Diphenhydramine Emergency Department Trends Show No Shift Since 2019

A study observed unchanged emergency department practices regarding diphenhydramine for anaphylaxis and urticaria despite 2020 guidelines discouraging using first-generation antihistamines.1

At least 1.6% of the general population experiences an anaphylaxis reaction, with this proportion rising. There has also been an increase in anaphylaxis cases treated in the emergency department, comprising 0.4% of admissions. A nationwide study reported that 405,145 visits for anaphylaxis occurred in emergency departments from 2008 to 2016, with a 2.3-fold increase in the prevalence of anaphylaxis during this time.2

Diphenhydramine is the most commonly used antihistamine in emergency departments.1 However, this IV treatment can lead to serious adverse events, such as sedation, decreased cognitive performance, dizziness, and overdose-related deaths.

Recently, the medical community has viewed diphenhydramine, the first-generation antihistamine, in a negative light due to its adverse events and the efficacy of second-generation antihistamines. Research has shown that second-generation antihistamines can achieve comparable outcomes with fewer adverse events. Unlike first-generation antihistamines, which can easily cross people’s blood-brain barrier into the central nervous system and cause drowsiness, second-generation antihistamines do not cause drowsiness and interact with fewer medications.3

The American Academy of Allergy, Asthma, & Immunology’s (AAAAI) updated 2020 anaphylaxis guidelines discourage the use of first-generation antihistamines in the acute phase or to prevent biphasic reactions.4

“Antihistamines and/or glucocorticoids are not reliable interventions to prevent biphasic anaphylaxis, although evidence supports a role for antihistamine and/or glucocorticoid premedication in specific chemotherapy protocols and rush aeroallergen immunotherapy,” wrote reviewers of the 2020 practice parameter update, by Marcus S. Shaker, MD, MSc, from the section of allergy and clinical immunology at Dartmouth-Hitchcock Medical Center. “Evidence is lacking to support the role of antihistamines and/or glucocorticoid routine premedication in patients receiving low- or iso-osmolar contrast material to prevent recurrent radiocontrast media anaphylaxis.”

Rather than antihistamines, the AAAAI recommends epinephrine as the first-line treatment for anaphylaxis and only using antihistamines as an adjunct therapy after stabilization.1 However, these guidelines come with some limitations since they were built upon evidence from low-certainty, non-randomized trials.

Investigators recognized the need for further research assessing common practices in anaphylaxis treatment and prevention. The team, led by Jazeb Ifikhar from the department of pediatrics at the University of Oklahoma School of Community Medicine, conducted a cross-sectional analysis to assess diphenhydramine usage in the US emergency departments for treating anaphylaxis and urticaria between 2019 and 2021. They also investigated the potential impact of the 2020 AAAI guidelines on diphenhydramine usage.

Using the Centers for Disease Control and Prevention’s National Hospital Ambulatory Medical Care Survey (2019 – 2021), the team leveraged emergency department data of patients with ICD-10 codes for anaphylaxis or urticaria who were prescribed or given ≥ 1 medication. Drug records were used to examine diphenhydramine administration.

Among 450 patients with anaphylaxis (n = 295) or urticaria (n = 131), 61.99% received a diphenhydramine prescription. Diphenhydramine rates were 57.99% for anaphylaxis cases, 69.45% for urticaria cases, and 73.4% for both anaphylaxis and urticaria.

Despite guidelines discouraging first-generation antihistamines, the analysis observed no significant change in diphenhydramine use from 2019 to 2021 (P = .9421).

“Our study indicates stagnant [emergency department] practices regarding diphenhydramine despite evolving guidelines,” investigators concluded. “Bridging the gap between evidence and practice is crucial for patient care for urticaria and anaphylaxis. Future research should identify barriers hindering guideline adoption in US [emergency departments].”

References

1. Ifikhar J, Sparks D, Hendrix-Dicken AD, Folger S, Hartwell M, Condren M. Shifting perspectives: diphenhydramine usage in anaphylaxis and urticaria across US emergency departments. Am J Emerg Med. Published online April 29, 2025. doi:10.1016/j.ajem.2025.04.055

2. Michelson KA, Dribin TE, Vyles D, Neuman MI. Trends in emergency care for anaphylaxis. J Allergy Clin Immunol Pract. 2020;8(2):767-768.e2. doi:10.1016/j.jaip.2019.07.018

3. Antihistamines. Cleveland Clinic. https://my.clevelandclinic.org/health/treatments/antihistamines. Accessed May 23, 2025.

4. Shaker MS, Wallace DV, Golden DBK, et al. Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis. J Allergy Clin Immunol. 2020;145(4):1082-1123. doi:10.1016/j.jaci.2020.01.017