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

First-Line Treatment for Restless Legs Syndrome (RLS)

The first-line treatment for Restless Legs Syndrome (RLS) should be addressing exacerbating factors and using gabapentin, gabapentin enacarbil, or pregabalin, rather than dopaminergic agents which were previously considered first-line. 1

Initial Management Algorithm

1. Address exacerbating factors:

   • Eliminate alcohol and caffeine consumption
   • Discontinue medications that may worsen RLS:
     • Antihistamines
     • Serotonergic drugs
     • Antidopaminergic medications
   • Treat untreated obstructive sleep apnea 1

2. Check iron status:

   • Measure serum ferritin and transferrin saturation (morning testing, 24 hours after iron supplements)
   • Supplement iron if:
     • Ferritin ≤ 75 ng/mL OR transferrin saturation < 20% → oral or IV iron
     • Ferritin between 75-100 ng/mL → IV iron only 1

3. Pharmacological treatment (in order of recommendation strength):

   • First-line medications (strong recommendations):
     • Gabapentin enacarbil (FDA-approved at 600mg once daily)
     • Gabapentin
     • Pregabalin 1, 2

Treatment Selection Considerations

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

  • Lower risk of augmentation (paradoxical worsening of symptoms with long-term use)
  • Effectiveness for both RLS and commonly comorbid anxiety 2

• Iron therapy:

  • IV ferric carboxymaltose has strong recommendation when iron parameters indicate deficiency
  • Ferrous sulfate (oral) has conditional recommendation for appropriate patients 1

• Avoid dopaminergic agents as first-line:

  • The AASM explicitly recommends against standard use of levodopa, pramipexole, and rotigotine due to high risk of augmentation with long-term use 1, 2
  • These may be considered only for short-term use in patients who prioritize immediate symptom relief over long-term risks 1

Second-Line Options

If first-line treatments fail:

• Extended-release oxycodone or other opioids (conditional recommendation) 1, 2
• Bilateral high-frequency peroneal nerve stimulation (non-pharmacological option) 1
• Dipyridamole (conditional recommendation) 1

Common Pitfalls to Avoid

1. Using dopaminergic agents as first-line therapy: This was previously standard practice but is no longer recommended due to augmentation risk 1, 3

2. Inadequate iron assessment: Always check iron parameters before initiating treatment and with symptom worsening 1, 4

3. Overlooking exacerbating factors: Addressing modifiable factors like caffeine, alcohol, and medication interactions should be the initial step 1

4. Failing to recognize augmentation: Watch for earlier symptom onset, increased intensity, or spread to other body parts during treatment 4

5. Inadequate dosing: Keep doses of medications to the minimum required for acceptable symptom reduction to minimize side effects 3

The treatment approach has evolved significantly from earlier practices when dopaminergic agents were considered first-line 5, 6. Current evidence strongly supports alpha-2-delta ligands as the preferred initial pharmacological intervention for RLS, with careful attention to iron status and exacerbating factors.