Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
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.
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.
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.
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.
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.
- Abou-Khalil, B., McLean, M., Castro, O., Courville, K. (1990) Gabapentin in the treatment of refractory partial seizures. Abstract. Epilepsia 31: pp. 644
- Abou-Khalil, B., Shellenberger, M.K., Anhut, H. (1992) Two open-label multicenter studies of the safety and efficacy of gabapentin in patients with refractory epilepsy. Abstract. Epilepsia 33: pp. 77
- Allen, E., Jawad, S., Wrae, S., Richens, A. (1987) Does the anticonvulsant gabapentin lack enzyme inducing properties?. 17th International Epilepsy Congress, Jerusalem
- Anhut, H., Leppik, I., Schmidt, B., Thomann, P. (1988) Drug interaction study of the new anticonvulsant gabapentin with phenytoin in epileptic patients. Abstract. Naunyn-Schmiedeberg’s Archives of Pharmacology 337: pp. R127
- Anon. Gabapentin prescribing information, USA, 1993
- Bartoszyk, G.D. (1983) Gabapentin and convulsions provoked by excitatory amino acids. Naunyn-Schmiedeberg’s Archives of Pharmacology 324: pp. R24
- Bartoszyk, G.D., Meyerson, N., Reimann, W., Satzinger, G., Hodenberg, A. New anticonvulsant drugs. Gabapentin. In: Meldrum, B.S., Porter, R.J. eds. (1986) Current problems in epilepsy. John Libbey, London, pp. 147-163
- Bartoszyk, G., Hamer, M. (1987) The genetic animal model of reflex epilepsy in the Mongolian gerbil. Differential efficacy of new anticonvulsive drugs and prototype antiepileptics. Pharmacological Research Communications 19: pp. 429-440 CrossRef
- Bauer, G., Bechinger, D., Castell, M., Deisenhammer, E., Egli, M. (1989) Gabapentin in the treatment of drug-resistant epileptic patients. Advances in Epileptology 17: pp. 219-221
- Ben-Menachem, E., Persson, L.I., Hedner, T. (1992) Selected CSF biochemistry and gabapentin concentrations in the CSF and plasma in patients with partial seizures after a single oral dose of gabapentin. Epilepsy Research 11: pp. 45-49 CrossRef
- Browne, T. Efficacy and safety of gabapentin. In: Chadwick, D. eds. (1993) New trends in epilepsy management: the role of gabapentin. Royal Society of Medicine Services, London, pp. 47-58
- Boyd, R.A., Brockbrader, H.N., Türck, D., Sedman, A.J., Posvar, E.L. (1990) Effect of subject age on the single dose pharmacokinetics of orally administered gabapentin (CI-945). Abstract. Pharmaceutical Research 7: pp. S215
- Bruni, J., Saunders, M., Anhut, H., Sauermann, W. (1991) Efficacy and safety of gabapentin (Neurontin): a multicenter, placebo-controlled, double-blind study. Abstract. Neurology 41: pp. 330
- Busch, J.A., Radulovic, L.L., Bockbrader, H.N., Underwood, B.A., Sedman, A.J. (1992) Effect of Maalox TC® on single-dose pharmacokinetics of gabapentin capsules in healthy subjects. Abstract. Pharmaceutical Research 9: pp. S315
- Comstock, T.I., Sica, D.A., Bockbrader, H.N., Underwood, B.A., Sedman, A.J. (1990) Gabapentin pharmacokinetics in subjects with various degrees of renal function. Abstract. Journal of Clinical Pharmacology 30: pp. 862
- Crawford, P., Ghadiali, E., Lane, R., Blumhardt, L., Chadwick, D. (1987) Gabapentin as an antiepileptic drug in man. Journal of Neurology, Neurosurgery, and Psychiatry 50: pp. 682-686 CrossRef
- Dodrill, C.B., Wilensky, A.J., Ojemann, L.M., Temkin, N.R., Shellenberger, K. (1992) Neuropsychological, mood, and psychosocial effects of gabapentin. Abstract. Epilepsia 33: pp. 117
- Fröscher, W. (1989) Therapy of refractory epilepsy. Zeitschrift für Allgemeinmedizin 65: pp. 478-483
- Garofalo E, Koto E, Feuerstein T. Experience with gabapentin overdose: five case studies. Presented at the 20th International Epilepsy Congress, July 3-8, 1993
- Graves, N.M., Leppik, I.E., Wagner, M.L., Spencer, M.M., Erdmann, G.R. (1990) Effect of gabapentin on carbamazepine levels. Abstract. Epilepsia 31: pp. 644-645
- Graves, N.M., Holmes, G.B., Leppik, E., Rask, C., Slavin, M. (1989) Pharmacokinetics of gabapentin in patients treated with phenytoin. Abstract. Pharmacotherapy 9: pp. 196
- Graves, N.M., Leppik, I.E. (1991) Antiepileptic medications in development. DICP, The Annals of Pharmacotherapy 25: pp. 978-986
- Haas, H.L., Wieser, H.-G. (1986) Gabapentin: action on hippocampal slices of the rat and effects in human epileptics. Abstract no. 9.
