What are the treatment options for restless leg syndrome?

Treatment Options 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 due to their efficacy and lower risk of augmentation compared to dopaminergic agents. 1, 2

Initial Assessment and Management

• Check serum iron studies, including ferritin and transferrin saturation, in all patients with clinically significant RLS, ideally in the morning after avoiding iron-containing supplements for at least 24 hours 1, 2
• Address potential exacerbating factors, including alcohol, caffeine, antihistaminergic medications, serotonergic medications, antidopaminergic medications, and untreated obstructive sleep apnea 1, 2
• Consider iron supplementation if serum ferritin ≤75 ng/mL or transferrin saturation <20% (different from general population guidelines) 1, 2

First-Line Pharmacological Treatment

• Alpha-2-delta ligands are strongly recommended as first-line therapy with moderate certainty of evidence: 1, 2
  • Gabapentin (strong recommendation, moderate certainty)
  • Gabapentin enacarbil (strong recommendation, moderate certainty)
  • Pregabalin (strong recommendation, moderate certainty)
• These medications have better long-term efficacy and lower risk of augmentation compared to dopaminergic agents 1

Iron Therapy Options

• Oral ferrous sulfate is conditionally recommended for patients with appropriate iron parameters (ferritin ≤75 ng/mL or transferrin saturation <20%) 1, 2
• IV ferric carboxymaltose is strongly recommended for patients with appropriate iron parameters who don't respond to oral therapy 1, 2
• For patients with end-stage renal disease and RLS, consider IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% 1, 2

Second-Line and Alternative Treatments

• Opioids (extended-release oxycodone and others) are conditionally recommended for refractory cases or when treating augmentation from dopaminergic agents 1, 3
• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-pharmacological option 1
• Regular physical activity should be considered as a non-pharmacological intervention 4

Medications to Use with Caution or Avoid

• Dopaminergic agents (levodopa, pramipexole, ropinirole, rotigotine) are not recommended for standard use due to risk of augmentation - a paradoxical worsening of symptoms with long-term use 1, 2, 3
• The American Academy of Sleep Medicine suggests against the standard use of:
  • Levodopa (conditional recommendation, very low certainty) 1, 2
  • Pramipexole (conditional recommendation, moderate certainty) 1, 2
  • Ropinirole (conditional recommendation, moderate certainty) 1
  • Transdermal rotigotine (conditional recommendation, low certainty) 1
• The American Academy of Sleep Medicine strongly recommends against cabergoline (strong recommendation, moderate certainty) 1, 2

Managing Augmentation

• Augmentation is characterized by worsening and earlier onset of symptoms in patients initially controlled on dopaminergic medications 1, 3
• If augmentation occurs, add an alpha-2-delta ligand or opioid before attempting to reduce the dopaminergic agent 3
• Once adequate symptom relief is achieved with the second agent, very slow down-titration and discontinuation of the dopaminergic agent is recommended 3

Special Populations

• For patients with end-stage renal disease and RLS, gabapentin is conditionally recommended (very low certainty of evidence) 1, 2
• For pediatric RLS, oral iron supplementation is conditionally recommended with very low certainty of evidence 1
• Treatment selection for RLS in pregnancy should consider pregnancy-specific safety profiles 2

Common Pitfalls and Caveats

• Dopaminergic agents were historically first-line treatments but are now not recommended for standard use due to the risk of augmentation 1, 3, 5
• When using alpha-2-delta ligands, evaluate risk factors for misuse and monitor for side effects including dizziness and somnolence 1
• Maintain ferritin levels higher (≥75 ng/mL) for RLS patients than would be typical for general population iron deficiency management 1, 2
• Distinguish RLS from mimics such as neuropathy, akathisia, positional discomfort, and nocturnal leg cramps 1