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

Iron Therapy for Restless Legs Syndrome with Iron Deficiency

Iron supplementation is strongly recommended for patients with Restless Legs Syndrome (RLS) who have iron deficiency, with specific parameters for supplementation being serum ferritin ≤75 ng/mL or transferrin saturation <20%. 1, 2

Assessment of Iron Status

• All patients with clinically significant RLS should undergo regular testing of serum iron studies, including ferritin and transferrin saturation (calculated from iron and total iron binding capacity) 1
• Testing should ideally be performed in the morning after avoiding all iron-containing supplements and foods for at least 24 hours prior to blood draw 2, 3
• The threshold for iron supplementation in RLS patients (ferritin ≤75 ng/mL or transferrin saturation <20%) is higher than for the general population due to the role of brain iron deficiency in RLS pathophysiology 1, 2

Iron Supplementation Recommendations

Oral Iron Therapy

• Oral ferrous sulfate is conditionally recommended as first-line iron therapy for patients with mild iron deficiency (ferritin ≤75 ng/mL or transferrin saturation <20%) 2, 3
• Side effects of oral iron may include constipation and other gastrointestinal symptoms, which can limit adherence 1
• Oral iron is poorly absorbed in those with ferritin >50-75 ng/mL, making IV iron potentially more effective for patients with ferritin in this range 1

Intravenous (IV) Iron Therapy

• IV ferric carboxymaltose is strongly recommended for patients with appropriate iron parameters who don't respond adequately to oral therapy 1, 2
• IV low molecular weight iron dextran and IV ferumoxytol are conditionally recommended alternatives 1, 2
• IV iron sucrose is conditionally recommended specifically for patients with RLS and end-stage renal disease with transferrin saturation <20% 1, 2
• IV iron formulations may be beneficial even when ferritin is between 75-100 ng/mL 2

Treatment Algorithm

1. First step: Check serum ferritin and transferrin saturation in all RLS patients 1
2. If ferritin ≤75 ng/mL or transferrin saturation <20%:
   • Begin with oral ferrous sulfate if ferritin is very low (<50 ng/mL) 2, 3
   • Consider IV iron directly if ferritin is 50-75 ng/mL due to poor oral absorption in this range 1, 2
   • Use IV iron if oral therapy is ineffective or poorly tolerated 1, 2
3. If ferritin between 75-100 ng/mL:
   • Consider IV iron therapy only (not oral iron) 2
4. If iron therapy alone is insufficient:
   • Add alpha-2-delta ligands (gabapentin, pregabalin) as first-line pharmacologic therapy 2, 3

Evidence for Efficacy

• Meta-analyses show that iron therapy is associated with significant improvement in RLS symptoms compared to placebo, with a mean decrease in International Restless Legs Syndrome (IRLS) severity score of 3.55-3.78 points 4, 5
• IV iron formulations may be more effective than oral iron, particularly in patients with ferritin levels >50 ng/mL 1, 5
• Both IV and oral iron can be effective for RLS patients with iron deficiency anemia, with no statistically significant difference between them in recent studies 6

Safety Considerations

• Always check iron parameters before initiating iron therapy to avoid potential iron overload in patients with hemochromatosis 7
• Monitor iron parameters once or twice yearly during ongoing iron therapy 7
• While iron therapy is associated with a higher rate of adverse events compared to placebo (RR 2.04), these events are generally not severe and do not typically lead to treatment discontinuation 5
• Patients with a history of iron deficiency should be evaluated for underlying causes; similarly, patients with elevated iron parameters should be evaluated for potential hemochromatosis before iron therapy 7

Pitfalls and Caveats

• Brain iron deficiency can exist despite normal peripheral iron stores, which is why RLS-specific thresholds for iron supplementation are higher than general population guidelines 1, 2
• Awareness of the importance of serum iron assessment and supplementation is still lacking among many clinicians and third-party payers 1
• Iron therapy should be considered before initiating dopaminergic agents, which carry a significant risk of augmentation (worsening of symptoms) with long-term use 2, 8
• Patients may require regular and affordable access to iron infusion, which is currently not always reimbursed by payers specifically for RLS 1