- Halstenson, C.E., Keane, W.F., Türck, D., Bockbrader, H.N., Eldon, M.A. (1992) Disposition of gabapentin (GAB) in hemodialysis (HD) patients. Abstract. Journal of Clinical Pharmacology 32: pp. 751
- Hengy, H., Kölle, E.-U. (1985) Determination of gabapentin in plasma and urine by high-performance liquid chromatography and pre-column labelling for ultraviolet detection. Journal of Chromatography 341: pp. 473-478 CrossRef
- Hill, D.R., Suman-Chauhan, N., Woodruff, G.N. (1993) Localization of [3H]gabapentin to a novel site in rat brain: autoradiographic studies. European Journal of Pharmacology — Molecular Pharmacology Section 244: pp. 303-309 CrossRef
- Hooper, W.D., Kavanagh, M.C., Dickinson, R.B. (1990) Determination of gabapentin in plasma and urine by capillary column gas chromatography. Journal of Chromatography 529: pp. 167-174 CrossRef
- Hooper, W.D., Kavanagh, M.C., Herkes, G.K., Eadie, M.J. (1991) Lack of a pharmacokinetic interaction between phenobarbitone and gabapentin. British Journal of Clinical Pharmacology 31: pp. 171-174 CrossRef
- Kondo, T., Fromm, G.H., Schmidt, B. (1991) Comparison of gabapentin with other antiepileptic and GABAergic drugs. Epilepsy Research 8: pp. 226-231 CrossRef
- Leppik, I.E., Shellenberger, M.K., Anhut, H. (1992) Two open-label multi-center studies of the safety and efficacy of gabapentin as addon therapy in patients with refractory partial seizures. Abstract. Epilepsia 33: pp. 117
- Leiderman D, Anhut H, Sauermann W, Baron B. Response to gabapentin by type of partial seizure. Presented at the 20th International Epilepsy Congress, Oslo, July 3-8, 1993
- Löscher, W., Hönack, D., Taylor, C.P. (1991) Gabapentin increases aminooxyacetic acid-induced GABA accumulation in several regions of rat brain. Neuroscience Letters 128: pp. 150-154 CrossRef
- Meijer, J.W.A. (1991) Drug monitoring in clinical trials of new antiepileptic drugs. Acta Neurologica Scandinavica 83: pp. 55-68 CrossRef
- Ojemann, L.M., Wilensky, A.J., Temkin, N.R., Chmelir, T., Ricker, B. (1992) Long-term treatment with gabapentin for partial epilepsy. Epilepsy Research 13: pp. 159-165 CrossRef
- Ojemann, L.M., Friel, P.N., Ojemann, G.A. (1988) Gabapentin concentrations in human brain. Abstract. Epilepsia 29: pp. 694
- Pedley, T.A. The challenge of intractable epilepsy. In: Chadwick, D. eds. (1993) New trends in epilepsy management: the role of gabapentin. Royal Society of Medicine Services, London, pp. 59-66
- Pierce MW, Anhut H, Sauermann W. Gabapentin as an effective treatment for patients with refractory partial seizures. Presented at the 20th International Epilepsy Congress, Oslo, July 3-8, 1993
- Prevo, A.J., Slootman, H.J., Harlaar, J., Vogelaar, T.W. (1985) A new antispastic agent: gabapentin: its effect on EMG analysis during voluntary movement in hemiplegia. Electroencephalography and Clinical Neurophysiology 61: pp. S221 CrossRef
- Pugh, C.B., Garnett, W.R. (1991) Current issues in the treatment of epilepsy. Clinical Pharmacy 10: pp. 335-358
- Reimann, W. (1983) Inhibition by GABA, baclofen and gabapentin of dopamine release from rabbit caudate nucleus: are there common or different sites of action?. European Journal of Pharmacology 94: pp. 341-344 CrossRef
