People who take sleeping pills often hope that sleeping pills will increase their sleep enough to make them more energetic in the day. They may hope that sleeping pills will improve their long-term health. Sleeping pill effects are just the opposite of what people hope.

Because life and death are often our primary concern, I would like to first to discuss the darkest aspect of sleeping pills:

 

WARNING: Sleeping pills could be hazardous to your health or cause death from cancer, heart disease, or other illnesses.

 

For over 30 years I have worked to assess the risks of sleeping pills. I have learned that sleeping pills are associated with significantly increased mortality.

 

This means that people who take sleeping pills die sooner than people who do not use sleeping pills.

 

I first became interested when I saw the work of Dr. E. Cuyler Hammond at the American Cancer Society. In 1975, I went to visit The American Cancer Society, starting a collaboration which lasted for many years.

In the CPSI (this was the first of two large studies), in 1959-1960, American Cancer Society volunteers gave questionnaires to over 1 million Americans and then determining six years later (in over 98%) whether the participants had survived. We found that 50% more of those who said that they "often" took sleeping pills had died, compared to participants of the same age, sex, and reported health status who "never" took sleeping pills .

To re-examine these risks, the American Cancer Society agreed to ask new questions about sleeping pills to participants in a new study, called The Cancer Prevention Study II or CPSII. In 1982, American Cancer Society volunteers gave health questionnaires to 1.1 million new participants. The survival of these people was ascertained in 1988.

In the new study, we again found that people who said that they used sleeping pills had significantly higher mortality . Again, people who took sleeping pills had much higher mortality. Even when people were matched for age, sex, race, and education, and a total of 32 health risk factors, those who reported taking sleeping pills 30 or more times per month had 25% more mortality than those who said that they took no sleeping pills . However, we did not determine which particular sleeping pills were associated with this risk. The smaller risk of taking sleeping pills just a few times per month was 10-15% increased mortality, compared to those who took no sleeping pills. Sleeping pills appeared unsafe in any amount.

 

 · 25% increased mortality among those taking sleeping pills nightly
 · 10-15% increased mortality among those taking sleeping pills occasionally

 

To provide a perspective on this mortality risk, we noted that the risk of taking sleeping pills 30 or more times per month was not much less than the risk of smoking 1 pack of cigarettes a day, when the analyses were done in a similar manner.

One cause of death was especially increased. Among men, those who took sleeping pills 30 times a month had 7 times the risk of suicide! Women who took sleeping pills 30 times a month had 2 times the risk of suicide. Nevertheless, the suicides were only a small portion of deaths associated with using sleeping pills. Deaths from other common causes such as heart disease, cancer, and stroke were also increased among sleeping pill users.

As of 2008, fifteen epidemiologic studies from Scandinavia to Japan have found that use of sleeping pills predicted increased mortality risk. Three of these studies have specifically found that use of sleeping pills predicted increased risk of death from cancer. It is not that the other studies found no cancer risk. They probably were just too small to check on cancer as a specific cause of death. Incidentally, these studies mainly covered usage of the older sleeping pills such as barbiturates and benzodiazepines, e.g., flurazepam (Dalmane), triazolam (Halcion), and temazepam (Restoril).

 

1.A. New sleeping pills cause cancer in animals

Were the epidemiologic studies just statistical accidents, or do sleeping pills really cause cancer? Recently, the Food and Drug Administration (FDA) started making available on the internet some of their documents about the review of those newer sleeping pills approved for marketing in the United States since 1998. You can find these documents yourself through the US Food & Drug Administration's Online Service, Drugs@FDA.

To my great surprise, I learned that rats and mice given high doses of zaleplon (Sonata), eszopiclone (Lunesta) as part of zopiclone, and ramelteon (Rozerem) developed cancer. The information available was a little vague to be certain, but it seems that these new sleeping pills all caused cancer in animals. I am no expert on experiments of this type, but FDA reviewers thought some of the results were worrisome. One of the reasons I am not sure I understand these results is that I cannot find that the companies have ever published the details in the medical literature. It is conceivable that the manufacturers do not want these cancer experiments understood. These drugs also broke chromosomes, which is a well-known specific chemical mechanism by which drugs cause cancer.

There was also some older and confusing information about zolpidem (Ambien). Although one of the old records seemed to say that animals given zolpidem developed three kinds of cancer, the new labeling approved for the extended release version of zolpidem (Ambien CR) says no evidence of carcinogenic potential was observed in either mice or rats. I would like to know how the company figures they do not owe people a warning.

 

1.B. Evidence that sleeping pills cause cancer in people

In 2005 and 2006, several new sleeping pills were introduced onto the U.S. market. The industry was hoping to increase hypnotics sales by several billion dollars a year. Because the companies wanted Food and Drug Administration (FDA) approval to market their drugs for long-term consumption, they did larger studies of long-term use than ever had been done before. Summaries of the data from these randomizing controlled trials can be found at the FDA internet site for zaleplon (Sonata), eszopiclone (Lunesta), and ramelteon (Rozerem). It turned out that because zaleplon was compared to zolpidem as well as to placebo, there was a bit of zolpidem data available also.

I have to admit that it is hard to understand the details of these controlled trials from the data which FDA has made available. I might misunderstand, and so my analysis ought to be checked. Because the manufacturers studied several doses of their drugs, it appeared the information represented over 2 times more years of exposure to the sleeping pills than to randomized placebo, but that could be wrong.

