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

Recommended Medications for Restless Legs Syndrome

Alpha-2-delta ligands (pregabalin or gabapentin) are the first-line pharmacological treatment for restless legs syndrome due to their efficacy and favorable long-term safety profile. 1

First-line Treatment Options

1. Alpha-2-delta Ligands

• Pregabalin or Gabapentin
  • Recommended as first-line therapy by the American Academy of Sleep Medicine
  • Particularly beneficial for patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD) with appropriate dose adjustments 1
  • Gabapentin has shown similar efficacy to dopamine agonists in head-to-head trials 2
  • Dosing considerations:
    • Lower starting doses and slower titration for elderly patients
    • Dose reduction in patients with impaired renal function

2. Iron Supplementation

• Should be initiated when:
  • Serum ferritin ≤ 75 ng/mL or transferrin saturation < 20% in adults 1
  • Serum ferritin < 50 ng/mL in children 1
• Administration route:
  • Oral iron for ferritin ≤ 75 ng/mL
  • IV iron when ferritin is between 75-100 ng/mL
  • IV iron sucrose is first-line for ESRD patients with ferritin < 200 ng/mL and transferrin saturation < 20% 1
• Monitoring: Regular testing of serum ferritin and transferrin saturation (morning testing, avoiding iron supplements for 24 hours before)

Second-line Treatment Options

Dopamine Agonists

• Ropinirole, pramipexole, or rotigotine patch
  • FDA-approved for moderate-to-severe RLS 3
  • Effective in reducing RLS symptoms in placebo-controlled trials 3
  • Ropinirole dosing: Starting at 0.25 mg once daily, titrated over 7 weeks to maximum 4 mg once daily, taken 1-3 hours before bedtime 3
  • Important caution: Recommended for short-term use only due to risk of augmentation (paradoxical worsening of symptoms) 1
  • Both pramipexole and ropinirole effectively suppress periodic leg movements during sleep 4
  • Common side effect: mild morning nausea 4

Opioids

• Low-dose opioids
  • Useful for facilitating taper and discontinuation of dopamine agonists
  • Appropriate for moderate to severe RLS that has failed other therapies 1
  • Extended-release oxycodone can be considered for severe to very severe RLS 1
  • Caution: Monitor for central sleep apnea and respiratory depression

Treatment Algorithm

1. Initial Assessment:

   • Check serum ferritin and transferrin saturation
   • Assess RLS severity using International RLS Rating Scale (IRLS)
   • Identify any secondary causes (pregnancy, renal failure, anemia)

2. Treatment Selection:

   • If iron deficient: Start iron supplementation based on parameters above
   • For primary pharmacological treatment: Start with alpha-2-delta ligands (pregabalin/gabapentin)
   • If inadequate response: Consider dopamine agonists (with caution for augmentation)
   • For severe, refractory cases: Consider low-dose opioids

3. Adjunctive Measures:

   • Regular aerobic and resistance exercise 1
   • Maintain regular sleep schedule
   • Avoid caffeine, alcohol, antihistamines, and certain antidepressants that may worsen symptoms
   • For patients on hemodialysis: Consider cool dialysate 1
   • Bilateral high-frequency peroneal nerve stimulation as an alternative therapy 1

Clinical Pearls and Pitfalls

• Augmentation risk: The major limitation of dopamine agonists is the development of augmentation, where symptoms worsen or occur earlier in the day. Regular monitoring is essential if these medications are used 1, 5

• Medication timing: Dopamine agonists should be taken 1-3 hours before bedtime for optimal effect 3

• Long-term efficacy: Maintenance of efficacy has been demonstrated with ropinirole in a 36-week trial, with significantly lower relapse rates compared to placebo 3

• Secondary RLS: Always treat underlying conditions (renal failure, iron deficiency, etc.) when present, though dopaminergic drugs may still be helpful in these cases 6

• Diagnostic criteria reminder: RLS diagnosis requires: (1) urge to move legs with/without paresthesia, (2) worsening with inactivity, (3) improvement with activity, and (4) worsening in evening/night 5