What are the best treatment options for an adult with severe periodic limb movements (PLMs) and restless‑legs syndrome (RLS)?

Treatment of Severe Periodic Limb Movements and Restless Legs Syndrome

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are the strongly recommended first-line pharmacological treatment for severe PLMs and RLS, with moderate certainty of evidence, after optimizing iron status. 1, 2

Initial Assessment and Iron Optimization

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

Iron supplementation thresholds specific to RLS:

• Adults: Supplement if ferritin ≤75 ng/mL or transferrin saturation <20% 1, 2
• Children: Supplement if ferritin <50 ng/mL 1

Iron repletion options:

• IV ferric carboxymaltose 750–1000 mg (one or two infusions) is strongly recommended for rapid correction, especially if oral iron fails or is not tolerated (strong recommendation, moderate certainty) 1, 2
• Oral ferrous sulfate 325 mg daily (or every other day) is a conditional alternative but works more slowly 1, 2

Iron optimization is critical because brain iron deficiency plays a key pathophysiologic role in RLS, even when serum iron appears normal. 1 Patients with ferritin 75–100 ng/mL may still benefit from IV iron despite being above the supplementation threshold. 1

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

Gabapentin dosing:

• Start 300 mg three times daily 1, 2
• Titrate by 300 mg/day every 3–7 days 1, 2
• Target maintenance dose: 1800–2400 mg/day divided TID 1, 2
• Maximum studied dose: 3600 mg/day 1
• Avoid single nighttime dosing—it fails to address daytime RLS symptoms and provides suboptimal 24-hour coverage 1

Pregabalin dosing:

• Start 50 mg TID or 75 mg BID 1
• After 3–7 days, increase to 300 mg/day 1
• Titrate by 150 mg every 3–7 days as tolerated 1
• Maximum dose: 600 mg/day 1
• Pregabalin allows twice-daily dosing with potentially superior bioavailability compared to regular gabapentin 1, 2

Gabapentin enacarbil (a prodrug of gabapentin) is also strongly recommended with moderate certainty of evidence. 1, 2

Why alpha-2-delta ligands are first-line:

• They do not cause augmentation—the paradoxical worsening of symptoms seen with dopamine agonists 1, 3
• They provide superior long-term outcomes compared to older dopaminergic approaches 1
• Common side effects (somnolence, dizziness) are typically transient and mild 1

Medications to Avoid or Use with Extreme Caution

Dopamine agonists (pramipexole, ropinirole, rotigotine) are NOT recommended for standard use due to a 7–10% annual risk of augmentation (conditional recommendation, moderate certainty). 1, 2

Augmentation characteristics:

• Earlier daily symptom onset (afternoon instead of evening) 1, 3
• Increased symptom intensity 1, 3
• Spread to arms or trunk 1, 3
• Paradoxical worsening despite dose increases 1, 3

Dopamine agonists may be considered only for short-term use in patients who prioritize immediate symptom relief over long-term safety—this is explicitly not the standard approach. 1

Strong recommendation against:

• Cabergoline (cardiac valvular fibrosis risk) 1, 2

Conditional recommendation against:

• Bupropion, carbamazepine, clonazepam, valproic acid, valerian 1, 2
• Clonazepam provides only sedation without reducing periodic limb movements 1

Second-Line Options for Refractory Cases

If symptoms remain severe despite adequate trials of alpha-2-delta ligands (at therapeutic doses for 4–6 weeks) and optimized iron status, consider:

Extended-release oxycodone or low-dose opioids (conditional recommendation, moderate certainty):

• Methadone 5–10 mg daily 1
• Buprenorphine (transdermal or sublingual) 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, 2

Before initiating opioids:

• Screen for opioid-use-disorder risk using validated tools 1
• Evaluate for untreated obstructive sleep apnea (opioids increase respiratory depression and central sleep apnea risk) 1
• Monitor respiratory status closely, especially during the first weeks 1
• Counsel about constipation (most common adverse effect) and prescribe prophylactic stool softeners 1

Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-invasive alternative (moderate certainty), though long-term data are limited. 1, 2

Non-Pharmacological Interventions

Eliminate or reduce exacerbating factors:

• Alcohol, caffeine, nicotine (especially within 3 hours of bedtime) 1, 2
• Antihistaminergic medications 1, 2
• Serotonergic medications (SSRIs, SNRIs) 1, 2
• Antidopaminergic medications (antipsychotics) 1, 2

Screen for and treat untreated obstructive sleep apnea, as it can worsen RLS symptoms. 1, 2

Moderate exercise in the morning or afternoon is recommended, but avoid vigorous exercise close to bedtime. 1

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
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (conditional recommendation, moderate certainty) 1, 2
• Vitamin C supplementation may enhance iron utilization (conditional recommendation, low certainty) 1, 2
• Avoid pregabalin in ESRD—it markedly increases the hazard of altered mental status and falls 1

Monitoring and Follow-Up

• Reassess RLS severity at 4–6 weeks after treatment initiation 1
• Repeat iron studies every 6–12 months, as brain iron deficiency may persist despite clinical improvement 1, 2
• Monitor for side effects of alpha-2-delta ligands (dizziness, somnolence) 1
• Evaluate both nighttime symptom relief and daytime functional outcomes (alertness, mood, quality of life) 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, 2
• Do not increase dopamine agonist doses if augmentation is suspected—this worsens the problem 1, 3
• Do not use single nighttime dosing of gabapentin—it provides inadequate 24-hour coverage 1
• Do not label RLS as refractory without first optimizing iron status (ferritin >75 ng/mL and transferrin saturation >20%) 1
• Do not use clonazepam as monotherapy—it lacks evidence of efficacy for RLS and only provides sedation 1
• Do not withhold opioids from appropriately screened patients with severe refractory RLS—evidence supports their use with low long-term abuse risk 1

Managing Dopaminergic Augmentation (If Already Present)

If a patient is already on a dopamine agonist and develops augmentation:

1. Add an alpha-2-delta ligand (e.g., gabapentin 300 mg TID, titrated to 1800–2400 mg/day) or an opioid before tapering the dopamine agonist 1, 3
2. Once adequate symptom control is achieved, down-titrate the dopamine agonist very slowly (reduce by 0.125–0.25 mg pramipexole-equivalent every 1–2 weeks) 1, 3
3. Anticipate rebound RLS and insomnia during the taper 1, 3
4. For severe augmentation, consider bypassing alpha-2-delta ligands and transitioning directly to an opioid 1