Efficacy and safety of high-dose baclofen for the treatment of alcohol dependence: A multicentre, randomised, double-blind controlled trial

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Abstract

Previous randomised placebo-controlled trials with low-to-medium doses of baclofen (30–60 mg) showed inconsistent results, but case studies suggested a dose-response effect and positive outcomes in patients on high doses of baclofen (up to 270 mg). Its prescription was temporary permitted for the treatment of alcohol dependence (AD) in France, and baclofen is now widely prescribed. Recently, a small RCT found a strong effect of a mean dose of 180 mg baclofen. In the present study the efficacy and safety of high doses of baclofen was examined in a multicentre, double-blind, placebo-controlled trial. 151 patients were randomly assigned to either six weeks titration and ten weeks high-dose baclofen (N=58; up to 150 mg), low-dose baclofen (N=31; 30 mg), or placebo (N=62). The primary outcome measure was time to first relapse. Nine of the 58 patients (15.5%) in the high-dose group reached 150 mg and the mean baclofen dose in this group was 93.6 mg (SD=40.3). No differences between the survival distributions for the three groups were found in the time to first relapse during the ten-weeks high-dose phase (χ2=0.41; p=0.813) or the 16-weeks complete medication period (χ2=0.04; p=0.982). There were frequent dose-related adverse events in terms of fatigue, sleepiness, and dry mouth. One medication related serious adverse event occurred in the high-dose baclofen group. Neither low nor high doses of baclofen were effective in the treatment of AD. Adverse events were frequent, although generally mild and transient. Therefore, large-scale prescription of baclofen for the treatment of AD seems premature and should be reconsidered.

Introduction

The World Health Organization (WHO) estimated that in 2012 3.3 million deaths were attributable to harmful alcohol use worldwide (WHO, 2014). In addition, harmful alcohol use is associated with more than 200 physical and mental disorders, including liver cirrhosis, cancers, injuries, and dementia, which in turn cause serious social and economic burden. The most extreme form of harmful alcohol use is alcohol dependence (AD); a chronic, frequently relapsing disorder. In Europe, about 3.5% of all drinkers meet criteria for AD (and generally high to very high drinking levels) and this subgroup of drinkers is estimated to be responsible for more than 60% of all premature (<65 years) deaths due to alcohol-attributable diseases (Rehm et al., 2013). In other words, the majority of alcohol-attributable burden is due to the relatively small group of drinkers with AD, presumably by means of heavy drinking. These numbers illustrate the importance of AD for public health and highlight the need for effective treatment. Over the past few decades, many drugs have been tested for AD treatment, but to date only disulfiram, accamprosate, and naltrexone have been approved for the indication AD by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), and nalmefene is approved only by the EMA. However, although efficacy of these agents was proven in several clinical trials, other trials failed to find significant effects and the magnitude of the treatment effect was generally quite small with standardized effect sizes ranging between 0.20 and 0.40 and numbers needed to treat (NNT) ranging from 6 to 11 (van den Brink, 2012). Therefore, new effective drugs would represent an important progress in the treatment of patients with AD.

One promising drug is baclofen, a potent, stereo-selective GABA-B receptor agonist that has been used for decades in the treatment of spasticity (Davidoff, 1985). The use of drugs that act on the GABA system seems promising for the treatment of AD, because GABA-B receptors are located in the same areas of the brain as the mesolimbic dopamine neurons, which are thought to be important in the mediation of alcohol intake, reinforcement, and relapse (Koob and Volkow, 2010). Furthermore, baclofen has a low liver metabolism, and no hepatic side effects have been reported so far (Addolorato et al., 2002, Addolorato et al., 2007). Its mechanism of action and its low abuse and dependence potential (Carter et al., 2009) makes baclofen an attractive potential drug for the treatment of AD. In rodent studies, baclofen has been found to cause reduced alcohol intake (e.g. Colombo et al., 2003). In humans, two early randomised, placebo-controlled low-dose (30 mg/day) baclofen trials in AD patients confirmed these beneficial effects (Addolorato et al., 2002, Addolorato et al., 2007), although another double blind, placebo-controlled randomised study failed to find any evidence for the efficacy of low-dose baclofen (Garbutt et al., 2010). Based on preclinical and some clinical observations, a dose-dependent effect of baclofen was hypothesized with higher doses resulting in better outcomes (Addolorato et al., 2011, Colombo et al., 2003). This hypothesis was confirmed in some case reports with baclofen doses up to 270 mg/day resulting in complete suppression of alcohol craving (Ameisen, 2005, Bucknam, 2007). Following a popular book on one of these cases (Ameisen, 2008), a French uncontrolled, open-label study reported positive effects of high dose baclofen (actual dose range: 20–330 mg/day; mean dose 147 mg/day) in 100 treatment compliant AD patients (de Beaurepaire, 2014). Based on these findings, but without data from a randomised controlled trial (RCT) on high-dose baclofen in alcohol dependent patients, a temporary recommendation of use (RTU) of baclofen was proclaimed in France in March 2014 to permit its medical prescription to AD patients for three years. Note that, even before the RTU, a significant increase of (high-dose) baclofen prescription was already observed in France: between 2007 and 2013 about 200,000 patients initiated baclofen treatment for AD and more than 9000 general practitioners were identified as first prescribers (Chaignot et al., 2015).

