The search for efficacious and safe medications for the treatment of alcohol dependence remains a key goal of treatment research. The discoveries that naltrexone and acamprosate are effective for alcohol dependence were major breakthroughs in the clinical management of alcohol dependence and have broadened the awareness of the role of pharmacotherapy for alcohol dependence. However, the overall effectiveness of naltrexone and acamprosate are modest (Kranzler and Van Kirk, 2001
) leading to efforts to find additional and possibly more effective medications.
Baclofen has emerged as a medication of potential interest for the treatment of alcohol dependence. The preclinical evidence, as reviewed in the Introduction, supports the hypothesis that baclofen reduces alcohol intake, reduces the reinforcing and motivational properties of alcohol, and prevents some of the neurobehavioral consequences of alcohol consumption such as induction of anxiety. The neuropharmacological basis of these actions is not fully understood but activation of GABAB
receptors by baclofen counteracts the ventral tegmental-nucleus accumbens dopamine response to alcohol (see Maccioni et al., 2009) and has other complex actions on various neurotransmitter systems of relevance to alcohol (see Knapp et al., 2007
Clinical trials, to date, have been limited with only 123 individuals studied in two placebo-controlled, randomized trials (Addolorato et al., 2002
). Nevertheless, these two trials are of considerable interest as they show a significant advantage of baclofen over placebo in enhancing abstinence and reducing drinking quantities and reducing anxiety and craving. Given the preclinical and early clinical evidence, the current trial was designed to further test the hypothesis that baclofen has efficacy for alcohol dependence.
The current trial did not find evidence for efficacy of baclofen for alcohol dependence on the primary outcome measure of %Heavy Drinking Days though a highly significant overall treatment effect was found indicating that participation in the trial itself was efficacious in reducing heavy drinking. Additionally, no effect of baclofen was noted on the secondary outcomes of %Days Abstinent or craving for alcohol. A modest baclofen effect on levels of state anxiety was found. Furthermore, evaluation by gender did not reveal evidence for any differential response to baclofen by gender. Finally, examining baclofen response by baseline levels of craving for alcohol or levels of anxiety found that neither high levels of craving nor high levels of anxiety were associated with response to baclofen. These data do not support the hypothesis that baclofen has efficacy for alcohol dependence; however, this work must be considered in the context of the overall clinical trial evidence with particular attention to variations across trials.
Clinical trials in alcohol dependence are well known to exhibit great variability that are thought to be related to the myriad of factors that affect outcome in alcohol dependent patients. Noteworthy examples of this variation include the failure of the large Veterans’ Administration trial to demonstrate efficacy of naltrexone (Krystal et al, 2001
) despite the overall evidence that naltrexone is effective (Kranzler and Van Kirk, 2001
) and the two large trials of acamprosate in the United States that failed to show efficacy (Anton et al., 2006
; Mason et al., 2006
) when, again, the preponderance of evidence shows that acamprosate is efficacious (Kranzler and Van Kirk, 2001
). Kiefer and Mann (2006)
, commenting about the patient population and design of the COMBINE trial have highlighted the fact that patients in the U.S. COMBINE trial appeared to have relatively low levels of physical dependence and that this may have impacted the response to a medication such as acamprosate which may be more effective in the presence of physical dependence. This factor may be relevant to understanding differences in the current trial compared to the positive Addolorato trials of baclofen (2002
). The Addolorato trials recruited patients with alcohol dependence who presented to an alcohol treatment unit whereas individuals in the current trial were recruited from advertising. This difference in recruitment was likely a key factor as to why the participants in the Italian trials, compared to the U.S. trial, drank nearly twice the amount of drinks/drinking day (10.7 (placebo)/17.6 (baclofen) vs. 6.9 (placebo)/7.3 (baclofen) respectively), had higher levels of withdrawal symptoms, and uniformly had a goal of abstinence. This indicates the Italian study population had more severe dependency characteristics than the U.S. population and a different treatment goal. Therefore, though it is not established that baclofen would have greater efficacy in more highly dependent patients, this hypothesis should be investigated.
It is of interest that baclofen did significantly reduce anxiety in the current trial similar to what Addolorato et al. (2002)
reported. However, no relationship between baseline levels of anxiety and response to baclofen were detected. Given the high rates of anxiety symptoms in alcohol dependence it would be of considerable clinical value to have a medication that could reduce anxiety, reduce alcohol use, did not have addiction liability and did not have dangerous interactions with alcohol. Preclinical work has shown that GABAB
systems are involved in anxiety behavior and that activation of the GABAB
receptor either by baclofen or by positive allosteric modulators of the receptor is anxiolytic (Cryan and Kaupmann, 2005
). Furthermore, baclofen counteracts the anxiogenic effects of alcohol in an animal model (Knapp et al., 2007
). Additionally, the addiction liability of baclofen appears low and laboratory investigation of baclofen at 40 mg and 80 mg doses combined with intoxicating levels of alcohol indicate a reasonable safety profile when baclofen is combined with alcohol (Evans and Bisaga, 2009
). Therefore, whereas there does appear to be a signal that baclofen may have anxiolytic effects in patients with alcohol dependence, the clinical impact of this remains ambiguous.
