Can a patient take antihistamines (e.g., diphenhydramine) long term?

Long-Term Antihistamine Use: Diphenhydramine Should Be Avoided

Diphenhydramine should NOT be used long-term for routine allergic conditions, and second-generation antihistamines (cetirizine, loratadine, fexofenadine, desloratadine) are the preferred agents for chronic use due to superior safety profiles and lack of sedation, cognitive impairment, and anticholinergic toxicity. 1, 2

Why Diphenhydramine Is Problematic for Long-Term Use

Safety Concerns

• Diphenhydramine has documented mortality risk, with 33 deaths reported in children under 6 years between 1969-2006, and additional deaths from accidents, intentional/unintentional overdoses, and sudden cardiac death in all age groups 3, 1
• The FDA explicitly recommends against using first-generation antihistamines like diphenhydramine in children below 6 years of age 3
• Diphenhydramine carries significant cardiac toxicity risk in overdose, making it particularly dangerous for long-term daily use 4

Cognitive and Functional Impairment

• Diphenhydramine causes clinically meaningful decrements in vigilance, cognitive function, and psychomotor performance compared to both placebo and second-generation antihistamines 5
• Effect sizes for cognitive impairment range from 0.4 to 0.8 (moderate to high) when comparing diphenhydramine to desloratadine 5
• Sedation, impaired cognitive function, poor sleep quality, dry mouth, dizziness, and orthostatic hypotension are common side effects that make long-term use particularly problematic 1

Special Population Risks

• Older adults and children have higher adverse side-effect profiles with diphenhydramine 2
• The National Cancer Institute reports that antihistamines cause daytime sedation and delirium, especially in older patients and patients with advanced cancer 6
• Diphenhydramine should never be used "to make a child sleepy" as this is explicitly contraindicated per FDA labeling 3

Recommended Alternatives for Long-Term Use

Second-Generation Antihistamines (Preferred)

• Second-generation antihistamines (cetirizine, fexofenadine, loratadine, desloratadine) do not elevate blood pressure, do not cause sedation, and are safe for long-term use in hypertensive patients 7
• These agents have improved potency and efficacy compared to first-generation antihistamines, with dramatically superior safety profiles 1, 8
• The Canadian Society of Allergy and Clinical Immunology recommends that newer generation antihistamines should be preferred over first-generation antihistamines for treatment of allergic rhinoconjunctivitis and urticaria 1

Specific Agent Selection

• For infants 6 months and older, cetirizine is the only evidence-based option with proven safety data, dosed at 0.25 mg/kg twice daily 3
• Loratadine is FDA-approved for children 2 years and older 3
• Desloratadine improved allergic rhinitis symptoms without adversely affecting cognitive performance in head-to-head trials against diphenhydramine 5

When Diphenhydramine May Be Considered (Short-Term Only)

Limited Acute Situations

• For mild acute food-induced allergic reactions (flushing, urticaria, isolated mild angioedema), H1 antihistamines can be used with ongoing observation 6
• Following anaphylaxis discharge, diphenhydramine every 6 hours for 2-3 days is recommended as adjunctive therapy, with alternative dosing using a non-sedating second-generation antihistamine explicitly mentioned as an option 6
• In anaphylaxis requiring adjunctive antihistamine therapy, diphenhydramine may be used at 1 mg/kg per dose (maximum 50 mg) in liquid oral formulation, under direct medical supervision 3

Critical Caveats

• Epinephrine remains the only first-line treatment for anaphylaxis; antihistamines are purely adjunctive and should never replace epinephrine 3
• When antihistamines alone are given for acute reactions, ongoing observation and monitoring are warranted to ensure lack of progression to anaphylaxis 6

Clinical Bottom Line

Countries such as Germany and Sweden have already restricted access to first-generation antihistamines, and multiple expert societies advocate exclusively for second-generation antihistamines 2. Despite diphenhydramine's availability in over 300 formulations, most over-the-counter, it has reached the end of its life cycle and represents a relatively greater public health hazard in its therapeutic class 2. For any patient requiring long-term antihistamine therapy, second-generation agents should be prescribed, and diphenhydramine should be reserved only for rare, short-term (2-3 days maximum) acute situations under medical supervision 6, 1, 2.