Can iron supplements alleviate symptoms in patients with Restless Legs Syndrome (RLS) and iron deficiency?

Iron Supplementation for RLS

Yes, patients with RLS should take iron supplements if their serum ferritin is ≤75 ng/mL or transferrin saturation is <20%, as this can significantly improve RLS symptoms and is a cornerstone of evidence-based management. 1, 2

Initial Assessment Required

Before starting any RLS treatment, check morning fasting serum ferritin and transferrin saturation after avoiding iron-containing supplements for at least 24 hours. 1, 2 This is a mandatory step because RLS uses different iron thresholds than general medicine—brain iron deficiency drives RLS pathophysiology even when peripheral iron appears adequate. 2

Iron Supplementation Thresholds

For adults with RLS:

• Supplement if ferritin ≤75 ng/mL or transferrin saturation <20% 1, 2
• Consider IV iron only (not oral) if ferritin is 75-100 ng/mL 2
• Iron supplementation generally not indicated if ferritin >100 ng/mL 2

For children with RLS:

• Supplement if ferritin <50 ng/mL 1, 2

These thresholds are substantially higher than general population cutoffs (<15-30 ng/mL) because brain iron stores require higher serum levels for adequate CNS penetration. 2

Treatment Options Based on Iron Status

First-line oral therapy (ferritin ≤75 ng/mL or transferrin saturation <20%):

• Ferrous sulfate 65 mg elemental iron daily is conditionally recommended 1, 2
• Common side effect is constipation, which may limit tolerability 2
• Oral iron absorption is poor when ferritin >50-75 ng/mL 2

Intravenous iron formulations (ferritin ≤75 ng/mL or transferrin saturation <20%):

• IV ferric carboxymaltose 1000 mg is strongly recommended with moderate certainty of evidence 1, 2
• IV low molecular weight iron dextran is conditionally recommended 1, 2
• IV ferumoxytol is conditionally recommended 1, 2
• IV iron sucrose is only effective in dialysis patients, not for general RLS 2

The slow-release, higher-dose IV formulations (ferric carboxymaltose, ferumoxytol, low molecular weight iron dextran) enable better CNS iron delivery compared to fast-release formulations like iron sucrose. 2

Evidence for Efficacy

Meta-analysis of randomized controlled trials demonstrates that iron supplementation reduces RLS severity by approximately 3.78 points on the International RLS Severity Scale (IRLS) compared to placebo. 3, 4 A 2019 meta-analysis found iron therapy increased the percentage of patients with IRLS improvement (RR 2.16,95% CI 1.56-2.98). 3 IV ferric carboxymaltose specifically improved quality of life scores by 8.67 points. 3

The most recent 2024 randomized double-blind trial comparing IV ferumoxytol to oral ferrous sulfate in RLS patients with iron deficiency anemia found both routes produced marked improvement in RLS symptoms with no statistically significant difference between groups and no serious adverse events. 5

Safety Profile

Iron therapy does not significantly increase adverse events compared to placebo (RR 1.48,95% CI 0.97-2.25). 4 When adverse events occur, they are typically mild and do not lead to treatment discontinuation. 3 The 2024 trial confirmed no serious adverse events with either oral or IV iron. 5

Duration of Treatment

Iron supplementation should be continued indefinitely with ongoing monitoring, as RLS symptoms may recur if iron stores decline below therapeutic thresholds. 1 Maintenance surveillance with iron studies every 6-12 months is necessary, even with symptom resolution, because brain iron deficiency may persist despite normal serum parameters. 1

Integration with Other RLS Treatments

Iron supplementation should be addressed before or concurrent with starting first-line pharmacological therapy (gabapentin, gabapentin enacarbil, or pregabalin). 1 Correcting iron deficiency can significantly improve RLS symptoms independent of other medications. 1 Never assume iron supplementation alone is sufficient for clinically significant RLS without considering guideline-recommended pharmacological treatments if symptoms persist. 1

Special Populations

End-stage renal disease patients:

• Use IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% 1
• This is the only population where iron sucrose demonstrates efficacy 2

Pregnancy:

• Iron supplementation is particularly important given pregnancy-specific RLS prevalence 1
• Oral formulations are preferred throughout gestation for safety 1

Critical Pitfalls to Avoid

• Do not use general population ferritin cutoffs (<15-30 ng/mL) for RLS—higher thresholds (≤75 ng/mL) are required 1, 2
• Do not assume all IV iron formulations are equivalent—iron sucrose lacks efficacy except in dialysis patients 2
• Do not test iron studies while the patient is taking supplements—wait 24 hours after the last iron-containing product 2
• Do not use oral iron for ferritin 75-100 ng/mL range, as absorption is poor; use IV iron only 2