Review of: Falk DE et al, Alcohol Clin Exp Res 2019;43(1):158–169

Gabapentin enacarbil extended-release (GE-XR) (Horizant) is an extended-release version of gabapentin. GE-XR is a prodrug, meaning that once ingested it is metabolized into gabapentin. It is currently approved for treatment of postherpetic neuralgia and restless legs syndrome. It differs from the immediate-release version in dosing (twice a day for the GE-XR, as opposed to three times a day) and has less variable blood levels. Several previous studies showed that IR gabapentin may be helpful for reducing withdrawal symptoms and promoting abstinence in alcohol use disorder (AUD) (Anton RF et al, Am J Psychiatry 2011;168(7):709–717; Mason BJ et al, JAMA Intern Med 2014;174(1):70–77). Since an extended release version might be easier to prescribe and increase adherence, researchers tested this XR formulation for AUD.

This randomized, double-blind, placebo-controlled trial assigned 346 adults with moderate AUD to two groups: the treatment group (n = 173) received GE-XR tablets titrated to 600 mg twice daily, whereas the control group (also n = 173) received identical placebo tablets. Moderate AUD was defined as ingestion of at least 21 standard drinks per week for women and at least 28 standard drinks per week for men (1 standard drink = 0.6 oz of pure alcohol). Participants were not currently using any other substances and were not diagnosed with a major psychiatric disorder. The trial lasted 26 weeks.

The primary outcome was change in the percentage of subjects with no heavy drinking days (defined as 4 or more drinks (women) or 5 or more drinks (men) per drinking day). There were several secondary outcomes, such as percentage of heavy drinking days, percentage of days abstinent, and others. For the primary outcome and all secondary outcomes, no statistical advantage was seen between the GE-XR group and placebo. Patients taking GE-XR actually did significantly worse than the placebo group in two of the secondary outcomes: average number of DSM-5 AUD criteria (3.4 vs 2.8, p = 0.046) and depressive symptoms on the Beck Depression Inventory-II (6.5 vs 5.2, p = 0.046).

For the safety assessment, patients in the GE-XR group reported significantly more fatigue (25.9%), somnolence (17.6%), and tremor (5.9%) than the placebo group. There were also more patients reporting suicidal ideation in the GE-XR group (7 vs 1, but just below significance level at p = 0.067).

CATR’s Take
This study had a strong design, adequate sample size, and a basis for success in the previous positive trials of IR gabapentin (Mason BJ et al, JAMA Intern Med 2014;174(1):70–77). However, GE-XR didn’t show any positive outcomes and even had worse outcomes for AUD and depressive symptoms. Negative findings may have potentially been due to the dosing used in this trial or altered bioavailability of the XR prodrug formulation in an AUD population. Regardless, GE-XR at the dose studied in this trial can’t be recommended for treating AUD at this time.