Epidemiologic and Molecular Pathophysiology of Chronic Opioid Dependence and the Place of Naltrexone Extended-Release Formulations in its Clinical Management

School of Psychiatry and Clinical Neurosciences, University of Western Australia.
Substance Abuse: Research and Treatment 09/2012; 6(1):115-33. DOI: 10.4137/SART.S9031
Source: PubMed


Naltrexone implants and depot injections (NI) are a novel form of treatment for opiate dependence (OD). Major questions relate to their absolute and relative efficacy and safety. Opportunely, six recent clinical trial data from several continents have uniformly provided dramatic evidence of the potent, dose-related and highly significant efficacy of NI, with minimal or manageable accompanying toxicity and safety concerns. The opiate-free lifestyle is attained significantly more often with NI adjusted O.R. = 6.00 (95% C.I. 3.86-9.50), P < 10(-10). Other drug use and drug craving are also rapidly reduced. The optimum manner in which to commence NI remains to be established. Of particular relevance is the relative safety of NI compared to the chronic opiate agonists (COA) usually employed, as the long-term toxicity of COA is only just being elucidated. Large population-based studies have found elevated rates of cardiovascular disease, six cancers, liver and respiratory disease, and all-cause mortality in COA. Whilst opiates have been shown to trigger numerous molecular pathways, the most interesting is the demonstration that the opiate morphinan's nucleus binds to the endotoxin groove of the TLR4-MD2 heterodimer. This has the effect of triggering a low grade endotoxaemic-like state, which over time may account for these protean clinical findings, an effect which is reversed by opiate antagonists. This emerging evidence suggests an exciting new treatment paradigm for OD and a corresponding increase in the role of NI in treatment.

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Available from: Albert Reece, Dec 18, 2013
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    • "In 2010, a review of naltrexone implants by the Australian National Health and Medical Research Council (NHMRC) concurred with the 2008 review that there was insufficient evidence to determine the efficacy of this approach, either alone or in comparison with conventional , first-line treatments such as opioid substitution therapy (OST) [4]. More recently, a review of sustained-release naltrexone formulations concluded that there was evidence of the safety, efficacy and patient acceptability of naltrexone implants [5]; however, this review failed to include all published studies of naltrexone implants, did not assess the quality of the evidence and did not employ weighting in meta-analysis. It also did not acknowledge the major limitation that none of the reviewed studies compared naltrexone implants with OST. "
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    ABSTRACT: Naltrexone implants are used to treat opioid dependence, but their safety and efficacy remain poorly understood. We systematically reviewed the literature to assess the safety and efficacy of naltrexone implants for treating opioid dependence. Studies were eligible if they compared naltrexone implants with another intervention or placebo. Examined outcomes were induction to treatment, retention in treatment, opioid and non-opioid use, adverse events, non-fatal overdose and mortality. Quality of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach. Data from randomised studies were combined using meta-analysis. Data from non-randomised studies were presented narratively. Five randomised trials (n = 576) and four non-randomised studies (n = 8358) were eligible for review. The quality of the evidence ranged from moderate to very low. Naltrexone implants were superior to placebo implants [risk ratio (RR): 0.57; 95% confidence interval (CI) 0.48, 0.68; k = 2] and oral naltrexone (RR: 0.57; 95% CI 0.47, 0.70; k = 2) in suppressing opioid use. No difference in opioid use was observed between naltrexone implants and methadone maintenance (standardised mean difference: -0.33; 95% CI -0.93, 0.26; k = 1); however, this finding was based on low-quality evidence from one study. The evidence on safety and efficacy of naltrexone implants is limited in quantity and quality, and the evidence has little clinical utility in settings where effective treatments for opioid dependence are used. Better designed research is needed to establish the safety and efficacy of naltrexone implants. Until such time, their use should be limited to clinical trials. [Larney S, Gowing L, Mattick RP, Farrell M, Hall W, Degenhardt L. A systematic review and meta-analysis of naltrexone implants for the treatment of opioid dependence. Drug Alcohol Rev 2013].
    Full-text · Article · Dec 2013 · Drug and Alcohol Review