What is the first‑line pharmacologic treatment for typical adult restless‑leg syndrome, and what alternatives are recommended for patients with low iron stores, intolerance to dopamine agonists, severe augmentation, or renal failure?

First-Line Pharmacologic Treatment for Restless Legs Syndrome

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are the first-line pharmacologic treatment for typical adult restless legs syndrome, replacing dopamine agonists due to their comparable efficacy and substantially lower risk of augmentation. 1

Initial Assessment Before Starting Medication

Before initiating any pharmacologic therapy, check morning fasting serum ferritin and transferrin saturation after avoiding iron supplements for at least 24 hours 1:

• Supplement with iron if ferritin ≤75 ng/mL OR transferrin saturation <20% 1, 2
• IV ferric carboxymaltose is strongly recommended for rapid correction (strong recommendation, moderate certainty) 1
• Oral ferrous sulfate is an alternative but works more slowly (conditional recommendation, moderate certainty) 1

Address exacerbating factors including alcohol, caffeine, antihistamines, serotonergic medications, antidopaminergic medications, and untreated obstructive sleep apnea 1

First-Line Pharmacologic Options

Gabapentin (Strongly Recommended)

• Start 300 mg three times daily 1, 2
• Increase by 300 mg/day every 3-7 days as tolerated 1, 2
• Target maintenance dose: 1800-2400 mg/day divided three times daily 1, 2
• Maximum studied dose: 3600 mg/day 1
• Avoid single nighttime dosing—this fails to address daytime symptoms and provides suboptimal coverage 1

Gabapentin Enacarbil (Strongly Recommended)

• Prodrug of gabapentin with potentially superior bioavailability 1
• Allows for more convenient dosing compared to regular gabapentin 1

Pregabalin (Strongly Recommended)

• Start 50 mg three times daily OR 75 mg twice daily 1
• After 3-7 days, increase to 300 mg/day 1
• May increase by 150 mg every 3-7 days as tolerated 1
• Maximum dose: 600 mg/day 1
• Advantage: twice-daily dosing with superior bioavailability compared to regular gabapentin 1, 2

All three alpha-2-delta ligands carry a strong recommendation with moderate certainty of evidence 1, 2

Why Dopamine Agonists Are No Longer First-Line

The American Academy of Sleep Medicine suggests against the standard use of dopamine agonists (pramipexole, ropinirole, rotigotine) due to high risk of augmentation (conditional recommendation, moderate certainty) 1, 3, 2:

• Augmentation occurs in a substantial proportion of patients, manifesting as paradoxical worsening with earlier daily symptom onset (afternoon instead of evening), increased intensity, and spread to arms or trunk 1, 4
• Annual augmentation incidence: 7-10% 1
• Even low-dose dopaminergics can cause augmentation 5
• Dopamine agonists may only be considered for short-term use in patients who prioritize immediate symptom relief over long-term safety 1, 3

The 2025 American Academy of Sleep Medicine guidelines represent a major shift from 2009 recommendations that favored dopamine agonists as first-line therapy 3. This change is based on accumulating evidence of augmentation risk with long-term dopaminergic use 6, 5, 4.

Alternative Treatment Pathways

For Patients with Low Iron Stores (Ferritin ≤75 ng/mL or Transferrin Saturation <20%)

• IV ferric carboxymaltose: 750-1000 mg in one or two infusions (strong recommendation, moderate certainty) 1
• Oral ferrous sulfate (conditional recommendation, moderate certainty) 1
• IV low molecular weight iron dextran or IV ferumoxytol (conditional recommendation) 1

For Patients with Intolerance to Dopamine Agonists or Severe Augmentation

• Switch to alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) 1, 2, 5
• For severe augmentation, consider extended-release oxycodone or other low-dose opioids (conditional recommendation, moderate certainty) 1, 2, 5
• Methadone and buprenorphine show relatively low risks of abuse/overdose in appropriately screened patients, with only small dose increases over 2-10 years 1
• Do NOT increase dopamine agonist dose if augmentation is suspected—this worsens the problem 1

For Patients with End-Stage Renal Disease

• Gabapentin: start 100 mg post-dialysis or at bedtime; maximum 200-300 mg daily (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 supplementation (conditional recommendation, low certainty) 1, 2
• Avoid pregabalin in ESRD due to increased hazard for altered mental status and falls 1

For Refractory Cases

• Extended-release oxycodone or other low-dose opioids (conditional recommendation, moderate certainty) 1, 2, 7
• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty) 1, 2
• Dipyridamole (conditional recommendation, low certainty) 1

Medications to Avoid

The American Academy of Sleep Medicine strongly recommends against:

• Cabergoline (strong recommendation, moderate certainty) 1, 2

Conditional recommendations against:

• Bupropion, carbamazepine, clonazepam, valproic acid, valerian 1, 2
• Levodopa (very high augmentation risk) 1
• Tizanidine (no evidence supporting use) 1

Critical Monitoring Points

• Monitor for augmentation signs: earlier symptom onset, increased intensity, spread to upper extremities 1, 4
• Common side effects of alpha-2-delta ligands include somnolence and dizziness, typically transient and mild 1
• Reassess iron studies every 6-12 months 1
• Screen for untreated obstructive sleep apnea before starting opioids (risk of respiratory depression and central sleep apnea) 1
• Monitor for misuse potential with alpha-2-delta ligands in at-risk populations 1