats in a sex-dependent manner. CP-55,940-exposed males exhibited higher self-administration rates under a FR1, but not under a PR schedule. In females, CP-55,940 did not modify morphine self-administration under either schedule. Moreover, CP-55,940 also increased mu-opioid receptor levels in the subcallosal streak of pre-treated animals and decreased mu-opioid receptor functionality in the nucleus accumbens shell but again, only in males. Our data indicate that adult male rats exposed to the cannabinoid in adolescence self-administer more morphine than females, but only when the demands required by the schedule of reinforcement are low, which might be related to the decrease in mu-opioid receptor functionality in the NAcc-shell observed in these animals.
Johnson, R E; Jones, H E; Jasinski, D R; Svikis, D S; Haug, N A; Jansson, L M; Kissin, W B; Alpan, G; Lantz, M E; Cone, E J; Wilkins, D G; Golden, A S; Huggins, G R; Lester, B M
This open-label prospective study examined maternal and neonatal safety and efficacy outcome measures during and following prenatal buprenorphine exposure. Three opioid-dependent pregnant women received 8 or 12 mg sublingual buprenorphine tablets daily for 15-16 weeks prior to delivery. Results showed that buprenorphine in combination with comprehensive prenatal care was safe and effective in these women. Prenatal exposure to buprenorphine resulted in normal birth outcomes, a mean of 4.33 days (minimum possible=4) hospitalization, and a 'relatively mild' neonatal abstinence syndrome comprised primarily of tremors (disturbed), hyperactive moro and shortened sleep after feeding. The infants required no pharmacological treatment. Onset of neonatal abstinence signs occurred within the first 12 h after birth, peaked by 72 h and returned to below pre-12 h levels by 120 h. It is concluded that buprenorphine has potential utility for the treatment of pregnant opioid-dependent women.
San, L; Camí, J; Fernández, T; Ollé, J M; Peri, J M; Torrens, M
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.
Nielsen, Rikke Vibeke; Fomsgaard, Jonna Storm; Siegel, Hanna; Martusevicius, Robertas; Nikolajsen, Lone; Dahl, Jørgen Berg; Mathiesen, Ole
Perioperative handling of surgical patients with opioid dependency represents an important clinical problem. Animal studies suggest that ketamine attenuates central sensitization and hyperalgesia and thereby reduces postoperative opioid tolerance. We hypothesized that intraoperative ketamine would reduce immediate postoperative opioid consumption compared with placebo in chronic pain patients with opioid dependency undergoing lumbar spinal fusion surgery. Primary outcome was morphine consumption 0 to 24 hours postoperatively. Secondary outcomes were acute pain at rest and during mobilization 2 to 24 hours postoperatively (visual analogue scale), adverse events, and persistent pain 6 months postoperatively. One hundred fifty patients were randomly assigned to intraoperative S-ketamine bolus 0.5 mg/kg and infusion 0.25 mg·kg·h or placebo. Postoperatively, patients received their usual opioids, paracetamol and IV patient-controlled analgesia with morphine. In the final analyses, 147 patients were included. Patient-controlled analgesia IV morphine consumption 0 to 24 hours postoperatively was significantly reduced in the ketamine group compared with the placebo group: 79 (47) vs 121 (53) mg IV, mean difference 42 mg (95% confidence interval -59 to -25), P < 0.001. Sedation was significantly reduced in the ketamine group 6 and 24 hours postoperatively. There were no significant differences regarding acute pain, nausea, vomiting, hallucinations, or nightmares. Back pain at 6 months postoperatively compared with preoperative pain was significantly more improved in the ketamine group compared with the placebo group, P = 0.005. In conclusion, intraoperative ketamine significantly reduced morphine consumption 0 to 24 hours after lumbar fusion surgery in opioid-dependent patients. The trend regarding less persistent pain 6 months postoperatively needs further investigation.
Hendrix, Craig W; Wakeford, John; Wire, Mary Beth; Lou, Yu; Bigelow, George E; Martinez, Elizabeth; Christopher, Jared; Fuchs, Edward J; Snidow, Jerry W
To investigate the steady-state pharmacokinetics of methadone enantiomers when coadministered with amprenavir. Prospective, open-label, within-subject pharmacokinetic study. University research center. Nineteen opioid-dependent, methadone-maintained, healthy individuals were enrolled. On study day 1, subjects received their usual once-daily dose of methadone alone. On study days 2-11, they received the same once-daily methadone dose plus amprenavir 1200 mg twice/day. Serial blood samples were collected over 24 hours on study days 1 and 11 for measurement of plasma R- and S-methadone, and over 12 hours on day 11 for serum amprenavir concentrations. Standard pharmacokinetic parameters were determined from the concentrations and compared between the two treatments (methadone alone vs methadone with amprenavir). Subjects served as their own control for methadone comparisons, and amprenavir comparisons were made by using a historic control group (38 healthy men). Opioid-effect measures were assessed throughout the study. Coadministration of amprenavir with methadone resulted in a 3-4-hour delay in plasma R- and S-methadone enantiomer peak concentrations at steady state (Cmax-ss). The active R-methadone enantiomer area under the plasma concentration-time curve during a dosing interval (AUCt-ss, Cmax-ss, and the minimum plasma concentration at steady state (Cmin-ss) were decreased by 13%, 25%, and 21%, respectively, after coadministration of methadone and amprenavir. The inactive S-enantiomer AUCt-ss, Cmax-ss, and Cmin-ss were decreased by 40%, 48%, and 52%, respectively. No clinically significant changes were noted in opioid pharmacodynamic effects, and there was no evidence of opioid withdrawal. No methadone dosage was changed in any subject. No a priori adjustment in methadone dosage is required during coadministration with amprenavir as there is only a small effect on R-methadone exposure and no evidence of opioid withdrawal.
Kidorf, Michael; Neufeld, Karin; Brooner, Robert K
Employment is associated with improved treatment outcome for opioid-dependent outpatients receiving methadone (e.g., Platt, 1995). Opioid-dependent individuals typically enter treatment unemployed and many remain unemployed despite reductions in heroin use. Additional interventions are needed to motivate employment seeking behaviors and outcome. This article reports on a promising approach to reduce the chronic unemployment commonplace in treatment-seeking, opioid-dependent patients--a "stepped care" service delivery intervention that incorporates multiple behavioral reinforcements to motivate patient participation in and adherence to the treatment plan. This therapeutic approach (Motivated Stepped Care--MSC; Brooner and Kidorf (2002) was refined and modified to motivate and support a range of positive treatment behaviors and outcomes in patients with opioid-dependence (Kidorf et al. 1999), including job-seeking and acquisition. Patients who are unemployed after one year of treatment are systematically advanced to more intensive steps of weekly counseling and remain there until employment is attained. Those who remain unemployed despite exposure to at least 4 weeks of counseling at the highest step of care (Step 3, which is 9 h weekly of counseling) are started on a methadone taper in preparation for discharge, which is reversible upon attaining a job. This article describes the MSC approach and presents rates of employment for patients who were judged capable of working (n = 228). A review of medical and billing records during August--September 2002 revealed that the great majority of these patients were employed (93%), usually in full-time positions. Employment was associated with less frequent advancement to higher intensities of weekly counseling because of drug use. Further, multiple indices of improved employment stability and functioning, including months of work, hours of work, and annualized salary, were associated with better drug use outcomes. These data
Heijning, B J; Herik, I K; Rots, N Y; Greidanus, T B
Abstract We tested the hypothesis of a cross-inhibition of oxytocin (OT) release by endogenous opioid peptides co-released with vasopressin (VP). This opioid cross-inhibition resulted in a selective block of OT release and hence in preferential release of VP. The effects of the opiate receptor antagonist naloxone were tested on neurohypophyseal VP release during dehydration, ethanol administration and sulphated cholecystokinin octapeptide (CCK-8S) application, assuming that the inhibition of pituitary OT release by endogenous opioids increases as neurohypophyseal VP output increases. A high VP output was found to coincide with increased inhibition of OT release: Subcutaneous injection of graded doses of naloxone (30 min prior to decapitation), augmented OT plasma levels significantly more in 24 h water-deprived male rats than in normally hydrated rats. Naloxone had no effect on VP release. Ethanol (10% in saline) administered intragastrically 50 min prior to decapitation and 20 min before subcutaneous naloxone (5 mg/kg) resulted in the inhibition of VP output. The ethanol treatment resulted in a rise in plasma OT levels that was additional to the effect of naloxone. These features were present in normally hydrated as well as in 24 h water-deprived animals, but were more pronounced in the latter group. Peripheral CCK-8S administration induces an abrupt and selective secretion of OT. Blocking the opioid inhibition of OT release with naloxone resulted in a significant rise of OT compared to that with CCK-8S alone. The magnitude of the opioid inhibition coincided with the activity of the VP system, and a higher dose of naloxone was needed to potentiate the CCK-8S effect on OT release in the water-deprived group than in euhydrated rats. No effect of CCK-8S and/or naloxone was found on VP plasma levels. The data indicate that opioid peptides co-released with VP (like dynorphin) may be responsible for cross-inhibition of OT release during dehydration. This suggests that
McNicholas, Laura F; Holbrook, Amber M; O'Grady, Kevin E; Jones, Hendrée E; Coyle, Mara G; Martin, Peter R; Heil, Sarah H; Stine, Susan M; Kaltenbach, Karol
To examine hepatic enzyme test results throughout the course of pregnancy in women maintained on methadone or buprenorphine. Participants were randomized to either methadone or buprenorphine maintenance. Blood chemistry tests, including liver transaminases and hepatitis C virus (HCV) status, were determined every 4 weeks and once postpartum. As part of a planned secondary analysis, generalized mixed linear models were conducted with aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) as the dependent variables. Six US sites and one European site that provided comprehensive treatment to pregnant opioid-dependent women. A total of 175 opioid-dependent pregnant women enrolled in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study. ALT, AST and GGT levels decreased for all subjects across pregnancy trimesters, rising slightly postpartum. HCV-positive subjects exhibited higher transaminases at all time-points compared to HCV-negative subjects, regardless of medication (all Ps < 0.05) condition. Both HCV-positive and negative buprenorphine-maintained participants exhibited lower GGT levels than those who were methadone-maintained (P < 0.05). Neither methadone nor buprenorphine appear to have adverse hepatic effects in the treatment of pregnant opioid-dependent women. © 2012 The Authors, Addiction © 2012 Society for the Study of Addiction.
Christensen, Darren R.; Landes, Reid D.; Jackson, Lisa; Marsch, Lisa A.; Mancino, Michael; Chopra, Mohit P.; Bickel, Warren K.
Objective To examine the benefit of adding an internet-delivered behavior therapy to a buprenorphine medication program and voucher-based motivational incentives. Method A block-randomized, unblinded, parallel, 12-week treatment trial was conducted with 170 opioid-dependent adult patients (mean age 34.3 years; 54.1% male; 95.3% white). Participants received an internet-based community reinforcement approach intervention plus contingency management (CRA+) and buprenorphine, or contingency management alone (CM-alone) plus buprenorphine. The primary outcomes, measured over the course of treatment, were longest continuous abstinence, total abstinence, and days retained in treatment. Results Compared to those receiving CM-alone, CRA+ recipients exhibited on average 9.7 total days more of abstinence, 95% CI: (2.3, 17.2), and had a reduced hazard of dropping out of treatment, Hazard Ratio (HR)=0.47; 95% CI: (0.26, 0.85). Prior treatment for opioid dependence significantly moderated the additional improvement of CRA+ for longest continuous days of abstinence. Conclusions These results provide further evidence that an internet-based CRA+ treatment is efficacious and adds clinical benefits to a contingency management/medication based program for opioid dependence. PMID:25090043
Zhang, Yi; Li, Qiang; Wen, Xiaotong; Cai, Weiwei; Li, Guanya; Tian, Jie; Zhang, Yi Edi; Liu, Jixin; Yuan, Kai; Zhao, Jizheng; Wang, Wei; Zhou, Zhenyu; Ding, Mingzhou; Gold, Mark S; Liu, Yijun; Wang, Gene-Jack
Resting-state magnetic resonance imaging has uncovered abnormal functional connectivity in heroin-dependent individuals (HDIs). However, it remains unclear how brain regions implicated in addictions are related in baseline state without conditioned cues in heroin dependent individuals during opioid maintenance treatment (HDIs-OMT). Previous connectivity analysis assessed the strength of correlated activity between brain regions but lacked the ability to infer directional neural interactions. In the current study, we employed Granger causality analysis to investigate directional causal influences among the brain circuits in HDIs-OMT and non-opioid users. The results revealed a weaker effective connectivity between the caudate nucleus implicated in mediating the reward circuit and other brain regions and also a weaker connectivity between the anterior cingulate cortex and medial prefrontal cortex implicated in mediating inhibitory control. Conversely, HDIs-OMT exhibited stronger effective connectivity between the hippocampus and amygdala implicated in mediating learning-memory, and the anterior cingulate cortex involved in mediating inhibitory control while the putamen mediated learned habits, suggesting that the hippocampus and amygdala may propel the memory circuit to override the control circuit and drive the learned habit in HDIs-OMT. Alterations in learning-memory and inhibitory control may contribute jointly and form a basis for relapse risk even after a period of heroin abstinence. Sustained neural effect of opioid dependence on methadone maintenance including hyperactivation in the memory circuit and impairment in the control circuit support the role of the memory circuitry in relapse and may help redefine targets for treatment.
Davids, Eugen; von Bünau, Ulla; Specka, Michael; Fischer, Barbara; Scherbaum, Norbert; Gastpar, Markus
The co-occurrence of attention-deficit hyperactivity disorder (ADHD) and substance use disorders has received considerable attention in recent clinical and scientific investigations. These two disorders are linked to one another in a variety of ways. The core symptoms of ADHD may be mimicked by the effects of psychoactive substance use, making it difficult to diagnose one disorder in the presence of the other. Individuals with ADHD may demonstrate earlier onset of the substance abuse and a pattern of more frequent or intense use. ADHD symptoms were explored as possible antecedents of opioid dependence. A total of 109 adult opioid-dependent, treatment-seeking male and female outpatients were investigated with an extended clinical semistructured interview to collect sociodemographic, drug-related, and clinical data. The results indicate that ADHD alone does not predispose the development of opioid dependence in our sample. Childhood ADHD symptoms may nevertheless be found more frequently related to school performance problems and difficulties in social adaptation, which was identified in more than half of our population. Patients with ADHD history seemed to experience a drug abuse career with more complications which need to be recognized with focused attention in order to start earlier treatment strategies.
Newman, Adam; Davies, Gregory A.; Dow, Kimberly; Holmes, Belinda; Macdonald, Jessica; McKnight, Sarah; Newton, Lynn
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
Zisblatt, Lara; Hayes, Sean M; Lazure, Patrice; Hardesty, Ilana; White, Julie L; Alford, Daniel P
Due to the high prevalence of prescription opioid misuse, the US Food and Drug Administration (FDA) mandated a Risk Evaluation and Mitigation Strategy (REMS) requiring manufacturers of extended-release/long-acting (ER/LA) opioids to fund continuing education based on an FDA curricular Blueprint. This paper describes the Safe and Competent Opioid Prescribing Education (SCOPE of Pain) train-the-trainer program and its impact on (1) disseminating the SCOPE of Pain curriculum and (2) knowledge, confidence, attitudes, and performance of the participants of trainer-led compared with expert-led meetings. SCOPE of Pain is a 3-hour ER/LA opioid REMS education. In addition to expert-led live statewide meetings, a 2-hour train-the-trainer (TTT) workshop was developed to increase dissemination nationally. The trainers were expected to conduct SCOPE of Pain meetings at their institutions. Participants of both the trainer-led and expert-led SCOPE of Pain programs were surveyed immediately post and 2 months post meetings to assess improvements in knowledge, confidence, attitudes, and self-reported safe opioid prescribing practices. During 9 months (May 2013 to February 2014), 89 trainers were trained during 9 TTT workshops in 9 states. Over 24 months (May 2013 to April 2015), 33% of the trainers conducted at least 1 SCOPE of Pain training, with a total of 79 meetings that educated 1419 participants. The average number of meetings of those who conducted at least 1 meeting was 2.8 (range: 1-19). The participants of the trainer-led programs were significantly more likely to be practicing in rural settings than those who participated in the expert-led meetings (39% vs. 26%, P < .001). At 2 months post training, there were no significant differences in improvements in participant knowledge, confidence, attitudes, and performance between expert-led and trainer-led meetings. The SCOPE of Pain TTT program holds promise as an effective dissemination strategy to increase guideline
Benningfield, Margaret M; Dietrich, Mary S; Jones, Hendrée E; Kaltenbach, Karol; Heil, Sarah H; Stine, Susan M; Coyle, Mara G; Arria, Amelia M; O'Grady, Kevin E; Fischer, Gabriele; Martin, Peter R
To examine the relationship of anxiety and depression symptoms with treatment outcomes (treatment discontinuation, rates of ongoing use of illicit drugs and likelihood of preterm delivery) in opioid-dependent pregnant women and describe their use of psychotropic medications. Secondary data analysis from a randomized clinical trial of treatment for opioid dependence during pregnancy. A total of 175 opioid-dependent pregnant women, of whom 131 completed treatment. Symptoms of anxiety and depression were captured with the 15-item Mini International Neuropsychiatric Interview (MINI) screen. Use of illicit drugs was measured by urine drug screening. Preterm delivery was defined as delivery prior to 37 weeks' gestation. Self-reported use of concomitant psychotropic medication at any point during the study was recorded. Women reporting only anxiety symptoms at study entry were more likely to discontinue treatment [adjusted odds ratio (OR) = 4.56, 95% confidence interval (CI) : 1.91-13.26, P = 0.012], while those reporting only depression symptoms were less likely to discontinue treatment (adjusted OR = 0.14, 95% CI : 0.20-0.88, P = 0.036) compared to women who reported neither depression nor anxiety symptoms. No statistically significant between-group differences were observed for ongoing illicit drug use or preterm delivery. A majority (61.4%) of women reported use of concomitant psychotropic medication at some point during study participation. Opioid agonist-treated pregnant patients with co-occurring symptoms of anxiety require additional clinical resources to prevent premature discontinuation. © 2012 The Authors, Addiction © 2012 Society for the Study of Addiction.
