High-dose baclofen for the treatment of alcohol dependence (BACLAD study): A randomized, placebo-controlled trial

Abstract

Previous randomized, placebo-controlled trials (RCTs) assessing the efficacy of the selective γ-aminobutyric acid (GABA)-B receptor agonist baclofen in the treatment of alcohol dependence have reported divergent results, possibly related to the low to medium dosages of baclofen used in these studies (30–80 mg/d). Based on preclinical observations of a dose-dependent effect and positive case reports in alcohol-dependent patients, the present RCT aimed to assess the efficacy and safety of individually titrated high-dose baclofen for the treatment of alcohol dependence. Out of 93 alcohol-dependent patients initially screened, 56 were randomly assigned to a double-blind treatment with individually titrated baclofen or placebo using dosages of 30–270 mg/d. The multiple primary outcome measures were (1) total abstinence and (2) cumulative abstinence duration during a 12-week high-dose phase. More patients of the baclofen group maintained total abstinence during the high-dose phase than those receiving placebo (15/22, 68.2% vs. 5/21, 23.8%, p=0.014). Cumulative abstinence duration was significantly higher in patients given baclofen compared to patients of the placebo group (mean 67.8 (SD 30) vs. 51.8 (SD 29.6) days, p=0.047). No drug-related serious adverse events were observed during the trial. Individually titrated high-dose baclofen effectively supported alcohol-dependent patients in maintaining alcohol abstinence and showed a high tolerability, even in the event of relapse. These results provide further evidence for the potential of baclofen, thereby possibly extending the current pharmacological treatment options in alcohol dependence.

Introduction

Alcohol use disorders (AUDs) are chronic and widespread diseases accounting for 44.4% of the years of life lost (YLLs) attributable to mental and substance use disorders worldwide (Whiteford et al., 2013). In the vast majority of alcohol-dependent patients, the clinical course is characterized by multiple relapses to drinking after detoxification treatment, with relapse rates ranging from 75% to 85% (Boothby and Doering, 2005, Bottlender et al., 2007). Besides attendance at self-help groups, and psychosocial and psychotherapeutic treatment approaches, only a few specific pharmacological interventions for alcohol-dependent patients exist to date. Since 1948, only 4 substances have been approved by the Federal Drug Administration (FDA), namely the aldehyde dehydrogenase inhibitor disulfiram, the putative glutamate modulator acamprosate (recent findings suggest a calcium-related mechanism of action) (Spanagel et al., 2014), and the opioid antagonist naltrexone (2 formulations, oral and injectable) (Zindel and Kranzler, 2014). In Europe, the opioid antagonist nalmefene has also been approved by the European Medicines Agency (EMA) for the reduction of alcohol consumption in alcohol-dependent patients (EMA, 2013). Although several, but not all, of these compounds have repeatedly been shown to be effective in clinical trials (Anton et al., 2006, Mann et al., 2013, Rosner et al., 2010a, Rosner et al., 2010b, Suh et al., 2006), the observed effects were only modest; for instance, acamprosate has been shown to reduce the risk of relapse by 14% and to increase cumulative abstinence duration by 11% compared to placebo in a meta-analysis (Rösner et al., 2010a). Naltrexone was found to reduce the risk of heavy drinking by 17% compared to placebo, heavy drinking days by 3%, drinking days by 4% and the amount of alcohol consumed per drinking day by 11 g (Rösner et al., 2010b). Therefore, further clinical evaluation of new pharmacological strategies is crucial to optimize treatment of alcohol-dependent patients.

In recent years, animal studies have suggested that the GABA-B receptor system is involved in alcohol-related behaviours (Colombo et al., 2004). The GABA-B receptor is located within several brain areas including the so-called mesolimbic reward system of the brain, and has been hypothesized to modulate dopaminergic neurotransmission (Bowery et al., 1987, Fadda et al., 2003), which plays an important role in the development and maintenance of alcohol dependence (Heinz, 2002, Koob and Volkow, 2010). The selective GABA-B receptor agonist baclofen is approved for the treatment of spasticity resulting from various neurological conditions. There is preclinical evidence from studies in rats that baclofen suppresses the acquisition and maintenance of alcohol drinking behavior as well as an increase in alcohol intake after a period of alcohol abstinence (Agabio and Colombo, 2014).

In alcohol-dependent patients, a few RCTs using baclofen have been published to date (Addolorato et al., 2002, Addolorato et al., 2011, Addolorato et al., 2007, Garbutt et al., 2010). These studies reported a high tolerability of baclofen (including in patients with comorbid liver cirrhosis) (Addolorato et al., 2007), but conflicting results in terms of efficacy (Caputo et al., 2014, Muller et al., 2014). Given the low ability of baclofen to cross the blood brain barrier (Taira, 2009), these inconsistent findings might be related to the rather low dosages of baclofen used in these trials (30–80 mg/d). Based on preclinical observations of a dose-dependent effect of baclofen on alcohol consumption in rodents treated with dosages up to 3 mg/kg (Colombo et al., 2003), as well as positive case reports in alcohol-dependent patients receiving high-dose baclofen up to 270 mg/d (Ameisen, 2005), the present RCT aimed to investigate the efficacy and safety of individually titrated high-dose baclofen (up to 270 mg/d) in alcohol-dependent patients using a 2-arm, parallel-group, double-blind, randomized and placebo-controlled design.