Can Intravenous Diphenhydramine Cause Extrapyramidal Syndromes?
No, intravenous diphenhydramine does not cause extrapyramidal syndromes—it is actually the primary treatment used to abort them. Diphenhydramine's anticholinergic and antihistaminic properties make it the standard therapeutic agent for reversing extrapyramidal symptoms caused by other medications. 1, 2
Diphenhydramine as Treatment for Extrapyramidal Symptoms
The primary legitimate use of diphenhydramine is the treatment of extrapyramidal symptoms (e.g., dystonia, akathisia) caused by antidopaminergic medications, not as a causative agent. 3
Standard Treatment Protocol
When akathisia or dystonia develops secondary to agents like prochlorperazine, metoclopramide, haloperidol, or perphenazine, administer 25–50 mg diphenhydramine intravenously to alleviate the movement disorder. 3, 2
Diphenhydramine provides protection against extrapyramidal symptoms and dystonic reactions through its anticholinergic properties. 2
In pediatric cases of drug-induced extrapyramidal syndromes, diphenhydramine administered intravenously followed by oral dosing has proven effective for symptom resolution. 4, 5
Clinical Evidence Supporting Diphenhydramine's Therapeutic Role
Case Reports and Clinical Series
A 17-year-old patient with severe extrapyramidal symptoms (ballismus, torticollis, tongue thrusting, oculogyric movements) after propofol anesthesia responded promptly to diphenhydramine as primary treatment. 6
In 22 pediatric cases of drug-induced extrapyramidal syndrome from clebopride, metoclopramide, and haloperidol, symptoms disappeared in all patients after intravenous diphenhydramine or biperiden administration. 4
Among 49 children with acute extrapyramidal syndromes from phenothiazines and haloperidol, diphenhydramine proved useful when administered intravenously followed by oral dosing. 5
Six patients who developed extrapyramidal dysfunction after perphenazine had resolution of symptoms, with five receiving intravenous diphenhydramine for successful treatment. 7
Medications That Actually Cause Extrapyramidal Syndromes
The drugs that cause extrapyramidal symptoms are antidopaminergic agents, not antihistamines like diphenhydramine. 1
High-Risk Medications
Promethazine (a phenothiazine) causes extrapyramidal effects ranging from restlessness to oculogyric crises, along with hypotension, respiratory depression, and neuroleptic malignant syndrome. 1
Droperidol produces hypotension, QTc prolongation, and extrapyramidal signs as major side effects. 1
Metoclopramide, prochlorperazine, haloperidol, and perphenazine are well-documented causes of acute dystonia, akathisia, and pseudoparkinsonism. 4, 7, 5
Adverse Effects of Diphenhydramine (Not Including EPS)
The documented adverse effects of diphenhydramine include hypotension, dizziness, blurred vision, dry mouth, epigastric discomfort, urinary retention, and wheezing—but not extrapyramidal symptoms. 1, 2
Anticholinergic Effects
Anticholinergic adverse effects include epigastric discomfort, dry mouth, constipation, urinary retention, blurred vision, and delirium, particularly in older adults. 3, 2
The American Geriatrics Society warns that diphenhydramine increases delirium risk approximately 1.7-fold in older adults. 3
Paradoxical Reactions
- Paradoxical reactions such as increased agitation or rage can occur unpredictably, especially in children and adolescents, but these are not extrapyramidal symptoms. 3, 2
Clinical Pitfall to Avoid
Do not confuse diphenhydramine's role as a treatment for extrapyramidal symptoms with being a cause of them. The confusion may arise because diphenhydramine is often given alongside medications that do cause extrapyramidal symptoms (like promethazine or metoclopramide), but it is administered specifically to prevent or treat those symptoms, not to cause them. 1, 3, 2