What is gabapentin?

What is Gabapentin?

Gabapentin is an antiepileptic medication FDA-approved for treating postherpetic neuralgia (nerve pain following shingles) and partial seizures as adjunctive therapy, though it is widely used off-label for various neuropathic pain conditions. 1

Chemical Structure and Formulation

• Gabapentin (1-(aminomethyl)cyclohexaneacetic acid) is structurally related to the neurotransmitter GABA but does not affect GABA binding, uptake, or degradation 1
• Available as film-coated tablets in 600 mg and 800 mg strengths, containing gabapentin with inactive ingredients including mannitol and hydroxypropyl cellulose 1

Mechanism of Action

• Gabapentin binds with high affinity to the α2δ-1 subunit of voltage-gated calcium channels, reducing calcium influx and decreasing synaptic neurotransmitter release into hyperexcited neurons 2, 3, 1
• Despite being a GABA analogue, it does not act as an agonist at GABAA or GABAB receptors 3
• The precise relationship between α2δ binding and therapeutic effects remains unknown 1

FDA-Approved Indications

• Postherpetic neuralgia (nerve pain following shingles) in adults 1
• Partial seizures as adjunctive therapy in adults and children ≥3 years of age 1

Evidence-Based Off-Label Uses

• First-line oral treatment for chronic HIV-associated neuropathic pain per Clinical Infectious Diseases guidelines 2
• Painful diabetic neuropathy at doses typically up to 3600 mg/day, though the American Geriatrics Society notes it is not FDA-approved for this indication 4, 2
• Second-line treatment for fibromyalgia-associated muscle pain when severe enough to interfere with quality of life, per the American Geriatrics Society 2
• Second-line treatment for central poststroke pain when first-line agents (amitriptyline, lamotrigine) fail 2

Pharmacokinetics

• Bioavailability is not dose-proportional and decreases as dose increases: 60% at 900 mg/day, declining to 27% at 4800 mg/day 1
• Not protein-bound (<3%), not metabolized, and eliminated unchanged by renal excretion 1, 5
• Half-life of 5-7 hours, unaltered by dose or multiple dosing 1
• Does not induce hepatic enzymes, minimizing drug-drug interactions 5, 6
• Food has minimal effect on absorption (14% increase in AUC and Cmax) 1

Dosing Strategy

• Starting dose: 100-300 mg at bedtime, increasing to 900-3600 mg daily in 2-3 divided doses 3
• The American Geriatrics Society recommends starting with lowest doses (100-200 mg/day) for older adults due to increased risk of somnolence, dizziness, and mental clouding 2
• Doses in clinical practice are often lower than trial doses (up to 3600 mg/day), potentially leading to suboptimal efficacy per the Journal of the American Geriatrics Society 2
• Renal dose adjustment is mandatory: plasma clearance is directly proportional to creatinine clearance 1
• If taking aluminum/magnesium-containing antacids (Maalox, Mylanta), wait at least 2 hours before next gabapentin dose 1

Common Adverse Effects

• Most frequent: somnolence, dizziness, fatigue, ataxia, and mental clouding 2, 5
• Peripheral edema occurs in approximately 7% of patients 2
• Dose-dependent risk of falls or fractures, with highest risk at doses ≥2400 mg/day (RR 1.90) 7
• Increased risk of altered mental status at doses 600-2399 mg/day 7
• Adverse effects are particularly problematic in older patients but may be attenuated with lower starting doses and gradual titration 4, 2

Serious Safety Warnings

• Suicidal thoughts or actions occur in approximately 1 in 500 patients taking antiepileptic drugs including gabapentin 1
• Stopping gabapentin suddenly can cause serious problems, including status epilepticus in epilepsy patients 1
• Serious or life-threatening allergic reactions affecting skin, liver, or blood cells may occur 1
• In children 3-12 years: emotional changes, aggressive behavior, concentration problems, restlessness, and hyperactivity 1
• Approximately 50% of patients prescribed gabapentinoids receive continuous treatment for ≥12 months, a practice of doubtful efficacy in many cases per The Lancet Psychiatry 4

Critical Clinical Pitfalls

• Avoid abrupt discontinuation: sudden cessation can lead to physical and psychological withdrawal symptoms; patients on long-term therapy should be offered careful tapering and support 4
• When taken with opioids, dangerous respiratory depression can occur 4
• Patients with HCV, HIV, or AUD have elevated baseline incidence of falls/fractures regardless of gabapentin exposure, though excess risk from gabapentin was not statistically significant in these subgroups 7
• Clinicians should monitor safety especially at doses ≥600 mg/day 7
• Half tablets not used within 28 days of breaking should be discarded 1

Special Populations

• Elderly: apparent oral clearance decreases from ~225 mL/min in patients <30 years to ~125 mL/min in those >70 years, largely explained by declining renal function 1
• Pregnancy: not known if gabapentin harms unborn babies; patients should register with the North American Antiepileptic Drug Pregnancy Registry (1-888-233-2334) 1
• Breastfeeding: gabapentin passes into breast milk 1
• Hemodialysis: gabapentin can be removed from plasma by hemodialysis 1