To the Editor
We thank the editorial authors for their thoughtful commentary in response to our Pro–Con debate.1,2 While we agree that analgesia must not be compromised, it is important to recognize that pain control is only one component of anesthetic outcomes that matter to patients. In a study examining the relative weight patients assign to recovery-related outcomes, postoperative nausea and vomiting accounted for 49% of the preference decision, compared with 27% for pain. This underscores the inherent trade-off in this debate, particularly as proponents of opioid-free anesthesia often cite reductions in postoperative nausea and vomiting as a central justification.3
We recognize the value of extending the opioid-free versus opioid-conventional debate to include emerging agents, including newly marketed G protein–biased μ-opioid receptor agonists such as oliceridine and tegileridine. Over the course of our review, we found substantial inconsistency within this literature, reflecting both variability in which phases of perioperative care that opioids are avoided and heterogeneity in the agents included within opioid-conventional and opioid-free protocols.4,5 Our Pro–Con article was intentionally focused on describing the existing evidence base, which largely comprises regimens using traditional opioids such as remifentanil, fentanyl, sufentanil, morphine, and hydromorphone. To our knowledge, no studies have specifically examined G protein–biased μ-opioid receptor agonists in the context of this question. We agree that these agents represent an important future consideration and would welcome studies evaluating whether they may offer advantages to opioid-free regimens for specific populations.
This discussion is particularly timely given the emergence of suzetrigine, the first nonopioid analgesic approved in over two decades.6 As a first-in-class NaV1.8 inhibitor, its integration into perioperative protocols has the potential to meaningfully reshape the opioid versus opioid-free anesthesia paradigm.7 We encourage continued comparative research in this space to better define the role of these therapies, and we appreciate the ongoing discourse that continues to advance the field.
References:
- 1.Cao S, Daniels M, Hah JM, Hao D. A&A pro-con debate: opioid-free versus opioid-conventional for patients undergoing general anesthesia. Anesth Analg. 2025;XX:XXX–XXX. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Bo L, Ji W, Peng S, Jinhai L. Beyond the binary: integrating novel G protein-biased opioids into the OFA debate. Anesth Analg. XXXX;XX:XXX–XXX. In press. [DOI] [PubMed] [Google Scholar]
- 3.Eberhart LH, Morin AM, Wulf H, Geldner G. Patient preferences for immediate postoperative recovery. Br J Anaesth. 2002;89:760–761. [PubMed] [Google Scholar]
- 4.Sessler DI, Ayad S, Bakal O, et al. ; VOLITION Study Team. Oliceridine for postoperative pain and opioid-related complications: the intravenous oliceridine and opioid-related complications (VOLITION) prospective cohort study. J Clin Anesth. 2025;105:111870. [DOI] [PubMed] [Google Scholar]
- 5.Wang T, Wang Y, Xie H, et al. Tegileridine for moderate-to-severe acute pain following abdominal surgery: a randomized, double-blind, phase 3 clinical trial. Cell Rep Med. 2025;6:102477. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Bertoch T, D’Aunno D, McCoun J, et al. Suzetrigine, a nonopioid Na V 1.8 inhibitor for treatment of moderate-to-severe acute pain: two phase 3 randomized clinical trials. Anesthesiology. 2025;142:1085–1099. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Chen SL, Liu MA, Swisher MW. Suzetrigine, a selective NaV1.8 inhibitor in acute and chronic pain: mechanistic insights, clinical outcomes, and future perspectives [published online ahead ofprint December 1, 2025]. Curr Opin Anaesthesiol. 2025;XX:XXX–XXX. doi: 10.1097/ACO.0000000000001599. [DOI] [PubMed] [Google Scholar]