- Richens, A. Clinical pharmacokinetics of gabapentin. In: Chadwick, D. eds. (1993) New trends in epilepsy management: the role of gabapentin. Royal Society of Medicine Services, London, pp. 41-46
- Saletu, B., Grünberger, J., Linzmayer, L. (1986) Evaluation of encephalotropic and psychotropic properties of gabapentin in man by pharmaco-EEG and psychometry. International Journal of Clinical Pharmacology, Therapy and Toxicology 24: pp. 362-373
- Schear, M.J., Wiener, J.A., Rowan, A.J. (1991) Long-term efficacy of gabapentin in the treatment of partial seizures. Abstract. Epilepsia 32: pp. 6
- Schlicker, E., Reimann, W., Göthert, M. (1985) Gabapentin decreases monoamine release without affecting acetylcholine release in the brain. Arzneimittel-Forschung 35: pp. 1347-1349
- Sivenius, J., Kälviäinen, R., Ylinen, A., Riekkinen, P. (1991) Double-blind study of gabapentin in the treatment of partial seizures. Epilepsia 32: pp. 539-542 CrossRef
- Stewart BH, Kugler AR, Thompson PR, Bockbrader HN. A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma. Pharmaceutical Research, in press, 1993
- Suman-Chauhan, N., Webdale, L., Hill, D.R., Woodruff, G.N. (1993) Characterisation of [3H]gabapentin binding to a novel site in rat brain: homogenate binding studies. European Journal of Phamacology — Molecular Pharmacology Section 244: pp. 293-301 CrossRef
- Taylor, C.P. Mechanism of action of new antiepileptic drugs. In: Chadwick, D. eds. (1993) New trends in epilepsy management: the role of gabapentin. Royal Society of Medicine Services, London, pp. 13-40
- Taylor, C.P., Vartanian, M.G., Yuen, P.-W., Bigge, C., Suman-Chauhan, N. (1993) Potent and stereospecific anticonvulsant activity of 3-isobutyl GABA relates to in vitro binding at a novel site labeled by tritiated gabapentin. Epilepsy Research 14: pp. 11-15 CrossRef
- Gabapentin in partial epilepsy. Lancet 335: pp. 1114-1117 CrossRef
- US Gabapentin Study Group. Gabapentin as add-on therapy in refractory partial epilepsy: a double-blind, placebo-controlled, parallel-group study. Neurology, in press, 1993
- Uthman, B.M., Hammond, E.J., Wilder, B.J. (1990) Absence of gabapentin and valproate interaction: an evoked potential and pharmacokinetic study. Abstract. Epilepsia 31: pp. 645 CrossRef
- Vollmer, K.-O., Anhut, H., Thomann, P., Wagner, F., Jähnchen, D. (1989) Pharmacokinetic model and absolute bioavailability of the new anticonvulsant gabapentin. Advances in Epileptology 17: pp. 209-211
- Vollmer, K.-O., Hodenberg, A.V., Kölle, E.U. (1986) Pharmacokinetics and metabolism of gabapentin in rat, dog and man. Arzneimittel-Forschung/Drug Research 36: pp. 830-839
- Vollmer, K.-O., Türck, D., Bockbrader, H.N., Busch, J.A., Chang, T. (1992) Summary of Neurotin (gabapentin) clincial pharmacokinetics. Abstract. Epilepsia 33: pp. 77
- Wilensky, A.J., Temkin, N.R., Ojemann, L.M., Ricker, B., Holubkov, A. (1992) Gabapentin and carbamazepine as monotherapy and combined: a pilot study. Abstract. Epilepsia 33: pp. 77
Volume 46, Issue 3 , pp 409-427
- Cover Date
- Print ISSN
- Online ISSN
- Springer International Publishing
- Additional Links
- Industry Sectors