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. 1996 Nov 9;313(7066):1169–1174. doi: 10.1136/bmj.313.7066.1169

New antiepileptic drugs: a systematic review of their efficacy and tolerability.

A G Marson 1, Z A Kadir 1, D W Chadwick 1
PMCID: PMC2352473  PMID: 8916746

Abstract

OBJECTIVES: To evaluate the efficacy and tolerability of the newly developed antiepileptic drugs gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin, and zonisamide in patients with refractory partial epilepsy. DESIGN: Systematic review of published and unpublished randomised controlled trials of add-on treatment with new antiepileptic drugs. SUBJECTS: 20 published and eight unpublished trials representing 3883 patients with refractory partial epilepsy. MAIN OUTCOME MEASURES: Proportion of patients who (a) showed 50% or greater reduction in frequency of seizures (50% responders) and (b) withdrew from each study for any reason. RESULTS: Odds ratios (95% confidence intervals) relative to placebo for 50% responders were 2.29 (1.53 to 3.43) for gabapentin, 2.32 (1.47 to 3.68) for lamotrigine, 3.03 (2.01 to 4.58) for tiagabine, 4.22 (2.80 to 6.35) for topiramate, 3.68 (2.45 to 5.51) for vigabatrin, and 2.47 (1.36 to 4.47) for zonisamide. Odds ratios for withdrawal were 1.36 (0.75 to 2.49) for gabapentin, 1.19 (0.79 to 1.79) for lamotrigine, 1.81 (1.21 to 2.70) for tiagabine, 2.42 (1.43 to 4.11) for topiramate, 2.58 (1.26 to 5.27) for vigabatrin, and 5.70 (1.76 to 18.49) for zonisamide. Comparing results for each drug showed that all of the 95% confidence intervals overlapped, indicating that they were not significantly different in terms of efficacy and tolerability. CONCLUSIONS: All six drugs were significantly better than placebo at reducing frequency of seizures. These results do not allow an evidence based choice between these drugs as we have no conclusive indication of differences in efficacy or tolerability.