There were 8 new skin cancers among study participants randomized to the sleeping pills and no new cancers among those who only received placebo. If we include tumors which may or may not have been cancers, there were 12 among those given sleeping pills and none among those given placebo. Even considering that there was over 2 times as much exposure to the sleeping pills, it looks like this indicates that new sleeping pills caused cancer. The best estimate would be that the cancer rate for participants randomized to sleeping pills was several times that of the luckier volunteers who received placebo. Because these data come from randomizing comparisons, if FDA checks that they are correct, they appear to be proof that new sleeping pills (as a group) cause cancer. However, the data are not sufficient to prove that any specific sleeping pill or brand causes cancer .

Let's put together the epidemiologic data, the animal data, and the data from combining these controlled trials for 4 drugs. The evidence is that a patient who takes a new sleeping pill is likely to be increasing his or her risk of getting cancer. I feel that my patients should be warned about this risk, even though the scientific evidence is not yet refined or fully conclusive.

How does the cancer risk of new sleeping pills and older sleeping pills compare? I know of more evidence from animal studies and randomizing clinical trials that the new sleeping pills cause cancer than with the older sleeping pills. This does not mean that the older sleeping pills were safer: just that I have found less information about their cancer risk from clinical trials and animal experiments. On the other hand, the epidemiologic trials showing higher mortality and higher cancer mortality were collected mainly with the older sleeping pills before any of the newer ones (except perhaps zolpidem) became available. In summary, we really do not know if the newer or older sleeping pills present more cancer risk.

 

1.C. More lethal risks of sleeping pills

As a young medical student in my first year of training, one of the first things I learned in our student laboratory was that the kindest way to "put an animal to sleep" permanently was to administer a barbiturate such as pentobarbital. A bit later, I learned that pentobarbital was being prescribed almost automatically as a sleeping pill for patients in the hospital (in a sublethal dose, hopefully.) Related drugs are used to execute the death penalty. Any medical student knows that these drugs can kill.

Doctors have a wonderfully complete understanding of how sleeping pills such as pentobarbital kill animals. These drugs bind with protein molecules called GABA receptors on the surface of nerve cells. The same protein receptor molecules bind at the same time with a neurotransmitter chemical called GABA, which gives them their name. Barbiturates and other sleeping pills accentuate the action of GABA, which is to cause the receptor molecule to allow chloride ions to enter the nerve cells. Since the chloride ions are negatively charged, they make the inside the nerve cell more negatively polarized, which in turn, makes the nerve cells less likely to fire (to generate nerve activity). When the nerve cells which stimulate the muscles of breathing are inhibited from firing action potentials by GABA and by sleeping pills, the animal stops breathing. When breathing stops, the animal dies within a few minutes from lack of oxygen in the lungs. No doubt these same mechanisms explain how barbiturates kill people who take too high a dosage, either accidentally or with suicidal intention.

In the 1970's, a new group of sleeping pills became popular, molecules which chemically are named benzodiazepines. The first sold as tranquilizers were chlordiazepoxide (Librium) and diazepam (Valium). Soon, the benzodiazepine flurazepam (Dalmane) was marketed as a sleeping pill, and flurazepam soon dominated the market. The main advantage of benzodiazepines is that they are less likely to produce acute overdose deaths than barbiturates . For the last 15 years, most new sleeping pills have been benzodiazepine agonists, which means that the chemical molecules are not classed as benzodiazepines but they act at the same receptors. All of these drugs seem to have less risk than barbiturates, but it is still possible that single doses of these newer sleeping pills are sometimes lethal.

Suicide, accidental overdose and cancer are probably not the most common ways in which sleeping pills kill, but the other ways are more poorly understood and less well documented. Here are some of the other possible mechanisms.

All of the sleeping pills can cause "hangover," that is, they not only reduce the action potentials of our brain cells during sleep, but they can also reduce brain cell activity during the day . This can make us sleepy, less alert, confused, and weak during the day. We will discuss psychological consequences of this hangover later, but here I mention the impairments of survival. Falls are much more common among elderly people who are taking hypnotics . Of patients given Lunesta, 10% had accidents as compared to 6% given placebo in one study, and falls were specifically more common with Lunesta. Because several studies show that people who are responsible for automobile accidents are unusually likely to have sleeping pills in their blood , it is thought that hangover may often cause automobile accidents, as well as other fatal accidents. The recent publicity about Ambien zombies driving like sleep walkers provides some extremely vivid examples.

In the last 20 years, physicians have become concerned about sleep apnea, a condition where there are pauses of breathing during sleep. Physicians suspect that sleep apnea can cause deaths during sleep. Not all studies are in agreement, but several studies have found that when a person with sleep apnea takes sleeping pills, there are more pauses in breathing and the pauses last longer, which could be dangerous. I was surprised to learn in the FDA data how well-documented it is that zolpidem makes sleep apnea worse. Because sleeping pills risk making apnea worse, many experts recommend that people with apnea should not be given sleeping pills. The problem is that almost everybody above age 40 has some sleep apnea, and the majority of people over 65 would meet commonly-used criteria for a diagnosis of sleep apnea Therefore, a large proportion of people taking sleeping pills must be making their apnea worse. Over a period of many years, anything which makes sleep apnea worse would be expected to cause high blood pressure, and therefore, to increase the risk of heart attacks, heart failure, and strokes.

A final concern in regard to mortality is how people care for themselves. Because sleeping pills, like tranquilizers, reduce worry about possible threats and risks in our lives, it is possible that the hangover effects of sleeping pills would reduce people's attentiveness in taking care of themselves.

Continued in Chapter 2