Recently, the first randomised controlled trial with high-dose baclofen was published: a randomised, double-blind, placebo-controlled trial on the efficacy of high-dose baclofen (up to 270 m/day; mean dose 180 mg/day) in 56 German AD patients (N=28 high-dose baclofen and N=28 placebo; Müller et al., 2015). In this small-scale study, the overall effect was very positive (e.g., 12 weeks continuous abstinence: baclofen 68% vs. placebo 24%; NNT=2.3), but there was no indication of a dose–response relation. In the present trial, the efficacy and safety of low doses (30 mg/day) and high doses of baclofen (up to 150 mg/day) were examined in a single RCT, which also allowed us to directly examine the presence of a dose–response relation.

Section snippets

Study design

The present study is a multicentre, randomised, double-blind, placebo-controlled trial. AD patients were randomised after detoxification to one of three conditions: low-dose baclofen, high-dose baclofen, or placebo. Deviant from the initial study design, the inclusion of patients in the low-dose baclofen group was stopped halfway. The trial consisted of a six-week titration phase and a ten-week high-dose phase, where the dose was stabilized.

The study protocol adhered to the principles of Good

Results

The design and the patient flow of the trial is shown in Figure 1. Of 481 patients initially screened for the study between December 1, 2012 and August 31 2015, 157 patients were randomised. Six patients were not able to start with the medication due to medical reasons, resulting in 58 patients randomised to the high-dose baclofen treatment, 31 to the low-dose baclofen treatment, and 62 to the placebo group. Table 2 shows demographic and clinical characteristics of the included patients at

Discussion

The present study examined the efficacy of low- and high-dose baclofen treatment compared to placebo in patients with AD. No differences between the low-dose baclofen group, the high-dose baclofen group, or the placebo group were found with regard to time to first relapse, proportion of patients that relapsed, proportion of patients continuously abstinent, cumulative abstinence duration, or drop-out rate. Furthermore, no effect of baclofen on craving, trait anxiety, or depression over time was

Contributors

EMB ES AG WvdB AB RWW contributed to study conception and design, supervision of the trial, data analysis, data interpretation and writing of the report.

EMB DdJ NS JWZ DvG PB TS contributed to patient recruitment, data collection, and review and approval of the report.

HD participated as independent physician.

MvT contributed to data analysis and data interpretation.

All authors contributed to and have approved the final manuscript. The corresponding author had full access to all data in the study

Conflict of interest

All authors declare no support from any organisation for the submitted work. WvdB reports personal fees from Lundbeck, grants from Alkermes, personal fees from Pfizer, personal fees from Mundipharma, personal fees from Teva, personal fees from D&A Pharma, personal fees from Bioproject, personal fees from Reckitt Benckiser/Indivior, personal fees from Novartis, outside the submitted work. RWW declares a speaker fee from Lundbeck, and, was co-applicant in two awarded grants from ERAB and was

Acknowledgments

Funding for this study was provided by a private donation through the University of Amsterdam Fund (​AUF 7344). We thank all patients for their participation in the study. Furthermore, we are grateful to all physicians and nurses of all treatment centres for their contribution. We also thank C Chmorikh and E Krediet, who assisted with the collection of the data.

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