In an adult with neuropathic pain or focal seizures, should I use pregabalin (Lyrica) or gabapentin (Neurontin) considering efficacy, tolerability, dosing convenience, renal function, and cost?

Pregabalin vs Gabapentin for Neuropathic Pain and Focal Seizures

Pregabalin is the superior choice for most adults with neuropathic pain or focal seizures due to its faster onset of action, more predictable dosing, twice-daily convenience, and superior efficacy demonstrated in head-to-head trials. 1

Key Pharmacokinetic Advantages of Pregabalin

Pregabalin has linear, dose-proportional absorption with >90% bioavailability at all doses, whereas gabapentin exhibits saturable, nonlinear absorption that drops from 60% to 33% bioavailability as doses increase from 900 to 3600 mg/day. 2 This fundamental difference makes pregabalin dosing far more predictable and reliable. 3, 4

• Pregabalin reaches maximum plasma concentration in 1 hour vs. 3-4 hours for gabapentin, enabling faster therapeutic effect. 2
• Pain relief with pregabalin occurs within 1.5-3.5 days, compared to gabapentin which requires 2+ months for an adequate trial (3-8 weeks titration plus 2 weeks at maximum dose). 3, 4
• Both drugs have ~6 hour elimination half-lives and are renally excreted without hepatic metabolism or CYP450 interactions. 2

Comparative Efficacy: Head-to-Head Evidence

A 2024 meta-analysis of 14 studies (3,346 patients) demonstrated pregabalin's superiority over gabapentin across multiple outcomes: 1

• Visual Analog Scale (VAS) pain scores were significantly lower with pregabalin at all time points up to 12-14 weeks (SMD -0.47,95% CI -0.74 to -0.19). 1
• Quality of life scores (SF-12/SF-36/EQ-5D) were significantly better with pregabalin (SMD 0.39,95% CI 0.11-0.68). 1
• Patients on pregabalin experienced 9 more days with no/mild pain (MD 9.00,95% CI 8.93-9.07) and 3 fewer days with severe pain (MD -3.00,95% CI -4.96 to -1.04). 1
• Opioid consumption was 50% lower in the pregabalin group (OR 0.50,95% CI 0.33-0.76). 1

Dosing Convenience and Titration Speed

Pregabalin Dosing Protocol

Start pregabalin at 150 mg/day (75 mg twice daily or 50 mg three times daily) and increase to the target dose of 300 mg/day within 1 week. 4, 5, 6

• The optimal benefit-to-risk ratio is achieved at 300 mg/day (150 mg twice daily or 100 mg three times daily). 4
• Reserve the maximum dose of 600 mg/day only for patients with inadequate pain relief at 300 mg/day who tolerate the medication well, as higher doses increase adverse effects without consistent additional benefit. 4
• Allow a minimum of 4 weeks at therapeutic dose before declaring treatment failure. 4
• Twice-daily dosing is sufficient due to linear pharmacokinetics. 4, 2

Gabapentin Dosing Protocol

Start gabapentin at 100-300 mg at bedtime on day 1, increase to 300 mg three times daily by day 3, then titrate by 300 mg every 3-7 days to reach the target therapeutic range of 1800-3600 mg/day in three divided doses. 3, 7

• The minimum effective dose is 1800 mg/day (600 mg three times daily), with maximum of 3600 mg/day (1200 mg three times daily). 3
• Three-times-daily dosing is mandatory because saturable absorption makes once- or twice-daily regimens ineffective. 3
• An adequate trial requires 3-8 weeks for titration plus 2 weeks at maximum tolerated dose—potentially 2 months or more. 3, 7
• Doses must be spaced no more than 12 hours apart. 3

Tolerability and Adverse Effects

Both medications share nearly identical adverse effect profiles, with dizziness, somnolence, peripheral edema, and weight gain as primary concerns. 4

• Pregabalin: dizziness (23-46%), somnolence (15-25%), peripheral edema (10%). 4
• Gabapentin: dizziness (19%), somnolence (14%), peripheral edema (7%), gait disturbance (9%). 3, 7
• Gabapentin had higher incidence of nausea and vomiting in comparative trials. 1
• Adverse effects are dose-dependent for both agents and can be managed with dose reduction. 3, 4

Special Population Considerations

Elderly Patients

Both medications require lower starting doses and slower titration in elderly patients due to increased fall risk from dizziness and age-related decline in renal function. 3, 4

• Pregabalin: start at 25-50 mg/day with slow weekly titration. 4
• Gabapentin: start at 100-200 mg/day with increases every 3-7 days or longer. 3, 7
• Always calculate creatinine clearance before initiating either medication, as normal serum creatinine can mask renal impairment in elderly patients with reduced muscle mass. 4, 7

Renal Impairment Dose Adjustments

Both medications require mandatory dose reduction based on creatinine clearance (calculate using Cockcroft-Gault equation). 3, 4

Pregabalin Renal Dosing 4

CrCl (mL/min)	Daily Dose Reduction
30-60	Reduce by ~50%
15-30	Reduce by ~75%
<15	Reduce by 85-90% (max 75 mg/day)

Gabapentin Renal Dosing 3, 7

CrCl (mL/min)	Daily Dose	Frequency
≥60	900-3600 mg	Three times daily
30-59	400-1400 mg	Twice daily
15-29	200-700 mg	Once daily
<15	100-300 mg	Once daily

Cost Considerations

Gabapentin is typically less expensive than pregabalin, as generic gabapentin has been available longer. However, the faster titration, superior efficacy, and twice-daily convenience of pregabalin may offset higher medication costs through improved outcomes and adherence. 1

When to Choose Gabapentin Over Pregabalin

Consider gabapentin as first-line only when:

• Cost is prohibitive and insurance does not cover pregabalin. 3
• Patient has HIV-associated neuropathic pain, where gabapentin 2400 mg/day is specifically recommended as first-line therapy with strong evidence. 3
• Patient can reliably adhere to three-times-daily dosing and has time for the extended 2-month titration period. 3

Critical Pitfalls to Avoid

Never combine gabapentin and pregabalin, as they share identical mechanisms of action and adverse effect profiles, creating unacceptable additive sedative burden without established efficacy benefits. 4 No randomized controlled trials support combination gabapentinoid therapy. 4

Do not switch from one gabapentinoid to the other if the first fails, as patients may respond to one, both, or neither—there is no evidence supporting sequential use. 3, 4

Never use once- or twice-daily gabapentin dosing, as saturable absorption makes this ineffective. 3

Do not declare treatment failure before completing adequate trials: 4 weeks at therapeutic dose for pregabalin 4 or 2 months for gabapentin. 3

Always taper gradually over minimum 1 week when discontinuing either medication to avoid withdrawal symptoms. 3, 4

Evidence-Based Combination Strategies

If monotherapy with either gabapentinoid is inadequate, add a tricyclic antidepressant (e.g., nortriptyline) rather than combining two gabapentinoids, as this combination provides superior pain relief compared to either agent alone. 3, 4

Low-dose gabapentinoid plus opioid achieves better analgesia at lower opioid doses than opioid monotherapy, but monitor closely for respiratory depression, especially in elderly patients. 4

Topical capsaicin 8% patch (single 30-minute application) provides pain relief lasting ≥12 weeks and can be safely combined with systemic gabapentinoids. 3, 4