What are the side effects of diphenhydramine (Benadryl)?

Diphenhydramine Side Effects

Diphenhydramine carries significant anticholinergic and sedative side effects that make it inappropriate for many patient populations, particularly older adults, and second-generation antihistamines should be preferentially used when available. 1, 2

Central Nervous System Effects

Sedation and Cognitive Impairment

• Marked drowsiness is the most common side effect, occurring in the majority of patients and significantly impairing driving ability and operating machinery 3
• Cognitive decline and delirium symptoms occur frequently, with hospitalized older patients showing a 1.7-fold increased risk for any delirium symptoms when exposed to diphenhydramine 4
• Specific cognitive effects include inattention (3.0-fold increased risk), disorganized speech (5.5-fold increased risk), and altered consciousness (3.1-fold increased risk) 4
• Impaired school and work performance due to sedation is well-documented 5

Paradoxical and Psychiatric Effects

• Paradoxical excitability may occur, especially in children, representing an unpredictable reaction that cannot be anticipated unless previously documented 5, 3
• Paradoxical increase in rage and agitation can occur particularly in children and adolescents 5
• At higher doses (>1.0 g), delirium, psychosis, confusion, and hallucinations become significant risks 6

Neurological Complications

• Seizures occur at doses above 1.0 g, with significantly increased frequency at doses >1.5 g 6
• Coma can develop at toxic doses, particularly above 1.5 g 6

Anticholinergic Effects

Urinary and Gastrointestinal

• Urinary retention is a major concern, with hospitalized patients showing a 2.5-fold increased risk for urinary catheter placement 4
• Dry mouth and constipation occur commonly due to anticholinergic blockade 7, 5
• Epigastric discomfort may develop 7

Ophthalmologic

• Blurred vision occurs frequently 7, 5
• Dryness of eyes is common 5
• Contraindicated in patients with glaucoma due to risk of acute angle-closure 1, 3

Cardiovascular Effects

Hemodynamic Changes

• Hypotension is a significant risk, particularly when administered intravenously or in combination with other CNS depressants 7, 5
• Tachycardia commonly occurs 7
• Cardiac toxicity can develop in overdose situations 2
• ECG disturbances may occur at moderate toxic doses (>0.3 g) 6

Respiratory Effects

• Wheezing can occur paradoxically despite its antihistamine properties 7
• However, diphenhydramine has a modest stimulatory effect on ventilation and may counteract opioid-induced hypoventilation 7

Drug Interactions and Enhanced Effects

• Alcohol, sedatives, and tranquilizers significantly increase drowsiness and sedation 3
• Hypnotic effects are markedly enhanced when combined with benzodiazepines or opioid narcotics 7
• The 4-6 hour duration often exceeds the time needed for therapeutic effect, potentially extending recovery time 5

Dose-Dependent Toxicity Profile

Mild Symptoms (most common at therapeutic doses)

• Somnolence, anticholinergic signs, tachycardia, nausea/vomiting occur in 55-64% of exposures 6

Moderate Symptoms (>0.3 g threshold)

• Agitation, confusion, hallucinations, and ECG disturbances occur in 22-27% of cases 6

Severe Symptoms (>1.0 g threshold)

• Delirium/psychosis, seizures, and coma occur in 14-18% of cases 6
• Hospitalization is required for any ingestion above 1.0 g 6

High-Risk Populations

Older Adults

• The American Geriatrics Society identifies diphenhydramine as inappropriate for older adults, with increased risk of delirium, urinary retention, impaired judgment, and falls 1
• Increased sensitivity and higher risk of adverse effects due to pre-existing comorbidities 5
• Longer hospital stays (median 7 vs 6 days) when exposed to diphenhydramine 4

Specific Contraindications

• Avoid in patients with bladder neck obstruction or enlarged prostate due to urinary retention risk 1, 3
• Avoid in patients with chronic bronchitis or breathing problems 3
• Avoid in patients with cardiac arrhythmia or hypertension 1
• Avoid in patients with hyperthyroidism 1

Pregnancy Considerations

• Administration during pregnancy has been associated with development of cleft palate 7
• Despite being frequently used during pregnancy with overall good safety data, this teratogenic risk must be considered 7

Clinical Pitfalls

• Approximately 24% of diphenhydramine doses in hospitalized patients are administered inappropriately 4
• Available in over 300 formulations, most over-the-counter, leading to widespread inappropriate use 8
• Second-generation antihistamines (loratadine, cetirizine, fexofenadine) provide equivalent efficacy with significantly fewer adverse effects and should be preferentially used 1, 2