Velez, Martha; Jansson, Lauren M
Opioid dependent pregnant and post-partum women and their infants are a complex and vulnerable population requiring individualized, comprehensive and multidisciplinary treatment. Though methadone maintenance in the setting of comprehensive service provision during pregnancy significantly improves pregnancy outcomes for opioid dependent women, its use has implications for the infant, most notably the Neonatal Abstinence Syndrome (NAS). NAS is comprised of physiologic signs and behaviors that indicate a dysfunctional regulation of the central and autonomic nervous systems, and is variable in its expression in affected infants. The disorganized rather than adaptive behaviors displayed by each infant undergoing the effects of in-utero opioid exposure may impair basic functions such as feeding, sleeping, and the ability to be alert and communicate clear cues to caregivers. Understanding and responding to neurobehavioral dysfunction of the newborn may help to promote the infant's self-organization and self-regulating abilities. However, the substance abusing mother's physical and psychological wellbeing may be debilitated in the perinatal period, and her ability to recognize and respond to the newborn's cues may be limited. A multi-tiered comprehensive assessment and intervention of the methadone-maintained mother, her child, and the mother/infant dyad can improve early maternal nurturing interactions, a crucial component of early infant development, particularly in this vulnerable population. The purpose of this article is to review the contribution of maternal opioid dependency to the difficulties experienced by the mother-infant dyad and their treatment providers in the postnatal period, and the non-pharmacological treatment of the infants with suggestions for practical measures with emphasis on the treatment of the mother and baby as an interactional dyad.
Velez, Martha; Jansson, Lauren M.
Opioid dependent pregnant and post-partum women and their infants are a complex and vulnerable population requiring individualized, comprehensive and multidisciplinary treatment. Though methadone maintenance in the setting of comprehensive service provision during pregnancy significantly improves pregnancy outcomes for opioid dependent women, its use has implications for the infant, most notably the Neonatal Abstinence Syndrome (NAS). NAS is comprised of physiologic signs and behaviors that indicate a dysfunctional regulation of the central and autonomic nervous systems, and is variable in its expression in affected infants. The disorganized rather than adaptive behaviors displayed by each infant undergoing the effects of in-utero opioid exposure may impair basic functions such as feeding, sleeping, and the ability to be alert and communicate clear cues to caregivers. Understanding and responding to neurobehavioral dysfunction of the newborn may help to promote the infant’s self-organization and self-regulating abilities. However, the substance abusing mother’s physical and psychological wellbeing may be debilitated in the perinatal period, and her ability to recognize and respond to the newborn’s cues may be limited. A multi-tiered comprehensive assessment and intervention of the methadone-maintained mother, her child, and the mother/infant dyad can improve early maternal nurturing interactions, a crucial component of early infant development, particularly in this vulnerable population. The purpose of this article is to review the contribution of maternal opioid dependency to the difficulties experienced by the mother-infant dyad and their treatment providers in the postnatal period, and the non-pharmacological treatment of the infants with suggestions for practical measures with emphasis on the treatment of the mother and baby as an interactional dyad. PMID:19727440
Carrieri, Patrizia Maria; Michel, Laurent; Lions, Caroline; Cohen, Julien; Vray, Muriel; Mora, Marion; Marcellin, Fabienne; Spire, Bruno; Morel, Alain; Roux, Perrine
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
Naji, Leen; Dennis, Brittany Burns; Bawor, Monica; Varenbut, Michael; Daiter, Jeff; Plater, Carolyn; Pare, Guillaume; Marsh, David C; Worster, Andrew; Desai, Dipika; MacKillop, James; Thabane, Lehana; Samaan, Zainab
Opioid use disorder (OUD) affects approximately 21.9 million people worldwide. This study aims to determine the association between age of onset of opioid use and comorbid disorders, both physical and psychiatric, in patients receiving methadone maintenance treatment (MMT) for OUD. Understanding this association may inform clinical practice about important prognostic factors of patients on MMT, enabling clinicians to identify high-risk patients. This study includes data collected between June 2011 and August 2016 for the Genetics of Opioid Addiction research collaborative between McMaster University and the Canadian Addiction Treatment Centers. All patients were interviewed by trained health professionals using the Mini-International Neuropsychiatric Interview and case report forms. Physical comorbidities were verified using patients' electronic medical records. A multi-variable logistic regression model was constructed to determine the strength of the association between age of onset of opioid use and the presence of physical or psychiatric comorbidity while adjusting for current age, sex, body mass index, methadone dose and smoking status. Data from 627 MMT patients with a mean age of 38.8 years (SD = 11.07) were analyzed. Individuals with an age of onset of opioid use younger than 18 years were found to be at higher odds for having a physical or psychiatric comorbid disorder compared to individuals with an age of onset of opioid use of 31 years or older (odds ratio 2.94, 95% confidence interval 1.20, 7.19, p = 0.02). A significant association was not found between the risk of having a comorbidity and an age of onset of opioid use between 18 and 25 years or 26 and 30 years, compared to an age of onset of opioid use of 31 years or older. Our study demonstrates that the younger one begins to use opioids, the greater their chance of having a physical or psychiatric co-morbidity. Understanding the risk posed by an earlier onset of opioid use for the later
Nishizawa, Daisuke; Han, Wenhua; Hasegawa, Junko; Ishida, Takafumi; Numata, Yukio; Sato, Tadahiro; Kawai, Atsuko; Ikeda, Kazutaka
Ethanol is considered to activate the brain reward system by increasing the release of an endogenous opioid receptor ligand, beta-endorphin. The polymorphism A118G in the mu-opioid receptor gene (OPRM1) causes the amino acid change Asn40Asp and has been reported to affect the affinity of the ligand for the receptor. The association of this polymorphism with the vulnerability to alcohol dependence has been studied in many populations, but not yet in Japanese people. In the present study, we compared the frequencies of the polymorphism OPRM1 A118G between patients with alcohol dependence and healthy control subjects living in a Japanese provincial prefecture. We also genotyped a polymorphism, G1510A, in the acetaldehyde dehydrogenase 2 gene (ALDH2), in which the A allele causes poor metabolism of acetaldehyde, a major metabolite of alcohol. Both OPRM1 118G and ALDH2 1510G were significantly associated with alcohol dependence. These results suggest that OPRM1 118G in addition to ALDH2 1510G might be one of the risk factors for alcohol dependence in Japanese people.
Moore, Sarah K.; Marsch, Lisa A.; Badger, Gary J.; Solhkhah, Ramon; Hofstein, Yariv
Objective To examine changes in behavioral and emotional problems among opioid-dependent adolescents during a four week combined behavioral and pharmacological treatment. Methods We examined scales of behavioral and emotional problems in youth using the Youth Self Report (YSR) measure at the time of substance abuse treatment intake and changes in scale scores during treatment Participants were 36 adolescents (ages 13–18 eligible) who met DSM-IV criteria for opioid dependence. Participants received a 28-day outpatient, medication-assisted withdrawal with either buprenorphine, or clonidine, as part of a double-blind, double-dummy comparison of these medications. All participants received a common behavioral intervention, composed of three individual counseling sessions per week, and incentives contingent on opioid-negative urine samples (collected three times/week) attendance and completion of weekly assessments. Results: Although a markedly greater number of youth who received buprenorphine remained in treatment relative to those who received clonidine, youth who remained in treatment showed significant reductions during treatment on two YSR grouping scales (Internalizing Problems and Total Problems) and four of the empirically based syndrome scales (Somatic, Social, Attention and Thought). On YSR competence and adaptive scales, no significant changes were observed. There was no evidence that changes in any scales differed across medication condition. Conclusions Youth who were retained demonstrated substantive improvements in a number of clinically meaningful behavioral and emotional problems, irrespective of pharmacotherapy provided to them. PMID:22107875
Winklbaur-Hausknost, Bernadette; Jagsch, Reinhold; Graf-Rohrmeister, Klaudia; Unger, Annemarie; Baewert, Andjela; Langer, Martin; Thau, Kenneth; Fischer, Gabriele
Lessons learned in research and treatment of opioid dependence demonstrate the need to include pregnant women in clinical trials. Two double-blind, double-dummy, randomized controlled trials (Pilot study, European sample(†) of MOTHER-trial) comparing buprenorphine and methadone in opioid-dependent pregnant women were conducted. In both studies, participants received voucher-based incentives for attendance and completion of study assessments. In the MOTHER trial, participants additionally received escalating voucher incentives for drug-free urine samples. Neonatal abstinence syndrome was treated with oral morphine solution based on standardized modified Finnegan scores. After a mean treatment period of 13.79 weeks in the Pilot study (PS, n = 18) and 20.78 weeks in the MOTHER-trial (MT, n = 41), respectively (p < 0.001), PS patients delivered at mean doses of 14.00 mg buprenorphine/52.50 mg methadone and MT participants at 13.44 mg buprenorphine/63.68 mg methadone. Nonsignificant differences regarding dropout rates were found (22% in PS versus 10% in MT), but dropout was significantly earlier in the MT (p = 0.013). Significantly higher rates of concomitant consumption of opioids and benzodiazepines occurred in the PS compared with the MT (p < 0.001), however, with no significant differences in neonatal data between both settings. Early treatment enrolment combined with contingency management contributes to reduced illicit drug use throughout pregnancy, surprisingly without influencing neonatal outcome parameters. Copyright © 2012 John Wiley & Sons, Ltd.
Dykstra, Linda A; Fischer, Bradford D; Balter, Rebecca E; Henry, Fredrick E; Schmidt, Karl T; Miller, Laurence L
This study explored the involvement of N-methyl-D-aspartate (NMDA) in the effects of μ-opioid agonists. A hot-plate procedure was used to assess antinociception and tolerance in mice in which the NR1 subunit of the NMDA receptor was reduced [knockdown (KD)] to approximately 10%, and in mice treated with the NMDA antagonist, (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959). The μ opioid agonists, morphine, l-methadone and fentanyl, were approximately three-fold less potent in the NR1 KD mice than in wild-type (WT) controls; however, the development of morphine tolerance and dependence did not differ markedly in the NR1 KD and the WT mice. Acute administration of the NMDA antagonist, LY235959, produced dose-dependent, leftward shifts in the morphine dose-effect curve in the WT mice, but not in the NR1 KD mice. Chronic administration of LY235959 during the morphine tolerance regimen did not attenuate the development of tolerance in the NR1 KD or the WT mice. These results indicate that the NR1 subunit of the NMDA receptor does not play a prominent role in μ opioid tolerance.
Yang, Qing-Zhen; Lu, Song-Song; Tian, Xiao-Zhu; Yang, Ai-Min; Ge, Wan-Wen; Chen, Qiang
In the present study, we investigated the antidepressive activity of opiorphin with central administration in the forced swim test in mice. Intracerebroventricular (i.c.v.) administration of opiorphin (1-6 μg/mouse) dose-dependently decreased the immobility time, which was reversed by nonselective opioid receptor antagonist naloxone, δ-selective naltrindole and μ-selective β-FNA. The data suggested that central administration of opiorphin produced an antidepressant-like effect by activating both μ and δ opioid receptors indirectly. In order to eliminate the possibility of a false-positive result in the forced swim test, locomotor activity was checked in both non-habituated and habituated mice. Opiorphin had no influence on non-habituated mice, though had weak effect on habituated mice. In addition, mice treated with opiorphin did not display any convulsive behaviors.
Schulte, M.; Hser, Y.; Saxon, A.; Evans, E.; Li, L.; Huang, D.; Hillhouse, M.; Thomas, C.; Ling, W.
We examined risk factors associated with Hepatitis C virus (HCV) infection among opioid-dependent patients enrolled into medication-assisted therapy (buprenorphine or methadone) to determine factors affecting chronic infection. Patients (N=1,039) were randomized as part of a larger, multisite clinical trial sponsored by the National Drug Abuse Treatment Clinical Trials Network assessing liver function. HCV status was first assessed with an antibody screen; if positive, then current infection was determined with an antigen screen testing for detectable virus. Patients were classified as HCV negative, HCV positive but have cleared the virus, or as having chronic HCV. Logistic regression analysis was used to examine demographic and behavioral correlates of the three groups. Thirty-four percent of patients were classified with chronic infection and 14% had evidence of prior infection with apparent clearing of the virus. Chronic infection was associated with recent injection drug use and cocaine use. Chronic HCV infection was also associated with being older and Hispanic. Age, ethnicity, and current drug use increase the likelihood of being chronically infected with HCV. Strategies targeting high risk subgroups can aid in preventing further disease escalation. PMID:25814381
Oertel, B G; Vermehren, J; Huynh, T T; Doehring, A; Ferreiros, N; Zimmermann, M; Geisslinger, G; Lötsch, J
Cytochrome P450 (CYP) inhibitors may reduce opioid analgesia by inhibiting CYP activity-dependent post-opioid receptor signaling pathways in the brain. This suggestion was predicated on observations of highly attenuated morphine antinociception in rodents after intracerebroventricular injection of fluconazole or carrying a neuron-specific deletion of the cytochrome P450 reductase. However, based on assessments of thermal and electrical pain tolerance, respiratory function, and side effects in 21 healthy volunteers, before and during steady-state concentrations of 1.5 and 3.0 ng/ml of remifentanil at the effect site (viz., the central nervous system), administration of 400 mg/day fluconazole for 8 days in a double-blind, placebo-controlled manner failed to attenuate opioid effects. Although CYP inhibitors such as fluconazole are unlikely to attenuate remifentanil analgesia in humans, extrapolation of the findings to other opioids is premature because differences among opioid effects, such as ligand-selective biased signaling at opioid receptors, leave the possibility that CYP-dependent opioid signaling in the brain might be limited to morphine and may not extend to remifentanil.
Duke, AN; Correia, CJ; Walsh, SL; Bigelow, GE; Strain, EC
Rationale Buprenorphine is a partial mu opioid receptor agonist with clinical efficacy as a pharmacotherapy for opioid dependence. A sublingual combination formulation was developed containing buprenorphine and naloxone with the intent of decreasing abuse liability in opioid dependent individuals. However, the addition of naloxone may not limit abuse potential of this medication when taken by individuals without opioid physical dependence. Objectives The present study investigated the effects of buprenorphine alone and in combination with naloxone administered intramuscularly and sublingually to non-dependent opioid abusers. Methods In a within-subject crossover design, non-dependent opioid-experienced volunteers (N=8) were administered acute doses of buprenorphine (4, 8, 16 mg) and buprenorphine/naloxone (4/1, 8/2, 16/4 mg) via both intramuscular and sublingual routes, intramuscular hydromorphone (2, 4 mg as an opioid agonist control), and placebo, for a total of 15 drug conditions. Laboratory sessions were conducted twice per week using a double blind, double-dummy design. Results Buprenorphine and buprenorphine/naloxone engendered effects similar to hydromorphone. Intramuscular administration produced a greater magnitude of effects compared to the sublingual route at the intermediate dose of buprenorphine and at both the low and high doses of the buprenorphine/naloxone combination. The addition of naloxone did not significantly alter the effects of buprenorphine. Conclusions These results suggest that buprenorphine and buprenorphine/naloxone have similar abuse potential in non-dependent opioid abusers, and that the addition of naloxone at these doses and in this dose ratio confers no evident advantage for decreasing the abuse potential of intramuscular or sublingual buprenorphine in this population. PMID:20577717
Kissler, Jessica L; Walker, Brendan M
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. PMID:26105136
Kissler, Jessica L; Walker, Brendan M
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.
