Iron Supplementation for Restless Legs Syndrome
While ferrous sulfate is the most commonly studied oral iron formulation for RLS, no specific iron preparation is absolutely required—what matters most is achieving adequate elemental iron delivery and correcting the underlying iron deficiency based on RLS-specific ferritin thresholds. 1
Iron Formulation Recommendations
Oral Iron Options
- Ferrous sulfate receives a conditional recommendation from the American Academy of Sleep Medicine for patients with ferritin ≤75 ng/mL or transferrin saturation <20%, based on limited RCT data showing efficacy 1, 2
- The typical dose studied is 65 mg of elemental iron (approximately 325 mg ferrous sulfate) 2
- Other oral iron formulations can be used, though ferrous sulfate has the most evidence in RLS specifically 1, 3
- Oral iron absorption is poor when ferritin >50-75 ng/mL, making it less effective in this range compared to IV formulations 1
- Common side effects include constipation, which may limit tolerability 1
Intravenous Iron Formulations (Preferred in Many Cases)
The American Academy of Sleep Medicine provides strong recommendations for specific IV iron preparations:
- IV ferric carboxymaltose (1000 mg): Strong recommendation with moderate certainty of evidence for patients with ferritin ≤75 ng/mL or transferrin saturation <20% 1, 2
- IV low molecular weight iron dextran: Conditional recommendation with very low certainty of evidence 1
- IV ferumoxytol: Conditional recommendation based on limited observational data 1
Critical distinction: IV iron sucrose showed no clinically significant benefit over placebo in high-quality studies, likely due to its fast-release, low-dose formulation that fails to achieve adequate CNS iron penetration 1. The exception is in end-stage renal disease patients with transferrin saturation <20%, where it receives conditional recommendation 1
RLS-Specific Iron Thresholds (Different from General Population)
Key practice point: Iron supplementation thresholds for RLS differ substantially from general medical practice 1:
- Adults: Supplement if ferritin ≤75 ng/mL OR transferrin saturation <20% 1
- Adults with ferritin 75-100 ng/mL: Use IV iron only (not oral) 1
- Children: Supplement if ferritin <50 ng/mL 1
Testing Requirements Before Treatment
The American Academy of Sleep Medicine mandates checking serum ferritin and transferrin saturation (calculated from iron and total iron binding capacity) in all patients with clinically significant RLS 1:
- Test in the morning after avoiding iron-containing supplements and foods for at least 24 hours 1, 4
- This testing greatly influences the decision between oral versus IV iron 1
Treatment Algorithm Based on Iron Status
For ferritin ≤75 ng/mL or transferrin saturation <20%:
- Start with oral ferrous sulfate (65 mg elemental iron) if patient preference favors oral route and ferritin is not severely depleted 1, 2
- Consider IV ferric carboxymaltose as first-line treatment, particularly for moderate-to-severe RLS or when rapid response is needed 2
For ferritin 75-100 ng/mL:
- Use IV iron only (oral iron poorly absorbed in this range) 1
For ferritin >100 ng/mL:
- Iron supplementation generally not indicated based on current evidence 1
Why Formulation Matters for IV Iron
The pharmacology of slow-release, higher-dose formulations (ferric carboxymaltose, ferumoxytol, low molecular weight iron dextran) enables H-ferritin binding and macrophage iron uptake necessary for CNS penetration, unlike fast-release formulations like iron sucrose 1. This explains the differential efficacy seen in clinical trials.
Common Pitfalls to Avoid
- Don't use general population ferritin cutoffs (<15-30 ng/mL)—RLS requires higher thresholds 1
- Don't assume all IV iron formulations are equivalent—iron sucrose lacks efficacy except in dialysis patients 1
- Don't forget to test iron studies before treatment—this is a good practice statement requirement 1
- Don't test iron studies while patient is taking supplements—wait 24 hours after last iron-containing product 1