What are the treatment options for restless leg syndrome (RLS)?

Treatment for Restless Legs Syndrome

The American Academy of Sleep Medicine now strongly recommends alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacological therapy for RLS, representing a major shift away from dopamine agonists due to the high risk of augmentation. 1

Initial Assessment and Iron Optimization

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

Iron supplementation is recommended when ferritin ≤75 ng/mL or transferrin saturation <20%—notably higher thresholds than general population guidelines because brain iron deficiency drives RLS pathophysiology even when serum levels appear normal. 1, 2

Iron Treatment Options:

• Oral ferrous sulfate: Conditional recommendation for patients meeting iron parameters (ferritin ≤75 ng/mL or transferrin saturation <20%) 1, 2
• IV ferric carboxymaltose: Strong recommendation with moderate certainty for patients with appropriate iron parameters who don't respond to oral therapy 1, 2
• IV ferumoxytol or low molecular weight iron dextran: Conditional recommendations as alternatives 1

Iron therapy should be continued 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

Start with gabapentin 300 mg three times daily, titrating by 300 mg/day every 3-7 days until reaching maintenance dose of 1800-2400 mg/day divided three times daily. 1, 2 Doses up to 3600 mg/day are well-tolerated in clinical studies. 1

Alternative alpha-2-delta ligands with strong recommendations:

• Gabapentin enacarbil: Prodrug allowing more convenient dosing 1
• Pregabalin: Allows twice-daily dosing with potentially superior bioavailability 1, 2

Common side effects include somnolence and dizziness, typically transient and mild. 1 Monitor for misuse potential in at-risk populations. 1

Medications to Avoid or Use with Extreme Caution

The American Academy of Sleep Medicine now recommends AGAINST standard use of dopamine agonists due to augmentation—a paradoxical worsening of symptoms with earlier onset, increased intensity, and anatomic spread. 3, 1

Specific recommendations against:

• Pramipexole: Conditional recommendation against (moderate certainty) 1
• Ropinirole: Conditional recommendation against (moderate certainty) 1
• Rotigotine transdermal: Conditional recommendation against (low certainty) 1
• Levodopa: Conditional recommendation against (very low certainty) 1
• Cabergoline: Strong recommendation against (moderate certainty) 1

Additional medications to avoid:

• Clonazepam: Conditional recommendation against—insufficient efficacy evidence, doesn't reduce periodic limb movements, causes sedation 1
• Bupropion, carbamazepine, valproic acid, valerian: All receive conditional recommendations against 1

Exacerbating Factors to Address

Identify and eliminate medications that worsen RLS:

• Antihistamines (including over-the-counter sleep aids) 1, 2
• Serotonergic antidepressants (SSRIs, SNRIs) 1, 2
• Antipsychotics/dopamine antagonists (including lurasidone) 1
• Tricyclic antidepressants 1

Lifestyle modifications:

• Reduce or eliminate caffeine and alcohol 2
• Screen for and treat obstructive sleep apnea 1, 2
• Implement moderate exercise and smoking cessation 2

Second-Line and Refractory Treatment Options

For patients who fail alpha-2-delta ligands or have refractory RLS, extended-release oxycodone and other low-dose opioids (methadone, buprenorphine) receive conditional recommendations. 1 Long-term studies show relatively low risks of abuse and only small dose increases over 2-10 years in appropriately screened patients. 1

Bilateral high-frequency peroneal nerve stimulation: Conditional recommendation as non-pharmacological alternative—wearable device placed below knees provides peroneal nerve stimulation. 3, 1

Dipyridamole: Conditional recommendation with low certainty evidence 1

Managing Dopamine Agonist Augmentation

If a patient is already on dopamine agonists and experiencing augmentation (earlier symptom onset, increased severity, anatomic spread):

1. Add an alpha-2-delta ligand or opioid first—do NOT immediately reduce the dopamine agonist due to severe rebound RLS and insomnia 4
2. Once adequate symptom control is achieved with the second agent, begin very slow down-titration of the dopamine agonist 4
3. Complete discontinuation may lead to dramatic long-term symptom relief 4

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: Conditional recommendation if ferritin <200 ng/mL and transferrin saturation <20% 1
• Vitamin C: Conditional recommendation 1
• Critical warning: Gabapentinoids carry 31-68% higher hazard for altered mental status and falls in dialysis patients 1

Pediatric RLS:

• Oral iron supplementation: Recommended for ferritin <50 ng/mL, monitoring for constipation 3, 1

Pregnancy:

• Iron supplementation is particularly important with favorable safety profile for oral formulations 1
• Special consideration needed for medication safety profiles 1

Critical Pitfalls to Avoid

• Never use magnesium or clonazepam as monotherapy without first addressing iron status and trying guideline-recommended treatments 1
• Avoid single nighttime dosing of gabapentin—fails to address daytime symptoms and provides suboptimal 24-hour coverage 1
• Do not abruptly discontinue dopamine agonists in augmented patients—severe rebound will occur 4
• Ketamine has no role in RLS treatment and does not appear in evidence-based guidelines 1
• Screen for untreated sleep apnea before using alpha-2-delta ligands or opioids, as these can worsen respiratory depression 1