Fisher, William H.; Clark, Robin; Baxter, Jeffrey; Barton, Bruce; O’Connell, Elizabeth; Aweh, Gideon
Persons who abuse opioids or are dependent on opioids are at elevated risk for arrest. Co-occurring behavioral health problems may exacerbate that risk, although the extent of any such increase has not been described. This study examines such risk factors among 40,238 individuals with a diagnosis of opioid abuse or dependence who were enrolled in the Massachusetts Medicaid program in 2010. Medicaid data were merged with statewide arrest data to assess the effects of co-existing mental illness, substance abuse, and previous arrests on arrest during 2010. Persons with serious mental illnesses (psychotic and bipolar disorders) and those with two or more pre-2010 arrests had significantly increased greater odds of arrest. We believe this to be the first study examining effects of co-occurring risk factors on arrest in a large population with opioid dependency/abuse. These findings identify predictors of arrest that could be used to design interventions targeting specific co-occurring risk factors. PMID:25012550
Campos-Jurado, Y; Martí-Prats, L; Zornoza, T; Polache, A; Granero, L; Cano-Cebrián, M J
The nigrostriatal dopamine system is implicated in the regulation of reward and motor activity. Dopamine (DA) release in dorsal striatum (DS) is controlled by the firing rate of DA neurons in substantia nigra pars compacta. However, influences at terminal level, such as those involving activation of mu opioid receptors (MORs), can play a key role in determining DA levels in striatum. Nonetheless, published data also suggest that the effect of opioid drugs on DA levels may differ depending on the DS subregion analyzed. In this study, in vivo microdialysis in rats was used to explore this regional dependence. Changes in basal DA levels induced by local retrodialysis application of DAMGO (selective MORs agonist) in three different subregions of DS along the rostro-caudal axis were studied. Our results indicate that whereas administration of 10μM DAMGO into the rostral and caudal DS significantly reduced DA levels, in medial DS an increase in DA levels was observed. These data reveal a regional-dependent MOR modulation of DA release in DS, similar to that described in the ventral striatum. Our findings may lead to a better understanding of the nigrostriatal DA system regulation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Rosenthal, Richard N; Lofwall, Michelle R; Kim, Sonnie; Chen, Michael; Beebe, Katherine L; Vocci, Frank J
The effectiveness of buprenorphine treatment of opioid dependence is limited by suboptimal medication adherence, abuse, and diversion. To determine whether 6-month buprenorphine implants are noninferior to daily sublingual buprenorphine as maintenance treatment for opioid-dependent patients with stable abstinence. Outpatient, randomized, active-controlled, 24-week, double-blind, double-dummy study conducted at 21 US sites from June 26, 2014, through May 18, 2015. Outpatients were prescribed daily sublingual buprenorphine for 6 months or more, were abstinent while taking 8 mg/d or less of sublingual buprenorphine for 90 days or longer, and were determined to be clinically stable by their physician. Participants were randomized to receive sublingual buprenorphine plus 4 placebo implants or sublingual placebo plus four 80-mg buprenorphine hydrochloride implants (expected efficacy, 24 weeks). The primary end point was between-group difference in proportion of responders (≥4 of 6 months without opioid-positive urine test result [monthly and 4 times randomly] and self-report). The noninferiority established for the lower bound of the 95% confidence interval was greater than -0.20 (P < .025). Secondary end points included cumulative percentage of negative opioid urine results, abstinence, and time to first illicit opioid use. Safety was assessed by adverse event reporting. Of 177 participants (mean age, 39 years; 40.9% female), 90 were randomized to sublingual buprenorphine with placebo implants and 87 to buprenorphine implants with sublingual placebo; 165 of 177 (93.2%) completed the trial. Eighty-one of 84 (96.4%) receiving buprenorphine implants and 78 of 89 (87.6%) receiving sublingual buprenorphine were responders, an 8.8% difference (1-sided 97.5% CI, 0.009 to ∞; P < .001 for noninferiority). Over 6 months, 72 of 84 (85.7%) receiving buprenorphine implants and 64 of 89 (71.9%) receiving sublingual buprenorphine maintained opioid abstinence (hazard ratio
Aden, Brandon; Dunning, Allison; Nosyk, Bohdan; Wittenberg, Eve; Bray, Jeremy W.; Schackman, Bruce R.
Objective To assess the impact of illicit drug use on health-related quality of life (health utility) among opioid-dependent, HIV-infected patients. Design Secondary analyses of data from the Buprenorphine-HIV Evaluation and Support (BHIVES) cohort of HIV-infected patients with opioid dependence in 9 U.S. HIV clinics between 2004 and 2009. Health status (Short Form-12 (SF-12)), combination antiretroviral treatment (ART) status, CD4 cell count, HCV antibody status, current drug use, and demographics were assessed at an initial visit and quarterly follow-up visits for up to one year. Short Form-6D health utility scores were derived from the SF-12. Multivariate mixed effects regression models were used to assess the impact of illicit drug use on health utility controlling for demographic, clinical and social characteristics. Results Health utility was assessed among 307 participants, 67% male, with median age 46 at 1089 quarterly assessments. In multivariate analyses, illicit opioid use, non-opioid illicit drug use, not being on ART and being on ART with poor adherence were associated with lower health utility. The observed decrement in health utility associated with illicit opioid use was larger for those on ART with good adherence (beta = −0.067; p<0.01) or poor adherence (−0.049; p<0.01) than for those not on ART. Conclusions Illicit opioid and non-opioid drug use are negatively associated with health utility in patients with HIV, however the relative effect of illicit opioid use is smaller than that of not being on ART. Postponing ART until initiation of opioid substitution therapy or abstinence may have limited benefits from the perspective of maximizing health utility. PMID:26218410
Zelinski, Lisa M.; Ohgami, Yusuke; Chung, Eunhee; Shirachi, Donald Y.; Quock, Raymond M.
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
Doosti, Fatemeh; Dashti, Saeedeh; Tabatabai, Seyed Meghdad; Hosseinzadeh, Hossein
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
Strain, Eric C.; Harrison, Joseph A.; Bigelow, George E.
A sublingual soluble film formulation of buprenorphine and naloxone (B/N) has been approved by the Food and Drug Administration. This preparation provides unit dose child resistant packaging amenable to tracking and accountability, offers more rapid dissolution, and has potentially preferred taste versus tablets. This study compared the ability of buprenorphine (B) and B/N films to suppress spontaneous withdrawal in opioid dependent volunteers. Methods Participants were maintained on morphine and underwent challenge sessions to confirm sensitivity to naloxone induced opioid withdrawal. Subjects were randomized onto either B (16mg, n=18) or B/N (16/4 mg, n=16) soluble films for five days. Primary outcome measure was the Clinical Opiate Withdrawal Scale (COWS) score. Results Thirty-four subjects completed induction onto soluble films. There was a significant decrease in COWS scores but no significant differences between groups. Conclusions Results support use of B and B/N soluble films as safe and effective delivery methods for opioid induction. PMID:21270789
Radzievsky, A A; Gordiienko, O V; Alekseev, S; Szabo, I; Cowan, A; Ziskin, M C
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.
Mizoguchi, H; Narita, M; Oji, D E; Suganuma, C; Nagase, H; Sora, I; Uhl, G R; Cheng, E Y; Tseng, L F
There appear to be different relationships between mu-opioid receptor densities and the acute and neuroadaptive mu-opioid agonist-induced responses of the multiple opioid neuronal systems, including important pons/medulla circuits. The recent success in creating mu-opioid receptor knockout mice allows studies of mu-opioid agonist-induced pharmacological and physiological effects in animals that express no, one or two copies of the mu-opioid receptor gene. We now report that the binding of mu-opioid receptor ligand, [3H][D-Ala2,NHPhe4,Gly-ol]enkephalin to membrane preparations of the pons/medulla was reduced by half in heterozygous mu-opioid receptor knockout mice and eliminated in homozygous mu-opioid receptor knockout mice. The endogenous mu-opioid agonist peptides endomorphin-1 and -2 activate G-proteins in the pons/medulla from wild-type mice in a concentration-dependent fashion, as assessed using [35S]guanosine-5'-o-(3-thio)triphosphate binding. This stimulation was reduced to half of the wild-type levels in heterozygous mice and eliminated in homozygous knockout mice. The intracerebroventricular injection of either endomorphin-1 or endomorphin-2 produced marked antinociception in the hot-plate and tail-flick tests in wild-type mice. These antinociceptive actions were significantly reduced in heterozygous mu-opioid receptor knockout mice, and virtually abolished in homozygous knockout mice. The mu-opioid receptors are the principal molecular targets for endomorphin-induced G-protein activation in the pons/medulla and the antinociception caused by the intracerebroventricular administration of mu-opioid agonists. These data support the notion that there are limited physiological mu-opioid receptor reserves for inducing G-protein activation in the pons/medulla and for the nociceptive modulation induced by the central administration of endomorphin-1 and -2.
McDermott, Katherine A; Griffin, Margaret L; Connery, Hilary S; Hilario, E Yvette; Fiellin, David A; Fitzmaurice, Garrett M; Weiss, Roger D
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. Using data from a multisite, 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 (N = 360). 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 versus use at various time points within the first month of treatment (week 1, weeks 1-2, 1-3, or 1-4) in predicting successful versus unsuccessful treatment outcome (based on abstinence or near-abstinence from opioids) in the last 4 weeks of buprenorphine-naloxone treatment (weeks 9-12). Outcome was best predicted by medication response after 2 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 2 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%). Evaluating prescription opioid-dependent patients after 2 weeks of buprenorphine-naloxone treatment may help determine the likelihood of successful outcome at
McDermott, Katherine A.; Griffin, Margaret L.; Connery, Hilary S.; Hilario, E. Yvette; Fiellin, David A.; Fitzmaurice, Garrett M.; Weiss, Roger D.
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
Kehoe, P; Shoemaker, W
Pregnant rats were given diets containing either 5% ethanol, an isocaloric (pair-fed) diet, or casein pellets. Offspring were tested at postnatal day 10 for isolation-induced ultrasonic vocalizations and subsequent stress-induced analgesia. Rats prenatally exposed to ethanol vocalized significantly less in the five minutes during isolation. The opiate, morphine, caused a greater suppression of vocalizations in alcohol-exposed pups compared to controls, while the increased calling normally seen with the opiate antagonist, naltrexone, was attenuated. In a test in which the pup withdraws a paw from a hot plate (48 degrees C), prenatal alcohol offspring demonstrated baseline latencies (no isolation) similar to controls but had greatly attenuated responses in their isolation-induced analgesia. Since both vocalization and analgesia responses have been determined to be modulated by the endogenous opioid system, the aberrant responses of the prenatal-ethanol-exposed offspring can be interpreted as failures to respond by opioid release/secretion to appropriate stimuli.
Chiang, T; Sansuk, K
Background and Purpose δ Opioid receptor agonists are being developed as potential treatments for depression and alcohol use disorders. This is particularly interesting as depression is frequently co‐morbid with alcohol use disorders. Yet we have previously shown that δ receptor agonists range widely in their ability to modulate alcohol intake; certain δ receptor agonists actually increase alcohol consumption in mice. We propose that variations in β‐arrestin 2 recruitment contribute to the differential behavioural profile of δ receptor agonists. Experimental Approach We used three diarylmethylpiperazine‐based non‐peptidic δ receptor selective agonists (SNC80, SNC162 and ARM390) and three structurally diverse δ receptor agonists (TAN‐67, KNT127 and NIH11082). We tested these agonists in cAMP and β‐arrestin 2 recruitment assays and a behavioural assay of alcohol intake in male C57BL/6 mice. We used β‐arrestin 2 knockout mice and a model of depression‐like behaviour to further study the role of β‐arrestin 2 in δ receptor pharmacology. Key Results All six tested δ receptor agonists were full agonists in the cAMP assay but displayed distinct β‐arrestin 2 recruitment efficacy. The efficacy of δ receptor agonists to recruit β‐arrestin 2 positively correlated with their ability to increase alcohol intake (P < 0.01). The effects of the very efficacious recruiter SNC80 on alcohol intake, alcohol place preference and depression‐like behaviour were β‐arrestin 2‐dependent. Conclusions and Implications Our finding that δ receptor agonists that strongly recruit β‐arrestin 2 can increase alcohol intake carries important ramifications for drug development of δ receptor agonists for treatment of alcohol use disorders and depressive disorders. © 2015 The British Pharmacological Society PMID:26507558
Chiang, T; Sansuk, K; van Rijn, R M
δ Opioid receptor agonists are being developed as potential treatments for depression and alcohol use disorders. This is particularly interesting as depression is frequently co-morbid with alcohol use disorders. Yet we have previously shown that δ receptor agonists range widely in their ability to modulate alcohol intake; certain δ receptor agonists actually increase alcohol consumption in mice. We propose that variations in β-arrestin 2 recruitment contribute to the differential behavioural profile of δ receptor agonists. We used three diarylmethylpiperazine-based non-peptidic δ receptor selective agonists (SNC80, SNC162 and ARM390) and three structurally diverse δ receptor agonists (TAN-67, KNT127 and NIH11082). We tested these agonists in cAMP and β-arrestin 2 recruitment assays and a behavioural assay of alcohol intake in male C57BL/6 mice. We used β-arrestin 2 knockout mice and a model of depression-like behaviour to further study the role of β-arrestin 2 in δ receptor pharmacology. All six tested δ receptor agonists were full agonists in the cAMP assay but displayed distinct β-arrestin 2 recruitment efficacy. The efficacy of δ receptor agonists to recruit β-arrestin 2 positively correlated with their ability to increase alcohol intake (P < 0.01). The effects of the very efficacious recruiter SNC80 on alcohol intake, alcohol place preference and depression-like behaviour were β-arrestin 2-dependent. Our finding that δ receptor agonists that strongly recruit β-arrestin 2 can increase alcohol intake carries important ramifications for drug development of δ receptor agonists for treatment of alcohol use disorders and depressive disorders. © 2015 The British Pharmacological Society
Montazerifar, Farzaneh; Karajibani, Mansour; Lashkaripour, Kobra
Background Opium abuse significantly affects the nutritional status of users and frequently leads to undernourishment. Methadone maintenance therapy has been used as one of the possible ways to prevent of infection diseases such as HIV and hepatitis B and C and improve the quality of life in opioid-dependent patients. Objectives The aim of this study was to assess the anthropometric and socio-demographic characteristics of opium addicted persons before and after 8 weeks of methadone maintenance therapy (MMT). Patients and Methods A clinical cross-sectional study was carried out on 55 opium users (15 women and 40 men; mean aged 31.6 ± 10 years), dependent on opium and its derivatives at the Addiction Treatment Clinic of the Baharan psychiatric Hospital, Zahedan, Sistan and Baluchistan Province, Iran, in 2011. The patients were examined before and after 8 weeks MMT. Weight and height of participants were taken and the body mass index (BMI) was calculated. Results Body weight increased significantly from 61.4 ± 14.4 to 65.3 ± 14.2 kg and BMI from 21.4 ± 4.2 to 23 ± 5.6 (kg/m2) after 8 weeks of methadone maintenance therapy in opium users (P < 0.01). The percentages of underweight, overweight and obese patients were; 27.3%, 18.2% and 3.6%, respectively pre-MMT, and 12.7%, 18.2% and 7.2%, respectively after MMT. Conclusions The study shows that methadone Maintenance Therapy led to improvements in nutritional status. PMID:24971244
Offending, custody and opioid substitution therapy treatment utilisation among opioid-dependent people in contact with the criminal justice system: comparison of Indigenous and non-Indigenous Australians.
