Substitute for diphenhydramine

There is no inherent advantage with respect to efficacy with H1 inverse agonists, although greater amounts of less potent agents will be needed for equivalent effects. The major difference among the H1 inhibitors is the reduced sedation and anti-cholinergic effects with the newer agents. Oral antihistamine therapy is equivalent to IV therapy. Following oral administration, wheal and flare skin responses are reduced within one hour of dosing for cetirizine and levocetirizine (1,2). Peak plasma levels are achieved within 0.7-2.6 hours with most agents. Thus, there is limited value for parenteral administration and no likely clinical benefit of diphenhydramine compared to other H1 inhibitors.

In summary, I would suggest an oral, 2nd or 3rd generations antihistamine (e.g. cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine). If a parenteral agent is desired, I would prefer IV promethazine (10-25 mg) if more rapid onset is desired. Parenteral, IM hydroxyzine is an option but the injection is relatively painful and without any specific advantage to my knowledge.

1. Church MK: Comparative inhibition by bilastine and cetirizine of histamine-induced wheal and flare responses in humans. Inflamm Res. 60:1107-1112
2. Simons FER, Simons KJ: Levocetirizine: pharmacokinetics and pharmacodynamics in children age 6 to 11 years. J Allergy Clin Immunol. 116:355-361

I hope this information is of help to you and your practice.

All my best.
Dennis K. Ledford, MD, FAAAAI