Medicine: This Will Keep You Awake

LIKE MOST BUSY DOCTORS, Center City internist Matthew Frankel makes a valiant effort to keep up with the latest pharmaceuticals. But with medications flooding the market, some simply escape his radar. So it wasn’t surprising that six years ago, he was unfamiliar with a new drug called Provigil, which was FDA-approved for excessive fatigue related to narcolepsy. It caught his attention when a letter from an insurance company landed on his desk, saying the company wouldn’t pay claims for Provigil without a validated diagnosis of narcolepsy. “I have several thousand patients, and fewer than a handful are true narcoleptics,” Frankel explains. “But fatigue is one of the most common complaints I get in my office. Everybody’s stressed and short on sleep.”

When an invitation to a dinner seminar about the drug came from Cephalon, the Chester County pharmaceutical company that manufactures Provigil, Frankel promptly accepted. While the lecture was informative, the real excitement came in the Q&A that followed. One doctor stood up and asked if Provigil could be used for patients who were simply tired. “Soon the audience is going back and forth about how they’re prescribing Provigil for this and that, what impressed them, how it worked like a stimulant but wasn’t addictive and didn’t cause jitters,” Frankel recalls. “I went to two or three of these seminars, and it was always the doctors, not the company, touting the drug for all kinds of problems.” Since then, Frankel has prescribed Provigil about 50 times — and would do it more if he weren’t uncomfortable prescribing drugs off-label.

If you haven’t yet heard of Provigil, you will. Although it’s supposed to be used for only three medical conditions — narcolepsy, shift-work sleep disorder and sleep apnea — you don’t have to be a drug salesman to see that its potential goes far beyond that. Indeed, it may be the perfect drug for our busy 21st-century lives. A potent waker-upper, it can give you the energy infusion of several cups of strong coffee or the kick-start of an amphetamine, but without the accompanying jitters and heart palpitations. Moreover, its rush is no more potent than that of a sugar-packed candy bar — and it’s considered perfectly safe and non-addictive.

That’s one reason why it’s fast becoming the physician’s off-label drug of choice for the exhaustion and lethargy associated with problems as varied as depression, head trauma, Parkinson’s disease and multiple sclerosis. It’s also why some people have started using it as a performance enhancer. The Air Force gives it to pilots to help them stay awake and alert on long missions, while athletes have admitted to using Provigil as a performance-booster. And it’s gaining an underground following among college students at exam time, as well as with competitive workaholics looking for an edge on the achievement treadmill.

In fact, in a sleep-deprived society where nobody ever seems to feel well-rested, it’s easy to see how a safe drug that keeps tiredness at bay would be deliciously appealing even to perfectly healthy people. Provigil could become, as Gary Glass, a forensic psychiatrist in Egg Harbor Township, predicts, “the Viagra of neurology”: the ultimate lifestyle drug.

The problem is that Provigil hasn’t been approved for any of these lifestyle uses — and Cephalon has to be careful how it straddles the fine line between on- and off-label marketing. In January 2002, the company was slapped with a warning letter from the FDA, accusing it of overreaching in its promotional materials. The company issued new brochures, and the incident was laid to rest, but Frank Baldino, Cephalon’s founder and CEO, isn’t taking any chances. When I ask how he feels about Provigil’s widespread popularity for unintended (and unapproved) purposes, he answers somewhat playfully, “Well, I have heard that Provigil is used quite broadly.”

The deeper issue is whether a drug intended to treat disease should be used by healthy people to enhance their lifestyle. Using Provigil for a recognized medical condition like narcolepsy is one thing. “But if you’re trying to boost performance or fight jet lag or take it because you want to work two jobs, that’s a lot more dubious,” says David Dinges, a Ph.D. researcher and chief of the Division of Sleep and Chronobiology at Penn’s School of Medicine. “What message do we send to our children — that it’s fine to improve your lifestyle by chemically manipulating your behavior?”

Penn bioethicist Art Caplan believes it’s already too late to ask that question. “In 30 or 40 years,” he says, talking about Provigil, “people will think it’s bizarre to walk around tired.”

