Coming Soon: A New PR Campaign To A TV Set Near You.

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http://www.nytimes.com/2004/01/13/health/13SLEE.html?th

 

January 13, 2004Putting a Price on a Good Night's SleepBy ANDREW POLLACK

 

Americans are about to be reminded again how much they need sleep — and sleeping

pills.

 

A new effort appears to be developing to expand the use of sleeping pills, which

because of their potential for abuse have long had a reputation as being in some

ways more dangerous than the insomnia they are meant to treat.

 

Some sleep experts say newer pills are safer than the ones that once caused

deaths from overdose. Moreover, some say, there is growing evidence that

insomnia is a serious medical condition, not just a nuisance.

 

" Slowly, we are beginning to identify that insomnia does have some risks

associated with it, and when that happens there will be more press to treat it

aggressively, " said Dr. Michael H. Bonnet, director of the sleep laboratory at

the Veterans Affairs Medical Center in Dayton, Ohio.

 

But part of the new push is driven by drug company marketing. Two new sleeping

pills are expected to be available by the end of next year and their

manufacturers hope to have them approved for broader and longer-term use than

recommended for previous pills. And the companies are expected to advertise

their products, and the problem of insomnia, heavily.

 

Sepracor, which makes one of the new drugs, recently financed a press seminar on

insomnia. The other drug will be marketed by Pfizer, whose vast sales force and

ample advertising have helped make best sellers of drugs like Viagra, the

cholesterol fighter Lipitor and the painkiller Celebrex.

 

" What Pfizer sees here is a wonderful opportunity for what they've done " with

those drugs, said Gary A. Lyons, president and chief executive of Neurocrine

Biosciences, which developed the drug, indiplon, and licensed it to Pfizer.

 

Only a small fraction of insomniacs now take prescription sleep-inducing drugs,

Mr. Lyons said. " This is unquestionably one of the largest potential

pharmaceutical markets in the world, " he added.

 

As a hint of what might come, a public relations campaign was mounted a decade

ago when Ambien, now the best-selling sleeping pill, was introduced.

 

" With a public fearful of sleep medications and reluctant to admit having

insomnia, Edelman and client Searle teamed up with the National Sleep Foundation

and leading academic institutions to address `Sleep in America,' " Edelman, a

public relations agency, recounted in a history of its first 50 years.

 

By emphasizing the safety problem of driving and working while sleepy, " Edelman

helped Searle revitalize a flagging sleep market, " the company wrote.

 

Dr. Daniel F. Kripke, professor of psychiatry at the University of California at

San Diego, said that drug companies and some sleep doctors, many of them

consultants for drug companies, were exaggerating the seriousness of insomnia.

 

" Frankly, worrying people about sleep is good for the drug companies, it's good

for the sleep clinics and maybe it helps people get research funding too, " said

Dr. Kripke, who runs a Web site, the Dark Side of Sleeping Pills, at

www.darksideofsleepingpills.com.

 

There is little evidence that sleeping pills meaningfully improve sleep over the

long run, he said. There is even evidence from a survey in the 1980's that

regular users of sleeping pills tend to die younger than non-users.

 

But most experts dismiss that evidence. " He's about the only person I know of

who supports that view, " said Dr. Andrew D. Krystal, associate professor of

psychiatry and director of the sleep research laboratory at Duke who has

consulted for Sepracor. He said the consensus was that insomnia is a serious

condition and that pills were becoming safer.

 

" I believe we'll see a shift toward people having effective treatments available

that doctors are willing to prescribe and patients are willing to take, " Dr.

Krystal said.

 

Estimates of the number of people with insomnia vary widely. About 40 percent of

adult Americans have at least occasional trouble sleeping, according to the

National Sleep Foundation, which promotes understanding of sleep disorders and

research on them. Some insomnia is temporary, caused by job worries, for

instance.

 

But an estimated 10 to 15 percent of adults have severe or chronic insomnia.

Many cases appear to be caused by an underlying condition like depression or

painful arthritis, and the best approach is to treat that underlying condition.

But for perhaps 15 to 30 percent of those with chronic insomnia, no known

underlying disorder can be found.

 

Several studies have shown that people with insomnia are more likely than others

to become depressed.

 

Lack of sleep, though not always caused by insomnia, can interfere with social

life, job performance and driving. At least one study has shown that sleep

deprivation results in poor glucose metabolism, a hallmark of diabetes.

 

Still, scientists cannot yet point to any study showing that treating insomnia

with sleeping pills staves off depression or other diseases. Yet some experts

say understanding the dangers of insomnia is only a matter of time.

 

" Some day we'll see that like smoking, this isn't good for you, " said Dr.

Michael L. Perlis, associate professor of psychiatry and director of the sleep

research laboratory at the University of Rochester.

 

Sleeping pills, technically called hypnotics, have gone through several

generations. Decades ago, the common pills were barbiturates, which were

addictive and led to many deaths from accidental or deliberate overdoses.

 

By the 1970's, they were largely displaced by drugs called benzodiazepines,

which included the sleeping pills Halcion and Restoril and the tranquilizer

Valium.

 

With these drugs it was much more difficult to die from an overdose, though they

could still be dangerous if paired with alcohol. Halcion was taken off the

market in some European countries and the recommended dose in the United States

was reduced after some users suffered amnesia, hallucinations and other side

effects. There is evidence that benzodiazepines can be addictive and that people

develop a tolerance, so the pills eventually lose effectiveness.

