Gabapentin Enacarbil for Sleep Disturbance in Restless Legs Syndrome

Abstract & Commentary

By Melissa J. Nirenberg, MD, PhD, Assistant Professor, Neurology and Neuroscience, Weill Cornell Medical College. Dr. Nirenberg reports no financial relationships relevant to this field of study.

Synopsis: Gabapentin enacarbil is effective for sleep disturbance in moderate-to-severe primary restless legs syndrome, but frequently causes sleepiness and dizzinesss.

Source: Winkelman JW, et al. Randomized polysomnography study of gabapentin enacarbil in subjects with restless legs syndrome. Mov Disord 2011; doi: 10.1002/mds.23771. [Epub ahead of print]

Restless legs syndrome (rls) is characterized by ir-resistible urges to move to alleviate uncomfortable or painful sensations in the legs. The symptoms are characteristically worse at night and increase with recumbency. RLS can be idiopathic (primary RLS), a side effect of medications (such as antidepressants), or secondary to other conditions (such as pregnancy, renal failure, or a low ferritin level). RLS often is accompanied by periodic limb movements of sleep (PLMS) — involuntary movements that can lead to nocturnal awakenings and associated sleep fragmentation.

In this study, the authors evaluate the safety and efficacy of gabapentin enacarbil, a prodrug of gabapentin, in the treatment of sleep disturbance in RLS. They used a multicenter, randomized, double-blind, placebo-controlled, crossover design with polysomnography to evaluate subjects with moderate-to-severe primary RLS. A total of 136 subjects were randomized, and 114 completed the study. The primary outcome measure was the mean change from baseline in wake time during sleep at weeks 4 and 10; a secondary endpoint was the mean change in frequency of PLMS associated with arousal at these same time points.

Results of the study showed significantly reduced wake time during sleep by 26 minutes (P < 0.0001), and a decreased frequency of periodic limb movements with arousal during sleep when compared with placebo. Side effects were common and similar to those of gabapentin; these included dizziness (20% vs 2% with placebo) and somnolence (13% vs 2% with placebo).


Until recently, the only FDA-approved treatments for RLS were the dopamine agonists ropinirole and pramipexole, both of which can have serious side effects such as impulse control disorders, orthostatic hypotension, and sudden-onset episodes of sleep. Moreover, long-term treatment with these medications can cause drug tolerance, augmentation, and rebound. Accordingly, there has been considerable interest in finding a safer, more effective treatment for RLS and associated sleep disturbance. Gabapentin may afford such benefits, but its usage remains off-label; in contrast, gabapentin enacarbil (Horizant) recently received FDA approval for this indication.

In this study, the authors show that gabapentin enacarbil reduces RLS-associated sleep disturbance. Strengths of the study include the randomized, multicenter, placebo-controlled design, and the use of objective, quantifiable outcome measures. Weaknesses include the short follow-up period, such that the study did not examine potential long-term complications such as augmentation and rebound. In addition, the primary outcome measure — wake time during sleep — does not distinguish between a non-specific sedating effect of the drug vs a specific effect on RLS-associated sleep disturbance. The effect size was also relatively small, and therefore of unclear clinical significance. The dosage used in this study was 1,200 mg daily; it should be noted that the recommended (FDA-approved) dosage is 600 mg/day.

The major question that remains unanswered is whether the short- and long-term efficacy, safety, and tolerability of gabapentin enacarbil are superior to that of other treatments for RLS and associated sleep disturbance. In particular, further studies are warranted to determine whether gabapentin enacarbil has any advantages over immediate-release gabapentin.