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By Alan Z. Segal, MD
Associate Professor of Clinical Neurology, Weill Cornell
Dr. Segal reports no financial relationships relevant to this field of study.
Synopsis: Chronic use of sleeping medications, particularly benzodiazepines, is associated with an increase in all-cause mortality, and should be avoided if at all possible.
Source: Weich S, et al. Effect of anxiolytic and hypnotic drug prescriptions on mortality hazards: Retrospective cohort study. BMJ 2014;348:g1996 doi:10.1136/bmj.g1996.
Poor sleep may have serious health consequences. both insomnia and short sleep duration have been associated with increased mortality as well as cognitive decline. Hypnotic and anxiolytic drugs have been associated with an increased risk of dementia, daytime fatigue, ataxia, falls, and traffic accidents. Medical ailments such as cancer, pneumonia, and other infections have been associated with use of these medications.
Prior studies have varied in setting, age distribution, and length of follow up. These studies have also been inadequately controlled for physical and psychiatric confounding variables. Use of other medications, socioeconomic status, smoking, and drug and alcohol misuse have also possibly confounded previous studies. These studies have also shown wide variations in their effect size, with mortality hazard ratios varying from 1.14 to 4.56. In the present study, the use of sedative hypnotic medications (primarily benzodiazepines and non-benzodiazepine GABA agonists — the so-called Z-drugs) were found to be associated with a significantly increased risk of death. The Z-drugs (zolpidem, zopiclone, and zalephon) are the most commonly prescribed medications for insomnia in the United States.
This large population cohort, enrolled between 1998 and 2001 from primary care practices in the United Kingdom, was studied for an average of 7.6 years. There were 34,727 patients prescribed anxiolytic or hypnotic drugs. These were matched with 69,418 patients with no prescriptions for these drugs. Matching included age, sex, and practice location, which was important in excluding differences in socioeconomic status.
Physical and psychiatric comorbidities were significantly more prevalent among those prescribed study drugs than among controls. Patients on study drugs were more likely than controls to be current smokers and had higher rates of all forms of disorders such as cancer and respiratory disease. Study drug users not unexpectedly had a higher incidence of sleep disorders, anxiety, and other psychiatric disorders. They received more prescriptions for non-study drugs. Controlling for these factors, the mortality hazard ratio for any use of study drug during the first year after recruitment was 3.32 (95% confidence interval [CI], 3.19-3.45). There was a positive dose response for all three classes of study drugs, with a hazard ratio of 4.51 (CI, 4.22-4.55) for patients who received > 90 defined daily doses of drug in the first year. There were approximately four excess deaths linked to drug use per 100 people followed. Benzodiazepines had higher hazard ratios than other study drugs.
Benzodiazepines (n = 22,116; 63.7%) were more commonly prescribed than Z-drugs (n = 7971; 23%). Other study drugs (most commonly hydroxyzine, buspirone, or promethazine) were prescribed in n = 4640 (13.4%). Of note, the study could not account for the use of other sleep aids, available over the counter, such as diphenhydramine. The most commonly prescribed drug was diazepam, followed by temazepam and zopiclone. Co-prescribing was common, with 30% of patients using more than one agent.
This study is impressive in its size and scope. It included more than 70 million patient years of high-quality, validated data. As the authors note, this study measured hypnotic drug use as a function of written prescriptions rather than patient-reported use. The validity of this method was strengthened by the exclusion of patients with single study drug prescriptions, thus focusing on those patients who required repeated follow-up prescriptions. Medications given to psychiatric patients directly by mental health providers would not be accounted for, but in the United Kingdom, the vast majority of medication is prescribed through primary care physicians.
Studies such as this are susceptible to significant confounding bias. As the authors note, however, very detailed health information was available for this population. This reduced the effect of drugs being given to those with pre-existing serious illness or those not able to sleep because of pain or other consequences of long-term or life-threatening illness.
It is important to note that this was not a dedicated sleep study. Psychiatric disease was very common in this population: 15,299 (44%) had an anxiety disorder and 19,770 (56.9%) had other psychiatric diagnoses. By contrast, only 9741 (28.2%) patients had a sleep disorder. It is not clear from the manuscript exactly how sleep disorders were diagnosed, as this group may have not only included insomniacs but others with circadian rhythm disorders, parasomnias, and possibly obstructive sleep apnea.
Because of this psychiatric predominance and possibly because of different prescribing practices in the United Kingdom, this study was strongly tilted toward benzodiazepines, rather than Z-drugs. However, as noted in the paper, the ill effects of Z-drugs and other hypnotics were still significant, with hazards ratios of 3.68, 3.19, and 2.06 for benzodiazepines, Z-drugs, and other study drugs, respectively.
The study did not have the ability to make conclusions about the cause of the increased mortality since the cause of death was not included in the database. Cause of death can be a difficult variable to analyze, since death certificates often list diagnoses such as pneumonia or heart failure, while the true cause of death may have been cancer or any other chronic progressive disorder. No information is available regarding accidents or other effects of excessive daytime sleepiness.
This study argues strongly for behavioral over pharmacological approaches to insomnia and anxiety. Drug therapy in the form of benzodiazepines, Z-drugs, or even seemingly "benign" medications such as hydroxyzine is associated with a significantly increased risk of death.