Is it safe to administer Benadryl (diphenhydramine) with Thorazine (chlorpromazine) intramuscularly (IM)?

Administering Benadryl with Thorazine IM

Yes, it is safe and often beneficial to administer diphenhydramine (Benadryl) with chlorpromazine (Thorazine) intramuscularly, as diphenhydramine can prevent or treat extrapyramidal symptoms and dystonic reactions caused by phenothiazines like chlorpromazine.

Rationale for Combined Administration

Prevention of Extrapyramidal Side Effects

• Chlorpromazine commonly causes extrapyramidal symptoms including dystonic reactions, which can be severe and present with various neurologic manifestations 1
• Diphenhydramine 25-50 mg IV/IM is the appropriate dose for treating dystonic reactions when they occur 2
• When prochlorperazine (another phenothiazine) was combined with diphenhydramine 50 mg, there was a 61% relative reduction in akathisia, with an absolute risk reduction of 22% (95% CI 6-38%, p=0.01) 3

Clinical Evidence Supporting Combination

• The combination of prochlorperazine 10 mg plus diphenhydramine 25 mg IV demonstrated superior efficacy for migraine-associated symptoms compared to hydromorphone alone 4
• Diphenhydramine has been successfully used as an adjunct to phenothiazines in multiple clinical settings, including endoscopic sedation and acute agitation management 5

Dosing Recommendations

For Adults

• Chlorpromazine IM: 12.5 mg every 4-12 hours, or 3-5 mg/hour IV 5
• Diphenhydramine: 25-50 mg IM or IV administered concurrently or shortly before the chlorpromazine 2, 3

Administration Considerations

• Diphenhydramine should be given slowly if administered IV to minimize risk of seizures 2
• The combination will increase sedation compared to chlorpromazine alone—mean sedation scores increased by an additional 21 mm on visual analog scale when diphenhydramine was added to phenothiazines 3

Critical Safety Monitoring

Cardiovascular Effects

• Both medications can cause orthostatic hypotension; monitor blood pressure closely 5
• Chlorpromazine causes hypotension in approximately 21-24% of patients 5

Respiratory Depression

• Monitor for significant sedation and respiratory suppression, particularly when combining these sedatives 2
• The additive CNS depressant effects require vigilant monitoring of respiratory status 5

Paradoxical Reactions

• Watch for paradoxical agitation, which can occur with both medications 5, 2
• Elderly patients may experience paradoxical excitement with antihistamines 5

Common Pitfalls to Avoid

• Do not administer diphenhydramine as a rapid IV bolus—this precipitates seizures 2
• Do not assume the combination eliminates all risk of extrapyramidal symptoms; some patients may still develop akathisia (14% even with prophylactic diphenhydramine) 3
• Do not neglect to monitor for anticholinergic toxicity when combining these medications, as both have anticholinergic properties 5
• Ensure adequate IV access and avoid extravasation, as phenothiazines can cause tissue necrosis 5

Clinical Algorithm

1. Assess baseline vital signs and mental status before administration 5
2. Administer diphenhydramine 25-50 mg IM first to provide prophylaxis against dystonic reactions 2, 3
3. Follow with chlorpromazine 12.5-25 mg IM for acute agitation or psychosis 5
4. Monitor continuously for 15-30 minutes post-administration for hypotension, respiratory depression, and extrapyramidal symptoms 2
5. Position patient appropriately to minimize orthostatic hypotension risk 5
6. Have additional diphenhydramine available for breakthrough dystonic reactions 1