What are the treatment options for a patient with Restless Legs Syndrome (RLS)?

Treatment of Restless Legs Syndrome

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are first-line pharmacological therapy for RLS, with iron supplementation initiated if ferritin ≤75 ng/mL or transferrin saturation <20%. 1, 2

Initial Assessment and Iron Management

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

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
• End-stage renal disease: IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% 1

Iron formulation options:

• IV ferric carboxymaltose (750-1000 mg in one or two infusions): Strongly recommended for rapid correction, especially if oral iron fails after 3 months 1, 2
• Oral ferrous sulfate (325-650 mg daily or every other day): Conditionally recommended but works more slowly 1, 3

Address Exacerbating Factors

Eliminate or modify these triggers before or concurrent with pharmacological treatment:

• Medications: Discontinue serotonergic antidepressants, dopamine antagonists (antipsychotics like lurasidone), antihistamines (especially diphenhydramine), and bupropion 1, 3
• Substances: Eliminate alcohol, caffeine, and nicotine, particularly within 3 hours of bedtime 1
• Comorbidities: Screen for and treat untreated obstructive sleep apnea 1

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

Gabapentin dosing (strongly recommended with moderate certainty): 1, 2

• Start at 300 mg three times daily (avoid single nighttime dosing, which fails to address daytime symptoms)
• Titrate by 300 mg/day every 3-7 days
• Target maintenance dose: 1800-2400 mg/day divided three times daily
• Maximum: 3600 mg/day (well-tolerated in clinical studies)
• Common side effects: Somnolence and dizziness (typically transient and mild)

Pregabalin (strongly recommended with moderate certainty): 1, 2

• Allows twice-daily dosing with potentially superior bioavailability compared to gabapentin
• Preferred for patients who value dosing convenience

Gabapentin enacarbil (strongly recommended with moderate certainty): 1, 2

• Prodrug of gabapentin with extended-release formulation
• FDA-approved specifically for RLS 4

Medications to AVOID or Use with Extreme Caution

Dopamine agonists are NO LONGER first-line due to augmentation risk (7-10% annual incidence): 1, 3, 5

• Pramipexole: Conditionally recommended AGAINST standard use (moderate certainty) 1
• Ropinirole: Conditionally recommended AGAINST standard use (moderate certainty) 1, 4
• Rotigotine (transdermal): Conditionally recommended AGAINST standard use (low certainty) 1
• Levodopa: Conditionally recommended AGAINST standard use (very low certainty) 1

Augmentation warning signs: Earlier symptom onset during the day, increased intensity, spread to upper extremities or trunk, paradoxical worsening despite dose increases 1, 5

Strongly or conditionally recommended AGAINST: 1, 2

• Cabergoline: Strongly recommended against (moderate certainty)
• Clonazepam: Conditionally recommended against (very low certainty)
• Bupropion, carbamazepine, valproic acid: Conditionally recommended against

Second-Line Treatment for Refractory Cases

Extended-release oxycodone and other low-dose opioids (conditionally recommended with moderate certainty): 1, 2, 5

• Reserved for moderate to severe refractory RLS
• Particularly effective for treating augmentation when transitioning off dopamine agonists
• Long-term studies show relatively low abuse/overdose risks in appropriately screened patients, with only small dose increases over 2-10 years
• Critical: Screen for untreated obstructive sleep apnea before initiating (risk of respiratory depression and central sleep apnea)

Other second-line options:

• Bilateral high-frequency peroneal nerve stimulation: Conditionally recommended as non-pharmacological option (moderate certainty) 1, 2
• Dipyridamole: Conditionally recommended (low certainty) 1

Special Populations

End-stage renal disease: 1, 2

• Gabapentin: Conditionally recommended (very low certainty); start 100 mg post-dialysis or at bedtime, maximum 200-300 mg daily
• AVOID pregabalin (increased hazard for altered mental status and falls)
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20%
• Vitamin C: Conditionally recommended (low certainty)

Pediatric RLS: 1, 2

• Ferrous sulfate conditionally recommended if ferritin <50 ng/mL (very low certainty)
• Monitor for constipation

Pregnancy: 1

• Iron supplementation particularly important given pregnancy-specific RLS prevalence (22%, especially third trimester)
• Consider medication safety profiles carefully; oral iron formulations favored throughout gestation

Treatment Algorithm Summary

1. Confirm diagnosis using four essential criteria (urge to move legs with uncomfortable sensations, provoked by rest, relieved by movement, worse in evening/night) 2, 6
2. Check morning fasting ferritin and transferrin saturation 1, 2, 6
3. Initiate iron supplementation if ferritin ≤75 ng/mL or transferrin saturation <20% 1, 2, 6
4. Address exacerbating factors (medications, substances, sleep apnea) 1, 6
5. Start gabapentin or pregabalin as first-line pharmacological treatment 1, 2, 6
6. Monitor for efficacy and side effects at 3-7 day intervals during titration 1, 2
7. Reassess iron studies every 6-12 months and evaluate daytime functioning (alertness, concentration, mood) 1

Critical Pitfalls to Avoid

• Never use dopamine agonists as first-line therapy despite FDA approval for ropinirole—augmentation risk outweighs benefits 1, 3, 5
• Never use single nighttime gabapentin dosing—fails to address daytime symptoms and provides suboptimal coverage 1
• Never assume "normal" ferritin (>50 ng/mL) is adequate for RLS—brain iron deficiency occurs at higher thresholds than systemic deficiency 1
• Never increase dopamine agonist doses if augmentation is suspected—this worsens the problem 1, 5
• Never initiate opioids without screening for untreated sleep apnea—risk of respiratory depression 1