Risks and Benefits of Nalmefene in the Treatment of Adult Alcohol Dependence: A Systematic Literature Review and Meta-Analysis of Published and Unpublished Double-Blind Randomized Controlled Trials

Background: Nalmefene 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 Methods and Findings: Three reviewers searched for published and unpublished studies in Medline, the Cochrane Library, Embase, ClinicalTrials.gov, Current Controlled Trials, and bibliographies and by mailing pharmaceutical companies,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. Conclusions: The value of nalmefene for treatment of alcohol addiction is not established. At best, nalmefene has limited efficacy in reducing alcohol consumption. In a systematic review and meta-analysis, Florian Naudet and colleagues assess whether medication with the opioid antagonist nalmefene can reduce consumption and other outcomes of alcohol addiction.Background: Many people enjoy an occasional alcoholic drink. But because alcohol is an addictive substance, some people (around one in 12 people in the US, for example) develop alcohol dependency (alcoholism). Such people have an excessive desire to drink or have lost control over their alcohol use, and may find it hard to relax or enjoy themselves without having a drink. As well as becoming psychologically dependent on alcohol, they can become physically dependent and may show withdrawal symptoms such as sweating, shaking, and nausea—or even delirium tremens, a psychotic condition that involves tremors, hallucinations, anxiety, and disorientation—when they attempt to reduce their drinking. Indeed, severely dependent drinkers often drink to relieve their withdrawal symptoms (“relief drinking”). Although alcohol dependency sometimes runs in families, it can also be triggered by stressful events, and the condition can damage health, emotional stability, finances, careers, and relationships. Why Was This Study Done?: To reduce harm, alcohol-dependent individuals are usually advised to abstain from drinking, but controlled (moderate) drinking may also be helpful. To help people reduce their alcohol consumption, the European Medicines Agency recently approved nalmefene—a drug that blocks the body’s opioid receptors and reduces the craving for alcohol—for use in the treatment of alcohol dependence in adults who consume more than 60 g (for men) or 40 g (for women) of alcohol per day (a small glass of wine contains about 12 g of alcohol; a can of beer contains about 16 g). However, several expert bodies have concluded that nalmefene shows no benefit over naltrexone, an older treatment for alcohol dependency, and do not recommend its use for this indication. Here, the researchers investigate the risks and benefits of nalmefene in the treatment of alcohol dependency in adults by undertaking a systematic review and meta-analysis of double-blind randomized controlled trials (RCTs) of nalmefene for this indication. A systematic review uses predefined criteria to identify all the research on a given topic, and a meta-analysis combines the results of several studies; a double-blind RCT compares outcomes in people chosen at random to receive different treatments without the researchers or the participants knowing who received which treatment until the end of the trial. What Did the Researchers Do and Find?: The researchers identified five RCTs that met the criteria for inclusion in their study. All five RCTs (which involved 2,567 participants) compared the effects of nalmefene with a placebo (dummy drug); none was undertaken in the population specified by the European Medicines Agency approval. Among the health outcomes examined in the meta-analysis, there were no differences between participants taking nalmefene and those taking placebo in mortality (death) after six months or one year of treatment, in the quality of life at six months, or in a summary score indicating mental health at six months. The RCTs included in the meta-analysis did not report other health outcomes such as accidents. Participants taking nalmefene had fewer heavy drinking days per month at six months and one year of treatment than participants taking placebo, and their total alcohol consumption was lower. However, more people withdrew from the nalmefene groups than from the placebo groups, often for safety reasons. Thus, attrition bias—selection bias caused by systematic differences between groups in withdrawals from a study that can affect the accuracy of the study’s findings—cannot be excluded. Indeed, when the researchers undertook an analysis in which they allowed for withdrawals, the alcohol consumption outcomes did not differ between the treatment groups. What Do These Findings Mean?: These findings show that there is no high-grade evidence currently available from RCTs to support the use of nalmefene for harm reduction among people being treated for alcohol dependency. In addition, they provide little evidence to support the use of nalmefene to reduce alcohol consumption among this population. Thus, the value of nalmefene for the treatment of alcohol addiction is not established. Importantly, these findings reveal a lack of information on clinically relevant outcomes in the evidence that led to nalmefene approval by the European Medicines Agency. Thus, these findings also call into question the decisions of this and other regulatory and advisory bodies that have approved nalmefene on the basis of the available evidence from RCTs, and highlight the need for further RCTs of nalmefene compared to placebo and naltrexone for the indication specified in the market approval. Additional Information: This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001924.