What is the first-line treatment for a patient with symptoms suggestive of Restless Legs Syndrome (RLS)?

First-Line Treatment for Restless Legs Syndrome

Check serum ferritin and transferrin saturation first, then initiate gabapentin, gabapentin enacarbil, or pregabalin as first-line pharmacological therapy—not dopamine agonists like ropinirole or pramipexole. 1

Initial Assessment and Iron Status

Before starting any medication, obtain morning fasting iron studies (serum ferritin and transferrin saturation) after avoiding iron supplements for at least 24 hours. 1

• If ferritin ≤75 ng/mL or transferrin saturation <20%, initiate iron supplementation as this can significantly improve RLS symptoms independent of other medications. 1
• IV ferric carboxymaltose is strongly recommended for patients meeting these iron parameters who don't respond to oral therapy. 1
• Oral ferrous sulfate is conditionally recommended as an alternative iron supplementation option. 1

First-Line Pharmacological 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 therapy with moderate certainty of evidence. 1 This represents a major shift from older guidelines that recommended dopamine agonists.

Gabapentin Dosing

• Start at 300 mg three times daily (900 mg/day total). 1
• Titrate by 300 mg/day every 3-7 days until reaching maintenance dose of 1800-2400 mg/day divided three times daily. 1
• Doses up to 3600 mg/day are well-tolerated in clinical studies. 1
• Common side effects include somnolence and dizziness, which are typically transient and mild. 1

Pregabalin Alternative

• Pregabalin allows twice-daily dosing and may have superior bioavailability compared to gabapentin. 1
• This is also strongly recommended as first-line therapy. 1

Why NOT Dopamine Agonists First-Line?

The American Academy of Sleep Medicine now suggests AGAINST the standard use of dopamine agonists (pramipexole, ropinirole, rotigotine) due to the significant risk of augmentation with long-term use. 1, 2

Understanding Augmentation

• Augmentation is a paradoxical worsening of RLS symptoms characterized by earlier onset during the day, increased symptom intensity, and spread to other body parts (e.g., from calves to thighs or arms). 3, 4
• This iatrogenic complication occurs commonly with dopamine agonists, particularly levodopa, and represents a major treatment failure. 4, 5
• While older guidelines from 2009 recommended dopamine agonists as first-line 3, the 2025 American Academy of Sleep Medicine guidelines explicitly recommend against their standard use. 1

Historical Context

• Ropinirole and pramipexole were FDA-approved for RLS and showed efficacy in clinical trials 6, 7, 8
• However, long-term clinical experience revealed unacceptable augmentation rates, leading to the paradigm shift toward alpha-2-delta ligands. 1, 4

Non-Pharmacological Interventions (Concurrent with Medication)

Address potential exacerbating factors simultaneously:

• Eliminate or reduce caffeine and alcohol. 1
• Discontinue antihistaminergic medications, serotonergic medications (SSRIs), and antidopaminergic medications if possible. 1
• Implement moderate exercise and smoking cessation. 3, 2
• Screen for and treat untreated obstructive sleep apnea. 1

Clinical Algorithm Summary

1. Confirm diagnosis using the four essential criteria: urge to move legs with uncomfortable sensations, worse at rest, relieved by movement, worse in evening/night. 3
2. Check morning fasting ferritin and transferrin saturation. 1
3. If ferritin ≤75 ng/mL or transferrin saturation <20%: Start iron supplementation (oral ferrous sulfate or IV ferric carboxymaltose). 1
4. Initiate gabapentin 300 mg three times daily (or pregabalin as alternative). 1
5. Titrate gabapentin by 300 mg/day every 3-7 days to maintenance dose of 1800-2400 mg/day. 1
6. Address exacerbating factors (caffeine, alcohol, offending medications). 1
7. Monitor for side effects (somnolence, dizziness) and efficacy. 1

Common Pitfalls to Avoid

• Do not start with dopamine agonists despite their FDA approval and older guideline recommendations—augmentation risk outweighs benefits for standard use. 1, 2
• Do not use single nighttime dosing of gabapentin—this fails to address daytime symptoms and provides suboptimal coverage. 1
• Do not overlook iron deficiency—even "normal" ferritin levels up to 75 ng/mL warrant supplementation in RLS patients. 1
• Do not continue medications that worsen RLS (antihistamines, SSRIs, antipsychotics)—these can trigger or exacerbate symptoms. 1