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, not dopamine agonists, due to superior long-term safety and lack of augmentation risk. 1

Initial Assessment and Iron Correction

Before initiating any pharmacological therapy, two critical steps must be completed:

• Check serum ferritin and transferrin saturation in all patients with clinically significant RLS, ideally in the morning after avoiding iron-containing supplements for at least 24 hours. 1, 2

• Supplement with iron if ferritin ≤75 ng/mL or transferrin saturation <20%—these are RLS-specific thresholds, not general population cutoffs. 1, 2

• For oral supplementation, use ferrous sulfate 65 mg elemental iron daily (conditional recommendation, moderate certainty). 2, 3

• For IV supplementation, use ferric carboxymaltose 1000 mg (strong recommendation, moderate certainty), particularly if ferritin is 75-100 ng/mL where oral iron is ineffective. 2, 3

• Address exacerbating factors: eliminate or reduce alcohol, caffeine, antihistamines, serotonergic antidepressants, antidopaminergic medications, and treat untreated obstructive sleep apnea. 1, 3

First-Line Pharmacological Treatment

Once iron status is optimized and exacerbating factors addressed:

• Gabapentin enacarbil (strong recommendation, moderate certainty of evidence). 1, 3

• Gabapentin (strong recommendation, moderate certainty of evidence). 1, 3

• Pregabalin (strong recommendation, moderate certainty of evidence). 1, 3

These alpha-2-delta ligands are preferred because they do not cause augmentation—a paradoxical worsening of RLS symptoms characterized by earlier onset, increased intensity, and anatomic spread that occurs with dopamine agonists. 1, 4

Critical Dosing Considerations

• Start gabapentin at 300 mg three times daily (900 mg/day total) and titrate up to 1800-2400 mg/day divided three times daily based on response. 1

• Single nighttime dosing is inadequate for 24-hour symptom coverage. 1

• Monitor for transient side effects including somnolence and dizziness, which typically resolve. 1

Dopamine Agonists: Use with Extreme Caution

The American Academy of Sleep Medicine now recommends AGAINST standard use of dopamine agonists due to the high risk of augmentation with long-term use. 1, 3

• Pramipexole: conditional recommendation AGAINST standard use (moderate certainty). 1, 3

• Ropinirole: conditional recommendation AGAINST standard use (moderate certainty). 1, 5

• Rotigotine: conditional recommendation AGAINST standard use (low certainty). 1

• Levodopa: conditional recommendation AGAINST standard use (very low certainty). 1, 3

• Cabergoline: strong recommendation AGAINST use (moderate certainty). 1, 3

While these agents showed efficacy in clinical trials 5, the long-term risk of augmentation outweighs short-term benefits. They may only be considered for patients who prioritize immediate symptom relief over long-term adverse effects and understand the augmentation risk. 1, 3

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) are conditionally recommended, particularly for refractory cases or treating augmentation from dopamine agonists. 1, 4, 6

• Long-term studies show relatively low risks of abuse and only small dose increases over 2-10 years when patients are appropriately screened. 1

• Monitor for respiratory depression and central sleep apnea, especially in patients with untreated obstructive sleep apnea. 1

• Bilateral high-frequency peroneal nerve stimulation is a non-pharmacological option with conditional recommendation based on moderate certainty of evidence. 1, 3

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

Managing Augmentation from Dopamine Agonists

If a patient is already on a dopamine agonist and develops augmentation (earlier symptom onset, increased intensity, anatomic spread):

• Do NOT abruptly discontinue the dopamine agonist—this causes profound rebound RLS and insomnia. 4

• Add an alpha-2-delta ligand or opioid first and titrate to adequate symptom control. 4, 6

• Only after achieving adequate control with the second agent, begin very slow down-titration and discontinuation of the dopamine agonist. 4

Special Populations

End-Stage Renal Disease

• Gabapentin is conditionally recommended (very low certainty). 1, 3
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (conditional recommendation, moderate certainty). 1, 3
• Vitamin C is conditionally recommended (low certainty). 1

Pregnancy

• Consider medication safety profiles specific to pregnancy. 1, 3
• Non-pharmacological approaches and iron supplementation are preferred. 2, 3
• Oral iron formulations have favorable safety profiles throughout gestation. 1

Pediatric RLS

• Iron supplementation if ferritin <50 ng/mL (conditional recommendation, very low certainty). 1, 2
• Monitor for constipation with oral iron. 1

Medications to Avoid

Never use these agents for RLS treatment:

• Bupropion (conditional recommendation against, moderate certainty). 1
• Carbamazepine (conditional recommendation against, low certainty). 1
• Clonazepam (conditional recommendation against, very low certainty). 1
• Valproic acid (conditional recommendation against, low certainty). 1
• Valerian (conditional recommendation against, very low certainty). 1
• Ketamine (no evidence-based support). 1

Lifestyle Modifications

• Eliminate alcohol, caffeine, and nicotine, especially within 3 hours of bedtime. 1
• Avoid heavy meals or drinking within 3 hours of bedtime. 1
• Regular morning/afternoon exercise, but avoid vigorous exercise close to bedtime. 1
• Optimize sleep environment: dark, quiet, comfortable temperature. 1
• Increase bright light exposure during the day, avoid at night. 1

Common Pitfalls to Avoid

• Do not use general population ferritin cutoffs (<15-30 ng/mL)—this misses the majority of RLS patients who would benefit from iron therapy. 2

• Do not start dopamine agonists as first-line therapy—this is outdated practice that leads to augmentation. 1, 3

• Do not use oral iron for ferritin 75-100 ng/mL—it will be ineffective; use IV iron instead. 2

• Do not test iron studies while patients are taking supplements—wait at least 24 hours after the last iron-containing product. 2

• Do not assume magnesium or clonazepam are appropriate monotherapy—they lack evidence and should not replace guideline-recommended treatments. 1