How should periodic limb movement disorder be treated, including assessment of iron deficiency, first‑line non‑pharmacologic measures, and appropriate first‑ and second‑line pharmacologic options?

Treatment of Periodic Limb Movement Disorder

Periodic limb movement disorder (PLMD) should be treated first by assessing and correcting iron deficiency (ferritin ≤75 ng/mL or transferrin saturation <20%), followed by alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacologic therapy, while avoiding dopamine agonists due to high augmentation risk. 1

Initial Assessment: Iron Status Evaluation

Before initiating any pharmacologic treatment, obtain morning fasting serum ferritin and transferrin saturation after avoiding iron-containing supplements for at least 24 hours. 1, 2

• Iron supplementation thresholds for PLMD/RLS are higher than general population guidelines: supplement when ferritin ≤75 ng/mL or transferrin saturation <20%. 1, 2
• Brain iron deficiency in the substantia nigra impairs dopamine transport and synthesis, which is the critical pathophysiological mechanism producing symptoms in these disorders. 2
• Both parameters are required because ferritin can be falsely elevated by inflammation, while transferrin saturation <20% indicates functional iron deficiency even when ferritin appears adequate. 3

Iron Supplementation Options

Oral iron: Ferrous sulfate 325–650 mg daily (or every other day to improve tolerability) is conditionally recommended as first-line iron therapy. 1

Intravenous iron: IV ferric carboxymaltose 750–1000 mg (given in one or two infusions) is strongly recommended for patients with appropriate iron parameters, particularly when oral iron is not tolerated or ineffective after 3 months. 1, 2

Non-Pharmacologic Measures

Address potential exacerbating factors before or concurrent with pharmacologic treatment: 1

• Eliminate or reduce: alcohol, caffeine, and nicotine, especially within 3 hours of bedtime 1
• Review and discontinue if possible: antihistaminergic medications, serotonergic antidepressants (SSRIs, SNRIs, mirtazapine), antidopaminergic medications (antipsychotics, metoclopramide), and untreated obstructive sleep apnea 1, 4
• Optimize sleep environment: dark, quiet, comfortable temperature with regular sleep-wake schedule 1
• Exercise timing: regular morning/afternoon exercise is beneficial, but avoid vigorous exercise close to bedtime 1

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

Alpha-2-delta ligands are strongly recommended as first-line pharmacologic treatment with moderate certainty of evidence, superior to dopamine agonists due to absence of augmentation risk. 1

Gabapentin Dosing

• Starting dose: 300 mg three times daily 1
• Titration: increase by 300 mg/day every 3–7 days as tolerated 1
• Target maintenance: 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

Gabapentin Enacarbil

• A prodrug of gabapentin that is strongly recommended with moderate certainty of evidence 1
• May offer more consistent absorption compared to regular gabapentin 1

Pregabalin

• Strongly recommended alternative that allows twice-daily dosing with potentially superior bioavailability compared to regular gabapentin 1
• Starting dose: 50 mg three times daily or 75 mg twice daily 1
• Titration: after 3–7 days, increase to 300 mg/day; thereafter may increase by 150 mg every 3–7 days as tolerated 1
• Maximum dose: 600 mg/day 1

Medications to Avoid or Use with Extreme Caution

Dopamine Agonists: NOT Recommended for Standard Use

The American Academy of Sleep Medicine suggests against the standard use of dopamine agonists (pramipexole, ropinirole, rotigotine, levodopa) due to high risk of augmentation—a paradoxical worsening of symptoms. 1

• Augmentation incidence: 7–10% annually 1
• Augmentation characteristics: earlier daily symptom onset (afternoon instead of evening), increased intensity, spread to arms or trunk 1
• These agents may be considered only for short-term use in patients who prioritize immediate symptom relief over long-term safety, but this is explicitly not the standard approach 1

Strongly Recommended Against

The following medications are specifically recommended against for PLMD treatment: 1

• Cabergoline (strong recommendation, moderate certainty)
• Bupropion (conditional recommendation, moderate certainty)
• Carbamazepine (conditional recommendation, low certainty)
• Clonazepam (conditional recommendation, very low certainty)
• Valproic acid (conditional recommendation, low certainty)
• Valerian (conditional recommendation, very low certainty)

Second-Line and Refractory Treatment Options

Opioids for Refractory Cases

Extended-release oxycodone and other low-dose opioids (methadone 5–10 mg daily, buprenorphine) are conditionally recommended for moderate to severe refractory PLMD, particularly when treating augmentation from dopamine agonists. 1

• 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 monitoring: screen for misuse risk and monitor for respiratory depression, particularly if obstructive sleep apnea is present 1

Alternative Non-Pharmacologic Option

• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended with moderate certainty of evidence as a newer noninvasive treatment option 1

Special Populations

End-Stage Renal Disease (ESRD)

• Gabapentin: start 100 mg post-dialysis or at bedtime; maximum 200–300 mg daily (conditional recommendation, very low certainty) 1
• IV iron sucrose: indicated when ferritin <200 ng/mL and transferrin saturation <20% (conditional recommendation, moderate certainty) 1
• Vitamin C supplementation: conditionally recommended to enhance iron utilization 1
• Avoid pregabalin in ESRD due to increased hazard for altered mental status and falls 1

Pediatric PLMD

• Iron supplementation is the first-line treatment when ferritin <50 ng/mL (lower threshold than adults), with monitoring for constipation 1, 5, 6
• Ferrous sulfate is conditionally recommended with very low certainty of evidence 1
• Most pharmacologic agents lack FDA approval in children; dopaminergic medications have limited data in pediatric populations 5, 6
• Behavioral interventions should be emphasized before pharmacologic options in children 6

Treatment Algorithm Summary

1. Check iron status (morning fasting ferritin and transferrin saturation after 24-hour supplement-free interval) 1
2. Supplement iron if ferritin ≤75 ng/mL or transferrin saturation <20% (oral ferrous sulfate or IV ferric carboxymaltose) 1
3. Address exacerbating factors (medications, caffeine, alcohol, untreated sleep apnea) 1
4. Initiate alpha-2-delta ligand (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacologic therapy 1
5. Avoid dopamine agonists as standard first-line therapy due to augmentation risk 1
6. Consider opioids only for refractory cases after failure of first-line agents 1
7. Monitor regularly for treatment response, side effects, and iron status every 6–12 months 1

Critical Pitfalls to Avoid

• Do not use dopamine agonists as first-line therapy given the high augmentation risk and current guideline recommendations favoring alpha-2-delta ligands 1
• Do not assume "normal" ferritin rules out iron deficiency in PLMD—use the higher threshold of ≤75 ng/mL specific to these disorders 1, 2
• Do not obtain iron studies without proper preparation—must be morning fasting after 24-hour supplement-free interval to avoid falsely elevated results 1, 3
• Do not increase dopamine agonist doses if augmentation is suspected—this worsens the problem; instead transition to alpha-2-delta ligands 1
• Do not use clonazepam, benzodiazepines, or muscle relaxants as primary therapy—these lack evidence and carry significant side effect risks 1