What are the treatment options for restless legs syndrome?

Treatment of Restless Legs Syndrome

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are the first-line pharmacological treatment for restless legs syndrome, replacing dopamine agonists due to their superior long-term safety profile and lower risk of augmentation. 1

Initial Assessment and Iron Optimization

Before initiating pharmacological therapy, check serum iron studies in all patients with clinically significant RLS:

• Obtain morning fasting ferritin and transferrin saturation after avoiding iron supplements for at least 24 hours 1
• Supplement 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 role in RLS pathophysiology 1
• IV ferric carboxymaltose is strongly recommended for patients meeting these iron parameters who don't respond to oral therapy (strong recommendation, moderate certainty) 1
• Oral ferrous sulfate is conditionally recommended for patients with appropriate iron parameters (conditional recommendation, moderate certainty) 1

Address exacerbating factors: Discontinue or avoid alcohol, caffeine, antihistamines, serotonergic medications (SSRIs, SNRIs), antidopaminergic medications (antipsychotics like lurasidone), and treat untreated obstructive sleep apnea 1

First-Line Pharmacological Treatment

Alpha-2-delta ligands are now the standard of care (strong recommendation, moderate certainty of evidence):

• Gabapentin: Start at 300 mg three times daily (900 mg/day total), titrate by 300 mg/day every 3-7 days until reaching maintenance dose of 1800-2400 mg/day divided three times daily 1
• Gabapentin enacarbil: Strongly recommended alternative with potentially superior bioavailability 1
• Pregabalin: Strongly recommended alternative allowing twice-daily dosing 1

Common side effects include somnolence and dizziness, which are typically transient and mild 1

Why Dopamine Agonists Are No Longer First-Line

The American Academy of Sleep Medicine now suggests against the standard use of dopamine agonists due to the significant risk of augmentation—a paradoxical worsening of RLS symptoms with long-term use:

• Pramipexole: Conditional recommendation against standard use (moderate certainty) 1, 2
• Ropinirole: Conditional recommendation against standard use (moderate certainty) 3
• Rotigotine transdermal patch: Conditional recommendation against standard use (low certainty) 1
• Levodopa: Conditional recommendation against standard use (very low certainty) 1

Despite FDA approval and demonstrated short-term efficacy 4, these agents may only be considered for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects 3

Augmentation warning signs include earlier onset of symptoms during the day, increased symptom intensity, and spread of symptoms to other body parts 2

Second-Line and Refractory Treatment Options

For patients who fail first-line therapy or develop augmentation:

• Extended-release oxycodone and low-dose opioids (methadone, buprenorphine) are conditionally recommended for moderate to severe or refractory cases 1
• Opioids are particularly effective for treating augmentation when decreasing or eliminating dopamine agonists, with evidence showing relatively low risks of abuse and only small dose increases over 2-10 years in appropriately screened patients 1
• Caution: Monitor for respiratory depression and central sleep apnea, especially in patients with untreated obstructive sleep apnea 1

Non-pharmacological option:

• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a newer noninvasive treatment (conditional recommendation, moderate certainty) 1

Medications to Avoid

The American Academy of Sleep Medicine strongly recommends against cabergoline (strong recommendation, moderate certainty) and conditionally recommends against:

• Bupropion (moderate certainty) 1
• Carbamazepine (low certainty) 1
• Clonazepam (very low certainty) 1
• Valproic acid (low certainty) 1
• Valerian (very low certainty) 1

Special Populations

End-stage renal disease patients:

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

Pediatric RLS:

• Oral ferrous sulfate is conditionally recommended if ferritin <50 ng/mL (very low certainty) 1

Pregnancy:

• Special consideration of medication safety profiles is required 1

Critical Clinical Pitfalls

• Do not use single nighttime dosing of gabapentin—this fails to address daytime RLS symptoms and provides suboptimal 24-hour coverage 1
• Monitor alpha-2-delta ligand misuse risk—there is increasing evidence these agents may be misused in certain populations 1
• Distinguish RLS from mimics including neuropathy, akathisia, positional discomfort, and nocturnal leg cramps 1
• If using dopamine agonists despite guidelines, start at the lowest dose (pramipexole 0.125 mg 2-3 hours before bedtime, titrate slowly every 4-7 days to maximum 0.5 mg) and monitor closely for augmentation 2