The major finding of this study was that bedtime administration of gabapentin significantly delayed the onset of relapse (defined as the duration of time to the first heavy drinking episode) in alcohol-dependent patients selected for clinical insomnia at both 6 and 12 weeks. Complete and continuous abstinence from any drinking was not associated with treatment group, but the proportion of subjects that relapsed to heavy drinking was smaller in the gabapentin vs. placebo group at both 6 and 12 weeks. Thus, gabapentin had a positive effect on relapse prevention during the 6 weeks of its administration, which persisted for another 6 weeks after its treatment ended.
A second important finding was that all subjects reported improved sleep during the 6-week trial. Contrary to expectation, gabapentin did not improve SPQ sleep scores any more than placebo did during the 6 weeks of its administration. Moreover, PSG-measured sleep parameters did not show improvement from baseline to 3 weeks in either treatment group. SWS or delta sleep describes the stages of sleep (Stages 3 and 4 combined) that characterize the deepest and potentially most refreshing sleep. Although gabapentin may increase SWS% in some populations (Bazil et al., 2005
; Foldvary-Schaefer et al., 2002
; Garcia-Borreguero et al., 2002
; Legros and Bazil, 2003
; Rao et al., 1988
) during equivalent time frames, it had no significant effect on SWS% in this short-term study of alcohol-dependent individuals with insomnia.
One difference in sleep between the two treatment groups, although not significant (p=.07) was notable because of its moderate ES
(.54). After discontinuation of study medication the gabapentin group had worse sleep (PSG scores) than the placebo group. The relative worsening of sleep after stopping gabapentin is suggestive of either withdrawal or a return to insomnia. Insomnia has been described in one case series as a gabapentin-related withdrawal symptom (Cora-Locatelli et al., 1998
) and also in an 81-year-old patient after a 1-week gabapentin taper (Tran et al., 2005
), but 6 weeks of persisting insomnia as a withdrawal symptom from gabapentin has not been reported previously (Norton, 2001
). Thus, a return to co-occurring insomnia seems more likely as an explanation.
The last major finding was that the participants which relapsed to heavy drinking during the 6-week trial had less improvement in insomnia than those that did not. This was an association and no inferences about causation can be made. Moreover, we did not find evidence that gabapentin’s positive effect on preventing relapse was mediated by its effects on sleep, since placebo-treated subjects also had improved sleep. Nevertheless, gabapentin, which is short-acting and administered three to four times daily to treat epilepsy and neuropathic pain, was taken in this study only at bedtime. Efficacy with once nightly administration is a practical advantage since somnolence is a common side effect of gabapentin as it was in this study (Beydoun et al., 1995
). Efficacy with once nightly administration may also have theoretical implications; because the mechanism by which gabapentin prevented relapse began during the nighttime without an obvious effect on sleep and then persisted during the day. This suggests some longer-acting neuronmodulator effect, rather than a shorter-acting effect on sleep. In other words, gabapentin may exert a nocturnal effect that improves drinking outcomes via a physiological mechanism not measured in this study.
A discrepancy between subjective and objective sleep results deserves mention. At baseline both treatment groups overestimated SOL and underestimated WASO compared to PSG values (). A similar discrepancy was noted by Currie et al., 2004b
) and was predictive of relapse in our sample independent of treatment group (Conroy et al., 2006
). The lack of differential improvement between treatment groups in PSG-recorded WASO during the first 6 weeks may reflect the short-acting nature of gabapentin, resulting in minimal impact on nocturnal awakenings.
This is the first controlled trial to investigate the efficacy of gabapentin to improve sleep in alcohol-dependent patients. It is also the first controlled study to investigate gabapentin’s efficacy to prevent relapse to heavy drinking after the acute alcohol withdrawal phase has passed. By contrast, studies of gabapentin to treat acute alcohol withdrawal reveal mixed results (Bonnet et al., 2003
; Mariani et al., 2006
; Voris et al., 2003
). The potential efficacy of gabapentin to prevent relapse is particularly notable because it has low addictive potential (with some recently reported exceptions [Pittenger and Desan, 2007
; Victorri-Vigneau et al., 2007
]), does not undergo hepatic metabolism and has few interactions with other medications (Beydoun et al., 1995
), is relatively safe when combined with alcohol (Bazil et al., 2005
; Bisaga and Evans, 2006
; Myrick et al., 2007
), and is not associated with fatal overdoses when taken alone (Klein-Schwartz et al., 2003
) Gabapentin was also safe and well-tolerated in this study.
Strengths of this randomized trial included its placebo-controlled, double-blind study design, strict selection criteria to rule out comorbid conditions affecting sleep, standardized characterization of subjects across a variety of sleep and drinking variables, and intention-to-treat analyses. In addition, adherence to study medication was measured by multiple methods; biochemical corroboration of self-reported alcohol use was obtained; integrity of the study blind was maintained; and both subjective and objective sleep measures were obtained.
The major limitation of this study was its small sample size which may have prevented detecting differences between treatment groups. Funding restraints prevented recruitment of a larger sample. Generalizing the results to other alcohol-dependent patients, therefore, is very limited, both because of the small sample size and the strict selection criteria that were utilized. Whether gabapentin also prevents relapse to heavy drinking in alcohol-dependent patients without insomnia is unknown. All subjects in this study had insomnia. In addition, the large number of statistical tests that we conducted increased the risk of a Type I error, so that positive results may also be questioned. Nevertheless, the main positive result – increased time to relapse in the gabapentin group – was a primary outcome variable chosen a priori
. The high attrition rate (7 of 21 subjects at 6 weeks) was another study limitation, even though it was comparable to rates observed in other clinical trials with alcohol-dependent subjects (Kranzler et al., 1996a
). The schedule of subject payments for which $150 of the total reimbursement ($325) could be obtained by week 3 of the study may have contributed to attrition at 6 and 12 weeks. In other words, subjects could obtain $150 during the first 3 weeks, but only a total of $175 during the next 9 weeks. Finally, subjects were allowed to sleep according to their usual schedules at home, in order to learn about the patterns of their sleep disturbance. A limitation of this methodology, however, is that some subjects manifested an irregular sleep schedule prior to their sleep laboratory studies; and this may have affected the results of their nocturnal PSG recordings. In particular, group effects could have been either amplified or diminished, particularly given the small sample size. Consequently, differential improvements in PSG parameters may have been obscured leading to false negative results. Irregular sleep patterns were not unexpected because poor sleep hygiene in alcohol-dependent patients has been previously reported (Currie et al., 2003
Future studies should employ larger sample sizes and examine the efficacy of gabapentin for relapse prevention in the absence of insomnia, determine optimal dosing, monitor subjects for longer periods of time, and assess for discontinuation syndromes. Testing gabapentin alone and in combination with cognitive-behavioral therapy for insomnia will also be important, given the early successes of the latter in treating alcohol-dependent subjects (Arnedt et al., 2007
; Currie et al., 2004a
). In addition, investigating gabapentin’s effects on mechanisms such as hyperarousal of the central nervous system (Feige et al., 2007
) homeostatic sleep drive impairment (Irwin et al., 2002
) and circadian rhythm abnormalities (Danel et al., 2003
) may uncover nocturnal physiological effects that were not measured in this study.