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 from 2015 to 2022. Using binary exposure variables and a comprehensive selection of preplanned patient- and procedure-related covariates for confounder control, the authors investigated whether intraoperative 5-HT3 antagonists affected the association between pre- or intraoperative acetaminophen and postoperative opioid consumption, gauged by opioid dose in milligram oral morphine equivalents (OME) administered in the postanesthesia care unit. A multivariable, zero-inflated negative binomial regression model was applied.
A total of 3,166 patients (5.8%) 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 postanesthesia care unit opioid dose was 7.5 mg OME (interquartile range, 7.5 to 14.3 mg OME) among 16,640 of 55,016 (30.2%) patients who received opioids, and the mean 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 = 0.013).
A dose-dependent association of pre- or intraoperative acetaminophen with decreased postoperative opioid consumption was not observed when 5-HT3 antagonists were coadministered, suggesting that physicians might consider reserving 5-HT3 antagonists as rescue medication for postoperative nausea or vomiting when acetaminophen is administered for pain prophylaxis.
- Acetaminophen and 5-hydroxytryptamine type 3 (5-HT3) antagonists are some of the most widely used perioperative medications
- One proposed analgesic mechanism of action for acetaminophen is 5-HT3 receptor agonism, with previous preclinical and healthy volunteer studies showing decreased analgesia in the presence of 5-HT3 antagonists
- This hospital registry study of 55,016 ambulatory surgery patients found that a dose-dependent reduction in postanesthesia care unit opioid consumption associated with pre- or intraoperative acetaminophen was not observed in cases in which a 5-HT3 antagonist was coadministered
- This apparent modification of the analgesic effect of acetaminophen was not observed with other commonly used antiemetics, such as dexamethasone or haloperidol
- Although this apparent reduction of analgesic effect persisted when a host of prespecified covariates were controlled for, a definitive randomized controlled trial is needed to confirm this effect and delineate any clinical relevance to surgical and patient subgroups
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