Gabapentin

Indications

• FDA-approved as adjunctive therapy for partial-onset seizures in adults and in children aged 3 years and older.
• FDA-approved for postherpetic neuralgia in adults, with the once-daily gastroretentive formulation labeled for the same indication.
• Gabapentin enacarbil is FDA-approved for moderate to severe primary restless legs syndrome and for postherpetic neuralgia.
• Off-label use for alcohol use disorder, where randomized trials show reduced heavy drinking, particularly with withdrawal symptoms.
• Off-label use for generalized and social anxiety, insomnia, hot flashes, and diabetic neuropathy, none of which are labeled indications.
• Off-label use in bipolar disorder is not supported, since controlled trials found gabapentin no better than placebo.

Mechanism of action

• Binds the alpha-2-delta auxiliary subunit of voltage-gated calcium channels, reducing channel trafficking to the presynaptic membrane.
• Reduced calcium influx lowers release of glutamate, substance P, and norepinephrine from hyperexcitable presynaptic terminals.
• Despite its name it does not bind GABA-A or GABA-B receptors and is not converted to GABA in the central nervous system.
• Effects on the descending noradrenergic pain pathway contribute to analgesia in neuropathic pain states.
• Anxiolytic and sleep effects likely follow from the same reduction in excitatory neurotransmitter release rather than from GABA mimicry.

Pharmacokinetics

• Absorption occurs by a saturable L-amino acid transporter, so bioavailability falls from about 60 percent at 900 mg to 33 percent at 3600 mg.
• Because absorption is saturable, dividing the total dose across three administrations gives more exposure than one large dose.
• Gabapentin is not metabolized and does not induce or inhibit hepatic enzymes, so pharmacokinetic drug interactions are minimal.
• It is excreted unchanged by the kidneys with a half-life of 5 to 7 hours, which lengthens to 50 hours or more in anuric patients.
• Gabapentin enacarbil is a prodrug absorbed by high-capacity transporters, giving more predictable exposure and once-daily dosing.

Dosing

• For seizures and neuropathic pain, start 300 mg on day 1, 300 mg twice daily on day 2, and 300 mg three times daily on day 3.
• Titrate to a usual effective range of 900-1800 mg/day in three divided doses, with a labeled maximum of 3600 mg/day.
• Off-label anxiety or alcohol use disorder dosing typically ranges from 900-1800 mg/day divided three times daily.
• Adjust for renal function: give 400 to 1400 mg daily at a creatinine clearance of 30 to 59 mL/min and 200 to 700 mg daily at 15 to 29.
• At a creatinine clearance below 15 mL/min give 100 to 300 mg once daily, plus a supplemental dose after each hemodialysis session.
• Do not leave more than 12 hours between doses, and taper over at least 1 week when stopping to avoid withdrawal and seizure risk.

Adverse effects

• Somnolence affects roughly 20 percent and dizziness roughly 17 percent, both of which are dose-related and worst during titration.
• Ataxia, tremor, nystagmus, and blurred vision are common at higher doses and increase fall risk in older adults.
• Peripheral edema and weight gain occur in a substantial minority and are frequent reasons for discontinuation in chronic use.
• Respiratory depression can occur when gabapentin is combined with opioids or used in patients with COPD or other respiratory compromise.
• Misuse for euphoria and for potentiating opioid effects is well documented, and withdrawal resembles that of sedative-hypnotics.
• Rare serious reactions include drug reaction with eosinophilia and systemic symptoms and anaphylaxis with angioedema.

Monitoring

• Assess renal function at baseline and periodically, since dose requirements track directly with creatinine clearance.
• Screen for sedation, gait instability, and falls at each visit, especially in older adults and those on other CNS depressants.
• Ask specifically about opioid, benzodiazepine, and alcohol use, and about escalating self-directed dose increases suggesting misuse.
• Check the state prescription drug monitoring program where gabapentin is scheduled or monitored, and document the indication.
• Watch for peripheral edema and weight change, and reassess the need for continued therapy at regular intervals.

Interactions

• Concurrent opioids raise gabapentin exposure and markedly increase the risk of sedation, respiratory depression, and overdose death.
• Additive central nervous system depression with benzodiazepines, alcohol, sedating antihistamines, and muscle relaxants.
• Aluminum and magnesium antacids reduce gabapentin absorption by about 20 percent, so separate the doses by at least 2 hours.
• There are no significant cytochrome P450 interactions, which makes gabapentin useful in patients on complex regimens.
• Use particular caution in COPD, obstructive sleep apnea, heart failure, and any condition already compromising respiratory drive.

Special populations

• Pregnancy data are limited but do not show a clear malformation signal; use the lowest effective dose and document the indication.
• Gabapentin passes into breast milk with a low relative infant dose, and nursing is generally acceptable with infant monitoring.
• Pediatric use is approved for adjunctive seizure therapy from age 3, with weight-based dosing and higher clearance than adults.
• Older adults need dose reduction for declining renal function and are the group most affected by sedation, ataxia, and falls.
• Gabapentin is not federally scheduled, but several states classify it as a Schedule V drug or require prescription monitoring.

Clinical pearls

• Dose by creatinine clearance, not by weight; renal impairment is the single most common cause of toxicity.
• Absorption is saturable, so three divided doses deliver more drug than one large dose.
• Combining gabapentin with opioids meaningfully raises overdose risk; document the reason for both.