A 52-year-old man from Delhi presents to the neurology clinic with a 6-month history of burning pain in both feet that began after a viral illness. The pain is constant, worse at night, and radiates up to the knees. He describes it as a 'pins and needles' sensation with occasional sharp, shooting pains. Examination reveals diminished vibration sense and absent ankle reflexes bilaterally. Nerve conduction studies confirm demyelinating polyneuropathy. The patient reports that gabapentin provides partial relief, but he remains distressed by the neuropathic pain. Which of the following best explains the mechanism by which gabapentin alleviates this patient's pain?

Explanation

## Mechanism of Gabapentin in Neuropathic Pain **Key Point:** Gabapentin is a gabapentinoid that does NOT act as a GABA agonist despite its name. Its primary mechanism in pain modulation is binding to the α2-δ subunit of voltage-gated calcium channels (specifically the α2-δ-1 subunit) on presynaptic terminals in the dorsal horn of the spinal cord. ### How This Reduces Pain 1. **Calcium Channel Binding** — Gabapentin binds to α2-δ subunits with high affinity, particularly on nociceptive afferents and interneurons in the dorsal horn. 2. **Reduced Neurotransmitter Release** — This binding decreases calcium influx at presynaptic terminals, thereby reducing the release of excitatory neurotransmitters (glutamate, substance P, CGRP) from nociceptive neurons. 3. **Dampened Nociceptive Signaling** — The net effect is reduced synaptic transmission of pain signals in the spinal cord, leading to analgesia. **High-Yield:** Gabapentin is highly effective in neuropathic pain (diabetic neuropathy, postherpetic neuralgia, peripheral nerve injury) precisely because it targets the calcium channels that drive nociceptive neurotransmitter release. It does NOT directly enhance GABA function. ### Clinical Efficacy in This Case The patient's demyelinating polyneuropathy creates ectopic firing and sensitization in damaged nerves. Gabapentin reduces this aberrant nociceptive input at the spinal level, explaining the partial pain relief observed. **Clinical Pearl:** Pregabalin (another α2-δ ligand) works by the same mechanism and is often used interchangeably with gabapentin for neuropathic pain, though pregabalin has more predictable pharmacokinetics. [cite:Guyton & Hall Textbook of Medical Physiology 13e Ch 48]