Acetaminophen 5-HT3 Antagonist Interaction: Reply

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In Reply: We thank Drs. Sessler and Reuter Pimenta for their interest in our study and for emphasizing the importance of careful clinical interpretation in large registry analyses.1 We appreciate the opportunity to discuss the potential clinical implications of our findings in more depth. The authors raise the concern that while statistically significant, the observed difference in postanesthesia care unit opioid dose between patients receiving acetaminophen (without a 5-hydroxytryptamine [serotonin] type 3 [5-HT3] antagonist, i.e., ondansetron) and patients not receiving acetaminophen was very small (–0.19 mg oral morphine equivalent, or –5.5%),2 questioning the overall efficacy of acetaminophen as the basis for the observed interaction with ondansetron in the perioperative setting. An important advantage of large registry analyses is the possibility of exploring variations in the strength of associations and effect estimates across different subpopulations. In our study, we identified scenarios where the effect of acetaminophen was modified, which were included in this overall estimate. For example, as mentioned by Drs. Sessler and Pimenta, acetaminophen was not effective in procedures longer than 97 min. By contrast, acetaminophen was more effective when given intravenously at the end of the procedure—here, acetaminophen was associated with a 27.9% reduction in opioid dose (–0.90 mg oral morphine equivalent [95% CI, –1.34 to –0.46]). Still, we would like to emphasize that the aim of our article was not to investigate the small effect of prophylactic acetaminophen, which has already been well described in previous studies.3,4 We agree that our data may reinforce the view that acetaminophen alone and in a broader range of patients has very limited effectiveness as prophylaxis for postoperative pain. Still, many providers will administer acetaminophen, which has virtually no side effects when given as a single dose, as part of a multimodal anesthesia regimen where even just a 5.5% reduction in postoperative opioid consumption needs to be seen in the context of additional techniques. Drs. Sessler and Reuter Pimenta then raise concerns that withholding 5-HT3 antagonists to avoid interaction with acetaminophen might compromise adequate prophylaxis for postoperative nausea and vomiting. We agree that management of postoperative nausea and vomiting, an outcome rated by patients often worse than pain,5 should not be compromised for the sake of the limited effectiveness of acetaminophen. However, while ondansetron is an effective and well-investigated antiemetic, a variety of alternative medications are available that allow physicians to administer an adequate number of antiemetic prophylaxes even in patients with multiple risk factors.6 In contrast with some of these other antiemetics, 5-HT3 antagonists are also very effective rescue medications in patients experiencing postoperative nausea and vomiting. It is, however, important to understand that they are only effective as such when no drug from the same class has been given as prophylaxis.7 Thus, in light of a variety of alternative antiemetics targeting other receptors and not interacting with acetaminophen, as shown in our exploratory analyses, it is not unreasonable to reserve 5-HT3 antagonists for rescue treatment of postoperative nausea and vomiting. In the end, it will be up to the individual anesthesia provider to balance their prophylactic regimen. Our study provides information to guide these decisions: anesthesiologists might opt for avoiding acetaminophen at all based on its low overall effectiveness. Alternatively, if they want to use acetaminophen, antiemetic prophylaxes that do not target the 5-HT3 receptor might be considered while reserving ondansetron or other 5-HT3 antagonists as a rescue medication. Competing Interests Dr. Schaefer received funding for investigator-initiated studies from Merck & Co. (Rahway, New Jersey) that do not pertain to this letter. He is an associate editor for BMC Anesthesiology. He received honoraria for lectures from Mindray Medical International Limited (Shenzhen, China). He received an unrestricted philanthropic grant from Jeffrey and Judith Buzen. Elena Ahrens is an associate editor for BMC Anesthesiology. Dr. Wachtendorf is an associate editor for BMC Anesthesiology. Nikolai Ratajczak declares no competing interests.

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