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in the Treatment of Adult Alcohol Dependence: A Systematic Literature Review and Meta-Analysis of Published and Unpublished Double-Blind Randomized Controlled Trials

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          Abstract

          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          Three reviewers searched for published and unpublished studies in Medline, the Cochrane Library, Embase, ClinicalTrials.gov, Current Controlled Trials, and bibliographies and by mailing pharmaceutical companies,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.

          Abstract

          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.

          Editors' Summary

          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.

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          Most cited references17

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          Selecting the language of the publications included in a meta-analysis: is there a Tower of Babel bias?

          Although they usually claim a very thorough search to retrieve every pertinent work, most meta-analyses published in English restrict their search to papers which were also published in English. We reviewed all the meta-analyses printed from 1 January 1991 to 1 April 1993 in 8 medical journals published in English and selected those who stated linguistic restrictions for inclusion in the analysis. The computerized search methods used in these meta-analyses were then duplicated looking specifically for publications written in the excluded languages. Each meta-analysis was then redone with identical statistical tests to determine if its conclusions would have been different if the paper(s) absent only for linguistic reasons had been included. A total of 36 meta-analyses of which 28 had language restrictions were identified. The computer searches yielded 19 papers scientifically acceptable but excluded for linguistic reasons. Eleven of these articles were retained as having the potential to modify their corresponding 7 meta-analyses. One meta-analysis which concluded that selective decontamination of the digestive tract in intensive care units did not produce a significant change in mortality between treatment and control patients (OR 0.70; 95% CI 0.45-1.09) would have arrived at a different conclusion (OR 0.67; 95% CI 0.47-0.95) if a paper written in German in a Swiss journal had been included in the analysis. Our study demonstrates that, in at least one out of 36 consecutive meta-analyses the exclusion of papers for linguistic reasons produced results different from those which would have been obtained if this exclusion criteria had not been used.
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            • Article: not found

            Attrition in randomized controlled clinical trials: methodological issues in psychopharmacology.

            Attrition is a ubiquitous problem in randomized controlled clinical trials (RCT) of psychotropic agents that can cause biased estimates of the treatment effect, reduce statistical power, and restrict the generalizability of results. The extent of the problem of attrition in central nervous system (CNS) trials is considered here and its consequences are examined. The taxonomy of missingness mechanisms is then briefly reviewed in order to introduce issues underlying the choice of data analytic strategies appropriate for RCTs with various forms of incomplete data. The convention of using last observation carried forward to accommodate attrition is discouraged because its assumptions are typically inappropriate for CNS RCTs, whereas multiple imputation strategies are more appropriate. Mixed-effects models often provide a useful data analytic strategy for attrition as do the pattern-mixture and propensity adjustments. Finally, investigators are encouraged to consider asking participants, at each assessment session, the likelihood of attendance at the subsequent assessment session. This information can be used to eliminate some of the very obstacles that lead to attrition, and can be incorporated in data analyses to reduce bias, but it will not eliminate all attrition bias.
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              • Article: not found

              Credibility of claims of subgroup effects in randomised controlled trials: systematic review.

              To investigate the credibility of authors' claims of subgroup effects using a representative sample of recently published randomised controlled trials. Systematic review. Core clinical journals, as defined by the National Library of Medicine, in Medline. Randomised controlled trials published in 2007. Using prespecified criteria, teams of trained reviewers independently judged whether authors claimed subgroup effects and the strength of their claims. Reviewers assessed each of these claims against 10 predefined criteria, developed through a search of existing criteria and a consensus process. Of 207 randomised controlled trials reporting subgroup analyses, 64 (31%) made claims for the primary outcome. Of those, 20 were strong claims and 28 claims of a likely effect. Authors included subgroup variables measured at baseline in 60 (94%) trials, used subgroup variable as a stratification factor at randomisation in 13 (20%), clearly prespecified their hypotheses in 26 (41%), correctly prespecified direction in 4 (6%), tested a small number of hypotheses in 28 (44%), carried out a test of interaction that proved statistically significant in 6 (9%), documented replication of a subgroup effect with previous related studies in 21 (33%), identified consistency of a subgroup effect across related outcomes in 19 (30%), and provided a compelling indirect evidence for the effect in 14 (22%). In the 19 trials making more than one claim, only one (5%) checked the independence of the interaction. Of the 64 claims, 54 (84%) met four or fewer of the 10 criteria. For strong claims, more than 50% failed each of the individual criteria, and only three (15%) met more than five criteria. Authors often claim subgroup effects in their trial report. However, the credibility of subgroup effects, even when claims are strong, is usually low. Users of the information should treat claims that fail to meet most criteria with scepticism. Trial researchers should report the conduct of subgroup analyses and provide sufficient evidence when claiming a subgroup effect or suggesting a possible effect.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Med
                PLoS Med
                plos
                plosmed
                PLoS Medicine
                Public Library of Science (San Francisco, CA USA )
                1549-1277
                1549-1676
                22 December 2015
                December 2015
                : 12
                : 12
                : e1001924
                Affiliations
                [1 ]INSERM Centre d’Investigation Clinique 1414, Centre Hospitalier Universitaire de Rennes, Rennes, France
                [2 ]Laboratoire de Pharmacologie Expérimentale et Clinique, Faculté de Médecine, Université de Rennes 1, Rennes, France
                [3 ]Département de Médecine Générale, Faculté de Médecine et de Pharmacie, Université de Poitiers, Poitiers, France
                University of Queensland, AUSTRALIA
                Author notes

                I have read the journal's policy and the authors of this manuscript have the following competing interests: All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that (1) No authors have support from any company for the submitted work; (2) PC was a trainee in Servier (pharmacokinetics department) for 6 months in 2013; LB, BR, RJM, BE have no relationships with any company that might have an interest in the submitted work in the previous 3 years; NF has relationships (Travel/accommodations expenses covered/reimbursed) with Servier, BMS, Lundbeck and Janssen who might have an interest in the work submitted in the previous 3 years, he was invited by Lundbeck to present an oral communication at a symposium on the neurobiology of alcohol dependence in 2014, he explicitly asked not to be paid for this presentation (and indeed was not paid); (3) No author’s spouses, partners, or children have any financial relationships that could be relevant to the submitted work; and (4) none of the authors has any non-financial interests that could be relevant to the submitted work.

                Conceived and designed the experiments: NF PC. Performed the experiments: PC NF LB. Analyzed the data: PC NF. Contributed reagents/materials/analysis tools: NF PC LB. Wrote the first draft of the manuscript: NF PC. Contributed to the writing of the manuscript: LB RJM BR BE. Agree with the manuscript’s results and conclusions: PC LB RJM BR BE NF. All authors have read, and confirm that they meet, ICMJE criteria for authorship.

                Article
                PMEDICINE-D-15-01682
                10.1371/journal.pmed.1001924
                4687857
                26694529
                a604713a-1556-45b0-ac3d-34104b2c52ec
                © 2015 Palpacuer et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 5 June 2015
                : 10 November 2015
                Page count
                Figures: 2, Tables: 4, Pages: 17
                Funding
                Supported by a local grant from Rennes CHU (CORECT : COmité de la Recherche Clinique et Translationelle). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                All data are in the S1 and S2 supporting information files. Study reports can be requested from the “Access to Documents” service at the European Medicines Agency ( http://www.ema.europa.eu/ema/index.jsp?curl=pages/document_library/document_listing/document_listing_000312.jsp&mid=WC0b01ac05807a4177).

                Medicine
                Medicine

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