What are the differences between Lyrica (pregabalin) and gabapentin?

Key Differences Between Lyrica (Pregabalin) and Gabapentin

Pregabalin offers superior pharmacokinetic predictability with linear absorption and faster titration to therapeutic effect, making it the preferred first-line gabapentinoid for most patients with neuropathic pain. 1

Mechanism of Action

Both medications bind to the α2-δ subunit of voltage-gated calcium channels, reducing calcium influx and decreasing synaptic neurotransmitter release into hyperexcited neurons. 1, 2 Neither drug acts as a GABA receptor agonist despite their structural similarity to GABA. 1

Critical Pharmacokinetic Differences

Absorption Characteristics

Pregabalin:

• Linear (first-order) absorption with ≥90% bioavailability regardless of dose 1, 2
• Peak plasma concentrations within 1 hour 2
• Dose increases produce proportional increases in blood levels, making titration predictable 1

Gabapentin:

• Nonlinear, saturable (zero-order) absorption that becomes less efficient at higher doses 1, 2
• Bioavailability drops from 60% at 900 mg/day to 33% at 3600 mg/day 2
• Peak plasma concentrations within 3-4 hours 2
• Requires three-times-daily dosing due to saturable absorption 1, 3

Elimination

Both drugs are eliminated unchanged by the kidneys (95% for pregabalin, similar for gabapentin), requiring mandatory dose reduction in renal impairment. 1 Neither is metabolized by hepatic enzymes, resulting in minimal drug-drug interactions. 2

Dosing Protocols

Pregabalin Dosing

• Starting dose: 75 mg twice daily or 50 mg three times daily (150 mg/day total) 1, 4
• Target therapeutic dose: 300 mg/day (150 mg twice daily or 100 mg three times daily) within 1 week 1, 4
• Maximum dose: 600 mg/day, reserved only for patients with inadequate response at 300 mg/day who tolerate the medication well 1, 4
• Dosing frequency: Twice daily or three times daily 1
• Time to therapeutic effect: Pain relief occurs within 1.5-3.5 days 1
• Adequate trial duration: Minimum 4 weeks at therapeutic dose 1

Gabapentin Dosing

• Starting dose: 100-300 mg at bedtime or 300 mg once daily 3
• Target therapeutic dose: 1800-3600 mg/day in three divided doses 1, 3
• Titration: Increase by 300 mg every 3-7 days as tolerated 3
• Dosing frequency: Three times daily (mandatory due to saturable absorption) 1, 3
• Time to therapeutic effect: Several weeks, requiring 2+ months for adequate trial 1
• Adequate trial duration: 3-8 weeks for titration plus 2 weeks at maximum tolerated dose 1, 3

Clinical Efficacy

Pregabalin

• Painful diabetic peripheral neuropathy: NNT of 4.04 for 600 mg/day and 5.99 for 300 mg/day 1
• Postherpetic neuralgia: NNT of 3.9-5.3 for substantial benefit at 300-600 mg/day 1
• The American Academy of Neurology recommends pregabalin as first-line treatment for neuropathic pain 1

Gabapentin

• Neuropathic pain: 32-38% of patients achieve ≥50% pain reduction at 1800-3600 mg/day versus 17-21% with placebo 3
• Recommended as an alternative to pregabalin 1

Side Effect Profiles

Both medications share nearly identical adverse effect profiles: 1, 4

• Dizziness: 23-46% with pregabalin 4; ~19% in elderly with gabapentin 3
• Somnolence: 15-25% with pregabalin 4; ~14% in elderly with gabapentin 3
• Peripheral edema: 10% with pregabalin 4; ~7% in elderly with gabapentin 3
• Weight gain: Both medications 1, 4
• Mental clouding and gait disturbance: Both medications 1

Gradual titration minimizes these dose-dependent side effects. 1, 4

Renal Impairment Adjustments

Both require mandatory dose reduction based on creatinine clearance: 1

Pregabalin:

• CLcr 30-60 mL/min: Reduce dose by ~50% 1
• CLcr 15-30 mL/min: Reduce dose by ~75% 1
• CLcr <15 mL/min: Reduce dose by 85-90% 1

Gabapentin:

• CLcr 30-59 mL/min: 400-1400 mg/day in two divided doses 3
• CLcr 15-29 mL/min: 200-700 mg/day as single daily dose 3
• CLcr <15 mL/min: 100-300 mg/day as single daily dose 3

Clinical Advantages of Pregabalin

Pregabalin may be preferred for initial trials due to: 1

• More predictable pharmacokinetics supporting easier and faster titration
• Twice-daily dosing option (versus mandatory three-times-daily for gabapentin)
• Faster achievement of pain relief (days versus weeks)
• Linear dose-response relationship

Critical Clinical Considerations

Sequential Use

Patients may respond to gabapentin, pregabalin, both, or neither. 1 There is no evidence supporting sequential use if one fails. 1

Combination Therapy

Combining gabapentin and pregabalin is not recommended. 1 They share identical mechanisms of action and overlapping adverse effect profiles, creating an unacceptable additive sedative burden without established efficacy benefits. 1 No randomized controlled trials demonstrate superiority of combination gabapentinoid therapy over optimizing the dose of either medication alone. 1

Elderly Patients

Lower starting doses and slower titration are appropriate for elderly patients due to increased risk of dizziness, somnolence, confusion, and falls. 1, 4, 3 Age-related decline in renal function often necessitates dose reduction even when serum creatinine appears normal. 1

Discontinuation

Never abruptly discontinue either medication—taper gradually over a minimum of 1 week to avoid withdrawal symptoms. 1, 4

Common Pitfalls to Avoid

• Do not use once-daily or twice-daily dosing for standard gabapentin—three-times-daily administration is mandatory due to saturable absorption 3
• Do not rush gabapentin titration—allow the full 2-month trial period before declaring treatment failure 3
• Do not routinely prescribe pregabalin 600 mg/day as standard dose—300 mg/day provides optimal benefit-to-risk ratio for most patients 1
• Do not assume normal renal function in elderly patients based on serum creatinine alone—always calculate creatinine clearance 1
• Do not combine gabapentin and pregabalin—no evidence supports this practice and it increases sedative burden 1