What are the treatment options for a patient with Restless Legs Syndrome (RLS)?

RLS Prescription Medications

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacological treatment for RLS, with dopamine agonists now relegated to limited short-term use only due to augmentation risk. 1, 2, 3

First-Line Medications

Alpha-2-Delta Ligands (Preferred)

• Gabapentin: Start 300 mg three times daily (900 mg/day total), titrate by 300 mg/day every 3-7 days to maintenance dose of 1800-2400 mg/day divided three times daily (strong recommendation, moderate certainty) 1, 2, 3
• Gabapentin enacarbil: Prodrug with superior bioavailability, strongly recommended as first-line (strong recommendation, moderate certainty) 2, 3
• Pregabalin: Allows twice-daily dosing with potentially superior bioavailability compared to gabapentin, strongly recommended as first-line (strong recommendation, moderate certainty) 1, 2, 3

Iron Supplementation (Co-First-Line When Indicated)

• IV ferric carboxymaltose: Strongly recommended for rapid correction if ferritin ≤75 ng/mL or transferrin saturation <20% (strong recommendation, moderate certainty) 1, 2, 3
• Oral ferrous sulfate: Alternative to IV iron but works more slowly (conditional recommendation, moderate certainty) 2, 3
• IV low molecular weight iron dextran: Conditionally recommended for appropriate iron parameters 2
• IV ferumoxytol: Conditionally recommended for appropriate iron parameters 2

Second-Line Medications (Refractory Cases)

Opioids

• Extended-release oxycodone: Conditionally recommended for moderate to severe refractory RLS, with evidence showing relatively low risks of abuse and overdose in appropriately screened patients (conditional recommendation, moderate certainty) 1, 2, 3
• Methadone: Effective for refractory cases, with long-term studies showing only small dose increases over 2-10 years 2
• Buprenorphine: Effective for refractory cases, particularly safe in advanced CKD 2

Other Options

• Dipyridamole: Conditionally recommended (conditional recommendation, low certainty) 2

Dopamine Agonists (Use with Extreme Caution - Short-Term Only)

The American Academy of Sleep Medicine suggests against standard use of all dopamine agonists due to high augmentation risk. 2, 3

• Pramipexole: Suggested against for standard use (conditional recommendation, moderate certainty); FDA-approved but only for short-term use in patients prioritizing immediate relief over long-term safety 2, 4
• Ropinirole: Suggested against for standard use (conditional recommendation, moderate certainty); FDA-approved but carries significant augmentation risk 2, 4
• Rotigotine (transdermal): Suggested against for standard use (conditional recommendation, low certainty) due to augmentation concerns 2, 3
• Levodopa: Suggested against for standard use (conditional recommendation, very low certainty) 2

Medications Explicitly NOT Recommended

• Cabergoline: Strongly recommended AGAINST (strong recommendation, moderate certainty) 2, 3
• Bupropion: Conditionally recommended against (conditional recommendation, moderate certainty) 2, 3
• Carbamazepine: Conditionally recommended against (conditional recommendation, low certainty) 2, 3
• Clonazepam: Conditionally recommended against (conditional recommendation, very low certainty) 2, 3
• Valproic acid: Conditionally recommended against (conditional recommendation, low certainty) 2, 3
• Valerian: Conditionally recommended against (conditional recommendation, very low certainty) 2

Special Population Medications

End-Stage Renal Disease

• Gabapentin: Conditionally recommended, start 100 mg post-dialysis or at bedtime, maximum 200-300 mg daily (conditional recommendation, very low certainty) 2, 3
• IV iron sucrose: Recommended if ferritin <200 ng/mL and transferrin saturation <20% (conditional recommendation, moderate certainty) 2, 3
• Vitamin C: Conditionally recommended (conditional recommendation, low certainty) 2, 3
• Fentanyl or buprenorphine: Safest opioids in stage 4-5 CKD as they don't accumulate toxic metabolites 2

Pediatric RLS

• Ferrous sulfate: Conditionally recommended if ferritin <50 ng/mL (conditional recommendation, very low certainty) 2, 3

Non-Pharmacological Option

• Bilateral high-frequency peroneal nerve stimulation: Conditionally recommended as noninvasive treatment (conditional recommendation, moderate certainty) 2, 3

Critical Prescribing Pitfalls

• Never use single nighttime dosing of gabapentin - fails to address daytime symptoms and provides suboptimal 24-hour coverage; three-times-daily dosing is necessary 1
• Never start dopamine agonists as first-line - augmentation risk makes them inappropriate for initial therapy 1, 2, 3
• Never abruptly discontinue dopamine agonists - causes profound rebound RLS and insomnia; add alpha-2-delta ligand or opioid first, then slowly taper DA 2, 5
• Always check iron studies first - ferritin ≤75 ng/mL or transferrin saturation <20% requires supplementation before or concurrent with other medications 1, 2, 3
• Monitor for augmentation - characterized by earlier symptom onset, increased intensity, and anatomic spread to upper body 2, 5