What is the treatment for restless legs syndrome (RLS) as a side effect of medication, according to UK guidelines?

Treatment of Medication-Induced Restless Legs Syndrome According to UK Guidelines

When restless legs syndrome develops as a medication side effect, the primary approach is to discontinue or switch the offending medication if clinically feasible, followed by assessment and correction of iron deficiency, and initiation of alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacological therapy. 1

Immediate Management Steps

1. Identify and Address the Causative Medication

• Discontinue or switch the offending agent if medically appropriate, as many medications can trigger or worsen RLS through dopamine antagonism or other mechanisms. 1

• Common culprits include:

  • Antipsychotics (e.g., lurasidone) that block dopamine receptors 1
  • Antidepressants (SSRIs, tricyclics, lithium) 1
  • Antihistamines (sedating antihistamines) 1
  • Stimulants (e.g., lisdexamfetamine/Vyvanse) 2
  • Dopamine antagonists (metoclopramide, prochlorperazine) 1

• If the medication cannot be stopped, consider alternatives with lower RLS risk within the same therapeutic class. 1

2. Assess and Correct Iron Status

• Check morning fasting serum ferritin and transferrin saturation (ideally after avoiding iron supplements for 24 hours). 1

• Supplement with iron if ferritin ≤75 ng/mL or transferrin saturation <20%—these are RLS-specific thresholds, higher than general population guidelines. 1

• Oral ferrous sulfate is conditionally recommended as first-line iron therapy. 1

• IV ferric carboxymaltose is strongly recommended for patients who don't respond to oral therapy or have appropriate iron parameters. 1

• Continue iron supplementation indefinitely with monitoring every 6-12 months, as RLS symptoms may recur if iron stores decline. 1

First-Line Pharmacological Treatment

Alpha-2-Delta Ligands (Preferred)

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands as first-line therapy over dopamine agonists due to superior long-term tolerability and absence of augmentation risk. 1

• Gabapentin: Start 300 mg at bedtime, titrate up to 1800-2400 mg/day divided into multiple doses (typically three times daily) as needed. 1, 2

• Gabapentin enacarbil: A prodrug with improved bioavailability, strongly recommended with moderate certainty of evidence. 1

• Pregabalin: Allows twice-daily dosing and may have superior bioavailability compared to gabapentin. 1

• Monitor for side effects: dizziness and somnolence are common but typically transient and mild. 1

• Avoid single nighttime dosing as it fails to address daytime RLS symptoms; divided dosing provides better 24-hour coverage. 1

Medications to Avoid

Dopamine Agonists Are NOT Recommended

The American Academy of Sleep Medicine suggests against the standard use of dopamine agonists (pramipexole, ropinirole, rotigotine) due to high risk of augmentation—a paradoxical worsening of symptoms with earlier onset, increased intensity, and anatomic spread. 1, 3

• Augmentation occurs in a significant proportion of patients on long-term dopaminergic therapy. 3, 4

• If a patient is already on a dopamine agonist when RLS develops, do not increase the dose; instead, add an alpha-2-delta ligand and slowly taper the dopamine agonist. 4

Other Medications to Avoid

• Levodopa: Suggested against due to very low certainty of evidence and high augmentation risk. 1

• Cabergoline: Strongly recommended against. 1

• Clonazepam: Not recommended due to insufficient evidence of efficacy, does not reduce objective disease markers, and has side effects including sedation and hepatotoxicity. 1, 2

• Bupropion, carbamazepine, valproic acid: Specifically recommended against by the American Academy of Sleep Medicine. 1

Second-Line and Refractory Cases

When First-Line Therapy Fails

• Extended-release oxycodone and other low-dose opioids (methadone, buprenorphine) are conditionally recommended for refractory cases, particularly when treating augmentation from dopaminergic agents. 1, 4

• Dipyridamole is conditionally recommended with low certainty of evidence. 1

• Bilateral high-frequency peroneal nerve stimulation is a non-pharmacological option with conditional recommendation. 1

Critical Monitoring and Follow-Up

• Reassess iron studies every 6-12 months even after symptom resolution, as brain iron deficiency may persist despite normal serum parameters. 1, 2

• Monitor for augmentation if dopamine agonists are used: earlier symptom onset during the day, increased intensity, spread to other body parts. 3, 4

• Evaluate for improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood). 1

Lifestyle Modifications as Adjunctive Therapy

• Eliminate or reduce alcohol, caffeine, and nicotine, especially within 3 hours of bedtime. 1

• Avoid heavy meals close to bedtime. 1

• Regular morning/afternoon exercise is recommended, but avoid vigorous exercise close to bedtime. 1

• Optimize sleep environment: dark, quiet, comfortable temperature. 1

Special Populations

End-Stage Renal Disease

• Gabapentin is conditionally recommended, starting with 100 mg post-dialysis or at bedtime, maximum 200-300 mg daily. 1

• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20%. 1

• Caution: Gabapentinoids carry higher risk of altered mental status and falls in dialysis patients, even at low doses. 1

Pregnancy

• Iron supplementation is particularly important given pregnancy-specific RLS prevalence, with oral formulations favored throughout gestation. 1

• Special consideration of medication safety profiles is essential. 1

Pediatric Patients

• Oral iron supplementation for ferritin <50 ng/mL, with monitoring for constipation. 1