Gabapentin
Gabapentin
Generic Name
Gabapentin
Mechanism
Gabapentin is a structural analogue of γ‑aminobutyric acid (GABA) but does not bind GABA receptors. Its main pharmacologic effect is:
• Binding to the α2δ subunit of voltage‑gated calcium channels in the central nervous system, reducing calcium influx at nerve terminals.
• This activity decreases the release of excitatory neurotransmitters (glutamate, substance P) and dampens neuronal hyperexcitability.
• The downstream consequence is reduced seizure activity, neuropathic pain transmission, and decreased spinal cord hyperalgesia.
*Key highlights:* antiepileptic and analgesic activity, no opioid or benzodiazepine receptor engagement.
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Pharmacokinetics
| Parameter | Detail |
| Absorption | Oral bioavailability ~60‑70 % at low doses (<300 mg), decreasing with higher doses (dose‑dependent linearity → non‑linear kinetics). Rapid, peak plasma 1–2 h after ingestion. |
| Distribution | Protein binding ~6 %; unbound plasma concentration is physiologically relevant. Limited CNS penetration at therapeutic levels. |
| Metabolism | No hepatic metabolism; excreted unchanged. |
| Elimination | Renally cleared (≈80 % unchanged). Half‑life 5–7 h in healthy adults (shorter in renal impairment, longer in hepatic dysfunction is negligible). |
| Special considerations | Accumulates in chronic kidney disease (CKD); dosing adjustment required (see dosing section). No cyclic dependence on hepatic enzymes → minimal drug interactions via CYP system. |
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Indications
- Partial‑onset seizures (monotherapy or adjunctive therapy).
- Post‑herpetic neuralgia and other chronic neuropathic pain conditions.
- Neuropathic pain secondary to spinal cord injury, diabetic neuropathy, trigeminal neuralgia (off‑label but widely practiced).
- Anxiety disorders & alcohol withdrawal (off‑label, adjunct).
- Sleep‑disordered breathing in obstructive sleep apnea (limited evidence).
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Contraindications
| Category | Precautions |
| Contraindicated in | Allergy to gabapentin or any excipient. |
| Caution | Renal dysfunction; risk of accumulation → neurotoxicity. |
| Warnings | CNS depression (somnolence, dizziness), especially when combined with alcohol or sedatives. Brain‑stem depression in very high doses. |
| Drug Interactions | Renally cleared—additive neuro‑cognitive effects with other GABAergic drugs (benzodiazepines, opioids) and with carbamazepine (increases clearance). |
| Pregnancy | Category C – data limited; use only if benefit outweighs risk. |
| Breastfeeding | Low transfer; risk to infant unclear. |
| Special Groups | Elderly: increased sensitivity; monitor for falls, delirium. |
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Dosing
| Condition | Loading / Starting Regimen | Titration | Maintenance | Max Dose |
| Partial seizures | 300 mg BID for 2 wk → 900 mg TID for next 2 wk | Up 300 mg once/month (if tolerated) | 900–2700 mg / day in divided doses | 3600 mg/day (rare; u/s surveillance) |
| Neuropathic pain (PHN, diabetic) | 300 mg daily → 600 mg 8‑h PO; then 900 mg TID | Same titration schedule | 1200–2400 mg/day | 3600 mg/day |
| Renal impairment | CKD CrCl > 30 mL/min: same as above. | CKD CrCl ≤ 30 mL/min: start 200 mg BID → titrate to 400 mg BID | 400–800 mg BID | 800 mg BID in severe CKD |
| Drug‑free “on‑set” | 400 mg daily | Increase 200 mg less frequently, up to 800 mg | 800 mg BID | 1600 mg BID (if needed) |
*Tip:* Use the immediate‑release formulation; delayed/extended release (Gabapentin ER) is mainly for seizure control (higher dosing).
Administration: Oral capsules/tablets; crush and dissolve in water if swallowing difficulties.
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Adverse Effects
| Class | Examples |
| Central nervous system | Dizziness, somnolence, ataxia, memory impairment, depression. |
| Peripheral | Peripheral edema (hands/feet), hypersensitivity/skin rash. |
| Metabolic | Nausea, anorexia, weight changes, SIADH (rare). |
| Respiratory | Severe RR depression only when combined with CNS depressants. |
| Allergic | Anaphylaxis, angioedema in rare cases. |
*Serious but uncommon:* Stevens‑Johnson syndrome, toxic epidermal necrolysis, severe systemic hypersensitivity.
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Monitoring
- Renal function (CrCl/eGFR) at baseline and every 4–6 wk during titration or change.
- Weight and edema — monitor for fluid accumulation.
- Neurologic assessment — observe for worsening somnolence, confusion, or ataxia.
- Pregnancy/breastfeeding — screen for fetal exposure.
- Laboratory — CBC, liver panel typically unnecessary but warranted if concomitant hepatotoxic drugs.
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Clinical Pearls
1. Dose‑dependent bioavailability means small increments at low doses yield proportionate increases in plasma levels, but at high doses absorption saturates → steeper rises in errors.
2. Titration schedule: increment by 300 mg every 1–2 weeks; avoid large jumps to reduce neuro‑cognitive fallout.
3. Renal adjustment is critical. Use creatinine clearance to compute adjusted maintenance dose (CrCl ≤30 mL/min → max 800 mg BID).
4. Return-to-work patients: due to ataxia risk, advise non‑hazardous jobs for the first 2–4 weeks of titration.
5. Corticosteroid interaction: chronic steroids may enhance gabapentin clearance, consider dose escalation.
6. Off‑label anxiety: small doses (100–300 mg/day) can reduce maladaptive arousal, but monitor for sedation.
7. Initiation cautions: instruct patients to avoid alcohol; combination therapy may precipitate severe CNS depression.
8. Safety in the elderly: start at 150 mg/day, titrate slowly; assess fall risk.
9. Abrupt discontinuation may precipitate withdrawal syndrome in long‑term use. Plan gradual taper.
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