A Brief History of Antiepileptic Medicines

The first antiepileptic drug was bromide, used in the late 19th century. Its side effects, however, made it a less than ideal medication. In 1912, phenobarbital became the main drug prescribed for epilepsy, and it is still used today. However, its usefulness was limited to generalized tonic clonic seizures and, to a lesser degree, simple and complex partial seizures. It had no effect on absence seizures. It had a sedative effect on some people and produced hyperactivity in children.

Between 1960 and 1974, only one new drug was approved for use.

In 1938, diphenylhydantoin, which had failed to be an effective sedative, was discovered to have seizure-preventing properties. It was marketed as Dilantin, and it is still a major drug in epilepsy treatment today. Its generic name was later changed to phenytoin. While Dilantin was effective in the same broad spectrum as phenobarbital, it too had no effect on absence seizures.

In 1945, trimethadione (Tridione) was developed as the first drug for use in absence seizures. For the next fifteen years a series of new antiepileptic drugs was developed, all of which were variations on the same basic chemical structure, which were effective against different types of seizures.

After 1960, the U.S. Food and Drug Administration (FDA) regulations became more strict, requiring that a new drug had to be not only safe but also proved effective against the particular illness it was used to treat. Since antiepileptic drugs had a relatively small sales volume and the costs of testing and marketing new drugs were substantial, U.S. drug companies virtually stopped investigating and developing new products to combat seizures.

Between 1960 and 1974, only one new drug, diazepam (Valium) was approved for use in the treatment of epilepsy. Its major contribution was effectiveness in the treatment of status epilepticus. In 1974, carbamazepine (Tegretol) was approved, and in 1978, valproic acid (Depakene).

Another pause in new drug development took place; however, the National Institute of Neurological Disorders and Stroke’s Antiepileptic Drug Development program, a unique partnership between government, academia, and industry, continued the search for compounds with antiepileptic activity. New drug investigations also continued overseas. As a result, a new crop of antiepileptic drugs, some of them unrelated to previous drugs, some specifically designed to have a particular physiological effect, appeared in the 1990s. A number of other new products are currently in development or in use overseas.

In general, the new medications are reported to have fewer serious side effects than the older ones, although felbamate’s unexpectedly elevated rate of aplastic anemia and liver failure runs counter to the trend and other effects may emerge as the new products are more widely used. As new drugs are approved, some of the older products (trimethadione, phenacemide and paramethadione) are being discontinued.