What are the treatment options for restless leg syndrome?

Treatment Options for Restless Legs Syndrome

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are the first-line pharmacological treatment for RLS, with iron supplementation for patients with ferritin ≤75 ng/mL or transferrin saturation <20%. 1, 2

Initial Assessment and Iron Correction

Before starting any medication, check morning fasting iron studies including serum ferritin and transferrin saturation, avoiding iron supplements for at least 24 hours prior. 1, 2 The threshold for iron supplementation in RLS differs from general population guidelines:

• Supplement with iron if ferritin ≤75 ng/mL or transferrin saturation <20% 1, 2
• IV ferric carboxymaltose is strongly recommended for rapid correction in patients meeting these parameters 1, 2
• Oral ferrous sulfate is an alternative but works more slowly 1, 2
• In pediatric RLS, supplement if ferritin <50 ng/mL 1, 2

This higher ferritin threshold reflects the critical role of brain iron deficiency in RLS pathophysiology, even when serum iron appears normal. 1

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

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands as first-line therapy with moderate certainty of evidence. 1, 2 These medications have replaced dopamine agonists due to superior long-term safety and lack of augmentation risk.

Gabapentin dosing: 1

• Start at 300 mg three times daily (900 mg/day total)
• Titrate by 300 mg/day every 3-7 days based on response
• Target maintenance dose: 1800-2400 mg/day divided three times daily
• Critical pitfall: Avoid single nighttime dosing—this fails to address daytime RLS symptoms and provides suboptimal 24-hour coverage 1

Pregabalin: 1, 2

• Allows twice-daily dosing with potentially superior bioavailability compared to gabapentin
• Strongly recommended as first-line therapy with moderate certainty of evidence

Gabapentin enacarbil: 1, 2

• A prodrug of gabapentin with extended-release properties
• Strongly recommended with moderate certainty of evidence

Common side effects include somnolence and dizziness, which are typically transient and mild. 1 Monitor for misuse potential in at-risk populations, and use caution in patients with untreated obstructive sleep apnea or chronic obstructive pulmonary disease. 1

Medications to Avoid: Dopamine Agonists

The American Academy of Sleep Medicine suggests against the standard use of dopamine agonists (pramipexole, ropinirole, rotigotine) due to high risk of augmentation. 1, 2, 3 This represents a major shift from older 2009 guidelines that recommended these as first-line therapy. 3

Augmentation is a paradoxical worsening of RLS characterized by: 1, 4

• Earlier onset of symptoms during the day
• Increased symptom intensity
• Spread of symptoms to other body parts (arms, trunk)
• Occurs in a significant proportion of patients on long-term dopamine agonist therapy

The American Academy of Sleep Medicine specifically recommends against: 1, 2

• Cabergoline (strong recommendation against, moderate certainty)
• Pramipexole (conditional recommendation against, moderate certainty)
• Ropinirole (conditional recommendation against, moderate certainty) 3, 5
• Transdermal rotigotine (conditional recommendation against, low certainty)
• Levodopa (conditional recommendation against, very low certainty)

While the FDA label demonstrates ropinirole's efficacy in reducing IRLS scores by 2.5-3.7 points more than placebo at 12 weeks 5, the long-term augmentation risk outweighs short-term benefits. Dopamine agonists may only be considered for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects. 3

Second-Line Options for Refractory Cases

Extended-release oxycodone and other low-dose opioids (methadone, buprenorphine) are conditionally recommended for moderate to severe refractory RLS, particularly when treating augmentation from dopamine agonists. 1, 2, 4 Evidence shows relatively low risks of abuse and overdose in appropriately screened patients, with long-term studies showing only small dose increases over 2-10 years. 1, 6

Critical caution: Screen for risk of respiratory depression and central sleep apnea, especially in patients with untreated obstructive sleep apnea. 1 When monitored appropriately, opioids can be very safe and durable for long-term therapy. 6

Non-Pharmacological Interventions

Address exacerbating factors before or alongside pharmacological treatment: 1, 2

Substances to eliminate or reduce: 1

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

Lifestyle modifications: 1

• Regular moderate exercise in morning/afternoon (avoid vigorous exercise close to bedtime)
• Optimize sleep environment (dark, quiet, comfortable temperature)
• Increase bright light exposure during day, avoid at night

Physical interventions with evidence: 7, 8

• Repetitive transcranial magnetic stimulation
• Compression devices
• Counterstrain manipulation
• Infrared therapy
• Standard acupuncture
• Bilateral high-frequency peroneal nerve stimulation (conditionally recommended by American Academy of Sleep Medicine) 1, 2

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

Special Populations

End-stage renal disease: 1, 2

• Gabapentin is conditionally recommended (very low certainty)
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (moderate certainty)
• Vitamin C is conditionally recommended (low certainty)
• Critical warning: Gabapentinoids carry 31-68% higher hazard for altered mental status and falls in dialysis patients, even at low doses 1

Pregnancy: 1

• Special consideration of medication safety profiles required
• Iron supplementation is particularly important given pregnancy-specific RLS prevalence
• Oral formulations favored throughout gestation

Pediatric RLS: 1, 2

• Ferrous sulfate conditionally recommended if ferritin <50 ng/mL (very low certainty)
• Monitor for constipation with oral iron supplementation

Managing Augmentation from Prior Dopamine Agonist Use

If a patient presents already on a dopamine agonist with augmentation: 1, 4

1. Add an alpha-2-delta ligand or opioid first—do not immediately stop the dopamine agonist
2. Titrate the new medication to adequate doses or symptom relief
3. Once controlled, begin very slow down-titration of the dopamine agonist
4. Expect profound rebound RLS and insomnia with even small dose reductions 4

Alternative short-term strategies while transitioning: 1

• Take dopamine agonist doses earlier in the day
• Split existing doses into early evening and bedtime administration

Medications Specifically Recommended Against

Beyond dopamine agonists, the American Academy of Sleep Medicine recommends against: 1, 2

• Bupropion (conditional, moderate certainty)
• Carbamazepine (conditional, low certainty)
• Clonazepam (conditional, very low certainty)—improves subjective sleep but does not reduce objective periodic limb movement index 1
• Valproic acid (conditional, low certainty)
• Valerian (conditional, very low certainty)
• Ketamine (not mentioned in any evidence-based guidelines) 1

Treatment Monitoring and Follow-Up

• Reassess iron studies every 6-12 months, as RLS symptoms may recur if iron stores decline 1
• Monitor for side effects of alpha-2-delta ligands (dizziness, somnolence) 1
• Evaluate improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood) 1
• Continue iron therapy indefinitely with ongoing monitoring, as brain iron deficiency may persist despite normal serum parameters 1