What are the potential interactions between diphenhydramine (antihistamine) and alprazolam (benzodiazepine)?

Diphenhydramine and Alprazolam Interaction

Combining diphenhydramine with alprazolam produces additive CNS depression and should be avoided or used with extreme caution, as both medications independently cause sedation and their combined effects significantly increase risks of oversedation, respiratory depression, cognitive impairment, and falls. 1

Mechanism of Interaction

The interaction between these two agents is primarily pharmacodynamic rather than pharmacokinetic:

• Alprazolam (a benzodiazepine) produces CNS depression by enhancing GABA-A receptor activity, leading to sedation, anxiolysis, muscle relaxation, and respiratory depression 1

• Diphenhydramine (a first-generation antihistamine) crosses the blood-brain barrier and causes CNS depression through H1-receptor blockade and anticholinergic effects, producing sedation, cognitive impairment, and psychomotor slowing 2, 3

• The FDA label for alprazolam explicitly warns that benzodiazepines produce additive CNS depressant effects when co-administered with antihistaminics 1

• While macrolide antibiotics like erythromycin can inhibit CYP3A metabolism and increase alprazolam levels, diphenhydramine does not significantly affect alprazolam's pharmacokinetics through CYP3A inhibition 2, 1

Clinical Consequences of Combined Use

Enhanced Sedation and Cognitive Impairment

• Research demonstrates that alprazolam and diphenhydramine both reduce saccadic peak velocity (a marker of CNS depression), with alprazolam causing greater reduction (-57°/s) than diphenhydramine (-14°/s), suggesting their combined effects would be substantially additive 4

• Both agents impair psychomotor performance, smooth pursuit eye movements, and adaptive tracking, with combined use expected to produce clinically significant functional impairment 5, 4

• Studies show first-generation antihistamines like diphenhydramine interact with benzodiazepines by increasing sedative effects, unlike second-generation antihistamines which do not enhance benzodiazepine sedation 6

Specific High-Risk Populations

Elderly patients face particularly elevated risks:

• The American Geriatrics Society identifies diphenhydramine as an inappropriate medication that induces delirium postoperatively in older adults and recommends avoiding its use due to increased risk of delirium, urinary retention, dry mouth, blurred vision, constipation, and impaired judgment 2

• Elderly patients exhibit higher plasma alprazolam concentrations due to reduced clearance, making them more sensitive to benzodiazepine effects and requiring the smallest effective doses to prevent ataxia and oversedation 1

• Combined use in elderly patients substantially increases fall risk, hip fracture risk, and delirium incidence 2

Respiratory Depression Risk

• The combination increases risk of respiratory depression, particularly concerning in patients with sleep apnea, chronic obstructive pulmonary disease, or other respiratory compromise 1

• While diphenhydramine has been reported to have modest stimulatory effects on ventilation and may counteract opioid-induced hypoventilation, this does not negate its additive CNS depressant effects when combined with benzodiazepines 3

Clinical Recommendations

When Combination Cannot Be Avoided

If clinical circumstances absolutely require concurrent use:

• Start with the lowest possible doses of both agents and titrate cautiously 1

• Monitor continuously for oversedation, respiratory depression, and cognitive impairment, particularly during the first 4-6 hours when diphenhydramine effects are maximal 3

• Assess vital signs including blood pressure (for hypotension) and respiratory rate 3

• Avoid use in elderly patients, those with respiratory compromise, or patients with bladder neck obstruction or glaucoma due to diphenhydramine's anticholinergic effects 2, 7

• Counsel patients to avoid alcohol and other CNS depressants, as these produce further additive effects 1, 8

• Warn patients about impaired driving ability and increased fall risk 6, 4

Safer Alternatives

For allergic conditions in patients taking alprazolam:

• Second-generation antihistamines (loratadine, cetirizine, fexofenadine) are strongly preferred as they do not cross the blood-brain barrier significantly and do not increase benzodiazepine sedative effects 6

• There is no therapeutic rationale for combining two H1-antihistamines, and second-generation agents have superior safety profiles for allergic rhinitis treatment 7

For sedation or anxiety management:

• Avoid polypharmacy with multiple sedating agents when possible 2

• Consider non-pharmacological interventions or single-agent therapy optimized to therapeutic effect 2

Critical Pitfalls to Avoid

• Do not assume diphenhydramine is "safe" because it is available over-the-counter—it carries significant CNS depressant and anticholinergic risks, especially in combination with benzodiazepines 2, 3

• Do not overlook the 4-6 hour duration of diphenhydramine effects, which often exceeds the time needed for symptom control and may prolong recovery 3

• Watch for paradoxical reactions with diphenhydramine (increased agitation, particularly in children and adolescents), which can complicate clinical management 3

• Recognize that withdrawal from chronic benzodiazepine use can be life-threatening (seizures), so any medication changes must be done gradually under physician supervision 1

• Be aware that the combination may mask anxiety symptoms while increasing fall risk and cognitive impairment, creating a false sense of therapeutic benefit 2, 4