Gisev, Natasa; Gibson, Amy; Larney, Sarah; Kimber, Jo; Williams, Megan; Clifford, Anton; Doyle, Michael; Burns, Lucy; Butler, Tony; Weatherburn, Don J; Degenhardt, Louisa
Although Indigenous Australians are over-represented among heroin users, there has been no study examining offending, time in custody, and opioid substitution therapy (OST) treatment utilisation among Indigenous opioid-dependent (including heroin) people at the population level, nor comparing these to non-Indigenous opioid-dependent people. The aims of this study were to compare the nature and types of charges, time in custody and OST treatment utilisation between opioid-dependent Indigenous and non-Indigenous Australians in contact with the criminal justice system. This was a population-based, retrospective data linkage study using records of OST entrants in New South Wales, Australia (1985-2010), court appearances (1993-2011) and custody episodes (2000-2012). Charge rates per 100 person-years were compared between Indigenous and non-Indigenous Australians by sex, age and calendar year. Statistical comparisons were made for variables describing the cumulative time and percentage of follow-up time spent in custody, as well as characteristics of OST initiation and overall OST treatment utilisation. Of the 34,962 people in the cohort, 6,830 (19.5%) were Indigenous and 28,132 (80.5%) non-Indigenous. Among the 6,830 Indigenous people, 4,615 (67.6%) were male and 2,215 (32.4%) female. The median number of charges per person against Indigenous people (25, IQR 31) was significantly greater than non-Indigenous people (9, IQR 16) (p < 0.001). Overall, Indigenous people were charged with 33.2% of the total number of charges against the cohort and 44.0% of all violent offences. The median percentage of follow-up time that Indigenous males and females spent in custody was twice that of non-Indigenous males (21.7% vs. 10.1%, p < 0.001) and females (6.0% vs. 2.9%, p < 0.001). The percentage of Indigenous people who first commenced OST in prison (30.2%) was three times that of non-Indigenous people (11.2%) (p < 0.001). Indigenous males spent less time in OST compared to non
McDermott, Carmel M; Schrader, Laura A
. Preincubation of the slice with the selective KOR antagonist, nor-binalthorphimine (BNI, 1 μm) inhibited the effect of U6 on the latency to first spike and spike half-width suggesting that these effects are mediated through KORs. The inclusion of GDP-βS (1 mm) in the recording pipette prevented all of the U6 effects, suggesting that all effects are mediated via a G-protein-dependent mechanism. Inclusion of the A-type K+ current blocker, 4-aminopyridine (4-AP, 5 mm) in the pipette also antagonised the effects of U6. Kv4.2 is one of the channel α subunits thought to be responsible for carrying the A-type K+ current. Incubation of hippocampus slices with U6 resulted in a decrease in the Kv4.2 subunit protein at the cell surface. These results are consistent with an increase in cell excitability in response to KOR activation and may reflect new possibilities for additional opioid functions. PMID:21606111
Winhusen, Theresa; Wilder, Christine; Wexelblatt, Scott L; Theobald, Jeffrey; Hall, Eric S; Lewis, Daniel; Van Hook, James; Marcotte, Michael
In recent years, the U.S. has experienced a significant increase in the prevalence of pregnant opioid-dependent women and of neonatal abstinence syndrome (NAS), which is caused by withdrawal from in-utero drug exposure. While methadone-maintenance currently is the standard of care for opioid dependence during pregnancy, research suggests that buprenorphine-maintenance may be associated with shorter infant hospital lengths of stay (LOS) relative to methadone-maintenance. There is no "gold standard" treatment for NAS but there is evidence that buprenorphine, relative to morphine or methadone, treatment may reduce LOS and length of treatment. Point-of-care clinical trial (POCCT) designs, maximizing external validity while reducing cost and complexity associated with classic randomized clinical trials, were selected for two planned trials to compare methadone to buprenorphine treatment for opioid dependence during pregnancy and for NAS. This paper describes design considerations for the Medication-assisted treatment for Opioid-dependent expecting Mothers (MOMs; estimated N = 370) and Investigation of Narcotics for Ameliorating Neonatal abstinence syndrome on Time in hospital (INFANTs; estimated N = 284) POCCTs, both of which are randomized, intent-to-treat, two-group trials. Outcomes would be obtained from participants' electronic health record at three participating hospitals. Additionally, a subset of infants in the INFANTs POCCT would be from mothers in the MOMs POCCT and, thus, potential interaction between medication treatment of mother and infant could be evaluated. This pair of planned POCCTs would evaluate the comparative effectiveness of treatments for opioid dependence during pregnancy and for NAS. The results could have a significant impact on practice. Copyright © 2014 Elsevier Inc. All rights reserved.
Mora, Andrea L; Salazar, Miguel; Pablo-Caeiro, Juan; Frost, Craig P; Yadav, Yashoo; DuPont, Herbert L; Garey, Kevin W
Risk factors for Clostridium difficile infection (CDI) include use of broad-spectrum antibiotics, advanced age and lack of an appropriate immune response. Whether antiperistaltics such as opioid analgesics also increase the risk of CDI is uncertain. The purpose of this preliminary study was to determine whether opioid analgesics increase the risk of developing CDI in hospitalized patients receiving broad-spectrum antibiotics. Hospitalized patients were assessed for incidence of CDI in relation to usage of opioid analgesics controlling for other known risk factors for CDI. During the study period, a total of 32,775 patients were identified of whom 192 had CDI. In univariate analysis, incidence of CDI increased significantly with moderate or high usage of opioids (P < 0.0001). One hundred of 21,396 (0.47%) patients who did not receive opioids developed CDI. Twenty-two of 6955 patients (0.32%) with mild usage of opioids developed CDI [odds ratio (OR): 0.68; 95% confidence interval (CI): 0.43-1.1; P = 0.10]. Thirty of 33,203 (0.93%) with moderate usage developed CDI (OR: 2.0; 95% CI: 1.3-3.0; P = 0.0009). Forty of 1029 (3.7%) patients with high usage of opioids developed CDI (OR: 8.3; 95% CI: 5.7-12.1; P < 0.0001). Similar results were observed using a multivariate Cox proportional hazard model. Moderate to high use of opioid analgesics were associated with an increased risk of CDI.
Reddy, Madhavi K; Anderson, Bradley J; Liebschutz, Jane; Stein, Michael D
The current standard for posttraumatic stress disorder (PTSD) diagnosis is a 3-factor model (re-experiencing, avoidance, and hyperarousal). Two 4-factor models of PTSD, the emotional numbing model (re-experiencing, avoidance, emotional numbing, and hyperarousal) and the dysphoria model (re-experiencing, avoidance, dysphoria, and hyperarousal), have considerable empirical support in the extant literature. However, a newer 5-factor model of PTSD has been introduced that is receiving interest. The 5-factor model differs from the four-factor models in its placement of three symptoms (irritability, sleep disturbance, and concentration difficulties) into a separate cluster termed dysphoric arousal. We empirically compared the theoretical factor structures of 3-, 4-, and 5-factor models of PTSD symptoms to find the best fitting model in a sample of opioid-dependent hospitalized patients. Confirmatory factor analyses were conducted on the 17 self-reported PTSD symptoms of the Posttraumatic Checklist - Civilian Version (PCL-C) in a sample of 151 men and women with opioid dependence. Both four-factor models fit the observed data better than the three-factor model of PTSD; the dysphoria model was preferred to the emotional numbing model in this sample. The recently introduced five-factor model fit the observed data better than either four factor model. PTSD is a heterogeneous disorder comprised of symptoms of re-experiencing, avoidance, numbing, and dysphoria. Three symptoms, irritability, sleep disturbance, and concentration difficulties, may represent a unique latent construct separate from these four symptom clusters in opioid-dependent populations who have experienced traumatic events. Published by Elsevier Ireland Ltd.
Abreu, Mariana; Aguado, Delia; Benito, Javier; García-Fernández, Javier; Segura, Ignacio A Gómez de
Perioperative opioids reduce inhalational anaesthetic requirements. The initial hypoalgesia may, however, be followed by a rebound hyperalgesia. To determine whether prior opioid administration influences inhalational anaesthetic requirements, which might be associated with opioid-induced hyperalgesia. A prospective, randomised, experimental study. Experimental Surgery, La Paz University Hospital, Madrid, Spain. Seventy-nine adult male Wistar rats. Sevoflurane minimum alveolar concentration (MAC) and mechanical nociceptive thresholds (MNTs) were assessed at baseline and 7 days later following opioid treatment with remifentanil 120 μg kg-1 h-1, buprenorphine 150 μg kg-1, methadone 8 mg kg-1 or morphine 10 mg kg-1 The duration of the effect of remifentanil on MAC and MNT was evaluated in addition to the preventive effect of ketamine 10 mg kg-1 on remifentanil-induced hyperalgesia. The effect of different opioid treatments on MAC and MNT was evaluated using analysis of variance (ANOVA). All studied opioids produced an immediate reduction in sevoflurane MAC, followed by an increase (16%) in baseline MAC 7 days later (P < 0.05), although the immediate MAC reduction produced by these opioids at that time was not different. Remifentanil produced a decrease in MNT (P < 0.05), which was associated with an increase in the MAC (P < 0.05) that persisted at 21 days. The effect of remifentanil on MNT and MAC was blocked by ketamine. Opioid-induced hyperalgesia was associated with an increase in the MAC in normal rats who had not undergone surgery. Both effects lasted 21 days and were prevented by ketamine.
Gladden, R Matthew; Martinez, Pedro; Seth, Puja
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
Greenwald, Mark K
This study examined whether acute opioid withdrawal and drug reinforcement opportunity increase opioid craving and seeking behavior. The author used a 3 x 2 within-subject randomized crossover design to assess craving and operant behavioral effects of 3 pretreatments (naloxone 0.1 mg/70 kg, fentanyl 0.75 mg/70 kg, or saline iv) and drug or money reinforcement opportunity in 8 methadone-maintained volunteers. Each pretreatment was paired with response-contingent (15 x fixed-ratio 100) delivery of drug (fentanyl 1.5 mg/70 kg iv) and money (rated equivalent of fentanyl) in different sessions. Naloxone significantly increased opioid craving, withdrawal signs, and symptoms, but not operant behavior, relative to saline and fentanyl pretreatment. However, drug versus money reinforcement opportunity did not significantly increase opioid craving or seeking behavior.
Jackson, Heide; Mandell, Kara; Johnson, Kimberly; Chatterjee, Debanjana; Vanness, David J.
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
Bunce, Scott C; Harris, Jonathan D; Bixler, Edward O; Taylor, Megan; Muelly, Emilie; Deneke, Erin; Thompson, Kenneth W; Meyer, Roger E
There is growing evidence for a neuroadaptive model underlying vulnerability to relapse in opioid dependence. The purpose of this study was to evaluate clinical measures hypothesized to mirror elements of allostatic dysregulation in patients dependent on prescription opioids at 2 time points after withdrawal, compared with healthy control participants. Recently withdrawn (n = 7) prescription opioid-dependent patients were compared with the patients in supervised residential care for 2 to 3 months (extended care; n = 7) and healthy controls (n = 7) using drug cue reactivity, affect-modulated startle response tasks, salivary cortisol, and 8 days of sleep actigraphy. Prefrontal cortex was monitored with functional near-infrared spectroscopy during the cue reactivity task. Startle response results indicated reduced hedonic response to natural rewards among patients recently withdrawn from opioids relative to extended care patients. The recently withdrawn patients showed increased activation to pill stimuli in right dorsolateral prefrontal cortex relative to extended care patients. Cortisol levels were elevated among recently withdrawn patients and intermediate for extended care relative to healthy controls. Actigraphy indicated disturbed sleep between recently withdrawn patients and extended care patients; extended care patients were similar to controls. Dorsolateral prefrontal cortex activation to drug and natural reward cues, startle responses to natural reward cues, day-time cortisol levels, time in bed, and total time spent sleeping were all correlated with the number of days since last drug use (ie, time in supervised residential treatment). These results suggest possible re-regulation of dysregulated hypothalamic-pituitary-adrenal axis and brain reward systems in prescription opioid-dependent patients over the drug-free period in residential treatment.
Kumar, Arjun; Liu, Nai-Jiang; Madia, Priyanka A.; Gintzler, Alan R.
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
Abrahams, Ron; Chase, Claudette; Desmoulin, Judy; Kahan, Mel; Knoppert, David; Koren, Gideon; Lyons, Laura; Ordean, Alice; Roukema, Henry; Uddin, Fatima
The sixth Ivey Chair Symposium, held at the University of Western Ontario in October 2011, was dedicated to an update on the complex issues surrounding opioid dependent mothers and their newborns. The day commenced with Loretta Finnegan who provided a historical overview of the complex issues surrounding the addicted mother and her baby suffering from neonatal withdrawal syndrome. It is remarkable that the tool devised by Dr Finnegan forty years ago is in wide use today, capturing accurately the severity of NAS and the need for follow up and treatment. She stressed that comprehensive approach to the care of pregnant drug-dependent mothers and their babies significantly reduces maternal and infant's morbidity. The risk of low birth weight and severe withdrawal can be reduced substantially when both patients in this dyad are optimally cared for. The seven speakers following her provided an update on the medicinal and non drug approach to treat the opioid-dependent mother and her newborn, including new Canadian guidelines which were just released.
Walter, Marc; Wiesbeck, Gerhard A; Degen, Bigna; Albrich, Jürgen; Oppel, Monika; Schulz, André; Schächinger, Hartmut; Dürsteler-MacFarland, Kenneth M
Heroin dependence (HD) is a chronic relapsing brain disorder characterized by a compulsion to seek and use heroin. Stress is seen as a key factor for heroin use. Methadone maintenance and the prescription of pharmaceutical heroin [diacetylmorphine (DAM)] are established treatments for HD in several countries. The present study examined whether DAM-maintained patients and methadone-maintained patients differ from healthy controls in startle reflex and cortisol levels. Fifty-seven participants, 19 of each group matched for age, sex and smoking status, completed a startle session which included the presentation of 24 bursts of white noise while eye-blink responses to startling noises were recorded. Salivary cortisol was collected three times after awakening, before, during and after the startle session. DAM was administered before the experiment, while methadone was administered afterwards. Both heroin-dependent patient groups exhibited significantly smaller startle responses than healthy controls (P < 0.05). Whereas the cortisol levels after awakening did not differ across the three groups, the experimental cortisol levels were significantly lower in DAM-maintained patients, who received their opioid before the experiment, than in methadone-maintained patients and healthy controls (P < 0.0001). Opioid maintenance treatment for HD is associated with reduced startle responses. Acute DAM administration may suppress cortisol levels, and DAM maintenance treatment may represent an effective alternative to methadone in stress-sensitive, heroin-dependent patients.
Hauser, Kurt F.; Stiene-Martin, Anne; Mattson, Mark P.; Elde, Robert P.; Ryan, S. Eric; Godleske, Chrystal C.
Morphine, a preferential μ opioid receptor agonist, alters astroglial development by inhibiting cell proliferation and by promoting cellular differentiation. Although morphine affects cellular differentiation through a Ca2+-dependent mechanism, few studies have examined whether Ca2+ mediates the effect of opioids on cell proliferation, or whether a particular Ca2+ signal transduction pathway mediates opioid actions. Moreover, it is uncertain whether one or more opioid receptor types mediates the developmental effects of opioids. To address these questions, the present study examined the role of μ opioid receptors and Ca2+ mobilization in morphine-induced astrocyte development. Morphine (1 μM) and non-morphine exposed cultures enriched in murine astrocytes were incubated in Ca2+-free media supplemented with < 0.005, 0.3, 1.0, or 3.0 mM Ca2+ ([Ca2+]o), or in unmodified media containing Ca2+ ionophore (A23187), nifedipine (1 μM), dantrolene (10 μM), thapsigargin (100 nM), or L-glutamate (100 μM) for 0–72 h. μ-Opioid receptor expression was examined immunocytochemically using specific (MOR1) antibodies. Intracellular Ca2+ ([Ca2+]i) was measured by microfluorometric analysis using fura-2. Astrocyte morphology and bromodeoxyuridine (BrdU) incorporation (DNA synthesis) were assessed in glial fibrillary acidic protein (GFAP) immunoreactive astrocytes. The results showed that morphine inhibited astroglial growth by activating μ opioid receptors. Astrocytes expressed MOR1 immunoreactivity and morphine’s actions were mimicked by the selective μ agonist PL017. In addition, morphine inhibited DNA synthesis by mobilizing [Ca2+]i in developing astroglia. At normal [Ca2+]o, morphine attenuated DNA synthesis by increasing [Ca2+]i; low [Ca2+]o (0.3 mM) blocked this effect, while treatment with Ca2+ ionophore or glutamate mimicked morphine’s actions. At extremely low [Ca2+]o (<0.005 mM), morphine paradoxically increased BrdU incorporation. Although opioids can increase
Sudakov, S K; Bogdanova, N G
The study examined the effect of peripheral (intragastric) ICI-204,448, an agonist of gastric κ-opioid receptors, on the psychostimulating and anxiolytic effects of caffeine in nicotinedependent rats at the stage of nicotine withdrawal. In these rats, the effects of caffeine (10 mg/kg) were perverted. In nicotine-dependent rats, caffeine produced an anxiolytic effect accompanied by pronounced stimulation of motor activity, in contrast to anxiogenic effect induced by caffeine in intact rats without nicotine dependence. During nicotine withdrawal, nicotine-dependent rats demonstrated enhanced sensitivity to nicotine. Intragastric administration of κ-opioid receptor agonist ICI-204,448 normalized the effect of caffeine in nicotinedependent rats. We have previously demonstrated that activation of peripheral κ-opioid receptors inhibited central κ-opioid activity and eliminated manifestations of nicotine withdrawal syndrome in nicotine-dependent rats, e.g. metabolism activation, stimulation of motor activity, and enhancement of food consumption. In its turn, inhibition of central κ-opioid structures activates the brain adenosine system, which can attenuate the caffeine-induced effects in nicotine-dependent rats.
