SCIENTIFIC REVIEW CLINICIAN’S CORNER AND CLINICAL APPLICATIONS The New Antiepileptic Drugs Scientific Review Suzette M. LaRoche, MD Context The past decade has brought many advances to the treatment of epilepsy, Sandra L. Helmers, MD including many new pharmacological agents. Primary care physicians often care for pa- tients with epilepsy and therefore should be familiar with the new options available. PILEPSY IS DEFINED AS A CHRONIC Objective To review data regarding the efficacy and tolerability of antiepileptic drugs neurological condition charac- introduced in the past decade. terized by recurrent, unpro- 1 Data Sources A search of the Cochrane Central Register of Controlled Trials was voked seizures. It is one of the performed to identify all published human and English-language randomized con- Emost common serious neurological dis- trolled trials evaluating the efficacy and tolerability of the antiepileptic drugs that have orders in the United States and often re- been approved for use in the United States since 1990. Additional reports evaluating quires long-term management. Each year pharmacokinetic properties were identified through a MEDLINE search as well as re- 150000 people in the United States are view of article bibliographies. newly diagnosed as having epilepsy, with Study Selection and Data Extraction Search terms included felbamate, gaba- the cumulative lifetime incidence ap- pentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonis- proaching 3%.2,3 The incidence is high- amide. Studies were selected if efficacy and tolerability were reported as major out- est during the first year of life and in el- come measures. Included studies (n=55) enrolled a minimum of 20 adult subjects and derly persons.2 Although most people had a treatment period of at least 6 weeks. with epilepsy become seizure-free with Data Synthesis Eight new antiepileptic drugs have been approved for use in the United appropriate therapy, 30% to 40% of pa- States in the past decade. Each new antiepileptic drug is well tolerated and demonstrates tients will continue to have seizures de- statistically significant reductions in seizure frequency over baseline. No randomized con- spite the use of antiepileptic drugs either trolled trials have compared the new antiepileptic drugs with each other or against the traditional antiepileptic drugs. Although there is no evidence to suggest that the newer alone or in combination.4 Patients with medications are more efficacious, several studies have demonstrated broader spectrum uncontrolled seizures experience signifi- of activity, fewer drug interactions, and overall better tolerability of the new agents. cant morbidity and mortality and face so- cial stigma and discrimination as well. Conclusions New antiepileptic drugs offer many options in the treatment of epi- lepsy, each with unique mechanisms of action as well as adverse effect profiles. The In the United States, only 17% of pa- new antiepileptic drugs are well tolerated with few adverse effects, minimal drug in- tients with new-onset epilepsy are ini- teractions, and a broad spectrum of activity. 5 tially seen by a neurologist. Further- JAMA. 2004;291:605-614 www.jama.com more, primary care physicians provide approximately 40% of the long-term that 45% had experienced a seizure well as intolerable adverse effects. Since management of epilepsy patients with or within the past year, 68% complained of 1993, 8 new medications have been ap- without initial consultation with a spe- drowsiness or difficulty in concentra- proved by the US Food and Drug Ad- 6 cialist. Unfortunately, a survey of gen- tion with their current medications, and ministration (FDA), expanding treat- eral practitioners revealed that only 40% 28% were prescribed polytherapy.8 ment options (TABLE 1). The newer of responders felt confident in their Therefore, general practitioners play a vi- antiepileptic drugs offer the potential ad- knowledge of epilepsy and two thirds tal role in the treatment of epilepsy pa- vantages of fewer drug interactions, were unfamiliar with the new antiepi- tients with ongoing seizures. unique mechanisms of action, and a 7 leptic drugs. A recent survey of 71 pa- Prior to 1993, the choice of an anti- broader spectrum of activity. With more tients with epilepsy who are treated ex- convulsant medication was limited to options, however, comes the challenge clusively by general practitioners showed phenobarbital, primidone, phenytoin, carbamazepine, and valproate. Al- Author Affiliations: Department of Neurology, Emory University (Drs LaRoche and Helmers), and Atlanta VA See also p 615 and Patient Page. though these “traditional” anticonvul- Medical Center (Dr LaRoche), Atlanta, Ga. sants have the advantage of familiarity