Baclofen for the Treatment of Alcohol Dependence and Possible Role of Comorbid Anxiety

Alcohol and Alcoholism Vol. 49, No. 6, pp. 654–660, 2014 Advance Access Publication 21 September 2014 doi: 10.1093/alcalc/agu062 Baclofen for the Treatment of Alcohol Dependence and Possible Role of Comorbid Anxiety K.C. Morley1,*, A. Baillie2, S. Leung3, G. Addolorato4, L. Leggio5,6,7 and P.S. Haber1,8 1 NHMRC Centre of Research Excellence in Mental Health and Substance Use, Discipline of Addiction Medicine, University of Sydney, Sydney, NSW, Australia, 2 NHMRC Centre of Research Excellence in Mental Health and Substance Use, Department of Psychology, Macquarie University, Sydney, NSW, Australia, 3 Central Clinical School, University of Sydney, Sydney, NSW, Australia, 4Institute of Internal Medicine, Catholic University of Rome, Rome, Italy, 5Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA, 6National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, USA, 7Department of Behavioral and Social Sciences, Brown University, Providence, RI, USA and 8Drug Health Services, Royal Prince Alfred Hospital, Sydney, NSW, Australia *Corresponding author: Discipline of Addiction Medicine, University of Sydney, Sydney, NSW 2006, Australia. E-mail: (Received 17 June 2014; first review notified 4 August 2014; in revised form 25 August 2014; accepted 26 August 2014) Abstract — Aim: To conduct a double-blind, placebo-controlled randomized clinical trial of baclofen in the treatment of alcohol dependence. Methods: Out of 69 participants consecutively screened, 42 alcohol-dependent patients were randomized to receive placebo, baclofen 30 mg/day or baclofen 60 mg/day for 12 weeks. All subjects were offered BRENDA, a structured psychosocial therapy for alcohol dependence that seeks to improve motivation for change, enhance strategies to prevent relapse and encourage compliance with treatment. Results: Intention-to-treat analyses revealed that alcohol consumption (heavy drinking days, drinks per drinking day) significantly reduced across all three groups during the treatment period. There were no statistically significant advantages to treatment on time to first heavy drinking day (relapse) (P = 0.08), nor time to first drink (lapse) (P = 0.18). A post hoc analysis stratifying according to whether there had been a comorbid anxiety disorder, revealed a beneficial effect of baclofen 30 mg/day versus placebo on time to lapse and relapse (P < 0.05). There was also a beneficial effect for baclofen 60 mg/day relative to placebo on time to relapse in this comorbid group (P < 0.05). Both doses of baclofen were well tolerated. There were no serious adverse events. Conclusions: In spite of the small sample for a 3-arm clinical trial, this study suggests a specific role of baclofen in alcohol-dependent individuals with comorbid anxiety. Replication in larger, fully-powered studies is required. INTRODUCTION In terms of years lost, alcohol is considered to be the most harmful substance in the world when associated death, disability, suffering and the full range of social harms are considered (Nutt et al., 2010). However, although alcohol use disorders are leading causes of preventable death, treatment options are still limited. At present there are only a few pharmacological treatments specifically indicated for alcohol dependence in Europe, the USA and Australia. Baclofen is a selective GABAB receptor agonist currently indicated for the treatment of muscle spasticity. Preclinical studies have found that baclofen reduces self-administration of alcohol, acquisition, maintenance and reinstatement of alcoholdrinking behavior and modifies motivational cues for alcohol (Colombo et al., 2004; Maccioni and Colombo, 2009). In humans, Addolorato and colleagues were the first group to conduct a double-blind, placebo-controlled, randomized clinical trial (n = 39) of baclofen in the treatment of alcohol dependence (Addolorato et al., 2002). This study indicated significantly higher rates of abstinence and reduced alcohol intake following 4 weeks of baclofen (30 mg/day) treatment. Following this, a preliminary open-label 12-week treatment study demonstrated that baclofen (30 mg/day) was welltolerated in alcohol-dependent participants and resulted in significant reductions in drinks per drinking day, self-reported craving and anxiety (Flannery et al., 2004). Subsequently, Addolorato et al. (2007) similarly reported higher rates of abstinence and significantly reduced craving after 12 weeks of treatment with baclofen (30 mg/day) compared with placebo (n = 84) in alcoholic patients with liver cirrhosis. These findings were confirmed in a subset of alcoholic patients with cirrhosis and HCV infection (Leggio et al., 2012). Additionally, human laboratory studies have demonstrated the safety of baclofen when co-administered with alcohol (Evans and Bisaga, 2009; Leggio et al., 2013). Additionally, a preliminary study suggested that baclofen may amplify the biphasic effects of alcohol (sedation and stimulation) and reduce alcohol selfadministration without reducing alcohol cue-induced craving (Leggio et al., 2013). More recently, Garbutt et al. (2012) found no beneficial effect of baclofen in 80 alcohol-dependent patients randomized to 12 weeks of baclofen (30 mg/day) versus placebo for most alcohol outcome measures including time to lapse, time to relapse, days abstinent or the percentage of heavy drinking days. This study showed an overall treatment effect, that is, all patients significantly improved their drinking outcomes regardless of the medication condition (Garbutt et al., 2012), which was possibly due to the enrollment of a population with a lower severity of alcohol dependence, compared with the previous positive studies (Addolorato et al., 2002, 2007). As such, different severity of alcohol dependence has been suggested as a possible key factor influencing baclofen response, including factors such as severity of drinking, withdrawal and anxiety (Leggio et al., 2010). Notably, Garbutt et al. (2012) observed a significant reduction in state anxiety in patients allocated to baclofen treatment. Previous studies have demonstrated the efficacy of GABAB subtype receptor agonists, including baclofen, in treating anxiety in patients with PTSD, panic disorder and in treating anxiety in alcohol-dependent patients (Breslow et al., 1989; Krupitsky et al., 1993; Drake et al., 2003). It is possible that baclofen may influence subjective expression of craving and consequently risk of relapse by suppressing anxiety and stress associated with alcohol dependence. Anxiety is one of the main symptoms of alcohol withdrawal syndrome, and a few studies have reported an effect of baclofen (30 mg/day) in significantly reducing alcohol withdrawal symptoms (Addolorato et al., 2006; Lyon et al., 2011). The Internatio (...truncated)