Pregabalin: A Comprehensive Monograph

1.0 Executive Summary

Pregabalin is a second-generation gabapentinoid, a small molecule drug classified as a structural analogue of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Despite this structural relationship, its therapeutic effects are not mediated through GABAergic pathways. Instead, pregabalin exerts its analgesic, anticonvulsant, and anxiolytic properties by binding with high affinity to the α2δ (alpha-2-delta) auxiliary subunit of voltage-gated calcium channels in the central nervous system. This action modulates calcium influx into hyperexcited neurons, thereby reducing the presynaptic release of several excitatory neurotransmitters.

In the United States, pregabalin is approved by the Food and Drug Administration (FDA) for the management of several neuropathic pain conditions, including diabetic peripheral neuropathy, postherpetic neuralgia, and pain associated with spinal cord injury. It is also a primary therapeutic agent for fibromyalgia and serves as an adjunctive therapy for partial-onset seizures in adult and pediatric patients. Beyond these approved uses, pregabalin is widely prescribed off-label for generalized anxiety disorder (GAD), an indication for which it holds formal approval in the European Union.

The pharmacological profile of pregabalin is characterized by favorable and predictable pharmacokinetics, including high oral bioavailability (≥90%), linear absorption, negligible plasma protein binding, and a lack of metabolism by the cytochrome P450 system. However, its elimination is almost entirely dependent on renal excretion of the unchanged drug. This characteristic, while minimizing hepatic drug-drug interactions, makes pregabalin a high-risk medication in patients with renal impairment, necessitating careful dose adjustments based on creatinine clearance.