What are the recommended medications for treating restless legs syndrome (RLS)?

Recommended Medications for Restless Legs Syndrome (RLS)

Alpha-2-delta ligands like pregabalin are recommended as first-line treatment for restless legs syndrome due to their favorable long-term safety profile and lower risk of augmentation compared to dopaminergic agents. 1

First-Line Treatment Options

Alpha-2-Delta Ligands

• Pregabalin: Recommended as a first-line option by the American Academy of Sleep Medicine with moderate certainty of evidence 1
• Gabapentin: Specifically recommended as first-line for patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD), with appropriate dose adjustments 1

Iron Supplementation

• Recommended if ferritin ≤75 ng/mL or transferrin saturation <20% 1
• Oral iron for most patients
• IV iron sucrose specifically for ESRD patients with ferritin <200 ng/mL and transferrin saturation <20% 1

Second-Line Treatment Options

Dopamine Agonists

• Ropinirole: FDA-approved for moderate-to-severe RLS 2

  • Dosing: Start at 0.25 mg once daily, 1-3 hours before bedtime
  • Titrate based on response and tolerability over 7 weeks
  • Maximum dose: 4 mg once daily 2
  • Proven effective in multiple randomized controlled trials with statistically significant improvements in RLS symptoms 2, 3

• Pramipexole: May be considered for short-term symptom relief (mean effective dose ~0.3 mg) 1

For Severe to Very Severe RLS

• Extended-release oxycodone is recommended as a second-line option 1

Important Considerations and Cautions

Risk of Augmentation with Dopaminergic Agents

• Augmentation is a paradoxical worsening of RLS symptoms due to treatment 4
• All dopamine agonists (ropinirole, pramipexole, rotigotine) carry this risk 4
• The American Academy of Sleep Medicine conditionally recommends against standard use of ropinirole due to augmentation risk with long-term use 1
• If dopamine agonists are used, keep dosage as low as possible without exceeding maximum recommended dose 4

Monitoring and Management

• Regularly assess iron status in patients with initial iron deficiency 1
• Monitor for side effects of medications:
  • Ropinirole: nausea, orthostasis, headache, daytime sleepiness 1, 3
  • Pramipexole: risk of impulse control disorders with long-term use 1

Non-Pharmacological Approaches

• Regular exercise tailored to patient capabilities 1
• Good sleep hygiene practices (consistent sleep-wake schedule, limiting stimulants) 1
• For specific populations:
  • Bilateral high-frequency peroneal nerve stimulation 1
  • Cool dialysate for patients on hemodialysis 1
  • Aerobic resistance exercise for physically capable patients 1

Treatment Algorithm

1. Assess iron status: Measure serum ferritin and transferrin saturation

   • If ferritin ≤75 ng/mL or transferrin saturation <20%, start iron supplementation

2. First-line pharmacological therapy:

   • Alpha-2-delta ligands: Pregabalin or gabapentin (for CKD/ESRD patients)

3. If inadequate response to first-line therapy:

   • For immediate symptom relief: Consider short-term dopamine agonist (ropinirole or pramipexole)
   • For severe to very severe symptoms: Consider extended-release oxycodone

4. For patients with specific conditions:

   • ESRD: Consider IV iron sucrose, vitamin C, or cool dialysate
   • Physically capable patients: Consider adding aerobic resistance exercise

While ropinirole has demonstrated efficacy in multiple clinical trials 2, 5, 6, 3, the more recent guidelines from the American Academy of Sleep Medicine prioritize alpha-2-delta ligands due to the lower risk of augmentation with long-term use 1, 4.