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Gabapentin

Gabapentin

Neurontin Gralise Horizant Fanatrex Gabarone

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Updated: December 06, 2025

Overview

Gabapentin is a gamma-aminobutyric acid (GABA) analog originally developed as an antiepileptic drug. It was first approved by the FDA in 1993 and has since become widely used for neuropathic pain management. While structurally related to GABA, gabapentin does not directly interact with GABA receptors and has a distinct mechanism of action involving voltage-gated calcium channels. Gabapentin demonstrates linear pharmacokinetics at lower doses but shows saturable absorption at higher doses. It is particularly effective for neuropathic pain conditions and partial seizures, with off-label uses including anxiety disorders and restless legs syndrome. The drug's favorable safety profile and lack of significant drug interactions contribute to its widespread clinical use.

Drug Class

Anticonvulsant, GABA analog Therapeutic categories: • Antiepileptic drug (AED) • Neuropathic pain agent • Adjunctive analgesic

Mechanism of Action

Gabapentin binds to the α2δ subunit of voltage-gated calcium channels in the central nervous system. This binding: • Reduces calcium influx at nerve terminals • Decreases release of excitatory neurotransmitters (glutamate, substance P, norepinephrine) • Modulates neuronal excitability without affecting GABA receptors • Inhibits formation of new synapses (synaptogenesis)

Pharmacokinetics

Absorption: • Bioavailability decreases with increasing doses (60% at 900 mg/day to 35% at 4800 mg/day) • Food delays absorption but doesn't affect extent • Saturable absorption via LAT-1 transporter in small intestine Distribution: • Volume of distribution: 0.6-0.8 L/kg • Minimal protein binding (<3%) • Crosses blood-brain barrier via system L amino acid transporters Metabolism: • Undergoes negligible hepatic metabolism (no CYP450 involvement) • Not metabolized to any significant degree Excretion: • Primarily eliminated unchanged by renal excretion • Renal clearance proportional to creatinine clearance Half-life: • 5-7 hours in adults with normal renal function • Prolonged in renal impairment (up to 52 hours in severe cases)

Pharmacodynamics

Central nervous system effects: • Reduces neuronal hyperexcitability • Modulates pain signaling pathways • Exhibits anticonvulsant properties Peripheral effects: • May reduce neuropathic pain through dorsal horn modulation • No significant cardiovascular effects at therapeutic doses • Minimal effects on cardiac conduction

Indications

• Partial onset seizures: Adjunctive therapy for partial seizures with or without secondary generalization in patients ≥3 years old • Postherpetic neuralgia: Management of neuropathic pain following acute herpes zoster infection • Neuropathic pain associated with diabetic peripheral neuropathy • Moderate-to-severe primary restless legs syndrome (extended-release formulation only)

Contraindications

Absolute: • Hypersensitivity to gabapentin or any component of the formulation Relative: • Severe renal impairment without dose adjustment • History of angioedema with previous gabapentin use • Concurrent use with CNS depressants (requires caution) • Patients with respiratory compromise

Dosage & Administration

Epilepsy (≥12 years): • Initial: 300 mg TID, titrate as needed up to 600 mg TID • Maintenance: 900-1800 mg/day in 3 divided doses (max 3600 mg/day) Postherpetic neuralgia: • Day 1: 300 mg once • Day 2: 300 mg BID • Day 3: 300 mg TID • Titrate up to 1800 mg/day (may go up to 3600 mg/day) Diabetic neuropathy: • Gralise formulation: Start 300 mg daily, titrate over 15 days to 1800 mg once daily with evening meal Renal impairment dosing: • CrCl ≥60 mL/min: Full dose • CrCl 30-59 mL/min: 200-700 mg/day in divided doses • CrCl 15-29 mL/min: 200-700 mg/day in divided doses • CrCl <15 mL/min: 100-300 mg/day in divided doses

