What are the treatment options for restless leg syndrome?

Treatment of Restless Legs Syndrome

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacological therapy for RLS, with dopamine agonists now relegated to limited use due to high augmentation risk. 1

Initial Assessment and Iron Optimization

Before initiating any pharmacological therapy, address the following critical steps:

• Check morning fasting serum ferritin and transferrin saturation in all patients with clinically significant RLS, avoiding iron supplements for at least 24 hours before testing 1, 2
• Supplement with iron if ferritin ≤75 ng/mL or transferrin saturation <20%—this threshold is higher than general population guidelines because brain iron deficiency plays a key pathophysiological role in RLS 1, 2
• Use IV ferric carboxymaltose (strong recommendation, moderate certainty) for patients meeting iron criteria who don't respond to oral therapy 1, 2
• Use oral ferrous sulfate (conditional recommendation, moderate certainty) for mild iron deficiency 1, 2

Critical pitfall: Do not skip iron assessment—correcting iron deficiency may dramatically improve symptoms and potentially lower augmentation risk with any subsequent pharmacotherapy 1

Eliminate Exacerbating Factors

• Discontinue or avoid: antihistaminergic medications, serotonergic antidepressants (SSRIs, SNRIs), antidopaminergic agents (antipsychotics like lurasidone), alcohol, caffeine (especially evening consumption), and nicotine 1, 2
• Screen for and treat obstructive sleep apnea, which can significantly worsen RLS symptoms 1, 2

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

The treatment hierarchy has fundamentally shifted—alpha-2-delta ligands are now preferred over dopamine agonists due to absence of augmentation risk:

Gabapentin Enacarbil (Preferred Alpha-2-Delta Ligand)

• FDA-approved dose: 600 mg once daily at approximately 5 PM with food 3
• This prodrug formulation provides superior bioavailability and allows convenient once-daily dosing 3
• Strong recommendation with moderate certainty of evidence 1, 3

Standard Gabapentin

• Start at 300 mg three times daily (900 mg/day total) 1
• Titrate by 300 mg/day every 3-7 days until reaching maintenance dose of 1800-2400 mg/day divided three times daily 1
• Maximum doses up to 3600 mg/day are well-tolerated in clinical studies 1
• Strong recommendation with moderate certainty of evidence 1, 2

Critical pitfall: Single nighttime dosing of gabapentin fails to address daytime RLS symptoms—use three-times-daily dosing for optimal 24-hour coverage 1

Pregabalin

• Allows twice-daily dosing with potentially superior bioavailability compared to standard gabapentin 1
• Strong recommendation with moderate certainty of evidence 1, 2

Common side effects of alpha-2-delta ligands include somnolence and dizziness, which are typically transient and mild 1

Dopamine Agonists: Now Second-Line with Major Caveats

The American Academy of Sleep Medicine now suggests AGAINST standard use of dopamine agonists due to augmentation—a paradoxical worsening of RLS characterized by earlier symptom onset, increased intensity, and anatomic spread to other body parts. 1, 2

When Dopamine Agonists May Be Considered (Rarely)

• Only for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects 1, 2
• Ropinirole and pramipexole: conditional recommendation AGAINST standard use (moderate certainty) 1, 2
• Transdermal rotigotine: conditional recommendation AGAINST standard use (low certainty) 1
• Levodopa: conditional recommendation AGAINST standard use (very low certainty) 1, 2
• Cabergoline: strong recommendation AGAINST use (moderate certainty) 1, 2

FDA labeling context: While ropinirole demonstrated efficacy in three 12-week trials with mean dose ~2 mg/day and showed statistically significant improvements in IRLS scores and CGI-I responder rates 4, the long-term augmentation risk has fundamentally changed treatment recommendations 1, 5

Treatment of Refractory RLS and Augmentation

For Patients Failing Alpha-2-Delta Ligands

• Extended-release oxycodone and other low-dose opioids (methadone, buprenorphine) are conditionally recommended for refractory cases 1, 2
• Evidence shows relatively low risks of abuse and overdose in appropriately screened patients, with only small dose increases over 2-10 years 1
• Critical caution: Screen for and treat obstructive sleep apnea before initiating opioids due to respiratory depression risk 1

Managing Dopaminergic Augmentation

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

• Do NOT abruptly discontinue the dopamine agonist—profound rebound RLS and insomnia will occur 5
• Add an alpha-2-delta ligand or opioid first and titrate to adequate symptom control 1, 5
• Only after achieving adequate control with the second agent, begin very slow down-titration and eventual discontinuation of the dopamine agonist 5
• Opioids are particularly effective for treating augmentation symptoms during this transition 1, 6

Non-Pharmacological and Alternative Treatments

• Bilateral high-frequency peroneal nerve stimulation: conditional recommendation with moderate certainty as a non-invasive option 1, 2
• Exercise, compression devices, counterstrain manipulation, infrared therapy, and standard acupuncture showed efficacy in reducing RLS severity in systematic review 7
• Avoid cold exposure, particularly in patients with Raynaud's phenomenon 1

Special Populations

End-Stage Renal Disease

• Gabapentin: conditional recommendation (very low certainty), start 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%: conditional recommendation (moderate certainty) 1, 2
• Critical warning: Gabapentinoids carry 31-68% higher hazard for altered mental status and falls in dialysis patients—use lowest effective doses 1

Pregnancy

• Iron supplementation is particularly important given pregnancy-specific RLS prevalence, with oral formulations favored throughout gestation 1
• Non-pharmacological approaches are preferred when possible 2
• Medication safety profiles must be carefully considered for any pharmacotherapy 1, 2, 3

Pediatric RLS

• Oral iron supplementation for ferritin <50 ng/mL: conditional recommendation (very low certainty) 1, 2
• Monitor for constipation as a common side effect 1

Medications to Explicitly Avoid

The American Academy of Sleep Medicine specifically recommends against:

• Bupropion (conditional, moderate certainty) 1
• Carbamazepine (conditional, low certainty) 1
• Clonazepam (conditional, very low certainty)—improves subjective sleep but doesn't reduce objective periodic limb movements and carries sedation/hepatotoxicity risks 1
• Valproic acid (conditional, low certainty) 1
• Valerian (conditional, very low certainty) 1

Long-Term Monitoring

• Continue iron supplementation indefinitely with monitoring every 6-12 months—RLS symptoms may recur if iron stores decline below therapeutic thresholds 1
• Monitor for augmentation if dopamine agonists are used despite recommendations against them 1
• Monitor for side effects of alpha-2-delta ligands, particularly dizziness and somnolence, though these are typically mild and transient 1