What is the treatment for restless leg syndrome?

Treatment for Restless Legs Syndrome

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacological therapy for RLS, with iron supplementation for patients with ferritin ≤75 ng/mL or transferrin saturation <20%. 1

Initial Assessment and Iron Management

Before starting any medication, check iron status in all patients with clinically significant RLS:

• Obtain morning serum ferritin and transferrin saturation after avoiding iron supplements for at least 24 hours 1, 2
• Supplement with iron if ferritin ≤75 ng/mL or transferrin saturation <20% (note this threshold is higher than general population guidelines) 1, 2
• Start with oral ferrous sulfate for mild iron deficiency (conditional recommendation, moderate certainty) 2
• Use IV ferric carboxymaltose if oral supplementation fails or for more rapid repletion (strong recommendation, moderate certainty) 1, 2

Address Exacerbating Factors

Identify and eliminate medications or substances that worsen RLS before initiating pharmacotherapy:

• Discontinue or substitute antihistamines, SSRIs, tricyclic antidepressants, and antipsychotics (dopamine antagonists like lurasidone can trigger or worsen RLS) 1
• Reduce or eliminate alcohol and caffeine 1, 2
• Treat untreated obstructive sleep apnea if present 1, 2

First-Line Pharmacological Treatment

Alpha-2-delta ligands are the preferred initial therapy due to superior long-term efficacy and lower risk of augmentation compared to dopaminergic agents:

• Gabapentin enacarbil (strong recommendation, moderate certainty) 1, 2
• Gabapentin (strong recommendation, moderate certainty) 1, 2
• Pregabalin (strong recommendation, moderate certainty) 1, 2

Monitor for side effects including dizziness and somnolence, particularly in patients with untreated sleep apnea or COPD 1

Medications to Avoid or Use with Extreme Caution

Dopamine agonists (pramipexole, ropinirole, rotigotine) are NOT recommended for standard use due to high risk of augmentation—a paradoxical worsening of symptoms with long-term use characterized by earlier onset during the day, increased intensity, and spread to other body parts 1, 2, 3:

• The American Academy of Sleep Medicine suggests AGAINST standard use of pramipexole (conditional recommendation, moderate certainty) 1, 3
• The American Academy of Sleep Medicine suggests AGAINST standard use of ropinirole (conditional recommendation, moderate certainty) 2
• The American Academy of Sleep Medicine suggests AGAINST standard use of transdermal rotigotine (conditional recommendation, low certainty) 1
• The American Academy of Sleep Medicine suggests AGAINST standard use of levodopa (conditional recommendation, very low certainty) 1, 2
• The American Academy of Sleep Medicine STRONGLY recommends AGAINST cabergoline (strong recommendation, moderate certainty) 1, 2

These agents may only be considered for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects, but this is not the standard approach 2

Second-Line and Refractory Treatment Options

For patients who fail first-line therapy or develop augmentation from dopaminergic agents:

• Extended-release oxycodone and other low-dose opioids (conditional recommendation) for moderate to severe or refractory cases 1
  • Long-term studies show relatively low risks of abuse with appropriate screening and only small dose increases over 2-10 years 1
  • Caution: Monitor for respiratory depression and central sleep apnea, especially in patients with untreated OSA 1
• Bilateral high-frequency peroneal nerve stimulation as a non-pharmacological option (conditional recommendation, moderate certainty) 1, 2
• Dipyridamole (conditional recommendation, low certainty) 1

Managing Augmentation from Dopamine Agonists

If augmentation develops (earlier symptom onset, increased intensity, spread to other body parts):

• Add an alpha-2-delta ligand or low-dose opioid FIRST before attempting to reduce the dopamine agonist 4
• Once adequate symptom control is achieved with the second agent, very slowly down-titrate and discontinue the dopamine agonist 4
• Abrupt discontinuation causes severe rebound RLS and insomnia, so the transition must be gradual 4

Special Populations

End-stage renal disease:

• Gabapentin (conditional recommendation, very low certainty) 1, 2
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (conditional recommendation, moderate certainty) 1, 2
• Vitamin C (conditional recommendation, low certainty) 1, 2

Pregnancy:

• Consider medication safety profiles specific to pregnancy 1, 2
• Non-pharmacological approaches may be preferred 2

Pediatric RLS:

• Oral iron supplementation for ferritin <50 ng/mL (conditional recommendation, very low certainty) 1, 2

Common Pitfall to Avoid

The most critical error is starting with dopamine agonists as first-line therapy. While ropinirole and pramipexole are FDA-approved for RLS 5 and were historically considered first-line 6, 7, 8, current 2025 guidelines from the American Academy of Sleep Medicine have shifted away from these agents due to the high risk of augmentation with long-term use 1, 2, 3. Augmentation can make RLS significantly worse than baseline and is difficult to reverse, requiring complex medication transitions 4.