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

First-Line Medication for Restless Legs Syndrome (RLS)

Gabapentin or pregabalin should be used as first-line pharmacological treatment for Restless Legs Syndrome (RLS), as strongly recommended by the American Academy of Sleep Medicine with moderate certainty of evidence. 1

First-Line Treatment Options

The American Academy of Sleep Medicine (AASM) strongly recommends the following as first-line treatments for RLS:

1. Alpha-2-delta ligands:

   • Gabapentin or gabapentin enacarbil
   • Pregabalin

2. Iron supplementation:

   • Indicated if ferritin ≤75 ng/mL or transferrin saturation <20%
   • Oral iron for most patients
   • IV iron sucrose specifically for patients with end-stage renal disease (ESRD) 1

Rationale for Alpha-2-Delta Ligands as First-Line

Alpha-2-delta ligands (gabapentin and pregabalin) are now preferred over dopaminergic agents due to:

• Similar efficacy to dopaminergic agents
• Significantly lower risk of augmentation (worsening of symptoms over time)
• Better long-term tolerability profile 1

Dopaminergic Agents: Now Second-Line

While historically considered first-line treatments, dopaminergic agents like ropinirole and pramipexole are now recommended as second-line options due to:

• Risk of augmentation with long-term use (9.2% six-month incidence with pramipexole) 1, 2
• Development of tolerance requiring dose increases (46% of patients in long-term studies) 2
• Side effects including nausea, orthostasis, headache, and daytime sleepiness 1
• Risk of impulse control disorders with long-term use 1

The AASM now suggests against the standard use of dopaminergic agents as first-line therapy, though they may be considered for short-term use in patients prioritizing immediate symptom relief 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 pharmacotherapy (if iron supplementation insufficient or iron levels normal):

   • Gabapentin/gabapentin enacarbil OR
   • Pregabalin

3. Second-line options (if first-line ineffective or not tolerated):

   • Short-term pramipexole (mean effective dose ~0.3 mg) 1
   • For severe to very severe RLS: Extended-release oxycodone 1

4. Non-pharmacological approaches:

   • Regular exercise tailored to patient capabilities
   • Good sleep hygiene practices
   • For specific populations: bilateral high-frequency peroneal nerve stimulation or cool dialysate for patients on hemodialysis 1

Special Populations

• CKD or ESRD patients: Gabapentin (with dose adjustment) is specifically recommended 1
• ESRD patients with iron deficiency: IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% 1
• Physically capable patients with inadequate response: Consider aerobic resistance exercise 1

Monitoring and Follow-up

• Regularly assess for augmentation with dopaminergic agents
• Periodically reassess iron status in patients with initial iron deficiency
• Adjust gabapentin dosing in patients with kidney disease
• Monitor for side effects specific to each medication class

Common Pitfalls to Avoid

1. Using dopaminergic agents as first-line therapy despite augmentation risk
2. Failing to check iron status before initiating pharmacotherapy
3. Not adjusting gabapentin dosing in patients with renal impairment
4. Continuing ineffective treatments without considering alternatives
5. Overlooking non-pharmacological approaches that may provide benefit

While older literature 3, 4, 5 suggested dopaminergic agents as first-line therapy, more recent evidence and guidelines have shifted toward alpha-2-delta ligands due to their more favorable long-term safety profile.