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Antihistamines were involved in at least 15% of recent overdose deaths, according to 2019-2020 data from 43 states and the District of Columbia.

Of 92,033 overdose deaths during this time period, 14.7% were antihistamine-positive and 3.6% were antihistamine-involved, reported Amanda Dinwiddie, MPH, of the CDC's National Center for Injury Prevention and Control in Atlanta, and co-authors.

Nearly all of these deaths included first-generation H1 antihistamines, primarily diphenhydramine (Benadryl; 71.1% of antihistamine-positive deaths and 66.5% of antihistamine-involved deaths), they noted in the .

First-generation H1 antihistamines are often used to treat allergy symptoms or aid sleep. They can cause sedative effects that may worsen when used with other sedative drugs like opioids.

They are also found in illicit drugs, Dinwiddie and co-authors noted.

"Diphenhydramine, a common over-the-counter first-generation H1 antihistamine, has been in illicit drug supply and can be used to reduce opioid-related side effects (e.g., itchy skin because of histamine release from opioid use)," they wrote.

Combining opioids and diphenhydramine can be especially dangerous, they added. " [Narcan] administration is important for any overdose with suspected opioid involvement. Because antihistamines do not respond to naloxone, co-involved opioid and antihistamine overdoses might require naloxone administration plus other immediate medical response measures to prevent death."

Dinwiddie and colleagues evaluated overdose deaths using data from the State Unintentional Drug Overdose Reporting System () for 43 states and the District of Columbia during 2019-2020. SUDORS captures data on fatal unintentional and undetermined-intent overdoses.

A death was defined as antihistamine-positive if any antihistamine was detected on postmortem toxicology or was listed on the death certificate. It was defined as antihistamine-involved if the drug class was listed as a cause of death. Fewer than 0.1% of overdose deaths involved antihistamines alone.

The proportions of antihistamine-involved and diphenhydramine-involved overdose deaths were highest among women, those ages 35 to 44, and white people. Demographic patterns of antihistamine-positive and diphenhydramine-positive deaths were similar, except that deaths were more frequent among men and in the Midwest region.

"Most antihistamine-involved and diphenhydramine-involved overdose deaths co-involved opioids (82.8% and 82.7%, respectively), primarily illicitly manufactured fentanyls," Dinwiddie and colleagues observed.

The findings have several limitations, the researchers acknowledged. The study included only 44 jurisdictions and may not be nationally representative. Moreover, drug-testing methods were not standard across jurisdictions.

Antihistamine positivity may reflect allergy or other treatments and not necessarily misuse, they added. "It is also possible that some persons did not knowingly consume antihistamines and were exposed to these drugs through adulteration of the illicit drug supply with antihistamines," they pointed out.

"Despite these limitations, these data highlight the importance of continued surveillance to understand the drugs and drug combinations contributing to overdose deaths and to guide awareness efforts about the potential dangers of the unpredictable illicit drug supply and the intentional or unintentional co-use of substances, including antihistamines and opioids," Dinwiddie and co-authors concluded.

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