Antiepileptic (or preferably antiseizure) drug treatment is the mainstay of the management of epilepsies. The laudable aim is freedom from seizures with minimal, if any, adverse drug reactions. This is achieved in about 50% to 70% of patients with a single, appropriately selected antiepileptic drug at target therapeutic doses. This seizurefree rate varies significantly with seizure type and epileptic syndrome. Polytherapy should be avoided if possible, but it is inevitable in about 30% to 50% of patients who fail to respond to single-drug therapy. Freedom of seizures should not be pursued at any cost and, in particular, at the expense of adverse drug reactions. The identification of adverse drug reactions, although sometimes difficult, is a crucial part of the management. The choice of antiepileptic drug is demanding because an antiepileptic drug beneficial for one type of epileptic seizure may be detrimental for another type of seizure. With the seemingly unstoppable development of a range of newer antiepileptic drugs over the past 2 decades, the available choice has been substantially widened, and the number of possible drug combinations for the treatment of epilepsy is almost limitless. Developing a framework to use antiepileptic drugs rationally, therefore, has become an issue of important practical necessity. In this article, the author provides an updated overview of the pharmacotherapy of epilepsy in adolescents and adults, with particular reference to the clinical pharmacology of antiepileptic drugs, approaches to treatment, and principles of drug selection.
• Antiepileptic drug treatment is generally recommended after 2 or more unprovoked seizures.
• The aim of antiepileptic drug treatment is to achieve seizure freedom without adverse drug reactions.
• Selection of antiepileptic drugs should be individualized based on the seizure type or epilepsy syndrome, potential adverse effects, and drug-to-drug interactions.
• The first-option antiepileptic drug should be the most likely to be efficacious and the most unlikely to cause adverse drug reactions.
• The correct antiepileptic drug dose is the smallest one that achieves seizure control without adverse drug reactions; optimal efficacy of an antiepileptic drug may be lost by exceeding tolerability limits.
• An antiepileptic drug appropriate for one type of seizure may be deleterious for another type.
• Two thirds of newly diagnosed patients will become seizure-free with antiepileptic drug therapy, mostly when taking their first or second drug schedule, and often requiring no more than modest or moderate drug doses.
• The International League Against Epilepsy (ILAE) defines drug-resistant epilepsy as “failure of adequate trials of 2 tolerated and appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom.”
• Patients with drug-resistant epilepsy should be referred to specialist centers for a comprehensive review of the diagnosis and management, and consideration of other therapeutic options, particularly epilepsy surgery.
Historical note and terminology
The history of the antiepileptic (antiseizure) drugs is masterly detailed in a 2-part review by Shorvon published in Epilepsia (68; 69) and in a monograph giving a thorough account of how these medications were discovered and developed by Scott (66). See also a brief review by Brodie (13).
The contemporary antiepileptic drug therapy started in 1857 with bromides, which were first mentioned in the English literature by Dr Edward Sieveking in his ‘‘Analyses of 52 cases of epilepsy observed by the author’’ (70). Although there are no randomized trials with bromide, there are enough clinical data to support its claim to be the first effective antiepileptic drug. However, it is highly neurotoxic and became obsolete once better tolerated alternatives were found though bromide has support even to this day as a potential ‘‘drug of tertiary choice in the treatment of children with epilepsy’’ (13).
Modern pharmacotherapy of epilepsy was heralded by the serendipitous discovery of the anticonvulsant properties of phenobarbital in 1912 by Alfred Hauptmann (75). As a young resident psychiatrist, Hauptmann lived over a ward of people with epilepsy who were falling out of bed during the night because of tonic-clonic seizures, thereby, keeping him awake. Phenobarbital had been marketed the previous year as a hypnotic by F. Bayer and Company. Hauptmann sedated his patients with phenobarbital so that he could get a good night’s sleep. Not only did his patients have fewer episodes during the night, but they did not seize the following day. He published his observation, and the rest is history. Phenobarbital is still the most widely prescribed antiepileptic drug in the developing world and remains a first popular choice in many industrialized countries, partly because of its modest cost (36; 75).
