What medication regimen should be recommended for a patient with a ferritin level less than 75 ng/mL and worsening Restless Legs Syndrome (RLS) symptoms while taking 300 mg of Gabapentin nightly?

Recommended Medication Regimen for Worsening RLS with Low Ferritin

You should immediately initiate iron supplementation (oral ferrous sulfate or IV ferric carboxymaltose) given the ferritin <75 ng/mL, and simultaneously increase the gabapentin dose from 300 mg nightly to a therapeutic range of 1800-2400 mg/day divided into three daily doses. 1, 2

Iron Supplementation is Critical and Must Be Addressed First

• With ferritin <75 ng/mL, iron supplementation is a mandatory good practice statement from the American Academy of Sleep Medicine, as brain iron deficiency is a core pathophysiologic mechanism in RLS 1
• Start oral ferrous sulfate (65 mg elemental iron) as a conditional recommendation with moderate certainty, OR consider IV ferric carboxymaltose (1000 mg) as a strong recommendation with moderate certainty 2, 3
• IV ferric carboxymaltose is preferred if you want faster symptom improvement and better CNS iron delivery, particularly since oral iron absorption is poor and may cause constipation 3
• Iron studies should have been checked in the morning after avoiding iron-containing supplements for 24 hours, and this correction alone can significantly improve RLS symptoms independent of other medications 1, 2

Gabapentin Dose is Severely Subtherapeutic

• The current 300 mg nightly dose is inadequate—this is merely a starting dose, not a therapeutic dose 2
• The American Academy of Sleep Medicine strongly recommends gabapentin as first-line therapy, but effective dosing requires titration to 1800-2400 mg/day divided three times daily (e.g., 600-800 mg three times daily) 2
• Single nighttime dosing at 300 mg fails to provide 24-hour symptom coverage and is insufficient for moderate-to-severe RLS 2
• Titration schedule: Increase by 300 mg every 3-7 days until reaching 1800-2400 mg/day divided into three doses 2

Why Not Switch to a Different Medication Class?

• Gabapentin remains the correct first-line choice per the American Academy of Sleep Medicine's strong recommendation with moderate certainty 1, 2
• The worsening symptoms are likely due to inadequate dosing combined with untreated iron deficiency, not gabapentin failure 2, 3
• Switching to dopamine agonists (pramipexole, ropinirole, rotigotine) is specifically recommended AGAINST by the American Academy of Sleep Medicine due to high risk of augmentation—a paradoxical worsening of symptoms with long-term use 2, 4
• Alternative alpha-2-delta ligands like gabapentin enacarbil (1200 mg once daily) or pregabalin (150-450 mg/day) are also strongly recommended and may offer better bioavailability if gabapentin titration proves difficult 2, 4

Treatment Algorithm

1. Immediately correct iron deficiency: Start oral ferrous sulfate OR IV ferric carboxymaltose based on patient preference and urgency 2, 3
2. Simultaneously increase gabapentin: Titrate from 300 mg nightly to 600 mg three times daily over 1-2 weeks, then assess response 2
3. Target dose: Aim for 1800-2400 mg/day divided three times daily (morning, afternoon, evening) 2
4. Monitor for side effects: Watch for somnolence and dizziness, which are typically transient and mild 2
5. Reassess in 4-6 weeks: After iron stores improve and gabapentin reaches therapeutic levels 2, 3

Critical Pitfalls to Avoid

• Do not use general population ferritin cutoffs (<15-30 ng/mL)—RLS requires higher thresholds (≤75 ng/mL) 3, 4
• Do not continue subtherapeutic gabapentin dosing and assume the medication has failed 2
• Do not switch to dopamine agonists as they carry high augmentation risk with long-term use 2, 4
• Do not forget to address exacerbating factors: Review medications for antihistamines, SSRIs, or antidopaminergics; assess for untreated sleep apnea; counsel on avoiding alcohol and caffeine 1, 4

If Symptoms Persist After Optimization

• Consider switching to gabapentin enacarbil (1200 mg once daily) or pregabalin (150-450 mg/day in divided doses) for better pharmacokinetics 2, 4
• Extended-release oxycodone or other low-dose opioids are conditionally recommended for refractory cases, but only after optimizing iron and alpha-2-delta ligands 2, 4
• Bilateral high-frequency peroneal nerve stimulation is a non-pharmacological option with conditional recommendation 2, 4