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Sunday, July 27, 2025

Gabapentin


Gabapentin is a structural analogue of gamma-aminobutyric acid (GABA), but it does not act directly on GABA receptors. It is an anticonvulsant and neuropathic pain modulator widely prescribed for epilepsy, postherpetic neuralgia, and various neuropathic pain conditions. Its off-label uses include fibromyalgia, anxiety disorders, and hot flashes, among others. It is generally well-tolerated but must be used with caution due to potential for sedation, dependence, and abuse, especially in combination with opioids.

Pharmacological Classification

  • Class: Anticonvulsant / Neuropathic pain agent

  • ATC Code: N03AX12

  • Molecular Formula: C₉H₁₇NO₂

  • Structure: Structural analogue of GABA

  • Legal Status:

    • Prescription-only in most countries

    • Controlled substance (Schedule V in the US; Class C in the UK since 2019)

Mechanism of Action

Gabapentin binds to the α2δ subunit of voltage-gated calcium channels (VGCCs) in the central nervous system (CNS). This binding:

  • Inhibits calcium influx into neurons

  • Reduces excitatory neurotransmitter release (e.g., glutamate, norepinephrine, substance P)

  • Results in reduced neuronal excitability

Though structurally similar to GABA, gabapentin does not enhance GABA activity, does not bind to GABA-A or GABA-B receptors, and does not inhibit GABA uptake or degradation.

Indications

Licensed Indications

  • Epilepsy

    • Adjunctive treatment for partial seizures with or without secondary generalization in adults and children ≥3 years

  • Neuropathic pain

    • Particularly postherpetic neuralgia

    • Also used in diabetic neuropathy

Off-Label Uses

  • Fibromyalgia

  • Generalized anxiety disorder (GAD)

  • Social anxiety

  • Bipolar disorder (as adjunctive therapy)

  • Migraine prophylaxis

  • Restless legs syndrome (RLS)

  • Alcohol withdrawal

  • Insomnia (especially secondary to neuropathic pain)

  • Hot flashes (e.g., in menopause or due to tamoxifen therapy)

  • Itch (pruritus) in end-stage renal disease or cholestasis

Formulations and Doses

Available Forms

  • Capsules: 100 mg, 300 mg, 400 mg

  • Tablets: 600 mg, 800 mg

  • Oral solution: 250 mg/5 mL

Neuropathic Pain

  • Initial dose: 300 mg once daily, increased gradually

  • Typical maintenance: 300–600 mg three times daily

  • Maximum: 3,600 mg/day (divided into three doses)

Epilepsy (Adjunctive therapy)

  • Adults: Starting at 300 mg/day, titrated over 3 days

  • Children: Dose based on weight and age

Renal Dose Adjustments

  • Necessary in patients with eGFR <60 mL/min

  • Lower starting doses and longer intervals between doses

Pharmacokinetics

  • Absorption: Via L-amino acid transport system; saturable kinetics

  • Bioavailability: Inversely related to dose

    • ~60% at 300 mg

    • ~35% at 1600 mg

  • Peak plasma levels: 2–3 hours after oral dose

  • Half-life: 5–7 hours

  • Metabolism: Not metabolized

  • Excretion: Unchanged in urine

Contraindications

  • Hypersensitivity to gabapentin or any excipient

  • Use with caution in:

    • Severe renal impairment

    • History of substance abuse

    • History of depression or suicidal ideation

Precautions and Warnings

  • Suicidal ideation and behavior: Monitor for mood changes

  • CNS depression: Risk of sedation, drowsiness, dizziness

  • Respiratory depression: Especially when combined with opioids or in those with COPD

  • Abuse potential: Emerging misuse trends, especially in opioid users

  • Withdrawal: Abrupt discontinuation may lead to anxiety, insomnia, nausea, pain, and seizures

  • Elderly: Increased sensitivity to sedative and cognitive effects

Adverse Effects

Very Common (≥10%)

  • Dizziness

  • Somnolence

  • Fatigue

  • Ataxia (loss of coordination)

  • Peripheral edema

Common (1–10%)

  • Nausea and vomiting

  • Dry mouth

  • Blurred vision

  • Weight gain

  • Tremor

  • Memory impairment

  • Emotional lability (e.g., mood swings)

Uncommon to Rare

  • Aggression or irritability (especially in children)

  • Depression or suicidal thoughts

  • Myoclonus

  • Stevens-Johnson syndrome (very rare)

  • Rhabdomyolysis (extremely rare)

Drug Interactions

Gabapentin has no significant CYP450 interactions, making it relatively safe from metabolic drug interactions.

Major Interactions

  • CNS depressants: Additive sedation (e.g., benzodiazepines, opioids, alcohol)

  • Opioids: Enhanced risk of respiratory depression (boxed warning from FDA)

  • Antacids containing magnesium/aluminum: Reduce gabapentin absorption (separate by 2 hours)

  • Morphine: May increase gabapentin concentrations

  • Drug abuse risk increases when combined with other sedatives

Use in Special Populations

Pregnancy

  • Category C (US)

  • No confirmed teratogenicity in humans but caution advised

  • Benefit-risk assessment required

Breastfeeding

  • Gabapentin is excreted into breast milk

  • No definitive adverse effects reported, but caution advised

Elderly

  • Increased risk of sedation, falls, and confusion

  • Start at lower doses and titrate slowly

Renal Impairment

  • Requires dose reduction

  • Gabapentin clearance is proportional to renal function

Withdrawal and Dependence

Withdrawal Symptoms

  • Insomnia

  • Anxiety

  • Nausea

  • Pain

  • Tremors

  • Sweating

  • Seizures (especially in epileptics)

Safe Discontinuation

  • Taper gradually over at least 1–2 weeks

  • Abrupt withdrawal discouraged

Abuse and Dependence

  • Increasing reports of misuse, especially with opioids, benzodiazepines, or alcohol

  • Effects sought by abusers: euphoria, sedation, dissociation

  • Classified as controlled in several countries due to this risk

Comparative Notes

  • Compared to pregabalin:

    • Gabapentin has slower absorption

    • More variable pharmacokinetics

    • Lower potency (higher doses required)

    • Less expensive, often first choice in public systems

  • Compared to opioids for neuropathic pain:

    • Safer for long-term use

    • Lower addiction risk (but still present)

    • Better tolerated with fewer systemic side effects

Patient Counseling Tips

  • Take consistently at the same times daily

  • Do not stop abruptly; risk of seizures or withdrawal

  • May cause drowsiness, dizziness—avoid driving or machinery until you know how it affects you

  • Avoid alcohol and sedatives unless advised by a doctor

  • Inform doctor if experiencing mood changes, depression, or suicidal thoughts

  • Separate from antacids by at least 2 hours

  • Store at room temperature, away from moisture

Available Brands

  • Neurontin® (Pfizer)

  • Gabapentin Teva

  • Gabantin, Gabatop, Gabasign

  • Generic versions widely available worldwide



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