Effect of modafinil on impulsivity and relapse in alcohol dependent patients: A randomized, placebo-controlled trial
Introduction
There is growing evidence that impulsive behavior plays an important role in the development, course and relapse of alcohol dependence (for review see De Wit, 2009, Verdejo-Garcia et al., 2008). Alcohol dependent patients (ADP) are characterized by higher levels of self-reported impulsivity, a faster discounting of delayed rewards and diminished response inhibition compared to healthy controls (Bjork et al., 2004, Dom et al., 2006, Von Diemen et al., 2008). Furthermore, these characteristics are important predictors of treatment outcome and relapse into alcohol use (Bowden-Jones et al., 2005, MacKillop and Kahler, 2009, Muller et al., 2008, Rubio et al., 2008). Nevertheless, to date, the reduction of craving has been the major focus of medication development for alcohol dependence, e.g. acamprosate and naltrexone. However, these treatment approaches have been moderately successful at best and relapse after treatment is the rule rather than the exception. Therefore, reducing impulsive behavior is a needed new treatment approach in alcohol dependence.
In that respect, modafinil is a promising compound. Modafinil (2-[(diphenylmethyl) sulfinyl] acetamide) is a wakefulness-promoting drug that is currently approved for the treatment of narcolepsy, but is also used for its cognitive enhancement (for review see Joos et al., 2010, Minzenberg and Carter, 2008). Modafinil improved symptoms of hyperactivity and impulsivity in children with ADHD (Biederman et al., 2005, Kahbazi et al., 2009, Swanson et al., 2006) and improved response inhibition in healthy individuals (Turner et al., 2003), adults with ADHD (Turner et al., 2004a), methamphetamine dependent individuals (Dean et al., 2011). A remarkable finding is that differences in baseline impulsivity levels may moderate the effect of modafinil on response inhibition. For example, Zack and Poulos (2009) reported an improvement in response inhibition (Stop Signal Task (SST)) in pathological gamblers who display high levels of self-reported baseline impulsivity (Eysenck Impulsivity Questionnaire), whereas no effect or even worsening of response inhibition occurred in their low impulsive counterparts. A similar effect was found in rats with high and low baseline levels of response inhibition (SST) (Eagle et al., 2007). Finally, modafinil demonstrated promising treatment effects in cocaine and methamphetamine dependent patients with significant more negative urine samples (Dackis et al., 2005, Shearer et al., 2009), longer periods of abstinence (Dackis et al., 2005, Anderson et al., 2009), a reduction of substance use (Hart et al., 2008, Shearer et al., 2009) and less craving (Hart et al., 2008, Anderson et al., 2009).
In summary, these results indicate that modafinil has the potential to reduce impulsive behavior and to reduce relapse rates in substance dependent patients although these effects might only occur in specific subgroups. Modafinil may therefore be a promising candidate for alcohol dependence treatment. However, so far no clinical trials have been conducted in ADP. Therefore we conducted a randomized double-blind placebo-controlled trial with modafinil in treatment seeking ADP. We hypothesized that a 10-wk treatment with modafinil in ADP would (1) reduce relapse and relapse severity during treatment and after treatment discontinuation, and (2) reduce impulsivity. Furthermore, it is hypothesized that treatment effects are mediated by reductions in impulsive behavior, i.e. participants whose impulsivity levels improved during treatment are expected to have a better outcome than patients without improvements in impulsivity. Finally, subgroups with high impulsivity at baseline are expected to benefit more from modafinil for alcohol dependence treatment than subgroups with low baseline impulsivity.
Section snippets
Participants
Study participants were treatment seeking ADP, meeting the following inclusion criteria: current DSM-IV diagnosis of alcohol dependence, age between 18 and 60 years and inclusion in the cognitive behavioral treatment program after detoxification. Exclusion criteria were: current DSM-IV dependence on substances other than alcohol (except for nicotine and cannabis); current use of psychoactive medications (except sleep medication with a maximum half-life of 8 h), current use of anti-alcohol
Participants flow
Of the 706 patients who were consecutively admitted to the treatment centers, 593 patients of those did not meet inclusion criteria and 30 eligible patients declined to participate. The remaining 83 eligible patients were eventually randomized to the modafinil (n=41) or the placebo (n=42) group. Their mean age was 41.8 years (SD=9.4 years) and most of them were males (85.5%) and inpatients (87.9%). The participants flow is presented in Figure 2. Overall, drop-out occurred equally within the
Discussion
This is the first randomized double-blind placebo-controlled trial with modafinil in a sample of alcohol dependent patients. Overall, the use of modafinil was well tolerated and no abuse potential of modafinil was reported. No significant main effects of modafinil were found for the primary alcohol outcome variables compared to placebo.
Despite these mainly negative results, the overall abstinence rates were higher in the modafinil compared to the placebo condition (T2: 54% vs. 42%; FU2: 29% vs.
Role of funding source
Funding for this study was provided by the Netherlands Organization for Scientific Research, ZonMW (Grant 31160003). ZonMW had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit this paper for publication.
Contributors
L. Joos, L. Schmaal, Dr. A.E. Goudriaan, Prof. Dr. W. Van den Brink, Prof. Dr. B.G.C. Sabbe and Prof. Dr. G. Dom conceptualized the study and oversaw the data analyses. E. Fransen supported the data analysis that were carried out for this manuscript. L. Joos executed the study and wrote the first draft of the manuscript, with support of the co-authors. All authors contributed to and have approved the final manuscript.
Conflict of interest
Wim van den Brink is a consultant for Merck Serono (acamprosate) and Lundbeck (nalmefene) and received speaker fees from Merck Serono, Lundbeck, Eli Lilly, Pfizer, and Schering-Plough. In addition, he received unrestricted grants for investigator initiated studies from Alkermes (naltrexone XR) and Neurosearch (tesofensine). Geert Dom has received speaker fees from Merck, Lundbeck, GlaxoSmithKline, Johnson & Johnson, and Astra Zeneca. All other authors have no conflict of interest to declare.
Acknowledgments
We thank the patients for their commitment and time and thank the participating hospitals: the Psychiatric Centre Brothers Alexians (Boechout, Belgium) and the Psychiatric Hospital Sint-Norbertus (Duffel, Belgium).
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