Abstract
BackgroundNalmefene is a recent option in alcohol dependence treatment. Its approval was controversial. We conducted a systematic review and meta-analysis of the aggregated data (registered as PROSPERO 2014:CRD42014014853) to compare the harm/benefit of nalmefene versus placebo or active comparator in this indication.Methods and FindingsThree reviewers searched for published and unpublished studies in Medline, the Cochrane Library, Embase, ClinicalTrials.gov, Current Controlled Trials, and bibliographies and by mailing pharmaceutical companies, the European Medicines Agency (EMA), and the US Food and Drug Administration. Double-blind randomized clinical trials evaluating nalmefene to treat adult alcohol dependence, irrespective of the comparator, were included if they reported (1) health outcomes (mortality, accidents/injuries, quality of life, somatic complications), (2) alcohol consumption outcomes, (3) biological outcomes, or (4) treatment safety outcomes, at 6 mo and/or 1 y. Three authors independently screened the titles and abstracts of the trials identified. Relevant trials were evaluated in full text. The reviewers independently assessed the included trials for methodological quality using the Cochrane Collaboration tool for assessing risk of bias. On the basis of the I2 index or the Cochrane’s Q test, fixed or random effect models were used to estimate risk ratios (RRs), mean differences (MDs), or standardized mean differences (SMDs) with 95% CIs. In sensitivity analyses, outcomes for participants who were lost to follow-up were included using baseline observation carried forward (BOCF); for binary measures, patients lost to follow-up were considered equal to failures (i.e., non-assessed patients were recorded as not having responded in both groups). Five randomized controlled trials (RCTs) versus placebo, with a total of 2,567 randomized participants, were included in the main analysis. None of these studies was performed in the specific population defined by the EMA approval of nalmefene, i.e., adults with alcohol dependence who consume more than 60 g of alcohol per day (for men) or more than 40 g per day (for women). No RCT compared nalmefene with another medication. Mortality at 6 mo (RR = 0.39, 95% CI [0.08; 2.01]) and 1 y (RR = 0.98, 95% CI [0.04; 23.95]) and quality of life at 6 mo (SF-36 physical component summary score: MD = 0.85, 95% CI [−0.32; 2.01]; SF-36 mental component summary score: MD = 1.01, 95% CI [−1.33; 3.34]) were not different across groups. Other health outcomes were not reported. Differences were encountered for alcohol consumption outcomes such as monthly number of heavy drinking days at 6 mo (MD = −1.65, 95% CI [−2.41; −0.89]) and at 1 y (MD = −1.60, 95% CI [−2.85; −0.35]) and total alcohol consumption at 6 mo (SMD = −0.20, 95% CI [−0.30; −0.10]). An attrition bias could not be excluded, with more withdrawals for nalmefene than for placebo, including more withdrawals for safety reasons at both 6 mo (RR = 3.65, 95% CI [2.02; 6.63]) and 1 y (RR = 7.01, 95% CI [1.72; 28.63]). Sensitivity analyses showed no differences for alcohol consumption outcomes between nalmefene and placebo, but the weight of these results should not be overestimated, as the BOCF approach to managing withdrawals was used.ConclusionsThe value of nalmefene for treatment of alcohol addiction is not established. At best, nalmefene has limited efficacy in reducing alcohol consumption.
Highlights
The net effect of alcohol consumption on health is detrimental in terms of global mortality and global disability [1]
While this approach still raises questions [2,3], nalmefene, an opioid antagonist, was recently approved by the European Medicines Agency (EMA) [4] for the treatment of alcohol dependence in order to help reduce alcohol consumption in adults who consume more than 60 g of alcohol per day or more than 40 g per day
The Swedish Dental and Pharmaceutical Benefits Agency concluded that the lack of advantage of nalmefene compared to existing treatments suggested that it did not warrant recommendation for reimbursement [9]
Summary
The net effect of alcohol consumption on health is detrimental in terms of global mortality and global disability [1]. Harm reduction by controlled drinking is a concept that has been developed as an alternative to abstinence. While this approach still raises questions [2,3], nalmefene, an opioid antagonist, was recently approved by the European Medicines Agency (EMA) [4] for the treatment of alcohol dependence in order to help reduce alcohol consumption in adults who consume more than 60 g of alcohol per day (for men) or more than 40 g per day (for women). The French National Authority for Health Transparency Committee was cautious and considered that nalmefene provided a minor improvement in actual benefit (ranking IV on a scale from I to V, with V = no improvement) compared to psychosocial support alone in the treatment of alcohol dependence. Alcohol dependency sometimes runs in families, it can be triggered by stressful events, and the condition can damage health, emotional stability, finances, careers, and relationships
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