I swear I don’t go looking for alarming news about benzodiazepines, drugs widely prescribed for insomnia and anxiety. But it shows up with some frequency, so, mindful of your fervidly held views on the subject, I am donning a hazmat suit to bring you the latest findings from the medical journal BMJ.
In previous posts, I reported that long-term use by older people of drugs called sedative-hypnotics, which includes benzos (like Ativan, Xanax, Valium and Klonopin) and the related “z-drugs” (Ambien, Lunesta), has for years caused concern among some researchers.
Some readers took exception, arguing that critics minimize the miseries of chronic sleeplessness, reflexively condemn all drug dependence or condescendingly assume older people can’t make smart decisions. “The Ambien I use is low dose and I am not an idiot,” commented a miffed Margaret Moffitt of Roanoke, Va.
The doctors and health organizations I have spoken to, however, point to much higher rates of falls and fractures, auto accidents and cognitive problems in older patients taking sedative-hypnotics, along with increased emergency room visits and hospital admissions. Hence, the American Geriatrics Society’s inclusion of these drugs in its Choosing Wisely list of treatments that doctors and patients should question.
Now French and Canadian researchers are reporting — in a study designed with particular care1 — that benzodiazepine use is linked to higher rates of subsequent Alzheimer’s disease, and that the association strengthens with greater exposure to the drugs.
“The more the cumulative days of use, the higher the risk of later being diagnosed with dementia,” Dr. Antoine Pariente, a pharmacoepidemiologist at the University of Bordeaux and a co-author of the study, told me in an interview.
He and his colleagues reviewed medical records of almost 1,800 older people diagnosed with Alzheimer’s in the public health insurance program in Quebec, and compared them with nearly 7,200 control subjects. Most were over age 80.
About half those with Alzheimer’s and 40 percent of the control subjects had used benzodiazepines, the researchers found. That translated to a 51 percent increase in the odds of a subsequent Alzheimer’s diagnosis among the benzodiazepine users.
It was not short-term use that drove that finding: Older people who took prescribed doses for 90 days or fewer over the course of the study — patients were followed for six years or longer — had no increased risk.
But those who took the drugs longer were more likely to be diagnosed with Alzheimer’s. In older patients who took daily doses for 91 to 180 days, the risk rose 32 percent, compared to those who took none. In those who took daily doses for more than 180 days, the risk was 84 percent higher.
The association persisted whether users took 180 doses over six months or over five years, Dr. Pariente said. It also held when the researchers controlled for health and demographic factors, including conditions like anxiety, depression and insomnia.
The link was stronger to longer-acting forms of the drug, like Valium, than to formulations that leave the body more quickly, like Ativan and Xanax.
Annoyed comments may already be on their way, so let me address a few likely objections:
Objection! This is just another example of “correlation, not causation.”
Does the study show that extended benzodiazepine use causes Alzheimer’s? No, an observational study like this can never directly answer that question. But “the stronger association observed for long term exposures reinforces the suspicion of a possible direct association,” the researchers wrote.
Dr. Malaz Boustani, a geriatrician at Indiana University Health and a co- author of an accompanying BMJ editorial, praised the study’s design, which attempts to correct for what is sometimes called “reverse causation bias”: the danger, as Dr. Pariente put it, that “it’s not the drug that caused the disease. It’s the early symptoms of the disease that caused the drug use.”
Because Alzheimer’s symptoms develop slowly and can include some of the very problems (like anxiety and insomnia) for which doctors prescribe benzos, the study looked at Alzheimer’s patients who had not taken benzodiazepines for five years before their diagnoses. Their use of the drugs occurred five to 10 years earlier than that.
“They really did everything possible to overcome methodological issues,” Dr. Boustani said of the researchers.
Objection! Taking benzos only occasionally — once or twice a week, perhaps — has no impact.
Not in this study. Whether these elderly Quebecois took 180 daily doses in a row or spread them out over years, their risk of later developing Alzheimer’s disease was nearly double that of people who did not take the drugs or who stopped at 90 doses.
And many people don’t stop at 90, or stop at all. “The problem is chronic use, especially in the very elderly,” Dr. Pariente said. “You develop a tolerance and a dependency.”
Objection! What about relative versus absolute risk?
For some ailments, an increase in risk of 51 percent or even 84 percent still means people face very low risk. But dementia affects roughly 25 to 30 percent of the population over 80; Alzheimer’s accounts for about 70 percent of that. The projected numbers are sobering. To date, the search for drugs, treatments, even basic causes has been discouraging.