Special Populations

Pediatric: • Safety established for partial seizures in children ≥3 years • Requires weight-based dosing (10-15 mg/kg/day initial) Geriatric: • Reduced renal clearance common • Start with lower doses and titrate slowly Renal impairment: • Requires dose reduction proportional to CrCl • Hemodialysis patients require supplemental dose after dialysis Hepatic impairment: • No specific dose adjustment needed (not hepatically metabolized) • Monitor for increased CNS effects

Adverse Effects

Common (>10%): • Somnolence (19-28%) • Dizziness (17-28%) • Peripheral edema (8-16%) • Fatigue (11-14%) Serious (<1%): • Angioedema and hypersensitivity reactions • Suicidal behavior and ideation • Respiratory depression (especially with opioids) • Sudden unexplained death in epilepsy (SUDEP) • Myopathy and rhabdomyolysis

Drug Interactions

• Antacids containing aluminum/magnesium: Reduce gabapentin absorption by 20% (administer ≥2 hours apart) • CNS depressants (alcohol, opioids, benzodiazepines): Potentiate sedation and respiratory depression • Hydrocodone: Increases hydrocodone exposure by 22% • Morphine: Increases gabapentin AUC by 44% when co-administered • No significant CYP450 interactions

Warnings & Precautions

• Black Box Warning: Increased risk of suicidal thoughts/behavior in patients taking AEDs • May cause life-threatening respiratory depression when used with CNS depressants • Withdrawal seizures possible with abrupt discontinuation (taper over ≥1 week) • Increased seizure frequency possible in patients with multifocal epilepsy • May impair cognitive and motor function (caution when operating machinery) • Potential for misuse and dependence in some patient populations

Pregnancy & Lactation

Pregnancy: • FDA Pregnancy Category C: Risk cannot be ruled out • North American AED Pregnancy Registry data show possible increased risk of cardiac malformations • Benefits may outweigh risks in uncontrolled seizures Lactation: • Excreted in human milk (0.2-1.3 mg/kg/day) • Consider risk/benefit balance • Monitor breastfed infants for sedation and poor feeding

Monitoring Parameters

• Renal function (serum creatinine, BUN, CrCl) at baseline and periodically • Seizure frequency and characteristics in epileptic patients • Pain assessment in neuropathic pain indications • Signs of mood changes, depression, or suicidal ideation • Weight gain and peripheral edema • Neurological status (ataxia, dizziness, somnolence) • Signs of respiratory depression when combined with opioids

Patient Counseling

• Take exactly as prescribed; do not abruptly discontinue • Report any thoughts of self-harm or mood changes immediately • May cause drowsiness - avoid alcohol and dangerous activities until effects known • Swallow whole; do not crush or chew extended-release formulations • If using immediate-release formulation, space doses evenly throughout waking hours • Inform all healthcare providers about gabapentin use before surgery • Store at room temperature away from moisture

Storage & Stability

• Immediate-release: Store at 20-25°C (68-77°F) • Extended-release (Gralise): Store below 30°C (86°F) • Horizant: Store at 25°C (77°F) with excursions permitted to 15-30°C (59-86°F) • Protect from moisture • Stable in original packaging; do not transfer to other containers

Clinical Pearls

• Titrate slowly (over 1-2 weeks) to minimize CNS side effects • Extended-release formulations are not interchangeable with immediate-release • Consider bedtime dosing to minimize daytime sedation • Off-label uses include: migraine prophylaxis, fibromyalgia, anxiety disorders, and alcohol withdrawal • Therapeutic drug monitoring not generally required (no established therapeutic range) • Be vigilant for signs of misuse, especially in patients with substance use disorders

References

• Lexicomp Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2023 • Micromedex® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA • FDA Prescribing Information: Neurontin (gabapentin) [Revised 2017] • American Academy of Neurology Guidelines: Antiepileptic Drug Selection (2013) • Neuropathic Pain Special Interest Group (NeuPSIG) Recommendations (2015)