What are the treatment options for a patient with restless legs syndrome?

Treatment of Restless Legs Syndrome

Start with alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacological therapy after addressing iron deficiency and eliminating exacerbating factors. 1, 2, 3

Initial Assessment and Iron Management

Before initiating any medication, check morning fasting iron studies (ferritin and transferrin saturation) after avoiding iron supplements for at least 24 hours. 1, 2, 3

Iron supplementation thresholds for RLS differ from general population guidelines:

• Supplement if ferritin ≤75 ng/mL or transferrin saturation <20% 1, 2, 3
• IV ferric carboxymaltose (1000 mg) is strongly recommended for rapid correction, particularly if oral iron fails after 3 months 1, 2, 4
• Oral ferrous sulfate (325-650 mg daily or every other day) is an alternative but works more slowly 1, 2, 4

Critical pitfall: Brain iron deficiency drives RLS pathophysiology even when serum iron appears normal by general medicine standards—this is why the 75 ng/mL threshold exists specifically for RLS. 1

Eliminate Exacerbating Factors

Discontinue or avoid these medications and substances before starting pharmacotherapy:

• Serotonergic antidepressants (SSRIs, SNRIs) 1, 4
• Dopamine antagonists (antipsychotics, metoclopramide) 1, 4
• Centrally acting H1 antihistamines (diphenhydramine, doxylamine) 1, 4
• Alcohol, caffeine, and nicotine, especially within 3 hours of bedtime 1, 3
• Screen for and treat untreated obstructive sleep apnea 1, 3

First-Line Pharmacological Treatment

Alpha-2-delta ligands are strongly recommended with moderate certainty of evidence: 1, 2, 3

Gabapentin Dosing

• Start at 300 mg three times daily (not single nighttime dosing, which fails to address daytime symptoms) 1
• Titrate by 300 mg/day every 3-7 days until reaching maintenance dose of 1800-2400 mg/day divided three times daily 1
• Maximum studied dose is 3600 mg/day 1
• Approximately 70% of patients achieve much or very much improved symptoms vs 40% with placebo 4

Gabapentin Enacarbil

• Prodrug with potentially superior bioavailability 1
• Strongly recommended with moderate certainty of evidence 1, 2, 3

Pregabalin

• Allows twice-daily dosing with potentially superior bioavailability compared to regular gabapentin 1, 3
• Strongly recommended with moderate certainty of evidence 1, 2, 3

Common side effects include somnolence and dizziness, which are typically transient and mild. 1 Monitor for misuse potential in at-risk populations. 1

Medications to Avoid or Use with Extreme Caution

Dopamine agonists (pramipexole, ropinirole, rotigotine) are no longer recommended for standard use due to augmentation risk: 1, 2, 3, 4

• Augmentation is a paradoxical iatrogenic worsening characterized by earlier symptom onset (spreading into daytime), increased intensity, and anatomic spread to upper extremities or trunk 1, 5
• Annual incidence of augmentation is 7-10% with dopamine agonists 4
• The American Academy of Sleep Medicine suggests against standard use of pramipexole (conditional recommendation, moderate certainty) 1, 2
• The American Academy of Sleep Medicine suggests against standard use of ropinirole (conditional recommendation, moderate certainty) 1
• The American Academy of Sleep Medicine suggests against standard use of transdermal rotigotine (conditional recommendation, low certainty) 1, 2

Despite FDA approval, dopamine agonists should only be considered for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects. 2, 6

Strongly recommended against:

• Cabergoline (strong recommendation, moderate certainty) 1, 2, 3
• Clonazepam (conditional recommendation, very low certainty) 1, 3
• Levodopa (conditional recommendation, very low certainty) 1, 2, 3
• Bupropion, carbamazepine, valproic acid (conditional recommendations) 1, 3

Second-Line Treatment for Refractory Cases

Extended-release oxycodone and other low-dose opioids (methadone 5-10 mg daily, buprenorphine) are conditionally recommended for: 1, 3, 4, 5

• Moderate to severe refractory RLS not responding to alpha-2-delta ligands
• Treating augmentation when transitioning off dopamine agonists
• Long-term studies show relatively low risks of abuse/overdose in appropriately screened patients, with only small dose increases over 2-10 years 1

Critical caution: Monitor for respiratory depression and central sleep apnea, especially in patients with untreated obstructive sleep apnea or COPD. 1

Non-Pharmacological Interventions

Bilateral high-frequency peroneal nerve stimulation is conditionally recommended with moderate certainty of evidence. 1, 2, 3

Lifestyle modifications with supporting evidence: 7

• Moderate exercise (avoid vigorous exercise close to bedtime) 3
• Compression devices 7
• Infrared therapy 7
• Standard acupuncture 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, 2, 3
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (conditional recommendation, moderate certainty) 1, 2, 3
• Vitamin C (conditional recommendation, low certainty) 1, 2
• Avoid pregabalin due to increased hazard for altered mental status and falls (50-68% higher hazard) 1

Pregnancy

• Iron supplementation is particularly important given pregnancy-specific RLS prevalence of 22% 1, 4
• Consider medication safety profiles; non-pharmacologic approaches may be preferred 2

Pediatric RLS

• Ferrous sulfate if ferritin <50 ng/mL (conditional recommendation, very low certainty) 1, 2

Managing Augmentation from Dopamine Agonists

If augmentation is present, do not increase the dopamine agonist dose—this worsens the problem. 1, 5

Transition strategy:

1. Add alpha-2-delta ligand or low-dose opioid while maintaining current dopamine agonist dose 5
2. Titrate the new agent to adequate symptom control 5
3. Very slowly down-titrate and discontinue the dopamine agonist (expect profound rebound RLS and insomnia with even small dose reductions) 5

Monitoring and Follow-Up

• Reassess iron studies every 6-12 months, as RLS symptoms may recur if iron stores decline 1
• Monitor for side effects of alpha-2-delta ligands (dizziness, somnolence) 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