New Drug for Narcolepsy
 By: Judy Foreman
04/09/02  

Mary Rourke, a 55-year old teacher from Salem, N.H., used to nod off all the time as a child, but people just shrugged and said, “Oh, she must be very tired,” she recalls.

Then, as an adult, she began having attacks in which her muscles would lose tone and she’d fall– every time she laughed or felt any strong emotion. “I was constantly falling,” she says. “If you told me a joke, I’d flip. I couldn’t be around people.”

In Massachusetts, a 49-year old nurse from Norwood who asked that her name not be published also used to crash helplessly to the floor whenever she laughed or got angry, a fact her children quickly learned to exploit. “I couldn’t yell at my kids when they were younger because if I got too mad, I couldn’t stand up,” she says.

Things were even worse for Bob Cloud, a 58-year old lawyer from Cincinnati, Ohio. It was bad enough falling asleep talking to judges, he says, but one day he went limp while swimming and had to be rescued.

At least, he says, that provided a “great educational opportunity” to tell stunned onlookers what was really wrong: A brain disorder called narcolepsy, characterized by extreme daytime sleepiness and caused by low levels of a brain chemical called hypocretin. In many cases, low hypocretin levels also cause cataplexy, sudden loss of muscle tone due to the intrusion of dreaming (REM) sleep in the waking state.

Though the true numbers are probably higher because many people go undiagnosed for years, narcolepsy is believed to affect at least 140,000 Americans and 3 million people worldwide – more than are affected by some better-known diseases like cystic fibrosis and muscular dystrophy.

Yet stunning brain research in the last three years, along with the hoped-for approval this spring of a controversial new cataplexy drug called Xyrem – known on the street as the date-rape drug, GHB - are catapulting this once-hidden condition into the limelight.

With luck, the research on narcolepsy and cataplexy – essentially, disruptions in the body’s normal sleep-wake cycles – may lead to novel treatments for insomnia and depression as well.

And there’s another reason for the limelight: A remarkable degree of cooperation on the Xyrem/GHB issue by Congress, the US Food and Drug Administration and law enforcement officials that shows that it is possible to treat the same substance as both legitimately needed by desperate patients and subject to criminal penalties when abused.  

In the illicit street form, GHB (gamma hydroxybutyrate), has been blamed for dozens of deaths and countless sexual assaults. The colorless, odorless liquid can be slipped into someone’s drink. It is so simple to concoct at home that “a 9-year old can make it,” says Bob Gagne, a public affairs consultant for Orphan Medical. “I stumbled upon a crockpot recipe” for one form of the drug on the Internet, he notes. Some people also drink industrial chemicals such as GBL (gamma butyrolactone) for their GHB-like effects.

Because GHB is also believed to promote the body’s production of growth hormone, some body builders take illicit forms of the drug to increase muscle bulk.

All in all, a dicey substance for a pharmaceutical company to pursue. But in the early 1990s, Congress, concerned that big, profit-minded pharmaceutical companies were showing little interest in making drugs for so-called “orphan diseases” passed legislation encouraging companies to make such drugs. (Orphan diseases are those that affect 200,000 or fewer people – a small market.)

So Orphan Medical, Inc. of Minnetonka, Minn. began researching Xyrem. It’s still not quite clear how it works, though it may act through a brain chemical called dopamine. It is clear that Xyrem seems to reduce cataplexy attacks, and restore restful sleep for narcoleptics, who, despite overpowering sleepiness during the day, wake up frequently at night. Indeed, Mary Rourke, Bob Cloud and the Massachusetts nurse have all taken Xyrem under research protocols – and all say it has significantly improved their lives.

Though GHB was classified in March, 2000 as a Schedule I (most restricted) controlled substance, its potential as the prescription drug Xyrem for cataplexy (but not narcolepsy) meant that it was recommended as “approvable” last summer by an advisory committee to the FDA. The agency usually follows the recommendations of such committees. To make sure it does not get into the wrong hands, Orphan Medical is setting up a special distribution system so that all prescriptions will be filled by one central pharmacy.

