What are the treatment options for restless leg syndrome?

Treatment for Restless Leg 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 the significant risk of augmentation. 1

Initial Assessment and Iron Management

Before initiating any pharmacological treatment, check serum iron studies in all patients with clinically significant RLS 1, 2:

• Draw morning fasting ferritin and transferrin saturation after avoiding iron supplements for at least 24 hours 1, 2
• Provide iron supplementation if ferritin ≤75 ng/mL or transferrin saturation <20% (note this threshold is higher than general population guidelines) 1, 2
• For oral supplementation, use ferrous sulfate (conditional recommendation, moderate certainty) 1, 2
• For IV iron, strongly consider ferric carboxymaltose (strong recommendation, moderate certainty) if oral therapy fails or ferritin is 75-100 ng/mL 1, 2

Address Exacerbating Factors

Identify and eliminate medications and substances that worsen RLS 1, 2, 3:

• Antihistamines (including over-the-counter sleep aids and allergy medications) 3
• Serotonergic medications (certain antidepressants like SSRIs) 1, 3
• Antidopaminergic medications (antipsychotics, anti-nausea drugs) 1, 3
• Alcohol and caffeine 1, 3
• Treat untreated obstructive sleep apnea if present 1, 3

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

The American Academy of Sleep Medicine strongly recommends these agents over dopamine agonists (strong recommendation, moderate certainty) 1, 2:

• Gabapentin enacarbil (prodrug with superior bioavailability, allows once or twice-daily dosing) 1, 2
• Gabapentin (start 300mg three times daily, titrate up to 1800-2400mg/day divided three times daily based on response) 1, 2
• Pregabalin (allows twice-daily dosing) 1, 2

Common side effects include somnolence and dizziness, which are typically transient and mild 1. Monitor for misuse potential in at-risk populations 1. These agents avoid the augmentation phenomenon that plagues dopamine agonists 1.

Dopamine Agonists: Use with Extreme Caution

The American Academy of Sleep Medicine now suggests against standard use of dopamine agonists due to augmentation risk 1, 2:

• Pramipexole: conditional recommendation against standard use (moderate certainty) 1, 2
• Ropinirole: conditional recommendation against standard use (moderate certainty) 1, 2
• Rotigotine transdermal: 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

While ropinirole demonstrated efficacy in FDA trials with 73.3% responders versus 56.5% placebo 4, the long-term risk of augmentation—a paradoxical worsening characterized by earlier symptom onset, increased intensity, and anatomic spread—makes these agents problematic for chronic management 1, 5. Reserve dopamine agonists only for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects 2.

Managing Augmentation from Dopamine Agonists

If augmentation develops on a dopamine agonist 1, 5:

• Add an alpha-2-delta ligand or opioid FIRST before attempting to reduce the dopamine agonist 1, 5
• Once adequate symptom control is achieved with the second agent, perform very slow down-titration of the dopamine agonist (even small reductions cause profound rebound RLS) 5
• Opioids (methadone, buprenorphine, extended-release oxycodone) are effective for refractory cases and augmentation with relatively low abuse risk in appropriately screened patients 1

Second-Line and Alternative Treatments

For patients who fail first-line therapy 1, 2:

• Extended-release oxycodone and other low-dose opioids (conditional recommendation) for moderate to severe or refractory cases 1
• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty) as a non-pharmacological option 1, 2
• Dipyridamole (conditional recommendation, low certainty) 1

Special Populations

End-stage renal disease patients 1, 2:

• Gabapentin (conditional recommendation, very low certainty) 1, 2
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (conditional recommendation, moderate certainty) 1, 2
• Vitamin C (conditional recommendation, low certainty) 1

Pregnancy 2:

• Treatment selection must consider pregnancy-specific safety profiles 2
• Non-pharmacologic approaches may be preferred 2

Pediatric RLS 1:

• Ferrous sulfate for serum ferritin <50 ng/mL (conditional recommendation, very low certainty) 1

Critical Pitfalls to Avoid

• Do not start dopamine agonists as first-line therapy—the augmentation risk outweighs short-term benefits 1, 2
• Do not abruptly discontinue dopamine agonists—this causes severe rebound; always add alternative therapy first 5
• Do not use single nighttime gabapentin dosing—this fails to address daytime symptoms and requires divided dosing for optimal effect 1
• Do not overlook iron deficiency—correcting iron status can dramatically improve symptoms independent of other medications 1, 2
• Monitor for respiratory depression with opioids, especially in patients with untreated OSA or COPD 1