Gabapentin

Gabapentin (1-[aminomethyl]-cyclohexaneacetic acid) first received marketing approval as an adjunctive AED for the treatment of focal epilepsies in 1993.^1,2

Authorised indications

UK-SmPC: (1) monotherapy in the treatment of focal seizures with and without secondary generalization in adults and adolescents aged 12 years and above and (2) adjunctive therapy of focal seizures with and without secondary generalisation in patients ≥6 years of age.

FDA-PI: (1) adjunctive therapy of focal seizures with and without secondary generalisation in patients over 12 years of age; (2) adjunctive therapy of focal seizures in children aged 3–12 years.

Clinical applications

Recommendations for gabapentin as an AED are limited to focal seizures. It is the least effective of all the other newer AEDs, even at higher doses of around 3000 mg/day.³ However, it is considered relatively safe with few ADRs. It is mainly used for non-epileptic disorders such as neuropathic pain.

It is contraindicated for generalised-onset seizures of any type (absences, myoclonic jerks, GTCSs) because it is either ineffective or may exaggerate them.^4,5,6

Dosage and titration

Adults: start with 300 mg/day and increase rapidly in increments of 300 mg/day up to a typical adult maintenance dose of 900–1800 mg/day given in three divided doses. Doses of up to 3600 mg/day have been used.

Children: start treatment with 15 mg/kg/day and increase to 30 mg/kg/day within a few days. The recommended maintenance dose is 50–100 mg/day. Children require relatively higher doses than adults, because clearance of gabapentin is greater in children than in adults. Dosing: three times daily.

TDM: usually not needed; its dose-dependent absorption increases its pharmacokinetic variability.^7,8

Reference range: 2–20 mg/l (12–120 μmol/l).

Main ADRs

Gabapentin has a relatively good adverse reaction profile.

Frequent and/or important: increased appetite and weight gain is a problem. Other reactions include dizziness, ataxia, nystagmus, headache, tremor, fatigue, diplopia, rhinitis and nausea. Significant behavioural disturbances, such as aggression, hyperexcitability and tantrums, have been reported, mainly in children.⁹ Caution is recommended in patients with a history of psychotic illness.

Serious: rarely, rash (0.5%), leucopenia (0.2%) and ECG changes and angina (0.05%).

Gabapentin may unmask myasthenia gravis.¹⁰

FDA warning: All patients who are currently taking or starting on gabapentin for any indication should be monitored for notable changes in behaviour that could indicate the emergence or worsening of suicidal thoughts or behaviour or depression (see page xxx).

Considerations in women

Pregnancy: category C but with teratogenic effects in animal exposure.¹¹

Breastfeeding: it is excreted in breast milk, but the effect on the nursing infant is unknown.

Interaction with hormonal contraception: none.

Others: weight gain may be of particular importance to women because of the associated risk for polycystic ovary syndrome.

Main mechanisms of action

The mechanism of action is uncertain. Gabapentin was developed because of its structural similarity to GABA and its ability to cross the blood–brain barrier. However, it does not appear to be a GABA agonist.

The mechanism responsible for its anti-epileptic activity and the relief of neuropathic pain is probably due to a modulating action of gabapentin on voltagegated calcium channels and neurotransmitter release.

Pharmacokinetics

Oral bioavailability: low <60%. Gabapentin is rapidly absorbed and reaches peak plasma levels within 2–4 hours after oral ingestion. Bioavailability is less than 60%, but is dose-dependent; absorption is progressively reduced with an increasing dosage. Food intake does not influence absorption.

Protein binding: none.

Metabolism: gabapentin is not metabolised and is excreted by the kidneys in unchanged form. Renal impairment reduces drug clearance and raises plasma gabapentin concentrations.

Elimination half-life: 5–9 hours.

Drug interactions

There are no significant interactions with other AEDs. However, see the note on renally eliminated drugs below.

Cimetidine reduces the renal clearance of gabapentin and antacids reduce the absorption of gabapentin by 20%.

Main disadvantages

A narrow-spectrum and low-efficiency AED that is limited to the treatment of focal seizures.

Therapeutic efficacy is weak in relation to other AEDs, the number of responders is disappointingly low even when higher doses are used and it is unusual for patients with severe focal epilepsies to derive much benefit.

References

1. Morris GL. Gabapentin. Epilepsia 1999;40 Suppl 5:S63–70.
2. McLean MJ, Gidal BE. Gabapentin dosing in the treatment of epilepsy. Clin Ther 2003;25:1382–406.
3. Shorvon SD. The choice of drugs and approach to drug treatments in partial epilepsy. In: Shorvon S, Perucca E, Fish D, Dodson E, eds. The treatment of epilepsy. Second edition, pp 317–33. Oxford: Blackwell Publishing, 2004.
4. Chadwick D, Leiderman DB, Sauermann W, Alexander J, Garofalo E. Gabapentin in generalized seizures. Epilepsy Res 1996;25:191–7.
5. Thomas P, Valton L, Genton P. Absence and myoclonic status epilepticus precipitated by antiepileptic drugs in idiopathic generalized epilepsy. Brain 2006;129 Pt 5:1281–92.
6. Striano P, Coppola A, Madia F et al. Life-threatening status epilepticus following gabapentin administration in a patient with benign adult familial myoclonic epilepsy. Epilepsia 2007;48:1995-8.
7. Tomson T, Dahl M, Kimland E. Therapeutic monitoring of antiepileptic drugs for epilepsy. Cochrane Database Syst Rev 2007;(1):CD002216.
8. Johannessen SI, Tomson T. Pharmacokinetic variability of newer antiepileptic drugs: when is monitoring needed? Clin Pharmacokinet 2006;45:1061–75.
9. Wolf SM, Shinnar S, Kang H, Gil KB, Moshe SL. Gabapentin toxicity in children manifesting as behavioral changes. Epilepsia 1995;36:1203–5.
10. Boneva N, Brenner T, Argov Z. Gabapentin may be hazardous in myasthenia gravis. Muscle Nerve 2000;23:1204–8.
11. Prakash, Prabhu LV, Rai R et al. Teratogenic effects of the anticonvulsant gabapentin in mice. Singapore Med J 2008;49:47-53.