Comparing Nalmefene and Naltrexone in Alcohol Dependence: Are there any Differences? Results from an Indirect Meta-analysis – Comment to Naudet

Florian Naudet has drawn up a letter to the editor [ 1 ] to comment on our paper “Comparing Nalmefene and Naltrexone in Alcohol Dependence: Are there any Differences? Results from an Indirect Meta-analysis” [ 2 ] in this journal. We would like to comment on this manuscript. The aim of our paper was to compare nalmefene and naltrexone in efficacy and safety parameters. Due to a lack of a direct clinical comparison of both drugs, we performed an indirect comparison of nalmefene and naltrexone. The methodological approach is generally accepted in the scientific community as discussed in the publication. Naudet listed some results of the meta-analysis and concluded that the superiority of nalmefene over naltrexone shows no statistically significant difference in any endpoint. It is relevant to differentiate the relevance of the patient-relevant outcome parameters. We analyzed the endpoints that are recommended by the EMA as primary endpoints in the “Guideline on the development of medicinal products for the treatment of alcohol dependence” (EMA, 2010) [ 3 ]. Primary endpoints in clinical trials with the goal of intermediate harm reduction are change to baseline in total consumption of alcohol as well as reduction in number of heavy drinking days. Both are considered primary endpoints (chapter 4.2.1, EMA 2010) [ 3 ]. Both endpoints can be measured in multiple ways as listed in Table 1 of the publication. Thus we decided to perform the meta-analysis as a cluster analysis. This is a generally accepted approach (see “Discussion” section of our paper). The “quantity of drinking” endpoint represents the more important endpoint. Table 1 Effect sizes Cluster Week Nalmefene Naltrexone Difference Frequency 24 –0.336 –0.145 –0.191 12 –0.275 –0.071 –0.204 Quantity 24 –0.372 –0.108 –0.264 12 –0.371 –0.227 –0.144 The EMA recommends a treatment duration in confirmatory trials with the goal of harm reduction of at least 3 months (chapter 4.3.3, EMA 2010) [ 3 ]. That is why the result “change from baseline in the cluster quantity of drinking” after 24 weeks of treatment is the most relevant result (p=0.022). The 12-week results are data from sensitivity analyses. Naudet cites as problematic that we selected RCTs according the