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Stanford Report, January 7, 1998

Wakefulness drug tested at Stanford: 1/7/98

'Wakefulness' drug tested at Stanford

BY ROSANNE SPECTOR

Sleep researchers at Stanford have played a major role in testing a novel drug that helps people stay awake without making them jittery or leaving them extremely sleepy afterward. The drug, modafinil (Provigil), last month gained preliminary approval from the Food and Drug Administration as a treatment for excessive sleepiness due to narcolepsy.

Dale Edgar, associate professor of psychiatry and behavioral sciences, led animal studies required for the drug's consideration by the FDA, while senior research scientist Dr. Jed Black directed studies of modafinil's effects on people with narcolepsy. The results of the first U.S. multi-center clinical trial of modafinil, of which Black's studies were a part, will be published this month in the journal Annals of Neurology.

Narcolepsy is a lifelong disease affecting about 125,000 people in the United States. Because the new drug lacks the side effects of stimulants such as methamphetamine, it promises to improve the lives of people with this disease, Edgar said.

It may also help those with other forms of excessive sleepiness, he said. "Excessive sleepiness, or hypersomnolence, can result from a number of sleep disorders, from jet lag or from work conditions such as shift work. A safe and effective medication that can improve wakefulness without stimulant side effects is long overdue," Edgar said.

His studies compared the behavior of rats on modafinil and rats on methamphetamine. Edgar found that those on modafinil remained alert but did not move about in their cages any more than laboratory rats normally do ­ unlike the rats on methamphetamine, which became hyperactive.

Moreover, modafinil did not leave the rats hypersomnolent when it wore off. Rats on methamphetamine "crashed" after the drug wore off, Edgar said, whereas those on modafinil recovered their missed sleep more gradually.

"Amphetamine-like stimulants, such as dexamphetamine, methamphetamine and methylphenidate, increase wakefulness, but they all have serious side effects. In addition to causing jitters and having a well-known potential for serious abuse, the amphetamine-like substances cause intense hypersomnolence as the drug wears off. The brain reacts as if it must catch up on all lost sleep at once," Edgar said.

"Modafanil doesn't seem to cause this 'rebound' effect. Sleep displaced by modafinil-induced wakefulness is recovered gradually over several days," he said.

"Excessive sleepiness is a growing problem in modern society, as many coffee drinkers will testify," Edgar noted. "Caffeine is a stimulant that is widely accepted throughout the world as safe, yet in preclinical studies it has more severe side effects than modafinil.

"Modafinil delays the inevitable need to sleep and appears to do so without the risk of severe hypersomnolence as the drug wears off. Hypersomnolence would be dangerous for people operating a motor vehicle or performing a critical task," he said.

He cautioned, however, against using any drug simply to get by on less sleep. The average adult needs about eight hours of sleep per day, Edgar said. "The chronic use of any wake-promoting medication to try to get by on less sleep is probably not a good idea," he said.

In addition to modafinil's clinical potential, its ability to induce wakefulness without triggering drug-related side effects gives researchers a valuable new tool for studying the role of sleep in health and well-being, Edgar said.

"No one really fully understands why we have to sleep. It's incredible but true," he said. "Now, with a drug like modafinil that essentially decreases the drive for sleep without introducing all kinds of side effects associated with the drug itself, we can carry out animal studies to get clear answers to our questions about sleep regulation."

Edgar and Wesley Seidel, a senior life-science research assistant, reported on their rat studies in the Nov. 6 Journal of Pharmacology and Experimental Therapeutics.

While Edgar looked at rats, Black studied modafinil's effects on people with narcolepsy. The unpublished results of his clinical trial seem to confirm work done in France showing that modafinil increases daytime alertness, Black said. The trial also shows that the drug has very few side effects. "It is very well tolerated and has far fewer side effects than traditional stimulants," he said.

"My expectation is that in terms of the drug's alertness effect, it will be roughly similar to [the common stimulants] Ritalin or Dexedrine. But there are a number of factors that make modafinil preferable: It's longer-acting, it appears to have no abuse potential and, very importantly, it doesn't lead to the increase in blood pressure that can occur in people taking traditional stimulants," Black said.

People taking modafinil avoid the jitteriness and "rushed" feeling familiar to coffee drinkers and users of many standard stimulants, he added. Participants in his trial said the drug made them feel naturally alert, not drugged, Black said.

"People taking modafinil say they don't feel artificially jolted into being alert. This is a big improvement over the other stimulants available to people with narcolepsy," he said.

In addition, narcoleptic patients taking modafinil are less likely to build up a tolerance to the drug ­ a potential problem for patients using traditional stimulants, Black said. "With modafinil, it doesn't seem necessary to increase the dose to overcome tolerance, or to go on a 'drug holiday' to regain sensitivity to the drug," he said.

The details of modafinil's activity are not yet understood.

"While we don't know the exact mechanism of action, it's very clear that it's quite different from the mechanism for traditional stimulants," Edgar said. "We know what modafinil is not. It selective promotes wakefulness, but unlike traditional stimulants, modafinil does not cause large increases in dopamine release in the brain."

Modafinil was developed by the French company Laboratoire L. Lafon and is already available by prescription in France and England. Lafon licensed it to Cephalon Inc. of Westchester, Pa., which applied for FDA approval one year ago. On Dec.29, the FDA granted the drug preliminary approval for use in people with narcolepsy. Full approval is contingent on satisfactory completion of product labeling and related matters.

Funding for Black's study came from Cephalon. Edgar's study was funded by Cephalon, the National Institutes of Health and the Air Force Office of Scientific Research's Program for Research Excellence and Transition. SR