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Selected References

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  1. Anhut H., Ashman P., Feuerstein T. J., Sauermann W., Saunders M., Schmidt B. Gabapentin (Neurontin) as add-on therapy in patients with partial seizures: a double-blind, placebo-controlled study. The International Gabapentin Study Group. Epilepsia. 1994 Jul-Aug;35(4):795–801. doi: 10.1111/j.1528-1157.1994.tb02513.x. [DOI] [PubMed] [Google Scholar]
  2. Ben-Menachem E., Henriksen O., Dam M., Mikkelsen M., Schmidt D., Reid S., Reife R., Kramer L., Pledger G., Karim R. Double-blind, placebo-controlled trial of topiramate as add-on therapy in patients with refractory partial seizures. Epilepsia. 1996 Jun;37(6):539–543. doi: 10.1111/j.1528-1157.1996.tb00606.x. [DOI] [PubMed] [Google Scholar]
  3. Binnie C. D., Debets R. M., Engelsman M., Meijer J. W., Meinardi H., Overweg J., Peck A. W., Van Wieringen A., Yuen W. C. Double-blind crossover trial of lamotrigine (Lamictal) as add-on therapy in intractable epilepsy. Epilepsy Res. 1989 Nov-Dec;4(3):222–229. doi: 10.1016/0920-1211(89)90007-7. [DOI] [PubMed] [Google Scholar]
  4. Brodie M. J., Richens A., Yuen A. W. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. UK Lamotrigine/Carbamazepine Monotherapy Trial Group. Lancet. 1995 Feb 25;345(8948):476–479. doi: 10.1016/s0140-6736(95)90581-2. [DOI] [PubMed] [Google Scholar]
  5. Cockerell O. C., Johnson A. L., Sander J. W., Hart Y. M., Shorvon S. D. Remission of epilepsy: results from the National General Practice Study of Epilepsy. Lancet. 1995 Jul 15;346(8968):140–144. doi: 10.1016/s0140-6736(95)91208-8. [DOI] [PubMed] [Google Scholar]
  6. Faught E., Wilder B. J., Ramsay R. E., Reife R. A., Kramer L. D., Pledger G. W., Karim R. M. Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 200-, 400-, and 600-mg daily dosages. Topiramate YD Study Group. Neurology. 1996 Jun;46(6):1684–1690. doi: 10.1212/wnl.46.6.1684. [DOI] [PubMed] [Google Scholar]
  7. French J. A., Mosier M., Walker S., Sommerville K., Sussman N. A double-blind, placebo-controlled study of vigabatrin three g/day in patients with uncontrolled complex partial seizures. Vigabatrin Protocol 024 Investigative Cohort. Neurology. 1996 Jan;46(1):54–61. doi: 10.1212/wnl.46.1.54. [DOI] [PubMed] [Google Scholar]
  8. Grünewald R. A., Thompson P. J., Corcoran R., Corden Z., Jackson G. D., Duncan J. S. Effects of vigabatrin on partial seizures and cognitive function. J Neurol Neurosurg Psychiatry. 1994 Sep;57(9):1057–1063. doi: 10.1136/jnnp.57.9.1057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Guidelines for antiepileptic drug trials in children. Commission on Antiepileptic Drugs of the International League Against Epilepsy. Epilepsia. 1994 Jan-Feb;35(1):94–100. [PubMed] [Google Scholar]
  10. Hauser W. A., Kurland L. T. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia. 1975 Mar;16(1):1–66. doi: 10.1111/j.1528-1157.1975.tb04721.x. [DOI] [PubMed] [Google Scholar]
  11. Jawad S., Richens A., Goodwin G., Yuen W. C. Controlled trial of lamotrigine (Lamictal) for refractory partial seizures. Epilepsia. 1989 May-Jun;30(3):356–363. doi: 10.1111/j.1528-1157.1989.tb05309.x. [DOI] [PubMed] [Google Scholar]
  12. Loiseau P., Yuen A. W., Duché B., Ménager T., Arné-Bès M. C. A randomised double-blind placebo-controlled crossover add-on trial of lamotrigine in patients with treatment-resistant partial seizures. Epilepsy Res. 1990 Nov;7(2):136–145. doi: 10.1016/0920-1211(90)90099-h. [DOI] [PubMed] [Google Scholar]
  13. Marson A. G., Chadwick D. W. How easy are randomized controlled trials in epilepsy to find on Medline? The sensitivity and precision of two Medline searches. Epilepsia. 1996 Apr;37(4):377–380. doi: 10.1111/j.1528-1157.1996.tb00575.x. [DOI] [PubMed] [Google Scholar]
  14. Marson A. G., Chadwick D. Comparing antiepileptic drugs. Curr Opin Neurol. 1996 Apr;9(2):103–106. doi: 10.1097/00019052-199604000-00008. [DOI] [PubMed] [Google Scholar]
  15. Matsuo F., Bergen D., Faught E., Messenheimer J. A., Dren A. T., Rudd G. D., Lineberry C. G. Placebo-controlled study of the efficacy and safety of lamotrigine in patients with partial seizures. U.S. Lamotrigine Protocol 0.5 Clinical Trial Group. Neurology. 1993 Nov;43(11):2284–2291. doi: 10.1212/wnl.43.11.2284. [DOI] [PubMed] [Google Scholar]
