How does gabapentin (Neurontin) treat neuropathic pain?

Mechanism of Action of Gabapentin in Neuropathic Pain

Gabapentin treats neuropathic pain primarily by binding to the α2δ-1 subunit of voltage-gated calcium channels, inhibiting calcium influx and reducing the release of excitatory neurotransmitters in pain pathways. 1

Primary Mechanism

• Gabapentin binds specifically to the α2δ subunit of voltage-gated calcium channels, which inhibits nociceptive neurons by reducing neurotransmitter release at pain synapses 2
• This binding prevents the trafficking of calcium channels (particularly N-type) from the cytoplasm to the plasma membrane of presynaptic terminals in dorsal root ganglion neurons and dorsal horn neurons 1
• By inhibiting calcium influx, gabapentin decreases the release of excitatory neurotransmitters involved in pain signal transmission 1

Pharmacokinetic Considerations

• Gabapentin has nonlinear pharmacokinetics due to saturable absorption, which affects its dosing requirements 2
• For neuropathic pain, effective doses typically range from 900-3600 mg/day in divided doses 3, 4
• Renal dose adjustment is required for patients with renal insufficiency, as gabapentin is primarily eliminated through the kidneys 5

Clinical Efficacy in Neuropathic Pain

• Gabapentin is recommended as a first-line oral pharmacological treatment for chronic HIV-associated neuropathic pain 3
• In postherpetic neuralgia, gabapentin provides substantial pain relief (at least 50% reduction) in approximately 32% of patients compared to 17% with placebo 4
• In diabetic neuropathy, about 38% of patients achieve substantial pain relief with gabapentin compared to 21% with placebo 4
• Pain reduction begins as early as week 1 of treatment and is maintained throughout the treatment period 6

Dosing Strategy for Optimal Effect

• Treatment should be initiated with a low starting dose (100-300 mg/day) to minimize adverse effects 3, 5
• Gradual titration is recommended: increasing by 100-300 mg every 1-7 days as tolerated 5
• A typical adult regimen will titrate to approximately 2400 mg per day in divided doses 3
• Lower starting doses (100-200 mg/day) are particularly important in older adults and those with renal impairment 3

Secondary Mechanisms and Additional Effects

• Gabapentin may also modulate other targets including transient receptor potential channels, NMDA receptors, and protein kinase C 1
• It can act on supraspinal regions to stimulate noradrenaline-mediated descending inhibition, contributing to its anti-hypersensitivity action 1
• Gabapentin has been shown to improve sleep scores in addition to pain relief, which is beneficial as sleep disturbance is common in chronic pain 3

Common Side Effects and Management

• The most common adverse effects include dizziness (19%), somnolence (14%), peripheral edema (7%), and gait disturbance (14%) 4
• Most side effects are mild to moderate and often transient, occurring primarily during the titration phase 7
• Adverse event withdrawals are more common with gabapentin (11%) than with placebo (8.2%) 4
• To minimize side effects, start with low doses and titrate slowly, particularly in elderly patients 3, 2

Important Clinical Considerations

• Full titration typically requires 3-8 weeks, with an additional 2 weeks at maximum tolerated dose needed to evaluate effectiveness 5
• If no response after reaching 1800 mg/day for 2 weeks, consider increasing to maximum 3600 mg/day or adding alternative therapy 5
• Abrupt discontinuation should be avoided; taper gradually to prevent withdrawal symptoms 2
• Newer gabapentin analogues may offer similar efficacy with fewer side effects, particularly motor incoordination 8