What are the treatment options for restless leg syndrome?

Treatment of Restless Legs Syndrome

Start with alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacologic therapy after checking and correcting iron status. 1, 2

Initial Assessment and Iron Management

Before initiating any pharmacologic treatment, complete the following steps:

• Check morning fasting serum ferritin and transferrin saturation after avoiding iron supplements for at least 24 hours 1, 2
• Supplement with iron if ferritin ≤75 ng/mL or transferrin saturation <20% - this threshold is higher than general population guidelines because brain iron deficiency plays a key role in RLS pathophysiology 1, 2
• Use oral ferrous sulfate for mild iron deficiency (conditional recommendation, moderate certainty) 1, 2
• Consider IV ferric carboxymaltose (strong recommendation, moderate certainty) if ferritin is 75-100 ng/mL or oral supplementation fails 1, 2

Address Exacerbating Factors

• Discontinue or avoid medications that worsen RLS: antihistamines, SSRIs, tricyclic antidepressants, antipsychotics (dopamine antagonists like lurasidone), lithium 1, 2
• Reduce or eliminate alcohol and caffeine 1, 2
• Screen for and treat obstructive sleep apnea if present 1, 2

First-Line Pharmacologic Treatment: Alpha-2-Delta Ligands

The American Academy of Sleep Medicine strongly recommends these agents over dopamine agonists due to superior long-term safety and absence of augmentation risk (strong recommendation, moderate certainty):

Gabapentin Enacarbil (Preferred for Convenience)

• Dose: 600 mg once daily at approximately 5 PM with food 3
• This is the FDA-approved dose and provides optimal symptom coverage 3

Gabapentin

• Start: 300 mg three times daily (900 mg/day total) 1
• Titrate: Increase by 300 mg/day every 3-7 days as needed 1
• Target maintenance: 1800-2400 mg/day divided three times daily 1
• Maximum studied dose is 3600 mg/day 1
• Single nighttime dosing is inadequate for 24-hour symptom control 1

Pregabalin

• Allows twice-daily dosing with superior bioavailability compared to gabapentin 1
• Strong recommendation, moderate certainty 1, 2

Common side effects: Somnolence and dizziness, typically transient and mild 1

Critical pitfall: Monitor for misuse potential in at-risk populations, though this risk is substantially lower than with opioids 1

Medications to AVOID

Dopamine Agonists (Pramipexole, Ropinirole, Rotigotine)

• The American Academy of Sleep Medicine now recommends AGAINST standard use due to high risk of augmentation - a paradoxical worsening of symptoms with earlier onset, increased intensity, and spread to other body parts 1, 2, 4
• Despite FDA approval 5, these agents should only be considered for short-term use in patients who prioritize immediate symptom relief over long-term safety 1, 2
• If already on a dopamine agonist with augmentation, do NOT abruptly discontinue - add an alpha-2-delta ligand or opioid first, then slowly taper the dopamine agonist 4

Other Medications to Avoid

• Levodopa: Conditional recommendation against (very low certainty) 1, 2
• Cabergoline: Strong recommendation against (moderate certainty) 1, 2
• Clonazepam: Does not reduce objective disease markers, only subjective sleep quality; carries sedation and hepatotoxicity risks 1
• Bupropion, carbamazepine, valproic acid, valerian: All have conditional recommendations against use 1

Second-Line Treatment: Opioids for Refractory Cases

• Extended-release oxycodone, methadone, or buprenorphine are conditionally recommended for moderate to severe RLS that fails first-line therapy 1, 2, 6
• Particularly effective for treating augmentation when transitioning off dopamine agonists 1, 4, 6
• Long-term studies show relatively low abuse risk and minimal dose escalation (2-10 years) when patients are appropriately screened 1
• Critical caution: Risk of respiratory depression and central sleep apnea, especially with untreated OSA 1

Non-Pharmacologic Options

• Bilateral high-frequency peroneal nerve stimulation: Conditional recommendation based on short-term studies (moderate certainty) 1, 2
• Regular physical activity: Should be recommended based on available evidence 7
• Pneumatic compression devices, yoga, acupuncture: May improve some outcomes but evidence is limited 8, 7

Special Populations

End-Stage Renal Disease

• 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, 2
• Avoid pregabalin - associated with 50-68% higher hazard of altered mental status and falls in dialysis patients 1

Pregnancy

• Iron supplementation is particularly important given pregnancy-specific RLS prevalence 1
• Non-pharmacologic approaches preferred when possible 2
• Medication safety profiles must be carefully considered 1, 2

Pediatric RLS

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

Treatment Monitoring

• Continue iron supplementation indefinitely with monitoring every 6-12 months, as symptoms may recur if iron stores decline 1
• Monitor for augmentation if dopamine agonists are used despite recommendations against them 1
• Watch for side effects of alpha-2-delta ligands, particularly in patients with untreated OSA or COPD 1