How to treat restless leg syndrome (RLS) potentially linked to iron deficiency?

Treatment of Restless Leg Syndrome Linked to Iron Deficiency

For patients with restless leg syndrome potentially linked to iron deficiency, iron supplementation should be the first-line treatment when serum ferritin is ≤75 ng/mL or transferrin saturation is <20%, followed by alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacologic therapy if symptoms persist. 1, 2

Iron Assessment and Supplementation

• 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
• Provide iron supplementation if serum ferritin ≤75 ng/mL or transferrin saturation <20% (note this threshold is higher than for the general population) 1, 2
• For mild iron deficiency, start with oral ferrous sulfate (conditional recommendation, moderate certainty) 1, 2
• Consider IV iron formulations when oral supplementation is ineffective or when more rapid correction is needed 1
• IV ferric carboxymaltose is strongly recommended (strong recommendation, moderate certainty) for patients with appropriate iron parameters who don't respond to oral therapy 1, 2
• IV low molecular weight iron dextran and IV ferumoxytol are conditionally recommended alternatives 1

First-Line Pharmacologic Treatment (If Symptoms Persist After Iron Correction)

• Alpha-2-delta ligands are strongly recommended as first-line therapy due to their efficacy and lower risk of augmentation compared to dopaminergic agents 1, 2
• Options include:
  • Gabapentin (strong recommendation, moderate certainty) 1, 2
  • Gabapentin enacarbil (strong recommendation, moderate certainty) 1, 2
  • Pregabalin (strong recommendation, moderate certainty) 1, 2
• Monitor for side effects including dizziness and somnolence, which may increase fall risk 1

Second-Line and Alternative Treatments

• Dopaminergic agents are no longer recommended as first-line treatment due to risk of augmentation (paradoxical worsening of symptoms with long-term use) 1, 2
• The American Academy of Sleep Medicine suggests against standard use of:
  • Levodopa (conditional recommendation against, very low certainty) 1, 2
  • Pramipexole (conditional recommendation against, moderate certainty) 1, 3
  • Ropinirole (conditional recommendation against, moderate certainty) 1, 4
  • Transdermal rotigotine (conditional recommendation against, low certainty) 1
• For refractory cases, extended-release oxycodone and other low-dose opioids are conditionally recommended, particularly when treating augmentation from dopaminergic agents 1

Non-Pharmacological Approaches

• Address potential exacerbating factors, including 1, 2:
  • Alcohol consumption
  • Caffeine intake
  • Antihistaminergic medications
  • Serotonergic medications
  • Antidopaminergic medications
  • Untreated obstructive sleep apnea
• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-pharmacological option 1

Special Considerations and Pitfalls

• Brain-iron deficiency plays a key role in RLS pathophysiology, even when serum iron appears normal, which is why higher ferritin targets (≥75 ng/mL) are recommended specifically for RLS patients 1
• Augmentation is a major concern with dopaminergic agents and presents as earlier symptom onset during the day, increased symptom intensity, and spread of symptoms to other body parts 1, 3
• When using dopaminergic agents (if necessary), start with the lowest possible dose and monitor closely for augmentation 3
• For patients with end-stage renal disease and RLS, gabapentin is conditionally recommended (very low certainty), as is IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% 1, 2
• Response to iron therapy may be less effective in African-Americans compared to White patients, suggesting potential need for higher doses or alternative approaches 5
• Ensure adequate treatment of iron deficiency - some patients may require more than the standard 1000-mg IV iron dose to achieve sufficient brain iron stores 5