Alpha2 Adrenergic Agonists for the Management of Opioid Withdrawal

ArticleinCochrane database of systematic reviews (Online) 3(2):CD002024 · February 2009with22 Reads
DOI: 10.1002/14651858.CD002024.pub3 · Source: PubMed
Withdrawal is a necessary step prior to drug-free treatment or as the end point of long-term substitution treatment. To assess the effectiveness of interventions involving the use of alpha2-adrenergic agonists to manage opioid withdrawal. We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2008), MEDLINE (January 1966-July 2008), EMBASE (January 1985-2008 Week 31), PsycINFO (1967 to 7 August 2008) and reference lists of articles. We also contacted manufacturers in the field. Controlled trials comparing alpha2-adrenergic agonists with reducing doses of methadone, symptomatic medications or placebo, or comparing different alpha2-adrenergic agonists to modify the signs and symptoms of withdrawal in participants who were opioid dependent. One author assessed studies for inclusion and undertook data extraction. Inclusion decisions and the overall process were confirmed by consultation between all authors. Twenty-four studies, involving 1631 participants, were included. Twenty-one were randomised controlled trials.Thirteen studies compared a treatment regime based on an alpha2-adrenergic agonist with one based on reducing doses of methadone. Diversity in study design, assessment and reporting of outcomes limited the extent of quantitative analysis.Alpha2-adrenergic agonists are more effective than placebo in ameliorating withdrawal, and despite higher rates of adverse effects, are associated with significantly higher rates of completion of treatment.For the comparison of alpha2-adrenergic agonist regimes with reducing doses of methadone, there were insufficient data for statistical analysis, but withdrawal intensity appears similar to or marginally greater with alpha2-adrenergic agonists, while signs and symptoms of withdrawal occur and resolve earlier. Participants stay in treatment longer with methadone. No significant difference was detected in rates of completion of withdrawal with adrenergic agonists compared to reducing doses of methadone, or clonidine compared to lofexidine. Clonidine is associated with more adverse effects than reducing doses of methadone. Lofexidine does not reduce blood pressure to the same extent as clonidine, but is otherwise similar to clonidine Clonidine and lofexidine are more effective than placebo for the management of withdrawal from heroin or methadone. No significant difference in efficacy was detected for treatment regimes based on clonidine or lofexidine, and those based on reducing doses of methadone over a period of around 10 days but methadone is associated with fewer adverse effects than clonidine, and lofexidine has a better safety profile than clonidine.
    • "However, the adverse effects of some adjunctive medications currently utilized to treat withdrawal symptoms limit their clinical utility. For example, adrenergic agonists, such as clonidine and lofexidine, produce negative hemodynamic effects (Gowing et al. 2003), and benzodiazepines have significant abuse liability risks (Lintzeriz & Nielson 2010). The current study was designed to explore the therapeutic potential of ibudilast, a glial cell modulator, as a non-opioid adjunct medication to attenuate withdrawal symptoms during detoxification. "
    [Show abstract] [Hide abstract] ABSTRACT: 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. © 2015 Society for the Study of Addiction.
