In our What’s New in the Patient Safety World columns for May 2012
“Safety
of Hypnotic Drugs” and November 2012 “More
on Safety of Sleep Meds” we discussed the issue of a possible link between
sedative/hypnotic drugs and mortality. One study (Kripke 2012)
found the risk for death was about 4.5 times higher in those patients who had
been prescribed hypnotics. They found a dose-response relationship where the
risk increased with increasing numbers of sleep pills taken. A second paper by
the same group and same database found that the risk of death was even higher
in the subset of patients having obesity (Langer
2012). The authors speculated about the role of sleep apnea and its
interaction with the sleep meds in this population. While those two studies may
have uncovered an association between mortality and use of hypnotics, they do
not confirm a cause-effect relationship.
Another study challenged the strength of the association
between hypnotic use and mortality (Hartz 2012).
One key question unanswered in previous studies showing a higher mortality in
patients using hypotics was whether sicker or higher
risk patients were more likely to use these drugs. The Hartz
study used data from the well-known long-term Women’s Health Initiative (WHI)
and was able to adjust for a host of other clinical factors. They did note that
those women using almost daily hypnotic drugs had a 62% increased risk of
mortality. However, after adjusting for a variety of risk factors associated
with poor health there was a great attenuation of the relationship between
hypnotic use and mortality (adjusted odds ratio 1.14) for those using hypnotics
almost daily and the relationship disappeared entirely for those using them
less frequently. However, since the study period for the WHI ended in 1998 most
women in the study did not take any of the currently used sedative/hypnotic
agents that may have been used in the more recent studies.
Now a new study again notes an association between
anxiolytic and hypnotic medications and increased mortality (Weich
2014). Researchers in the UK, using the General Practice Research
Database were able to compare mortality risks in over 100,000 patients prescribed
anxiolytics or hypnotic medications compared to age- and sex-matched controls
followed for a mean of 7.6 years. They found that mortality rates for those
patients prescribed such drugs were over three times higher than those not
taking such medications, even after adjustment for likely confounding factors.
Moreover, there appeared to be a dose-dependent association in that the
mortality rates were even higher in those taking such drugs for at least 90
days per year. While benzodiazepines were the most widely prescribed and had
the highest association with mortality, the association and dose-dependent
effect were seen for all drugs studied, including the so-called “Z drugs” (zolpidem, zaleplon, and zopiclone). The authors do point out that, because this is
an observational study, confounding due to unknown factors cannot be excluded.
Also, they cannot exclude a bias related to indications for prescribing such
drugs.
Over the years we’ve
discussed many of the safety issues related to sedative/hypnotic drugs
(see the links to prior columns below). They frequently are contributing
factors to patient falls, hip fractures, delirium, and opioid-related
respiratory depression. Sometimes we’ll see withdrawal syndromes in patients
who have been receiving such drugs chronically. They may also play a role in
predisposing some patients to aspiration. Anecdotally, they are a frequent
contributor to events occurring in patients with sleep apnea and a recent study
(Li 2014)
demonstrates a reliable association between a history of high-dosage hypnotics
and sleep related breathing disorders. Zolpidem has
been associated with increased visits to the emergency department and another
recent study (Huang
2014) has shown an association between zolpidem
use and infections.
And, of course, sedative/hypnotics have been linked to
next-day impairment of activities requiring mental alertness, such as driving.
In our March 2013 What’s New in the
Patient Safety World column “Sedative/Hypnotics
and Falls” we noted that the FDA (FDA 2013) had recommended lower doses of certain drugs
containing zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist) because of potential next-day
impairment of activities requiring mental alertness, such as driving. Just
recently the FDA (FDA 2014)
issued a similar alert recommending lower doses for eszopiclone
(Lunesta). The FDA cited studies in healthy adults
showing next-morning psychomotor and memory impairment after dosing with 3 mg. eszopiclone compared to placebo and that such impairments
were most severe at 7.5 hours but still present 11 hours after dosing. The new
FDA recommendation is for a starting dose of Lunesta
of 1mg. at bedtime.
