Introduction
Gabapentin is a widely prescribed anticonvulsant medication originally developed as a structural analog of gamma-aminobutyric acid (GABA). First approved by the FDA in 1993 for epilepsy, it has since gained multiple approved indications and extensive off-label use. Despite its structural similarity to GABA, gabapentin does not act directly on GABA receptors but exerts its effects through a unique mechanism involving voltage-gated calcium channels.
Mechanism of Action
Gabapentin's primary mechanism of action involves binding to the α2δ subunit of voltage-gated calcium channels in the central nervous system. This binding reduces calcium influx at nerve terminals, which subsequently decreases the release of excitatory neurotransmitters such as glutamate, norepinephrine, and substance P. Unlike traditional antiepileptic drugs, gabapentin does not enhance GABAergic inhibition directly, nor does it affect sodium channels. Its action results in reduced neuronal excitability and dampened pain signal transmission, making it effective for both seizure control and neuropathic pain management.
Indications
FDA-approved indications:- Partial-onset seizures with and without secondary generalization (as adjunctive therapy in patients ≥3 years)
- Postherpetic neuralgia (in adults)
- Neuropathic pain associated with diabetic neuropathy
- Fibromyalgia
- Bipolar disorder maintenance
- Restless legs syndrome
- Migraine prophylaxis
- Anxiety disorders
- Alcohol withdrawal syndrome
- Various chronic pain syndromes
Dosage and Administration
Adults:- Epilepsy: Initial dose 300 mg three times daily; may titrate up to 1800-3600 mg/day in divided doses
- Neuropathic pain: Initial dose 300 mg once daily on day 1, 300 mg twice daily on day 2, then 300 mg three times daily on day 3; may titrate up to 1800-3600 mg/day
- CrCl ≥60 mL/min: 300-1200 mg three times daily
- CrCl 30-59 mL/min: 200-700 mg twice daily
- CrCl 15-29 mL/min: 200-700 mg once daily
- CrCl <15 mL/min: 100-300 mg once daily
- Take with or without food
- Do not crush or chew extended-release formulations
- For patients requiring dose reduction or discontinuation, taper gradually over at least one week
Pharmacokinetics
Absorption: Bioavailability is approximately 60% at lower doses (300 mg) but decreases with increasing doses due to saturable absorption. Food has minimal effect on absorption. Distribution: Volume of distribution is 0.6-0.8 L/kg. Protein binding is negligible (<3%). Crosses blood-brain barrier and placenta. Metabolism: Not significantly metabolized in humans; no hepatic cytochrome P450 involvement. Elimination: Excreted unchanged primarily renally. Elimination half-life is 5-7 hours in patients with normal renal function. Dialyzable.Contraindications
- Hypersensitivity to gabapentin or any component of the formulation
- Concomitant use with other gabapentin products due to potential additive effects
Warnings and Precautions
Boxed Warning:- Antiepileptic drugs increase the risk of suicidal thoughts or behavior
- CNS depression: May impair mental and/or physical abilities
- Respiratory depression: Risk increased with concomitant opioid use
- Withdrawal symptoms: Abrupt discontinuation may precipitate seizures
- Tumorigenic potential: Pancreatic acinar cell tumors observed in rodent studies
- Drug reaction with eosinophilia and systemic symptoms (DRESS)
- Anaphylaxis and angioedema
- Driving impairment: Patients should not drive until they understand how gabapentin affects them
Drug Interactions
Major interactions:- Opioids: Increased risk of respiratory depression and CNS depression
- Alcohol: Enhanced CNS depressant effects
- Antacids: Reduced gabapentin absorption (administer gabapentin至少 2 hours after antacids)
- Hydrocodone: Increased hydrocodone concentrations
- Other CNS depressants (benzodiazepines, barbiturates, sedatives)
- Morphine: Increased gabapentin concentrations
Adverse Effects
Common (≥5%):- Dizziness (28%)
- Somnolence (21%)
- Peripheral edema (8%)
- Fatigue (11%)
- Ataxia (8%)
- Nystagmus (8%)
- Suicidal ideation and behavior
- Respiratory depression
- Severe dermatologic reactions (Stevens-Johnson syndrome, DRESS)
- Rhabdomyolysis
- Clinical worsening of seizures with abrupt withdrawal
- Angioedema
Monitoring Parameters
- Seizure frequency and characteristics (for epilepsy indication)
- Pain assessment and functional status (for pain indications)
- Mental status changes, depression, or suicidal ideation
- Signs of CNS depression
- Renal function (at baseline and periodically)
- Weight gain and peripheral edema
- Signs of hypersensitivity reactions
- Respiratory status, especially with concomitant opioid use
Patient Education
- Take medication exactly as prescribed; do not stop abruptly
- Avoid alcohol and other CNS depressants
- Be aware of potential dizziness and drowsiness; use caution when driving or operating machinery
- Report any mood changes, depression, or suicidal thoughts immediately
- Notify healthcare provider if pregnancy is planned or suspected
- Inform all healthcare providers about gabapentin use
- Keep medication out of reach of children
- Report any signs of allergic reaction (rash, swelling, difficulty breathing)
- Be aware that gabapentin may cause weight gain and peripheral edema
References
1. FDA Prescribing Information: Neurontin (gabapentin). 2017. 2. Backonja M, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus. JAMA. 1998;280(21):1831-1836. 3. Rowbotham M, et al. Gabapentin for the treatment of postherpetic neuralgia. JAMA. 1998;280(21):1837-1842. 4. Johannessen Landmark C, et al. Pharmacological management of epilepsy: recent advances and future prospects. Drugs. 2015;75(4):339-355. 5. Bockbrader HN, et al. Clinical pharmacokinetics of gabapentin. Drugs Today. 1995;31(9):613-619. 6. Goodman CW, Brett AS. Gabapentin and Pregabalin for Pain - Is Increased Prescribing a Cause for Concern? N Engl J Med. 2017;377(5):411-419. 7. UpToDate: Gabapentin drug information. Accessed 2023. 8. Clinical Pharmacology [database online]. Tampa, FL: Elsevier; 2023.