What are the treatment options for Restless Legs Syndrome (RLS)?

Treatment of Restless Legs Syndrome

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

Initial Assessment and Iron Management

Check iron status first in all patients with clinically significant RLS:

• Obtain morning fasting serum ferritin and transferrin saturation after avoiding iron supplements for at least 24 hours 2, 3
• Supplement with oral ferrous sulfate if ferritin ≤75 ng/mL or transferrin saturation <20% (note this threshold is higher than general population guidelines) 1, 2, 3
• Consider IV ferric carboxymaltose for patients with ferritin 75-100 ng/mL or when oral supplementation fails 2, 3

Address exacerbating factors before starting medications:

• Discontinue or substitute medications that worsen RLS: antihistamines, SSRIs, tricyclic antidepressants, antipsychotics (dopamine antagonists like lurasidone), lithium 1, 2, 3
• Eliminate or reduce alcohol, caffeine 1, 2, 3
• Treat untreated obstructive sleep apnea 2, 3

First-Line Pharmacological Treatment

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands as first-line therapy (strong recommendation, moderate certainty of evidence):

• Gabapentin enacarbil (prodrug with better bioavailability) 1, 2, 3
• Gabapentin (requires three-times-daily dosing for optimal 24-hour coverage) 1, 2, 3
• Pregabalin (allows twice-daily dosing) 1, 2, 3

Dosing specifics for gabapentin:

• Start at 300 mg three times daily (900 mg/day total) 1
• Titrate by 300 mg/day every 3-7 days as needed 1
• Target maintenance dose: 1800-2400 mg/day divided three times daily 1
• Maximum well-tolerated dose: 3600 mg/day 1
• Common side effects include transient somnolence and dizziness 1

Critical advantage over dopaminergic agents: Alpha-2-delta ligands avoid the augmentation phenomenon—a paradoxical worsening of RLS symptoms with earlier onset during the day, increased intensity, and spread to other body parts that occurs with long-term dopamine agonist use 1, 4, 5

Dopaminergic Agents: Use with Extreme Caution

The American Academy of Sleep Medicine suggests AGAINST the standard use of dopamine agonists due to high augmentation risk:

• Pramipexole: conditional recommendation against standard use (moderate certainty) 1, 2
• Ropinirole: conditional recommendation against standard use (moderate certainty) 2
• Rotigotine transdermal: conditional recommendation against standard use (low certainty) 1, 2
• Levodopa: conditional recommendation against standard use (very low certainty) 1, 2
• Cabergoline: strong recommendation AGAINST use (moderate certainty) 2, 3

If dopamine agonists are used (only for short-term symptom relief in select patients):

• Start pramipexole at 0.125 mg orally 2-3 hours before bedtime 1
• Titrate slowly by doubling dose every 4-7 days to maximum 0.5 mg 1
• Monitor closely for augmentation signs: earlier symptom onset, increased intensity, anatomic spread 1
• Despite FDA approval, ropinirole showed efficacy in trials 6, but current guidelines prioritize long-term outcomes over short-term symptom reduction

Managing Dopaminergic Augmentation

If augmentation develops on dopamine agonists:

• Do NOT abruptly discontinue the dopamine agonist—this causes profound rebound RLS and insomnia 4
• Add an alpha-2-delta ligand (gabapentin or pregabalin) or low-dose opioid first 1, 4
• Once adequate symptom control achieved with the second agent, perform very slow down-titration of the dopamine agonist 4
• Alternative temporary measures: dose earlier in day or split into early evening and bedtime doses 1

Second-Line and Refractory RLS Treatment

For moderate-to-severe or refractory cases:

• Extended-release oxycodone and other low-dose opioids (methadone, buprenorphine) are conditionally recommended 1, 2
• Long-term studies show relatively low abuse risk and only small dose increases over 2-10 years in appropriately screened patients 1
• Caution: Risk of respiratory depression and central sleep apnea, especially with untreated OSA or COPD 1

Non-pharmacological option:

• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty) 1, 2

Special Populations

End-stage renal disease patients:

• Gabapentin: conditional recommendation, start 100 mg post-dialysis or at bedtime, maximum 200-300 mg daily (very low certainty) 1, 2
• Critical safety warning: Gabapentinoids carry 31-68% higher hazard for altered mental status and falls in dialysis patients 1
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% 1, 2
• Vitamin C: conditional recommendation 1

Pregnancy:

• Consider medication safety profiles specific to pregnancy 2, 3
• Non-pharmacological approaches preferred 3

Pediatric RLS:

• Oral ferrous sulfate for ferritin <50 ng/mL (conditional recommendation, very low certainty) 1, 2

Non-Pharmacological Approaches

Implement concurrently with pharmacological treatment:

• Moderate regular exercise 1, 7
• Smoking cessation 1
• Good sleep hygiene 8, 9
• Massaging affected legs, hot baths 8

Insufficient evidence for routine recommendation:

• Magnesium supplementation (not included in AASM guidelines; may consider as adjunctive therapy only after addressing iron and implementing first-line treatments) 1
• Yoga, acupuncture, pneumatic compression devices, light therapy, cognitive-behavioral therapy, valerian, Chinese herbs 7

Critical Pitfalls to Avoid

• Never start dopamine agonists as first-line therapy—augmentation occurs in significant proportion of patients and dramatically worsens long-term outcomes 1, 2, 4
• Never use magnesium as monotherapy without first addressing iron deficiency and considering guideline-recommended treatments 1
• Never abruptly stop dopamine agonists if augmentation develops—add alternative agent first, then taper slowly 4
• Never ignore iron status—ferritin ≤75 ng/mL warrants supplementation even if "normal" by general population standards 1, 2, 3
• Never prescribe single nighttime gabapentin dosing—inadequate for 24-hour symptom coverage; requires three-times-daily dosing 1