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Sleeping Pills Are Deadly? Says Who, Exactly?

March 1, 2012

As most readers know, we’re paying more attention than ever before to conflicts of interest in medicine.   If an individual physician, researcher, speaker, or author is known to have a financial relationship with a drug company, we publicize it.  It’s actually federal law now.  The idea is that doctors might be biased by drug companies who “pay” them (either directly—through gifts, meals, or cash—or indirectly, through research or educational grants) to say or write things that are favorable to their drug.

A recent article on the relationship between sedative/hypnotics and mortality, published this week in BMJ Open (the online version of the British Medical Journal) and widely publicized, raises additional questions about the conflicts and biases that individual researchers bring to their work.

Co-authors Daniel Kripke, of UC San Diego, and Robert Langer, of the Jackson Hole Center for Preventive Medicine, reviewed the electronic charts of over 30,000 patients in a rural Pennsylvania health plan.  Approximately 30% of those patients received at least one prescription for a hypnotic (a benzodiazepine like Klonopin or Restoril, or a sleeping agent like Lunesta or Ambien) during the five-year study period, and there was a strong relationship between hypnotics and risk of death.  The more prescriptions one received, the greater the likelihood that one would die during the study period.  There was also a specifically increased risk of cancer in groups receiving the largest number of hypnotic prescriptions.

The results have received wide media attention.  Mainstream media networks, major newspapers, popular websites, and other outlets have run with sensational headlines like “Higher Death Risk With Sleeping Pills” and “Sleeping Pills Can Bring On the Big Sleep.”

But the study has received widespread criticism, too.  Many critics have pointed out that concurrent psychiatric diagnoses were not addressed, so mortality may have been related more to suicide or substance abuse.  Others point out the likelihood of Berkson’s Bias—the fact that the cases (those who received hypnotic prescriptions) may have been far sicker than controls, despite attempts to match them.  The study also failed to report other medications patients received (like opioids, which can be dangerous when given with sedative/hypnotics) or to control for socioeconomic status.

What has not received a lot of attention, however, is the philosophical (and financial) bias of the authors.  Lead author Daniel Kripke has been, for many years, an outspoken critic of the sleeping pill industry.  He has also widely criticized the conventional wisdom that people need 8 or more hours of sleep per night.  He has written books about it, and was even featured on the popular Showtime TV show “Penn & Teller: Bullshit!” railing against drug companies (and doctors) who profit by prescribing sleep meds.  Kripke is also one of the pioneers of “bright light therapy” (using high-intensity light to affect circadian rhythms)—first in the area of depression, and, most recently, to improve sleep.  To the best of my knowledge, he has no financial ties to the makers of light boxes.  Then again, light boxes are technically not medical devices and, therefore, are not regulated by the FDA, so he may not be required to report any affiliation.  Nevertheless, he clearly has had a decades-long professional interest in promoting light therapy and demonizing sleeping pills.

Kripke’s co-author, Robert Langer, is an epidemiologist, a past site coordinator of the Women’s Health Initiative, and a staunch advocate of preventive medicine.  More importantly, though (and advertised prominently on his website), he is an expert witness in litigation involving hormone replacement therapy (HRT), and also in cancer malpractice cases.  Like Kripke, he has also found a place in the media spotlight; he will be featured in “Hot Flash Havoc,” a movie about HRT in menopausal women, to be released later this month.

[Interestingly, Kripke and Langer also collaborated on a 2011 study showing that sleep times >6.5 hrs or <5 hrs were associated with increased mortality.  One figure looked virtually identical to figure 1 in their BMJ paper (see below).  It would be interesting to know whether mortality in the current study is indeed due to sedative prescriptions or, if the results of their earlier paper are correct, simply due to the fact that the people requesting sedative prescriptions in the first place are the ones with compromised sleep and, therefore, increased mortality.  In other words, maybe the sedative is simply a marker for something else causing mortality—the same argument raised above.]

Do the authors’ backgrounds bias their results?  If Kripke and Langer were receiving grants and speakers’ fees from Forest Labs, and published an article extolling the benefits of Viibryd, Forest’s new antidepressant, how would we respond?  Might we dig a little deeper?  Approach the paper with more skepticism?  Is the media publicizing this study (largely uncritically) because its conclusion resonates with the “politically correct” idea that psychotropic medications are bad?  Michael Thase (a long-time pharma-sponsored researcher and U Penn professor) was put in the hot seat on “60 Minutes” a few weeks ago about whether antidepressants provide any benefit, but Kripke and Langer—two equally prominent researchers—seem to be getting a free ride, as far as the media are concerned.

I’m not trying to defend the drug industry, and I’m certainly not defending sedatives.  My own bias is that I prefer to minimize my use of hypnotics in my patients—although my opposition is not so much because of their cancer or mortality risk, but rather the risk of abuse, dependence, and their effect on other psychiatric and medical symptoms.  The bottom line is, I want to believe the BMJ study.  But more importantly, I want the medical literature to be objective, fair, and unbiased.

Unfortunately, it’s hard—if not impossible—to avoid bias, particularly when you’ve worked in a field for many years (like Kripke and Langer) and have a strong belief about why things are the way they are.  In such a case, it seems almost natural that you’d want to publish research providing evidence in support of your belief.  But when does a strongly held belief become a conflict of interest?  Does it contribute to a bias in the same way that a psychopharmacologist’s financial affiliation with a drug company might?

These are just a few questions that we’ll need to pay closer attention to, as we continue to disclose conflicts of interest among medical professionals.  Sometimes bias is obvious and driven by one’s pocketbook, other times it is more subtle and rooted in one’s beliefs and experience.  But we should always be wary of the ways in which it can compromise scientific objectivity or lead us to question what’s really true.

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