While the nature of most studies linking sedative/hypnotic
drugs to these undesirable outcomes precludes conclusion of a cause-and-effect
relationship, the frequency with which these associations appears in observational
and retrospective cohort studies is strong enough to make you question
prescribing these drugs for your patients. Prescribing sleep meds, whether for
inpatients or outpatients, is often done without much thought. All too often
they are thought of as being relatively harmless. Knowing the potential downside
is an important first step. On the inpatient side, putting in place various
system fixes (eg. removing them from standardized
order sets, using clinical decision support tools, etc.) may play a more important
role. On the outpatient side, knowing and understanding how to promote good
sleep hygiene is extremely important in helping patients avoid the need for
such drugs in the first place. You need to help patients adopt practices that
promote good nocturnal sleep. That includes things like counseling them about
eating and drinking habits in relation to time of day (eg.
avoiding caffeinated beverages at night or avoiding large volumes of fluid that
will lead to awakening to void). And you need to make sure that noise and light
levels are not barriers to sleep and that the ambient temperature is conducive
to sleep. Similarly, activities earlier in the day may be important. Getting
some exercise, particularly outdoors, may benefit sleep as well as overall health.
Attention to patterns of any naps may also identify why a patient has trouble
sleeping at night.
Some of our previous
columns on safety issues associated with sleep meds:
August 2009 “Bold
Experiment: Hospitals Saying No to Sleep Meds”
March 23, 2010 “ISMP
Guidelines for Standard Order Sets”
May 2012 “Safety
of Hypnotic Drugs”
November 2012 “More
on Safety of Sleep Meds”
March 2013 “Sedative/Hypnotics
and Falls”
June 2013 “Zolpidem
and Emergency Room Visits”
August 6, 2013 “Let
Me Sleep!”
References:
Kripke DF, Langer RD, Kline LE.
Hypnotics' association with mortality or cancer: a matched cohort study. BMJ Open 2012; 2: e000850 doi:10.1136/bmjopen-2012-000850
Published 27 February 2012
http://bmjopen.bmj.com/content/2/1/e000850.full.pdf+html
Langer RD, Kripke DF, Kline LE.
Abstract 052: Short-acting Hypnotic Drugs Increase Mortality and Obese Patients
are Particularly Vulnerable. Circulation.
2012; 125: A052
Hartz A, Ross JJ. Cohort study of
the association of hypnotic use with mortality in postmenopausal women. BMJ
Open 2012; 2(5). pii:
e001413. http://bmjopen.bmj.com/content/2/5/e001413.long
Weich S, Pearce HL, Croft P, et
al. Effect of anxiolytic and hypnotic drug prescriptions on mortality hazards:
retrospective cohort study. BMJ 2014;
348:g1996 (Published 19
March 2014)
http://www.bmj.com/content/348/bmj.g1996.pdf%2Bhtml
Li CT, Bai YM, Lee
YC, et al. High dosage of hypnotics predicts subsequent sleep-related breathing
disorders and is associated with worse outcomes for depression. Sleep 2014; 37(4):
803-809
http://www.ncbi.nlm.nih.gov/pubmed/24688165
Huang CY, Chou FH, Huang YS, et al. The association between zolpidem and infection in patients with sleep disturbance.
J Psychiatr Res 2014 Mar 27. pii: S0022-3956(14)00090-9 [Epub ahead of
print]
http://www.journalofpsychiatricresearch.com/article/S0022-3956%2814%2900090-9/abstract
FDA. FDA Drug Safety Communication: Risk of next-morning
impairment after use of insomnia drugs; FDA requires lower recommended doses
for certain drugs containing zolpidem (Ambien, Ambien
CR, Edluar, and Zolpimist).
January 10, 2013
http://www.fda.gov/Drugs/DrugSafety/ucm334033.htm
FDA. FDA Drug Safety Communication: FDA warns of next-day
impairment with sleep aid Lunesta (eszopiclone) and lowers recommended dose. FDA Safety
Announcement 5/15/2014
http://www.fda.gov/downloads/Drugs/DrugSafety/UCM397277.pdf
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