Clark, Robin E; Baxter, Jeffrey D; Barton, Bruce A; Aweh, Gideon; O'Connell, Elizabeth; Fisher, William H
Objective To assess the impact of a 2008 dose-based prior authorization policy for Massachusetts Medicaid beneficiaries using buprenorphine + naloxone for opioid addiction treatment. Doses higher than 16 mg required progressively more frequent authorizations. Data Sources Mediciaid claims for 2007 and 2008 linked with Department of Public Health (DPH) service records. Study Design We conducted time series for all buprenorphine users and a longitudinal cohort analysis of 2,049 individuals who began buprenorphine treatment in 2007. Outcome measures included use of relapse-related services, health care expenditures per person, and buprenorphine expenditures. Data Collection/Extraction Methods We used ICD-9 codes and National Drug Codes to identify individuals with opioid dependence who filled prescriptions for buprenorphine. Medicaid and DPH data were linked with individual identifiers. Principal Findings Individuals using doses >24 mg decreased from 16.5 to 4.1 percent. Relapses increased temporarily for some users but returned to previous levels within 3 months. Buprenorphine expenditures decreased but total expenditures did not change significantly. Conclusion Prior authorization policies strategically targeted by dose level appear to successfully reduce use of higher than recommended buprenorphine doses. Savings from these policies are modest and may be accompanied by brief increases in relapse rates. Lower doses may decrease diversion of buprenorphine. PMID:25040021
Mannelli, Paolo; Wu, Li-Tzy; Peindl, Kathleen S.; Swartz, Marvin S.; Woody, George E.
BACKGROUND The approval of extended release injectable naltrexone (XR-NTX; Vivitrol®) has introduced a new option for treating opioid addiction, but studies are needed to identify its place within the spectrum of available therapies. The absence of physiological opioid dependence is a necessary and challenging first step for starting XR-NTX. Outpatient detoxification gives poor results and inpatient detoxification is either unavailable or too brief for the physiological effects of opioids to resolve. Here we present findings from an open label study that tested whether the transition from opioid addiction to XR-NTX can be safely and effectively performed in an outpatient setting using very low dose naltrexone and buprenorphine. METHODS Twenty treatment seeking opioid addicted individuals were given increasing doses of naltrexone starting at 0.25 mg with decreasing doses of buprenorphine starting at 4 mg during a 7-day outpatient XR-NTX induction procedure. Withdrawal discomfort, craving, drug use, and adverse events were assessed daily until the XR-NTX injection, then weekly over the next month. RESULTS Fourteen of the 20 participants received XR-NTX and 13 completed weekly assessments. Withdrawal, craving, and opioid or other drug use were significantly lower during induction and after XR-NTX administration compared with baseline, and no serious adverse events were recorded. CONCLUSIONS Outpatient transition to XR-NTX combining upward titration of very low dose naltrexone with downward titration of low dose buprenorphine was safe, well tolerated, and completed by most participants. Further studies with larger numbers of subjects are needed to see if this approach is useful for naltrexone induction. PMID:24602363
Mannelli, Paolo; Wu, Li-Tzy; Peindl, Kathleen S; Swartz, Marvin S; Woody, George E
The approval of extended release injectable naltrexone (XR-NTX; Vivitrol(®)) has introduced a new option for treating opioid addiction, but studies are needed to identify its place within the spectrum of available therapies. The absence of physiological opioid dependence is a necessary and challenging first step for starting XR-NTX. Outpatient detoxification gives poor results and inpatient detoxification is either unavailable or too brief for the physiological effects of opioids to resolve. Here we present findings from an open label study that tested whether the transition from opioid addiction to XR-NTX can be safely and effectively performed in an outpatient setting using very low dose naltrexone and buprenorphine. Twenty treatment seeking opioid addicted individuals were given increasing doses of naltrexone starting at 0.25mg with decreasing doses of buprenorphine starting at 4 mg during a 7-day outpatient XR-NTX induction procedure. Withdrawal discomfort, craving, drug use, and adverse events were assessed daily until the XR-NTX injection, then weekly over the next month. Fourteen of the 20 participants received XR-NTX and 13 completed weekly assessments. Withdrawal, craving, and opioid or other drug use were significantly lower during induction and after XR-NTX administration compared with baseline, and no serious adverse events were recorded. Outpatient transition to XR-NTX combining upward titration of very low dose naltrexone with downward titration of low dose buprenorphine was safe, well tolerated, and completed by most participants. Further studies with larger numbers of subjects are needed to see if this approach is useful for naltrexone induction. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Jones, Hendrée E.; Heil, Sarah H.; Tuten, Michelle; Chisolm, Margaret S.; Foster, Julianne M.; O Grady, Kevin E.; Kaltenbach, Karol
Background The relationship between cigarette smoking and neonatal and maternal clinical outcomes among opioid-agonist-treated pregnant patients is sparse. Objectives (1) Is smoking measured at study entry related to neonatal and maternal outcomes in pregnant women receiving opioid-agonist medication? (2) Is it more informative to use a multi-item measure of smoking dependence or a single-item measure of daily smoking? (3) Is the relationship between smoking at study entry and outcomes different between methadone and buprenorphine? Methods Secondary analyses examined the ability of the Tobacco Dependence Screener (TDS) and self-reported past 30-day daily average number of cigarettes smoked, both measured at study entry, to predict 12 neonatal and 9 maternal outcomes in 131 opioid-agonist-maintained pregnant participants. Results Past 30-day daily average number of cigarettes smoked was significantly positively associated with total amount of morphine (mg) needed to treat neonatal abstinence syndrome (NAS), Adjusted Odds Ratio (AOR)=1.06(95% CI: 1.02,1.09), number of days medicated for NAS, AOR=1.04(95% CI: 1.01,1.06), neonatal length of hospital stay in days, AOR=1.03(95% CI: 1.01,1.05), and negatively associated with 1- AOR=.995(95% CI: .991,.999) and 5-minute Apgar scores, AOR=.996(95% CI: .994,.998). Simple effect tests of the two significant TDS X medication condition effects found TDS was unrelated to non-normal presentation and amount of voucher money earned in the methadone [AORs=.90 (95%CI: .74,1.08, p>.24) and 1.0 (95%CI: .97, 1.03, p>.9)] but significant in the buprenorphine condition, [AORs=1.57 (95%CI: 1.01,2.45, p<.05) and 1.08 (95%CI: 1.04,1.12, p<.01)]. Conclusions Regardless of prenatal methadone or buprenorphine exposure, heavier smoking was associated with more compromised birth outcomes. PMID:23279924
Metz, Verena E; Comer, Sandra D; Wuerzl, Johanna; Pribasnig, Anna; Fischer, Gabriele
This study investigated pregnant opioid-dependent women undergoing maintenance therapy, applying a multidisciplinary, case-management approach at the Addiction Clinic of the Medical University of Vienna, Austria. It aimed at characterizing the patients' basic demographic and clinical parameters and evaluating their overall quality of life (QoL) prepartum and postpartum. Three hundred ninety women were treated between 1994 and 2009 with buprenorphine (n = 77), methadone (n = 184), or slow-release oral morphine (SROM) (n = 129) on an outpatient basis throughout their pregnancy and postpartum period. All patients were subject to standardized prepartum and postpartum medical and psychiatric assessments, including QoL assessments using a German adaptation of the Lancashire QoL Profile (Berliner Lebensqualitaetsprofil), and regular supervised urine toxicologies. No medication group differences were revealed regarding basic demographic or clinical data. Mean maintenance doses (SD) at time of delivery were as follows: 64 mg (36 mg) methadone, 10 mg (6 mg) buprenorphine, 455 mg (207 mg) SROM. However, buprenorphine-medicated women showed significantly less concomitant benzodiazepine consumption than methadone- or SROM-maintained women (p = 0.005), and significantly less concomitant opioid consumption than methadone-maintained women (p = 0.033) during the last trimester. Overall QoL was good prepartum and postpartum in all measured domains except "finances" and "prospect of staying in the same housing situation," and no differences were observed in QoL among the three medication groups (p = 0.177). QoL improved significantly after delivery in most of the domains (p < 0.001). Although opioid-dependent pregnant women face high-risk pregnancies and show variability in addiction severity, they report good QoL independent of the medication administered. These results show that individually tailored treatment interventions are effective for this patient population and suggest a Qo
Wiest, Katharina L.; Asphaug, Victoria J.; Carr, Kathryn E.; Gowen, Emily A.; Hartnett, Timothy T.
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
Brooner, Robert K; Kidorf, Michael S; King, Van L; Stoller, Kenneth B; Neufeld, Karin J; Kolodner, Ken
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.
Morozova, Olga; Dvoryak, Sergii; Altice, Frederick L.
Background Ukraine’s volatile syndemics of tuberculosis (TB) and HIV among people who inject drugs (PWIDs) introduces numerous treatment challenges for each condition, including high mortality and development of multi-drug resistant TB (MDR-TB). Methods A prospective, non-randomized 90-day observational study was conducted in six Ukrainian TB treatment sites to assess the effectiveness of integrating methadone maintenance (MMT) with TB treatment using: (1) 90-day TB treatment retention; (2) time to treatment discontinuation; (3) TB medication adherence; and (4) subject disposition, including mortality. Of the 110 participants enrolled, 57 received MMT and 53 did not (non-MMT). Results All of the primary outcomes were significantly better in MMT versus non-MMT groups, including 90-day TB treatment completion (89.5% versus 73.6%; p = 0.031), time to TB treatment discontinuation (p = 0.039) and TB medication adherence (97.1% versus 86.2%; p<0.001) after controlling for death. The major reasons for treatment non-completion in the non-MMT group included death (N=3), administrative discharge from the clinic (N =5), loss to follow-up (N =2), and arrest (N=4). Overall, 90-day mortality was high (8.2%). After controlling for covariates differing between the two groups at baseline, the only independent predictor of completing 90 days of TB treatment was receipt of MMT in an integrated treatment setting (AOR = 3.05; 95% CI 1.08–8.66). Conclusions MMT integrated into inpatient TB treatment significantly improves retention in TB treatment and TB medication adherence among PWIDs. These findings call for policy change to increase the number of MMT sites in TB facilities and make MMT a low-threshold treatment option for opioid dependence in Ukraine. PMID:24360402
Kandel, Denise B; Hu, Mei-Chen; Griesler, Pamela; Wall, Melanie
Prescription opioid (PO) overdose deaths increased sharply over the last decade. Changes in PO deaths in combination with other psychoactive substances may provide a partial explanation. PO deaths from the National Multiple-Cause-of-Death Files for 2002-03 (N=15,973) and 2014-15 (N=41,491) were analyzed. We calculated (1) changes in proportions of deaths in combination with benzodiazepines, antidepressants, heroin, alcohol, cocaine between the two periods, and (2) proportions of increase in deaths attributable to each substance among PO and synthetic opioids other than methadone (SO-M) deaths, by age, gender, race/ethnicity. Between 2002-03 and 2014-15, PO deaths increased 2.6 times; SO-M deaths 5.6 times, especially for ages 18-34, males, African-Americans. For PO deaths, most frequent combinations at both periods were with benzodiazepines; for SO-M, benzodiazepines, antidepressants in 2002-03, heroin, benzodiazepines in 2014-15. The largest increases occurred in combination with heroin among all PO (4.6% to 15.4%, change ratio=3.3[95%CI=3.1-3.6]), but especially SO-M deaths (1.2% to 24.5%, change ratio=21.3[95%CI=15.0-30.3]). Deaths involving cocaine decreased among PO, increased among SO-M deaths. One-fifth of increased PO or SO-M deaths were attributable to any of the five substances. Increased PO deaths were equally attributable to benzodiazepines and heroin; deaths attributable to heroin were higher among ages 18-49, males, and non-Hispanic whites. Increased SO-M deaths were attributable mostly to heroin among all groups. Increased PO overdose deaths over the last decade may be partially explained by increased deaths in combination with other psychoactive substances. Use of other substances should be considered in efforts toward reducing prescription opioid overdoses. Copyright © 2017 Elsevier B.V. All rights reserved.
Wachholtz, Amy; Gonzalez, Gerardo
Medication assisted treatment for opioid dependence alters the pain experience. This study will evaluate changes pain sensitivity and tolerance with opioid treatments; and duration of this effect after treatment cessation. 120 Individuals with chronic pain were recruited in 4 groups (N = 30): 1-methadone for opioid addiction; 2-buprenorphine for opioid addiction; 3-history of opioid maintenance treatment for opioid addiction but with prolonged abstinence (M = 121 weeks; SD = 23.3); and 4-opioid naïve controls. Participants completed a psychological assessment and a cold water task including, time to first pain (sensitivity) and time to stopping the pain task (tolerance). Data analysis used survival analyses. A Kaplan-Meier-Cox survival analysis showed group differences for both pain sensitivity (log rank = 15.50; p < .001) and tolerance (log rank = 20.11; p < .001). Current or historical use of opioid maintenance resulted in differing pain sensitivity compared to opioid naïve (p's < .01). However, tolerance to pain was better among those with a history of opioid maintenance compared to active methadone patients (p < .05), with the highest tolerance found among opioid naïve control group participants (p's < .001). Correlations within the prolonged abstinent group indicated pain tolerance was significantly improved as length of opioid abstinence increased (R = .37; p < .05); but duration of abstinence did not alter sensitivity (ns). Among individuals with a history of prolonged opioid maintenance, there appears to be long-term differences in pain sensitivity that do not resolve with discontinuation of opioid maintenance. Although pain sensitivity does not change, pain tolerance does improve after opioid maintenance cessation. Implications for treating co-morbid opioid addiction and pain (acute and chronic) are discussed. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Stein, M D; Bailey, G L; Thurmond, P; Paull, N
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. 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. 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). 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. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Berger, Amy Chang; Whistler, Jennifer L.
Mu opioid receptor (MOR) agonists such as morphine are extremely effective treatments for acute pain. In the setting of chronic pain, however, their long-term utility is limited by the development of tolerance and physical dependence. Drug companies have tried to overcome these problems by simply “dialing up” signal transduction at the receptor, designing more potent and efficacious agonists and more long-lasting formulations. Neither of these strategies has proven to be successful, however, because the net amount of signal transduction, particularly over extended periods of drug use, is a product of much more than the pharmacokinetic properties of potency, efficacy, half-life, and bioavailability, the mainstays of traditional pharmaceutical screening. Both the quantity and quality of signal transduction are influenced by many regulated processes, including receptor desensitization, trafficking, and oligomerization. Importantly, the efficiency with which an agonist first stimulates signal transduction is not necessarily related to the efficiency with which it stimulates these other processes. Here we describe recent findings that suggest MOR agonists with diminished propensity to cause tolerance and dependence can be identified by screening drugs for the ability to induce MOR desensitization, endocytosis, and recycling. We also discuss preliminary evidence that heteromers of the delta opioid receptor and the MOR are pronociceptive, and that drugs that spare such heteromers may also induce reduced tolerance. PMID:20437553
Marco, A; López-Burgos, A; García-Marcos, L; Gallego, C; Antón, J J; Errasti, A
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.
Gray, Teresa R.; Dams, Riet; Choo, Robin E.; Jones, Hendree E.; Huestis, Marilyn A.
