, Volume 46, Issue 3, pp 409-427
Date: 18 Oct 2012

Gabapentin

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Abstract

Synopsis

Gabapentin is an antiepileptic drug with an unknown mechanism of action apparently dissimilar to that of other antiepileptic agents, and possessing some desirable pharmacokinetic traits. The drug is not protein bound, is not metabolised and does not induce liver enzymes, diminishing the likelihood of drug interactions with other antiepileptic agents and drugs such as oral contraceptives. Although gabapentin is a structural analogue of the neurotransmitter γ-aminobutyric acid (GABA), which does not cross the blood-brain barrier, gabapentin penetrates into the CNS and its activity is seemingly distinct from GABA-related effects.

Present clinical evaluation is largely restricted to proof of efficacy trials of gabapentin as addon therapy in patients with partial epilepsy resistant to conventional treatment. Gabapentin (usually 600 to 1800 mg/day) provides notable benefit, reducing seizure frequency by ⩾ 50% in 18 to 28% of patients with refractory partial seizures, as shown in 3 double-blind, placebo-controlled trials. Overall, seizure frequency decreased by 18 to 32% during 3-month treatment periods. Patients with complex partial seizures, and partial seizures secondarily generalised, are particularly likely to respond to gabapentin. Current experience with the drug in other seizure types, and as monotherapy, is limited.

Mild adverse events, commonly somnolence, fatigue, ataxia and dizziness, have been reported in about 75% of gabapentin recipients. While the drug has been well tolerated when administered to a few patients for periods of up to 5 years, its long term tolerability profile has yet to be fully expounded.

Thus, with its favourable pharmacokinetic profile, and efficacy in some refractory patients, gabapentin is poised to fill a niche as an adjunct to the treatment of partial epilepsy. Promising results obtained thus far warrant further work to clarify its long term tolerability, its possible efficacy in other seizure types, its position relative to other agents and its use as monotherapy. In the meantime, gabapentin is likely to provide a much-needed option in a therapeutic area requiring complex management.

Pharmacodynamic Properties

Gabapentin is active in many standard animal seizure models, protecting against convulsions induced by chemicals (e.g. picrotoxin, bicuculline, strychnine), and some non-chemical stimuli (e.g. audiogenic, maximal electroshock). The profile of its anticonvulsant activity in animal studies thus predicts its clinical efficacy in patients with partial seizures and secondarily generalised tonic-clonic seizures.

Despite its structural similarity to γ-aminobutyric acid (GABA), gabapentin apparently does not act via mechanisms related to this neurotransmitter, but most probably by events modulated through its interaction with a receptor thought to be associated with the L-system amino acid carrier protein.

Sedative effects have occurred in rodents given gabapentin ⩾400 mg/kg (orally or intragastrically). There is some evidence of slight improvement in psychomotor function in healthy volunteers who received one dose of gabapentin 200mg, and there have been spontaneous reports of improved memory and perception in a few patients.

Pharmacokinetic Properties

Mean maximum plasma gabapentin concentrations are attained 2 to 3 hours after a single oral 300mg dose, and measured 2.7 to 2.99 mg/L in healthy volunteers. Absorption kinetics of gabapentin are dose-dependent, rather than dose-proportional, possibly due to a saturable transport system. Thus, bioavailability of a single 300mg oral dose of gabapentin is 60%, but decreases with increasing dose.

As demonstrated in rats, gabapentin is extensively distributed in body tissues, concentrating particularly in pancreas and kidney. Unlike GABA, gabapentin has some lipophilicity and readily crosses the blood-brain barrier, producing a CSF: plasma concentration ratio of 0.09 to 0.14 as measured in 5 patients. Its volume of distribution is large, estimated as 50 to 60L in healthy volunteers. The drug is not bound to human plasma proteins.

Elimination of gabapentin is wholly accountable by renal clearance, in contrast to many antiepileptic drugs which are metabolised. The elimination half-life of gabapentin is about 5 to 7 hours after a single oral dose of 200 to 400mg. As expected, renal impairment reduces drug clearance and augments plasma gabapentin concentrations in a linear fashion.

A dose-response pattern is apparent for plasma gabapentin concentrations and for clinical effect within the dosage range 600 to 1800 mg/day. However, monitoring of plasma gabapentin concentrations is unnecessary, and dosage of gabapentin should be adjusted according to clinical response.

