What are the recommended medications for treating Restless Legs Syndrome (RLS)?

Medication Choice for Restless Legs Syndrome

First-Line Treatment Recommendation

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are the recommended first-line medications for RLS, not dopamine agonists. 1

The American Academy of Sleep Medicine strongly recommends these agents with moderate certainty of evidence, representing a significant shift from older treatment paradigms that favored dopaminergic medications. 1

Treatment Algorithm

Step 1: Address Iron Deficiency First

• Check serum ferritin and transferrin saturation in all patients with clinically significant RLS, ideally in the morning after avoiding iron supplements for at least 24 hours. 1
• If ferritin ≤75 ng/mL or transferrin saturation <20%, initiate iron supplementation before or concurrent with pharmacological treatment. 1
  • IV ferric carboxymaltose is strongly recommended (strong recommendation, moderate certainty). 1
  • Oral ferrous sulfate is conditionally recommended (conditional recommendation, moderate certainty). 1
• Note that RLS requires higher ferritin targets (≥75 ng/mL) than general population guidelines due to brain iron deficiency playing a key role in pathophysiology. 1

Step 2: Identify and Remove Exacerbating Factors

• Discontinue or substitute medications that worsen RLS: antihistamines, serotonergic antidepressants (SSRIs), antidopaminergic agents (antipsychotics like lurasidone), and tricyclic antidepressants. 1
• Reduce or eliminate alcohol and caffeine intake. 1
• Treat untreated obstructive sleep apnea if present. 1

Step 3: Initiate First-Line Pharmacological Treatment

Alpha-2-delta ligands (all with strong recommendations, moderate certainty): 1

• Gabapentin: Start 300 mg, titrate up to 800-1200 mg typically (mean effective dose ~800 mg in studies). 2
• Gabapentin enacarbil: Strongly recommended, prodrug formulation with improved bioavailability. 1
• Pregabalin: Strongly recommended alternative. 1

Key advantages over dopamine agonists:

• Lower risk of augmentation (progressive iatrogenic worsening of RLS symptoms). 1, 3
• Lower rates of dizziness and somnolence with long-term use. 1
• No risk of impulse control disorders associated with dopaminergic agents. 1

Important monitoring considerations:

• Monitor for dizziness and somnolence, particularly in patients with untreated OSA or COPD. 1
• Evaluate for misuse risk factors, as alpha-2-delta ligands have increasing evidence of potential misuse in certain populations. 1

Medications to Avoid or Use with Extreme Caution

Dopamine Agonists (Now Second-Line or Avoided)

The American Academy of Sleep Medicine suggests AGAINST standard use of: 1, 4

• Pramipexole (conditional recommendation against, moderate certainty). 1
• Ropinirole (conditional recommendation against, moderate certainty). 1, 4
• Rotigotine transdermal (conditional recommendation against, low certainty). 1
• Levodopa (conditional recommendation against, very low certainty). 1

Critical caveat about dopamine agonists: Despite FDA approval of ropinirole for RLS 5 and historical use as first-line therapy 6, 7, these agents carry significant risk of augmentation—a paradoxical worsening characterized by earlier symptom onset during the day, increased intensity, and spread to other body parts. 1, 3 This represents a major shift in treatment guidelines based on long-term outcome data prioritizing quality of life over short-term symptom control.

Dopamine agonists may only be considered for:

• Short-term treatment in patients who explicitly prioritize immediate symptom relief over long-term adverse effects. 1
• Situations where alpha-2-delta ligands are contraindicated or not tolerated. 1

Strongly Recommended Against

• Cabergoline (strong recommendation against, moderate certainty). 1
• Bupropion, carbamazepine, clonazepam, valproic acid, valerian (all conditional recommendations against). 1

Treatment for Refractory Cases or Augmentation

When First-Line Treatment Fails

Opioids are conditionally recommended for refractory RLS or augmentation management: 1

• Extended-release oxycodone, methadone, or buprenorphine. 1
• Evidence shows relatively low risks of abuse and overdose in appropriately screened patients, with only small dose increases over 2-10 years. 1
• Critical warning: Use caution due to risk of respiratory depression and central sleep apnea, especially in patients with untreated OSA. 1

Managing Dopaminergic Augmentation

If a patient is already on a dopamine agonist and develops augmentation: 3

• Do NOT abruptly discontinue the dopamine agonist due to profound rebound RLS and insomnia. 3
• Add an alpha-2-delta ligand or opioid first. 3
• Once adequate symptom control is achieved with the second agent, perform very slow down-titration and discontinuation of the dopamine agonist. 3
• Alternative short-term strategies: take doses earlier in the day or split into early evening and bedtime doses. 1, 4

Special Populations

End-Stage Renal Disease

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

Pediatric RLS

• Oral ferrous sulfate for serum ferritin <50 ng/mL (conditional recommendation, very low certainty), monitoring for constipation. 1

Pregnancy

• Special consideration of medication safety profiles required; most pharmacological agents have limited safety data. 1
• Iron supplementation is particularly important if deficient. 1

Non-Pharmacological Option

• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty) for patients preferring non-pharmacological approaches or with contraindications to medications. 1