What are the risks of using Benadryl (diphenhydramine) in elderly patients and what are the recommended alternatives?

Paradoxical Effects of Benadryl (Diphenhydramine) in Elderly Patients

Diphenhydramine should be avoided in elderly patients due to significant risks of anticholinergic toxicity, paradoxical agitation, cognitive impairment, and falls—safer alternatives include second-generation antihistamines for allergies or low-dose sedating antidepressants for sleep. 1, 2

Understanding Paradoxical and Anticholinergic Effects

Diphenhydramine causes paradoxical effects in older adults through its potent anticholinergic properties, which elderly patients tolerate poorly due to age-related decline in acetylcholine physiology. 2 The most concerning paradoxical effect is paradoxical agitation or excitement rather than the expected sedation, which can have serious clinical and even forensic implications. 1, 3

Specific Risks in Elderly Patients

Central Nervous System Effects:

• Confusion, delirium, and acute cognitive impairment are common anticholinergic effects that worsen with age. 1, 2
• Oversedation leading to falls, fractures, and subdural hematomas. 1, 2
• Slowed comprehension and impaired judgment. 1
• Paradoxical aggression and agitation instead of sedation. 1, 3

Peripheral Anticholinergic Effects:

• Urinary retention, particularly problematic in men with benign prostatic hypertrophy. 1, 2
• Constipation and gastrointestinal disturbances. 2
• Impaired vision and dry mouth/eyes. 1, 2

Cardiovascular Concerns:

• Caution required in patients with ischemic heart disease or hypertension. 1
• May worsen blood pressure control. 2

Why Elderly Patients Are More Vulnerable

The American Geriatrics Society Beers Criteria specifically identifies diphenhydramine as potentially inappropriate for adults aged 65 years and older. 1, 2 This heightened vulnerability stems from:

• Reduced renal function leading to prolonged drug elimination and accumulation. 2
• Age-related changes in acetylcholine physiology making anticholinergic effects more pronounced. 2
• Higher likelihood of polypharmacy with cumulative anticholinergic burden from multiple medications. 2
• Increased sensitivity to CNS-active medications. 1

Recommended Alternatives

For Allergic Conditions:

• Second-generation antihistamines (cetirizine, loratadine, fexofenadine) are strongly preferred due to minimal anticholinergic effects and lack of CNS penetration. 2

For Sleep Disturbances:

• Low-dose sedating antidepressants such as trazodone or mirtazapine provide safer alternatives with better side effect profiles. 4
• Non-pharmacologic approaches including sleep restriction-sleep compression therapy, cognitive behavioral therapy for insomnia, relaxation training, and establishing bedtime routines. 5, 6
• Melatonin for sleep initiation without anticholinergic burden. 4

For Anxiety:

• Cognitive behavioral therapy and other psychological interventions as first-line treatment. 5
• Low-dose sedating antidepressants for anxiety with comorbid depression. 4
• Avoid benzodiazepines which also cause paradoxical agitation in elderly patients. 1

Clinical Management Considerations

When Diphenhydramine Use Cannot Be Avoided:

• Use the lowest effective dose (12.5 mg rather than standard 25-50 mg doses). 1
• Limit duration to the shortest possible course. 2
• Monitor closely for confusion, oversedation, urinary retention, and falls. 1
• Avoid in patients with glaucoma, benign prostatic hypertrophy, or dementia. 1, 2

Deprescribing Strategy:

• Regularly review medication regimens to identify and reduce anticholinergic burden. 2
• The cumulative effect of multiple anticholinergic medications significantly increases adverse outcomes. 2
• Approximately one-third of independent living older adults take anticholinergic medications that may be unnecessary. 2

Common Pitfalls to Avoid

Do not use diphenhydramine as:

• A routine sleep aid in elderly patients—this represents inappropriate prescribing per Beers Criteria. 1
• Treatment for behavioral symptoms in dementia—this worsens cognitive function. 1
• A sedative for preoperative anxiety—safer alternatives like melatonin exist. 4

Recognize high-risk situations:

• Patients already on other anticholinergic medications (tricyclic antidepressants, oxybutynin, muscle relaxants) face compounded risk. 1, 2
• Emergency situations requiring diphenhydramine (severe allergic reactions, transfusion reactions) represent the rare legitimate indication where benefits outweigh risks. 1

Monitor for toxicity:

• In overdose situations, diphenhydramine can cause agitation, hallucinations, seizures, and QRS widening requiring emergency department evaluation. 7
• Children and adults ingesting ≥7.5 mg/kg or 300 mg require emergency department referral. 7