Concomitant administration of gabapentin does not influence the pharmacokinetics of conventional antiepileptic drugs [valproic acid, phenobarbital (phenobarbitone), carbamazepine or phenytoin] and oral contraceptives, nor are the pharmacokinetics of gabapentin modified by antiepileptic drugs. This potentially advantageous property of gabapentin is attributable to its lack of protein binding, absence of metabolic clearance, and inability to induce liver enzyme activity.

Clinical Efficacy

Several placebo-controlled proof of efficacy trials have confirmed the benefit of gabapentin as add-on therapy in some patients with partial seizures resistant to conventional treatment. Approximately 18 to 28% of patients with refractory seizures in these trials experienced reductions in seizure frequency of at least 50% during 3 months’ treatment with gabapentin 600 to 1800mg daily, versus 8.4 to 10% in placebo groups. Overall seizure frequency decreased by approximately 18 to 32% with gabapentin, and increases in seizure frequency occurred in almost twice as many placebo recipients (38 to 49%) as gabapentin recipients (19 to 33%). Response ratio values and global evaluations by patient and physician strengthen the evidence for a beneficial effect of gabapentin. Complex partial seizures and partial seizures with secondary generalisation seem particularly amenable to gabapentin therapy.

Over longer term gabapentin administration (⩽2400 mg/day usually for up to 2 years but as long as 5 years in a few patients) in noncomparative trials, approximately 70% of patients showed some improvement in seizure control, 25 to 50% exhibited decreases in seizure frequency of ⩾50%, and 20 to 30% remained unchanged or experienced more frequent seizures. An overall responder rate of 36% at 84 days was recorded among 400 patients treated with gabapentin for ⩽5 years. Early indications of benefit with gabapentin as monotherapy await confirmation, as does its efficacy relative to other antiepileptic drugs.

Tolerability

Somnolence (20%), dizziness (18%) ataxia (13%) and fatigue (11%) are the most common adverse events observed during gabapentin therapy, as reported in 1748 patients, whereas in placebo groups somnolence (9.8%), headache (9%), dizziness (7.8%) and nausea/vomiting (7.5%) were most frequent. These and other symptoms have usually been mild, abating with continued gabapentin therapy, but have led to treatment withdrawal in 7% of patients in premarketing trials. The overall proportion of patients reporting adverse events during gabapentin administration has been calculated to be about 75%, versus 55% for placebo.

No changes in haematological or other laboratory test results have been observed with gabapentin therapy, other than isolated cases of reduced white blood cell count possibly also related to concomitant carbamazepine therapy. The clinical significance, if any, of the development of pancreatic carcinoma in male rats administered very high doses of gabapentin for 2 years remains unclear.

The long term tolerability of gabapentin has not been described in detail as yet. Confirmation is required of current data suggesting that gabapentin is well tolerated during extended treatment periods.

Dosage and Administration

A dosage range of gabapentin 600 to 1800mg daily, divided into 3 doses given every 8 hours, has been used most often as add-on therapy in patients with refractory partial seizures in clinical trials. Dosage should be titrated to response. Dosage reduction is necessary in patients with impaired renal function. Gabapentin withdrawal, or addition of other antiepileptic drugs, should be performed slowly to avoid rebound seizures.

Various sections of the manuscript reviewed by: B.F.D. Bourgeois, Department of Neurology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA; M.J. Brodie, Epilepsy Research Unit, Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, Scotland; D. Chadwick, University Department of Neurology, Walton Hospital, Liverpool, England; P.M. Crawford, Department of Neurology, Special Centre for Epilepsy, Bootham Park Hospital, Bootham, York, England; W.D. Hooper, Department of Medicine, Royal Brisbane Hospital, Herston, Queensland, Australia; H. Meinardi, Instituut voor epilepsiebestrijding, Heemstede, The Netherlands; L.M. Ojemann, Epilepsy Center, Department of Neurological Surgery, University of Washington School of Medicine, Harborview Medical Center, Seattle, Washington, USA; R.E. Ramsay, Veterans Administration Medical Center, Neurology Service, Miami, Florida, USA; D. Schmidt, Epilepsy Research Group UKRV, Free University of Berlin, Berlin, Federal Republic of Germany; J. Sivenius, Department of Neurology, Kuopio University Central Hospital, Kuopio, Finland; B.M. Uthman, Veterans Administration Medical Center, Miami, Florida, USA; C.H. van der Meyden, Department of Neurology, University of Pretoria, Pretoria, South Africa; H.G. Wieser, Neurology Department, University Hospital Zurich, Zurich, Switzerland; T. Yanagita, First Department of Pharmacology, The Jikel University School of Medicine, Kawasaki, Japan.