  16. Mattson R. H., Cramer J. A., Collins J. F., Smith D. B., Delgado-Escueta A. V., Browne T. R., Williamson P. D., Treiman D. M., McNamara J. O., McCutchen C. B. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med. 1985 Jul 18;313(3):145–151. doi: 10.1056/NEJM198507183130303. [DOI] [PubMed] [Google Scholar]
  17. Messenheimer J., Ramsay R. E., Willmore L. J., Leroy R. F., Zielinski J. J., Mattson R., Pellock J. M., Valakas A. M., Womble G., Risner M. Lamotrigine therapy for partial seizures: a multicenter, placebo-controlled, double-blind, cross-over trial. Epilepsia. 1994 Jan-Feb;35(1):113–121. doi: 10.1111/j.1528-1157.1994.tb02920.x. [DOI] [PubMed] [Google Scholar]
  18. Privitera M., Fincham R., Penry J., Reife R., Kramer L., Pledger G., Karim R. Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 600-, 800-, and 1,000-mg daily dosages. Topiramate YE Study Group. Neurology. 1996 Jun;46(6):1678–1683. doi: 10.1212/wnl.46.6.1678. [DOI] [PubMed] [Google Scholar]
  19. Reynolds E. H., Shorvon S. D., Galbraith A. W., Chadwick D., Dellaportas C. I., Vydelingum L. Phenytoin monotherapy for epilepsy: a long-term prospective study, assisted by serum level monitoring, in previously untreated patients. Epilepsia. 1981 Aug;22(4):475–488. doi: 10.1111/j.1528-1157.1981.tb06158.x. [DOI] [PubMed] [Google Scholar]
  20. Richens A., Davidson D. L., Cartlidge N. E., Easter D. J. A multicentre comparative trial of sodium valproate and carbamazepine in adult onset epilepsy. Adult EPITEG Collaborative Group. J Neurol Neurosurg Psychiatry. 1994 Jun;57(6):682–687. doi: 10.1136/jnnp.57.6.682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Ring H. A., Heller A. J., Farr I. N., Reynolds E. H. Vigabatrin: rational treatment for chronic epilepsy. J Neurol Neurosurg Psychiatry. 1990 Dec;53(12):1051–1055. doi: 10.1136/jnnp.53.12.1051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Schapel G. J., Beran R. G., Vajda F. J., Berkovic S. F., Mashford M. L., Dunagan F. M., Yuen W. C., Davies G. Double-blind, placebo controlled, crossover study of lamotrigine in treatment resistant partial seizures. J Neurol Neurosurg Psychiatry. 1993 May;56(5):448–453. doi: 10.1136/jnnp.56.5.448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Schmidt D., Jacob R., Loiseau P., Deisenhammer E., Klinger D., Despland A., Egli M., Bauer G., Stenzel E., Blankenhorn V. Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial. Epilepsy Res. 1993 May;15(1):67–73. doi: 10.1016/0920-1211(93)90011-u. [DOI] [PubMed] [Google Scholar]
  24. Sivenius J., Kälviäinen R., Ylinen A., Riekkinen P. Double-blind study of Gabapentin in the treatment of partial seizures. Epilepsia. 1991 Jul-Aug;32(4):539–542. doi: 10.1111/j.1528-1157.1991.tb04689.x. [DOI] [PubMed] [Google Scholar]
  25. Smith D., Baker G., Davies G., Dewey M., Chadwick D. W. Outcomes of add-on treatment with lamotrigine in partial epilepsy. Epilepsia. 1993 Mar-Apr;34(2):312–322. doi: 10.1111/j.1528-1157.1993.tb02417.x. [DOI] [PubMed] [Google Scholar]
  26. Spilker B., Segreti A. Validation of the phenomenon of regression of seizure frequency in epilepsy. Epilepsia. 1984 Aug;25(4):443–449. doi: 10.1111/j.1528-1157.1984.tb03441.x. [DOI] [PubMed] [Google Scholar]
  27. Tassinari C. A., Michelucci R., Chauvel P., Chodkiewicz J., Shorvon S., Henriksen O., Dam M., Reife R., Pledger G., Karim R. Double-blind, placebo-controlled trial of topiramate (600 mg daily) for the treatment of refractory partial epilepsy. Epilepsia. 1996 Aug;37(8):763–768. doi: 10.1111/j.1528-1157.1996.tb00649.x. [DOI] [PubMed] [Google Scholar]
  28. Verity C. M., Hosking G., Easter D. J. A multicentre comparative trial of sodium valproate and carbamazepine in paediatric epilepsy. The Paediatric EPITEG Collaborative Group. Dev Med Child Neurol. 1995 Feb;37(2):97–108. doi: 10.1111/j.1469-8749.1995.tb11978.x. [DOI] [PubMed] [Google Scholar]
  29. Willmore L. J., Shu V., Wallin B. Efficacy and safety of add-on divalproex sodium in the treatment of complex partial seizures. The M88-194 Study Group. Neurology. 1996 Jan;46(1):49–53. doi: 10.1212/wnl.46.1.49. [DOI] [PubMed] [Google Scholar]

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