- Several allergy experts have proposed retiring first-generation antihistamine diphenhydramine.
- Second-generation antihistamines have fewer side effects and work as well as their predecessors.
- Diphenhydramine is recognized to have high adverse side effects, particularly in children and older adults.
Some allergy specialists are questioning whether one of the most familiar and oldest antihistamines, diphenhydramine, needs to be retired in favor of second-generation drugs that have fewer side effects and work as well.
The World Allergy Organization Journal published “Diphenhydramine: Is it time to say a final goodbye” in February, but as experts have shared it with each other and increasingly discussed it on social media, the paper’s getting more attention now.
The paper was written by Dr. James H. Clark and Dr. Robert M. Naclerio, both of Johns Hopkins University School of Medicine, and by Dr. Eli O. Meltzer of the University of California, San Diego and La Jolla.
They wrote that medications have a natural life cycle as better ones are developed and said the drug “has reached the end of its life cycle.” They recommend eliminating it as an option, but at least removing its over-the-counter availability.
Per the paper, “Diphenhydramine, once a pioneering antihistamine, is now overshadowed by second-generation antihistamines with similar efficacy and fewer adverse effects. Current data suggest that the adverse side-effect profile of diphenhydramine is higher among children and older adults. This has led to countries such as Germany and Sweden restricting access to first-generation antihistamines and societal guidelines advocating for the use of second-generation antihistamines.”
The Canadian Society of Allergy and Clinical Immunology also says first-generation antihistamines should be behind-the-counter.
More than 300 different formulations exist, most of them over-the-counter. Perhaps the best-known branded version is Benadryl. The paper notes diphenhydramine is also in Sominex and some combination medications like Robitussin Severe Multi-Symptom Cough Cold + Flu Nighttime and Sudafed PE Day/Night Sinus Congestion products.
The researchers noted that “diphenhydramine’s problematic therapeutic ratio has been known since the 1980s, and this significant disadvantage has not to date succeeded in stopping over a million prescriptions being written each year. The behind-the-counter status would help the pharmacist suggest safer alternatives and hopefully prevent many adverse consequences, including abuse.”
Better second-generation options
The newer drugs target antihistamine receptors, while the earlier drugs are “non-selective” and bind to many more receptors throughout the body. That’s why side effects can be related to so many different organs and parts of the body.
There are, per the journal paper, many safer alternatives. And price is not an issue with second-generation antihistamines, either, it noted. They cost about the same and can be purchased almost anywhere.
Of a drug’s life cycle, the authors wrote: “Over time, as a medicine’s usage grows, its indications may be expanded, and its safety profile becomes better understood. Eventually, competition from newer medications with equal or better efficacy or fewer adverse events exceeds the comparative risk-benefit ratio of the earlier medication, often decreasing it to the point where it should be retired.”
Among the possible adverse effects of diphenhydramine noted in the journal are urinary retention, drowsiness, dizziness, hallucinations, cognitive problems, blurry or dry eyes, tachycardia, heart arrhythmia, skin flushing, dry mouth and constipation. The paper says diphenhydramine can interfere with sleep, and also notes “its demonstrated abuse potential.”
Researchers wrote about the TikTok "Benadryl challenge during the pandemic — which led to deaths and hospitalizations" as proof of that.
“Anything you would use Benadryl for can be replaced with cetirizine (Zyrtec), loratadine (Claritin), fexofenadine (Allegra), or [levocetirizine (Xyzal)],” Dr. David Stukus, of Nationwide Children’s Hospital in Columbus, Ohio, wrote in an Instagram post about the paper. “If you’re asking if any of these are safer or better, the answer is YES!!!”
He continued, “Can I use one of these for an acute allergic reaction? Yes! Hives? Yes! Seasonal allergies? Yes! What if I take one of these daily and need another one? Yes! The answer is going to be yes!”
Other studies have found some risks, as well. In January, Harvard Health wrote that “common anticholinergic drugs like Benadryl are linked to increased dementia risk.” While the study, published in the JAMA Internal Medicine journal, noted the research didn’t prove causation, there was an association that increased with how often and how long the drug was used. The report also noted that it is known that anticholinergic drugs increase fall risk and also confusion.
Anticholinergic drugs include not only some antihistamines including diphenhydramine, but also some tricyclic antidepressants, overactive bladder medications and some drugs for Parkinson’s disease symptoms.
What’s next for diphenhydramine?
But per MedpageToday, experts call it unlikely that diphenhydramine will leave the U.S. market. As one expert notes, Benadryl is the only readily available intravenous antihistamine in most areas of the country.
The Harvard Health article noted that “one of the best ways to make sure you’re taking the most effective drugs is to dump all your medications — prescription and nonprescription — into a bag and bring them to your next appointment with your primary care doctor."