Should Diphenhydramine be included in an Acute Agitation Regimen?
Acute agitation in the emergency department is a common issue that frequently requires the use of chemical sedation to preserve safety for patients and healthcare workers. A commonly employed treatment regimen is the combination of haloperidol 5 mg + lorazepam 2 mg + diphenhydramine 50 mg (B-52). Diphenhydramine is included in this treatment regimen primarily to prevent extrapyramidal symptoms [1,2]. However, the incidence of extrapyramidal symptoms (EPS) with haloperidol is quite low when treating agitation in the emergency department (ED) [3,4]. Therefore, the excessive and prolonged sedation from adding prophylactic diphenhydramine may outweigh the intended benefit and should be reserved for treatment of EPS if symptoms occur.
Jeffers et al. conducted a multicenter, retrospective, cohort study which compared the efficacy and safety of haloperidol, lorazepam, and diphenhydramine (B-52) (n=200) vs. haloperidol and lorazepam (52) (n=200) in treating patients >18 years old with acute agitation in the ED . Their primary outcome was the administration of additional agitation medication(s) within 2 hours.
|Outcomes||52 (n=200)||B52 (n=200)||p-Value|
|Administration of additional sedative within 2 h, n (%)||40 (20)||28 (14)||0.11|
|Median ED LOS (hours)||13.8||17||0.03|
|Use of restraints, n (%)||53 (26.5)||86 (43)||0.001|
|Hypotension, n (%)||7 (3.5)||32 (16)||<0.001|
|Administration of anticholinergic within 2 days, n (%)||15 (7.5%)||6 (3%)||0.04|
|Itching/allergies, n (%)||1 (0.5)||1 (0.5)||1.00|
|Home benztropine, n (%)||2 (1)||4 (2)||0.41|
|Insomnia, n (%)||4 (2)||0 (0)||0.06|
|Unknown, n (%)||8 (4)||1 (0.5)||0.02|
Overall, the B-52 combination resulted in more oxygen desaturation, hypotension, physical restraint use, and longer length of stay. However, the conclusions from this study may be limited as it was a relatively small study and it used surrogate markers to assess clinical endpoints.
Further discussion regarding the onset and duration of IM medications for acute agitation may be found in this blog post.
- The risk of extrapyramidal symptoms following haloperidol for agitation in the ED is relatively low
- Diphenhydramine may not be necessary when using haloperidol + lorazepam to treat agitation in the ED
- ED length of stay is increased with the addition of diphenhydramine to haloperidol + lorazepam
Want to learn more about EM Pharmacology?
- Mokhtari A, Yip O, Alain J, Berthelot S. Prophylactic administration of diphenhydramine to reduce neuroleptic side effects in the acute care setting: a systematic review and meta-analysis. J Emerg Med. 2021 Feb;60(2):165–74. doi: 10.1016/j.jemermed.2020.09.031. PMID: 33131965.
- Vinson DR, Drotts DL. Diphenhydramine for the prevention of akathisia induced by prochlorperazine: a randomized, controlled trial. Ann Emerg Med. 2001 Feb;37(2):125–31. doi: 10.1067/mem.2001.113032. PMID: 11174228.
- Klein LR, Driver BE, Miner JR, Martel ML, Hessel M, Collins JD, et al. Intramuscular midazolam, olanzapine, ziprasidone, or haloperidol for treating acute agitation in the emergency department. Ann Emerg Med. 2018 Oct;72(4):374–85. doi: 10.1016/j.annemergmed.2018.04.027. PMID: 29885904.
- Schneider A, Mullinax S, Hall N, Acheson A, Oliveto AH, Wilson MP. Intramuscular medication for treatment of agitation in the emergency department: A systematic review of controlled trials. Am J Emerg Med. 2021 Aug;46:193–9. doi: 10.1016/j.ajem.2020.07.013. PMID: 33071100.
- Jeffers T, Darling B, Edwards C, Vadiei N. Efficacy of combination haloperidol, lorazepam, and diphenhydramine vs. Combination haloperidol and lorazepam in the treatment of acute agitation: a multicenter retrospective cohort study. J Emerg Med. 2022 Mar 11;S0736-4679(22)00057-9. doi: 10.1016/j.jemermed.2022.01.009. PMID: 35287982.
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