What are the treatment options for Restless Leg Syndrome (RLS)?

Treatment Options for Restless Legs Syndrome (RLS)

Pregabalin and gabapentin (alpha-2-delta ligands) are strongly recommended as first-line pharmacologic therapy for restless legs syndrome due to their efficacy, favorable long-term safety profile, and lack of augmentation risk compared to dopaminergic agents. 1

Initial Assessment and Management

• Check serum ferritin and transferrin saturation as first steps
• Treat iron deficiency if present (ferritin ≤75 ng/mL or transferrin saturation <20%)
• Address exacerbating factors:
  • Eliminate alcohol and caffeine
  • Discontinue antihistamines, serotonergic and antidopaminergic medications

Treatment Algorithm

First-Line Treatments

1. Iron Therapy (if deficient)

   • Oral ferrous sulfate for most patients with ferritin ≤75 ng/mL
   • IV ferric carboxymaltose for inadequate response to oral iron
   • IV iron sucrose for ESRD patients with ferritin <200 ng/mL and transferrin saturation <20%

2. Alpha-2-Delta Ligands

   • Pregabalin (preferred first-line option)
   • Gabapentin or gabapentin enacarbil (alternative if pregabalin ineffective)
   • Dose adjustment required for patients with CKD or ESRD

Second-Line Treatments

1. Dopamine Agonists (short-term use only)

   • Ropinirole (0.25-4 mg once daily, 1-3 hours before bedtime) 2
   • Pramipexole (mean effective dose ~0.3 mg)
   • Caution: Only for short-term symptom relief due to risk of augmentation with long-term use

2. Opioids

   • Extended-release oxycodone for moderate to severe RLS that failed other therapies
   • Monitor for: Respiratory depression and central sleep apnea

Non-Pharmacological Approaches

• Regular aerobic and resistance exercise for physically capable patients
• Consistent sleep-wake schedule
• Elimination of stimulants
• Cool dialysate for patients on hemodialysis
• Bilateral high-frequency peroneal nerve stimulation

Special Considerations

Augmentation

Augmentation is a paradoxical worsening of symptoms due to dopaminergic treatment and represents a major challenge in RLS management 1. If it occurs:

• Gradually taper and discontinue dopamine agonists
• Transition to alpha-2-delta ligands or opioids

Special Populations

• End-stage renal disease: Gabapentin with dose adjustment, IV iron sucrose if indicated
• Pregnancy: Prioritize non-pharmacological approaches due to safety concerns

Evidence Quality and Efficacy

Ropinirole has demonstrated efficacy in multiple randomized controlled trials, showing significant improvement in RLS symptoms compared to placebo 2. However, the American Academy of Sleep Medicine conditionally recommends against its standard use due to augmentation risk with long-term therapy 1.

Alpha-2-delta ligands have emerged as preferred first-line agents due to their efficacy and lack of augmentation risk. While older literature suggested dopaminergic agents as first-line therapy 3, 4, 5, more recent guidelines have shifted toward alpha-2-delta ligands based on their better long-term safety profile 1.

Non-pharmacological interventions show promise but have limited high-quality evidence. Regular exercise has the strongest support among non-drug approaches 6, 7.

Common Pitfalls to Avoid

• Using dopamine agonists as long-term therapy (risk of augmentation)
• Failing to check iron status before initiating pharmacologic therapy
• Overlooking potentially exacerbating medications
• Inadequate dose adjustment of medications in patients with renal impairment
• Not recognizing augmentation when it develops