What is the best medication for restless legs syndrome (RLS)?

Best Medication for Restless Legs Syndrome

For adults with restless legs syndrome (RLS), alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are the recommended first-line medications based on strong evidence for efficacy and lower risk of long-term complications. 1

First-Line Treatment Algorithm

1. Address modifiable factors first:

   • Eliminate alcohol and caffeine consumption
   • Discontinue antihistaminergic, serotonergic, and antidopaminergic medications if possible
   • Treat untreated obstructive sleep apnea if present 1

2. Check iron status:

   • Measure serum ferritin and transferrin saturation (in the morning, after 24-hour avoidance of iron supplements/foods)
   • If ferritin ≤75 ng/mL or transferrin saturation <20%:
     • Oral ferrous sulfate (conditional recommendation, moderate evidence) 1
     • For ferritin between 75-100 ng/mL, consider IV iron therapy 1

3. First-line pharmacotherapy (strong recommendations with moderate evidence):

   • Gabapentin enacarbil (extended-release formulation)
   • Gabapentin (immediate-release)
   • Pregabalin 1

Second-Line Options

If alpha-2-delta ligands are ineffective or not tolerated:

• IV iron therapy options (for appropriate iron status patients):

  • IV ferric carboxymaltose (strong recommendation) 1
  • IV low molecular weight iron dextran (conditional recommendation) 1
  • IV ferumoxytol (conditional recommendation) 1

• Other pharmacological options:

  • Dipyridamole (conditional recommendation, low evidence) 1
  • Extended-release oxycodone or other opioids (conditional recommendation, moderate evidence) 1
  • Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate evidence) 1

Important Cautions

The 2025 AASM guidelines specifically recommend against the standard use of several medications that were previously considered first-line treatments:

• Dopamine agonists (pramipexole, ropinirole, rotigotine) are no longer recommended as first-line due to risk of augmentation with long-term use 1

  • Augmentation is a phenomenon where symptoms begin earlier in the day, increase in intensity, or spread to other body parts with continued treatment 2, 3
  • While ropinirole was previously FDA-approved for RLS 4, 5, newer evidence suggests better alternatives

• Levodopa is not recommended for standard use due to high risk of augmentation (up to 82% of patients) 6, 1

• Other medications specifically not recommended include:

  • Bupropion, carbamazepine, clonazepam, valproic acid, cabergoline, valerian 1

Special Populations

• End-stage renal disease patients with RLS:

  • Gabapentin is suggested (conditional recommendation) 1
  • IV iron sucrose for those with ferritin <200 ng/mL and transferrin saturation <20% 1
  • Vitamin C supplementation (conditional recommendation) 1

• Children with RLS:

  • Ferrous sulfate for those with appropriate iron status (conditional recommendation) 1
  • Iron supplementation for serum ferritin <50 ng/mL 1

• Pregnancy:

  • RLS is common during pregnancy; medication selection must consider pregnancy-specific safety profiles 1

Clinical Pearls

• Morning iron testing is essential for accurate results (avoid iron supplements/foods for 24 hours prior)
• Iron supplementation guidelines for RLS differ from general population guidelines
• Alpha-2-delta ligands (gabapentin compounds and pregabalin) have replaced dopamine agonists as first-line therapy due to lower risk of augmentation
• Dopamine agonists may still be used for short-term symptom relief when patients prioritize immediate symptom control over long-term adverse effects