Double‐Blind Placebo Challenge Confirmation of Diphenhydramine Allergy

ABSTRACT Diphenhydramine, a first‐generation H 1 –antihistamine commonly used for allergic symptom relief and infusion premedication, rarely causes true systemic hypersensitivity. When suspected reactions are mild and subjective—particularly in anxious patients—objective confirmation is essential. In our case, a 52‐year‐old woman with immune thrombocytopenia, common variable immunodeficiency on monthly IVIG, type 2 diabetes, and anxiety reported two pruritic episodes (tongue and truncal itching) following diphenhydramine premedication for rituximab and IVIG infusions. We initially staged open oral challenge (6.25 mg then 50 mg diphenhydramine); pruritus occurred 20 min after the first dose and 30 min after the second (relieved with loratadine). The next day, a double‐blind, placebo‐controlled intravenous challenge was conducted using two identically masked syringes (0.5 mL saline vs. 25 mg diphenhydramine), separated by a 2‐h interval under continuous monitoring. The patient had no symptoms after placebo infusion. Within minutes of the active diphenhydramine infusion, she experienced reproducible throat itchiness without objective cutaneous or systemic signs. Clinicians should consider a double‐blind, placebo‐controlled challenge in confirming immediate (type I) hypersensitivity to medication particularly when the reaction is rare or when nocebo effects may confound history.