What is the best medication for restless‑leg syndrome in adults?

Best Medication for Restless Legs Syndrome

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are the best first-line medications for RLS in adults, with strong evidence supporting their efficacy and safety profile superior to dopamine agonists. 1

First-Line Treatment: Alpha-2-Delta Ligands

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands as first-line therapy with moderate certainty of evidence, representing a major shift from older guidelines that favored dopamine agonists. 1 This recommendation prioritizes long-term quality of life and avoids the serious complication of augmentation that plagues dopaminergic therapy.

Specific medication options include:

• Gabapentin: Start 300 mg three times daily, increase by 300 mg/day every 3-7 days, target maintenance 1800-2400 mg/day divided TID, maximum 3600 mg/day 1
• Pregabalin: Allows twice-daily dosing with superior bioavailability compared to regular gabapentin 1
• Gabapentin enacarbil: A prodrug of gabapentin with consistent absorption 1

All three agents have equivalent strong recommendations with moderate certainty of evidence. 1

Critical Step Before Any Medication: Iron Assessment

Check morning fasting serum ferritin and transferrin saturation after avoiding iron supplements for ≥24 hours. 1 This is non-negotiable because iron deficiency is a reversible cause of RLS.

Iron supplementation thresholds specific to RLS (different from general population):

• Adults: Supplement if ferritin ≤75 ng/mL OR transferrin saturation <20% 1
• Children: Supplement if ferritin <50 ng/mL 1

Iron therapy options:

• Oral ferrous sulfate: Conditional recommendation for appropriate iron parameters 1
• IV ferric carboxymaltose: Strong recommendation for rapid correction, especially if oral iron fails after 3 months 1

Why NOT Dopamine Agonists as First-Line

The American Academy of Sleep Medicine suggests AGAINST standard use of dopamine agonists (pramipexole, ropinirole, rotigotine) due to high augmentation risk. 1, 2 This represents a critical change from older 2009 guidelines. 2

Augmentation is a devastating complication characterized by:

• Earlier symptom onset during the day 1, 3
• Increased symptom intensity 1, 3
• Spread to arms or trunk 1, 3
• Paradoxical worsening despite dose increases 4, 3
• Annual incidence of 7-10% with dopamine agonists 1

While ropinirole demonstrated efficacy in FDA trials with mean IRLS score improvements of 2.5-3.7 points versus placebo 5, the long-term augmentation risk outweighs short-term benefits for most patients. 1

Dopamine agonists may only be considered for short-term use in patients who prioritize immediate symptom relief over long-term safety. 1, 2

Second-Line and Refractory RLS Treatment

For patients who fail alpha-2-delta ligands and iron optimization:

• Extended-release oxycodone and other low-dose opioids: Conditionally recommended for moderate to severe refractory RLS 1, 4
• Long-term studies show relatively low abuse risk with only small dose increases over 2-10 years in appropriately screened patients 1
• Particularly effective for treating augmentation when transitioning off dopamine agonists 1, 4

Non-pharmacological option:

• Bilateral high-frequency peroneal nerve stimulation: Conditional recommendation with moderate certainty 1

Medications to Absolutely Avoid

Strong recommendations AGAINST:

• Cabergoline 1
• Bupropion 1
• Carbamazepine 1
• Clonazepam 1
• Valproic acid 1
• Valerian 1
• Levodopa (very low certainty, high augmentation risk) 1

Special Populations

End-stage renal disease:

• Gabapentin: Start 100 mg post-dialysis or at bedtime, maximum 200-300 mg daily 1
• IV iron sucrose if ferritin <200 ng/mL AND transferrin saturation <20% 1
• Vitamin C supplementation 1

Pregnancy:

• Iron supplementation particularly important given pregnancy-specific RLS prevalence 1
• Oral formulations favored throughout gestation 1

Critical Pitfalls to Avoid

• Never start dopamine agonists as first-line therapy given current evidence favoring alpha-2-delta ligands 1, 2
• Do not increase dopamine agonist doses if augmentation is suspected—this worsens the problem 2
• Address exacerbating factors: alcohol, caffeine, antihistamines, SSRIs, antipsychotics, untreated sleep apnea 1
• Monitor for side effects of alpha-2-delta ligands: dizziness and somnolence, particularly in patients with untreated sleep apnea 1

Treatment Algorithm Summary

1. Check iron studies (ferritin, transferrin saturation) 1
2. Supplement iron if ferritin ≤75 ng/mL or transferrin saturation <20% 1
3. Start alpha-2-delta ligand (gabapentin, pregabalin, or gabapentin enacarbil) 1
4. Titrate to effective dose over several weeks 1
5. If refractory, consider extended-release oxycodone or other low-dose opioids 1
6. Reassess iron studies every 6-12 months even after symptom resolution 1