Mortality and Cancer Risks, Which Pills to Avoid & Better Alternatives
By Daniel F. Kripke, M.D.
Why Haven’t You Heard This Opinion of Sleeping Pills From Every Expert?
The idea that sleeping pills have a dark side is nothing new, as shown by the quote from an 1893 textbook by Dr. Woods. See Chapter 5 for expert opinions and guidelines. Indeed, generations of physicians have shared my negative opinion, based on their own clinical experiences. Probably, the majority today agree. They are a silent majority, with little to be gained by making their opinions public.
The sleeping pills industry has had billions of dollars of yearly sales, and it has thought of many subtle ways of keeping its products popular. To be frank, the manufacturers of sleeping pills have often given the leaders of sleep research large monetary grants to test their products. As a young scientist, I did some of that testing myself before I saw that sleeping pills were doing more harm than good. These research colleagues are very nice people who are not the sort to bite the hand that feeds them. Some of the most prominent leaders of sleep research have been supported mainly by drug company grants and consulting fees. I still receive drug company offers, though now I refuse them. The drug companies have used many subtle free offers and not-so-subtle methods of influencing the wider group of sleep clinicians to mute their critical attitude towards sleeping pills.
For example, several years ago, manufacturers offered free chocolate cream pie at a national sleep meeting for attendees to watch a bizarre comic session in which leaders of the sleep community mocked the FDA for its efforts to regulate sleeping pills. I suppose a good deal of money was spent for those free chocolate cream pies and the advertising of that ridicule of the FDA.
For many years, the National Sleep Foundation launched a yearly publicity campaign about the dangers of insomnia, encouraging everybody to sleep eight hours. Scientific evidence to support eight hours sleep is almost nonexistent. Could this campaign have been influenced by the fact that much of the National Sleep Foundation’s money came from sleeping pill manufacturers? The public relations firm for Ambien bragged that National Sleep Foundation publicity was effective in increasing sleeping pill sales. I believe more recently, the National Sleep Foundation has broadened its support to mattress and pillow manufacturers and I do not know what other groups with something to sell. The Foundation no longer details their sources on their web site.
The American Academy of Sleep Medicine received strong financial support from sleeping pill manufacturers in the past, but they do not seem to openly list that financing any more.
Unfortunately, almost nobody advertises for behavioral treatments of insomnia or for hypnotic abstinence. The advertising for bright light treatment is minuscule compared to pharmaceutical advertising.
8.A. Why haven’t you heard from the FDA?
When we reported that people who took sleeping pills died 4.6 times faster and suffered more cancer, I made quite certain that the FDA had reviewed the new studies. Also, by that time, the Agency’s own internal documents showed that the FDA knew that for the majority of patients, Ambien doses were likely to be ineffective, unsafe, or both. Forgive my naivety. Ignoring, at that time, 21 studies showing that people who take sleeping pills die sooner or suffer more cancer, some suggesting that sleeping pills were as dangerous as cigarettes, the FDA still claimed (in August, 2012) that sleeping pills were “safe and effective.” It may not surprise you that just a few years later, the FDA public relations person who made that “safe and effective” claim for hypnotics was employed by a sleeping pill company, no doubt well-paid. The FDA decided to require no black box warnings about mortality and cancer risks for zolpidem and similar drugs, nor did the FDA require further studies to confirm whether the mortality and cancer risks are substantial.
When the FDA took no practical steps to warn the public about sleeping pill mortality and cancer risks, and gave only minimalizing mention of proven depression and infection risks, I formally petitioned the FDA in October 2015 to require more warnings and more research to clarify how much sickness and early death were caused by sleeping pills. Although the law required (as the FDA admitted) that the Agency respond to my petition within six months, the FDA gave no substantial reply, responding mainly that the problem was too complex for them. Also, evidently fearing that my concerns would be proven well founded, neither the FDA nor the manufacturers dared to initiate the large clinical trials needed to more accurately determine the magnitude of the unnecessary mortality and disability that sleeping pills cause.
Perhaps we should not be surprised when the FDA fails to protect the public. A 2009 report of the Congressional Government Accountability Office questioned the FDA’s ability to protect Americans from unsafe medical products. A 2012 National Institute of Medicine report found that the FDA’s current oversight was not adequately assuring the safety of marketed drugs.
The FDA Amendments Act of 2007 gave the FDA authority to require additional safety studies on marketed drugs when needed, but these were not ordered for sleeping pills. The Act provided authority to require risk evaluation and mitigation strategies, but the FDA disclosed no such evaluation and mitigation strategy to deal with cancer and mortality risks of sleeping pills. To give another example, in a September, 2012 lawsuit and press release, Public Citizen alleged that the FDA was acting unlawfully in failing to protect the public from an Alzheimer’s Disease drug, because it had “chosen to support the profit interests of a large pharmaceutical company.”