FRANK BALDINO IS RARELY at a loss for words. A peripatetic workaholic who can have breakfast in Nice and lunch in Geneva, and end the day with a horseback ride or a margarita by the pool of his Chadds Ford farm, Baldino, 53, has built Cephalon into a 3,000-employee company that’s already outgrown its glass-and-red-concrete headquarters in a bucolic industrial complex in Frazer. “He’s impressively multi-dimensional,” says Rob McCord, a venture capitalist and chairman of the Eastern Technology Council, one of several boards Baldino sits on. “The breadth of his thinking can be intimidating.”

Variously described by associates as charismatic and brooding, charming and arrogant, Baldino comes from an Italian family ruled by a matriarchal mamma whose mantra was “College, college, college.” He’d already displayed a scientific bent by his 11th birthday, when he asked for a microscope instead of a bicycle. After earning a doctorate in pharmacology from Temple, he spent several years as a senior biologist in the life sciences division of DuPont. His nascent entrepreneurial instinct told him that even if he discovered a major drug, he’d never have a huge impact on the Wilmington behemoth. So he left in 1987 and raised a half million dollars to start Cephalon, a company he envisioned as a New Age pharma embracing cutting-edge technology. In less than five years it went public, and grew to 130 employees.

In 1997, however, Cephalon’s survival was abruptly threatened when the FDA rejected its application for a new drug to treat ALS, a.k.a. Lou Gehrig’s disease. Suddenly, its pipeline was empty, because in one of his typical risk-taking moves, Baldino had decided to sink much of his company’s assets into the drug’s development. He recalls signing off on the press release that announced the bad news — as he left the building, the power failed, making it literally and figuratively one of the darkest days of his life. What rescued him and Cephalon was Provigil.

Back in the late ’70s, scientists at a little laboratory in France were studying the antidepressant potential of a compound called modafinil. One of the cannier researchers noticed that rats dosed with modafinil paced their cages 24/7, while the control rats slept soundly, curled up in a corner. A light bulb went off. Forget depression. Why couldn’t this drug be used to keep people awake, especially those suffering from untreatable conditions like narcolepsy, whose victims inexplicably fall asleep anywhere, anytime? In the early 1990s, as modafinil was being talked about in France’s scientific community, it came to the attention of Baldino, who was on the prowl for a promising drug to balance the uncertainty of the research-and-development division of his burgeoning biotech. The scientist in Baldino, who had published more than 100 studious papers in peer-review journals, immediately grasped that modafinil was an entirely new kind of arousal drug. The businessman in him saw the enormous market potential.

In 1993 he bought the rights to the undervalued compound for $1,000,000. Today he calls that licensing “the best deal I ever made.” (Eight years later, he purchased the entire French laboratory for $450 million.) It took about six years for modafinil to navigate the FDA approval process in the U.S.; luckily for Cephalon, it was green-lighted not long after that ALS drug tanked. Under the brand name Provigil, modafinil exploded onto the American market and generated $25 million in sales the first year — nearly double its projection. Today, the drug that woke up a tired country accounts for nearly half of Cephalon’s billion-dollar-plus revenue.

Nobody seems particularly concerned that scientists haven’t figured out how Provigil works. After all, lithium, a popular treatment for manic depression, is another effective drug whose mechanism isn’t clearly understood. This much is known about Provigil: It’s very different from classic stimulants like caffeine or amphetamines. Ritalin, Dexedrine and Adderall, a few of the better-known amphetamine-like drugs, get into the brain and fan out, attaching themselves to scattered sites called dopamine receptors. In contrast, Provigil appears to latch on principally to the frontal cortex — the thinking part of the brain that’s the seat of functions like wakefulness, focus and impulse control. By bonding to this particular site and ignoring the motor and reward systems, Provigil spares you the jumpy and jaggy side effects of amphetamines. At worst, it causes discomfiting but nonthreatening complaints like headache, nausea and mild anxiety.

One reason people may not care why Provigil works is that it works so well. Alan Carini (not his real name) is a 60-year-old retired marketing research manager and narcoleptic who’s been taking Provigil for the past four years. “I used to come home from work and immediately need a nap,” says Carini. “I never went out socially, and I always fell asleep at my desk. I couldn’t risk driving. Most weekends I spent in bed. Now I feel like a normal person. If I’d had a drug like this earlier in my life, I know I wouldn’t have missed out on as much. Maybe I’d have gotten promoted at work, or even gotten married.”

