Gabapentin enacarbil for the treatment of moderate to severe primary restless legs syndrome (Willis-Ekbom disease): 600 or 1,200 mg dose?

Abstract

Gabapentin enacarbil is a prodrug of the anticonvulsant gabapentin. The efficacy and safety of gabapentin enacarbil for the treatment of moderate to severe primary restless legs syndrome (RLS) has been evaluated in several clinical trials in the United States and Japan. Although most clinical trials assessed gabapentin enacarbil at doses greater than 600 mg/day and demonstrated the overall safety and efficacy (defined as improvements in the coprimary endpoints of the international RLS rating scale [IRLS] total score and Clinical Global Impression-Improvement response), the US Food and Drug Administration approved the 600 mg once-daily dosage because doses higher than 600 mg/day were considered to provide no additional benefits and were associated with higher rates of adverse events, such as somnolence and dizziness. Nonetheless, the results of clinical trials and post hoc meta-analyses have indicated that the 1,200 mg once-daily dosage was the most validated gabapentin enacarbil treatment for not only subjective RLS symptoms but also severe sleep disturbance associated with RLS. A Japanese dose-finding study showed that 900 mg/day, the intermediate dose between 600 and 1,200 mg, failed to show a significant improvement in IRLS total score, probably because many of the patients who discontinued treatment did so early, suggesting that a half-landing dose may cause more adverse effects than favorable ones in some RLS patients early in the treatment. Gabapentin enacarbil may have two distinct therapeutic doses for the treatment of RLS: 600 mg/day or lower doses for the treatment of subjective RLS symptoms and 1,200 mg/day or higher doses for the treatment of both subjective RLS symptoms and associated problems such as severe sleep disturbances.

Restless legs syndrome—current therapies and management of augmentation

“…Factors that indicate a dopamine agonist as the preferred therapy ■ Increased number of periodic limb movements in sleep at night 5,16,42,48,58,59,81 ■ Periodic limb movements and motor symptoms during the day 15,51,61,83 ■ Comorbid depression 40,47,107,108, Factors that indicate α-2-δ ligands as the preferred therapy ■ Sleep disturbance with insomnia in addition to RLS 5,24,63,71,73,75,79 ■ Comorbid pain syndrome 74 ■ Polyneuropathy 74 ■ History of or recurrent impulse control disorder 68,69,104 ■ Comorbid generalized anxiety disorder 70,77 Factors that indicate oxycodone-naloxone or other opioids as the preferred therapy ■ Previous failure of other treatments 10 is an established treatment for attacks of RLS or RLS that is triggered in specific situations, such as pro longed sitting, but no controlled data on this approach has been published. Pramipexole has also been used in this context, as it is shortacting and has a rapid onset of action.…”

“…30 Indeed, most clinical trials of gaba pentin enacarbil, including those in pain and epilepsy, have demonstrated the efficacy and safety of doses above 600 mg daily, but the FDA considered higher doses to be associated with more adverse effects, such as somnolence and dizziness, with no additional benefit. 73 In practice, treatment is usually started with a dose of 300 mg each evening, which is increased to 600 mg or 1,200 mg if RLS symptoms do not improve sufficiently to achieve a satisfactory quality of sleep.…”

Quantitative Comparison of the Efficacies of 5 First‐Line Drugs for Primary Restless Leg Syndrome

“…Dose selection of gabapentin enacarbil for treating RLS has been a controversial topic . In the included studies, high doses of gabapentin enacarbil (1800 mg and 2400 mg) showed no superiority to lower doses in reducing the IRLS score .…”

Restless legs syndrome: clinical presentation diagnosis and treatment

“…Doses higher than 600 mg were thought to provide no additional benefits and increase the chance of adverse reactions. However, the results of post hoc meta-analyses have indicated that the 1,200 mg once-daily dosage was effective not only in relieving subjective RLS symptoms but also severe sleep disturbance associated with RLS [135].…”