What if, instead of regarding these findings as scolding about drugs, we saw them as a possible finding about Alzheimer’s prevention? “Stopping these medications is such an easy, cost-effective potential therapy,” Dr. Boustani said.
Maybe that is a bit optimistic. But remember that in a different Quebec study, a brochure alone helped 27 percent of long-term, elderly benzo users to taper down (no one should simply stop these drugs cold) and discontinue their prescriptions within six months. Another 11 percent reduced their dosage.
People don’t want to part with their sleeping pills, I told Dr. Boustani, remembering our earlier discussions. They don’t see why they should.
His reply: “Tell them: ‘Here is the information. Take this into account when you decide to take a sleeping pill or not.’ ”
“If you’re willing to take the risk, O.K.,” he added. “You’re making an informed decision.”
By Paula Span
1Benzodiazepine use and risk of Alzheimer’s disease: case-control study (2014) BMJ 2014; 349 doi: http://dx.doi.org.cyber.usask.ca/10.1136/bmj.g5205 (Published 09 September 2014) Sophie Billioti de Gage, Yola Moride, Thierry Ducruet, Tobias Kurth, Hélène Verdoux, Marie Tournier, Antoine Pariente, Bernard Bégaud.
From this study:
"This case-control study based on 8980 individuals representative of elderly people living in the community in Quebec showed that the risk of Alzheimer’s disease was increased by 43-51% among those who had used benzodiazepines in the past. Risk increased with density of exposure and when long acting benzodiazepines were used. Further adjustment on symptoms thought to be potential prodromes for dementia—such as depression, anxiety, or sleep disorders—did not meaningfully alter the results."
"Our findings are congruent with those of five previous studies, two of which explored the modifying effect of the dose used. In four studies, the role of a putative protopathic bias could not be ruled out because an insufficient duration of follow-up; a lack of statistical power in subgroup analyses8; and no consideration of the most relevant time window for exposure and ascertainment of confounders. The most recent study found a similar 50% increased risk within the 15 years after the start of benzodiazepine use (average length of follow-up 6.2 years). This excess risk was delayed and thus not indicative of a reverse causality bias. Another study found a positive association, though lacked significance because of its limited sample size. The earliest work observed a paradoxical protective effect of benzodiazepines, which could be partly explained by the misclassification of past users as a part of the reference group."
"Finally, we cannot rule out alternative hypotheses. For example, anxiety and sleep disorders, two of the main indications for benzodiazepines, could be associated with early β amyloid lesions in brain, and persistent mid-life anxiety could be associated with a greater risk of dementia in older people. Therefore, benzodiazepine use might be an early marker of a condition associated with an increased risk of dementia and not the cause.
Benzodiazepines and risk of Alzheimer’s disease
Prescribers and patients need a proper surveillance system for cognitive side effects
A growing number of observational studies have shown the critical role of potentially inappropriate medications for increasing the risk of cognitive impairment. In a linked paper, Billioti de Gage and colleagues extend the pharmacoepidemiological research on the adverse cognitive effects of benzodiazepines with an investigation of their link with Alzheimer’s disease.1 Their results suggest that long term exposure to benzodiazepines might be a modifiable risk factor for this condition.
The authors conducted a nested case-control study of about 2000 older members of a public drug plan in the province of Quebec, Canada. They observed a cumulative dose-effect association between exposure to benzodiazepines (at least 90 days) and risk of developing Alzheimer’s disease and found that exposure lasting more than 180 days was associated with a nearly twofold increase in risk. In further analyses, they showed that longer acting benzodiazepines were associated with greater risk of developing Alzheimer’s disease compared with shorter acting benzodiazepines, adding support for a causal association.
The interpretation of these findings is strengthened by rigorous methods. For example, the authors minimized selection bias by randomly selecting both the case and control subjects from a well defined and generalizable cohort of older adults living in the community. They also limited recall, temporal, and indication biases associated with drug dispensing by using exposure windows of at least five years before the index diagnostic date for cases and their controls matched on age, sex, and follow-up. Findings were adjusted for many potential confounders with multivariate conditional logistic regression analysis. Confounders included underlying medical conditions such as depression and anxiety that commonly trigger use of benzodiazepines and are also considered risk factors for Alzheimer’s disease. Finally the study’s sponsor had no influence on the design and the conduct of the study.
