Major
Probable
Description
Diphenhydramine, a sedating antihistamine, substantially increases CNS and respiratory depression when combined with opioids like oxycodone.
Mechanism
Diphenhydramine blocks histamine H1 receptors and has significant anticholinergic and sedative activity; combined with opioid-mediated CNS depression, respiratory compromise is enhanced.
Clinical Significance
Postmarketing case reports and FDA safety data highlight increased overdose risk; the combination is sometimes used illicitly for euphoria.
Management
Avoid combination; use non-sedating antihistamines (loratadine, cetirizine) in patients receiving opioid therapy.