How should I manage a patient with nighttime restless‑legs syndrome, including non‑pharmacologic measures, iron supplementation if ferritin ≤50 µg/L, and appropriate pharmacologic therapy?

Treatment for Restless Legs at Night

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

Initial Assessment and Iron Management

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

Iron supplementation thresholds for RLS differ from general population:

• Supplement if ferritin ≤75 ng/mL OR transferrin saturation <20% in adults 2, 4
• In children, supplement if ferritin <50 ng/mL 1, 2
• Use oral ferrous sulfate 325-650 mg daily or every other day 4
• Consider IV ferric carboxymaltose (750-1000 mg) for rapid correction if oral iron fails after 3 months or symptoms are severe 2

Address Exacerbating Factors

Discontinue or avoid medications that worsen RLS: 2

• Serotonergic antidepressants (SSRIs, tricyclics) 2, 4
• Dopamine antagonists (antipsychotics like lurasidone) 2
• Antihistamines (diphenhydramine, centrally acting H1 blockers) 2, 4

Lifestyle modifications: 2

• Eliminate alcohol, caffeine, and nicotine within 3 hours of bedtime 2
• Moderate exercise (aerobic, resistance, flexibility) in morning/afternoon, but avoid vigorous exercise close to bedtime 2, 3
• Optimize sleep environment: dark, quiet, comfortable temperature 2

First-Line Pharmacological Treatment

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

Gabapentin Dosing:

• Start 300 mg three times daily 2
• Titrate by 300 mg/day every 3-7 days 2
• Target maintenance dose: 1800-2400 mg/day divided three times daily 2
• Maximum studied dose: 3600 mg/day 2

Gabapentin Enacarbil (prodrug):

• Strongly recommended alternative with potentially superior bioavailability 2
• Allows for more convenient dosing 2

Pregabalin:

• Strongly recommended alternative 1, 2
• Allows twice-daily dosing with superior bioavailability compared to regular gabapentin 2

Common side effects: Somnolence and dizziness, typically transient and mild 2

Medications to AVOID as First-Line

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, 4

• Annual augmentation incidence: 7-10% 4
• Augmentation features: earlier symptom onset, increased intensity, spread to arms/trunk 2
• May be considered only for short-term use in patients prioritizing immediate relief over long-term safety 1

Strongly recommended AGAINST: 1, 2

• Cabergoline (strong recommendation) 1
• Bupropion 1
• Carbamazepine 1
• Clonazepam 1, 2
• Valproic acid 1
• Valerian 1

Second-Line and Refractory RLS

For patients who fail first-line therapy or have augmentation from dopamine agonists: 2

Extended-release oxycodone and low-dose opioids:

• Conditionally recommended for moderate to severe refractory cases 2, 4
• Methadone 5-10 mg daily or buprenorphine are options 2, 4
• Long-term studies show relatively low abuse risk with appropriate screening and only small dose increases over 2-10 years 2
• Monitor for respiratory depression, especially with untreated sleep apnea 2

Alternative options:

• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation) 2
• Dipyridamole (conditional recommendation, low certainty) 2

Special Populations

End-Stage Renal Disease:

• Gabapentin: Start 100 mg post-dialysis or at bedtime, maximum 200-300 mg daily 1, 2
• IV iron sucrose if ferritin <200 ng/mL AND transferrin saturation <20% 1, 2
• Vitamin C supplementation 1, 2

Pregnancy:

• Iron supplementation particularly important 2
• Favor oral formulations throughout gestation 2
• Consider medication safety profiles carefully 2

Monitoring and Follow-Up

Reassess iron studies every 6-12 months, even with symptom resolution, as brain iron deficiency may persist despite normal serum parameters. 2

Monitor for:

• Side effects of alpha-2-delta ligands (dizziness, somnolence) 2
• Signs of augmentation if using dopamine agonists 2
• Improvement in nighttime symptoms AND daytime functioning (alertness, concentration, mood) 2

Critical Pitfalls to Avoid

• Do NOT use dopamine agonists as first-line therapy given high augmentation risk 1, 2, 4
• Do NOT assume "normal" ferritin (>50 ng/mL) is adequate—RLS requires higher thresholds (≤75 ng/mL) 2, 4
• Do NOT increase dopamine agonist doses if augmentation is suspected—this worsens the problem 2
• Do NOT use single nighttime gabapentin dosing—requires three times daily dosing for optimal 24-hour coverage 2
• Do NOT skip iron assessment before starting medications 2, 3