Corresponding Author and Reprints: Suzette M. CME available online at as well as proven efficacy, many pa- LaRoche, MD, Emory Clinic, Bldg A, 1365 Clifton Rd, www.jama.com Atlanta, GA 30322 (e-mail: Suzette_LaRoche tients are left with refractory seizures as @emoryhealthcare.org). ©2004 American Medical Association. All rights reserved. (Reprinted) JAMA, February 4, 2004—Vol 291, No. 5 605 Downloaded From: https://jamanetwork.com/ on 09/27/2021 ANTIEPILEPTIC DRUGS trials and fewer yet have been FDA ap- Table 1. Antiepileptic Drugs Approved Since 1993* proved for use as monotherapy. This pre- Approved Approved for Year Approved Approved for for Partial Generalized sents a dilemma that has led to frequent Antiepileptic Drug Approved Patient Age, y Monotherapy Seizures Seizures off-label use because monotherapy of- Felbamate (Felbatol)† 1993 Ն2 ߜߜߜfers many advantages over poly- Gabapentin (Neurontin) 1993 Ն3 ߜ therapy, including fewer adverse ef- Lamotrigine (Lamictal) 1994 Ն2 ߜߜߜfects, less drug interactions, lower cost, Topiramate (Topamax) 1996 Ն2 ߜߜand improved compliance. The reason Tiagabine (Gabatril) 1997 Ն12 ߜ for fewer monotherapy approvals stems Levetiracetam (Keppra) 1999 Ն16 ߜ from the difficulty in trial design. There Oxcarbazepine (Trileptal) 2000 Ն4 ߜߜ are 2 common approaches to mono- Zonisamide (Zonegran) 2000 Ն16 ߜ therapy trials. An active-control com- *Approved for use by the US Food and Drug Administration. †Not indicated as first-line antiepileptic treatment. parison typically randomly assigns patients with new-onset seizures to re- ceive either the study drug or a well- of determining what role the new anti- either the study drug or placebo in addi- established antiepileptic drug at low epileptic drugs play in optimizing treat- tion to their original medication(s). therapeutic doses. Conversion to mono- ment in addition to understanding im- Patients were followed up for 6 to 8 therapy trials assigns patients to be con- portant adverse effects and drug weeks to establish a baseline seizure fre- verted from their current antiepileptic interactions of these increasingly pre- quency, then randomly assigned to drug(s) to either a subtherapeutic dose scribed medications. The purpose of this either placebo or study drug and fol- of the test drug (referred to as pseudo- article is to familiarize primary care cli- lowed up for 8 to 12 weeks while sei- placebo) or a higher dose of the test drug nicians with the efficacy, tolerability, and zure frequency and tolerability were that is thought to be efficacious. Effi- pharmacokinetic properties of the new monitored. The primary outcome mea- cacy is measured as completion rate or antiepileptic drugs. sure was a reduction in seizure fre- mean time to exiting the study. Exit cri- quency over baseline compared with teria consist of either an increase in sei- METHODS placebo. A “responder rate” is reported zure frequency above baseline, a pro- We searched the Cochrane Central Reg- as the number of patients who achieved longed generalized seizure, or status ister of Controlled Trials to identify all a 50% or greater reduction in seizure epilepticus. In addition, the percentage published human and English- frequency from baseline. of patients discontinuing due to ad- language randomized controlled clini- There are obvious limitations to this verse effects is reported. Agents that show cal trials evaluating the efficacy and tol- trial design. Efficacy is often underes- efficacy in placebo-controlled trials are erability of antiepileptic drugs that have timated and responder rates are typi- considered acceptable proof of efficacy been FDA approved since 1990. Addi- cally less than 50% because the study for FDA approval; however, this trial de- tional reports evaluating pharmacoki- population with refractory seizures has sign raises obvious ethical concerns. To netic properties were identified through typically not responded to multiple an- demonstrate efficacy in active-control a MEDLINE search as well as review of tiepileptic drugs and is therefore not comparison trials, the study drug must article bibliographies. Search terms in- comparable to patients in a typical clini- show superiority over the control and not cluded felbamate, gabapentin, la- cal practice. Toxicity is often overesti- merely equivalency.9 motrigine, topiramate, tiagabine, leveti- mated because adverse effects may be racetam, oxcarbazepine, and zonisamide. additive and not specifically due to the RESULTS Studies were selected if efficacy and tol- add-on therapy. In addition, many of Felbamate erability were reported as major out- the new antiepileptic drugs were ti- Felbamate was the first new antiepilep- come measures. Included studies trated more rapidly during clinical trials tic drug