How to manage Restless Legs Syndrome (RLS) in patients with iron deficiency?

Management of Restless Legs Syndrome in Iron Deficiency

Iron supplementation is the cornerstone of treatment for RLS patients with iron deficiency, with IV ferric carboxymaltose as the preferred first-line option for ferritin ≤75 ng/mL or transferrin saturation <20%, followed by alpha-2-delta ligands (gabapentin, pregabalin, or gabapentin enacarbil) if symptoms persist. 1

Initial Assessment and Iron Testing

Check serum ferritin and transferrin saturation in all patients with clinically significant RLS - this is mandatory before initiating treatment. 1, 2

• Draw blood in the morning after the patient has avoided iron-containing supplements and foods for at least 24 hours to ensure accurate results. 2
• Use RLS-specific iron thresholds, not general population cutoffs - this is a critical distinction that many clinicians miss. 2

Iron Supplementation Algorithm Based on Ferritin Levels

For Ferritin ≤75 ng/mL or Transferrin Saturation <20%:

IV ferric carboxymaltose (1000 mg) is strongly recommended as first-line therapy with moderate certainty of evidence. 2 This formulation has superior efficacy compared to oral iron because:

• Slow-release, higher-dose IV formulations enable H-ferritin binding and macrophage iron uptake necessary for CNS penetration, which is essential for treating the brain iron deficiency underlying RLS. 2
• Meta-analysis data shows IV ferric carboxymaltose improves IRLS scores by -2.79 points and RLS-QOL scores by 8.67 points. 3

Oral ferrous sulfate (65 mg elemental iron) is conditionally recommended as an alternative, though it has limitations. 2

• Oral iron absorption is poor when ferritin is already >50-75 ng/mL, making it less effective in this range. 2
• Common side effects include constipation, which may limit tolerability. 2
• A 2024 randomized double-blind trial found both IV and oral iron produced marked improvement in RLS symptoms with no statistically significant difference between groups, though this study was conducted in patients with iron deficiency anemia specifically. 4

For Ferritin 75-100 ng/mL:

Use IV iron ONLY - do not use oral iron in this range. 2 Oral iron is poorly absorbed when ferritin exceeds 50-75 ng/mL, making it ineffective. 2

For Ferritin >100 ng/mL:

Iron supplementation is generally not indicated based on current evidence. 2

Additional Pharmacological Treatment When Iron Alone Is Insufficient

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are strongly recommended as first-line pharmacological therapy with moderate certainty of evidence. 1

• These agents are preferred over dopamine agonists because they have lower risk of augmentation (a paradoxical worsening of RLS symptoms with long-term use). 1, 5
• Gabapentin, gabapentin enacarbil, and pregabalin all have strong recommendations with moderate certainty of evidence. 1
• Monitor for side effects including dizziness and somnolence, particularly in patients with untreated obstructive sleep apnea or chronic obstructive pulmonary disease. 1

Medications to Avoid

Dopamine agonists (pramipexole, ropinirole, rotigotine) are NOT recommended for standard use due to high risk of augmentation. 1

• Augmentation is characterized by worsening and earlier onset of symptoms, increased symptom intensity, and spread of symptoms to other body parts. 1
• If augmentation occurs from prior dopamine agonist use, substitute an alpha-2-delta ligand or opioid, but add the new medication first before attempting very slow down-titration of the dopamine agonist to avoid profound rebound RLS. 5

The American Academy of Sleep Medicine strongly recommends against cabergoline with moderate certainty of evidence. 1

Address Exacerbating Factors

Identify and eliminate medications and conditions that worsen RLS:

• Antihistaminergic medications, serotonergic medications (SSRIs, tricyclic antidepressants), antidopaminergic medications (antipsychotics), and lithium can all exacerbate RLS symptoms. 1
• Alcohol and caffeine should be avoided. 1
• Untreated obstructive sleep apnea must be addressed, as it commonly worsens RLS. 1

Special Populations

Pediatric RLS:

• Supplement iron if ferritin <50 ng/mL (lower threshold than adults). 2
• Monitor for constipation with oral iron supplementation. 1

End-Stage Renal Disease:

• Use gabapentin (conditional recommendation, very low certainty) or IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20%. 1
• Vitamin C is conditionally recommended for this population. 1

Common Pitfalls to Avoid

• Do not use general population ferritin cutoffs (<15-30 ng/mL) - RLS requires higher thresholds (≤75 ng/mL). 2
• Do not assume all IV iron formulations are equivalent - iron sucrose lacks efficacy except in dialysis patients; ferric carboxymaltose is preferred. 2
• Do not test iron studies while the patient is taking supplements - wait 24 hours after the last iron-containing product. 2
• Do not start dopamine agonists as first-line therapy - the risk of augmentation makes them inappropriate for initial treatment despite their efficacy. 1, 5

Evidence Quality and Strength

Meta-analysis of iron supplementation shows moderate benefit, with IRLS score improvement of -3.78 points (95% CI -6.25 to -1.31) compared to placebo, though heterogeneity exists across studies (I²=66%). 6 The 2025 American Academy of Sleep Medicine guidelines provide the most current and comprehensive treatment algorithm, prioritizing iron correction before or concurrent with pharmacological therapy. 1, 2