What is the recommended treatment for restless leg syndrome with iron deficiency?

Iron Supplementation for Restless Legs Syndrome with Iron Deficiency

For patients with restless legs syndrome (RLS) and iron deficiency, oral ferrous sulfate is recommended as first-line therapy when serum ferritin is ≤75 ng/mL or transferrin saturation is <20%, while IV ferric carboxymaltose is strongly recommended for patients with inadequate response to oral iron. 1

Assessment of Iron Status

• Check serum ferritin and transferrin saturation in all RLS patients
• Initiate iron therapy if:
  • Ferritin ≤75 ng/mL OR
  • Transferrin saturation <20%

Iron Supplementation Protocol

First-line Treatment:

• Oral ferrous sulfate for most patients with iron deficiency 1
• Regularly reassess iron status in patients with initial deficiency

Second-line Treatment:

• IV ferric carboxymaltose for patients with inadequate response to oral iron 1
• IV iron sucrose specifically for end-stage renal disease (ESRD) patients with ferritin <200 ng/mL and transferrin saturation <20% 1

Evidence for Efficacy

Iron supplementation has demonstrated meaningful clinical benefits for RLS symptoms. Meta-analyses show iron therapy results in:

• Significant decrease in International Restless Legs Scale (IRLS) scores by approximately 3.55-3.78 points compared to placebo 2, 3
• Improved quality of life on continuous scales 2
• Greater improvement in patients on dialysis 2

The American Academy of Sleep Medicine guidelines strongly support iron supplementation as an effective treatment for RLS with iron deficiency 1.

Safety Considerations

• Important safety precaution: Always measure serum transferrin saturation and ferritin levels before initiating iron therapy 4
• Monitor iron parameters once or twice yearly during ongoing therapy 4
• Screen for hemochromatosis before starting iron therapy, especially in patients with elevated pre-treatment transferrin saturation or serum ferritin levels 4
• While iron therapy may increase the risk of adverse events (RR 2.04), these are typically not severe and rarely lead to treatment discontinuation 3

Alternative Treatments for RLS

If iron therapy is insufficient or inappropriate, consider these options:

First-line Pharmacological Options:

• Alpha-2-delta ligands (gabapentin, pregabalin) - recommended as first-line therapy due to favorable long-term safety profile 1
  • Starting dose: 100-300 mg gabapentin at bedtime
  • Titration: Increase by 100-300 mg every 1-7 days
  • Effective dose range: 600-1200 mg daily
  • Maximum dose: 3600 mg/day in 3 divided doses

Second-line Options:

• Extended-release oxycodone for moderate to severe RLS that has failed other therapies 1
• Short-term dopamine agonists (pramipexole, ropinirole) for immediate symptom relief, with caution regarding augmentation risk 1

Non-Pharmacological Approaches:

• Regular exercise, particularly aerobic resistance exercise 1
• Good sleep hygiene practices 1
• For patients on hemodialysis: cool dialysate 1
• Bilateral high-frequency peroneal nerve stimulation 1

Special Populations

• ESRD patients: Use IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20%; consider gabapentin with dose adjustment 1
• Pregnant patients: Prioritize non-pharmacological approaches due to safety concerns 1

Monitoring and Follow-up

• Regularly reassess iron status in patients with initial iron deficiency
• Monitor for side effects of medications
• For patients on dopamine agonists, watch for signs of augmentation (paradoxical worsening of symptoms)

Iron supplementation represents a pathophysiologically targeted approach to RLS treatment, addressing the underlying brain iron insufficiency that contributes to dopaminergic dysfunction in many RLS patients 5.