Clinical Review| Volume 60, ISSUE 2, P165-174, February 2021

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Prophylactic Administration of Diphenhydramine to Reduce Neuroleptic Side Effects in the Acute Care Setting: A Systematic Review and Meta-Analysis



      Neuroleptics are commonly prescribed drugs to treat acute conditions (e.g., migraines) in the emergency department, but can cause serious adverse effects. Using diphenhydramine to prevent these adverse effects is very common but remains controversial.


      We performed a systematic review to determine whether prophylactic administration of diphenhydramine reduces the incidence of neuroleptic adverse effects in patients with acute conditions.


      Medline, Embase, Cochrane, PsycInfo, and Web of Science were searched for randomized controlled trials evaluating any neuroleptic with diphenhydramine vs. the same neuroleptic with any inactive agent. Primary outcome was incidence of any extrapyramidal adverse effect. Secondary outcomes were akathisia, rescue medication, subjective restlessness, neuroleptic malignant syndrome, and sedation. Independent reviewers scanned identified citations, extracted data, and assessed risk of bias. Meta-analysis was performed using random effect models.


      Of 1566 identified citations, nine studies (n = 1648 patients) met eligibility criteria. Four studies were specifically designed to compare the incidence of neuroleptic adverse effects with and without co-administration of diphenhydramine. Four studies were at high risk of bias. In primary analysis, diphenhydramine had no effect on the incidence of extrapyramidal symptoms (7 studies, n = 1393, risk ratio [RR] 0.75; 95% confidence interval [CI] 0.44–1.31) or akathisia (5 studies, n = 1094; RR 0.78; 95% CI 0.33–1.82) or any of the secondary outcomes. In subgroup analysis, diphenhydramine was associated with a significant decrease in extrapyramidal adverse effects compared with placebo (4 studies, n = 705; RR 0.61; 95% CI 0.41–0.90). Dosage analysis yielded no further information.


      When compared with placebo, diphenhydramine was associated with a significant reduction of extrapyramidal adverse effects. Overall quality of evidence is low. Further studies are warranted.


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