Subjective craving for alcohol as measured by the PACS or Obsessive Compulsive Drinking Scale (OCDS) (Anton et al., 1995
) has been shown to predict drinking outcomes in clinical trials (Flannery et al., 2003
). Addolorato et al. (2002
) found that baclofen reduced craving for alcohol as measured by the OCDS significantly more than placebo. This is of interest as it suggests that baclofen might reduce drinking behavior through an effect on craving for alcohol. In the current trial, we did not find that baclofen reduced craving more than placebo and individuals with high baseline craving for alcohol did not show a baclofen effect. Therefore, based on the present study, the effect of baclofen on craving for alcohol is not clear.
Overall, our failure to find significant efficacy for baclofen despite the promising preclinical data and two positive placebo-controlled clinical trials raises two other important points. First, there is the question of whether a 30 mg/d dose of baclofen is an adequate dose for most patients and second, can a baclofen-responsive patient be identified?
With regards to dose, the clinical trials to date have used a baclofen dose of 30 mg/day--in the low therapeutic range for muscle spasticity but anticipated to have fewer side effects, an important consideration for early clinical trials. However, there are case studies that suggest that larger doses of baclofen may be required for efficacy in some individuals. Ameisen (2005)
, a physician, self-prescribed baclofen by titrating from 30 mg/day to 270 mg/day and then reducing the dose to 120 mg/day due to somnolence. He reported suppression of alcohol consumption and a profound reduction in anxiety and craving. Buchman (2006) described a patient with alcohol dependence who had failed naltrexone, acamprosate, and topiramate but who had marked improvement in alcohol consumption associated with a sense of relaxation at a dose of 100-140 mg/day of baclofen. These cases are noteworthy because they raise the possibility of a meaningful dose-response relationship for baclofen as a treatment for alcohol dependence and that 30 mg of baclofen may be an insufficient dose for some patients. Dose-response studies to examine the efficacy and safety of higher doses of baclofen in alcohol dependence are clearly needed.
The question of a baclofen-responsive patient is another issue that deserves attention. The heterogeneity of alcohol dependence and the great variability in response across individuals in clinical trials in alcohol dependence speaks to the likelihood that there are individual characteristics associated with a positive response to specific pharmacotherapies. The best example here may be the emerging evidence that polymorphisms within the μ-opioid receptor gene predict naltrexone response (see Oroszi et al., 2009
). To date, no prospective studies have examined any putative characteristic that might identify a baclofen-responsive patient. Based on some of the preclinical and clinical trial data one could postulate that symptoms such as high anxiety or high levels of alcohol withdrawal symptoms could be predictors though we did not find evidence that anxiety symptoms were predictive in the current trial. Here again, prospective clinical trials are needed.
With regards to tolerability, the current trial found that baclofen was generally well tolerated. Importantly, no serious adverse events were reported and, despite ongoing alcohol consumption by many individuals, no evidence for significant alcohol/baclofen interactions was observed. This is consistent with the recent laboratory study of Evans and Bisaga (2009)
which also failed to show significant safety concerns when intoxicating levels of alcohol were consumed in the presence of baclofen. More individuals receiving baclofen did experience sedation than placebo in keeping with this known side-effect of baclofen, but, overall, this was benign. These findings suggest that trials with higher doses of baclofen in an alcohol dependent population are feasible based on tolerability.
In summary, the current trial did not find evidence that baclofen at a dose of 10 mg three times per day was superior to placebo in the treatment of alcohol dependence. No baclofen effect was found on heavy drinking or abstinent days. The presence of high levels of anxiety or high craving was not associated with a baclofen response though there was some evidence that baclofen has anxiolytic effects. Given the heterogeneity of alcohol dependence and the fact that Addolorato et al. (2002
) have reported a therapeutic benefit to baclofen in alcoholism, it cannot be concluded that baclofen has no value in the pharmacotherapy of alcohol dependence. Additional clinical trials examining dose and controlling for individual patient characteristics are needed to better understand the role of baclofen and GABAB
agonists in general as possible pharmacotherapies for alcohol dependence.