Gabapentinoids (gabapentin and pregabalin) and tricyclic antidepressants (TCAs) target distinct but complementary mechanisms within the neuropathic pain cascade, making them first-line agents and effective combination partners. Gabapentinoids bind with high affinity to the alpha-2-delta-1 subunit of voltage-gated calcium channels (VGCCs) located on presynaptic terminals in the dorsal horn of the spinal cord and at dorsal root ganglion neurons. In neuropathic pain states, alpha-2-delta-1 expression is dramatically upregulated (increased 3-5 fold in DRG neurons after nerve injury), increasing calcium influx at presynaptic terminals and amplifying release of excitatory neurotransmitters (glutamate, substance P, calcitonin gene-related peptide). By binding alpha-2-delta-1, gabapentinoids reduce calcium channel trafficking to the cell surface, decrease presynaptic calcium influx, and consequently reduce excitatory neurotransmitter release into the dorsal horn. This dampens central sensitization and wind-up. Gabapentin has saturable absorption via the L-amino acid transporter in the small intestine, resulting in non-linear pharmacokinetics (bioavailability drops from approximately 60% at 300 mg to 35% at 1600 mg), requiring TID dosing. Pregabalin has linear, dose-proportional absorption (greater than 90% bioavailability), enabling more predictable dose-response relationships and BID dosing. Both are eliminated renally...