Introduction Oral fluid testing is widely used for detecting drug exposure, but data describing methadone and metabolites in oral fluid during pharmacotherapy for opioid-dependence are relatively limited. Method 414 oral fluid specimens from 16 opioid-dependent pregnant women receiving daily methadone were analyzed for methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), and methadol by liquid chromatography-mass spectrometry. Results All oral fluid specimens contained methadone greater than 1 ng/mL; 88% were positive for EDDP and 12% for methadol. Over 95% of oral fluid specimens exceeded the 20 ng/mL methadone cutoff set by the European Driving Under the Influence of Drugs, Alcohol and Medicines (DRUID) study. Methadone and EDDP oral fluid concentrations were highly variable within and between participants, did not predict methadone dose, but were negatively correlated with pH. Conclusion Methadone was readily identified in oral fluid at concentrations greater than 20 ng/mL following daily 30–110 mg/day methadone pharmacotherapy. As no specimens contained only EDDP or methadol, there was no advantage to including these analytes for identification of methadone exposure. As nearly all oral fluid specimens from methadone-maintained patients exceeded the DRUID guideline, the 20 ng/mL cutoff appears to be sensitive enough to detect daily methadone exposure; however, additional indicators of behavioral and/or motor impairment would be necessary to provide evidence of driving impairment. PMID:20667673
Moore, Barbara C.; Easton, Caroline J.; McMahon, Thomas J.
Because very little is known about the coparenting relationships of drug-abusing men, this comparative study was designed to examine the lifetime prevalence and recent frequency of intimate partner violence in the coparenting relationships of 106 fathers enrolled in methadone maintenance treatment. When compared with 118 community controls, the opioid-dependent fathers reported greater prevalence of physical, sexual, and psychological aggression directed at the mother of their youngest biological child over the course of the relationship. They also reported more frequent physical, sexual, and psychological aggression directed at the mother during the previous year. Similarly, the opioid-dependent fathers reported both greater prevalence of physical and sexual aggression directed at them by the mother of their youngest child over the course of the relationship and more frequent sexual aggression directed at them over the previous year. The results highlight the need for clinicians to consider risk for intimate partner violence in coparenting relationships when planning family-oriented intervention designed to meet the needs of fathers, mothers, and children affected by chronic drug abuse. PMID:21486264
Wisner, Anne; Dufour, Evelyne; Messaoudi, Michaël; Nejdi, Amine; Marcel, Audrey; Ungeheuer, Marie-Noelle; Rougeot, Catherine
Mammalian zinc ectopeptidases play important roles in turning off neural and hormonal peptide signals at the cell surface, notably those processing sensory information. We report here the discovery of a previously uncharacterized physiological inhibitor of enkephalin-inactivating zinc ectopeptidases in humans, which we have named Opiorphin. It is a QRFSR peptide that inhibits two enkephalin-catabolizing ectoenzymes, human neutral ecto-endopeptidase, hNEP (EC 18.104.22.168), and human ecto-aminopeptidase, hAP-N (EC 22.214.171.124). Opiorphin displays potent analgesic activity in chemical and mechanical pain models by activating endogenous opioid-dependent transmission. Its function is closely related to the rat sialorphin peptide, which is an inhibitor of pain perception and acts by potentiating endogenous μ- and δ-opioid receptor-dependent enkephalinergic pathways. Here we demonstrate the functional specificity in vivo of human Opiorphin. The pain-suppressive potency of Opiorphin is as effective as morphine in the behavioral rat model of acute mechanical pain, the pin-pain test. Thus, our discovery of Opiorphin is extremely exciting from a physiological point of view in the context of endogenous opioidergic pathways, notably in modulating mood-related states and pain sensation. Furthermore, because of its in vivo properties, Opiorphin may have therapeutic implications. PMID:17101991
Wisner, Anne; Dufour, Evelyne; Messaoudi, Michaël; Nejdi, Amine; Marcel, Audrey; Ungeheuer, Marie-Noelle; Rougeot, Catherine
Mammalian zinc ectopeptidases play important roles in turning off neural and hormonal peptide signals at the cell surface, notably those processing sensory information. We report here the discovery of a previously uncharacterized physiological inhibitor of enkephalin-inactivating zinc ectopeptidases in humans, which we have named Opiorphin. It is a QRFSR peptide that inhibits two enkephalin-catabolizing ectoenzymes, human neutral ecto-endopeptidase, hNEP (EC 126.96.36.199), and human ecto-aminopeptidase, hAP-N (EC 188.8.131.52). Opiorphin displays potent analgesic activity in chemical and mechanical pain models by activating endogenous opioid-dependent transmission. Its function is closely related to the rat sialorphin peptide, which is an inhibitor of pain perception and acts by potentiating endogenous mu- and delta-opioid receptor-dependent enkephalinergic pathways. Here we demonstrate the functional specificity in vivo of human Opiorphin. The pain-suppressive potency of Opiorphin is as effective as morphine in the behavioral rat model of acute mechanical pain, the pin-pain test. Thus, our discovery of Opiorphin is extremely exciting from a physiological point of view in the context of endogenous opioidergic pathways, notably in modulating mood-related states and pain sensation. Furthermore, because of its in vivo properties, Opiorphin may have therapeutic implications.
Ivers, Jo-Hanna; Fitzgerald, Jacqueline; Whelan, Christopher; Sweeney, Brion; Keenan, Eamon; Fagan, Andrew; McMarrow, Jason; Meany, Jim; Barry, Joe; Frodl, Thomas
White matter impairment is associated with opioid dependence. However, the specific neuropathology related to opioid dependence is still not fully understood. The main aims of this study were to: (1) assess the association between white matter impairment and duration of dependence; (2) examine whether this impairment correlates with treatment outcome measures in opioid-dependent patients post-detoxification. Fifty-eight opioid-dependent patients participated, 20 females and 38 males, across three groups: less than 10 years use (n = 18), 10-15 years use (n = 26) and 16-25+ years use (n = 14). Diffusion tensor imaging was used to assess white matter impairment; whole brain voxel-wise analysis of fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were performed by Tract-Based-Spatial-Statistics to pinpoint abnormalities in white matter. The longer the subjects were dependent on opioids, the more widespread and severely the white-matter integrity was disrupted. A general linear model was used to examine patients who relapsed compared to those who were abstinent at follow-up. No statistical difference was found between groups (p > 0.05). Partial correlations were performed to investigate the relationship between clinical outcome measures (physical health, psychological well being and quality of life and hope for the future) and white-matter microstructural differences. Significant correlations were found between AD in the posterior corona radiata (L) and MD in the superior longitudinal fasciculus and a clinical measure for HOPE at 9-month follow-up. Nevertheless, it must be noted that the calculation of numerous correlations raises the possibility of a type I error, namely; to incorrectly conclude the occurrence of a significant correlation. The ability to investigate the structure-clinical relationship may improve our understanding of the pathological abnormalities associated with opioid dependence and
Hathway, Gareth J.; Vega-Avelaira, David; Fitzgerald, Maria
We have previously shown that the balance of electrically evoked descending brainstem control of spinal nociceptive reflexes undergoes a switch from excitation to inhibition in preadolescent rats. Here we show that the same developmental switch occurs when μ-opioid receptor agonists are microinjected into the rostroventral medulla (RVM). Microinjections of the μ-opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) into the RVM of lightly anaesthetised adult rats produced a dose-dependent decrease in mechanical nociceptive hindlimb reflex electromyographic activity. However, in preadolescent (postnatal day 21 [P21]) rats, the same doses of DAMGO produced reflex facilitation. RVM microinjection of δ-opioid receptor or GABAA receptor agonists, on the other hand, caused reflex depression at both ages. The μ-opioid receptor-mediated descending facilitation is tonically active in naive preadolescent rats, as microinjection of the μ-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) into the RVM at this age decreases spinal nociceptive reflexes while having no effect in adults. To test whether tonic opioid central activity is required for the preadolescent switch in RVM descending control, naloxone hydrochloride was delivered continuously from subcutaneous osmotic mini-pumps for 7-day periods, at various postnatal stages. Blockade of tonic opioidergic activity from P21 to P28, but not at earlier or later ages, prevented the normal development of descending RVM inhibitory control of spinal nociceptive reflexes. Enhancing opioidergic activity with chronic morphine over P7 to P14 accelerated this development. These results show that descending facilitation of spinal nociception in young animals is mediated by μ-opioid receptor pathways in the RVM. Furthermore, the developmental transition from RVM descending facilitation to inhibition of pain is determined by activity in central opioid networks at a critical period of
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
To examine predictors of opioid abstinence in buprenorphine/naloxone (Bup/Nal)-assisted psychosocial treatment for opioid-dependent youth. 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 individual and group drug counseling. Logistic regression models were constructed to identify baseline and during-treatment predictors of opioid-positive urine (OPU) at week 12. Predictors were selected based on significance or trend toward significance (i.e., p < .1), and backward stepwise selection was used, controlling for treatment group, to produce final independent predictors at p ≤ .05. Youth presenting to treatment with previous 30-day injection drug use and more active medical/psychiatric problems were less likely to have a week-12 OPU. Those with early treatment opioid abstinence (i.e., weeks 1 and 2) and those who received additional nonstudy treatments during the study were less likely to have a week-12 OPU and those not completing 12 weeks of treatment were more likely to have an OPU. Youth with advanced illness (i.e., reporting injection drug use and additional health problems) and those receiving ancillary treatments to augment study treatment were more likely to have lower opioid use. Treatment success in the first 2 weeks and completion of 12 weeks of treatment were associated with lower rates of OPU. These findings suggest that youth with advanced illness respond well to Bup/Nal treatment and identify options for tailoring treatment for opioid-dependent youth presenting at community-based settings. Buprenorphine/Naloxone-Facilitated Rehabilitation for Opioid Dependent Adolescents; http://www.clinicaltrials.gov; NCT00078130. Copyright © 2011 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.
Gisev, Natasa; Shanahan, Marian; Weatherburn, Don J; Mattick, Richard P; Larney, Sarah; Burns, Lucy; Degenhardt, Louisa
Although opioid substitution therapy (OST) immediately after prison release reduces mortality, the cost-effectiveness of treatment has not been examined. Therefore, we undertook a cost-effectiveness analysis of OST treatment upon prison release and the prevention of death in the first 6 months post-release. Population-based, retrospective data linkage study using records of OST entrants (1985-2010), charges and court appearances (1993-2011), prison episodes (2000-11) and death notifications (1985-2011). New South Wales, Australia. A cohort of 16,073 people with a history of opioid dependence released from prison for the first time between 1 January 2000 and 30 June 2011. OST treatment compared to no OST treatment at prison release. Mortality and costs (treatment, criminal justice system-court, penalties, prison-and the social costs of crime) were evaluated at 6 months post-release. Analyses included propensity score matching, bootstrapping and regression. A total of 13,468 individuals were matched (6734 in each group). Twenty (0.3%) people released onto OST died, compared with 46 people (0.7%) not released onto OST. The final average costs were lower for the group that received OST post-release ($7206 versus $14,356). The incremental cost-effectiveness ratio showed that OST post-release was dominant, incurring lower costs and saving more lives. The probability that OST post-release is cost-effective per life-year saved is 96.7% at a willingness to pay of $500. Opioid substitution treatment (compared with no such treatment), given on release from prison to people with a history of opioid dependence, is cost-effective in reducing mortality in the first 6 months of release. © 2015 Society for the Study of Addiction.
Roussos-Ross, Kay; Reisfield, Gary; Elliot, Iain; Dalton, Susan; Gold, Mark
To investigate the length of stay for observation and treatment of neonatal abstinence syndrome (NAS), as well as the hospital costs associated with the medical care of affected newborns. A retrospective chart review was conducted at Shands Hospital at the University of Florida, Gainesville, Florida. Data were collected for newborns diagnosed with NAS, including their hospital length of stay and the associated hospital charges, from December 1, 2008, to November 30, 2011. One hundred-sixty eligible newborns were included in the study. During the 3-year study period, hospital charges related to the diagnosis and treatment of NAS increased from $1.1 million per year to $1.8 million per year. Compared with the cost of caring for newborns without the risk of NAS, an additional $4.1 million was spent in the medical care of these newborns. The costs associated with treating newborns with NAS are exponentially higher than the costs associated with newborns not affected with NAS. The societal costs associated with treatment of newborns with NAS, as well as infant symptomatology experienced with NAS, can be reduced by encouraging physicians to be proactive in screening for drug use, urging women who use chronic opioids to actively engage in family planning and contraception, and encouraging pregnant women who use opioids to seek substance treatment.
Warner, Margaret; Chen, Li Hui; Makuc, Diane M
Data from the National Vital Statistics System Mortality File. From 1999 through 2006, the number of fatal poisonings involving opioid analgesics more than tripled from 4,000 to 13,800 deaths. Opioid analgesics were involved in almost 40% of all poisoning deaths in 2006. In 2006, the rate of poisoning deaths involving opioid analgesics was higher for males, persons aged 35-54 years, and non-Hispanic white persons than for females and those in other age and racial/ethnic groups. In about one-half of the deaths involving opioid analgesics, more than one type of drug was specified as contributing to the death, with benzodiazepines specified with opioid analgesics most frequently. The age-adjusted death rate for poisoning involving opioid analgesics varied more than eightfold among the states in 2006. All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as to source, however, is appreciated.
Pilowsky, Daniel J; Wu, Li-Tzy; Burchett, Bruce; Blazer, Dan G; Woody, George E; Ling, Walter
Background In response to the rising rate of treatment admissions related to illicit use of amphetamines (eg, methamphetamine), we examined the prevalence of amphetamine use among treatment-seeking, opioid-dependent adults, explored whether amphetamine users were as likely as nonamphetamine users to enroll in opioid-dependence treatment trials, and determined whether amphetamine users manifested greater levels of medical and psychiatric comorbidity than nonusers. Methods The sample included 1257 opioid-dependent adults screened for participation in three-multisite studies of the National Drug Abuse Treatment Clinical Trials Network (CTN001-003), which studied the effectiveness of buprenorphine for opioid detoxification under varying treatment conditions. Patients were recruited from 23 addiction treatment programs across the US. Medical and psychiatric comorbidity were examined by past-month amphetamine use (current vs former) and route of administration. Five mutually exclusive groups were examined, ie, nonusers, current amphetamine injectors, current amphetamine noninjectors, former amphetamine injectors, and former amphetamine noninjectors. Results Of the sample (n = 1257), 22.3% had a history of regular amphetamine use. Of the 280 amphetamine users, 30.3% reported injection as their primary route. Amphetamine users were more likely than nonusers to be white and use more substances. Amphetamine users were as likely as nonusers to enroll in treatment trials. Bivariate analyses indicated elevated rates of psychiatric problems (depression, anxiety, hallucinations, cognitive impairment, violence, suicidal thoughts/attempts) and medical illnesses (dermatological, hepatic, cardiovascular, respiratory, neurological, seizure, allergy conditions) among amphetamine users. After adjusting for demographic variables and lifetime use of other substances: current amphetamine users and former injectors showed an increased likelihood of having medical illnesses and
Jones, Hendrée E; Kaltenbach, Karol; Heil, Sarah H; Stine, Susan M; Coyle, Mara G; Arria, Amelia M; O'Grady, Kevin E; Selby, Peter; Martin, Peter R
How best to measure the occurrence of adverse events during a randomized clinical trial is an issue that has not been adequately examined in the research literature. Focus of this study was on the examination of the relative frequency of occurrence of adverse events directly recorded during the conduct of the trial compared to an indirect determination of adverse events derived from data collected as part of the trial. A secondary analysis of nonserious adverse events that occurred in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) Study was undertaken. MOTHER was a randomized clinical trial of methadone versus buprenorphine in 175 opioid-dependent pregnant women. The two methods of recording adverse events failed to agree on where differences in the frequency of occurrence of adverse events between the medication conditions might exist. Moreover, indirect assessment indicated all participants had experienced at least one adverse event, yet indirect coverage of adverse events was incomplete. Findings suggest indirect examination of occurrence of adverse events should be cautiously undertaken, because indirect assessment of adverse events makes no distinction between what might be simply typical variation in behavior rather than systematic changes in behavior attributable to study condition, and lacks coverage of the full spectrum of adverse events. Contemporaneous direct measurement of adverse events likely yield reasonably valid estimates of the rate of occurrence of the adverse events, while indirect measu-rement of adverse events may not be sufficiently reliable. Copyright © American Academy of Addiction Psychiatry.
Tetrault, Jeanette M; Moore, Brent A; Barry, Declan T; O'Connor, Patrick G; Schottenfeld, Richard; Fiellin, David A; Fiellin, Lynn E
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.
Addiction in developmental perspective: influence of conduct disorder severity, subtype, and attention-deficit hyperactivity disorder on problem severity and comorbidity in adults with opioid dependence.
