Is gabapentin used to treat restless‑legs syndrome (RLS)?

Gabapentin for Restless Legs Syndrome

Yes, gabapentin is strongly recommended as first-line therapy for restless legs syndrome (RLS), with the American Academy of Sleep Medicine providing a strong recommendation based on moderate certainty of evidence. 1, 2

First-Line Treatment Status

• Gabapentin, gabapentin enacarbil, and pregabalin (alpha-2-delta ligands) are the preferred initial pharmacological treatments for moderate to severe RLS, replacing dopamine agonists which carry high augmentation risk. 1, 2

• The 2025 American Academy of Sleep Medicine guidelines explicitly prioritize these agents over dopaminergic medications due to superior long-term safety profiles and absence of augmentation—a paradoxical worsening of symptoms that occurs with dopamine agonists. 1, 2

Evidence Supporting Gabapentin Use

• Gabapentin significantly improves both subjective RLS symptoms and objective measures, including reduction in periodic leg movements during sleep (PLMS) and PLMS index, with improvements sustained over 4-10 months of follow-up. 3, 4

• In head-to-head comparison, gabapentin 300-1,200 mg daily provided similarly effective symptom control as ropinirole 0.25-1.50 mg daily, with both agents reducing International RLS Study Group questionnaire scores significantly. 3

• Gabapentin enacarbil (the prodrug formulation) demonstrates superior bioavailability and sustained efficacy in 12-week trials, with lower relapse rates compared to placebo in maintenance studies and no reports of augmentation or QT-interval prolongation. 5, 6, 7

Proper Dosing Strategy

• Start gabapentin at 300 mg three times daily (not single nighttime dosing), then titrate by 300 mg/day every 3-7 days until reaching maintenance dose of 1,800-2,400 mg/day divided three times daily. 1

• Single nighttime dosing fails to address daytime RLS symptoms and provides suboptimal 24-hour coverage—a common prescribing error. 1

• Maximum studied dose is 3,600 mg/day, though most patients achieve adequate control at 1,800-2,400 mg/day. 1

• For gabapentin enacarbil specifically, the FDA approved 600 mg once-daily dosing, though clinical trials suggest 1,200 mg once-daily may be more effective for severe sleep disturbance associated with RLS, despite higher rates of somnolence and dizziness. 5

Critical Pre-Treatment Assessment

• Check morning fasting serum ferritin and transferrin saturation before starting gabapentin, ideally after avoiding iron supplements for ≥24 hours. 1, 2

• Supplement with iron if ferritin ≤75 ng/mL or transferrin saturation <20%—thresholds specific to RLS that differ from general population guidelines. 1, 2

• IV ferric carboxymaltose is strongly recommended for rapid correction when these parameters are met, while oral ferrous sulfate is a slower alternative. 1, 2

Advantages Over Dopamine Agonists

• The American Academy of Sleep Medicine now suggests against standard use of pramipexole, ropinirole, and rotigotine due to augmentation risk (7-10% annual incidence), which manifests as earlier symptom onset, increased intensity, and spread to arms/trunk. 1, 2

• Gabapentin carries no augmentation risk and provides more favorable long-term outcomes, making it the preferred choice even though dopamine agonists were historically considered first-line. 1, 2

Special Populations

• In end-stage renal disease, start gabapentin at 100 mg post-dialysis or at bedtime, with maximum 200-300 mg daily (conditional recommendation, very low certainty). 1, 2

• Pregabalin should be avoided in dialysis patients due to increased hazard for altered mental status and falls (50-68% higher risk). 1

• Gabapentin is conditionally recommended for RLS in pregnancy, with careful consideration of medication safety profiles. 1

Common Pitfalls to Avoid

• Do not use gabapentin as monotherapy without first correcting iron deficiency—iron status directly impacts RLS pathophysiology independent of gabapentin effects. 1

• Do not prescribe single nighttime dosing—this outdated approach fails to provide adequate daytime symptom control. 1

• Monitor for somnolence and dizziness, which are the most common adverse events but typically mild to moderate and transient. 1, 6

• Evaluate for untreated obstructive sleep apnea before starting gabapentin, as alpha-2-delta ligands may worsen respiratory depression in this population. 1

• Address exacerbating factors including alcohol, caffeine, antihistamines, serotonergic medications, and antidopaminergic agents. 1, 2

Alternative Alpha-2-Delta Ligands

• Pregabalin is equally strongly recommended as first-line therapy, allowing twice-daily dosing with potentially superior bioavailability compared to regular gabapentin. 1, 2

• Pregabalin dosing starts at 50 mg three times daily or 75 mg twice daily, increasing to 300 mg/day after 3-7 days, then by 150 mg every 3-7 days as tolerated, with maximum 600 mg/day. 1

• Regular gabapentin and pregabalin are cost-effective alternatives to gabapentin enacarbil, providing equivalent efficacy at negligible cost. 1

Refractory Cases

• Extended-release oxycodone and other low-dose opioids are conditionally recommended for moderate to severe refractory RLS, particularly when treating augmentation from dopamine agonists. 1, 2

• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-pharmacological option. 1, 2