Evidence‑Based Management of Restless Legs Syndrome (RLS)

1. Guideline Position on Quinine

• The 2025 American Academy of Sleep Medicine (AASM) clinical practice guideline does not list quinine as a treatment option for RLS, reflecting a lack of endorsement for its use. 1, 2, 3

2. First‑Line Pharmacologic Therapies (Strong Recommendations)

• Gabapentin enacarbil – recommended as a first‑line agent for adults with RLS; evidence graded as strong recommendation, moderate certainty. 1, 4
• Gabapentin – recommended as a first‑line agent for adults with RLS; evidence graded as strong recommendation, moderate certainty. 1, 4
• Pregabalin – recommended as a first‑line agent for adults with RLS; evidence graded as strong recommendation, moderate certainty. 1, 4
• Intravenous ferric carboxymaltose – recommended for patients with confirmed iron deficiency; evidence graded as strong recommendation, moderate certainty. 1, 4

3. Second‑Line Pharmacologic Therapies (Conditional Recommendations)

• Ferrous sulfate – suggested for patients with appropriate iron status; evidence graded as conditional recommendation, moderate certainty. 1, 5
• Extended‑release oxycodone and other opioids – suggested for patients who have not responded to first‑line agents; evidence graded as conditional recommendation, moderate certainty. 1, 5
• Dipyridamole – suggested for selected patients; evidence graded as conditional recommendation, low certainty. 1, 5

4. Diagnostic Clarifications

• Clinicians should distinguish RLS from nocturnal leg cramps, as the two conditions have different pathophysiology and treatment strategies. 3, 6

5. Therapies to Avoid as First‑Line

• Dopamine agonists (e.g., pramipexole, ropinirole, rotigotine) are not recommended as first‑line therapy because they carry a risk of augmentation, which occurs in approximately 7–10 % of patients per year. 1, 7