Carpentier, Pieter-Jan; Knapen, Lieke J M; van Gogh, Mijke T; Buitelaar, Jan K; De Jong, Cornelis A J
This retrospective cross-sectional study examines whether conduct disorder and attention deficit hyperactivity disorder are associated with problem severity and psychiatric comorbidity in 193 middle-aged, opioid-dependent patients. Conduct disorder history, attention deficit hyperactivity disorder, psychiatric comorbidity, and problem severity were assessed by structured interviews and validated instruments. A conduct disorder history was confirmed in 116 (60.1%) participants. Conduct disorder patients had significantly higher problem severity scores, more frequent comorbid substance use disorders, and more severe psychiatric comorbidity. Attention deficit hyperactivity disorder was found to increase the risk for psychiatric comorbidity. Conduct disorder persistence is a useful model for elucidating complex psychiatric comorbidity of opioid-dependent patients.
Hartung, Daniel M; McCarty, Dennis; Fu, Rongwei; Wiest, Katharina; Chalk, Mady; Gastfriend, David R
Through improved adherence, once-monthly injectable extended-release naltrexone (XR-NTX) may provide an advantage over other oral agents approved for alcohol and opioid dependence treatment. The objective of this study was to evaluate cost and utilization outcomes between XR-NTX and other pharmacotherapies for treatment of alcohol and opioid dependence. Published studies were identified through comprehensive search of two electronic databases. Studies were included if they compared XR-NTX to other approved medicines and reported economic and healthcare utilization outcomes in patients with opioid or alcohol dependence. We identified five observational studies comparing 1,565 patients using XR-NTX to other therapies over 6 months. Alcohol dependent XR-NTX patients had longer medication refill persistence versus acamprosate and oral naltrexone. Healthcare utilization and costs was generally lower or as low for XR-NTX-treated patients relative to other alcohol dependence agents. Opioid dependent XR-NTX patients had lower inpatient substance abuse-related utilization versus other agents and $8170 lower total cost versus methadone.
Maremmani, Icro; Gerra, Gilberto
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. © American Academy of Addiction Psychiatry.
Mirakbari, Seyed Mostafa; Innes, Grant D; Christenson, Jim; Tilley, Jessica; Wong, Hubert
Patients frequently arrive in emergency departments (EDs) after being resuscitated from opioid overdose. Autopsy studies suggest that multidrug intoxication is a major risk factor for adverse outcomes after acute heroin overdose in patients. If this is true, there may be high-risk drug combinations that identify patients who require more intensive monitoring and prolonged observation. Our objective was to determine the impact of co-intoxication with alcohol, cocaine, or CNS depressant drugs on short-term adverse event rates in patients resuscitated from acute opioid overdose. Data were extracted from the database of a prospective opioid overdose cohort study conducted between May 1997 and 1999. Patients were prospectively enrolled if they received naloxone for presumed opioid overdose. Investigators gathered clinical, demographic, and other predictor variables, including co-intoxicants used. Patients were followed to identify prespecified adverse outcome events occurring within 24 h, and multiple logistic regression was used to determine the association of concomitant drug use on short-term adverse event rates. Of 1155 patients studied, 58 (5%) had pure opioid overdose and 922 (80%) reported co-intoxicants, including alcohol, cocaine, and CNS depressants. Overall, out of 1056 patients with known outcome status there were 123 major adverse events (11.6%) and 194 minor adverse events (18.4%). After adjustment for age, gender, HIV status, cardiovascular disease, pulmonary disease and diabetes, we found that coadministration of alcohol, cocaine, or CNS depressants, alone or in combination, was not associated with increased risk of death or adverse events during the 24 h follow-up period. In patients resuscitated from acute opioid overdose, short-term outcomes are similar for patients with pure opioid overdose and multidrug intoxications. A history of cointoxication cannot be used to identify high-risk patients who require more intensive ED monitoring or prolonged
Zahari, Zalina; Lee, Chee Siong; Ibrahim, Muslih Abdulkarim; Musa, Nurfadhlina; Mohd Yasin, Mohd Azhar; Lee, Yeong Yeh; Tan, Soo Choon; Mohamad, Nasir; Ismail, Rusli
Methadone is a substrate of the P-glycoprotein efflux transporter, which is encoded by ABCB1 (MDR1), and thus, ABCB1 polymorphisms may influence the transport of methadone at the blood-brain barrier, affecting its adverse effects. This study investigated the association between ABCB1 polymorphisms and cold pressor pain responses among opioid-dependent patients on methadone maintenance therapy (MMT). Malay male opioid-dependent patients receiving MMT (n = 148) were recruited. Cold pressor pain responses (pain threshold, pain tolerance, and pain intensity) were measured at 0, 2, 4, 8, 12, and 24 hours post-methadone dose. DNA was extracted from whole blood and genotyped for ABCB1 polymorphisms including 1236C>T (rs1128503), 2677G>T/A (rs2032582), and 3435C>T (rs1045642) using the allelic discrimination real-time polymerase chain reaction. Repeated-measure analysis of variance between-group analysis was used to compare the three cold pressor pain responses and ABCB1 polymorphisms (1236C>T, 2677G>T/A, and 3435C>T) according to genotypes and allelic additive models, genotype dominant and recessive models, haplotypes, and diplotypes. Patients with 2677 GG or 2677G allele had the lowest pain threshold compared with 2677G>T/A genotypes or alleles (p = .007 and .002, respectively). Haplotype analysis showed a significant association between ABCB1 haplotypes and pain threshold (p = .02). Patients with 2677G allele had the lowest pain tolerance compared to those with 2677T and 2677A alleles (2677G < 2677T < 2677A allele carriers; p = .05). In terms of pain intensity scores, patients with 2677 GG or 2677G allele had the highest scores compared to other 2677G>T/A genotypes or alleles (p = .04 and .008, respectively). Haplotype analysis revealed a significant difference between patients with CGC haplotype and those without this haplotype (p = .02). To the best of our knowledge, this study provides the first evidence that ABCB1 polymorphisms are associated with cold pressor pain
Soares, William E; Wilson, Donna; Rathlev, Niels; Lee, Joshua D; Gordon, Michael; Nunes, Edward V; O'Brien, Charles P; Friedmann, Peter D
Opioid use disorders have reached epidemic proportions, with overdose now the leading cause of accidental death in the United States. Extended release naltrexone (XR-NTX) has emerged as a medication treatment that reduces opioid use and craving. However, the effect of XR-NTX therapy on acute healthcare utilization, including emergency department visits and inpatient hospitalizations, remains uncertain. The objective of the current study is to evaluate hospital-based healthcare resource utilization in adults involved in the criminal justice system with a history of opioid use disorder randomized to XR-NTX therapy compared with treatment as usual (TAU) during a 6-month treatment phase and 12months post-treatment follow up. This retrospective exploratory analysis uses data collected in a published randomized trial. Comparisons of the number of emergency department visits and hospital admissions (for drug detox, psychiatric care and other medical reasons) were performed using chi square tests for any admission and negative binomial models for number of admissions. Of the 308 participants randomized, 96% had utilization data (76% complete 6months, 67% complete follow up). No significant differences were seen in overall healthcare utilization (IRR=0.88, 95%CI 0.63-1.23, p=0.45), or substance use-related drug detox hospitalizations (IRR=0.83, 95%CI 0.32-2.16, p=0.71). Despite having more participants report chronic medical problems at baseline (43% vs. 32%, p=0.05), those receiving XR-NTX generally experienced equivalent or lower rates of healthcare utilization compared to TAU. The XR-NTX group had significantly lower medical/surgical related hospital admissions (IRR=0.55, 95%CI 0.30-1.00, p=0.05) during the course of the entire study. XR-NTX did not significantly increase rates of healthcare utilization compared to TAU. Provider concerns regarding healthcare utilization should not preclude the consideration of XR-NTX as therapy for opioid use disorders. Copyright © 2017
Kren, Nancy P; Zagon, Ian S; McLaughlin, Patricia J
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. © 2015 by the Society for Experimental Biology and Medicine.
Fraser, Veronique; Boikos, Constantina; Richardson, Robin; Harper, Sam
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
Jones, Hendrée E; Heil, Sarah H; Tuten, Michelle; Chisolm, Margaret S; Foster, Julianne M; O'Grady, Kevin E; Kaltenbach, Karol
The relationship between cigarette smoking and neonatal and maternal clinical outcomes among opioid-agonist-treated pregnant patients is sparse. (1) Is smoking measured at study entry related to neonatal and maternal outcomes in pregnant women receiving opioid-agonist medication? (2) Is it more informative to use a multi-item measure of smoking dependence or a single-item measure of daily smoking? (3) Is the relationship between smoking at study entry and outcomes different between methadone and buprenorphine? Secondary analyses examined the ability of the tobacco dependence screener (TDS) and self-reported past 30-day daily average number of cigarettes smoked, both measured at study entry, to predict 12 neonatal and 9 maternal outcomes in 131 opioid-agonist-maintained pregnant participants. Past 30-day daily average number of cigarettes smoked was significantly positively associated with total amount of morphine (mg) needed to treat neonatal abstinence syndrome (NAS), Adjusted Odds Ratio (AOR)=1.06 (95% CI: 1.02, 1.09), number of days medicated for NAS, AOR=1.04 (95% CI: 1.01, 1.06), neonatal length of hospital stay in days, AOR=1.03 (95% CI: 1.01, 1.05), and negatively associated with 1-AOR=.995 (95% CI: .991,.999) and 5-min Apgar scores, AOR=.996 (95% CI: .994,.998). Simple effect tests of the two significant TDS×medication condition effects found TDS was unrelated to non-normal presentation and amount of voucher money earned in the methadone [AORs=.90 (95% CI: .74, 1.08, p>.24) and 1.0 (95% CI: .97, 1.03, p>.9)] but significant in the buprenorphine condition [AORs=1.57 (95% CI: 1.01, 2.45, p<.05) and 1.08 (95% CI: 1.04, 1.12, p<.01)]. Regardless of prenatal methadone or buprenorphine exposure, heavier cigarette smoking was associated with more compromised birth outcomes. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Makarenko, Iuliia; Mazhnaya, Alyona; Polonsky, Maxim; Marcus, Ruthanne; Bojko, Martha J; Filippovych, Sergii; Springer, Sandra; Dvoriak, Sergii; Altice, Frederick L
Coverage with opioid agonist treatments (OAT) that include methadone and buprenorphine is low (N=8400, 2.7%) for the 310,000 people who inject drugs (PWID) in Ukraine. In the context of widespread negative attitudes toward OAT in the region, patient-level interventions targeting the barriers and willingness to initiate OAT are urgently needed. A sample of 1179 PWID with opioid use disorder not currently on OAT from five regions in Ukraine was assessed using multivariable logistic regression for independent factors related to willingness to initiate OAT, stratified by their past OAT experience. Overall, 421 (36%) PWID were willing to initiate OAT. Significant adjusted odds ratios (aOR) for covariates associated with the willingness to initiate OAT common for both groups included: higher injection frequency (previously on OAT: aOR=2.7; never on OAT: aOR=1.8), social and family support (previously on OAT: aOR=2.0; never on OAT: aOR=2.0), and positive attitude towards OAT (previously on OAT: aOR=1.3; never on OAT: aOR=1.4). Among participants previously on OAT, significant correlates also included: HIV-negative status (aOR=2.6) and depression (aOR=2.7). Among participants never on OAT, however, living in Kyiv (aOR=4.8) or Lviv (aOR=2.7), previous imprisonment (aOR=1.5), registration at a Narcology service (aOR=1.5) and recent overdose (aOR=2.6) were significantly correlated with willingness to initiate OAT. These findings emphasize the need for developing interventions aimed to eliminate existing negative preconceptions regarding OAT among PWID with opioid use disorder in Ukraine, which should be tailored to meet the needs of specific characteristics of PWID in geographically distinct setting based upon injection frequency, prior incarceration, and psychiatric and HIV status. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Stancliff, Sharon; Joseph, Herman; Furst, Terry; Fong, Chunki; Comer, Sandra D.; Roux, Perrine
The aim of this pilot study was to assess the effectiveness of buprenorphine among marginalized opioid dependent individuals in terms of retention in and cycling in and out of a harm-reduction program. This pilot study enrolled 100 participants and followed them from November 2005 to July 2008. The overall proportion of patients retained in the program at the end of 3, 6, 9, and 12 months was 68%, 63%, 56%, and 42%, respectively. This pilot study demonstrated that buprenorphine could be successfully used to treat marginalized heroin users. PMID:22873189
Collins, Ruth; Boggs, Bob; Taggart, Noel; Kelly, Martin; Drillington, Aileen; Swanton, Ivy; Patterson, Diane
A pilot study was performed to assess the effectiveness of treatment in an opioid dependent population using the Maudsley Addiction Profile (MAP) tool1.The primary outcome of the study was to assess if treatment had an effect on 1. Substance use (quantity and frequency of use), 2. Health risk behaviour (injecting and sharing injecting equipment), 3. Health symptoms (physical and psychological) and 4. Personal /Social functioning (relationships, employment and crime). A secondary outcome was also sought.The study took place in 2007 in an inner city Belfast hospital specialising in the treatment of addiction, over a two month period. Fifteen patients, all opioid dependent and receiving outpatient community treatment, were interviewed at baseline (prior to the commencement of treatment) and at eight weeks follow up.Three patients were lost to follow up. Two patients stopped using altogether. Of the remaining patients, improvements were seen in most areas. There was a decrease in the use of heroin (71.28%), cocaine (99.72%), crack cocaine (100%), cannabis (99.94%) and alcohol (33.17%). There was a reduction in injecting behaviour (60.93%). Improvements were observed in health with a reduction in physical (41.35%) and psychological (35%) symptoms. Overall personal and social functioning improved regarding interactions with family and friends. A reduction in crime was also observed (75%).Opinions and views of staff involved in the study were generally positive.This patient population presents with multiple and complex needs. Effective treatment needs to address these needs and not just drug addiction alone. The Maudsley Addiction Profile tool highlights this.
Gelernter, Joel; Kranzler, Henry R.; Sherva, Richard; Koesterer, Ryan; Almasy, Laura; Zhao, Hongyu; Farrer, Lindsay A.
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
Maloney, Elizabeth; Degenhardt, Louisa; Darke, Shane; Nelson, Elliot C.
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…
Maloney, Elizabeth; Degenhardt, Louisa; Darke, Shane; Nelson, Elliot C.
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…
Chronic opioid therapy during pregnancy is perilous, but not simply because of neonatal effects: it is perilous because women are at particular risk for misprescription, misuse, dependence, overdose, and death. Opioids may be teratogens and should be avoided in the periconception period. Accidental childhood poisoning and purposeful teen experimentation are increased with opioid prescriptions in the home. Risks to pregnancy span the pre- and periconception period; neonatal risk following in utero opioid exposure is well documented. When the authors' patients request opioids for chronic pain, they care for them in a comprehensive and compassionate matter, which often will require therapeutic approaches other than chronic opioid therapy. Copyright © 2014 Elsevier Inc. All rights reserved.
Alam, Asim; Juurlink, David N
The objectives for preparing this article were to review the historical context and epidemiology surrounding the North American prescription opioid crisis, to summarize the evidence regarding the benefits and harms of long-term opioid therapy for non-cancer pain, and to outline ways in which anesthesiologists may help ameliorate the problem. We searched PubMed, Google Scholar, and EMBASE™ for relevant articles using various search terms, including pain, opioid epidemic, history of opioid use, perioperative care, and addiction. Related citations were further explored and searched depending on the specific subtopic of interest. In the 1980s and early 1990s, opioids were infrequently used for the treatment of chronic pain. Thereafter, however, physicians were gradually inculcated with the message that long-term opioid therapy was a safe and effective treatment option for patients with chronic non-cancer pain. Pharmaceutical companies supported this growing movement and employed aggressive and sometimes misleading marketing strategies for new opioid formulations. As a result, the practice of prescribing opioids flourished in the late 1990s. The surge in prescribing opioids was accompanied by a marked increase in opioid-related morbidity and mortality. This change in practice transpired despite the absence of randomized trials showing clinically significant benefit from the long-term use of opioids. Subsequently, however, a large and growing body of evidence has emerged quantifying the harms associated with long-term opioid therapy. Anesthesiologists widely prescribe opioids for acute and chronic pain; yet, as a group, they may be largely unaware of the current state of this growing epidemic and what role they can play to rectify this problem. Anesthesiologists are well positioned to take a leadership role in the management of postoperative discharge opioid therapy in an effort to curb the overutilization of opioids. Furthermore, anesthesiologists who regularly
Maher, D P; Wong, W; White, P F; McKenna, R; Rosner, H; Shamloo, B; Louy, C; Wender, R; Yumul, R; Zhang, V
Evidence suggests that opioid-sparing anaesthetic techniques might be associated with increased cancer-free postoperative survival. This could be related to suppression of natural killer cells by opioid analgesics in the perioperative period. This retrospective analysis tested the hypothesis that greater opioid use in the postoperative period is associated with a higher incidence of recurrences after surgery for lung cancer. The medical records of 99 consecutive patients who underwent video-assisted thoracoscopic surgery with lobectomy for Stage I or IIa biopsy-proven non-small-cell lung cancer (NSCLC) were reviewed. Perioperative information including patient characteristics, laboratory data, and surgical, anaesthetic, nursing, and pharmacy reports were collected. Doses of opioids administered intra-operatively and for the first 96 h after operation were converted into equianalgesic doses of oral morphine using a standard conversion table. Data were then compared with the National Cancer Registry's incidence of disease-free survival for 5 yr. A total of 99 patients with similar characteristics were included in the final analysis, 73 of whom were NSCLC recurrence-free at 5 yr and 26 had NSCLC recurrence within 5 yr. Total opioid dose during the 96 h postoperative period was 124 (101) mg of morphine equivalents in the cancer-free group and 232 mg (355) mg in the recurrence group (P=0.02). This retrospective analysis suggests an association between increased doses of opioids during the initial 96 h postoperative period with a higher recurrence rate of NSCLC within 5 yr. © The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: firstname.lastname@example.org.
