What is the efficacy of pregabalin (Lyrica) compared to gabapentin enacarbil (Horizant) in a patient with severe restless leg syndrome?

Direct Comparison of Gabapentin Enacarbil and Pregabalin for Severe RLS

No head-to-head trials have directly compared gabapentin enacarbil to pregabalin, but both are equally recommended as first-line therapy by the American Academy of Sleep Medicine with identical strength of recommendation (strong) and certainty of evidence (moderate). 1

Evidence-Based Equivalence

• The American Academy of Sleep Medicine places gabapentin enacarbil and pregabalin in the same tier of first-line recommendations for RLS, with no preference stated between them. 1

• Both medications are alpha-2-delta ligands that work through the same mechanism—binding to voltage-gated calcium channels in the central nervous system. 2

• Pregabalin has been directly compared to pramipexole in a 52-week randomized controlled trial (N=719), demonstrating superior outcomes with significantly lower augmentation rates (2.1% vs. 7.7%, P=0.001) and greater symptom improvement on the IRLS scale (4.5-point greater reduction vs. placebo, P<0.001). 3

Practical Differences That May Guide Selection

Dosing Convenience

• Pregabalin allows twice-daily dosing with potentially superior bioavailability compared to regular gabapentin, making it more convenient than gabapentin enacarbil's once or twice-daily regimen. 1

• Pregabalin's effective dose range is 150-600 mg/day, with the ED90 (dose providing 90% maximal efficacy) at 123.9 mg/day. 4

Cost Considerations

• Regular gabapentin and pregabalin cost significantly less than gabapentin enacarbil, making them more cost-effective alternatives for severe RLS patients. 1

• Gabapentin enacarbil is a prodrug formulation designed for improved bioavailability, but this comes at substantially higher cost without proven superiority over pregabalin. 1

Efficacy Data

• Pregabalin demonstrated 63% improvement in IRLS scores versus 38.2% with placebo (P<0.05) in a 12-week trial, with mean effective dose of 322.50 mg/day. 5

• Pregabalin significantly reduced periodic limb movements (PLM index, P<0.001) and improved sleep architecture with increased slow wave sleep (P<0.01). 5

• The separation of treatment effect between pregabalin and placebo emerged at week 1 and continued through week 6 across all dose groups. 4

Side Effect Profile

• Both medications share similar adverse effects: dizziness and somnolence are the most common, appearing dose-related. 2, 4, 5

• Pregabalin trials reported six cases of suicidal ideation in the 52-week study, which requires careful monitoring. 3

• Adverse events with pregabalin are generally mild but common, including unsteadiness, daytime sleepiness, and headache—particularly important to screen in working populations when administered in the afternoon. 5

Clinical Algorithm for Severe RLS

For patients with severe RLS, choose pregabalin over gabapentin enacarbil based on:

1. Cost-effectiveness: Pregabalin provides equivalent efficacy at significantly lower cost. 1

2. Robust evidence base: Pregabalin has a 52-week head-to-head trial against dopamine agonists demonstrating sustained efficacy and minimal augmentation (2.1%). 3

3. Dosing flexibility: Twice-daily dosing with superior bioavailability. 1

4. Add-on potential: Pregabalin can be added to existing dopamine agonist therapy in patients with inadequate response, showing significant IRLS improvement (P<0.001) and insomnia improvement (P=0.036). 6

Critical Monitoring Points

• Screen for suicidal ideation when initiating pregabalin, particularly in patients with psychiatric comorbidities. 3

• Monitor for dizziness and somnolence, which may increase fall risk—dose-titrate slowly starting at 75-150 mg and adjust as needed. 6

• Reassess iron studies (ferritin ≤75 ng/mL or transferrin saturation <20%) before escalating doses, as correcting iron deficiency can significantly improve symptoms independent of medication. 1