Which is safer, diphenhydramine (Benadryl) or hydroxyzine (Vistaril)?

Hydroxyzine is Safer Than Diphenhydramine

Hydroxyzine should be preferred over diphenhydramine due to its superior safety profile, particularly regarding cognitive impairment, anticholinergic burden, and mortality risk in vulnerable populations. 1, 2

Key Safety Differences

Cognitive and Anticholinergic Effects

• Both diphenhydramine and hydroxyzine carry significant anticholinergic risks including CNS impairment, delirium, slowed comprehension, vision impairment, urinary retention, constipation, sedation, and falls—particularly dangerous in elderly patients 1
• The 2021 Mayo Clinic guidelines specifically list both agents in their deprescribing table for older adults, warning of broad muscarinic receptor blockade that causes cognitive impairment and delirium 1
• First-generation antihistamines like both agents are associated with cognitive decline that worsens in elderly populations, with particular concern about cardiovascular events in susceptible patients 1

Mortality and Serious Adverse Events

• Diphenhydramine has been directly linked to death from accidents, intentional or unintentional overdoses, and sudden cardiac death 2
• The Canadian Society of Allergy and Clinical Immunology issued a 2019 position statement declaring that first-generation antihistamines like diphenhydramine should only be used as a last resort, with consideration for behind-the-counter pharmacy restriction due to their dangers 2

Clinical Efficacy Comparison

• Hydroxyzine demonstrates superior delirium management compared to haloperidol with a significantly higher improvement rate (23.9% vs 8.5%, P=.009) and comparable time to improvement, suggesting better clinical outcomes 3
• Hydroxyzine can be dosed strategically at bedtime (50 mg qhs) to maintain H1-receptor antagonism while mitigating reaction time degradation and adverse symptoms seen with divided dosing 4

Specific Clinical Contexts

When Hydroxyzine May Be Preferred

• For patients requiring nighttime sedation with antihistamine effect: hydroxyzine 10-50 mg at bedtime provides effective histamine blockade the following morning while reducing daytime cognitive impairment 1, 4
• In renal impairment: hydroxyzine dose should be halved in moderate renal impairment, but remains usable; it should be avoided in severe renal or hepatic impairment due to sedation concerns 1
• For delirium management: hydroxyzine shows promise as a safer alternative to antipsychotics with fewer side effects 3

When Both Should Be Avoided

• Elderly patients: both agents appear on deprescribing lists due to anticholinergic burden, cognitive impairment, and fall risk 1
• Pregnancy: hydroxyzine is specifically contraindicated in early pregnancy, while diphenhydramine has a longer safety record (though chlorpheniramine is often preferred when antihistamines are necessary) 1
• Patients prone to cardiovascular events: both carry concerns, particularly in MCAS patients 1
• Severe hepatic impairment: both should be avoided as sedation is inappropriate and may precipitate coma 1

Critical Caveats

Paradoxical Reactions

• Diphenhydramine carries risk of paradoxical increase in rage and agitation, particularly in children and adolescents, which cannot be predicted unless previously documented 5

Hypotension Risk

• Both agents can cause hypotension, especially when combined with other CNS depressants, requiring careful hemodynamic monitoring 5
• Diphenhydramine should be given slowly IV to minimize hypotension risk 5

Duration of Action

• Both have 4-6 hour durations that may exceed the time needed for symptom control, potentially extending recovery time 5

Practical Algorithm

For acute allergic symptoms or urticaria:

1. First choice: Use second-generation antihistamines (cetirizine, fexofenadine, desloratadine) which are safer with reduced CNS effects 6, 2
2. If first-generation required: Choose hydroxyzine over diphenhydramine, dosed at bedtime when possible 4, 2
3. Avoid both in: elderly patients, those with dementia, severe renal/hepatic impairment, or pregnancy (especially hydroxyzine) 1

For procedural sedation:

• If first-generation antihistamine needed, hydroxyzine has demonstrated better safety profile in recent comparative data 3
• Continuous monitoring mandatory until patient awake and ambulatory 5