Inui, Tadashi; Shimura, Tsuyoshi
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. Copyright © 2014 Elsevier B.V. All rights reserved.
Metz, Verena E; Jones, Jermaine D; Manubay, Jeanne; Sullivan, Maria A; Mogali, Shanthi; Segoshi, Andrew; Madera, Gabriela; Johnson, Kirk W; Comer, Sandra D
Ibudilast, a nonselective phosphodiesterase inhibitor, is used clinically in Asia for the treatment of asthma and poststroke dizziness. Recent preclinical studies have suggested that it also inhibits glial cell activation in rodents, and may alter opioid-mediated effects, including analgesia and withdrawal symptoms. The effects of ibudilast on the abuse potential of opioids in humans are largely unknown. The present study was designed to examine the influence of ibudilast on subjective (including drug craving), reinforcing, and analgesic effects of oxycodone in human volunteers diagnosed with opioid dependence (equivalent to moderate-severe opioid use disorder). Non-treatment-seeking opioid-dependent male volunteers (n=11) underwent an in-patient detoxification with morphine, followed by maintenance on placebo (0 mg b.i.d.) and active ibudilast (50 mg b.i.d.). Under each maintenance dose, six experimental sample and choice sessions were completed involving oral oxycodone administration (0, 15, and 30 mg/70 kg, p.o.). Subjective effects of oxycodone and drug craving were measured with visual analog scales (VAS) and a Drug Effects Questionnaire. The cold pressor test was used to produce pain, and a modified progressive-ratio choice procedure was used to measure the reinforcing effects of oxycodone. Under the active ibudilast condition compared with the placebo condition, ratings of drug liking following 15 mg of oxycodone were decreased significantly. The mean drug breakpoint value was also significantly lower in the active vs the placebo ibudilast condition under the 15 mg oxycodone condition, but not significantly lower under the 30 mg oxycodone condition. Heroin craving was significantly reduced under active ibudilast vs placebo, and similar effects were observed for tobacco and cocaine craving. Furthermore, mean subjective ratings of pain were lower in the active ibudilast condition. Our data suggest that ibudilast may be useful for treating opioid
Lucas, Gregory M; Beauchamp, Geetha; Aramrattana, Apinun; Shao, Yiming; Liu, Wei; Fu, Liping; Jackson, J Brooks; Celentano, David D; Richardson, Paul; Metzger, David
Buprenorphine/naloxone (BUP/NX) is not licenced for use in China or Thailand and there was little clinical experience with this drug combination in these countries at the inception of HIV Prevention Trial Network (HPTN) 058, a randomized trial comparing risk reduction counselling combined with either short-term or long-term medication assisted treatment with BUP/NX to prevent HIV infection and death amongst opioid-dependent injectors. We conducted a safety phase that included the first 50 subjects enrolled at each of the three initial study sites (N=150). Clinical and laboratory assessments were conducted at baseline and weekly for the first 4 weeks. Changes in laboratory parameters were estimated with random effects models. BUP/NX was well tolerated by study subjects and opioid withdrawal scores decreased substantially during the 3-day induction. Two participants experienced grade 3 clinical adverse events, which were categorized as probably not related to the study drug. Grade 2 or 3 increases in alanine aminotransferase (ALT) occurred in 25 (17%) subjects. The magnitude of ALT increase over 4-week follow-up was strongly associated with baseline ALT elevation. In Chinese and Thai opioid-dependent injectors, we found BUP/NX to be effective in reducing opioid withdrawal symptoms and safe during short-term use. ALT increases were observed over 4-week-follow-up, which are consistent with reports from Western populations. Long-term safety and efficacy evaluations are indicated. Copyright Â© 2011 Elsevier B.V. All rights reserved.
Edelman, E Jennifer; Chantarat, Tongtan; Caffrey, Sarah; Chaudhry, Amina; O'Connor, Patrick G; Weiss, Linda; Fiellin, David A; Fiellin, Lynn E
Opioid dependence is a major risk factor for HIV infection, however, the impact of buprenorphine/naloxone treatment on HIV risk behaviors among HIV-infected opioid-dependent patients is unknown. We conducted a longitudinal analysis of 303 HIV-infected opioid-dependent patients initiating buprenorphine/naloxone treatment. Outcomes included self-reported past 90-day needle-sharing and non-condom use. We assessed trends over the 12 months using the Cochran-Armitage trend test. Using generalized estimating equations, after multiple imputation, we determined factors independently associated with needle-sharing and non-condom use, including time-updated variables. We then conducted a mediation analysis to determine whether substance use explained the relationship between time since treatment initiation and needle-sharing. Needle-sharing decreased from baseline to the fourth quarter following initiation of buprenorphine/naloxone (9% vs. 3%, p<0.001), while non-condom use did not (23% vs. 21%, p=0.10). HIV risk behaviors did not vary based on the presence of a detectable HIV-1 RNA viral load. Patients who were homeless and used heroin, cocaine/amphetamines or marijuana were more likely to report needle-sharing. Heroin use fully mediated the relationship between time since treatment initiation and needle-sharing. Women, patients who identified as being gay/lesbian/bisexual, those married or living with a partner and who reported heroin or alcohol use were more likely to report non-condom use. Older patients were less likely to report non-condom use. While buprenorphine/naloxone is associated with decreased needle-sharing among HIV-infected opioid-dependent patients, sexual risk behaviors persist regardless of viral load. Targeted interventions to address HIV risk behaviors among HIV-infected opioid-dependent populations receiving buprenorphine/naloxone are needed. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Davis, Corey S; Carr, Derek
Opioid overdose, which has reached epidemic levels in the United States, is reversible by administration of the medication naloxone. Naloxone requires a prescription but is not a controlled substance and has no abuse potential. In the last half-decade, the majority of states have modified their laws to increase layperson access to the medication. We utilized a structured legal research protocol to systematically identify and review all statutes and regulations related to layperson naloxone access in the United States that had been adopted as of September, 2015. Each law discovered via this process was reviewed and coded by two trained legal researchers. As of September, 2015, 43 states and the District of Columbia have passed laws intended to increase layperson naloxone access. We categorized these laws into three domains: (1) laws intended to increase naloxone prescribing and distribution, (2) laws intended to increase pharmacy naloxone access, and (3) laws intended to encourage overdose witnesses to summon emergency responders. These laws vary greatly across states in such characteristics as the types of individuals who can receive a prescription for naloxone, whether laypeople can dispense the medication, and immunity provided to those who prescribe, dispense and administer naloxone or report an overdose emergency. Most states have now passed laws intended to increase layperson access to naloxone. While these laws will likely reduce overdose morbidity and mortality, the cost of naloxone and its prescription status remain barriers to more widespread access. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
McCarty, Dennis; Perrin, Nancy A; Green, Carla A; Polen, Michael R; Leo, Michael C; Lynch, Frances
Few health plans provide maintenance medication for opioid dependence. This study assessed the cost of treating opioid-dependent members in a commercial health plan and the impacts of methadone maintenance on costs of care. Individuals with diagnoses of opioid dependence (two or more diagnoses per year) and at least 9 months of health plan eligibility each year were extracted from electronic health records for the years 2000 through 2004 (1,518 individuals and 2,523 observations across the study period-some individuals were in multiple years). Analyses examined the patterns and costs of health care for three groups of patients: (1) one or more methadone visits during the year (n=1,298; 51%); (2) no methadone visits and 0 or 1 visits in the Addiction Medicine Department (n=370; 15%); (3) no methadone visits and 2 or more visits in addiction medicine (n=855; 34%). Primary care (86%), emergency department (48%) and inpatient (24%) visits were common. Mean total annual costs to the health plan were $11,200 (2004 dollars) per member per year. The health plan's costs for members receiving methadone maintenance were 50% lower ($7,163) when compared to those with two or more outpatient addiction treatment visits but no methadone ($14,157) and 62% lower than those with one or zero outpatient addiction treatment visits and no methadone treatment ($18,694). Use of opioid maintenance services was associated with lower total costs of care for opioid-dependent members in a commercial health plan. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
McCarty, Dennis; Perrin, Nancy A.; Green, Carla A.; Polen, Michael R.; Leo, Michael C.; Lynch, Frances
Background Few health plans provide maintenance medication for opioid dependence. This study assessed the cost of treating opioid dependent members in a commercial health plan and the impacts of methadone maintenance on costs of care. Methods Individuals with diagnoses of opioid dependence (two or more diagnoses per year) and at least nine months of health plan eligibility each year were extracted from electronic health records for the years 2000 through 2004 (1,518 individuals and 2,523 observations across the study period – some individuals were in multiple years). Analyses examined the patterns and costs of health care for three groups of patients: 1) one or more methadone visits during the year (n = 1,298; 51%); 2) no methadone visits and 0 or 1 visits in the Addiction Medicine Department (n = 370; 15%); and 3) no methadone visits and 2 or more visits in addiction medicine (n = 855; 34%). Results Primary care (86%), emergency department (48%) and inpatient (24%) visits were common. Mean total annual costs to the health plan were $11,200 (2004 dollars) per member per year. The health plan’s costs for members receiving methadone maintenance were 50% lower ($7,163) when compared to those with two or more outpatient addiction treatment visits but no methadone ($14,157) and 62% lower than those with one or zero outpatient addiction treatment visits and no methadone treatment ($18,694). Conclusions Use of opioid maintenance services was associated with lower total costs of care for opioid dependent members in a commercial health plan. PMID:20627427
Zweben, J E; Payte, J T
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. PMID:2190427
Daly, Elizabeth R; Dufault, Kenneth; Swenson, David J; Lakevicius, Paul; Metcalf, Erin; Chan, Benjamin P
Opioid-related overdoses and deaths in New Hampshire have increased substantially in recent years, similar to increases observed across the United States. We queried emergency department (ED) data in New Hampshire to monitor opioid-related ED encounters as part of the public health response to this health problem. We obtained data on opioid-related ED encounters for the period January 1, 2011, through December 31, 2015, from New Hampshire's syndromic surveillance ED data system by querying for (1) chief complaint text related to the words "fentanyl," "heroin," "opiate," and "opioid" and (2) opioid-related International Classification of Diseases ( ICD) codes. We then analyzed the data to calculate frequencies of opioid-related ED encounters by age, sex, residence, chief complaint text values, and ICD codes. Opioid-related ED encounters increased by 70% during the study period, from 3300 in 2011 to 5603 in 2015; the largest increases occurred in adults aged 18-29 and in males. Of 20 994 total opioid-related ED visits, we identified 18 554 (88%) using ICD code alone, 690 (3%) using chief complaint text alone, and 1750 (8%) using both chief complaint text and ICD code. For those encounters identified by ICD code only, the corresponding chief complaint text included varied and nonspecific words, with the most common being "pain" (n = 3335, 18%), "overdose" (n = 1555, 8%), "suicidal" (n = 816, 4%), "drug" (n = 803, 4%), and "detox" (n = 750, 4%). Heroin-specific encounters increased by 827%, from 4% of opioid-related encounters in 2011 to 24% of encounters in 2015. Opioid-related ED encounters in New Hampshire increased substantially from 2011 to 2015. Data from New Hampshire's ED syndromic surveillance system provided timely situational awareness to public health partners to support the overall response to the opioid epidemic.
Conroy, Elizabeth; Degenhardt, Louisa; Mattick, Richard P.; Nelson, Elliot C.
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…
Wong, Jeffrey G.; Holmboe, Eric S.; Becker, William C.; Fiellin, David A.; Jara, Gail B.; Martin, Judith
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…
Wong, Jeffrey G.; Holmboe, Eric S.; Becker, William C.; Fiellin, David A.; Jara, Gail B.; Martin, Judith
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…
Conroy, Elizabeth; Degenhardt, Louisa; Mattick, Richard P.; Nelson, Elliot C.
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…
Jones, Hendree E; Johnson, Rolley E; Jasinski, Donald R; O'Grady, Kevin E; Chisholm, Christian A; Choo, Robin E; Crocetti, Michael; Dudas, Robert; Harrow, Cheryl; Huestis, Marilyn A; Jansson, Lauren M; Lantz, Michael; Lester, Barry M; Milio, Lorraine
This study was designed to compare the neonatal abstinence syndrome (NAS) in neonates of methadone and buprenorphine maintained pregnant opioid-dependent women and to provide preliminary safety and efficacy data for a larger multi-center trial. This randomized, double-blind, double-dummy, flexible dosing, parallel-group controlled trial was conducted in a comprehensive drug-treatment facility that included residential and ambulatory care. Participants were opioid-dependent pregnant women and their neonates. Treatment involved daily administration of either sublingual buprenorphine or oral methadone using flexible dosing of 4-24 mg or 20-100 mg, respectively. Primary a priori outcome measures were: (1) number of neonates treated for NAS; (2) amount of opioid agonist medication used to treat NAS; (3) length of neonatal hospitalization; and (4) peak NAS score. Two of 10 (20%) buprenorphine-exposed and 5 of 11 (45.5%) methadone-exposed neonates were treated for NAS (p=.23). Total amount of opioid-agonist medication administered to treat NAS in methadone-exposed neonates was three times greater than for buprenorphine-exposed neonates (93.1 versus 23.6; p=.13). Length of hospitalization was shorter for buprenorphine-exposed than for methadone-exposed neonates (p=.021). Peak NAS total scores did not significantly differ between groups (p=.25). Results suggest that buprenorphine is not inferior to methadone on outcome measures assessing NAS and maternal and neonatal safety when administered starting in the second trimester of pregnancy.
... relievers for acute pain, and high daily doses. Addiction and Overdose Anyone who takes prescription opioids can ... in a primary care setting struggles with opioid addiction. 4,5,6 Once addicted, it can be ...
Katsuura, Yoshihiro; Heckmann, Jennifer A; Taha, Sharif A
Infusion of a μ-opioid receptor (MOR) agonist into the nucleus accumbens (NAcc) drives voracious food intake, an effect hypothesized to occur through increased tastant palatability. While intake of many palatable foods is elevated by MOR stimulation, this manipulation has a preferential effect on fatty food ingestion. Consumption of high-fat foods is increased by NAcc MOR stimulation even in rats that prefer a carbohydrate-rich alternative under baseline conditions. This suggests that NAcc MOR stimulation may not simply potentiate palatability signals and raises the possibility that mechanisms mediating fat intake may be distinct from those underlying intake of other tastants. The present study was conducted to investigate the physiological mechanisms underlying the effects of NAcc MOR stimulation on fatty food intake. In experiment 1, we analyzed lick microstructure in rats ingesting Intralipid to identify the changes underlying feeding induced by infusion of a MOR-specific agonist into the NAcc. MOR stimulation in the NAcc core, but not shell, increased burst duration and first-minute licks, while simultaneously increasing the rate and duration of Intralipid ingestion. These results suggest that MOR activation in the core increases Intralipid palatability and attenuates inhibitory postingestive feedback. In experiment 2, we measured the effects of MOR stimulation in the NAcc core on consumption of nonnutritive olestra. A MOR-specific agonist dose dependently increased olestra intake, demonstrating that caloric signaling is not required for hyperphagia induced by NAcc MOR stimulation. Feeding induced by drug infusion in both experiments 1 and 2 was blocked by a MOR antagonist. In experiment 3, we determined whether MOR activation in the NAcc core could attenuate sati