Chapter 9
Needs For Hypnotics Research

There is a preponderance of evidence that the sleeping pills I have listed in Chapter 1 of this ebook are so risky that they should not be used. We do not need more research before we stop using these pills for sleep.

Today, nobody can be certain that any of the prescription sleeping pills (or melatonin) is safe for long-term use or even that they help sleep with long-term use (meaning several years).

There must be quite a few billionaires who have seen family members develop cancer or die after taking sleeping pills. One would think that charitable donors would want clear information about when sleeping pills are safe and whether any sleeping pills are worth the risks. A few tens of millions of dollars donated to universities or private foundations could advance medical research about sleeping pill safety a long way.

It is not a unique idea that long-term studies should be done. The National Institutes of Health (NIH) are doing long-term studies of diet and exercise, hormone replacement and vitamins, cholesterol-lowering drugs and aspirin. Of the psychoactive drugs, long-term studies have been supported for anti-depressant and anti-psychotic drugs, mood stabilizers (such as lithium), tranquilizers, narcotic agonists and antagonists, and stimulants for treatment of hyperactive kids. Truthfully, hypnotics are the only class of psychotropic drugs for which long-term studies have not been supported by the NIH. In a 1997 search of the CRISP list of NIH-supported projects, I found about 140 clinical studies of other psychotropic drugs, but none on sleeping pills. This is neglectful, considering the proportion of total psychotropic drug sales which the sleeping pill market occupies.

Although I have received generous grant funding in other areas of sleep research, the federal agencies have never been willing to support any studies of sleeping pills which I have proposed. I do not take it personally, since I know other investigators have the same problem. There is a mind set against funding studies of sleeping pills and a lot of passing the buck among different NIH Institutes. You could count on one hand (and have fingers left) the total number of clinical trials of hypnotic drugs funded by NIH in its entire half-century history. Of the few funded, the purpose was usually to compare some other treatment with sleeping pills, not directly to test sleeping pills.

Lack of government curiosity about sleeping pill prescribing is exceptional. As mentioned above, government agencies denied that they had data on overall U.S. consumption of sleeping pills. They are certainly more careful in studying other addicting drugs.

You might expect that with increasing evidence that sleeping pills cause cancer and excess mortality, the manufacturers might not wish to do long-term studies of their products which would prove the cancer and mortality risks. On the other hand, a company which really believed their product was safe should do such trials to prove it. If they are not doing the trials, you can assume that they themselves are not sure their product is safe.

Before I denounce the drug companies excessively, let me mention that the same heavy prescribing of hypnotics existed in Communist countries before the dissolution of the Soviet block, and there was a similar lack of studies behind the Iron Curtain. One should not ascribe the scientific neglect of sleeping pills entirely to the profit motive.

I think there is enough evidence now to stop using the drugs I have described as dangerous in Chapter 1 for sleep. Moreover, I expect that many similar studies of electronic records will confirm the associations with mortality and cancer for those drugs. Additional studies can add to the accuracy of our risk estimates and perhaps explain some of the pathologic mechanisms, but we already know that the risks are too high. It would be scientifically more definitive to have controlled trials of these risk-associated drugs to confirm whether or not they cause mortality and cancer, but as I have mentioned, I do not think think controlled trials of those drugs to assess lethality and cancer will ever be done.

For potential substitute drugs such as trazodone, doxepin, and melatonin, we do not have equivalent electronic records studies, nor for the still-newer drugs in the development pipeline. Perhaps electronic records studies of the current substitute drugs will eventually reflect on their association (if any) with mortality and cancer. Nevertheless, for any sleeping pill kept in use or for any newer drug, we ought to have long-term controlled trials of sufficient size to determine if the drugs do or do not cause excess mortality, cancer, depression, infection, and other serious adverse effects.

The cost of studies which would establish the long-term benefits/risks ratios of the most popular hypnotics would probably be $10-20 million for a period of several years. This would mean devoting less than 1% of sleeping pill costs for long-term research, in a sleeping-pill-giving industry which grosses over 2 billion dollars a year. The retail costs of the hypnotics drugs themselves may surpass two billion, and in addition, the fees of the prescribing doctors, the necessary laboratory tests, etc. amplify the total cost. Compare this with other areas of drug research, where the research costs may reach 25% of sales, or aircraft, computer and defense industries, where the R&D costs may reach 50% of total costs.

The Congress would have several choices for how to finance this research. It could require the manufacturers by law to perform the needed research. It could impose a user-fee on hypnotics (either at the retail level or the manufacturer level) to do the studies. A cost of a nickel a pill added to pills which cost as much as $8–$10 each would be a trivial cost to the consumer and well worth while in keeping consumers safe. To the extent that this small cost might discourage people from using sleeping pills, it would be doing them a favor. Such a user-fee might be regarded like the levies on other addicting substances such as cigarettes and alcohol. Congress could take the money out of the overall appropriations for health services research or for the National Institutes of Health, or it could conceivably appropriate new funds from general revenues. It is for the Congress to decide from where the money should come, but one way or another, the studies should be done.

There is a new genetic analysis technique which may make it possible to explore whether particular sleeping pills cause death and cancer without expensive and risky controlled clinical trials. This research approach relies on Mendelian randomization, the random process by which we are born with various genetic differences, to assess the causal role of various risk factors. Because Mendelian randomization studies might be possible with genetic testing and clinical records already collected for other purposes, these studies might only require more analysis of existing data. With its authority under the 2007 FDA Amendments Act, the FDA should require the manufacturers of the common sleeping pills to perform these studies. In addition, the NIH, which has banked much suitable data, should urgently support the analyses.