Diphenhydramine (Benadryl), is ubiquitous in the emergency department (ED) and has historically been a component of many treatment algorithms. Urticaria? Take some diphenhydramine. Allergic reaction or anaphylaxis? Give them diphenhydramine. Migraine? Let’s add some diphenhydramine to the mix. Yet, there is essentially no reason to administer diphenhydramine to ED patients. Alternatives to diphenhydramine exist that are less sedating, possess fewer anticholinergic effects, and are equally efficacious. In fact, many professional society guidelines have urged emergency physicians to stop using diphenhydramine for years.
Explore This IssueACEP Now: Vol 41 – No 07 – July 2022
Not-So-Commonly Known Side Effects
Diphenhydramine is the most popular first-generation antihistamine in the United States—a medicine cabinet staple—probably because it has been around for over 70 years. However, many suggest that the medication would not be approved today as an over-the-counter medication. There are significant safety concerns regarding diphenhydramine. As a first-generation antihistamine, diphenhydramine readily crosses the blood-brain barrier. As a result, it is associated with sleepiness, even persisting the morning after a single evening dose. Its sedative effects throughout the central nervous system can last longer than 12 hours, far beyond its therapeutic actions. Sleepiness alone, however, isn’t the only side effect. This class of antihistamines that diphenhydramine is associated with cause impaired cognition and psychomotor performance, including during driving, and has been linked to accidental injury.1 One randomized trial found that a dose of diphenhydramine was associated with markers of impaired driving worse than a blood alcohol concentration of roughly 0.1 percent.2
In addition to the cognitive side effects, first-generation antihistamines have poor selectivity to the brain’s H1 histamine receptors and can result in heightened anticholinergic and antimuscarinic responses. Older patients are particularly at risk of cognitive decline and other adverse effects.3 In addition to these adverse events, diphenhydramine is abused by some to generate hallucinations or a sensation of being “high” (particularly associated with rapid intravenous administration).
Alternatives, like second- and third-generation antihistamines, offer more favorable risk-benefit profiles. These medications less readily cross the blood-brain barrier, translating to less sedation, less cognitive impairment, and less potential for abuse. Oral second-generation antihistamines such as cetirizine, fexofenadine, and levocetirizine work at least as fast as diphenhydramine.1
Allergic Reactions and Anaphylaxis
Of the indications for diphenhydramine, immediate hypersensitivity reactions such as allergic conditions and anaphylaxis may seem obvious. Yet, a 2020 practice statement from the American Academy of Allergy Asthma, and Immunology (AAAAI) recommends against the administration of any antihistamine in the acute phase of anaphylaxis or for the prevention of biphasic reactions.4 Indeed, the treatment for anaphylaxis is epinephrine and antihistamines do not have life-saving effects in this disease process. The practice update states that antihistamines may be used as adjuncts but, in this case, they advocate for the use of second-generation H1-blockers. One argument for the continued use of diphenhydramine is the ability to administer the medication intravenously or intramuscularly. However, diphenhydramine does not need to be given emergently in anaphylaxis or allergic reactions. It is an adjunct, an aid for symptomatic control and, as such it can be given orally after epinephrine has stabilized the patient.