What is the recommended treatment plan for restless‑leg syndrome, including diagnosis confirmation, iron supplementation, non‑pharmacologic measures, and pharmacologic options?

Restless Leg Syndrome Treatment

Initial Assessment and Iron Status Evaluation

Check morning fasting serum ferritin and transferrin saturation in all patients with clinically significant RLS before starting any treatment, after avoiding iron-containing supplements for at least 24 hours. 1, 2

• Supplement iron if ferritin ≤75 ng/mL or transferrin saturation <20% in adults (higher thresholds than general population due to brain iron deficiency in RLS pathophysiology). 1, 2
• For children, supplement if ferritin <50 ng/mL. 1, 2
• For end-stage renal disease patients, use ferritin <200 ng/mL and transferrin saturation <20% as thresholds. 1, 3

Iron Supplementation Options

First-line iron therapy:

• Oral ferrous sulfate (325-650 mg daily, 65 mg elemental iron) receives conditional recommendation with moderate certainty. 1, 2, 3
• IV ferric carboxymaltose (1000 mg single infusion) is the only IV formulation with strong recommendation and moderate certainty of evidence, based on five RCTs showing improvements in disease severity, sleep quality, and quality of life. 1, 2, 3

When to choose IV over oral iron:

• Ferritin 75-100 ng/mL: use IV iron only (oral poorly absorbed in this range). 2, 3
• Oral iron not tolerated or ineffective after 3 months. 3
• Need for rapid correction in severe cases. 1

Avoid iron sucrose for general RLS population—it lacks efficacy except in dialysis patients with ESRD. 2, 3

Address Exacerbating Factors

Eliminate or reduce medications and substances that worsen RLS: 1

• Alcohol, caffeine, and nicotine (especially within 3 hours of bedtime)
• Antihistaminergic medications
• Serotonergic medications (SSRIs, SNRIs)
• Antidopaminergic medications (antipsychotics like lurasidone)
• Untreated obstructive sleep apnea

First-Line Pharmacologic Treatment

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are strongly recommended as first-line therapy with moderate certainty of evidence. 1, 4, 5

Gabapentin Dosing

• Start 300 mg three times daily (900 mg/day total). 1
• Increase by 300 mg/day every 3-7 days as needed. 1
• Target maintenance dose: 1800-2400 mg/day divided three times daily. 1
• Maximum studied dose: 3600 mg/day. 1
• Common side effects: somnolence and dizziness (typically transient and mild). 1

Pregabalin Dosing

• Start 50 mg three times daily or 75 mg twice daily. 1
• After 3-7 days, increase to 300 mg/day. 1
• Thereafter, may increase by 150 mg every 3-7 days as tolerated. 1
• Maximum dose: 600 mg/day. 1
• Advantage: twice-daily dosing with superior bioavailability compared to regular gabapentin. 1

Special Population: End-Stage Renal Disease

• Gabapentin: start 100 mg post-dialysis or at bedtime; maximum 200-300 mg daily. 1, 3
• Avoid pregabalin in ESRD due to increased hazard for altered mental status and falls. 1
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20%. 1, 3
• Vitamin C supplementation may enhance iron utilization. 1

Medications to Avoid or Use with Extreme Caution

Dopamine agonists (pramipexole, ropinirole, rotigotine) are NOT recommended for standard use due to high risk of augmentation—a paradoxical worsening of symptoms with earlier onset, increased intensity, and spread to arms/trunk. 1, 4, 5, 6

• Annual augmentation incidence: 7-10%. 1
• May be considered only for short-term use in patients who prioritize immediate relief over long-term safety. 1
• If already on a dopamine agonist, do not increase the dose if augmentation is suspected—this worsens the problem. 1

Strong recommendation against:

• Cabergoline, bupropion, carbamazepine, clonazepam, valproic acid, valerian. 1
• Levodopa (very low certainty of evidence, high augmentation risk). 1

Second-Line Options for Refractory Cases

Extended-release oxycodone and other low-dose opioids (methadone, buprenorphine) receive conditional recommendation for moderate to severe refractory RLS, particularly when treating augmentation from dopamine agonists. 1, 5, 6

• Long-term studies show relatively low risks of abuse/overdose in appropriately screened patients, with only small dose increases over 2-10 years. 1
• Caution: risk of respiratory depression and central sleep apnea, especially in patients with untreated OSA. 1

Other conditional recommendations:

• Bilateral high-frequency peroneal nerve stimulation (non-pharmacological option). 1
• Dipyridamole (low certainty of evidence). 1

Managing Augmentation from Dopamine Agonists

Augmentation characteristics: 1, 4, 5

• Earlier symptom onset during the day
• Increased symptom intensity
• Spread to arms or trunk
• Paradoxical worsening despite dose increases

Management strategy: 1, 4, 5

1. Do not increase dopamine agonist dose—this exacerbates augmentation.
2. Add alpha-2-delta ligand (gabapentin or pregabalin) or opioid at therapeutic doses.
3. Once adequate symptom relief achieved with second agent, begin very slow down-titration of dopamine agonist.
4. Expect profound rebound RLS and insomnia during taper—maintain second agent throughout.
5. For severe augmentation, consider switching directly to opioid, bypassing alpha-2-delta ligands.

Monitoring and Follow-Up

• Reassess iron studies every 6-12 months during ongoing therapy. 1
• Monitor for side effects of alpha-2-delta ligands (dizziness, somnolence). 1
• Check serum phosphate after repeat IV iron courses to detect hypophosphatemia. 2, 3
• IV ferric carboxymaltose may require up to 12 weeks for full clinical benefit. 3
• Evaluate improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood). 1

Critical Pitfalls to Avoid

• Do not use general population ferritin cutoffs (<15-30 ng/mL)—RLS requires higher thresholds (≥75 ng/mL). 2, 3
• Do not assume all IV iron formulations are equivalent—only ferric carboxymaltose has strong evidence; iron sucrose lacks efficacy except in dialysis patients. 2, 3
• Do not test iron studies while patient is taking supplements—wait at least 24 hours after last iron-containing product. 2, 3
• Do not use dopamine agonists as first-line therapy—augmentation risk is substantial and undermines long-term outcomes. 1, 4, 5
• Do not use clonazepam, tizanidine, or other non-evidence-based agents—they lack efficacy data and have significant safety concerns. 1