What is diphenhydramine?

What is Diphenhydramine

Diphenhydramine is a first-generation antihistamine (histamine H1-receptor antagonist) with anticholinergic and sedative properties, primarily used to treat allergic reactions, but its problematic side effect profile and availability of safer alternatives have led experts to recommend moving away from its routine use. 1, 2, 3

Pharmacological Classification and Mechanism

• Diphenhydramine functions as a histamine H1-receptor antagonist that quickly distributes throughout the body, including the central nervous system, with onset of action within several minutes and duration of effect lasting 4-6 hours 1
• The drug possesses significant anticholinergic properties that contribute to both its therapeutic effects and adverse reactions, including sedation, dry mouth, urinary retention, and constipation 4, 1, 5
• It has documented central cough-suppressing activity and may provide protection against extrapyramidal symptoms when used with antipsychotic medications 4, 1

Clinical Applications

Approved and Common Uses

• Allergic reactions: The American Academy of Allergy, Asthma, and Immunology recommends diphenhydramine as second-line therapy (never alone) in anaphylaxis management at doses of 1-2 mg/kg or 25-50 mg parenterally 1
• Allergic rhinitis: Used for symptomatic treatment, though intranasal corticosteroids are more effective as first-line therapy 4
• Sedation adjunct: Standard dosing of 25-50 mg IV can enhance sedation synergy when combined with benzodiazepines, reducing meperidine requirements by approximately 10 mg and midazolam by 0.6 mg 1
• Upper airway cough syndrome: First-generation antihistamine/decongestant combinations may be effective even in "silent" postnasal drip without obvious upper respiratory findings 4

Formulations and Availability

• Available in over 300 formulations, most of which are over-the-counter, with standard oral dosing of 25 mg per 10 mL 2, 3

Adverse Effects and Safety Concerns

Common Side Effects

• Anticholinergic effects: Dry mouth, blurred vision, urinary retention, constipation, epigastric discomfort, and potential for delirium, especially in elderly patients 1, 5, 2
• Central nervous system effects: Marked drowsiness, sedation, impairment in school and driving performance, and risk of paradoxical increase in rage and agitation particularly in children and adolescents 4, 1, 2
• Cardiovascular effects: Hypotension (especially when given rapidly IV or with other CNS depressants), dizziness, and cardiac toxicity in overdose 1, 6, 7

High-Risk Populations

• Children under 6 years: Between 1969 and 2006, there were 69 fatalities associated with antihistamines in children age 6 years and younger, with diphenhydramine accounting for 33 deaths; the FDA's advisory committees recommended against OTC cough and cold medications for children below 6 years 4
• Elderly patients: The American Geriatrics Society identifies diphenhydramine as an inappropriate medication that induces delirium postoperatively and recommends avoiding its use in older adults due to increased risk of cognitive impairment, urinary retention, and falls 8
• Specific contraindications: Should be avoided in patients with bladder neck obstruction, glaucoma, chronic bronchitis, enlarged prostate, or existing urinary difficulties 8, 2

Drug Interactions

• The hypnotic effect is significantly increased when combined with alcohol, benzodiazepines, opioid narcotics, sedatives, or tranquilizers, requiring continuous monitoring by trained personnel 1, 2

Critical Clinical Pitfalls

Inappropriate Use Patterns

• No therapeutic rationale exists for combining diphenhydramine with second-generation antihistamines like loratadine, as both treat the same symptoms through the same H1-antihistamine mechanism 8
• The FDA warns against using diphenhydramine "to make a child sleepy" and cautions about excitability that may occur, especially in children 2
• Diphenhydramine should not be used with any other product containing diphenhydramine, even topical formulations 2

Monitoring Requirements When Used

• Continuous monitoring is mandatory until the patient is awake and ambulatory when used in chemical restraint combinations 1
• Vital signs assessment must include blood pressure monitoring for hypotension and respiratory rate for potential respiratory depression 1
• Watch for allergic reactions, paradoxical reactions, and anticholinergic crisis 1

Evidence-Based Recommendations to Discontinue Routine Use

Expert Consensus Against Continued Use

• A 2025 comprehensive review concluded that diphenhydramine has reached the end of its life cycle and represents a relatively greater public health hazard, recommending it should no longer be widely prescribed or readily available over-the-counter 3
• A 2022 expert opinion definitively stated "it is time to move on from diphenhydramine" given the negative side effects and wide availability of alternative antihistamine medications 6
• Countries including Germany and Sweden have already restricted access to first-generation antihistamines based on their problematic therapeutic ratio 3

Superior Alternatives

• Second-generation antihistamines (cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine) are generally preferred due to superior safety profile, lack of sedation, and similar or better efficacy 4, 8
• These newer agents have been shown to be well tolerated with very good safety profiles in young children, unlike diphenhydramine 4
• Oral fexofenadine (180 mg) showed no statistically significant difference in time to 50% reduction of histamine-induced flare compared to diphenhydramine (50 mg oral or IM), but with a more favorable risk-to-benefit ratio 9