Benzodiazepines May Boost Pneumonia Risk, Especially in Seniors

Batya Swift Yasgur, MA, LSW

January 14, 2019

Use of benzodiazepines and related drugs (BZRDs) is associated with greater risk for pneumonia, especially in older adults, new research suggests.

Investigators affiliated with the Seventh Hospital of Hangzhou, China, reviewed and meta-analyzed 10 studies, encompassing more than 120,000 pneumonia cases, and found that the odds for developing pneumonia were 1.25-fold higher in BZRD users compared with individuals who had not taken BZRDs.

This increased risk was found among current and recent BZRD users, but not among past users.

"Current or recent exposure to BZRD is associated with increased pneumonia risk," the authors state.

"Clinicians need to weight the benefit-risk balance of BZRD use, especially those with other risk factors for pneumonia," they conclude.

The study was published online January 8 in the International Journal of Geriatric Psychiatry.

Hot Debate

The prevalence of BZRD use among the elderly is high, with as many as 40% of older adults taking these agents, despite associated adverse events including falls, fractures, cognitive dysfunction, dementia, and behavioral disorders, the authors note.

The incidence of pneumonia, a leading cause of morbidity and mortality among individuals age 65 years and older, has increased over the past decade, leading to concerns that BZRD use may be associated with increased risk of contracting the disorder, the authors continue.

However, the association is "still much debated," they note.

Since no previous review has investigated this question, the researchers conducted a systematic literature review and meta-analysis to assess the association between BZRD exposure and the subsequent development of pneumonia.

To be included in the meta-analysis, studies were required to have a case-control, nest-control, or cohort design; include an unexposed reference group; investigate the association in the general population; and contain outcome measures utilizing odds ratios (ORs), relative risks (RRs), hazard ratios (HRs), and 95% confidence intervals (CIs). 

The primary outcome was overall risk of pneumonia in the general population.

The researchers also performed several subgroup analyses, distinguishing between study designs (case-control vs cohort); age groups (<65 years vs ≥65 years), as well as type of BZRD (BZD vs non-BZD), BZD half-life (long-, intermediate-, or short-acting), BZRD exposure duration, and methodological quality of the study.

They identified zolpidem, zaleplon, and eszopiclone as non-BZRD agents. 

Exposure windows were characterized as current use (the most recent prescription sold within 30 days or overlapping with the index date); recent use (prescription within 31-90 days of the index date); and past use (prescription beyond 90 days).

The meta-analysis included 12 citations of 10 studies, involving more than 120,000 pneumonia cases from six case-control studies and four cohort studies.

Study dates ranged from 1999 to 2018.

Four studies focused only on subjects aged 65 years or older, while six of them included both elderly and other adult participants. Of these, four distinguished between these age groups.

Of the studies, eight were of "high quality" and two were of "low quality" (Newcastle‐Ottawa Scale [NOS] ≥7 and <7, respectively).

Elderly Most Affected

In a random effects meta-analysis of all 10 studies, BZRD use was found to be significantly associated with increased risk of pneumonia (pooled OR = 1.25; 95% CI, 1.09 ‐ 1.44; P < .001).  

"Considerable" heterogeneity was found across the studies (I2 = 97%), with sensitivity analyses showing no substantial change in the pooled risk estimates on excluding any single study.

BZRD use was consistently associated with an increased risk of pneumonia in the subgroup analyses, according to cohort study design, use duration, age class, type of BZRD, and high-quality studies.

Regarding the half‐life of the BZRD, short‐ and intermediate‐acting BZRDs were found to be associated with a significantly increased risk of pneumonia vs long-acting BZRDs (short-acting: pooled OR, 1.51 [1.22 - 1.87]; I2 = 89.6%; intermediate-acting: pooled OR, 1.31 [1.13 ‐ 1.52]; I2 = 94.9%; long-acting: pooled OR, 1.23 [1.02 ‐ 1.49]; I2 = 90.6%, all Ps < .001).

The researchers observed a time‐dependent relationship between BZRD use and pneumonia risk. When compared with the group that had never used BZRDs, the pooled OR for the risk of pneumonia in current and recent users was 1.4 (95% CI, 1.22 ‐ 1.6) and 1.38 (95% CI, 1.06 ‐ 1.8), respectively, vs 1.11 (95% CI, 0.96 ‐ 1.27) in past users.

Moreover, additional subgroup analyses revealed that the highest OR was found in current short‐acting BZRD users (OR = 2.06; 95% CI, 1.35 ‐ 3.13).

The risk of an association between BZRD use and pneumonia was found to be considerably higher in people aged 65 years or older vs those younger than 65 years (OR 1.29 [1.15 ‐ 1.45]; I2 = 93.6% vs 1.8 [1.39 ‐ 2.34]; I2 = 12.3%, respectively, both Ps < .001).

Four drugs — diazepam, lorazepam, temazepam, and zopiclone — showed a significantly increased risk when all available data were considered.

Subgroup analysis of each individual drug, based on exposure windows, found that current chlordiazepoxide or clonazepam use did not show a significantly increased risk of pneumonia.

"On the basis of case‐control and cohort studies, our meta‐analysis suggests that current or recent BZRD use is associated with a modest increase in risk of pneumonia," the authors comment.

They add that there was "considerable heterogeneity across the studies," which may have affected their findings.

"Additional large-scale, well-designed studies with consideration of individual BZRD, current other drug use, and comorbid illness are needed to confirm or refute these results," the authors recommend.

Overtreated, Overdosed

Commenting on the study for Medscape Medical News, Irene Campbell-Taylor, MB ChB, PhD, a Nova Scotia-based clinical neuroscientist with a private practice focusing primarily on geriatrics, said that the study "does not sufficiently distinguish between viral and bacterial pneumonia, which is a relevant consideration."

Because benzodiazepines relax muscles, they can relax the esophageal sphincter, allowing acid, pepsin, and bile salts to reflux, especially during sleep.

This places the person at risk for aspiration pneumonitis (Mendelson syndrome), an injury caused by the inhalation of gastric contents, explained Campbell-Taylor, who was not involved with the study.

"This [injured] area provides a nexus for bacterial pneumonia, because we all aspirate some saliva every day and saliva is filled with bacteria, which is drawn to the area of damage and can cause pneumonia," she said.

The elderly are "overtreated and overdosed with psychotropic agents, including benzodiazepines," she noted, pointing out that the half-life of these medications is prolonged in this population, due to increasing age-related changes in the liver and kidneys.

"Older people require doses much lower than they are given, which increases problems, such as cognitive impairment, that are associated with benzodiazepines in any age group," she said.

Also commenting on the study for Medscape Medical News, Nicholas Vozoris, MD, assistant professor of respirology and sleep medicine, University of Toronto, Canada, who was not involved with the study, said that BZRDs "are known to be associated with a variety of possible side effects, but a recently and increasingly recognized side effect is increased risk for pneumonia."

This "potential side effect needs to be considered in prescribers’ minds when thinking about initiating a benzodiazepine, and it needs to be discussed with patients," he said.

"Furthermore, this study shows that risk of pneumonia extends to both shorter- and longer-acting benzodiazepines, both traditional and newer benzodiazepine-like drugs (ie, Z-drugs), and not only current drug users but also those individuals who in recent months have used a benzodiazepine but are not on one now," Vozoris noted.

The study authors agree. "Clinicians should ensure that BZRD drugs are prescribed only for patients with clear indications," they write.

The authors, Campbell-Taylor, and Vozoris have disclosed no relevant financial relationships.

Int J Geriatr Psychiatry. Published online January 8, 2019. Abstract

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