What is the role of gabapentin (GBP) in the treatment of epilepsy?

Updated: Jan 28, 2020
  • Author: Juan G Ochoa, MD; Chief Editor: Selim R Benbadis, MD  more...
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Gabapentin (GBP) was developed to have a structure similar to that of GABA; however, experimental evidence showed that GBP has, in fact, little or no action on the GABA receptor. It is highly soluble in water. It enhances GAD but does so weakly. It binds with the alpha2 delta subunit of calcium channels in the cerebral neocortex, hippocampus, and spinal cord; this mechanism of action may be important for its efficacy in pain.

At this time, the exact mechanism by which GBP increases the intracellular concentration of GABA is unknown. In vivo magnetic resonance spectroscopy studies have shown that GBP increases brain levels of GABA and its metabolites homocarnosine and pyrrolidinone. It also may reduce monoamines and affect serotonin release.

GBP is a competitive inhibitor of the enzyme branched chain amino acid transferase, which metabolizes the branched-chain amino acids (leucine, isoleucine, and valine) to glutamate. Through this mechanism, GBP may reduce brain glutamate levels. [47, 48, 49]

GBP has a bioavailability of less than 60%; bioavailability is affected mainly by variable absorption, which depends on an L-amino acid transporter. Absorption may be impaired in some clinical situations in which active transport usually is compromised. In addition, single doses of GBP greater than 1200 mg decrease the bioavailability to 35%.

Once absorbed, the drug readily crosses the blood-brain barrier and achieves a plasma-to-CSF ratio of approximately 1:10. Peak serum levels are achieved within 2-4 hours of oral administration. The volume of distribution in adults is about 0.64-1.04 L/kg at steady state.

GBP is not bound to plasma proteins and is not metabolized. It does not induce hepatic enzymes. It is excreted entirely in an unchanged form. The renal clearance of 120-130 mL/min is correlated linearly with creatinine clearance. The elimination half-life of the drug is 5-9 hours.

Steady-state levels are achieved within a few days, and the half-life does not change with chronic administration, nor is it influenced by concomitant medications. Few data on the correlation between serum level and effectiveness are reported. In patients with renal disorders, the dose should be adjusted according to creatinine clearance; it is removed during hemodialysis.

GBP has no pharmacokinetic drug interactions. However, antacids can reduce the bioavailability of GBP.

Several open and double-blind trials have been conducted with GBP. In the United States, patients were randomized to receive 600 mg, 1200 mg, or 1800 mg of GBP or placebo; the percentage of patients who had a reduction of seizures of 50% or more was 18-26% with GBP and 8% with placebo. A large multicenter study carried out in the United Kingdom randomized patients to receive add-on therapy with either GBP 1200 mg or placebo and showed a reduction in partial seizures of 50% or more in 28% of patients taking GBP and 9.8% of patients taking placebo.

A double-blind study in children with partial epilepsy showed response rates of 17% on GBP and 7% on placebo, whereas in other double-blind, placebo-controlled studies, GBP had no effect in childhood absence seizures. These trials were performed at a relatively low dose, and a better response was obtained in trials using a higher dose; however, the latest trials were not double blind.

In clinical practice, higher doses often are used. GBP is useful in the treatment of partial and secondarily generalized tonic-clonic seizures but is ineffective in myoclonus and in most generalized seizure disorders. The drug appears to have only a modest efficacy, particularly at lower doses.

GBP is available as capsules of 100 mg, 300 mg, 400 mg, and 600 mg and tablets of 800 mg. Rapid titration is well tolerated in some patients, but usually the drug is titrated at weekly intervals to a maximum of 3600-4800 mg/d.

Its lack of drug interactions, lack of plasma protein binding, and renal excretion make GBP particularly useful in patients with renal or hepatic disease and in patients on complex drug regimens. Patients with coexistent migraine headache or neuropathic pain may benefit from this drug.

GBP is relatively well tolerated; it does have some adverse effects, particularly in high doses, but these usually are relatively minor. No significant serious idiosyncratic or systemic adverse effects have been reported. The incidence of rash is 0.5% and of neutropenia, 0.2%. Electroencephalographic (EEG) changes and/or angina were found in 0.05%. No cases of hepatotoxicity have been recorded.

In the early double-blind studies, 44% of patients reported adverse effects with 900 mg of GBP. Similar adverse effects were recorded in later studies with 1200 mg. In a US study of patients taking 1800 mg/d, somnolence was recorded in 36% of patients, dizziness in 24%, ataxia in 26%, nystagmus in 17%, headache in 9%, tremor in 15%, fatigue in 11%, diplopia in 11%, rhinitis in 11%, and nausea or vomiting in 6%. Most of these effects were mild.

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