A local broadcaster depends on Provigil to help him handle the excessive sleepiness brought on by a medication he must take. “On the nights when my shift extends way past midnight and that wave of heavy lids hits with three hours yet to go, I take half a Provigil,” he says. “It’s like stripping caffeine of the parts that make you jumpy and nervous, and what’s left is the part that keeps you awake. It’s strong but not exhilarating. A real godsend.”

Even the United States Air Force has jumped on the bandwagon, in part due to an incident a few years back in which two American pilots accidentally killed four Canadian soldiers in Afghanistan, and their defense lawyers blamed the mistake on Air Force-issued Dexedrine. “We’re always looking for drugs that will safely enhance performance, especially under sleep deprivation,” says John Caldwell, a principal research psychologist with the Air Force research labs. In a series of double-blind studies testing Provigil against placebos, caffeine, and drugs like Dexedrine, the pilots given Cephalon’s wonder drug were shown to be less confused, more vigorous and alert, and better able to easily fall asleep after use. It’s currently taken by bomber teams and F-15 operators. “Unless something bizarre happens,” Caldwell says, “Provigil is here to stay.”

Is there a potential for addiction or abuse with Provigil? Not only is the answer no, but something astonishing happened when researchers at Penn studied the issue. Charles Dackis, of Penn’s Charles O’Brien Center for Drug Addiction, began hearing anecdotal reports from cocaine addicts that Provigil actually blocked their desire for coke. As soon as the drug got its FDA approval, Dackis started testing it on hundreds of coke addicts who were trying to kick the habit. The results were remarkable. “We know Provigil blocks the euphoria, and we think it also blocks the craving,” Dackis says. “In my 25 years treating addicts, never before has anybody told us they flushed their coke down the toilet.” The O’Brien Center is already using the drug in its clinical practice, and other drug treatment facilities around the country are actively testing it, too. One of Dackis’s patients, a 22-year, $1,000-a-week blow addict, told me that after his first dose of Provigil, “I just lost interest in cocaine. I didn’t want it anymore.”

At present, nearly 30 clinical trials in the United States are studying Provigil for everything from chemotherapy fatigue to schizophrenia. Some of those may lead to more FDA on-label approved uses, but most doctors aren’t waiting around for that to happen. Psychiatrists like Fort Washington’s Scott Fleischer are doling out Provigil to patients with depression, fibromyalgia, MS and dementia, where fatigue and lethargy aren’t the basic problem but are debilitating symptoms. “When it works, it’s really good,” Fleischer says. He’s given samples to some of his depressed patients who could barely get out of bed, and they tell him it’s like they’ve gotten their lives back. Then they find out they can’t get the prescription covered by insurance because they don’t have narcolepsy or sleep apnea, and they’re despondent because they can’t afford $7 a pill.

It doesn’t take a math genius to figure out that there aren’t nearly enough people suffering from narcolepsy, sleep apnea and shift-work sleep disorder to account for the millions Cephalon is raking in from Provigil. The off-label use of the drug certainly doesn’t bother Baldino. “When you’ve got a problem affecting millions of people and you provide a solution to the medical community, they’re going to take advantage of it,” he says. “How physicians use Provigil and for what purpose is their purview, not mine.”

That said, the company is trying to expand the drug’s approved uses — though not always successfully. This past August, the FDA, citing a problematic side effect, rejected Cephalon’s application for approval for Sparlon, a variant of Provigil geared to treat the huge attention deficit market. Baldino took the disappointment in his goal-oriented stride. “That’s life in a regulated world,” he says, “and this is a tough business.”

The company is also addressing the generic threat it faces when it loses market exclusivity with Provigil in six years, by developing an even more effective version, called Nuvigil, that could have more impact on cognitive functioning. Baldino’s view of the future? “Awake, alert and smart is the way to go,” he says.

PROVIGIL DOESN’T WORK FOR EVERYONE. A pain specialist at Penn tried it a couple of times after he heard raves from hospital residents, who take it for their chronic sleep deprivation. “It’s like your mind is alert but your body is tired,” he complains. “I felt jumpy, and I couldn’t process well. I’d get stuck in the middle of a thought.”

And sleep specialists, whose mission is to promote better sleep practices, not supply drugs to combat what nature can handle just fine on its own, are especially wary. “What worries me is the focus on getting away with less sleep, as opposed to getting the sleep you need,” says physician Victor Kim, a board-certified sleep specialist at Temple University’s Sleep Clinic.

