What is the first line therapy for a patient with Restless Legs Syndrome (RLS)?

First-Line Therapy for Restless Legs 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, but only after addressing iron deficiency and exacerbating factors. 1, 2, 3

Initial Management: Address Iron Status First

Before starting any medication, check morning fasting serum ferritin and transferrin saturation after avoiding iron-containing supplements for at least 24 hours. 1, 2, 3

Iron supplementation is indicated if:

• Serum ferritin ≤75 ng/mL, OR 1, 2, 3
• Transferrin saturation <20% 1, 2, 3

Iron supplementation options:

• IV ferric carboxymaltose is strongly recommended for rapid correction (strong recommendation, moderate certainty) 1, 2, 3
• Oral ferrous sulfate is an alternative but works more slowly (conditional recommendation, moderate certainty) 1, 2, 3

Eliminate Exacerbating Factors

The American Academy of Sleep Medicine recommends identifying and addressing factors that worsen RLS before initiating pharmacotherapy: 1, 2, 3

• Discontinue or avoid: alcohol, caffeine (especially evening consumption), antihistaminergic medications, serotonergic medications (SSRIs, SNRIs), antidopaminergic medications (antipsychotics), and nicotine 1, 2, 3
• Screen for and treat untreated obstructive sleep apnea 1, 2, 3

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

All three alpha-2-delta ligands receive strong recommendations with moderate certainty of evidence: 1, 2, 3

Gabapentin

• Starting dose: 300 mg three times daily (900 mg/day total) 2, 3
• Titration: Increase by 300 mg/day every 3-7 days until symptoms controlled 2, 3
• Maintenance dose: 1800-2400 mg/day divided three times daily 2, 3
• Critical pitfall: Avoid single nighttime dosing—this fails to address daytime RLS symptoms and provides suboptimal 24-hour coverage 2

Gabapentin Enacarbil

• Prodrug of gabapentin with potentially improved bioavailability 2
• Strongly recommended (strong recommendation, moderate certainty) 1, 2, 3

Pregabalin

• Advantage: Allows twice-daily dosing with potentially superior bioavailability compared to regular gabapentin 2, 3
• Strongly recommended (strong recommendation, moderate certainty) 1, 2, 3

Common side effects of alpha-2-delta ligands include somnolence and dizziness, which are typically transient and mild. 2 Monitor for misuse potential in at-risk populations. 2

Why Alpha-2-Delta Ligands Are First-Line (Not Dopamine Agonists)

The American Academy of Sleep Medicine now suggests against standard use of dopamine agonists (pramipexole, ropinirole, rotigotine) due to high risk of augmentation—a paradoxical worsening of symptoms characterized by: 1, 2, 3

• Earlier onset of symptoms during the day 1, 2
• Increased symptom intensity 1, 2
• Spread to upper extremities or trunk 2
• Worsening despite dose increases 2

Dopamine agonists may only be considered for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects. 1, 2

Second-Line Options for Refractory Cases

If alpha-2-delta ligands fail or are not tolerated: 1, 2, 3

• Extended-release oxycodone and other low-dose opioids are conditionally recommended for moderate to severe refractory RLS (conditional recommendation, moderate certainty) 1, 2, 3
• Long-term studies show relatively low risks of abuse/overdose in appropriately screened patients, with only small dose increases over 2-10 years 2, 4
• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-pharmacological option (conditional recommendation, moderate certainty) 1, 2, 3

Medications to Avoid

The American Academy of Sleep Medicine specifically recommends against: 1, 2

• Cabergoline (strong recommendation against, moderate certainty) 1, 2
• Clonazepam (conditional recommendation against, very low certainty)—improves subjective sleep quality but does not reduce objective disease markers 2
• Bupropion, carbamazepine, valproic acid (conditional recommendations against) 1, 2

Critical Pitfalls to Avoid

• Do not start pharmacotherapy without first checking and correcting iron status—iron deficiency plays a key role in RLS pathophysiology even when serum iron appears normal 2, 3
• Do not use gabapentin as single nighttime dosing—requires three-times-daily dosing for adequate 24-hour symptom control 2
• Do not increase dopamine agonist doses if augmentation is suspected—this worsens the problem 2
• Do not assume "normal" caffeine or alcohol consumption is acceptable—even moderate amounts, especially in the evening, can significantly worsen RLS symptoms 2

Monitoring and Follow-Up

• Reassess iron studies every 6-12 months, as RLS symptoms may recur if iron stores decline 2
• Monitor for side effects of alpha-2-delta ligands, particularly dizziness and somnolence 2
• Evaluate improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood) 2