For an adult with restless‑legs syndrome, ferritin 74 ng/mL and transferrin saturation 40%, what is the next step in management?

Management of Restless Legs Syndrome with Ferritin 74 ng/mL and Transferrin Saturation 40%

Start gabapentin, gabapentin enacarbil, or pregabalin as first-line pharmacologic therapy; iron supplementation is indicated because ferritin is ≤75 ng/mL, even though transferrin saturation is adequate. 1

Iron Supplementation Strategy

• Initiate oral ferrous sulfate 325–650 mg daily (65 mg elemental iron) or consider IV ferric carboxymaltose 1000 mg as a single infusion. 1 Both options receive guideline support for ferritin ≤75 ng/mL, though IV ferric carboxymaltose carries a strong recommendation with moderate certainty of evidence, while oral iron receives a conditional recommendation. 1

• The transferrin saturation of 40% indicates adequate iron delivery to support erythropoiesis, but RLS-specific thresholds differ from general population cutoffs because brain iron deficiency can persist despite normal serum parameters. 1, 2, 3 The American Academy of Sleep Medicine mandates supplementation when ferritin is ≤75 ng/mL or transferrin saturation is <20%. 1, 2

• Oral iron absorption is poor when ferritin exceeds 50–75 ng/mL, making IV formulations more effective in this borderline range. 1 However, because this patient's ferritin is exactly 74 ng/mL (just below the 75 ng/mL threshold), oral iron remains a reasonable first option if cost or access to infusion is a barrier. 1

• If you choose oral iron, prescribe ferrous sulfate 325 mg (65 mg elemental iron) once daily or every other day on an empty stomach; reassess symptoms and repeat iron studies after 3 months. 1, 4 If ineffective or not tolerated (constipation is common), switch to IV ferric carboxymaltose. 1

• If you choose IV iron, administer ferric carboxymaltose 1000 mg as a single infusion; clinical benefit may require up to 12 weeks. 1 Monitor serum phosphate if repeat courses are needed within 3 months to detect hypophosphatemia. 1

First-Line Pharmacologic Therapy (Alpha-2-Delta Ligands)

• Gabapentin, gabapentin enacarbil, or pregabalin are strongly recommended as first-line agents with moderate certainty of evidence. 1, 5, 4 In randomized trials, approximately 70% of patients treated with gabapentinoids had much or very much improved RLS symptoms versus 40% with placebo (P < 0.001). 4

• Gabapentin dosing: Start 300 mg three times daily; if symptoms persist after 3–7 days, increase by 300 mg/day every few days until reaching the recommended maintenance dose of 1800–2400 mg/day divided three times daily; maximum studied dose is 3600 mg/day. 1

• Pregabalin allows twice-daily dosing and has superior bioavailability compared with regular gabapentin, making it a strongly recommended alternative. 1, 5

• Common side effects include somnolence and dizziness, which are typically transient and mild. 1 These agents avoid the augmentation phenomenon (paradoxical worsening of symptoms) seen with dopamine agonists. 1, 5, 4

Medications to Avoid

• Dopamine agonists (pramipexole, ropinirole, rotigotine) are NOT recommended for standard use because of a 7–10% annual risk of augmentation—a paradoxical worsening of symptoms with earlier onset, increased intensity, and spread to arms or trunk. 1, 5, 4

• Strong recommendation against cabergoline, bupropion, carbamazepine, clonazepam, valproic acid, and valerian. 1, 5

• Discontinue exacerbating medications if possible, including serotonergic antidepressants, dopamine antagonists, and centrally acting H1 antihistamines (e.g., diphenhydramine). 4

Monitoring and Follow-Up

• Repeat iron studies (ferritin and transferrin saturation) every 6–12 months during ongoing therapy, even if symptoms resolve, because brain iron deficiency may persist despite normal serum parameters. 1, 6

• Reassess RLS symptoms using the International Restless Legs Scale (IRLS) at 3 months and evaluate for improvement in both nighttime symptoms and daytime functioning (alertness, concentration, mood). 1, 7

• If oral iron is ineffective after 3 months or not tolerated, switch to IV ferric carboxymaltose. 1

• If gabapentinoid monotherapy is insufficient, ensure iron status has been optimized before escalating to second-line agents such as extended-release oxycodone or other low-dose opioids for refractory cases. 1, 5, 4

Critical Pitfalls to Avoid

• Do not use general population ferritin cutoffs (<15–30 ng/mL) for RLS; the disease-specific threshold is ≤75 ng/mL. 1, 2

• Do not assume all IV iron formulations are equivalent; iron sucrose lacks efficacy except in dialysis patients. 1 Ferric carboxymaltose is the only IV formulation with a strong recommendation and moderate certainty of evidence. 1

• Do not perform iron studies while the patient is taking iron supplements; wait ≥24 hours after the last iron-containing product and draw blood in the morning after fasting. 1, 2

• Do not start dopamine agonists as first-line therapy given the high augmentation risk and current guideline recommendations favoring alpha-2-delta ligands. 1, 5, 4