A rapidly-increasing body of evidence has demonstrated serious risks of hypnotic drugs (sleeping pills). These were documented in more than 50 new publications since 2015. To better define the causal magnitude of hypnotic harms, in 2015 I had petitioned the U.S. Food and Drug Administration (FDA) to require large randomized placebo-controlled safety trials. In December 2018, when the FDA finally got around to replying to my petition – more than two years past their mandatory deadline – I was appalled that the Agency’s response ignored all 50 new publications and declared no need for further research. 
How did the FDA’s long-delayed response manage to paper over the increasingly obvious risks of sleeping pills? The Agency offered the outrageous claim that hypnotic mortality risks were not important so long as they did not consistently double a patient’s risk of dying: “While a few studies reported statistically significant hazard ratios of 2.0 or higher, most found either a significant hazard ratio below 2.0 or no significant association between hypnotics and all-cause mortality.” This was a statistical falsification, since as of November, 2018, there were 11 studies reporting significant hazard ratios of 2.0 or higher, which is more than a few. Note that the FDA did not mention that all of the 22 adequate-sized studies (with at least 14,000 participants) had found statistically significant mortality hazards for hypnotics. If smaller studies were included, 35 of 46 had found statistically significant hazards.
Does the FDA follow a policy of approving drugs that kill patients if the hazard ratio is less than 2.0? The FDA reported no meta-analyses of their own and ignored the published independent meta-analysis confirming significant mortality hazards associated with hypnotics, for example, a mortality hazard ratio of 1.73 associated with the Z-drug hypnotics. The FDA was even defending FDA medical approval of barbiturate sleeping pills that nobody recommends any more except for death row.
The FDA claimed that studies of cancer risk did not support an association of hypnotics with increased cancer risk, failing to report any meta-analyses of their own and ignoring two published meta-analyses that inferred significant cancer risks. There were randomized controlled trials data from FDA files showing an excess of cancers among patients randomized to hypnotics. The FDA claimed “lack of clear biological mechanisms,” ignoring evidence already revealed in FDA files that some hypnotics are clastogenic (cause mutations of chromosomes). The FDA did not employ their animal testing facility to clarify hypnotic carcinogenicity in rodents, though the Agency could have supplemented the manufacturers’ inadequate studies that had already reported evidence of carcinogenicity in animals.
The FDA further ignored summaries of randomized clinical trials taken largely from FDA files which proved that hypnotics caused infections and depressions. Likewise, the FDA presented no meta-analyses of their own unpublished data regarding infection and depression risks.
The 2018 FDA response endorsing 10 types of hypnotics was inconsistent with recently-issued opinions disapproving most use of hypnotics from the American Geriatrics Society, the American College of Physicians, the American Academy of Sleep Medicine, and the European Sleep Society, all of which the Agency response disregarded.  Why did the FDA pay no heed to these most recent distinguished expert opinions? It appears that the FDA literature review might have actually been written in 2015 without then generating a response to my petition, and that since then, the FDA has elected to ignore new scientific evidence and major new professional recommendations.
Did the FDA unveil its response to my petition on December 3, 2018 only because the November 2018 election selected a Congress that might look into FDA inaction regarding how hypnotics augment the suicide epidemic?
In the following chapter (Chapter 9), I take a satirical swipe at the Food and Drug Administration’s inaction, wondering if the FDA has in mind a secret means of reducing climate change by trimming the American population.
8.B. What if your family was injured?
If somebody in your family died or developed cancer after taking sleeping pills, you may have an entitlement to reimbursement for injury. Equally important, injured families could spread warnings. When the medical community was no match for the cigarette companies, lawyers and law suits helped disclose cigarette risks. Many state and local governments are now suing opioid manufacturers and providers for pushing opioid addicting drugs that are killing so many thousands. A substantial percentage of patients dying from opioids were at the same time receiving addicting sleeping pills and similar benzodiazepine agonists, for which similar litigation is needed.
We now need litigation for failures to disclose sleeping pill risks. If your family member died while regularly taking sleeping pills, and that risk was not disclosed, consult your attorney. If your family member developed a cancer while taking sleeping pills, especially esophageal or lung cancers or lymphoma, and that risk was not disclosed, consult your attorney. In Wyeth v. Levine, the U.S. Supreme Court ruled that drug manufacturers are liable if failing to warn patients, even when the FDA has not required a warning in the labeling. If the drug companies, the many doctors taking gifts and money from drug companies, the FDA, and the insurance systems will not alert the public to the risks of sleeping pills, injured families might have to give the warnings through legal assistance. You may contribute to better warnings if injured patient families and whistle blowers file enough lawsuits, recovering damages like the $4.85 billion which one company paid to settle Vioxx claims. You might help save hundreds of thousands of lives.
