What are the treatment options for restless legs syndrome?

Treatment Options for Restless Legs Syndrome

For adults with restless legs syndrome (RLS), the American Academy of Sleep Medicine strongly recommends gabapentin, gabapentin enacarbil, or pregabalin as first-line pharmacologic treatment options. 1, 2, 3

Initial Assessment and Management

• Before initiating pharmacologic therapy, identify and address exacerbating factors including alcohol, caffeine, antihistamines, serotonergic medications, antidopaminergic medications, and untreated obstructive sleep apnea 2
• Test serum iron studies including ferritin and transferrin saturation in all patients with clinically significant RLS 2
• Testing should be done in the morning after avoiding iron-containing supplements and foods for at least 24 hours 2

Treatment Algorithm

Step 1: Iron Supplementation

• Provide iron supplementation if serum ferritin ≤ 75 ng/mL or transferrin saturation < 20% 2
• For mild iron deficiency, use oral ferrous sulfate (conditional recommendation, moderate certainty) 1, 2
• For patients with ferritin between 75-100 ng/mL or when oral supplementation is ineffective, use IV iron formulations 2
• IV ferric carboxymaltose is strongly recommended (strong recommendation, moderate certainty) 1, 2
• IV low molecular weight iron dextran and IV ferumoxytol are conditionally recommended options 1

Step 2: First-Line Pharmacologic Treatment

• Alpha-2-delta ligands are strongly recommended as first-line agents:
  • Gabapentin enacarbil (strong recommendation, moderate certainty) 1, 2, 3
  • Gabapentin (strong recommendation, moderate certainty) 1, 2, 3
  • Pregabalin (strong recommendation, moderate certainty) 1, 2, 3

Step 3: Alternative Treatment Options

• Dipyridamole (conditional recommendation, low certainty) 1
• Extended-release oxycodone and other opioids (conditional recommendation, moderate certainty) 1, 4
• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty) 1

Important Cautions

• Dopaminergic agents (levodopa, pramipexole, ropinirole, rotigotine) are no longer recommended as first-line therapy due to risk of augmentation - a paradoxical worsening of symptoms with long-term use 1, 2, 4
• The AASM specifically suggests against the standard use of:
  • Levodopa (conditional recommendation against, very low certainty) 1, 2
  • Pramipexole (conditional recommendation against, moderate certainty) 1, 2
  • Ropinirole (conditional recommendation against, moderate certainty) 1, 2
  • Transdermal rotigotine (conditional recommendation against, low certainty) 1, 2
  • Bupropion (conditional recommendation against, moderate certainty) 1
  • Carbamazepine (conditional recommendation against, low certainty) 1

Special Populations

• For patients with end-stage renal disease and RLS, gabapentin is conditionally recommended 2, 3
• For pregnant patients, non-pharmacologic approaches may be preferred due to safety concerns 2
• For patients with severe refractory RLS who have failed other therapies, opioids may be considered as they can be effective for severe cases 4, 5

Treatment of Augmentation

• If dopaminergic augmentation occurs (worsening of RLS symptoms from dopamine agonist therapy), add an alpha-2-delta ligand or opioid before attempting to reduce the dopamine agonist 4
• Once adequate symptom relief is achieved with the second agent, very slow down-titration and discontinuation of the dopamine agonist is recommended 4