Acetaminophen and 5-hydroxytryptamine-type-3 (5-HT3) receptor antagonists are administered as standard prophylaxes for postoperative pain, nausea, and vomiting. Preclinical studies however suggest that 5-HT3 antagonists may compromise acetaminophen’s analgesic effect. This hospital registry study investigates whether 5-HT3 antagonists mitigate the analgesic effect of prophylactic acetaminophen in a perioperative setting.


This study included 55,016 adult patients undergoing general anesthesia for ambulatory procedures at a tertiary healthcare center in Massachusetts, United States of America, from 2015 to 2022. Using binary exposure variables and a comprehensive selection of pre-planned patient- and procedure-related covariates for confounder control, we investigated whether intraoperative 5-HT3 antagonists affected the association between pre- or intraoperative acetaminophen and postoperative opioid consumption, gauged by opioid dose in mg oral morphine equivalents (OME) administered in the post-anesthesia care unit (PACU). A multivariable, zero-inflated negative binomial regression model was applied.


3,166 (5.8%) patients received only acetaminophen, 15,438 (28.1%) only 5-HT3 antagonists, 31,850 (57.9%) both drugs, and 4,562 (8.3%) neither drug. The median PACU opioid dose was 7.5 mg OME (interquartile range 7.5 to 14.3 mg OME) among 16,640/55,016 (30.3%) patients who received opioids and the average opioid dose was 3.2 mg OME across all patients (maximum cumulative dose: 20.4 mg OME). Acetaminophen administration was associated with a 5.5% (95%CI -9.6% to -1.4%;p=0.009; adjusted absolute difference -0.19 mg OME;95%CI -0.33 to -0.05;p=0.009) reduction in opioid consumption among patients who did not receive a 5-HT3 antagonist, while there was no effect in patients who received a 5-HT3 antagonist (adjusted absolute difference 0.00 mg OME; 95%CI -0.06 to 0.05;p=0.93,p-for-interaction=0.012).


A dose-dependent association of pre- or intraoperative acetaminophen with decreased postoperative opioid consumption was not observed when 5-HT3 antagonists were co-administered, suggesting that physicians might consider reserving 5-HT3 antagonists as rescue medication for postoperative nausea or vomiting when acetaminophen is administered for pain prophylaxis.