What alternatives can be considered for a patient with severe restless leg syndrome who cannot afford gabapentin enacarbil (Gabapentin Enacarbil), given that pregabalin (Pregabalin) is less effective?

Alternative Treatments for Severe Restless Leg Syndrome When Gabapentin Enacarbil Is Unaffordable

Regular gabapentin (not the enacarbil formulation) is your best alternative—it receives the same strong recommendation from the American Academy of Sleep Medicine with moderate certainty of evidence, costs significantly less than gabapentin enacarbil, and your statement that "pregabalin is not nearly as effective" is actually incorrect according to current evidence. 1

Correcting a Critical Misconception

Your premise contains an important error: pregabalin is equally effective to gabapentin enacarbil for severe RLS and receives an identical strong recommendation with moderate certainty of evidence from the 2025 AASM guidelines. 1 A landmark 2014 New England Journal of Medicine trial directly compared pregabalin (300 mg daily) with pramipexole and demonstrated that pregabalin provided significantly improved treatment outcomes with a 4.5-point greater reduction in IRLS scores compared to placebo (P<0.001), and 71.4% of patients achieved "very much improved" or "much improved" status. 2 The augmentation rate with pregabalin was only 2.1% over 52 weeks, significantly lower than the 7.7% rate with higher-dose pramipexole. 2

First-Line Cost-Effective Alternatives (All Strongly Recommended)

Option 1: Regular Gabapentin (Most Cost-Effective)

• The AASM strongly recommends regular gabapentin with the same strength of recommendation and certainty of evidence as gabapentin enacarbil. 1
• Start at 300 mg three times daily (900 mg/day total) and titrate by 300 mg/day every 3-7 days until reaching maintenance dose of 1800-2400 mg/day. 3, 4
• Doses up to 3600 mg/day are well-tolerated in clinical studies. 3
• Critical pitfall to avoid: Do not use single nighttime dosing—this fails to address daytime RLS symptoms and provides suboptimal coverage. 3
• The cost is negligible compared to gabapentin enacarbil. 1
• Common side effects include somnolence and dizziness, typically transient and mild. 1

Option 2: Pregabalin (Superior Pharmacokinetics)

• Pregabalin is strongly recommended as first-line therapy with moderate certainty of evidence—identical to gabapentin enacarbil. 1
• Allows twice-daily dosing with potentially superior bioavailability compared to regular gabapentin. 3, 4
• Start at 75 mg twice daily (150 mg/day), increase to 150 mg twice daily (300 mg/day) within 1 week based on efficacy and tolerability. 1, 5
• Patients not responding to 300 mg/day may increase to 225 mg twice daily (450 mg/day). 5
• Cost is negligible compared to gabapentin enacarbil. 1
• A 2021 study demonstrated pregabalin as effective add-on therapy with significant IRLS score improvement (p<0.001) and improved insomnia scores (p=0.036) without serious adverse effects. 6

Before Starting Any Medication: Address Iron Status

• Check morning fasting serum ferritin and transferrin saturation before initiating any pharmacological treatment. 3, 4, 7
• Supplement with iron if ferritin ≤75 ng/mL or transferrin saturation <20% (different threshold than general population). 3, 4, 7
• IV ferric carboxymaltose is strongly recommended for rapid correction in patients meeting these iron parameters who don't respond to oral therapy. 1, 4, 7
• Oral ferrous sulfate is conditionally recommended as an alternative but works more slowly. 4, 7

Second-Line Options for Refractory Cases

Extended-Release Oxycodone and Low-Dose Opioids

• Conditionally recommended for moderate to severe refractory RLS, particularly when treating augmentation from dopaminergic agents. 3, 7
• Evidence shows relatively low risks of abuse and overdose in appropriately screened patients, with long-term studies showing only small dose increases over 2-10 years. 3
• Caution: Risk of respiratory depression and central sleep apnea, especially in patients with untreated obstructive sleep apnea. 3

Bilateral High-Frequency Peroneal Nerve Stimulation

• Conditionally recommended as a non-pharmacological option with moderate certainty of evidence. 3, 7

Dipyridamole

• Conditionally recommended with low certainty of evidence. 3

Medications to Avoid

• The AASM suggests against standard use of dopamine agonists (pramipexole, ropinirole, rotigotine) due to high risk of augmentation—a paradoxical worsening of symptoms with long-term use. 3, 4, 7
• Augmentation is characterized by earlier symptom onset during the day, increased intensity, and spread to other body parts. 3
• The AASM strongly recommends against cabergoline. 7
• Conditionally recommended against: bupropion, carbamazepine, clonazepam, valproic acid. 3, 7

Non-Pharmacological Interventions to Implement Concurrently

• Eliminate or reduce alcohol, caffeine, and nicotine, especially in the evening. 4, 7
• Discontinue antihistaminergic and serotonergic medications if possible. 4, 7
• Screen for and treat untreated obstructive sleep apnea. 4, 7
• Implement moderate exercise (but avoid vigorous exercise close to bedtime). 3

Clinical Algorithm Summary

1. Check morning fasting ferritin and transferrin saturation. 4, 7
2. If ferritin ≤75 ng/mL or transferrin saturation <20%, initiate iron supplementation (IV ferric carboxymaltose for rapid correction or oral ferrous sulfate). 4, 7
3. Start regular gabapentin (300 mg TID, titrate to 1800-2400 mg/day) OR pregabalin (75 mg BID, titrate to 300-450 mg/day). 3, 4, 7
4. Address exacerbating factors (caffeine, alcohol, medications). 4, 7
5. Monitor for side effects (somnolence, dizziness) and efficacy at 3-7 day intervals during titration. 3, 4
6. If inadequate response after optimal dosing, consider extended-release oxycodone or bilateral peroneal nerve stimulation. 3, 7