Comparative Effectiveness of Haloperidol, Droperidol, and Ondansetron for Cannabinoid Hyperemesis Syndrome in the Emergency Department
Joseph O’Brien, Mayher Patel, Joseph Brown, Ryan Tucker, John RagueABSTRACT
Background
Cannabinoid hyperemesis syndrome (CHS) is an increasingly frequent emergency department (ED) presentation. Although ondansetron is commonly used, emerging evidence suggests haloperidol and droperidol may provide more effective symptom control. Robust comparative effectiveness data, particularly regarding short‐term ED recidivism, remain limited.
Methods
We conducted a multicenter retrospective cohort study using the TriNetX Research Network from 2014 to 2024. Adults presenting to the ED with vomiting‐related and cannabis‐related ICD‐10 diagnoses who received haloperidol, droperidol, or ondansetron during the index encounter were included. Patients with alternative causes of vomiting or major confounding conditions were excluded. Propensity‐score matching was performed for three pairwise comparisons: haloperidol versus ondansetron, droperidol versus ondansetron, and droperidol versus haloperidol. The primary outcome was 72‐h ED recidivism. Secondary outcomes included 72‐h hospital admission, 7‐day ED recidivism, and coded adverse events. Multivariable Cox proportional hazards modeling evaluated independent predictors of 72‐h ED recidivism.
Results
After matching, haloperidol was associated with lower 72‐h ED recidivism compared with ondansetron (8.2% vs. 15.1%; OR 0.50, 95% CI 0.41–0.62; p < 0.0001). Droperidol was also associated with lower 72‐h ED recidivism compared with ondansetron (7.4% vs. 14.0%; OR 0.49, 95% CI 0.32–0.76; p = 0.0014). Droperidol and haloperidol did not differ significantly in 72‐h ED recidivism (7.5% vs. 9.8%; OR 0.75, 95% CI 0.47–1.20; p = 0.23). In the multivariable model, haloperidol (HR 0.62, 95% CI 0.49–0.79) and droperidol (HR 0.68, 95% CI 0.56–0.83) were independently associated with lower return risk, whereas ondansetron was not. Coded adverse events were rare across all groups.
Conclusions
In this large multicenter cohort, haloperidol and droperidol were associated with lower short‐term ED recidivism than ondansetron among adults meeting a suspected CHS phenotype. These findings support prospective studies evaluating haloperidol and droperidol for ED management of CHS, including optimal dosing, route, medication sequencing, discharge treatment, and safety monitoring.