Older Canadian adults whose physicians prescribed first-generation antihistamines in the hospital were more likely to experience delirium, a cross-sectional study suggested.

“Dermatologists are often called to inpatient wards to help manage various itchy conditions, such as drug rashes, and often the default medications prescribed for these [conditions] by hospitalists are sedating antihistamines,” principal author Aaron Drucker, MD, dermatologist and clinician scientist at the University of Toronto and Women’s College Hospital, Toronto, told Medscape Medical News. “These [drugs] are usually not helpful and can be harmful, so we wanted to draw attention to that.”

The analysis found that patients admitted to physicians who commonly prescribe first-generation antihistamines had 41% increased odds of experiencing delirium compared with patients admitted to low prescribers.

Furthermore, because first-generation antihistamines are sedating, Drucker noted, “I worry about falls in older adults.”

The study was published on October 22 in the Journal of the American Geriatrics Society.

A Modifiable Risk?

Researchers analyzed data on 328,140 inpatient admissions of adults aged 65 years or older between 2015 and 2022 across 17 hospitals in Ontario. The main exposure was the proportion of 755 attending physicians’ admissions that included a first-generation antihistamine prescription.

The main outcome was inpatient delirium, identified using a machine learning tool. Multivariable mixed-effects logistic regression was used to estimate the association between the physicians’ first-generation antihistamine prescribing rate and individual inpatients’ risk for delirium.

A total of 11,507 (3.5%) admissions were associated with a first-generation antihistamine prescription. Physicians in the lowest quartile prescribed a first-generation antihistamine during 2.1% of admissions compared with 5.4% of physicians in the highest prescribing quartile.

Delirium occurred in 32.3% of admissions to the lowest-prescribing physician quartile and 36.6% of admissions to the highest-prescribing quartile.

After adjustment, every 1% absolute increase in first-generation antihistamine prescribing was associated with an 8% increase in the odds of delirium. 

Patients with physicians in the highest quartile had 41% increased odds of delirium compared with those with physicians in the lowest prescribing quartile.

The results were consistent after adjustment for patient characteristics, when applying different definitions of delirium, and across strata of various important patient characteristics.

The authors suggested that first-generation antihistamine prescribing “may be a modifiable risk factor for delirium among older inpatients.”

The study had limitations, the authors acknowledged. The diagnosis of delirium from a machine learning tool and the International Classification of Diseases-10 codes is at the hospitalization level, meaning that the authors were unable to examine the direct temporal association between first-generation antihistamine utilization among individual inpatients and their risk for subsequent delirium.

In addition, using a machine learning tool to identify delirium is not the gold standard, which would be chart review or active case findings.

Furthermore, physicians who prescribe higher rates of first-generation antihistamines also may be more likely to precipitate delirium in other ways, such as through higher rates of Foley catheter use or other psychotropic medication use, which the authors did not account for.

Nevertheless, they concluded, “These findings suggest that inpatient first-generation antihistamines may be associated with an increased risk of delirium, and their prescribing should be approached carefully for older adults.”

“If an antihistamine is indicated, a second-generation, nonsedating antihistamine should be as effective and preferred because it is safe,” said Drucker. His team is comparing the risk for delirium with first- and second-generation antihistamines. “If evidence continues to mount that first-generation antihistamines are harmful for older inpatients, then quality improvement initiatives to reduce their use would be helpful.”

‘Discourage Use’

“These results align with previous research connecting these medications to cognitive slowing, reduced alertness, falls, and slower reaction times,” Mark Olfson, MD, MPH, professor of epidemiology, psychiatry, medicine, and law at Columbia University Irving Medical Center in New York City, told Medscape Medical News.

“Although further research using well-controlled, prospective designs and individual-level treatment data is needed to verify this association, it remains prudent to discourage the use of first-generation antihistamines by older adults,” said Olfson, who was not involved in the study.

In the US, he noted, “Medicare does not impose any specific restrictions that prevent the prescription of first‑generation antihistamines. However, over‑the‑counter [OTC] allergy medications, which account for much of the use of first‑generation antihistamines, are generally not covered by Medicare.” 

Although these OTC antihistamines can be a precipitating factor for delirium, he said, “Older hospitalized patients are much more likely to have underlying risk factors for delirium, such as dementia, stroke, or cardiac or pulmonary disease.”

The study was supported by the WCHAMSG Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centers of Ontario. Drucker reported receiving compensation from the British Journal of Dermatology (reviewer and section editor), American Academy of Dermatology (guidelines writer), Canadian Dermatology Today (manuscript writer), and Canadian Agency for Drugs and Technologies in Health (consultant). 

Drucker also reported receiving research grants to his institution from the National Eczema Association, Eczema Society of Canada, Canadian Dermatology Foundation, Canadian Institutes for Health Research, US National Institutes of Health, and Physicians Services Incorporated Foundation. Olfson reported having no relevant financial relationships. 

Marilynn Larkin, MA, is an award-winning medical writer and editor whose work has appeared in numerous publications, including Medscape Medical News and its sister publication MDEdge, The Lancet (where she was a contributing editor), and Reuters Health.