    Full-text · Article · May 2015
    • "Importantly, even when combining several signs into a global score, we could not detect a significant withdrawal syndrome in SvPas (Fig. 3c). We speculate that this striking insensitivity might be explained by low expression of the mu opioid receptor along noradrenergic pathways critically mediating opiate physical dependence (Delfs et al. 2000; Gowing et al. 2014). Heroin abstinence leads to low sociability and despair-like responses in a strain-dependent manner The present study failed to detect any effect of heroin abstinence on anxiety-like behaviors in any of the three strains examined, in two paradigms (LD and OF). "
    [Show abstract] [Hide abstract] ABSTRACT: Opiate addiction is a brain disorder emerging through repeated intoxication and withdrawal episodes. Epidemiological studies also indicate that chronic exposure to opiates may lead in susceptible individuals to the emergence of depressive symptoms, strongly contributing to the severity and chronicity of addiction. We recently established a mouse model of heroin abstinence, characterized by the development of depressive-like behaviors following chronic heroin exposure. While genetic factors regulating immediate behavioral responses to opiates have been largely investigated, little is known about their contribution to long-term emotional regulation during abstinence. Here, we compared locomotor stimulation and physical dependence induced by heroin exposure, as well as emotional dysfunction following abstinence, across mice strains with distinct genetic backgrounds. Mice from three inbred strains (C57BL/6J, Balb/cByJ, and 129S2/SvPas) were exposed to an escalating chronic heroin regimen (10-50 mg/kg). Independent cohorts were used to assess drug-induced locomotor activity during chronic treatment, naloxone-precipitated withdrawal at the end of chronic treatment, and emotional-like responses after a 4-week abstinence period. Distinct behavioral profiles were observed across strains during heroin treatment, with no physical dependence and low locomotor stimulation in 129S2/SvPas. In addition, different behavioral impairments developed during abstinence across the three strains, with increased despair-like behavior in 129S2/SvPas and Balb/cByJ, and low sociability in 129S2/SvPas and C57BL/6J. Our results indicate that depressive-like behaviors emerge during heroin abstinence, whatever the severity of immediate behavioral responses to the drug. In addition, inbred mouse strains will allow studying several aspects of mood-related deficits associated with addiction.
    Article · Dec 2014
    • "A RSS of 1-2 or 5-6 occurred in more number of observations in Group C than in Group D. The short distribution half-life of dexmedetomidine (6 min) makes it an ideal drug for IV titration. [4] This could be the reason for the rapid titration to target sedation and the lesser number of observations pertaining to inadequate sedation in Group D. Although more than 60% patients of both groups attained acceptable sedation, signifi cantly more number of patients in clonidine treated group required additional sedation by diazepam on account , September 28, 2016, IP:] of fall of BP on increasing infusion rate to maximum set level. Requirement of additional sedation in this group was about 43% more than dexmedetomidine treated group. "
    [Show abstract] [Hide abstract] ABSTRACT: Background and Objectives:Patients on mechanical ventilation in intensive care unit (ICU) are often uncomfortable because of anxiety, pain, and endotracheal intubation; therefore, require sedation. Alpha-2 agonists are known to produce sedation. We compared clonidine and dexmedetomidine as sole agents for sedation.Study Design:Prospective, randomized, controlled open-label study.Materials and Methods:A total of 70 patients requiring a minimum of 12 h of mechanical ventilation with concomitant sedation, were randomly allocated into two groups. Group C (n = 35) received intravenous (IV) clonidine (1 μg/kg/h titrated up to 2 μg/kg/h to attain target sedation), and Group D (n = 35) received IV dexmedetomidine for sedation (loading 0.7 μg/kg and maintenance 0.2 μg/kg/h titrated up to 0.7 μg/kg/h to achieve target sedation). A Ramsay Sedation Score of 3-4 was considered as target sedation. Additional sedation with diazepam was given when required to achieve target sedation. The quality of sedation, hemodynamic changes and adverse effects were noted and compared between the two groups.Results:Target sedation was achieved in 86% observations in Group D and 62% in Group C (P = 0.04). Additional sedation was needed by more patients in Group C compared with Group D (14 and 8 in Groups C and D, respectively, P = 0.034), mainly due to concomitant hypotension on increasing the dose of clonidine. Hypotension was the most common side-effect in Group C, occurring in 11/35 patients of Group C and 3/35 patients of Group D (P = 0.02). Rebound hypertension was seen in four patients receiving clonidine, but none in receiving dexmedetomidine.Conclusion:Both clonidine and dexmedetomidine produced effective sedation; however, the hemodynamic stability provided by dexmedetomidine gives it an edge over clonidine for short-term sedation of ICU patients.
    Full-text · Article · Jul 2014
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