Merrill Mitler travels frequently, often sleeping consecutive days in different time zones. When his body clock feels out of sync with his schedule, he swallows a medicine that was approved to treat sleepiness associated with a rare disorder he doesn't have.
Americans last year bought $150 million worth of the drug modafinil, which was approved to treat narcolepsy, an unusual disorder that causes people to fall asleep suddenly. Three-quarters of the pills were swallowed by people who didn't have narcolepsy. Doctors are prescribing the drug to patients with other disorders and, increasingly, to people with no disorder at all.
Three years after it was approved, the medicine is raising questions about how many healthy Americans might soon want it simply to sleep less -- yet another example of a medicine being used not to treat illness, but to support a lifestyle choice.
Unlike amphetamines and conventional stimulants, modafinil does not give people a jolt. Doctors believe it is not addictive and say it is generally safe, with only occasional side effects such as headache or nausea. But no one knows what might happen if people use the drug to do away with sleep for prolonged periods.
"The biggest questions are societal," said Thomas Scammell, a neurologist at Harvard Medical School. "What's to keep us from working 24-7? . . . To take a drug and try to counter this natural necessity of sleep is to defy nature. It's like if I can give you a pill to take away your appetite -- does it mean it's okay not to eat?"
The drug's manufacturer, Cephalon Inc. of West Chester, Pa., had promoted it as effective for more than just narcolepsy. But after the Food and Drug Administration charged in January that Cephalon's promotional materials were "false, lacking in fair balance or otherwise misleading," the company promised to limit its promotional pitches to narcolepsy. The company plans eventually to present studies to the FDA that would expand the drug's approval for sleepiness associated with a variety of psychiatric and neurological disorders.
Studies are also underway to test whether modafinil can help healthy truck drivers navigate night journeys and get to their destinations safely by dawn. The military is investigating whether modafinil can help healthy soldiers stay awake for lengthy periods in combat. A large trial is studying the medicine's effectiveness among shift workers.
At one site of this study, the Scripps Research Institute in San Diego, psychologist Mitler is evaluating whether modafinil can help people fight their normal circadian rhythms. His use of the medicine suggests he knows the result.
"Do you need a pill to treat a normal condition?" Mitler said. "There is all sorts of precedent for that -- we take aspirin for sore muscles associated with exercise. Muscles are supposed to hurt when they are not trained. Yet we medicalize it in order to treat the discomfort."
"The side effects of caffeine are much more severe than the side effects of modafinil," said Mitler, who believes that decisions about modafinil are best left to individuals and their doctors.
Americans have long been fascinated by sleep -- or rather, with not sleeping: Students glorify in tales of all-nighters; sleeping on the job has often been grounds for getting fired; and the ultimate capitalist utopia is the 24-hour workday.
A spokeswoman for Cephalon acknowledged that the company sought to expand the market for modafinil beyond narcoleptics. Studies are showing that the medicine, which is sold as Provigil, could help people with sleepiness associated with depression, Parkinson's disease and other disorders, she said.
"There are so many conditions where people have pathological sleepiness where we can help them," said the spokeswoman, Sheryl Williams. "Can we stop people from using the product for other things? Absolutely not, but the right place to be is in treating serious medical problems."
Once a drug is approved for one use, doctors are free to prescribe it for others. Williams said most of the medicine's "off-label" use was in treating psychiatric and neurological conditions. "We have not seen in our tracking data a significant proportion of patients with nonmedical conditions," she said.
But treating sleepiness can blur the line between medical disorders and lifestyle problems, since sleepiness is not a disorder. The shift workers in Mitler's study, for example, are known to be at heightened risk for accidents and to have increased medical problems associated with their irregular sleep. But there may not be anything intrinsically wrong with them since their problems often go away when they resume normal schedules.
Yet, doctors have classified sleep disturbances caused by the workers' lifestyle as a disorder. The American Psychiatric Association, for instance, says, "Circadian Rhythm Sleep Disorder" can occur when people's "circadian sleep-wake cycle is normal" but there is a "conflict between the pattern of sleep and wakefulness generated by the circadian system and the desired pattern of sleep and wakefulness required by shift work."
"These individuals are impaired," Mitler said. "Whether you call it a disorder or not is less important than the fact that they are impaired. Physicians have found themselves in the mix simply by declaring this a treatable disorder."
Cephalon eventually would like modafinil to be recognized as a treatment for all sleepiness associated with any disorder. But in warning the company about its promotional materials in January, the FDA noted that "Provigil is not approved to treat such symptoms as sleepiness, tiredness, decreased activity, lack of energy and fatigue."
"Provigil is indicated to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy," the FDA wrote to a senior official at the company Jan. 3. "Provigil is not approved for use as a daytime stimulant."
After Cephalon agreed to alter its marketing materials, the FDA considered the matter resolved.
Notwithstanding the FDA's protests, there is every indication that modafinil is effective in keeping healthy people awake. It may soon be common for shift workers, soldiers and truck drivers to pop the pills before embarking on long journeys or difficult projects.
Nancy Wesensten, a researcher at the Walter Reed Army Institute of Research in Silver Spring, has shown that healthy people who have been kept awake for 54 hours -- more than two nights -- still function effectively when given modafinil. The drug seems to work on other species, too: At the University of Pennsylvania, scientist Joan Hendricks has even found that modafinil helps sleep-deprived fruit flies perk up.
"It has a much gentler effect on promoting wakefulness" than amphetamines and conventional stimulants, said Scammell, the Harvard neurologist. "Many people feel comfortably awake -- they don't feel wound up, jazzed or euphoric. That's what makes it attractive to doctors. We are always worried that amphetamines may not be used properly. The abuse potential [of modafinil] is low."
He pointed out that the exact mechanism of modafinil is not understood. For example, while many researchers believe that the medicine doesn't affect the brain's dopamine system -- a neural mechanism known to underlie many addictions -- this hasn't been conclusively demonstrated. About 1 in 10 people on modafinil have headaches, and smaller numbers feel some nausea, he said.
Scammell, Mitler and others who study the medicine warn that talk of replacing sleep altogether is foolish. Other chemicals have been similarly touted -- and then found to be harmful.
"People were using [amphetamines] to stay awake for a number of days at a time -- there were a lot of problems associated with that," said John Caldwell, a research psychologist at the U.S. Army Aeromedical Research Lab at Fort Rucker, Ala., who has conducted experiments to show that sleep-deprived helicopter pilots perform better when given modafinil.
"Who knows what will happen with modafinil?" he said. "We don't know why sleep has the restorative effect it does. Given we don't understand the nature of sleep, I don't think it's a good idea to try to replace it with a drug of any description."