Gabapentin (Neurontin)

Overview

Brand name: Neurontin

Structure and Mechanism

• 1-(aminomethyl)cyclohexaneacetic acid (C9H17NO2)
• It is structurally related to gamma-aminobutyric acid (GABA).
• However, does not modify GABA binding, is not converted into a GABA agonist, and does not inhibit GABA uptake/degradation
• Instead, a binding site on a voltage-activated calcium channel subunit has been identified

Pharmacokinetics

• Not appreciably metabolized in humans
• Eliminated from the systemic circulation by renal excretion
• Elimination half-life ≅ 5 to 7 hours
• In elderly patients and those with impaired renal function, plasma clearance is reduced
• Mean half-life increased from 6.5 h (CrCl >60 mL/min) to 52 h (CrCL <30 mL/min)
• Gabapentin can be removed from plasma by hemodialysis
• Bioavailability is not proportional to dose (i.e. bioavailability of gabapentin ≅ 60% (900mg), 47% (1200mg), 34% (2400mg), 33% (3600mg), and 27% (4800mg) per day, given in 3 divided doses. 

Medical Indications

• In animal models of analgesia, gabapentin prevents allodynia and hyperalgesia.
• Gabapentin is indicated for:
  • Neuropathic pain caused by postherpetic neuralgia 
  • Adjunctive therapy in the treatment of partial seizures with or without secondary generalization
  • Neuropathic pain caused by diabetic peripheral neuropathy and spinal cord injury 
  • Restless leg syndrome (gabapentin enacarbil)
• Gabapentin is frequently used off-label for:
  • Neuropathy caused by other etiologies such as chronic regional pain syndrome (CRPS), cancer, multiple sclerosis, phantom limb pain, HIV
  • Vasomotor symptoms (i.e. hot flashes)
  • Acute pain
  • Mood disorder (e.g. anxiety, bipolar)

Dosing

• Dosing for chronic pain management ≅ 10-15 mg/kg/day in 3 divided doses
• Typically, started with 300mg daily and then uptitrated
• Up to 3600mg daily: however, additional benefit for doses >1800 mg/day has not been demonstrated
• Often dosed at bedtime or three times daily
• Reduction needed with decreased CrCl (e.g. in chronic kidney disease, older adults)

“Dosing Guidelines for Gabapentin Administration Based on Renal Function in Adults and Children 12 Years or Older 7”

Table Source:    https://cdn.sanity.io/files/0vv8moc6/ajmc/e42673bf4fc237ede07e02d31eefadc1d2586f36.pdf/AJMC2003marTidwell253-279.pdf

UCSF Protocols for Enhanced Recovery after Surgery (ERAS)

Scheduled doses of gabapentin have been added to the ERAS pathways of multiple services (e.g. breast and colorectal surgery) to reduce pain and opioid requirements after surgery.

Most commonly gabapentin has been prescribed as 600mg PO at bedtime or 300mg PO tid in these protocols.

Special Considerations

Risks and Side Effects

• Dizziness, somnolence, and peripheral edema
• Suicidal ideation
• Respiratory depression concomitant with other depressants (e.g. opioids, sedatives) 
• Pregnancy Category C (fetotoxic in animal studies, limited human data)
• Excreted into breast milk
• Beers Criteria (2019)
• Potential for withdrawal