What is the first‑line treatment for restless legs syndrome?

First-Line Treatment for Restless Legs Syndrome

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are strongly recommended as first-line therapy for restless legs syndrome, with dopamine agonists now relegated to second-line status due to their high risk of augmentation. 1, 2

Initial Assessment Before Starting Medication

Before initiating any pharmacologic therapy, you must address two critical factors:

• Check morning fasting serum ferritin and transferrin saturation after withholding iron supplements for at least 24 hours 2
• Supplement iron if ferritin ≤ 75 ng/mL or transferrin saturation < 20%—these are RLS-specific thresholds, higher than general population cut-offs 1, 2
• Identify and eliminate RLS-exacerbating factors: alcohol, caffeine, antihistamines, serotonergic antidepressants, antidopaminergic medications, and untreated obstructive sleep apnea 2

First-Line Pharmacologic Options (Strong Recommendations)

The American Academy of Sleep Medicine strongly recommends the following alpha-2-delta ligands with moderate certainty of evidence 1, 2:

Gabapentin

• Start 300 mg three times daily 2
• Titrate by 300 mg/day every 3–7 days to target maintenance dose of 1800–2400 mg/day divided TID 1, 2
• Maximum studied dose is 3600 mg/day 2
• Common side effects include somnolence and dizziness, typically transient and mild 2

Pregabalin

• Start 50 mg TID or 75 mg BID 2
• After 3–7 days, increase to 300 mg/day; thereafter raise by 150 mg every 3–7 days as tolerated 2
• Maximum dose 600 mg/day 2
• Allows twice-daily dosing with potentially superior bioavailability compared to regular gabapentin 2

Gabapentin Enacarbil

• Prodrug of gabapentin, also strongly recommended 2
• Provides more consistent absorption than regular gabapentin 3

Iron Supplementation Options

If iron parameters are low:

• Oral ferrous sulfate 325 mg daily (or every other day to improve tolerability) is conditionally recommended 2
• IV ferric carboxymaltose 750–1000 mg in one or two infusions is strongly recommended for patients who cannot tolerate oral iron, fail oral therapy, or have ferritin 75–100 ng/mL despite oral treatment 2

Why Dopamine Agonists Are No Longer First-Line

The 2025 American Academy of Sleep Medicine guidelines represent a major shift from older recommendations 2:

• Dopamine agonists (pramipexole, ropinirole, rotigotine) carry a 7–10% annual risk of augmentation—a paradoxical worsening characterized by earlier symptom onset, increased intensity, and spread to arms or trunk 1, 2
• The American Academy of Sleep Medicine now conditionally recommends against their standard use (moderate certainty of evidence) 1, 2
• They may be considered only for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects 2

Non-Pharmacologic Approaches (Concurrent Implementation)

• Moderate exercise, smoking cessation, alcohol avoidance, caffeine reduction or elimination 1
• Mental alerting activities, massaging affected legs, hot baths 3
• Optimize sleep environment: dark, quiet, comfortable temperature 2

Medications to Avoid

The American Academy of Sleep Medicine specifically recommends against 2:

• Cabergoline (strong recommendation—cardiac valvular fibrosis risk)
• Bupropion, carbamazepine, clonazepam, valproic acid, valerian (conditional recommendations—insufficient efficacy or safety concerns)

Treatment Algorithm Summary

1. Assess iron status (ferritin, transferrin saturation) and supplement if ferritin ≤ 75 ng/mL or transferrin saturation < 20% 1, 2
2. Eliminate exacerbating factors (medications, substances, untreated sleep apnea) 2
3. Start alpha-2-delta ligand (gabapentin 300 mg TID or pregabalin 50 mg TID/75 mg BID) 1, 2
4. Titrate to effective dose over 3–7 days based on symptom response 2
5. Monitor for side effects (dizziness, somnolence) and evaluate both nighttime symptom relief and daytime functioning 2
6. Reassess iron studies every 6–12 months, as brain iron deficiency may persist despite clinical improvement 2

Common Pitfalls to Avoid

• Do not use dopamine agonists as first-line therapy given current evidence favoring alpha-2-delta ligands and high augmentation risk 1, 2
• Do not apply general-population ferritin cut-offs (< 15 ng/mL); RLS requires higher thresholds (≤ 75 ng/mL) 2
• Do not use clonazepam as monotherapy—it only provides sedation without addressing underlying RLS pathology 1, 2
• Do not assume "normal" caffeine or alcohol consumption is acceptable—even moderate evening intake significantly worsens RLS symptoms 2