A randomised, double-blind, placebo-controlled, efficacy study of nalmefene, as-needed use, in patients with alcohol dependence

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Abstract

This study evaluated the efficacy of as-needed use of the opioid system modulator nalmefene in reducing alcohol consumption in patients with alcohol dependence. Seven hundred and eighteen patients (placebo=360; nalmefene=358), ≥18 years of age, with a diagnosis of alcohol dependence, ≥6 heavy drinking days and an average alcohol consumption ≥WHO medium drinking risk level in the 4 weeks preceding screening, were randomised (1:1) to 24 weeks of as-needed placebo or nalmefene 18 mg/day.

The co-primary efficacy analyses showed a significantly superior effect of nalmefene compared to placebo in the change from baseline to month 6 in heavy drinking days (group difference: −1.7 days/month [95% CI −3.1; −0.4]; p=0.012) and a better but not significant effect in reducing total alcohol consumption (group difference: −5.0 g/day last month [95% CI −10.6; 0.7]; p=0.088). A subgroup analysis showed that patients who did not reduce their drinking prior to randomisation benefitted more from nalmefene. Improvements in Clinical Global Impression and reductions in liver enzymes were greater in the nalmefene group than in the placebo group. Adverse events were more common with nalmefene; the incidence of adverse events leading to dropout was similar in both groups.

This study provides evidence for the efficacy of nalmefene, which constitutes a new pharmacological treatment paradigm in terms of treatment goal (reduced drinking) and dosing regimen (as-needed), in alcohol dependent patients unable to reduce alcohol consumption on their own.

Introduction

Europe has the highest overall consumption of alcohol (World Health Organization, 2010), and in general, the European Union can be characterised by a lower proportion of abstainers and a higher proportion of the population drinking more than 20 g of pure alcohol per day than the rest of the world (World Health Organization, 2011). Worldwide, the European region suffers the highest impact of alcohol with 6.5% of all deaths and 11.6% of all disability-adjusted life years attributable to alcohol (Rehm et al., 2009).

Most of the alcohol-attributable mortality is due to alcohol dependence, presumably by means of heavy drinking (Rehm et al., 2013). Approximately 15 million persons in the European Union are alcohol-dependent (Wittchen et al., 2011). There is a large treatment gap, with less than 10% of people in Europe with a diagnosis of any alcohol disorder (including alcohol dependence) actually receiving any treatment (Alonso et al., 2004).

Reduction of alcohol consumption is increasingly accepted as a viable treatment goal (European Medicines Agency (EMEA), 2010, Luquiens et al., 2011). However, the three currently registered pharmacological treatments for alcohol dependence are indicated only for the maintenance of abstinence following detoxification.

A large proportion of patients in abstinence-oriented treatments experience relapses (Anton et al., 2006, Mann et al., 2004, Merkx et al., 2011, Miller et al., 2001), and abstinence-oriented treatments might not be desirable or acceptable to many patients (Gastfriend et al., 2007, Marlatt and Witkiewitz, 2002). Allowing patients to choose between abstinence and reduced drinking as their treatment goal may enhance engagement with the treatment, ultimately leading to better treatment outcomes for the population at large (Adamson et al., 2010, Heather et al., 2010). Furthermore, research has shown that any reduction in alcohol consumption for a person who consumes more than 10 g of alcohol per day will reduce the annual and life-time risk of alcohol-related death (Rehm et al., 2011).

Therefore, there is clearly a need for new pharmacological treatments allowing for reduction of alcohol consumption as a treatment goal.

Nalmefene is an opioid system modulator, which in several studies in patients with alcohol use disorders has been associated with a reduction of heavy drinking. Although Anton et al. (2004) were unable to show a reduction in alcohol use compared to placebo, other studies in patients with alcohol-use disorders indicate that treatment with nalmefene causes a reduction of heavy drinking (Karhuvaara et al., 2007, Mason et al., 1994, Mason et al., 1999). A recently published large phase 3 study in patients with alcohol dependence showed that nalmefene, taken on an as-needed basis was superior to placebo in reducing alcohol consumption (Mann et al., 2013).

Here, we present results from another recently completed phase 3 study in patients with alcohol dependence that assessed the efficacy and safety of as-needed use of nalmefene in reducing alcohol consumption, measured as the monthly changes from baseline in the number of heavy drinking days (days in last month) and mean total alcohol consumption (g/day in last month) during a treatment period of 24 weeks.

