People are bombarded on television and in magazines by advertisements for new medicines. These advertisements are accompanied by pages of small print full of the results of clinical trials. The use of placebos in the clinical trials that help prove the effectiveness and safety of medications has become a hot issue in the world of epilepsy and has spiced up the typically sterile pages of medical journals.

A placebo is any innocuous substance or treatment—such as a sugar pill—used in place of a real course of treatment. The word is derived from the Latin verb "placere" (to please). A placebo has no therapeutic value and therefore is perfect in clinical trials as a control substance that can be compared with a drug being tested to judge its effectiveness. If patients who take a placebo experience improvement in their condition, that is called a "placebo effect."

Placebo and Placebo Effect: Mind Over Body

The argument that placebo-controlled studies are unnecessary is a popular one, held in high esteem by The World Medical Association and the Declaration of Helsinki, the association's pronouncement protecting patients involved in biomedical research. According to Kenneth J. Rothman, professor of Epidemiology and Biostatistics at Boston University, the recently revised Declaration of Helsinki "...made an unequivocal statement about placebo. That it should never be used in place of an accepted treatment."

According to Dr. Steven C. Schachter, medical director of the office of clinical trials for Beth Israel Deaconess Medical Center in Boston, the placebo effect does exist in epilepsy. "The evidence in favor of there being a real effect comes from placebo-controlled studies where, I'd say, nine out of ten placebo-controlled studies show that patients in the placebo group overall do better," says Schachter. "When a placebo is used to compare a new drug, generally the new drug does better than the placebo, but the placebo group does better on the placebo than they did before they were in the study."

The main measures of placebo effect in epilepsy are seizure frequency and seizure severity because these are easily quantified. The patient is evaluated, the measures are taken, and the results are recorded. "The most important thing to measure is the seizure frequency. That's what gets drugs approved by the FDA," says Schachter. But there are other measurements, too, such as quality-of-life questionnaires and psychological testing. Tests are performed on the patient to determine clarity of thinking, the ability to concentrate, and the presence of side effects.

Case Study: Medical Ethics vs. Results

When we look at specific placebo-controlled trials, we encounter a murky swirl of semantics and medical ethics. In the March 1999 issue of Neurology, when Schachter and a group of associates published "Oxcarbazepine: double-blind, randomized, placebo-control, monotherapy trial for partial seizures," a clinical trial designed to study the efficacy and safety of oxcarbazepine, the active ingredient in the seizure medicine known as Trileptal, the debate once again came to a head. In the same issue, Dr. David Chadwick and Dr. Michael Privitera, two dissenting epileptologists, countered with an editorial that outlined their ethical objections to Schachter's study. Their chief concern was that patients in the study, who were under close, 24-hour observation in a hospital, were withdrawn from other seizure medicines and would have an increased risk for seizure if they received the placebo.

"Any individual seizure can potentially be life-threatening whether it occurs in the hospital or outside the hospital," said Schachter. "It boils down to the potential consequences of a seizure... When you do a research project, you don't go out of your way to undertreat somebody in epilepsy because any single seizure could be very serious.... The Declaration of Helsinki basically stipulates that patients get the best available treatment. To me that makes most sense for people who are just starting out with a condition. In other words, you wouldn't want to give a placebo to a patient who has just been diagnosed, because we have effective treatments. But a patient who's had epilepsy for 20 years, there is no best treatment for them. Nothing works."

In an article that appeared in The Boston Globe later in 1999, Privitera said, "Scientifically, these studies are very good and tell you exactly what you want to know." He added, however, that, "No one is asking, 'Is this the right thing for the patient in the trial?'" This is a question that greatly complicates the medical ethics debate.

Patient Motivation: Get Better, But at What Risk?

Despite the darker side of seizure risks—Chadwick and Privitera's editorial cited "increased risk of psychosocial disadvantage, accidental injury, and sudden unexplained death"—patients are willing to take great risks in the hopes of having fewer seizures.

"These are people, for the most part, who have had epilepsy for 15, 20, 25 years, who have had hundreds of seizures in their life," says Schachter. "They understand the risks of any individual seizure, but they've been living with those risks. . . .This is a choice the patients make and they're willing to make that choice."

With patient participation there exists an irony: because patients are willing to take a chance, they are essentially at odds with the doctors, scientists, and advocacy groups fighting to protect their rights.

The Debate Continues

Aggressive research will always play a role in finding the cure for disease, but those involved with clinical trials must always question the motivation of their clinical pursuits.

"Rather than throw out the entire concept of placebo-controlled studies, I think where I would hope this debate goes is towards modifying the design of placebo studies to further reduce the risk," says Schachter. "The physicians have an obligation to make these study designs as safe as possible. I think that's the positive outcome of this debate... This is all a work in progress."