It is not surprising that benzodiazepines are associated with adverse cognitive effects. In 2012, Tannenbaum and colleagues published a systematic review that found an association between benzodiazepines and cognitive impairment in 38 out of 39 studies, but the impairment was presumed to be transient and reversible.2 The findings of the present study challenge such a reversible cognitive effect and suggest that the adverse cognitive outcomes of benzodiazepines might include neurodegenerative disease. Others have suggested that benzodiazepines and other potentially inappropriate drugs are commonly prescribed for older adults and are associated with worse cognitive outcomes over a long follow-up.3 4 These studies, however, also remind us of the complex relation between dementia (including Alzheimer’s) and use of benzodiazepines. Older adults who received a diagnosis of dementia were more likely to be taking benzodiazepines and other potentially inappropriate medications five to six years before, raising the possibility of reverse causation as benzodiazepines can be used to treat prodromal symptoms of dementia including anxiety and sleep disturbances.
As life expectancy increases, the developed world is facing a rapid rise in the number of older adults with multiple chronic conditions.5 Managing multiple conditions requires, on average, treatment with at least five drugs,6 and one of the most critical negative consequences of polypharmacy is the development of adverse drug effects.7 Some side effects, such as renal injury and anaemia, are well documented, readily identified, and easily monitored with objective laboratory tests. Other side effects, including cognitive side effects, are much harder to recognize because there is no routine laboratory test or standardized post-marketing surveillance system.7
In 2012, the American Geriatrics Society updated its list of inappropriate drugs for older adults to include three classes of drugs with adverse cognitive effects: anticholinergics, H2 antihistamines, and benzodiazepines.7 Despite evidence of such cognitive side effects, a review of published literature indicates that up to half of older adults continue to use these.8 Currently, there is no standardized approach to help to identify and monitor the cognitive side effects of drug treatments. As a result, potential long term consequences of drugs such as benzodiazepines remain hidden and contribute to a growing burden of cognitive impairment among older adults. Identification of drugs with adverse cognitive effects requires dedicated monitoring of cognitive function, which is often absent from routine hospital and ambulatory clinical care.9
To fill this gap, we support the development of a structured reproducible approach to the identification and accurate monitoring of the adverse cognitive effects of all drug treatments used by older adults with multiple chronic conditions, particularly by those at risk of Alzheimer’s disease. Ideally, this would establish a global surveillance system for adverse cognitive effects that uses readily available clinical factors and drug exposures from a growing number of electronic medical record systems. Better surveillance for cognitive side effects could improve therapeutic decisions among doctors treating high risk older adults with multiple chronic conditions and hopefully, eventually, help to reduce the burden of cognitive impairment worldwide.
Kristine Yaffe Roy, Marie Scola, Malaz Boustani, and Richard M Fairbanks. Benzodiazepines and risk of Alzheimer’s disease, BMJ 2014; 349 doi: http://dx.doi.org.cyber.usask.ca/10.1136/bmj.g5312 (Published 09 September 2014)
1Billioti de Gage S, Moride Y, Ducruet T, Kurth T, Verdoux H, Tournier M, et al. Benzodiazepine use and risk of Alzheimer’s disease: case-control study. BMJ 2014;349:g5205.
2Tannenbaum C, Paquette A, Hilmer S, Holroyd-Leduc J, Carnahan R. A systematic review of amnestic and non-amnestic mild cognitive impairment induced by anticholinergic, antihistamine, GABAergic and opioid drugs. Drugs Aging 2012;29:639-58
3Koyama A, Steinman M, Ensrud K, Hillier TA, Yaffe K. Ten-year trajectory of potentially inappropriate medications in very old women: importance of cognitive status. J Am Geriatr Soc 2013;61:258-63.
4Koyama A, Steinman M, Ensrud K, Hillier TA, Yaffe K. Long-term cognitive and functional effects of potentially inappropriate medications in older women. J Gerontol Ser A Biol Sci Med Sci 2014;69:423-9.
5Anderson GF. Chronic care: making the case for ongoing care. Robert Wood Johnson Foundation, 2010.
6Ernst FR, Grizzle AJ. Drug-related morbidity and mortality: updating the cost-of-illness model. J Am Pharm Assoc (Wash)2001;41:192-9.
7American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2012;60:616-31.
8Fox C, Smith T, Maidment I, Chan WY, Bua N, Myint PK, et al. Effect of medications with anti-cholinergic properties on cognitive function, delirium, physical function and mortality: a systematic review. Age Ageing 2014;afu096 [epub ahead of print].
9Boustani M, Baker MS, Campbell N, Munger S, Hui SL, Castelluccio P, et al. Impact and recognition of cognitive impairment among hospitalized elders. J Hosp Med 2010;5:69-75.
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