Despite multiple studies evaluating various therapeutic agents, few have emerged as superior agents for the management of alcohol use disorders. As a result, off-label agents, including gabapentin, are being utilized more frequently in clinical practice. Gabapentin has gained popularity as one of the more commonly studied off-label agents. Gabapentin's relatively low abuse potential, side effect profile, and limited hepatic metabolism make it an attractive option compared with benzodiazepines and other anticonvulsants. Several randomized, placebo- and active-controlled trials have evaluated off-label use of gabapentin for the treatment of alcohol detoxification and dependence. Study results and interpretation from the more robust available data are summarized within this article.
Gabapentin is utilized for a variety of disease states that extend beyond its US Food and Drug Administration–approved indications for epilepsy and postherpetic neuralgia.1 These disease states include neuropathic pain, fibromyalgia, and restless leg syndrome. Growing evidence supports gabapentin as a promising option for the management of alcohol detoxification and dependence.
Although its exact mechanism of action is unknown, it is widely accepted that gabapentin modulates both gamma-aminobutyric acid (GABA) and glutamate tone.1-4 Modulation of these neurotransmitters is desirable to target the GABA deficit and glutamate excess that are prominent during alcohol withdrawal.2,3 Several additional characteristics make gabapentin an attractive option for the management of alcohol use disorders. With its relatively low abuse potential, gabapentin use can avoid concerns regarding prescribing controlled substances, such as benzodiazepines, on an outpatient basis. Additionally, gabapentin causes considerably less sedation and psychomotor impairment compared with benzodiazepines,1-4 which again may be of particular concern in the outpatient setting. Lastly, gabapentin does not undergo any appreciable hepatic metabolism.1 Patients with alcohol-related hepatic impairment may experience increased adverse effects related to poor metabolism of therapies traditionally used in treatment of alcohol detoxification or dependence.2-4 These features have led to further study in animals and humans, which have shown promising results.
Various studies have evaluated gabapentin's effect on withdrawal symptoms and cravings in the acute alcohol detoxification stage (Table 1).2,5-8 Two studies specifically evaluated the use of gabapentin for detoxification in the outpatient setting. Myrick and colleagues conducted the largest (n = 68) double-blind, active-controlled, dose comparison trial evaluating gabapentin's impact on withdrawal symptoms in outpatients.2 The authors found that gabapentin 1200 mg/day, divided in 3 doses, significantly reduced alcohol withdrawal symptoms compared with gabapentin 900 mg/day and lorazepam. Despite reaching statistical significance, the authors noted the difference was of minimal clinical significance compared with lorazepam. The higher dose of gabapentin also reduced cravings but did not demonstrate any consistent impact on reduced drinking. Stock et al also compared gabapentin with chlordiazepoxide in the outpatient population but found conflicting results.5 These authors concluded that gabapentin and chlordiazepoxide produced similar reductions in withdrawal symptoms and cravings; however, the smaller sample size of this study may have contributed to the nonsignificant findings.
Similar results were found in the inpatient setting. Mariani et al compared gabapentin with phenobarbital in 61 inpatients.6 The authors found no significant difference between the 2 treatments with regards to withdrawal symptoms or cravings although the small sample size might have limited the study's ability to detect significant differences in the measured outcomes. Furthermore, patients in both groups were able to receive additional rescue phenobarbital potentially masking gabapentin's effect on outcomes. Although there was no statistically significant difference between groups, there was a numerical trend toward more rescue phenobarbital use in the gabapentin group that could have potentially reached statistical significance with a larger patient sample. The use of phenobarbital as an active comparator may limit the applicability of the study results as phenobarbital is not frequently utilized to manage patients in acute alcohol withdrawal. Bonnet and colleagues conducted a randomized, double-blind, placebo-controlled trial evaluating the impact of gabapentin on symptom-triggered clomethiazole administration in an inpatient population.7 Clomethiazole is a sedative hypnotic commonly used in Europe for the treatment of acute alcohol withdrawal.9 Gabapentin 1600 mg/day, divided in 4 doses, failed to impact the amount of clomethiazole needed by inpatients in acute alcohol withdrawal.7 The latter study may more closely reflect how gabapentin is used in inpatient populations. Gabapentin is often prescribed to inpatients in conjunction with benzodiazepines administered via the symptom-triggered method. Little evidence exists evaluating this practice, and as demonstrated by the results of the Bonnet et al study, existing evidence does not support it.
Additional studies have been conducted assessing the impact of gabapentin on drinking-related outcomes in the alcohol-dependence setting (Table 2).3,4,10 In 2007, Furieri and colleagues conducted a randomized, double-blind, placebo-controlled trial in 60 alcohol-dependent outpatients.4 The authors found that gabapentin 300 to 600 mg/day reduced the number of drinking days, heavy drinking days, and cravings when compared with placebo. The positive findings were noteworthy considering the relatively low gabapentin doses used. In 2011, Anton et al conducted a randomized, double-blind, active- and placebo-controlled trial using a larger sample size. The study evaluated gabapentin 1200 mg/day plus naltrexone 50 mg/day versus naltrexone 50 mg/day versus placebo.3 Gabapentin and naltrexone were administered concomitantly for the first 6 weeks and then discontinued. Naltrexone was continued for another 10 weeks. Gabapentin plus naltrexone decreased the percentage of heavy drinking days and number of drinks per day compared to the naltrexone and placebo groups. The difference between groups diminished over time and was no longer statistically significant at 16 weeks. More recently, Mason and colleagues performed a randomized, double-blind, placebo-controlled, dose-comparison study and found gabapentin 1800 mg/day, divided in 3 doses, significantly improved abstinence rates, number of heavy drinking days, and alcohol cravings compared with gabapentin 900 mg/day and placebo.10 These dose-dependent effects persisted 12 weeks postgabapentin discontinuation. These results directly conflict with the Anton et al study, which found that benefits of gabapentin did not persist after its discontinuation.3 Differences in study design make it somewhat difficult to compare results from the 2 studies. The dose-dependent effects demonstrated in the study conducted by Mason and colleagues allude to potentially increased benefits when gabapentin is used at higher doses. Similar results were found in the Myrick et al study evaluating gabapentin use for alcohol detoxification management. Although compelling, these results need to be replicated prior to implementation in clinical practice.
Based on available evidence, gabapentin appears to be a viable option for monotherapy in the management of alcohol dependence. Several studies identified positive effects on drinking-related outcomes.3,4,10 At this time, it is unclear how long beneficial effects may persist. Additionally, the target gabapentin dose is unclear as the doses varied greatly among the studies. Higher doses may be more beneficial, but these results have yet to be replicated. Gabapentin's role in the management of alcohol detoxification has not been fully elucidated. Gabapentin failed to separate from active control in the majority of existing studies.2,5-7 Small sample sizes may have limited these studies' ability to detect significant findings. Studies comparing gabapentin with placebo may better indicate gabapentin's impact on alcohol withdrawal; however, the ethical considerations of administering placebo to patients in active withdrawal likely prevent these studies from being conducted. Larger, active-controlled studies are needed to adequately identify if gabapentin favorably impacts outcomes in the alcohol detoxification setting.
Disclosures: Funding: None. Conflict of Interest: None.