 

In 1983, the National Institutes of Health issued a consensus statement from

experts urging doctors not to prescribe such pills for more than three or four

months. The Drug Enforcement Administration considers the drugs Schedule IV

controlled substances because of a limited potential for abuse.

 

In the 1990's, drugs known as non-benzodiazepines, exemplified by Ambien and

Sonata, entered the market. Because many doctors perceive it as safer than the

older drugs, Ambien, now sold by Sanofi-Synthelabo of France, accounts for

two-thirds of prescriptions of nonbarbiturate hypnotics, according to IMS

Health, a market research firm.

 

Though chemically different from the older drugs, Ambien works in a similar way.

All the drugs bind to receptors in the nervous system meant for a

neurotransmitter called GABA. The binding enhances the transmitter's effects,

which slow the nervous system. Though the older drugs bind to all three of the

main types of GABA receptors, Ambien, known generically as zolpidem, binds

mainly to the one type thought to promote sleep.

 

Though some studies in animals have suggested that this causes fewer side

effects, Ambien has never been tested in clinical trials lasting more than a few

weeks. So its label recommends use for only 7 to 10 days, with prescriptions not

to exceed 30 days. Like the older drugs, it is still a controlled substance and

its label mentions the potential for dependence and tolerance.

 

Dr. James K. Walsh, president of the National Sleep Foundation and head of a

sleep research center affiliated with two hospitals in St. Louis, said newer

drugs were being unfairly tarnished by " some myths and regulatory restraints

that have evolved over the years. "

 

Those restraints have " led patients to be fearful of medications that they don't

need to be fearful about, in my opinion, " said Dr. Walsh, who is a consultant to

many drug companies.

 

The labeling of the drugs for only short-term use is a problem, some doctors

say, because those most in need of treatment are chronic insomniacs. " There's a

real logical inconsistency between what we know about insomnia and how we treat

it, " said Dr. Daniel J. Buysse, professor of psychiatry at the University of

Pittsburgh.

 

While some people do take the sleeping pills for months at a time, others use

over-the-counter antihistamines or prescription antidepressants that have

sedation as a side effect. But those drugs have not been approved for insomnia,

Dr. Walsh said, so scientists know less about their effects on sleep than they

do for sleeping pills.

 

Some sleep specialists have been urging the National Institutes of Health to

develop a new consensus statement about insomnia and its treatment, and that is

expected to happen in the next year or two. The N.I.H. has already stamped the

1983 statement obsolete.

 

The move toward longer use of sleeping pills could be spurred by the new pills

coming to market, which for the first time are being tested for months instead

of weeks. Sepracor, which is based in Marlborough, Mass., sponsored a clinical

trial showing that its drug, Estorra, worked for six months without loss of

effectiveness, providing about 35 minutes more sleep per night than a placebo.

 

The Food and Drug Administration is expected to decide whether to approve

Estorra by the end of February, after postponing its deadline of last November.

Indiplon, the Neurocrine and Pfizer drug, is in the final stages of clinical

trials and could reach the market next year.

 

Estorra and indiplon work the same way as Ambien. Estorra, known generically as

eszopiclone, is a derivative of zopiclone, a non-benzodiazepine sold outside the

United States. " These are quantitative not qualitative differences, " said Dr.

Thomas Roth, director of the sleep center at Henry Ford Hospital in Detroit.

" We're not talking about a new chemical class. "

 

So besides seeking approval for longer-term use, the newcomers will try to

distinguish their drugs from Ambien by how long their drugs last in the body. If

a drug does not last long enough, people can wake up again, a problem that has

hurt sales of Sonata. If the drug lasts too long, people can feel groggy when

they are supposed to be awake, a side effect that increases the risk of

accidents.

 

Estorra lasts somewhat longer than Ambien so perhaps could provide longer sleep.

Sepracor says the drug does not cause hangovers.

 

Neurocrine Biosciences, based in San Diego, is developing two forms of indiplon.

A short-acting form would be for people who wake up in the middle of the night

or too early in the morning and want to go back to sleep without oversleeping.

 

The other version of indiplon will have a coating that releases some drug

immediately to induce sleep at bedtime and a core that will release more later

to keep people sleeping through the night.

 

Sanofi-Synthelabo is developing a similar pulsed-release version of Ambien,

which it hopes to have on the market by the end of 2005, to fend off not only

the new rivals but also generic versions of Ambien that will be allowed in 2006.

 

Some scientists say true breakthroughs will require drugs that work through new

mechanisms, like adjusting the body's natural sleep-wake cycle.

 

Takeda Chemical Industries, Japan's largest pharmaceutical company, is in

late-stage trials of a drug, Ramelteon, that mimics melatonin, a hormone

released in the brain in response to darkness that helps induce sleep.

 

Many people take nutritional supplements containing melatonin, though experts

say it is not clear they are effective.

 

Dr. Stephen M. Sainati, vice president at Takeda Global Research and

Development, says that while melatonin binds to three receptors and had multiple

effects, Ramelteon binds to only the one connected with sleep. He said the drug

should have " absolutely no abuse liability whatsoever. " Takeda hopes to file for

approval by early 2005, he said.

 

Drugs working through yet other mechanisms are further back in development.

 

Dr. Bonnet, of Dayton, who is also a professor of neurology at Wright State

University, said that even with improvements in sleeping pills, doctors might be

cautious about prescribing them.

 

" We've forgotten the mistakes of the past so now we can go back and repeat

them, " Dr. Bonnet said. " People are going to pause and think, `Are we really

beyond those problems?' "

 

Copyright 2004 The New York Times Company |

 

 

 

 

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