The stories have been all over the news recently. A woman gets out of bed during the night and walks to the kitchen. There, in front of her husband, she rips open a bag of hamburger buns and devours the contents. Then, without saying a word, she returns to bed. A woman immobilized by a full-body cast somehow gets out of bed in the middle of the night, cooks herself bacon and eggs, and wakes up the next morning bewildered by the evidence of what she has done. A motorist involved in a minor traffic accident appears disoriented to police, and claims to have no memory of hitting another vehicle.
All of these people have one thing in common – they had taken zolpidem (Ambien), a popular prescription sleep aid, just before going to bed. Then, while apparently still asleep, they got up and felt a powerful urge to eat, or to get behind the wheel of their car and drive somewhere.
Some sleep specialists believe there is a direct correlation between zolpidem and these peculiar behaviors. “We're trying to retain a reasonable perspective,” said Mark Mahowald, MD, Director of the Minnesota Regional Sleep Disorders Center in Minneapolis. “The two things that predispose to these behaviors are alcohol and anything that causes sedation, such as sleeping medications. But these behaviors can occur in the absence of drugs or alcohol. Zolpidem appears to be a common culprit. However, it is also the most widely prescribed sleep aid. So whether it has a unique ability to cause these behaviors remains to be determined.”
A STUDY IN PROGRESS
Dr. Mahowald is working with Carlos Schenck, MD, a senior staff psychiatrist at the Sleep Disorders Center and Associate Professor of Psychiatry at the University of Minnesota, on a paper that will attempt to link zolpidem to nocturnal sleep-related eating disorder (NS-RED). They have identified 32 zolpidem users who have no memory of getting up to eat in the middle of the night after taking it. [Neurology Today first learned about the planned trial from an article in The New York Times in March. A class action suit against the company that makes the sleeping pill is under way.]
“This behavior is an admixture of wakefulness and sleep,” said Dr. Mahowald. “We can simultaneously have parts of the brain that are asleep and other parts that are awake. The motor part of the brain lets these people perform complex and protracted behaviors. However, the part of the brain responsible for monitoring what they do is asleep. From a scientific point of view, this behavior is fascinating.”
DEBATE ON CAUSES OF NIGHT-EATING
Other scientists are more skeptical that zolpidem is the cause of these episodes of NS-RED and sleep driving, however. They point out that more than 26 million prescriptions of the medication were written last year – nearly six times more than the combined number of prescriptions written for the two nearest competitors, eszopiclone (Lunesta) and zoleplon (Sonata).
“We have seen patients with sleep-related eating disorders for over 25 years at our sleep center who are taking no medication at all,” said Michael Thorpy, MD, Director of the Sleep-Wake Disorders Center at Montefiore Medical Center in New York, and Associate Professor of Neurology at Albert Einstein College of Medicine. “Zolpidem is out there in 26 million prescriptions, which is probably about 100 million doses in the last 12 months and so, by chance, people with a tendency for sleep-related eating may well have been taking the medication. I don't know if there is anything specific about it that would cause this behavior. I think if eszopiclone had been used in comparable numbers, we probably would have seen a similar correlation. All these drugs work in a similar way.”
While the chemical structure of zolpidem is unrelated to benzodiazepines, barbiturates or other hypnotics, it interacts with the GABA receptor complex and possesses some of the same properties as benzodiazepines, including the ability to induce deep sleep. Since these drugs act quickly, with effects intensified by even small amounts of alcohol, the directions clearly state that they should be taken just before going to bed, and should not be taken after drinking alcoholic beverages.
Sanofi-Aventis, the French company that makes the drug, notes in the package insert that a sleep-related eating disorder may occur in some people who take zolpidem, although the company also has pointed out that these behaviors are not necessarily caused by the drug.
Christian Guilleminault, MD, Associate Director of the Sleep Disorders Clinic and Research Center and Professor of Psychiatry and Behavioral Sciences at the Stanford University School of Medicine, asserts that some of the people taking zolpidem are probably predisposed to sleep-related disorders, such as eating, driving, and sleepwalking.
“With hypnotics we know that about 3 percent of patients will have sleep inertia – [they wake up feeling groggy] – with some degree of amnesia,” he said. “To say that one hypnotic is causing more side effects than any other is not a valid approach.”
But the circumstantial evidence linking the use of zolpidem to sleep-related disorders continues to grow. For example, a clear cause-and-effect relationship appears to exist in some people between taking zolpidem and developing a sleep-eating disorder, says Michael H. Silber, MD, Director of the Sleep Disorders Center at the Mayo Clinic in Rochester, MN, and President-elect of the American Academy of Sleep Medicine.
“There's a temporal relationship between stopping the drug and stopping the sleep eating,” he said. “We've seen this on numerous occasions.”
In addition, some patients who were night-eaters, consuming enormous quantities of food in the middle of the night while fully awake, converted to NS-RED after starting zolpidem. After taking the drug, they would awake the next morning with no memory of eating.
“These temporal relationships make us pretty confident that the drug does cause sleep eating,” Dr. Silber said. “Also, in a more theoretical sense, there's no question that people taking zolpidem do sometimes sleep-walk and do things at night they do not remember, so this is not utterly bizarre.”
Dr. Silber and colleagues first reported on nocturnal sleep-related eating disorder four years ago (Sleep Med 2002:3:323-327). At the time, Dr. Silber had seen about five cases. Now he has seen about 20 with NS-RED in zolpidem-users.
NIGHT-EATING SYNDROME VS. NS-RED
Dr. Schenck and colleagues identified NS-RED in 1991 (Sleep 1991;14(5):419–431). The disorder is quite different from the “night-eating syndrome,” identified in 1955 by Albert Stunkard, MD, at the University of Pennsylvania School of Medicine (American J Med 1955;19(1):78–86).
People with night-eating syndrome consume at least 35 percent of their total daily calories after the evening meal, and often wake at night with a powerful desire to eat more, according to Dr. Stunkard. Some believe that they cannot fall back asleep until they eat. Unlike people with NS-RED, they are fully aware that they are eating and remember it in the morning. Also, they do not consume odd foods.
“Occasionally we would find someone who couldn't remember eating at night,” Dr. Stunkard said. “They would talk about how they ate bizarre things, such as buttered cigarettes. Almost all had tried sleeping pills. These pills help people get to sleep, but then they wake up feeling confused. We began to appreciate that zolpidem may be associated, and we have seen several cases of zolpidem-related NS-RED. Our impression is that it's a lot more common than before, but it may simply be that many more people are taking it.”
No one has called for zolpidem to be removed from the market, but the relationship between the drug and sleep-related disorders has aroused greater caution.
“Zolpidem is a useful drug under correct circumstances, when used judiciously for the right reasons,” Dr. Stunkard said. “Physicians should be educated to warn their patients about side-effects including sleep-walking, sleep- eating, and amnestic reactions, and patients should be educated about this so if they get any of these strange reactions they can stop the drug.”
ARTICLE IN BRIEF
- ✓ A study is under way to examine the link between nocturnal sleep-related disorder and zolpidem, a widely prescribed sleeping pill. Sleep experts discuss and debate that proposed link.