Gabapentin Enacarbil Dosing for Restless Legs Syndrome
The FDA-approved and recommended dose of gabapentin enacarbil for Restless Legs Syndrome is 600 mg once daily, taken at approximately 5 PM with food. 1
Pre-Treatment Requirements
Before initiating gabapentin enacarbil, complete the following mandatory assessments:
Check iron studies (morning fasting ferritin and transferrin saturation) and supplement if ferritin ≤75 ng/mL or transferrin saturation <20%, as iron deficiency plays a key role in RLS pathophysiology. 1, 2
Review and discontinue exacerbating medications including antihistamines, serotonergic agents (SSRIs, SNRIs), antidopaminergics (antipsychotics), alcohol, and caffeine. 1, 2
Screen for untreated obstructive sleep apnea, which can worsen RLS symptoms and increase risk of respiratory depression with gabapentinoids. 1, 2
Standard Dosing Protocol
- Dose: 600 mg once daily 1
- Timing: Approximately 5 PM 1
- Administration: With food (critical for optimal absorption of this prodrug formulation) 1
Dose Considerations: 600 mg vs 1200 mg
While the FDA approved only the 600 mg dose due to higher adverse event rates at 1200 mg, the evidence reveals important nuances:
The 1200 mg dose demonstrated superior efficacy for both subjective RLS symptoms and severe sleep disturbances in multiple trials, with significantly greater reductions in wake time during sleep (-26 minutes vs placebo) and periodic limb movements with arousal. 3, 4, 5
The 600 mg dose showed mixed results—some trials found it similar to placebo for symptom improvement, while pooled analyses in severe RLS showed significant benefit. 3, 6, 5
Intermediate doses (900 mg) failed to show significant improvement and may cause more adverse effects than benefits due to early discontinuation. 3
Clinical approach: Start with 600 mg as FDA-approved; if inadequate response after 2-4 weeks and patient tolerates initial dose well, consider escalation to 1200 mg for patients with severe symptoms or significant sleep disturbance, accepting higher rates of somnolence (21-24%) and dizziness (14-19%). 3, 6, 5
Long-Term Maintenance
Gabapentin enacarbil maintains efficacy for at least 9 months, with only 9% relapse rate compared to 23% with placebo in responders. 7
Key advantage over dopaminergic agents: No risk of augmentation (paradoxical worsening of symptoms with earlier onset, increased intensity, and anatomic spread). 1, 2
Special Populations
Pregnancy: Consider pregnancy-specific safety profiles when treating RLS in pregnant women. 1
Renal impairment: Gabapentin enacarbil requires dose adjustment; standard gabapentin (not the enacarbil prodrug) is preferred in end-stage renal disease at 100-300 mg daily. 8
Common Pitfalls to Avoid
Do not dose at bedtime—the 5 PM timing is critical as RLS symptoms worsen in the evening and peak at night. 1
Do not skip the food requirement—gabapentin enacarbil is a prodrug requiring intestinal transporters that are optimized with food intake. 1
Do not initiate without checking iron status first—correcting iron deficiency may significantly improve symptoms independent of medication. 1, 2
Monitor for somnolence and dizziness, which are the most common adverse events and may increase fall risk, particularly in elderly patients. 4, 6, 5