What is the first line treatment for Restless Legs Syndrome (RLS)?

First-Line Treatment for Restless Legs Syndrome

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are strongly recommended as first-line therapy for Restless Legs Syndrome due to their efficacy and lower risk of augmentation compared to dopaminergic agents. 1, 2

Treatment Algorithm

Initial Assessment

• Check serum iron studies, including ferritin and transferrin saturation, in all patients with clinically significant RLS 2
• Consider iron supplementation if serum ferritin ≤75 ng/mL or transferrin saturation <20% 2
• Address potential exacerbating factors including alcohol, caffeine, antihistamines, serotonergic medications, and antidopaminergic medications 2, 3

First-Line Pharmacological Treatment

• Start with alpha-2-delta ligands:
  • Gabapentin 1, 2
  • Gabapentin enacarbil 1, 2
  • Pregabalin 1, 2

Second-Line and Alternative Treatments

• IV ferric carboxymaltose for patients with appropriate iron parameters who don't respond to oral therapy 2
• Extended-release opioids for refractory cases 2, 4
• Bilateral high-frequency peroneal nerve stimulation as a non-pharmacological option 2

Medications to Avoid or Use with Caution

• The American Academy of Sleep Medicine suggests against the standard use of dopaminergic agents including:
  • Levodopa (conditional recommendation, very low certainty of evidence) 2
  • Pramipexole (conditional recommendation, moderate certainty of evidence) 1, 2
  • Ropinirole (conditional recommendation, moderate certainty of evidence) 2, 5
  • Transdermal rotigotine (conditional recommendation, low certainty of evidence) 2

Why Alpha-2-Delta Ligands are Preferred Over Dopaminergic Agents

• Dopaminergic agents, while effective in the short term, carry a significant risk of augmentation with long-term use 1, 4
• Augmentation is characterized by:
  • Earlier onset of symptoms during the day
  • Increased symptom intensity
  • Spread of symptoms to other body parts 1, 4
• Alpha-2-delta ligands have:
  • Similar efficacy to dopaminergic agents 2
  • Lower risk of augmentation 1, 2
  • Better long-term safety profile 2, 6

Non-Pharmacological Approaches

• Moderate exercise (avoid high-intensity exercise close to bedtime) 3
• Smoking cessation 3
• Alcohol avoidance 3
• Caffeine reduction or elimination 3
• Maintain consistent sleep schedule 3

Special Considerations

• For patients with end-stage renal disease and RLS, gabapentin is suggested with dose adjustment 2
• For pediatric RLS, ferrous sulfate is conditionally recommended 2
• Patients with low ferritin should receive iron supplementation before or concurrently with other treatments 1, 2

Common Pitfalls and Caveats

• Dopaminergic agents were historically first-line treatments but are now second-line due to augmentation risk 7, 8
• When using alpha-2-delta ligands, monitor for side effects including dizziness and somnolence 2
• If dopaminergic agents must be used, keep doses as low as possible to minimize augmentation risk 6
• Augmentation may require treatment withdrawal and switching to alternative medication 1, 4
• Avoid medications that can worsen RLS symptoms, including antihistamines, many antipsychotics, and certain antidepressants 2, 3