Endnotes for Chapter 8
65. Kripke, DF. Chronic hypnotic use: Deadly risks, doubtful benefit. Sleep Medicine Reviews.2000;4:5-20. [return]
67. Farkas, R. Center for Drug Evaluation and Research Approval Package for: Application Number: 019908Orig1s032s034, 021774Orig1s013s015. 2013. Silver Spring, MD, FDA. [return]
68. United States. Comptroller General. General Accounting Office. FDA Faces Challenges Meeting Its Growing Medical Product Responsibilities and Should Develop Complete Estimates of Its Resource Needs, GAO-09-581, Jun 19, 2009, available as a free PDF document at the GAO website, www.gao.gov/new.items/d09581.pdf. [return]
69. IOM (Institute of Medicine). 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. Available for download as a free PDF from the National Academies Press at dx.doi.org/10.17226/13219. [return]
70. Bradbery, Angela. Public Citizen Sues FDA for Failing to Act on Request to Ban Dangerous Dose of Alzheimer’s Drug Aricept. Public Citizen, Inc. September 5, 2012. Text of press release available online at www.citizen.org. In November 2012, the FDA decided it had not made a mistake in approving the drug and rejected Public Citizen’s petition. Wolfe, Sydney. FDA Rejects Petition to Ban Aricept 23: Did Drug Companies, FDA Collude in Approving Dangerous Alzheimer’s Drug? Public Citizen, Inc. November 6, 2012. Statement of Dr. Wolfe available online at www.citizen.org. [return]
72. Kripke DF. Petitioner requests the Commissioner of Food and Drugs require that manufacturers of each of these drugs (zolpidem, temazepam, eszopiclone, zaleplon, triazolam, flurazepam, and quazepam, in all brands and forms prescribed to treat insomnia or patient reported sleep disorders) conduct comprehensive post-market randomized placebo-controlled trials quantifying risks and benefits to patients. Accessed December 3, 2018. Silver Spring, MD, USA, U.S. Food & Drug Administration, Center for Drug Evaluation and Research, at www.regulations.gov.. [return]
73. Page 9 of December 3, 2018 Letter from FDA CDER to Daniel F. Kripke, Primary Document, Kripke DF. Petitioner requests the Commissioner of Food and Drugs require that manufacturers of each of these drugs (zolpidem, temazepam, eszopiclone, zaleplon, triazolam, flurazepam, and quazepam, in all brands and forms prescribed to treat insomnia or patient reported sleep disorders) conduct comprehensive post-market randomized placebo-controlled trials quantifying risks and benefits to patients. Accessed December 3, 2018. Silver Spring, MD, USA, U.S. Food & Drug Administration, Center for Drug Evaluation and Research, at www.regulations.gov.. [return]
75. Parsaik AK, Mascarenhas SS, Khosh-Chashm D et al. Mortality associated with anxiolytic and hypnotic drugs-A systematic review and meta-analysis. Aust N Z J Psychiatry 2016;50(6):520-533.. [return]
76. Zhang T, Yang X, Zhou J et al. Benzodiazepine drug use and cancer risk: a dose-response meta analysis of prospective cohort studies. Oncotarget 2017;8(60):102381-102391; Kim DH, Kim HB, Kim YH, Kim JY. Use of Hypnotics and Risk of Cancer: A Meta-Analysis of Observational Studies. Korean J Fam Med 2018;39(4):211-218; Kripke DF. Possibility that certain hypnotics might cause cancer in skin. J Sleep Res 2008;17(3):245-250. [return]
79. Fick DM. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc 2015;63(11):2227-2246; Wilt, T. J., MacDonald, R., Brasure, M. , Olson, C. M., Carlyle, M., Fuchs, E., Khawaja, I. S., Diem, S., Koffel, E., Ouellette, J., Butler, M., and Kane, R. L., Pharmacologic Treatment of Insomnia Disorder: An Evidence Report for a Clinical Practice Guideline by the American College of Physicians. Ann Intern.Med 165(2), 103-112. 5-3-2016.; Sateia MJ, Buysse D, Krystal AD, Neubauer DN, Heald JL. Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline J Clin Sleep Med 2017;13(2):307-349; Riemann D, Baglioni C, Bassetti C et al. European guideline for the diagnosis and treatment of insomnia. J Sleep Res 2017;26(6):675-700. [return]
80. Wyeth v. Levine, 555 U.S. 555 (2009). The full text of the majority opinion by Justice John Paul Stevens, as well as the concurrences and dissent, are available at Cornell University Law School's online Legal Information Institute, at www.law.cornell.edu/supct/html/06-1249.ZS.html, while a summary of its holdings may be found at Wikipedia, en.wikipedia.org/wiki/Wyeth_v._Levine. [[return]
Table of Contents
The Dark Side of Sleeping Pills, in all its formats, including this eBook, copyright ©1997-2019 by Daniel F. Kripke, M.D. All rights reserved.