As hypothesized, gabapentin, when combined with naltrexone, appeared to be well–tolerated and to improve overall efficacy above that noted for naltrexone-alone and for placebo. Surprisingly, perhaps, naltrexone-alone was not superior to placebo in this study, and in fact, on some measures, worse. This is consistent with the results from the COMBINE Study (4
), where naltrexone added nothing to the efficacy of the combined behavioral intervention (CBI). In the current study CBI was employed as the standard psychosocial intervention and was delivered, primarily, by the same therapists who delivered it for the COMBINE Study at our site, which was finished after this study had begun. In the COMBINE Study, only those who received naltrexone with a less intensive medical management approach showed efficacy over placebo. In that sense, the results of the current study are exactly what would have been predicted by the COMBINE Study, i.e. that CBI might mask the efficacy of naltrexone’s pharmacological effects. Despite this, it appeared that adding gabapentin to naltrexone was better than naltrexone-alone or placebo on several drinking, craving, and blood-marker outcome variables especially during the first six weeks when subjects were receiving gabapentin. While some of the positive effects seen of combining gabapentin and naltrexone during this time could still be observed over the next 10 weeks, for the most part these were no longer significant, implying that gabapentin effects occurred only while study subjects were actually taking it. We had hypothesized a priori that gabapentin might work best during the initial phases of abstinence when acute, and protracted, alcohol withdrawal effects might be the most pronounced. The hope was that by using gabapentin to ameliorate symptoms like insomnia, irritability, and withdrawal craving during this period, naltrexone might have a greater chance of working, and would continue to work once gabapentin was stopped. This hypothesis could not be validly confirmed.
While we did find an additive response of gabapentin to naltrexone in those with a history of current, or past, alcohol withdrawal, and also found some favorable effects on sleep while individuals were taking gabapentin, the importance of these findings is not clear. Others reported that gabapentin worked better than placebo in preventing relapse in patients who had undergone benzodiazepine detoxification, but did not compare them to non-detoxified individuals (10
). Our group recently reported that gabapentin worked significantly better than placebo only in those with clinically significant alcohol withdrawal at the time of study entry (11
). In that study gabapentin was adjunctive to an initial intravenous flumazenil, so the direct effect of gabapentin, by itself could not be validly affirmed. Group specificity (working only in those with alcohol withdrawal symptoms) and gabapentin’s longer-term period of dosing (over about 6–7 weeks, similar to the current trial) compared to flumazenil (2 days) does imply that gabapentin might have been the primary component of the effective treatment. Of note, in that study, those without current alcohol withdrawal actually did significantly worse on gabapentin compared to placebo, a finding consistent with reports in animals (26
). In the current study, this effect was not observed. However, the group size of the current post hoc exploratory analysis was small, and the definition of alcohol withdrawal history was defined post hoc, limiting the validity of this finding and requiring replication. Nevertheless, the confluence of results suggests that more evaluation of gabapentin by itself is necessary especially in alcoholics who do, and do not have current, or possibly past, alcohol withdrawal symptoms.
Interestingly, when gabapentin was stopped, there appeared to be some increase in drinking, with worsening in sleep (data not shown) - also noticeable, to some degree in the placebo group. It is hard to determine if this was a physiological response to discontinuing gabapentin or just an effect of taking fewer pills, especially those at bedtime. In a controlled sleep study, gabapentin improved alcohol-disrupted sleep (27
) and normalized sleep in non-treatment seeking alcoholics (28
). Our group reported that gabapentin normalized sleep during alcohol withdrawal better than lorazepam but only in those with histories of multiple detoxifications (29
). Karam-Hage and Brower (30
) had originally proposed that gabapentin might work to reduce relapse drinking by “normalizing” sleep, particularly in those who might drink to assist with sleep. However, in a more recent study in alcoholic insomniacs, they found that, while gabapentin delayed onset to heavy drinking after initial abstinence, its efficacy was not attributable to improved sleep (15
There was initial concern about the safety of gabapentin especially when it was ingested with alcohol. Several controlled studies done by us (31
) and others (14
) have assuaged that concern to a large degree. In this clinical trial, while there were some low-grade symptoms e.g. dizziness reported more frequently in the naltrexone plus gabapentin group, in general the medication was well tolerated, consistent with data from other relapse prevention trials with gabapentin alone (10
). Of note, since gabapentin is excreted in the urine, there would not be any expected interaction with naltrexone on liver metabolism and/or toxicity and none were noted in this trial.
Since gabapentin works on different neurophysiologic systems than naltrexone this combination of medication has some appeal. Naltrexone, as an opioid receptor antagonist, appears to reduce the reinforcing aspects of alcohol cues and consumption (3
), while reducing craving and slip drinking (33
). Gabapentin, working to normalize GABA and glutamate balance, might work best at restoring normal overall brain activity and tone and be most useful in those that have imbalances in these systems-like those experiencing acute or protracted alcohol withdrawal symptoms. As such, this combination of medication makes pharmacological sense and is consistent with what is known about the neuroscience of addiction in general, and specifically, the effects of alcohol on the brain. However, it is possible, since GABA and glutamate systems also play a role in reinforcement, extinction, and cue-induced learning (34
), that gabapentin might play a primary role in preventing alcohol relapse and reducing drinking similar to other anticonvulsants, like topiramate (35
), that have similar basic pharmacological and brain effects. It should be noted, however, in some pilot work done by our group in a laboratory paradigm designed to test the alcohol anti-reinforcement effects of medication, that gabapentin did not appear to block craving and drinking behavior (36
) in the same way that naltrexone had done previously (32
). However, others have found some effects of gabapentin on alcohol cue-induced craving (28
Limitations of this study include being a single site study with a limited number of individuals with alcohol dependence who did not have other significant psychiatric conditions, who were not on psychiatric medications, who were medically stable, and who, for the most part, were motivated towards abstinence. Individuals received an efficacious psychosocial intervention along with medication and were encouraged to comply with medications and the study protocol. In addition, since this study was started prior to knowledge of the potential prediction of naltrexone response by a mu opioid receptor genetic polymorphism (38
) we could not account for this potential confound. Finally, the independent effect of gabapentin alone could not be evaluated in this study design.
In sum, the addition of gabapentin to naltrexone for the treatment of alcohol dependence seems efficacious and well tolerated. While there are hints that this combination might work best in those who have previously experienced alcohol withdrawal symptoms, further study is needed to confirm this speculation. In addition, these data combined with that of others, suggest that future studies should explore the use of gabapentin-alone while taking into account current, or past, acute and protracted alcohol withdrawal signs and symptoms including sleep difficulties and craving. A better understanding of the role of gabapentin, and other anticonvulsants, on reinforcement and extinction issues is needed.