Section snippets

Patients

This randomised, double-blind, placebo-controlled, parallel-group study included patients from 57 sites in Belgium, the Czech Republic, France, Italy, Poland, Portugal, and Spain. Patients were recruited from in- and out-patient clinics, from the study site's patient pool, and by spontaneous referrals to the study site. Advertisements were used in the Czech Republic, France, Italy, and Spain. Eligible patients were men and women aged ≥18 years with a primary diagnosis of alcohol dependence

Study sample

From March, 2009 to July, 2010, 941 patients were screened, of whom 718 were randomised (Figure 1). There were no clinically relevant differences in baseline demographic or clinical characteristics between the groups (Table 1). All but eight patients were Caucasian, approximately 70% were men, and the mean age was 45 years. Mean age of onset of alcohol problems was 32 years.

In the month before screening, patients had on average 19 heavy drinking days and drank on average 90 g of alcohol per day.

Discussion

This study is the second study in the recently completed clinical phase 3 programme using nalmefene as-needed as a means of reducing alcohol consumption in patients with alcohol dependence. Patients were predominantly middle-aged men, with the majority having a high or very high drinking risk level; the average baseline consumption was 90 g alcohol per day. In line with EMA recommendations, patients with significant withdrawal symptoms were not eligible for participation and thus some of the

Role of the funding source

The sponsor was involved in the study design, data collection, data analysis, and interpretation of the data, but not in the decision to submit the report for publication. An employee of the sponsor provided medical writing assistance in the preparation of the report. The corresponding author had full access to all study data and had final responsibility for the decision to submit for publication.

Contributors

Antoni Gual was the signatory investigator for the study. All authors were involved in the design of the study, data analysis and interpretation. Antoni Gual, Yuan He and Lars Torup wrote the manuscript in collaboration with a medical writer. All authors reviewed and approved the manuscript before submission.

Conflict of interest

Antoni Gual has received honoraria and travel grants from Lundbeck, Janssen, D&A Pharma and Servier.

Yuan He and Lars Torup are Lundbeck employees.

Wim van den Brink has received honoraria from Lundbeck, Merck Serono, Schering-Plough, Reckitt Benckiser, Pfizer, and Eli Lilly, speaker fees from Lundbeck, investigator initiated industry grants from Alkermes, Neurotech, and Eli Lilly, is a consultant to Lundbeck, Merck Serono, Schering-Plough, and Teva, and has performed paid expert testimony for

Acknowledgements

We thank all patients for their participation in the ESENSE 2 Study, all research staff and the ESENSE 2 Study Group (see Supplementary material) for their contributions. We also thank Johan Hellsten, an employee of Lundbeck for providing medical writing assistance in the preparation, revision, and editing of the manuscript.

References (46)

  • S.J. Adamson et al.

    Initial preference for drinking goal in the treatment of alcohol problems: II. Treatment outcomes

    Alcohol Alcohol.

    (2010)
  • J. Alonso et al.

    Use of mental health services in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project

    Acta. Psychiatr. Scand. Suppl.

    (2004)
  • American Psychiatric Association (APA)

    Diagnostic and Statistical Manual of Mental Disorders, Fourth Ed., Text Revision (DSM-IV-TR)

    (2000)
  • R.F. Anton et al.

    A multi-site dose ranging study of nalmefene in the treatment of alcohol dependence

    J. Clin. Psychopharmacol.

    (2004)
  • R.F. Anton et al.

    Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial

    J. Am. Med. Assoc.

    (2006)
  • E.E. Epstein et al.

    Is alcohol assessment therapeutic? Pretreatment change in drinking among alcohol-dependent women

    J. Stud. Alcohol

    (2005)
  • European Medicines Agency (EMEA), 2010. Guideline on the development of medicinal products for the treatment of alcohol...
  • J.C. Garbutt et al.

    Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence a randomized controlled trial

    J. Am. Med. Assoc.

    (2005)
  • N. Heather et al.

    Initial preference for drinking goal in the treatment of alcohol problems: I. Baseline differences between abstinence and non-abstinence groups

    Alcohol Alcohol.

    (2010)
  • P. Heinälä et al.

    Targeted use of naltrexone without prior detoxification in the treatment of alcohol dependence: a factorial double-blind, placebo-controlled trial

    J. Clin. Psychopharmacol.

    (2001)
  • S. Karhuvaara et al.

    Targeted nalmefene with simple medical management in the treatment of heavy drinkers: a randomized double-blind placebo-controlled multicenter study

    Alcohol. Clin. Exp. Res.

    (2007)
  • H.R. Kranzler et al.

    Targeted naltrexone for early problem drinkers

    J. Clin. Psychopharmacol.

    (2003)
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