Diphenhydramine side effects
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Common Side Effects of Diphenhydramine
Diphenhydramine, a first-generation antihistamine, is widely used for allergies, sleep, and other conditions, but it is known for causing several side effects. The most frequently reported side effects include drowsiness, dry mouth, and sedation. These effects are due to its anticholinergic properties, which can also lead to blurred vision, constipation, and urinary retention, especially in higher doses or with intravenous administration Khan2025Clark2025.
Cognitive and Neurological Adverse Effects
Older adults are particularly vulnerable to cognitive side effects from diphenhydramine. Studies show that hospitalized patients aged 70 and older who received diphenhydramine had a higher risk of delirium, including symptoms like inattention, disorganized speech, and altered consciousness. There was also an increased risk of urinary catheter placement and longer hospital stays, with a clear dose-response relationship—higher doses led to more adverse effects Adinoff2002Agostini2001Clark2025. In children, diphenhydramine can cause somnolence, agitation, and hallucinations, with seizures occurring in a small percentage of cases .
Cardiac Side Effects and Toxicity
Although rare, diphenhydramine can cause serious cardiac side effects such as QT interval prolongation, which can lead to dangerous heart rhythms. This risk is higher in patients with kidney problems or those taking high doses. The drug can inhibit sodium and potassium channels in the heart, leading to these effects. Toxicity is dose-dependent, and severe outcomes like seizures, ventricular dysrhythmias, and the need for intubation have been reported, especially in cases of overdose Shah2015Hughes2021.
Severe and Life-Threatening Reactions
In cases of overdose, diphenhydramine can cause severe antimuscarinic toxicity, including neuromuscular excitation and symptoms similar to serotonin toxicity. Severe outcomes such as seizures, acidemia, QRS prolongation, and even death have been documented, particularly in intentional overdoses or cases involving child abuse Palmer2020Hughes2021Hoang2022. Most deaths in children were associated with supratherapeutic doses or abuse .
Comparison with Second-Generation Antihistamines
Diphenhydramine’s side effect profile is considered worse than that of newer, second-generation antihistamines, which are less likely to cause sedation and cognitive impairment. Because of these risks, some countries have restricted its use, and experts recommend switching to safer alternatives, especially for children and older adults .
Use in Specific Clinical Settings
Diphenhydramine is sometimes used to prevent side effects from other medications, such as neuroleptics or to reduce postoperative bladder discomfort. While it may reduce certain symptoms like catheter-related bladder discomfort without significant additional side effects, its overall benefit in preventing neuroleptic side effects is not well established, and the quality of evidence is low Mokhtari2020Li2019.
Conclusion
Diphenhydramine is associated with a range of side effects, from common issues like drowsiness and dry mouth to serious risks such as cognitive impairment, cardiac arrhythmias, and severe toxicity in overdose. These risks are especially pronounced in children and older adults. Safer alternatives are available, and careful consideration should be given before using diphenhydramine, particularly in vulnerable populations.
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