What are the differences in mechanism of action between pregabalin and gabapentin?

Differences in Mechanism of Action Between Pregabalin and Gabapentin

Both pregabalin and gabapentin bind to the α2-δ subunit of voltage-gated calcium channels, but pregabalin has superior pharmacokinetic properties with linear absorption, higher bioavailability, and more predictable dose-response relationship compared to gabapentin's saturable absorption. 1, 2

Primary Mechanism of Action

• Both medications were originally designed as anticonvulsants but are widely used for neuropathic pain conditions 3
• Both bind to the α2-δ subunit (type 1) of voltage-gated calcium channels in the central nervous system 1
• This binding inhibits the release of excitatory neurotransmitters including glutamate, norepinephrine, and substance P, which stabilizes neurons from ectopic discharge 3
• Neither drug actually binds to GABA receptors despite being GABA analogues 1

Key Pharmacokinetic Differences

Absorption

• Pregabalin is absorbed more rapidly, with maximum plasma concentrations reached within 1 hour 2
• Gabapentin is absorbed more slowly, with maximum plasma concentrations reached within 3-4 hours 2
• Pregabalin has linear (first-order) absorption, with plasma concentrations increasing proportionately with increasing dose 2
• Gabapentin exhibits saturable absorption (zero-order process), making its pharmacokinetics less predictable 2

Bioavailability

• Pregabalin maintains ≥90% bioavailability regardless of dosage 2
• Gabapentin's bioavailability decreases from 60% to 33% as dosage increases from 900 to 3600 mg/day 2

Pharmacodynamic Differences

• Pregabalin has 6 times higher binding affinity for the α2-δ subunit compared to gabapentin 1
• Pregabalin may be more effective than gabapentin as an antiepileptic based on the magnitude of seizure frequency reduction 2
• For neuropathic pain, pregabalin at 450 mg/day appears to provide comparable pain reduction to the maximum effect of gabapentin 2

Additional Mechanisms Recently Discovered

• Recent research indicates both drugs may also act through:
  • Modifying N-methyl-D-aspartate (NMDA) glutamate receptors 4
  • Interactions with neurexin-1α 4
  • Effects on thrombospondin proteins 4
• These additional mechanisms may contribute substantially to their therapeutic effects beyond calcium channel modulation 4

Clinical Implications of These Differences

• Pregabalin's linear pharmacokinetics allow for more predictable dosing and potentially faster titration 2
• Pregabalin may require less frequent dosing (twice daily) compared to gabapentin (three times daily) due to its superior pharmacokinetic profile 3
• Both medications are used as third-line agents for neuropathic pain conditions after first-line treatments have failed 3
• Both drugs are eliminated renally with similar half-lives of approximately 6 hours 2

Common Side Effects for Both Medications

• Dizziness, somnolence, dry mouth, and constipation 3
• Weight gain and peripheral edema, especially in elderly patients 5
• Neither drug has significant drug-drug interactions involving cytochrome P450 5
• Both require dose adjustment in patients with renal impairment 5

Understanding these mechanistic and pharmacokinetic differences helps explain why pregabalin may provide more predictable clinical responses despite sharing the same primary mechanism of action as gabapentin.