Efficacy and safety of naltrexone for amfetamine and methamfetamine use disorder: a systematic review of randomized controlled trials

Introduction: Amfetamine and methamfetamine abuse remains a prevalent health problem, increasing the burden on healthcare. Naltrexone, a mu-opioid receptor antagonist, has been suggested as a promising treatment for amfetamine and methamfetamine use disorder. Objective: To review the current evidence for the efficacy and safety of naltrexone as a pharmacological treatment for amfetamine and methamfetamine use disorder. The primary outcome was defined as abstinence or reduction of use. Secondary outcomes were, attenuated "positive" subjective effects (e.g., "feel good," "craving," etc.) of amfetamine or methamfetamine after naltrexone treatment, adverse events and physiological changes (e.g., blood pressure, heart rate). Methods: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A systematic literature search was conducted on 2 April 2017, and updated on 31 March 2018. Records were retrieved from databases including PubMed, EMBASE Classic plus EMBASE 1980 via Ovid, and the databases were searched using keywords and/or headings: (naltrexone AND amfetamine AND dependence) OR (naltrexone AND amfetamine AND craving) OR (vivitrol AND amfetamine) OR (revia AND amfetamine) OR (naltrexone AND amfetamine) OR (naltrexone AND methamfetamine dependence) OR (naltrexone AND methamfetamine AND craving) OR (vivitrol AND methamfetamine) OR (revia AND methamfetamine) OR (naltrexone AND ice) OR (naltrexone AND crystal meth) OR (naltrexone AND methamfetamine). Studies investigating the effects of naltrexone on amfetamine or methamfetamine use were eligible for inclusion. All studies were rated as low risk of bias using the Cochrane tool for risk of bias. Results: Among 591 identified studies, there were four randomized controlled trials. Two studies investigated the effects of naltrexone on amfetamine use disorder and two on methamfetamine use. Compared to placebo, the abstinence rate was increased significantly (p < 0.05) by naltrexone in one of two amfetamine studies, whereas there was no statistical difference in the only study reporting methamfetamine use. In one out of two amfetamine studies, naltrexone significantly attenuated either craving levels or subjective effects (e.g., "want more," "like effect") relative to placebo (p < 0.05). Additionally, only in one of two methamfetamine studies did naltrexone produce a significant reduction (p < 0.05) in craving levels or attenuated subjective effects. Both amfetamine and methamfetamine studies showed good tolerability of naltrexone, with few adverse events seen. Conclusions: There is presently insufficient evidence to support the use of naltrexone in amfetamine and metamfetamine use disorders. There is a compelling need for high-quality studies to further evaluate the potential use of naltrexone.