What is the approach to managing a patient with Restless Legs Syndrome (RLS)?

Management of Restless Legs Syndrome (RLS)

The first-line treatment for patients with Restless Legs Syndrome (RLS) should be alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) along with assessment and correction of iron deficiency. 1, 2

Initial Assessment and Non-Pharmacological 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
• Consider iron supplementation if serum ferritin ≤75 ng/mL or transferrin saturation <20% (different from general population guidelines) 1
• Address potential exacerbating factors including alcohol, caffeine, antihistaminergic medications, serotonergic medications, antidopaminergic medications, and untreated obstructive sleep apnea 1
• Regular physical activity should be recommended for symptom relief 3

Pharmacological Treatment Algorithm

First-Line Therapy

• Alpha-2-delta ligands (strong recommendations with moderate certainty of evidence):
  • Gabapentin enacarbil 1, 2
  • Gabapentin 1, 2
  • Pregabalin 1, 2

Iron Therapy Options

• For patients with appropriate iron parameters (ferritin ≤75 ng/mL or transferrin saturation <20%):
  • IV ferric carboxymaltose (strong recommendation, moderate certainty) 1
  • IV low molecular weight iron dextran (conditional recommendation, very low certainty) 1
  • IV ferumoxytol (conditional recommendation, very low certainty) 1
  • Oral ferrous sulfate (conditional recommendation, moderate certainty) 1

Second-Line Therapy Options

• Dipyridamole (conditional recommendation, low certainty) 1
• Extended-release oxycodone and other opioids (conditional recommendation, moderate certainty) 1
• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty) 1

Special Populations

• For RLS with end-stage renal disease (ESRD):
  • Gabapentin (conditional recommendation, very low certainty) 1
  • IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (conditional recommendation, moderate certainty) 1
  • Vitamin C (conditional recommendation, low certainty) 1

Medications to Avoid or Use with Caution

• Dopamine agonists are no longer recommended as first-line therapy due to risk of augmentation 2, 4
• The AASM suggests against standard use of:
  • Levodopa (conditional recommendation, very low certainty) 1
  • Pramipexole (conditional recommendation, moderate certainty) 1
  • Transdermal rotigotine (conditional recommendation, low certainty) 1
  • Ropinirole (conditional recommendation, moderate certainty) 1, 5
• The AASM strongly recommends against:
  • Cabergoline (strong recommendation, moderate certainty) 1, 2
• Other medications to avoid:
  • Bupropion, carbamazepine, clonazepam, valproic acid, valerian, and triazolam 1, 2

Management of Refractory RLS

• For patients with inadequate response to first-line therapy, consider combination therapy 6, 7
• If augmentation occurs with dopaminergic agents, add an alpha-2-delta ligand or opioid before slowly tapering the dopaminergic agent 6, 4
• For severe refractory cases, high-potency opioids may be considered 7

Monitoring and Follow-up

• Regular assessment for symptom control and medication side effects 4
• Periodic reassessment of iron status, especially in patients with ongoing symptoms 1
• Monitor for augmentation in patients on dopaminergic agents, characterized by earlier symptom onset, increased severity, and anatomic spread of symptoms 6, 4

Pitfalls and Caveats

• Dopamine agonists (previously first-line) can cause augmentation, a progressive worsening of RLS symptoms with long-term use 6, 4
• Abrupt discontinuation of dopaminergic agents can cause severe rebound symptoms; taper slowly after adding alternative therapy 6
• Distinguish RLS from mimics such as neuropathy, akathisia, positional discomfort, and nocturnal leg cramps 1
• RLS in pregnancy requires special consideration of medication safety profiles 1