What is the recommended treatment for Restless Legs Syndrome (RLS) patients with iron deficiency using iron infusion?

Iron Infusion for Restless Legs Syndrome

The American Academy of Sleep Medicine strongly recommends IV ferric carboxymaltose (1000 mg) as first-line iron therapy for RLS patients with ferritin ≤75 ng/mL or transferrin saturation <20%, with moderate certainty of evidence. 1, 2

Mandatory Pre-Treatment Assessment

Before any iron therapy, you must check serum ferritin and transferrin saturation in all patients with clinically significant RLS 1, 3:

• Draw blood in the morning after fasting 2, 3
• Patient must avoid iron-containing supplements and foods for at least 24 hours before testing 2, 3
• These RLS-specific thresholds differ from general population cutoffs 2, 3

Treatment Algorithm Based on Iron Status

Ferritin ≤75 ng/mL OR Transferrin Saturation <20%

First-line options (choose one):

• IV ferric carboxymaltose 1000 mg (strong recommendation, moderate certainty) 1, 2, 4

  • Administered as single dose per course for patients ≥50 kg 5
  • Can be given undiluted as slow IV push over 15 minutes OR diluted in ≤250 mL normal saline (concentration ≥2 mg iron/mL) infused over ≥15 minutes 5
  • Superior to oral iron due to better CNS penetration via H-ferritin binding and macrophage iron uptake 2

• Oral ferrous sulfate 65 mg elemental iron daily (conditional recommendation, moderate certainty) 1, 2, 3

  • Less effective due to poor absorption, especially when ferritin >50-75 ng/mL 2
  • Common side effect: constipation 2

Alternative IV formulations (conditional recommendations):

• IV low molecular weight iron dextran (very low certainty) 1, 2

  • May provide dramatic improvement in refractory cases but results inconsistent 6
  • Higher anaphylactic reaction risk compared to other formulations 6

• IV ferumoxytol (very low certainty, based on observational data) 1, 2

Ferritin 75-100 ng/mL

Use IV iron formulations ONLY 2, 3:

• Oral iron is poorly absorbed and ineffective in this range 2, 3
• IV ferric carboxymaltose remains the preferred option 2

Ferritin >100 ng/mL

Iron supplementation generally not indicated based on current evidence 2

Special Populations

End-Stage Renal Disease (ESRD)

• IV iron sucrose if ferritin <200 ng/mL AND transferrin saturation <20% (conditional recommendation, moderate certainty) 1, 3
• Iron dextran 1000 mg showed significant symptom reduction at 2 weeks in ESRD patients (median improvement -3 points; P=0.01) 7

Pediatric Patients

• Iron supplementation recommended when ferritin <50 ng/mL 1, 3
• IV iron sucrose (average dose 3.6 mg/kg over 2 hours) showed improved sleep in 62.5% of children who failed oral iron 8
• Monitor for constipation with oral formulations 1

Why RLS Requires Higher Iron Thresholds

Brain iron deficiency plays a central role in RLS pathophysiology, even when serum iron appears normal by general population standards 2, 3. RLS patients require ferritin ≥50-75 ng/mL for optimal neurological function and CNS iron availability 2, 3. The slow-release, higher-dose IV formulations enable the H-ferritin binding necessary for CNS penetration, unlike fast-release formulations 2.

Monitoring and Repeat Treatment

• Continue iron therapy indefinitely with ongoing monitoring, as RLS symptoms may recur if iron stores decline 1
• Check serum phosphate levels in patients requiring repeat courses within 3 months 5
• Maintenance surveillance with iron studies every 6-12 months, even with symptom resolution 1
• For heart failure patients with iron deficiency, administer maintenance dose of 500 mg at 12,24, and 36 weeks if ferritin <100 ng/mL or ferritin 100-300 ng/mL with transferrin saturation <20% 5

Critical Pitfalls to Avoid

• Never use general population ferritin cutoffs (<15-30 ng/mL) for RLS—this misses the majority of patients who would benefit 2, 3
• Do not assume all IV iron formulations are equivalent—iron sucrose lacks efficacy except in dialysis patients 2, 3
• Never test iron studies while patient is taking supplements—wait at least 24 hours after last iron-containing product 2, 3
• Avoid oral iron for ferritin 75-100 ng/mL—it will be ineffective due to poor absorption 2, 3
• Monitor for extravasation during IV administration—brown discoloration may be long-lasting 5

Safety Profile

Meta-analysis showed adverse events did not differ significantly between IV iron and placebo (OR 1.68,95% CI 0.92-3.07, P=0.093) 4. Iron therapy overall did not result in significantly more side effects than placebo (RR 1.39,95% CI 0.85-2.27) 9.