What is the best first‑line medication for typical idiopathic restless‑leg syndrome?

Best First-Line Medication for Restless Leg Syndrome

Alpha-2-delta ligands—specifically gabapentin, gabapentin enacarbil, or pregabalin—are the best first-line medications for typical idiopathic restless leg syndrome, with dopamine agonists like ropinirole and pramipexole now explicitly recommended against for standard use due to high augmentation risk. 1

Why Alpha-2-Delta Ligands Are First-Line

• The American Academy of Sleep Medicine issues a strong recommendation with moderate certainty of evidence for gabapentin, gabapentin enacarbil, or pregabalin as first-line therapy for RLS 1
• These agents avoid augmentation—the paradoxical worsening of symptoms (earlier daily onset, increased intensity, spread to arms/trunk) that occurs in a substantial proportion of patients on dopamine agonists 1, 2
• Gabapentin should be started at 300 mg three times daily, increased by 300 mg/day every 3-7 days, targeting maintenance doses of 1800-2400 mg/day divided three times daily, with maximum studied doses up to 3600 mg/day 1
• Pregabalin offers the advantage of twice-daily dosing (starting 50 mg TID or 75 mg BID, increasing to 300 mg/day after 3-7 days, maximum 600 mg/day) and may have superior bioavailability compared to regular gabapentin 1

Why Dopamine Agonists Are No Longer Recommended

• The American Academy of Sleep Medicine issues a conditional recommendation with moderate certainty of evidence AGAINST the standard use of ropinirole for RLS 1, 2
• The same recommendation against standard use applies to pramipexole and rotigotine due to augmentation risk 1
• Augmentation occurs in 7-10% annually and presents as earlier symptom onset (afternoon instead of evening), increased intensity, and spread to upper extremities or trunk 1
• While the FDA label for ropinirole demonstrates efficacy (mean IRLS score improvements of 2.5-3.7 points vs placebo, with 53-73% responder rates vs 40-57% placebo) 3, these trials were not designed to assess long-term augmentation risk, which has since been established in observational studies 1
• Dopamine agonists may be considered only for short-term use in patients who prioritize immediate symptom relief over long-term safety—this is explicitly not the standard approach 1

Essential Pre-Treatment Assessment

• Check morning fasting serum ferritin and transferrin saturation after avoiding iron supplements for ≥24 hours before starting any medication 1
• Supplement with oral ferrous sulfate if ferritin ≤75 ng/mL or transferrin saturation <20% (conditional recommendation, moderate certainty) 1
• IV ferric carboxymaltose is strongly recommended for patients with appropriate iron parameters who don't respond to oral therapy 1
• Address exacerbating factors including alcohol, caffeine, antihistamines, serotonergic medications, antidopaminergic medications, and untreated obstructive sleep apnea 1

Treatment Algorithm

1. Assess iron status first: ferritin ≤75 ng/mL or transferrin saturation <20% warrants supplementation 1
2. Initiate alpha-2-delta ligand: gabapentin 300 mg TID (titrate to 1800-2400 mg/day) OR pregabalin 50 mg TID or 75 mg BID (titrate to 300-600 mg/day) 1
3. Monitor for side effects: dizziness and somnolence are common but typically transient 1
4. Reassess at 6-12 months: check iron studies and evaluate symptom control 1
5. For refractory cases: consider extended-release oxycodone or other low-dose opioids (conditional recommendation, moderate certainty) 1

Critical Pitfalls to Avoid

• Do NOT start with dopamine agonists despite older literature (including 2003-2010 studies 4, 5, 6) recommending them as first-line—the 2025-2026 American Academy of Sleep Medicine guidelines supersede this older evidence 1, 2
• Do NOT increase ropinirole dose if augmentation is suspected—this worsens the problem; instead, transition to an alpha-2-delta ligand 1, 2
• Do NOT use clonazepam, carbamazepine, valproic acid, cabergoline, or bupropion—these lack evidence and/or have significant safety concerns 1
• Do NOT assume "normal" ferritin (>50 ng/mL) is adequate—RLS requires higher thresholds (≤75 ng/mL) than general population guidelines 1

Special Populations

• End-stage renal disease: gabapentin 100 mg post-dialysis or at bedtime (maximum 200-300 mg daily); IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% 1
• Pediatric RLS: oral ferrous sulfate if ferritin <50 ng/mL 1
• Pregnancy: iron supplementation is particularly important; consider medication safety profiles carefully 1

Strength of Evidence

The 2025-2026 American Academy of Sleep Medicine guidelines 1 represent the highest-quality, most recent evidence and should guide all treatment decisions. While the FDA label for ropinirole 3 demonstrates short-term efficacy, and older research 7, 4, 5 supported dopamine agonists, the guideline's systematic review of augmentation risk (from observational studies not captured in initial RCTs) has fundamentally changed the treatment paradigm. Alpha-2-delta ligands are now unequivocally first-line.