Is diphenhydramine (antihistamine) a suitable treatment option?

Should Diphenhydramine Be Used?

Diphenhydramine should generally be avoided in modern clinical practice, with second-generation antihistamines preferred when antihistamine therapy is needed, and it should never be used as monotherapy for anaphylaxis or as a substitute for epinephrine. 1, 2, 3

When Diphenhydramine May Be Considered (Limited Indications)

Adjunctive Use in Anaphylaxis (Second-Line Only)

• Diphenhydramine 25-50 mg IV/IM may be used as adjunctive therapy only after epinephrine administration for relief of urticaria and itching in anaphylaxis 1
• It does not relieve stridor, shortness of breath, wheezing, gastrointestinal symptoms, or shock 1
• Critical caveat: H1 antihistamines have very limited scientific evidence supporting their use in emergency anaphylaxis treatment and should never substitute for epinephrine 1
• Second-generation antihistamines like cetirizine 10 mg may be preferable due to rapid onset and less sedation 1

Procedural Sedation (With Significant Reservations)

• When used as adjunct to benzodiazepines/opioids for procedures, diphenhydramine 25-50 mg IV can reduce requirements of other sedatives (approximately 10 mg less meperidine, 0.6 mg less midazolam) 1, 4
• Must be given slowly IV to minimize hypotension risk 4
• Duration of 4-6 hours often exceeds needed sedation time, potentially delaying discharge 1, 4

Opioid-Induced Pruritus (When Other Options Fail)

• May be beneficial for opioid-induced pruritus after other causes are excluded 1
• Consider only if pruritus persists despite symptomatic management 1

Prophylaxis Against Extrapyramidal Symptoms

• Provides protection against dystonic reactions when haloperidol is used 4

When Diphenhydramine Should NOT Be Used

Radiocontrast Media Premedication

• Not recommended for patients with history of mild reactions to contrast media 1
• For moderate-to-severe prior reactors, premedication regimens that include diphenhydramine are considered optional, not mandatory 1
• Direct risks include anticholinergic and sedative effects that impair driving ability and necessitate coordination with a driver 1
• Indirect risks include diagnostic delay due to time required for premedication 1

As Primary Therapy for Any Allergic Condition

• Second-generation antihistamines are superior with similar efficacy and fewer adverse effects 2, 3
• Countries like Germany and Sweden have restricted access to first-generation antihistamines 3

Critical Safety Concerns

Cardiovascular Toxicity

• Diphenhydramine acts as a sodium channel blocker causing QRS prolongation and cardiac toxicity similar to tricyclic antidepressants 5, 6
• Cardiac arrest has been reported following single therapeutic doses (1.25 mg/kg IV) in infants 6
• Hypotension risk, particularly when combined with other CNS depressants 1, 4

Paradoxical Reactions

• Cannot predict paradoxical increase in rage and agitation, particularly in children and adolescents, unless previously documented 4
• Excitability may occur, especially in children 7

Sedation and Impairment

• Marked drowsiness, cognitive and psychomotor impairment 1, 7
• Decreased awareness of anaphylaxis symptoms when sedated 1
• Impairs driving and school performance 4

Anticholinergic Effects

• Urinary retention, dry mouth, blurred vision, constipation, potential for delirium (especially elderly) 1, 4
• Increased sensitivity in older adults with comorbid conditions 4

Respiratory Effects

• Despite modest stimulatory effect on ventilation, respiratory depression can occur when combined with other CNS depressants 1, 7

Monitoring Requirements When Use Is Unavoidable

• Continuous vital sign monitoring including blood pressure and respiratory rate 4
• Monitor until patient is awake and ambulatory 4
• Watch for allergic reactions, paradoxical reactions, and anticholinergic crisis 4
• Avoid alcohol and other CNS depressants 7

Overdose Management

• Stop diphenhydramine immediately, assess ABCs, maintain IV access 5
• For QRS prolongation: sodium bicarbonate 1-2 mEq/kg IV bolus 5
• For seizures/severe agitation: benzodiazepines 5
• For hypotension: IV fluids, then vasopressors if needed 5

Bottom Line

The therapeutic ratio of diphenhydramine is problematic, and it represents a relatively greater public health hazard in its class. 3 With over 300 formulations available (mostly over-the-counter), its continued widespread availability is concerning given superior alternatives exist. 3 When antihistamine therapy is indicated, second-generation agents should be first-line. 1, 2, 3 The limited scenarios where diphenhydramine may still be considered require careful risk-benefit assessment, slow IV administration, and continuous monitoring. 4, 5