To be sure, there are skeptics. Dr. John Winkelman, medical director of the sleep health center at Boston’s Brigham and Women’s Hospital, says, “I think the jury is still out on Xyrem because of concerns about potential abuse.”

But other doctors are as positive as patients. “Many people are transformed by it,” says Dr. Emmanuel Mignot, a professor of psychiatry and behavioral science at Stanford University Medical School.

Some people with cataplexy have as many as 15 to 20 falls a day, says Dr. Michael Biber, medical director of Neurocare, Inc. in Newton. “People are unbelievably disabled.” Yet on Xyrem, which he has tried on three patients so far,  people can become “almost completely free of symptoms.”

But just as important as the advent of Xyrem is the remarkable confluence of brain research on the triggers for narcolepsy, notes Dr. Jerome Siegel, professor of psychiatry and behavioral sciences at UCLA and chief of neurobiology research at the Sepulveda VA Medical Center in Los Angeles.

“What is extraordinary is that everything has been done in the last three years,” adds Mignot, the Stanford narcolepsy researcher.

In 1998, while looking for brain chemicals believed to control appetite,  two independent teams – one in San Diego, one in Dallas - discovered a neurotransmitter in a part of the brain called the hypothalamus. It quickly acquired two names - hypocretin and orexin – and it is made by only by a few cells in the hypothalamus. Significantly, hypocretin-producing cells in the hypothalamus connect to other parts of the brain and brainstem that control arousal and muscle tone.

Curious, the Texas team went on to see what would happen if they deleted, or “knocked out,” the gene for hypocretin in mice. To their surprise, mice with the missing hypocretin gene seemed to wander around normally, then suddenly drop in their tracks, just like narcoleptics with cataplexy. Also like narcoleptics, the knock-out mice began their night’s sleep abnormally - with REM, instead of non-REM sleep.

Meanwhile, unaware of this work, Mignot’s team at Stanford University was trying to figure out the genetic causes of narcolepsy in dogs.

Within weeks of each other in 1999, the Stanford and Texas teams reported work that dovetailed perfectly. The Stanford team found that dogs with narcolepsy have a mutation in the gene for the hypocretin receptor. The Texas team found that mice missing the gene for hypocretin itself showed behavior remarkably similar to narcolepsy.

“It was quite amazing and convincing,” says Siegel of UCLA. The cause of narcolepsy suddenly seemed obvious: lack of hypocretin, or its receptor.

In early January, 2000, Mignot’s team reported that human narcolepsy patients had low levels of hypocretin in the fluid that bathes the brain and spinal cord. Another key clue.

But an important step remained. So both Mignot’s group at Stanford and Siegel’s at UCLA obtained brain tissue from narcoleptics who had died and they, too, published their findings in the fall of 2000 within weeks of each other. Both teams found that almost all of the hypocretin-producing cells in the hypothalamus of people with narcolepsy were missing.

Moreover, Siegel’s group found that there was scar tissue where hypocretin-producing cells should have been, a clue that (unlike dogs, in whom narcolepsy is often hereditary) people who develop narcolepsy are born normal and subsequently suffer damage to these cells, most likely because of a misguided attack on these cells by the immune system.

It’s still not clear why many people with narcolepsy also have cataplexy while others don’t. But a number of companies are now scrambling to make narcolepsy drugs that mimic hypocretin to restore normal levels.

In the meantime, prescription stimulants such as Provigil, Ritalin and Dexedrine often help people with narcolepsy stay awake during the day. And anti-depressants such as Tofranil and Prozac can partially control cataplexy. If Xyrem is approved, it may prove a valuable addition to the medical arsenal.

Longterm sufferers like Mary Rourke are crossing their fingers. Because she participated in a research study on Xyrem, Rouke has been allowed to take the drug, even though her participation in the study is over. She says it has changed her life.

Recently, she was standing in her classroom when a student snuck up behind her and said, “Boo!”

“If I hadn’t been taking this drug,” she says, “I would have gone right down.”

Judy Foreman is a Lecturer on Medicine at Harvard Medical School and an affiliated  scholar  at the Women’s Studies Research Center  at Brandeis University.. Her column appears every other week. Past columns are available on www.myhealthsense.com.


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