Diphenhydramine impaired driving performance more than alcohol, raising concerns about its continued over-the-counter availability, according to a review.
Researchers published a review in the World Allergy Organization Journal evaluating the safety and continued use of diphenhydramine, a first-generation H₁-antihistamine introduced in 1946. The authors conducted a comprehensive analysis of pharmacologic properties, adverse event data, and prescribing patterns to assess the clinical appropriateness of diphenhydramine compared with second-generation antihistamines.
The researchers reviewed prescribing trends and found that more than 1.5 million diphenhydramine prescriptions are written annually in the U.S. However, over-the-counter availability accounts for far greater use, with diphenhydramine appearing in more than 300 nonprescription formulations, including single-agent and combination allergy, cough, cold, and sleep medications. A national Harris Poll cited in the review revealed that 62% of adults and 51% of children with physician-diagnosed allergic rhinitis were managed with over-the-counter oral antihistamines. Only 32% of respondents reported being “very or extremely” satisfied with this approach.
The authors, led by James H. Clark, of the Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, and colleagues, highlighted diphenhydramine’s "problematic therapeutic ratio" and high incidence of sedation, drowsiness, and psychomotor dysfunction due to its central nervous system penetration and non-selectivity for H₁-receptors. The drug’s elimination half-life was shown to vary widely—approximately 4 hours in children and up to 18 hours in older adults—raising concerns about residual sedation and impaired function. A simulated driving study found diphenhydramine impaired performance to a greater extent than alcohol. Additionally, pediatric data indicated that diphenhydramine accounted for 30.1% of accidental cough and cold medication ingestions in children younger than 4 years, with 43.8% of affected patients requiring hospitalization and 22.0% admitted to critical care.
The review noted that second-generation antihistamines offer similar or superior efficacy with fewer adverse effects, more superior pharmacokinetics, and minimal sedation. Intravenous cetirizine, recently approved for use in urticaria, demonstrated a 24-hour duration of action, less sedation, shorter emergency department stays, and fewer treatment-related adverse events compared with intravenous diphenhydramine.
Given the documented adverse events, abuse potential—including cases associated with the “Benadryl Challenge” on social media—and the existence of safer alternatives, the researchers concluded that diphenhydramine poses a significant public health risk. They recommendedultimately withdrawing it from both prescription and over-the-counter markets.
The authors reported no conflicts of interest.