What medications are used to treat Restless Legs Syndrome (RLS)?

Medications for Restless Legs Syndrome (RLS)

First-Line Treatment: Alpha-2-Delta Ligands

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacological therapy for RLS, replacing dopamine agonists due to superior long-term safety profiles and avoidance of augmentation. 1

Specific Alpha-2-Delta Ligand Options:

• Gabapentin: Strong recommendation with moderate certainty of evidence 1
• Gabapentin enacarbil: Strong recommendation with moderate certainty of evidence 1
• Pregabalin: Strong recommendation with moderate certainty of evidence, established as effective for up to 1 year 1, 2

Dosing Considerations:

• Gabapentin typically starts at 300mg three times daily (900mg/day total) and can be titrated up to 2400mg/day, with doses up to 3600mg/day well-tolerated 1
• Titration should occur every 3-7 days by 300mg/day increments until reaching maintenance dose of 1800-2400mg/day divided three times daily 1
• Common side effects include somnolence and dizziness, which are typically transient and mild 1

Iron Supplementation (Critical First Step)

Before initiating any pharmacological treatment, check serum ferritin and transferrin saturation in all patients with clinically significant RLS, ideally in the morning after avoiding iron supplements for at least 24 hours. 1

Iron Therapy Recommendations:

• Oral ferrous sulfate: Conditional recommendation with moderate certainty if ferritin ≤75 ng/mL or transferrin saturation <20% 1
• IV ferric carboxymaltose: Strong recommendation with moderate certainty for patients with appropriate iron parameters who don't respond to oral therapy 1
• IV low molecular weight iron dextran and IV ferumoxytol: Conditional recommendations for patients with appropriate iron parameters 1
• Iron therapy should be continued indefinitely with ongoing monitoring, as RLS symptoms may recur if iron stores decline 1

Second-Line Treatment: Opioids

Extended-release oxycodone and other low-dose opioids (methadone, buprenorphine) are conditionally recommended for refractory cases or when treating augmentation from dopaminergic agents. 1

• Evidence suggests relatively low risks of abuse and overdose in appropriately screened patients 1
• Long-term studies show only small dose increases over extended periods (2-10 years) 1
• Critical caution: Risk of respiratory depression and central sleep apnea, especially in patients with untreated obstructive sleep apnea 1

Non-Pharmacological Options

• Bilateral high-frequency peroneal nerve stimulation: Conditional recommendation based on initial success in short-term studies 1

Medications to AVOID or Use with Extreme Caution

Dopamine Agonists (Now Recommended AGAINST for Standard Use):

The American Academy of Sleep Medicine suggests against the standard use of dopamine agonists due to the high risk of augmentation—a paradoxical worsening of symptoms with earlier onset, increased intensity, and anatomic spread. 1, 3

• Pramipexole: Conditional recommendation AGAINST standard use (moderate certainty) 1
• Ropinirole: Conditional recommendation AGAINST standard use (moderate certainty) 1, 3
  • Note: Despite FDA approval for RLS 4, current guidelines recommend against standard use due to augmentation risk 1, 3
• Transdermal rotigotine: Conditional recommendation AGAINST standard use (low certainty) due to adverse effects with long-term use 1
• Levodopa: Conditional recommendation AGAINST standard use (very low certainty) with high risk of augmentation 1
• Cabergoline: Strong recommendation AGAINST use (moderate certainty) 1

Other Medications to Avoid:

• Clonazepam: Conditional recommendation AGAINST (very low certainty of evidence) - insufficient efficacy evidence, does not reduce periodic limb movement index, and causes sedation 1
• Bupropion: Conditional recommendation AGAINST (moderate certainty) 1
• Carbamazepine: Conditional recommendation AGAINST (low certainty) 1
• Valproic acid: Conditional recommendation AGAINST (low certainty) 1
• Valerian: Conditional recommendation AGAINST (very low certainty) 1

Special Populations

End-Stage Renal Disease:

• Gabapentin: Conditional recommendation with very low certainty, starting with 100mg post-dialysis or at bedtime, maximum 200-300mg daily 1
• IV iron sucrose: Conditional recommendation if ferritin <200 ng/mL and transferrin saturation <20% 1
• Vitamin C: Conditional recommendation (low certainty) 1
• Critical warning: Gabapentinoids associated with 50-68% higher hazard for altered mental status and falls in dialysis patients 1

Pediatric RLS:

• Oral ferrous sulfate: Conditional recommendation with very low certainty if ferritin <50 ng/mL, with monitoring for constipation 1

Pregnancy:

• Special consideration of medication safety profiles required 1
• Iron supplementation particularly important given pregnancy-specific RLS prevalence, with safety profile favoring oral formulations 1

Critical Pitfalls to Avoid

• Never use dopamine agonists as first-line therapy despite older literature (2007-2013) recommending them 5, 6, 7 - current 2025 guidelines have reversed this recommendation due to augmentation concerns 1
• Never start pharmacological treatment without first assessing and addressing iron status 1
• Avoid medications that exacerbate RLS: alcohol, caffeine, antihistaminergic medications, serotonergic medications, antidopaminergic medications (including antipsychotics like lurasidone) 1
• Monitor for augmentation if dopamine agonists are used: earlier symptom onset during the day, increased intensity, spread to other body parts 1
• Address untreated obstructive sleep apnea before initiating treatment, as it can exacerbate RLS 1