Mortality Risk of Hypnotics: Strengths and Limits of Evidence

Abstract

Sleeping pills, more formally defined as hypnotics, are sedatives used to induce and maintain sleep. In a review of publications for the past 30 years, descriptive epidemiologic studies were identified that examined the mortality risk of hypnotics and related sedative-anxiolytics. Of the 34 studies estimating risk ratios, odds ratios, or hazard ratios, excess mortality associated with hypnotics was significant (p \ 0.05) in 24 studies including all 14 of the largest, contrasted with no studies at all suggesting that hypnotics ever prolong life. The studies had many limitations: possibly tending to overestimate risk, such as possible confounding by indication with other risk factors; confusing hypnotics with drugs having other indications; possible genetic confounders; and too much heterogeneity of studies for meta-analyses. There were balancing limitations possibly tending towards underestimates of risk such as limited power, excessive follow-up intervals with possible follow-up mixing of participants taking hypnotics with controls, missing dosage data for most studies, and over-adjustment of confounders. Epidemiologic association in itself is not adequate proof of causality, but there is proof that hypnotics cause death in overdoses; there is thorough understanding of how hypnotics euthanize animals and execute humans; and there is proof that hypnotics cause potentially lethal morbidities such as depression, infection, poor driving, suppressed respiration, and possibly cancer. Combining these proofs with consistent evidence of association, the great weight of evidence is that hypnotics cause huge risks of decreasing a patient's duration of survival. Key PointsMost sleeping pills e.g., benzodiazepines and ''Z'' benzodiazepine agonists (like eszopiclone) are associated with early death, and they most probably cause serious increases in mortality.Benzodiazepine agonist sleeping pills and diphenhydramine should not be prescribed for insomnia, except in long-term controlled trials and hospice care.

Hypnotic drug risks of mortality, infection, depression, and cancer: but lack of benefit

“…To find 39 of 40 studies showing a positive risk ratio was very highly significant, P<0.000001. Also, the evidence of association satisfied all nine Bradford Hill criteria for inferring causality 12 , though skepticism despite meeting these criteria may be warranted 13 . There remain questions concerning the magnitude of the causality.…”

“…There remain questions concerning the magnitude of the causality. The randomized placebo-controlled trials I have suggested would help clarify this causality magnitude 12 .…”

What do hypnotics cost hospitals and healthcare?

“…Similarly, the American College of Physicians (ACP) recommended that cognitive behavioral therapy should be the first-choice treatment for insomnia, and the ACP guideline expressed doubt on whether hypnotics were worth the risks, even as secondary choices for short-term use 2,3 .…”

I petitioned the FDA to restrict hypnotics: here is why

“…Indeed, at this writing, there have been 34 epidemiologic studies of hypnotics mortality risks, of which 33 found hypnotics associated with increased mortality (P<0.000001) [4]. One small study demonstrated no general mortality risk, only a cancer mortality risk.…”

“…Hypnotics still carry no warnings about mortality or cancer risks. Perhaps, despite the strong preponderance of evidence [4], the …”