Dawn of A New Sleep Drug?
Prescription Pills Hope To Trump Sedatives; Less ‘Hangover’ Effect
For those who have trouble sleeping, there may soon be new ways to summon the sandman.
Several pharmaceutical companies are working on new approaches to treat insomnia. The compounds are meant to work differently than current leading sleep aids such as Ambien and Lunesta, which, while generally safe, can have troubling side effects because they act on many areas of the brain. By contrast, many of the drugs being developed target particular systems responsible for sleep and wakefulness. The hope is that they will have fewer side effects and less potential for addiction and cognition problems the next day.
New drugs are in the works to treat insomnia, which affects 10% to 30% of Americans (and more women than men). Andrea Peterson explains.
About 30% of American adults have insomnia symptoms each year, scientific studies estimate. Some 10% of the population has chronic insomnia, which is generally defined as having difficulty sleeping at least three times a week for a month or more. Chronic insomnia sufferers also feel tired, cranky or foggy-headed during the day.
Insomnia comes in various forms. Some people have a tough time falling asleep and others wake in the middle of the night and have trouble getting back to sleep. Some people rise for the day too early. Insomnia can increase the risk for other conditions, including heart disease, diabetes and depression.
Merck & Co. is investigating a compound that inhibits the action of orexin receptors, which in turn interferes with the activity of orexin, a chemical in the brain that produces alertness. The company hopes to file for Food and Drug Administration approval by next year. Last fall, Somaxon Pharamaceuticals Inc. launched Silenor, a drug that blocks histamine receptors, which are important in regulating wakefulness. Neurim Pharmaceuticals Ltd. is seeking FDA approval of Circadin, a prescription form of the sleep-promoting hormone melatonin. The drug, which delivers melatonin in a prolonged-release formulation, is already available in Europe, Asia and the Middle East. Other research efforts are targeting specific serotonin receptors, a move that could promote deeper stages of sleep. There is also growing interest in a form of cognitive behavioral therapy that treats insomnia.
The most popular prescription drugs to help with sleep, such as Ambien CR and Lunesta, work on a neurotransmitter known as GABA that is found throughout the brain. Several new, more targeted, approaches are in the works or have recently been approved, including:
- A drug that inhibits the action of orexin receptors, which in turn interferes with the activity of orexin, a chemical in the brain that produces wakefulness.
- Compounds that work on serotonin, a neurotransmitter related to alertness.
- Prescription melatonin, which bathes the brain in the sleep-inducing hormone.
- A drug that blocks histamine receptors, which are important in regulating wakefulness.
Sanofi-Aventis’s insomnia medicine Ambien
Some companies have halted work on new insomnia drugs. GlaxoSmithKline PLC and Actelion Ltd. in January said they discontinued development of an orexin-receptor antagonist, citing safety concerns. Glaxo didn’t elaborate, but said at the time that it had conducted additional clinical studies in part to assess the drug’s “tolerability profile.” In 2009, Sanofi-Aventis shelved its plan to develop eplivanserin, a serotonin antagonist. The company’s announcement said it had received an FDA request for additional information regarding “benefit-risk,” but didn’t give specifics. And last week, the FDA denied Transcept Pharmaceuticals Inc. approval of a form of zolpidem, the generic form of Ambien, that patients could dissolve under the tongue if they wake up in the middle of the night and have trouble getting back to sleep. The FDA cited concerns that residual amounts of the drug in a patient’s body could be unsafe if the person were to drive the next day.
Americans spent about $2 billion on prescription sleep drugs in 2010, according to IMS Health, which tracks pharmaceutical sales. Although the number of prescriptions written rose 23% to about 60 million last year from 48.9 million in 2006, total dollar sales slid as cheaper generic versions of drugs like Ambien have entered the market. Sales of prescription sleeping pills were $3.6 billion in 2006, IMS said. Beyond that, doctors say many people self-treat their insomnia with alcohol or over-the-counter medications, including Tylenol PM and Benadryl, which usually contain some form of an antihistamine.
The most common sleep-aid drugs, called benzodiazepine receptor agonists, alter the activity of gamma-aminobutyric acid (GABA), a neurotransmitter that is thought to facilitate sleep. These are sedatives that “slow the brain down and put it to sleep,” says James K. Walsh, executive director and senior scientist of sleep medicine at St. Luke’s Hospital in St. Louis, who has done consulting work with various drug companies. GABA is found throughout the brain and doesn’t affect only sleep.
The GABA drugs are effective, doctors say, but can come with significant side effects including daytime drowsiness, sometimes called the hangover effect, and memory and balance problems. They can be dangerous when combined with other sedatives, notably alcohol, and there are some concerns that the medications can be addictive and abused. The drugs also can cause people to engage in strange nocturnal activities—eating, sex and driving—that they don’t recall the next day. “Often you get the story that it worked for a few weeks, then it stopped working and [the patient has] to take more,” says Michael J. Sateia, professor of psychiatry, sleep medicine at Dartmouth Medical School, who has done work for some drug companies.
Drug companies say they expect the compounds being developed will have fewer side effects, be less addictive and interact less with alcohol. They say early clinical trials have so far supported those hypotheses, although evidence is preliminary.
Sleep No More
10% of the U.S. population has chronic insomnia. 60 Million prescriptions for sleep aids were written last year. 30% of Americans suffer symptoms of insomnia in any given year. 2 times as many elderly women as men have trouble sleeping. 3 forms of insomnia: difficulty getting to sleep, waking up during the night and rising extremely early.
In a phase IIb clinical trial of Merck’s new orexin drug, the most common side effects included dizziness, vivid dreams and drowsiness. Somaxon’s Silenor, approved for use by those who have trouble staying asleep at night, can cause drowsiness, the company said. The company says that, unlike Silenor, antihistamines like Benadryl don’t strongly hit the specific histamine receptor that is closely associated with sleep. The active ingredient in Silenor, doxepin, has been used for years in higher doses as an antidepressant.
Studies show that cognitive behavioral therapy for insomnia, known as CBT-I, can be as effective as medication for treating chronic insomnia. The Veterans Health Administration launched a program last year to train clinicians to deliver CBT-I to veterans, and so far more than 140 clinicians have been trained. CBT-I typically includes “sleep restriction,” or limiting the amount of time patients spend in bed when they’re unable to sleep, and “stimulus control,” which means keeping the bedroom off-limits for such things as TVs and computers. “There are patients who literally move their entire house into their bedroom,” which then becomes associated with a host of distractions instead of sleep, says Michael Perlis, director of the behavioral sleep medicine program at the University of Pennsylvania, who has done work for drug companies. Patients are also taught “sleep hygiene”—avoiding caffeine and alcohol and sleeping in a cool, dark room, for example.
Nearly everyone experiences a few nights of tossing and turning here and there, what is known as transient insomnia. To prevent it from mushrooming into a chronic problem, try to “tough it out,” says Dr. Perlis. That means no napping or going to sleep earlier the next night. And if you do conk out and end up taking a nap, Dr. Perlis says to “balance the books” by going to bed even later than usual the next night.
Many medical conditions can contribute to insomnia including depression, sleep apnea, heart failure, arthritis and chronic pain. There is mounting evidence that a predisposition to insomnia may be partly genetic as well.
Stress, alcohol and caffeine use and menopause can also fuel insomnia. Sleeping pills “are not an alternative to taking a look at your life and figuring out why you’re having a sleeping problem,” says Sandra Fryhofer, an internist in Atlanta, Ga., and a past president of the American College of Physicians.
Wall Street Journal Health Industry July 19 2011