Kim’s concern is valid. It turns out that Ivy League schools in particular are seeing a growing gray-market trade in Provigil (mostly purchased on the Internet). Taking enhancement drugs to improve test performance is a hotly debated topic among both students and faculty. Two articles have appeared in the Daily Pennsylvanian questioning the implications of Provigil as the new way to pull an all-nighter. Last spring, at an ethics conference at Penn under the sponsorship of the Penn Bioethics Journal, a packed session provocatively titled “Stimulant Use on College Campuses” focused almost entirely on modafinil. The ethical issue wasn’t so much should or shouldn’t it be used; kids are always going to find something to help them stay up and cram. The greater concern was over the inherent pressures to take Provigil in order to compete at school and at work if that’s what everyone else is doing.

Andrew Rosenthal, a recent Penn graduate and founding editor of the Journal, calls Provigil the overachiever’s dream drug. “It’s not a party drug,” he says. “It’s favored by kids who want an academic competitive edge. Students are really impressed by how they can stay awake and study late on it without feeling wired. Is that such a bad thing? It is a legal drug.” What concerns naysayers is whether it’s fair for some people to use a drug to enhance cognitive performance if it isn’t available to everyone at the student health center. That disadvantages kids who can’t get hold of any or don’t want to use medicinal study aids.

The questions of parity and pressure also bother Art Caplan, the wonderfully opinionated director of Penn’s Center for Bioethics. When you start to think about enhancement drugs, there are two problems, he says. One is access — the rich/poor axis. Rich kids can get the stuff with money or connections, and poor kids can’t. The other is coercion. “It’s not hard to imagine a scenario where everybody at my office or in my dorm is taking the stuff, and if I’m going to keep up, I have to take it whether I like it or not,” Caplan says. “I’m just waiting for the day that bosses start pushing it on workers.” But then, surprisingly, Caplan adds, “The world has always been and always will be an unfair place. Like it or not, enhancement is the wave of the future in medicine.” We’re already seeing that with Botox, cosmetic dentistry and breast implants.

Nobody gets overheated and says we should do away with courses that help people do better on SATs, Caplan argues. “But when it comes to biological or pharmacological intervention, we get goofy because it seems like we’re changing human nature. We like to reward things in life based on innate skill, and Provigil seems to be cheating. But if you take French lessons or study with a memory expert to get ahead, that’s fine. I think the whole notion of naturalness is nonsense. If you asked me to put my money on a chip pointing to where we’re headed, we’re all going down the Provigil route.”

THE TEMPTATION WILL BE HARD TO RESIST. I have to confess, I’ve already given in. For the record, let me state I’ve never even had a Valium. On the rare occasions I take a sleeping pill, I break it into three pieces. The idea of a drug that messes with my mind scares the hell out of me. But I’ve now tried Provigil twice. The first time, I was on deadline for this article. I got to bed way after midnight; then, the fire alarm in my building went off at 4 a.m. and I couldn’t fall back to sleep when the all-clear sounded. By morning I was so pooped that my head kept falling onto my keyboard. I’d gotten a five-pill sample pack of Provigil from a doc as part of my research, and now was the perfect time to try it.

I nervously stared at the little white oval in my hand, gulped it down with some water, and hoped I wouldn’t turn into a raving lunatic. For reasons I can’t explain, it seemed okay to take a drug to help me sleep, but a drug to keep me awake and sparking on all cylinders felt unnatural. Yet within a half hour, I was a new woman. The yawning vanished. I was alert and focused, and I worked like a demon at the computer until dinner. The only side effect was mild nausea, annoying but tolerable.

A few weeks later, on a trip to Europe, I couldn’t sleep on the plane, arrived totally wiped out, and had to be on the go all day. I pulled out two Provigils — one for me, and one for my husband, who had to drive for several hours to reach our destination. This time, I wasn’t even nauseous. We both sailed through the day and went to bed around 11. It was too good to be true, and that’s what scared me. It just feels wrong to take a prescription drug when I basically have nothing wrong with me that a nap or a good night’s sleep wouldn’t cure.

I still have two pills left. I’m haunted by the words of Art Caplan as he walked me to the door of his office: “Who wouldn’t want to take something that makes them alert but not crazy?”