Treatment of 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 if ferritin ≤75 ng/mL or transferrin saturation <20%. 1
Initial Assessment and Iron Management
Before starting any medication, check morning fasting iron studies including serum ferritin and transferrin saturation, ideally after avoiding iron-containing supplements for at least 24 hours. 1, 2
Iron supplementation thresholds specific to RLS (different from general population):
- Supplement if ferritin ≤75 ng/mL OR transferrin saturation <20% 1, 2
- IV ferric carboxymaltose is strongly recommended for rapid correction in patients meeting these parameters (strong recommendation, moderate certainty) 1, 2
- Oral ferrous sulfate is an alternative but works more slowly (conditional recommendation, moderate certainty) 1, 2
- Continue iron therapy indefinitely with ongoing monitoring every 6-12 months, as RLS symptoms may recur if iron stores decline 1
First-Line Pharmacological Treatment: Alpha-2-Delta Ligands
Gabapentin dosing (avoid the common pitfall of single nighttime dosing):
- Start at 300 mg three times daily (900 mg/day total) 1
- Titrate by 300 mg/day every 3-7 days until reaching maintenance dose of 1800-2400 mg/day divided three times daily 1
- Single nighttime dosing fails to address daytime RLS symptoms and provides suboptimal coverage 1
- Common side effects include somnolence and dizziness, typically transient and mild 1
Pregabalin as an alternative:
- Allows twice-daily dosing with potentially superior bioavailability compared to gabapentin 1, 2
- Strongly recommended as first-line therapy (strong recommendation, moderate certainty) 1, 2
Gabapentin enacarbil:
- Prodrug of gabapentin, strongly recommended with moderate certainty 1
Medications to Avoid or Use with Extreme Caution
Dopamine agonists are now recommended AGAINST for standard use due to high risk of augmentation:
- Pramipexole: conditional recommendation against standard use, moderate certainty 1, 3, 2
- Ropinirole: conditional recommendation against standard use, moderate certainty 1, 2
- Transdermal rotigotine: conditional recommendation against standard use, low certainty 1, 2
- Levodopa: conditional recommendation against standard use, very low certainty 1
Augmentation is characterized by:
- Earlier onset of symptoms during the day 1, 3
- Increased symptom intensity 1, 3
- Spread of symptoms to other body parts (arms, trunk) 1, 3
Other medications strongly or conditionally recommended against:
- Cabergoline: strong recommendation against (moderate certainty) 1, 2
- Clonazepam: conditional recommendation against (very low certainty) 1, 2
- Bupropion, carbamazepine, valproic acid: conditional recommendations against 1, 2
Addressing Exacerbating Factors
Eliminate or reduce the following substances, especially in the evening:
- Alcohol, caffeine, and nicotine too close to bedtime 1
- Avoid heavy meals or drinking within 3 hours of bedtime 1
- Even moderate amounts of caffeine or alcohol in the evening can significantly worsen RLS symptoms 1
Discontinue or avoid medications that worsen RLS:
- Antihistaminergic medications 1
- Serotonergic medications (SSRIs, SNRIs) 1
- Antidopaminergic medications (antipsychotics like lurasidone) 1
- Screen for and treat untreated obstructive sleep apnea 1
Second-Line Options for Refractory Cases
When first-line treatments fail or are not tolerated:
- Extended-release oxycodone and other low-dose opioids (methadone, buprenorphine) are conditionally recommended for moderate to severe refractory RLS 1, 2
- Evidence shows relatively low risks of abuse and overdose in appropriately screened patients, with long-term studies showing only small dose increases over 2-10 years 1
- Particularly effective for treating augmentation when transitioning off dopamine agonists 1, 2
- Critical caution: Monitor for respiratory depression and central sleep apnea, especially in patients with untreated obstructive sleep apnea or COPD 1
Other second-line options:
- Dipyridamole: conditional recommendation, low certainty 1
- Bilateral high-frequency peroneal nerve stimulation: conditional recommendation, moderate certainty 1, 2
Special Populations
End-stage renal disease patients:
- Gabapentin: conditional recommendation, very low certainty (start 100 mg post-dialysis or at bedtime, maximum 200-300 mg daily) 1
- 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
- Critical warning: Gabapentinoids are associated with 50-68% higher hazard for altered mental status and falls in dialysis patients 1
Pediatric RLS:
- Ferrous sulfate if ferritin <50 ng/mL: conditional recommendation, very low certainty 1, 2
- Monitor for constipation with oral iron supplementation 1
Pregnancy:
- Iron supplementation is particularly important given pregnancy-specific RLS prevalence 1
- Safety profile favors oral formulations throughout gestation 1
Managing Augmentation from Dopamine Agonists
If augmentation develops on a dopamine agonist:
- Add an alpha-2-delta ligand (gabapentin or pregabalin) or low-dose opioid FIRST before attempting to reduce the dopamine agonist 4
- Once adequate symptom relief is achieved with the second agent, begin very slow down-titration of the dopamine agonist 4
- Profound rebound RLS and insomnia occur with even small dose reductions of dopamine agonists, making the addition of alternate treatment essential before tapering 4
Monitoring and Follow-Up
- Reassess iron studies every 6-12 months 1
- Monitor for side effects of alpha-2-delta ligands (dizziness, somnolence) 1
- Evaluate for improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood) 1
- Monitor for signs of augmentation if dopamine agonists are used despite recommendations against standard use 1, 3