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Mar 3, 2012

An article published Feb 27, 2012 in the British Medical Journal titled Hypnotics' association with mortality or cancer: a matched cohort study is something we should know about for a few reasons. First, many of us take some form of sedative hypnotic before night shifts and second, it’s been in the news. Your patients are going to want to know what to do.

Read it: http://bmjopen.bmj.com/content/2/1/e000850.full.pdf+html

This was a population based study that found those prescribed sedative hypnotics (most commonly zolpidem and temazepam) for sleep issues had a greater than threefold increase of death during the study period as well as an increased risk for cancer.

When I first saw this study, my eyes just about popped out of my head. My first job out of residency was all nights and I could never fall asleep before shifts, so by the 4th night in a row, I was really tired. Then I took a zolpidem at 5pm, woke up at 10pm,  and it was night shift 2.0. Wide awake and ready to roll. It was like a cold glass of water on a hot summer day. But just as the Joe Jackson song goes, everything, it seems, gives you cancer.

This paper suggests a correlation between death/cancer and sedative hypnotics prescribed for sleep, but the real question is whether these drugs were directly responsible for the outcome or a marker for higher likelihood of underlying disease.

As a  side note, the group studied was not a bunch of shift working, hard charging emergency providers who were taking these meds strategically to feel rested for a particular interval. There may have been some that cohort (us) scattered in the mix, but this was the general population, who were likely prescribed these meds for the usual reasons.

Back to the first question: Were the insomniacs just sicker to start with? They were compared to a cohort with similar demographics and problem list comorbidities who were followed in the same clinics. The main body of the study says that there were not significant differences between the two groups but, the supplemental data, which is several mouse clicks away, shows that that is not the case. The prescription group had significantly higher incidence of prior disease (including coronary artery disease, chronic kidney disease, asthma, obesity, GERD, etc).

The next question is why. Why would these drugs cause higher mortality and risk of cancer?

Death: There’s the obvious answer that they impair thinking. If used during activities such as driving, or mixed with other meds or alcohol, could lead to death. They may also worsen sleep apnea which in turn could exacerbate other underlying comorbidities. Cause of death was not given in the study, so one can only surmise. I doubt there will be a controlled double blinded trial to see if they directly kill people.

Cancer: Many factors may be at play with malignancy. Zolpidem increases risk of GERD, which increases risk of Barrett’s esophagus which can lead to esophageal cancer. But that is a stretch. Lymphoma, lung, colon and prostate cancer were also increased with the hazard ratio for sedative hypnotics being greater than that of smoking. It may be, however, that patients on these meds were also more likely to have more medical care and disease surveillance (detection bias).

There are many problems with this study and I don’t think we can say the sky is falling based on the author’s conclusions alone. Correlation does not equal causation. One huge omission is that cause of death was not included.   When looking at the supplemental data of the study, I get a sense of confirmation bias where some data was plucked out to support the hypotheses that these drugs are deadly. While not a perfect study by any stretch, it gives food for thought. There does appear to be a correlation with bad outcome and sedative-hypnotic prescriptions, even at low frequency (<18 pills per year). I’d say, just know that these drugs have potential consequences, much like many of the meds we prescribe.

Rapid fire...

Should we black box them? No.

Do they help some people? Yes.

Are they overused? Yes.

Should we encourage better sleep hygiene and healthier lifestyle? Yes.

Should you stop taking Ambien? Long term, daily use - I think so.  Short term, PRN - remains to be seen.