Phenytoin, the first nonsedating antiepileptic drug, was introduced in the late 1930s as a result of systematic screening of compounds using novel animal seizure models. When Tracy Putnam was appointed to the directorship of the neurologic unit at Boston City Hospital in 1934, he set out to discover a less sedative antiepileptic drug than phenobarbital .With the help of Frederic Gibbs, he established the first electroencephalophic laboratory for the routine study of ‘‘brain waves.’. A makeshift apparatus was assembled to demonstrate that phenobarbital markedly raised the convulsive threshold in cats. Parke-Davis, and Company supplied Putnum’s research team with a number of nonsedative phenyl compounds. Only one of these, phenytoin was not too toxic for routine administration. Luckily, it was markedly effective in protecting cats from electrically induced convulsions. Putnam gave phenytoin to one of his young assistants, Houston Merritt, for clinical evaluation in 1936. The first patient to receive the drug had suffered daily seizures for many years and became permanently seizure-free on commencing treatment with phenytoin. The subsequent publication established this new drug in the therapeutic armamentarium. Phenytoin is still a widely used antiepileptic drug in the United States.
During the 1940s, troxidone became established for the treatment of petit mal. Parke-Davis subsequently initiated a major research project to find a less toxic drug for this indication, which resulted in the licensing of ethosuximide in 1958. Its current value for absence seizures has been confirmed in a double-blind, randomized comparative trial with sodium valproate and lamotrigine (29).
The next major drug to be licensed was carbamazepine, which became widely available in the mid-1960s and is arguably supported by the best evidence base. It was synthesized by Schindler at Geigy in 1953 as a possible competitor for the antipsychotic chlorpromazine. The first study with carbamazepine in epilepsy was not carried out until 1963, after which it was rapidly licensed as an anticonvulsant in 1965 in the United Kingdom. That same year, the antiepileptic activity of valproate was serendipitously recognized by Pierre Eymard while working as a research student at the University of Lyon. He dissolved a series of insoluble khellin and coumarin derivatives in valproate. Rather surprisingly, all of them appeared to have anticonvulsant properties. Subsequently valproate was subjected to extensive clinical investigation. Its sodium salt was first marketed as an antiepileptic drug in France in 1967.
The value of the benzodiazepines for the treatment of epilepsy was rapidly recognized following their synthesis and development by Leo Sternbach while he was working for the Swiss pharmaceutical company, Roche, in the 1960s. In 1965, Henry Gastaut published a report regarding the efficacy of diazepam in treating status epilepticus. His follow-up paper with clonazepam 6 years later was even more positive. Clobazam is probably the most widely used oral benzodiazepine for a range of refractory epilepsies. Rectal and intravenous diazepam, buccal and intranasal midazolam, and lorazepam are drugs of choice for acute repetitive seizures and convulsive status epilepticus.
The modern era of antiepileptic drug development began in 1975 when the National Institute of Neurological Disorders and Stroke in the United States established the Anticonvulsant Drug Development Program. More than 28,000 new chemical entities from academic and pharmaceutical chemists have since been screened, resulting in the licensing of an increasing list of antiepileptic drugs (69; 13). Thus, after a hiatus of nearly 20 years, there has been accelerated development of newer antiepileptic drugs, with the licensing of at least 16 compounds globally since the late 1980s. In chronological order, these were: vigabatrin, zonisamide, oxcarbazepine, lamotrigine, felbamate, gabapentin, topiramate, tiagabine, levetiracetam, pregabalin, rufinamide, stiripentol, lacosamide, eslicarbazepine, perampanel (69), and brivaracetam (26; 42). Twelve other antiepileptic drugs are in phase I-III clinical development (11), and still there are clear incentives to develop newer and more efficacious medications for epilepsy (23).
Table 1. Generic Antiepileptic Drugs
Ezogabine or retigabine*
* Ezogabine (retigabine) was discontinued June 2017 (https://www.epilepsy.com/sites/core/files/atoms/files/Potiga%20Prescribing%20Update%20Aug%202016.pdf). According to the manufacturers, GlaxoSmithKline, this drug “will no longer be commercially available after June 30, 2017 due to the very limited usage of the medicine and the continued decline in new patient initiation. Discontinuation is not due to efficacy or safety reasons. Healthcare providers are advised to begin seeking alternative medicines for existing patients as soon as possible and to ensure all patients are withdrawn from this product by the end of June 2017 at the latest.” This drug is no longer considered in updates of this article.