Indications for Iron Replacement in Restless Legs Syndrome
Iron supplementation is indicated in RLS when serum ferritin is ≤75 ng/mL or transferrin saturation is <20% in adults, and when ferritin is <50 ng/mL in children. 1, 2
Mandatory Initial Assessment
Before initiating any RLS treatment, you must check morning fasting serum ferritin and transferrin saturation after the patient has avoided iron-containing supplements and foods for at least 24 hours. 1, 2 This is not optional—the American Academy of Sleep Medicine recommends checking iron studies in all patients with clinically significant RLS. 1
RLS-Specific Iron Thresholds (Different from General Population)
The iron thresholds for RLS are substantially higher than those used for general iron deficiency because brain iron deficiency plays a central role in RLS pathophysiology, even when serum iron appears normal by standard criteria. 2
Adult thresholds for iron supplementation:
Pediatric threshold:
End-stage renal disease (ESRD) patients:
Treatment Algorithm Based on Iron Parameters
When Ferritin ≤75 ng/mL or Transferrin Saturation <20%:
First-line options include:
- Oral ferrous sulfate (65 mg elemental iron daily)—conditional recommendation with moderate certainty 1, 4
- IV ferric carboxymaltose (1000 mg)—strong recommendation with moderate certainty, preferred for rapid correction 1, 3, 4
Key decision point: IV iron is strongly preferred over oral iron when rapid symptom control is needed or when oral iron has failed after 3 months. 3, 4
When Ferritin is 75-100 ng/mL:
Use IV iron formulations exclusively, as oral iron is poorly absorbed and ineffective in this range. 2 Even though this falls above the guideline threshold, some patients may benefit from IV iron in this range. 2
When Ferritin >100 ng/mL:
Iron supplementation is generally not indicated unless transferrin saturation remains <20%, suggesting functional iron deficiency. 2
Evidence Supporting These Thresholds
Meta-analysis demonstrates that iron supplementation (oral or IV) significantly decreases the International RLS Severity Score by -3.55 points and doubles the percentage of patients showing improvement (RR 2.16). 5 Serum ferritin levels are inversely correlated with RLS symptom severity, with the greatest improvements seen in patients with initial ferritin ≤18 μg/L. 6
IV ferric carboxymaltose specifically improves both the IRLSS score (by -2.79 points) and quality of life measures. 5, 4 The evidence is strongest for ferric carboxymaltose at 1000 mg, which has Class I evidence supporting its use as first-line treatment in adults with ferritin <300 μg/L. 4
Critical Pitfalls to Avoid
- Do not use general population ferritin cutoffs (<15-30 ng/mL) for RLS management—this misses the majority of RLS patients who would benefit from iron therapy. 2
- Do not test iron studies while patients are taking supplements—wait at least 24 hours after the last iron-containing product. 1, 2
- Do not use oral iron for ferritin 75-100 ng/mL—it will be ineffective due to poor absorption in this range; use IV iron instead. 2
- Do not assume all IV iron formulations are equivalent—iron sucrose lacks efficacy except in dialysis patients. 2, 4
Integration with Overall RLS Treatment
Iron supplementation should be addressed before or concurrent with first-line pharmacological therapy (alpha-2-delta ligands such as gabapentin or pregabalin). 1, 3 Correcting iron deficiency can significantly improve RLS symptoms independent of other medications and may reduce the need for higher doses of pharmacological agents. 1
Monitoring and Repeat Treatment
After initial iron treatment, ferritin levels decline at an average rate of 6.6 μg/L per week initially, though this rate decreases with repeated treatments. 7 Symptoms typically return approximately 6 months after a single 1000 mg IV iron infusion. 7 Monitor ferritin every 6-12 months and consider repeat iron supplementation when ferritin falls below threshold and symptoms recur. 1