Efficacy of As-Needed Nalmefene in Alcohol-Dependent Patients With at Least a High Drinking Risk Level

Results From a Subgroup Analysis of Two Randomized Controlled 6-Month Studies

Wim van den Brink; Henri-Jean Aubin; Anna Bladström; Lars Torup; Antoni Gual; Karl Mann

Disclosures

Alcohol Alcohol. 2013;48(5):570-578. 

In This Article

Abstract and Introduction

Abstract

Aims: The aim of the study was to investigate the efficacy and safety of as-needed use of nalmefene 18 mg versus placebo in reducing alcohol consumption in patients who did not reduce their alcohol consumption after an initial assessment, i.e. the pooled subgroup of patients with at least a high drinking risk level (men: >60 g/day; women: >40 g/day) at both screening and randomization from the two randomized controlled 6-month studies ESENSE 1 (NCT00811720) and ESENSE 2 (NCT00812461).

Methods: Nalmefene 18 mg and placebo were taken on an as-needed basis. All the patients also received a motivational and adherence-enhancing intervention (BRENDA). The co-primary outcomes were number of heavy drinking days (HDDs) and mean total alcohol consumption (g/day) in Month 6 measured using the Timeline Follow-back method. Additionally, data on clinical improvement, liver function and safety were collected throughout the study.

Results: The pooled population consisted of 667 patients: placebo n = 332; nalmefene n = 335. There was a superior effect of nalmefene compared with placebo in reducing the number of HDDs [treatment difference: −3.2 days (95% CI: −4.8; −1.6); P < 0.0001] and total alcohol consumption [treatment difference: −14.3 g/day (−20.8; −7.8); P < 0.0001] at Month 6. Improvements in clinical status and liver parameters were greater in the nalmefene group compared with the placebo group. Adverse events and adverse events leading to dropout were more common with nalmefene than placebo.

Conclusion: As-needed nalmefene was efficacious in reducing alcohol consumption in patients with at least a high drinking risk level at both screening and randomization, and the effect in this subgroup was larger than in the total population.

Introduction

Nalmefene is an opioid system modulator with antagonist activity at the μ and δ receptors and partial agonist activity at the κ receptor (Bart et al., 2005). Nalmefene as-needed has been shown to reduce the total amount of alcohol consumption and number of heavy drinking days (HDDs) and to improve liver function and clinical status in two published 6-month studies in patients with alcohol dependence (Gual et al., 2013; Mann et al., 2013).

Importantly, a large improvement in both 6-month trials was observed in the first 2 weeks between screening and the start of the treatment: in the Mann et al. study, 18% of the patients greatly reduced their alcohol consumption prior to treatment, whereas this was true for 33% of the patients in the Gual et al. study. This phenomenon has been reported previously (Epstein et al., 2005; Litten et al., 2012) and means that a substantial fraction of the patients was treated without a prospect of further improvement. Inclusion of these patients in the pre-specified efficacy analysis may have resulted in a substantial underestimation of the treatment effect. Patients who continued their high level of alcohol consumption after initial assessment and were still drinking at high risk levels at the start of treatment are the patients who are expected to derive the highest clinical benefit from nalmefene, and thus constitute the target population. Nalmefene was recently granted a market authorization in the European Union for the reduction of alcohol consumption in adult patients with alcohol dependence who have a high drinking risk level according to the World Health Organization (WHO, 2000: men: >60 g/day and women: >40 g/day) and who continue to have that 2 weeks after initial assessment (European Medicines Agency, 2013).

This article describes a post hoc analysis of the efficacy, safety and tolerability of as-needed nalmefene (18 mg) in the subgroup of patients with at least a high drinking risk level at both screening and randomization, based on the two double-blind, randomized, placebo-controlled 6-month nalmefene efficacy studies: ESENSE 1 (Mann et al., 2013; NCT00811720) and ESENSE 2 (Gual et al., 2013; NCT00812461).

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