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

First-Line Treatment for Restless Leg Syndrome

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are strongly recommended as first-line therapy for patients with Restless Leg Syndrome (RLS). 1, 2

Initial Assessment and Management

• Check serum iron studies in all patients with clinically significant RLS, including ferritin and transferrin saturation, ideally in the morning after avoiding iron-containing supplements for at least 24 hours 1, 2
• Provide iron supplementation if serum ferritin ≤75 ng/mL or transferrin saturation <20% 1, 2
  • Oral ferrous sulfate for mild iron deficiency (conditional recommendation) 2
  • IV iron formulations (particularly ferric carboxymaltose) when oral supplementation is ineffective or when ferritin is between 75-100 ng/mL (strong recommendation) 2
• Address potential exacerbating factors before starting medication 1, 2:
  • Avoid alcohol and caffeine 3
  • Discontinue antihistaminergic medications 3
  • Discontinue serotonergic medications if possible 3
  • Discontinue antidopaminergic medications if possible 3
  • Treat untreated obstructive sleep apnea 3

Pharmacological Treatment Algorithm

First-Line Options (Strong Recommendations)

• Gabapentin 1, 2
• Gabapentin enacarbil 1, 2
• Pregabalin 1, 2

These alpha-2-delta ligands are strongly recommended with moderate certainty of evidence due to their efficacy and lower risk of augmentation compared to dopaminergic agents 1, 2.

Second-Line Options

• Extended-release opioids for refractory cases or when treating augmentation from dopaminergic agents (conditional recommendation) 1
• Bilateral high-frequency peroneal nerve stimulation as a non-pharmacological option (conditional recommendation) 1

Medications to Avoid or Use with Caution

• Dopaminergic agents are not recommended for standard use due to risk of augmentation - a paradoxical worsening of symptoms with long-term use 1, 2, 4
  • Levodopa (conditional recommendation against standard use) 1, 2
  • Pramipexole (conditional recommendation against standard use) 1, 2
  • Ropinirole (conditional recommendation against standard use) 1
  • Transdermal rotigotine (conditional recommendation against standard use) 1
• The American Academy of Sleep Medicine specifically recommends against cabergoline (strong recommendation), bupropion, carbamazepine, clonazepam, and valproic acid 1

Special Considerations

• For patients with end-stage renal disease and RLS, consider:

  • Gabapentin (conditional recommendation, very low certainty) 1
  • IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (conditional recommendation) 1
  • Vitamin C (conditional recommendation) 1

• For pregnant patients with RLS:

  • Treatment selection should consider pregnancy-specific safety profiles 2
  • Non-pharmacologic approaches may be preferred 2

Managing Augmentation

• Augmentation is characterized by worsening and earlier onset of symptoms in patients initially controlled on dopaminergic medications 1, 4
• Signs include earlier symptom onset during the day, increased symptom intensity, and spread of symptoms to other body parts 1
• If augmentation occurs, add an alpha-2-delta ligand or opioid before attempting to reduce the dopaminergic medication 4
• Once adequate symptom relief is achieved with the second agent, very slowly down-titrate and discontinue the dopaminergic agent 4

The shift from dopaminergic agents to alpha-2-delta ligands as first-line therapy represents an important evolution in RLS treatment based on the recognition of augmentation as a significant long-term complication of dopaminergic therapy 4, 5.