What is the difference between Gabapentin and Pregabalin in terms of their use in treating epilepsy and neuropathic pain?

Gabapentin vs. Pregabalin: Key Differences

Pregabalin offers more predictable pharmacokinetics with linear absorption and faster onset of action compared to gabapentin, but both medications have nearly identical mechanisms of action and adverse effect profiles. 1

Mechanism of Action

Both medications bind to the α2δ subunit of voltage-gated calcium channels and inhibit excitatory neurotransmitter release, making them mechanistically identical despite being first-generation (gabapentin) and second-generation (pregabalin) gabapentinoids. 2, 3

Critical Pharmacokinetic Differences

The most clinically significant difference lies in their absorption patterns:

• Pregabalin has linear pharmacokinetics with ≥90% bioavailability regardless of dose, meaning dose increases produce proportional increases in blood levels, making titration straightforward and predictable. 1, 3

• Gabapentin has nonlinear, saturable absorption that becomes progressively less efficient at higher doses—bioavailability drops from 60% at 900 mg/day to only 33% at 3600 mg/day. 1, 3

• Pregabalin reaches maximum plasma concentration within 1 hour, while gabapentin requires 3-4 hours. 3

• Pregabalin demonstrates pain relief within 1.5-3.5 days, compared to gabapentin which requires 2+ months for adequate trial. 1

Dosing Protocols

Pregabalin Dosing:

• Start at 75 mg twice daily or 50 mg three times daily (150 mg/day total). 1, 2
• Increase to target dose of 300 mg/day within 1 week (150 mg twice daily or 100 mg three times daily). 1, 4
• Maximum dose is 600 mg/day, but doses above 300 mg/day are not consistently more effective and cause significantly more adverse effects—reserve only for patients with inadequate pain relief at 300 mg/day who tolerate the medication well. 1, 2
• Adequate trial duration is 4 weeks at therapeutic dose (typically 300 mg/day). 1, 4

Gabapentin Dosing:

• Start at 100-300 mg at bedtime or 100-300 mg three times daily. 1, 2
• Titrate gradually by 100-300 mg every 1-7 days as tolerated. 1
• Target therapeutic dose is 1800-3600 mg/day in three divided doses, with maximum of 3600 mg/day. 1, 2
• Titration period requires 3-8 weeks plus 2 weeks at maximum dose for adequate trial. 1

Efficacy Comparison

• For neuropathic pain, pregabalin 450 mg/day appears comparable to the predicted maximum effect of gabapentin. 3
• Pregabalin may be more effective as an antiepileptic based on magnitude of seizure frequency reduction. 3
• Both medications have similar efficacy for neuropathic pain conditions, with number needed to treat (NNT) of 3.9-5.3 for pregabalin at 300-600 mg/day for postherpetic neuralgia. 1
• Gabapentin has stronger evidence base for first-line treatment of neuropathic pain, with guidelines recommending pregabalin only after inadequate response to gabapentin. 2

Adverse Effect Profiles

Both medications have nearly identical adverse effect profiles, with no clinically meaningful differences: 1

• Primary side effects include dizziness (23-46%), somnolence (15-25%), peripheral edema (10%), dry mouth, and constipation—all dose-dependent. 1, 5
• Elderly patients are more susceptible to falls, confusion, sedation, balance disorder, tremor, and coordination abnormalities. 1, 2
• Both medications can cause weight gain and peripheral edema, particularly in elderly patients. 1, 6
• Visual disturbances occur at comparable rates with both medications. 1

Special Population Considerations

Renal Impairment:

• Both drugs are eliminated unchanged by the kidneys (95% pregabalin, similar for gabapentin), requiring mandatory dose reduction in renal impairment. 1, 6
• For pregabalin: reduce dose by ~50% for CrCl 30-60 mL/min, 75% for CrCl 15-30 mL/min, and 85-90% for CrCl <15 mL/min. 1

Elderly Patients:

• Consider lower starting doses and slower titration due to increased risk of adverse effects including dizziness, somnolence, confusion, and falls. 1, 2

Critical Clinical Pitfalls to Avoid

• Do not abruptly discontinue either medication—taper gradually over minimum of 1 week to avoid withdrawal symptoms. 1, 2

• Do not combine gabapentin and pregabalin in routine practice—they have additive pharmacodynamic effects causing unacceptable sedative burden, especially dangerous in elderly patients or those with fall risk. 1

• Do not routinely prescribe pregabalin 600 mg/day as standard dose—300 mg/day provides optimal benefit-to-risk ratio for most patients, with 600 mg/day reserved only for those with ongoing pain despite adequate trial at 300 mg/day who tolerate medication well. 1

• Do not assume pregabalin works if gabapentin failed—no evidence supports sequential use, and switching may not reduce side effects like dizziness. 1

Cost Considerations

Generic gabapentin is typically less expensive than pregabalin, which may influence medication selection when efficacy is comparable. 2