Anxiolytic, Hypnotic Medications May Triple Mortality Risk

Deborah Brauser

March 28, 2014

Use of anxiolytic or hypnotic medications may significantly increase mortality risk, new research suggests.

A retrospective cohort study of more than 100,000 age- and sex-matched patients showed that those who used anxiolytics and/or hypnotics were 3 times more likely to die prematurely during the 7 -year follow-up period than those who did not use these drugs.

In addition, significant dose-response associations were shown for benzodiazepines and the "Z drugs" – zaleplon (Sonata, Pfizer Inc), zolpidem, and zopiclone.

"These results add to evidence of an association with mortality, but must be treated with caution," write Scott Weich, professor of psychiatry in the Division of Mental Health and Wellbeing at the Warwick Medical School in Coventry, United Kingdom, and colleagues.

The investigators note that this is because of the study's observational nature and because of factors that were not examined, such as socioeconomic status.

"These results are prone to bias arising from unmeasured and residual confounding," they write.

The study was published online March 19 in BMJ.

16 Million Prescriptions

According to the researchers, more than 16 million prescriptions for hypnotics and anxiolytics were written in UK primary care practices between 2011 and 2012, with benzodiazepines accounting for 62% and Z drugs accounting for 32%.

For this study, records were examined from the General Practice Research Database for 34,727 patients from 273 primary practices in the UK. All were older than 15 years and were first prescribed the study drugs between 1998 and 2001.

In addition, each of these patients was age- and sex-matched to 2 other individuals who did not take the drugs and who acted as the control group (n = 69,418).

The primary outcome measure was all-cause mortality during the follow-up period, as shown in the practice records. Study drugs referred to benzodiazepines, Z drugs, and other anxiolytic and hypnotic medications.

Results showed that coprescribing was common, with 76.3% of the group using study drugs also being prescribed at least 1 benzodiazepine, 38.8% being prescribed Z drugs, and 33.5% being prescribed 1 or more of the other examined medications.

Diazepam was the most commonly prescribed of all study drugs (47.9%), followed by temazepam (35.1%) and zopiclone (34.1%).

The age-adjusted hazard ratio (HR) for mortality was 3.46 (95% confidence interval [CI], 3.34 - 3.59) for the patients who used any of the study drugs during the first year after baseline compared with those who did not take any of the drugs.

After further adjusting for potential confounders, the HR for mortality for this group was still 3.32 (95% CI, 3.19 - 3.45).

In addition, "after excluding deaths in the first year, there were approximately four excess deaths linked to drug use per 100 people followed for an average of 7.6 years after their first prescription," report the investigators.

Dose-Dependent Link

The adjusted HR for mortality was 4.51 (95% CI, 4.22 - 4.82) for the patients who received more than 90 daily doses of any study drug in 1 year.

Although there was a dose-dependent link for all 3 classes of medications, the HRs were largest for benzodiazepines (3.89 for any daily dose vs 3.5 for Z drugs and 2.18 for other study drugs).

These numbers increased to 6.75, 4.83, and 3.34, respectively, for those prescribed more than 90 daily doses in the first year of follow-up.

When examining patient characteristics, the researchers found that the patients who had study drug prescriptions were more likely than those without prescriptions to be smokers, to have higher rates of all forms of physical morbidity (including cancer and respiratory disorders), and to have higher rates of sleep, anxiety, and other psychiatric disorders.

"In patients who were prescribed these drugs, there was an estimated overall statistically significant doubling of the hazard of death (hazard ratio 2.08), after adjusting for a wide range of potential confounders, including physical and psychiatric comorbidities, sleep disorders, and other drugs," write the investigators.

"Crude cumulative mortality in those given drugs was 26.46 per 100 people over the full follow-up period compared with 16.82 per 100 controls," they add.

But they again note that, as with all observational studies, there is the possibility of bias in the findings.

"While we largely excluded immortal time bias and selection bias, we are unable to exclude the possibility that the results were due to confounding by indication or to residual confounding by unmeasured or incompletely measured factors," note the investigators.

The study authors have reported no relevant financial relationships.

BMJ. Published online March 19, 2014. Full article

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