What is the recommended treatment approach for an adult with restless‑legs syndrome?

Treatment of Restless Legs Syndrome

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are the strongly recommended first-line pharmacological treatment for adults with restless legs syndrome, with moderate certainty of evidence. 1

Initial Assessment and Iron Management

Before starting any medication, check morning fasting serum ferritin and transferrin saturation after avoiding iron-containing supplements for at least 24 hours. 1

Iron supplementation thresholds for RLS differ from general population guidelines:

• Adults: Supplement if ferritin ≤75 ng/mL or transferrin saturation <20% 1, 2
• Children: Supplement if ferritin <50 ng/mL 1

Iron supplementation options:

• Oral ferrous sulfate: Conditional recommendation with moderate certainty for patients meeting iron parameters 1
• IV ferric carboxymaltose: Strong recommendation with moderate certainty for rapid correction, especially if oral iron is not tolerated or ineffective after 3 months 1, 2

Address exacerbating factors including alcohol, caffeine, antihistaminergic medications, serotonergic medications, antidopaminergic medications, and untreated obstructive sleep apnea. 1, 2

First-Line Pharmacological Treatment

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands as first-line therapy (strong recommendation, moderate certainty of evidence): 1

Gabapentin dosing:

• Start 300 mg three times daily 1
• Increase by 300 mg/day every 3-7 days as needed 1
• Target maintenance dose: 1800-2400 mg/day divided three times daily 1
• Maximum studied dose: 3600 mg/day 1

Pregabalin is an equally strong alternative that allows twice-daily dosing with potentially superior bioavailability compared to regular gabapentin. 1, 2 Start at 75 mg once daily 1-2 hours before bedtime, titrating to 150-300 mg daily as needed. 3

Gabapentin enacarbil (a prodrug of gabapentin) is also strongly recommended with moderate certainty of evidence. 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. 1, 2

• Annual augmentation incidence: 7-10% 1
• Augmentation presents as earlier symptom onset during the day, increased intensity, and spread to arms/trunk 1
• The American Academy of Sleep Medicine suggests against standard use of pramipexole (conditional recommendation, moderate certainty), ropinirole, and transdermal rotigotine (conditional recommendation, low certainty) 1
• These agents may only be considered for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects 1, 2

The American Academy of Sleep Medicine strongly recommends against:

• Cabergoline (strong recommendation, moderate certainty) 1, 2
• Bupropion (conditional recommendation, moderate certainty) 1
• Carbamazepine (conditional recommendation, low certainty) 1
• Clonazepam (conditional recommendation, very low certainty) 1
• Valproic acid (conditional recommendation, low certainty) 1
• Valerian (conditional recommendation, very low certainty) 1

The American Academy of Sleep Medicine suggests against standard use of levodopa (conditional recommendation, very low certainty). 1, 2

Second-Line Treatment Options for Refractory Cases

Extended-release oxycodone and other low-dose opioids (methadone, buprenorphine) are conditionally recommended for moderate to severe refractory RLS, particularly when treating augmentation from dopamine agonists. 1 Long-term studies show relatively low risks of abuse/overdose in appropriately screened patients, with only small dose increases over 2-10 years. 1

Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-pharmacological option with moderate certainty of evidence. 1

Dipyridamole is conditionally recommended with low certainty of evidence. 1

Special Populations

End-stage renal disease (ESRD):

• Gabapentin: Start 100 mg post-dialysis or at bedtime; maximum 200-300 mg daily (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
• Avoid pregabalin in ESRD due to increased hazard for altered mental status and falls 1

Pregnancy:

• Consider pregnancy-specific safety profiles for each treatment 1, 2
• Iron supplementation is particularly important given pregnancy-specific RLS prevalence 1
• Non-pharmacologic approaches may be preferred 2

Pediatric RLS:

• Oral ferrous sulfate if ferritin <50 ng/mL (conditional recommendation, very low certainty) 1

Managing Augmentation from Dopamine Agonists

If augmentation occurs (earlier symptom onset, increased intensity, spread to other body parts), do not increase the dopamine agonist dose—this worsens the problem. 1

Management strategy:

1. Add an alpha-2-delta ligand or opioid while maintaining the current DA dose 4
2. Once adequate symptom relief is achieved with the second agent, begin very slow down-titration and discontinuation of the DA 4
3. Opioids are particularly effective for relieving worsening symptoms when decreasing or eliminating dopamine agonists 1

Treatment Monitoring

• Reassess iron studies every 6-12 months 1
• Monitor for side effects of alpha-2-delta ligands (dizziness, somnolence), which are typically transient and mild 1
• Evaluate improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood) 1
• Regular monitoring for augmentation is essential if dopamine agonists are used 1

Critical Pitfalls to Avoid

• Do not use dopamine agonists as first-line therapy given the high augmentation risk and current guideline recommendations favoring alpha-2-delta ligands 1
• Do not assume "normal" ferritin levels are adequate—RLS requires higher thresholds (≤75 ng/mL) than general population guidelines 1
• Do not use single nighttime dosing of gabapentin—this fails to address daytime RLS symptoms and requires divided dosing for optimal 24-hour coverage 1
• Do not increase dopamine agonist doses if augmentation is suspected—this paradoxically worsens symptoms 1