Patients with prescriptions for hypnotics had approximately 4.6 times the hazard of dying over an average observation period of 2.5 years as compared to non-users. These findings were robust with adjustment for multiple potential confounders and consistent using multiple strategies to address confounding by health status. A dose–response effect was seen. Among users in the highest tertiles of annualised dosages, the HRs for death were 5.3, 5.7 and 6.6, respectively, for all hypnotics, zolpidem alone and temazepam alone. This top third of users were prescribed 92.8% of all the prescription doses of hypnotics (supplemental figure 2). Those in the top third were also 35% more likely to develop a new major cancer.
Perhaps the most striking finding was that an increased hazard for death was present even in the lowest tertile of hypnotic use, such that hypnotic drugs were associated with a 3.6-fold increased risk of dying for patients using <18 hypnotic pills per year. Several strategies to discover biases that could account for this hazard, even at low levels of use, revealed none. Nonetheless, some residual confounding is inevitable in our results as a consequence of factors that were inadequately assessed. However, considering the minimal impact of the major confounders for which we did control upon the HRs, we think it unlikely that confounding explains the high mortality that we found associated with hypnotics.
Multiple causal pathways by which hypnotics might lead to mortality have been demonstrated. Though the acute lethality of benzodiazepine agonists seems less than that of barbiturates, it has been demonstrated in animals given high doses of benzodiazepine agonists, especially in combination with alcohol. Moreover, benzodiazepines and agonists are often present in mixed-drug overdoses.10
Compilation of randomised controlled trials has shown that hypnotics increase incident depression.12
Several non-randomised studies have reported an increase in suicide associated with hypnotics use,8
and depression may increase mortality through other mechanisms besides suicide.16
Controlled trials show that hypnotics impair motor and cognitive skills, such as driving.18
Hypnotics have been associated with increased automobile crashes and an increase in falls, due to hangover sedation.19–22
In some patients, hypnotics increase sleep apnoea, prolong apnoeas or suppress respiratory drive, though among other patients, there may be mild improvement.23–25
Sleep apnoeas, in turn, may lead to motor vehicle crashes, hypertension, heart failure, arrhythmias, cardiovascular diseases and death.26
Hypnotics may cause somnambulistic night-eating syndromes resulting in poor diet and obesity27
as well as other automaton-like behaviours, which can be dangerous.28
Indeed, in controlled trials, participants randomised to hypnotics experience more adverse medical events overall than those randomised to placebo.21
Zolpidem has been shown to increase gastroesophageal regurgitation.31
In our sample, hypnotic prescriptions were associated with increased diagnoses of oesophageal regurgitation and peptic ulcer disease (supplemental files). Increased regurgitation could cause oesophageal damage and cancer. In randomised controlled trials, patients receiving hypnotics reported significantly more infections.32
Joya et al32
inferred that increased upper respiratory irritation and infection might result from the increased gastroesophageal regurgitation caused by hypnotics. Infections, in turn, are major causes of mortality and cancer.33
Sparse data from randomised controlled trials of hypnotics suggested increased rates of cancer,34
and those findings are supported by studies demonstrating carcinogenic effects of hypnotics in laboratory rodents and by evidence that hypnotics can cause chromosomal damage.34
Our finding that for lymphomas, lung, colon and prostate cancers, the HR for hypnotic usage was even greater than the HR for current smoking (supplemental table 11) argues for specific biologic mechanisms. It is possible that patients receiving hypnotics experienced more medical care than non-users, providing greater surveillance and potential cancer detection as contrasted to non-users, even though the Cox models matched users and non-users by numbers of comorbidities. However, it would be hard to imagine how greater surveillance of hypnotic users could explain two- to threefold higher HR for some cancers with no excess mortality for other cancers (see supplemental table 11), whereas specific biological effects of hypnotics would more plausibly explain the differences in HR between cancers.
In addition to the residual confounding discussed above, the data available for this study had further limitations, which should be noted. Importantly, the EHR provided information on medication orders but not on dispensing. Accordingly, we were unable to verify that the medications ordered were dispensed by a pharmacy, and, if dispensed, whether the patient ingested the prescribed hypnotic. Moreover, controls not receiving hypnotic prescriptions might have taken hypnotics prescribed for others or over-the-counter antihistamine sleep drugs equivalent to prescribed antihistamines. Such errors of overestimation of hypnotic consumption among users or underestimation among controls would lead to underestimation of the true hypnotic hazards.
We were unable to control for depression, anxiety and other emotional factors because of Pennsylvania laws protecting the confidentiality of these diagnoses. However, several previous studies reporting hypnotic risks have controlled for these confounders.7
Mallon et al
found that when depression, hypnotic use and other risk factors were entered into a multivariate model for all-cause mortality, hypnotic use was the strongest risk factor among men (stronger than cigarette smoking). In that analysis, depression was not an independent risk factor for death in either men or women.7
Moreover, one might expect an emotional confounder to cause insomnia, leading, in turn, to use of hypnotics, but several large studies have reported that insomnia is not a significant mortality risk factor, especially when hypnotic usage is controlled.7
Nevertheless, to the extent that social and psychological problems lead patients to receive hypnotics, and to the extent that these problems cause death through pathways independent of hypnotics, our findings might reflect some confounding by those conditions.