Opioid-free anesthesia: comparable analgesia with potential superiority in safety and quality of recovery

To the Editor,

We read with great interest the systematic review and network meta-analysis by Tripodi et al. on opioid-free versus opioid-based anesthesia (OFA vs OBA) [1]. Their stated aim was to compare the effectiveness and safety of OFA regimens against opioid-based anesthesia (OBA).

However, the primary endpoint chosen to define “effectiveness” was restricted to postoperative pain, as if the purpose of anesthesia could be reduced to analgesia alone. Pain management cannot be limited to pain intensity alone; it must also include quality of recovery and the burden of adverse events. More importantly, the principal goal of anesthesia is to provide surgeons with optimal operating conditions while ensuring patient safety through stable organ perfusion and physiological support. This extends far beyond pain control, encompassing suppression of stress responses, modulation of the surgical inflammatory cascade, and preparation for safe recovery. Minimizing not only pain and postoperative nausea and vomiting (PONV), but also the wider range of complications that may follow surgery and anesthesia. Indeed, the benefits of OFA may extend throughout the entire perioperative period, influencing both physiological stability and patient-reported outcome measures (PROMs) [2].

Even in the absence of large randomized controlled trials (RCTs), there is broad consensus that multimodal anesthesia with reduced opioid use is preferable to opioid-based anesthesia alone, precisely to limit opioid-related adverse effects [3]. If reducing opioid exposure is already considered beneficial, why hesitate to proceed to a fully opioid-free intraoperative regimen, particularly when stable anesthesia is achieved just as effectively, if not more so? OFA is not simply the replacement of an opioid with a non-opioid analgesic; it aligns seamlessly with the concept of multimodal anesthesia.

The second pillar of the analysis was safety, but in practice this was assessed mainly through hemodynamic stability, where OFA proved superior. Other outcomes, such as PONV, were analyzed only as secondary endpoints. Here again OFA showed superiority, yet because these endpoints were not predefined as primary, they were excluded from the authors’ main conclusions.

It is also important to recognize the limitations of RCT methodology. RCTs are designed to address a single focused question under controlled conditions, typically exclude large patient groups, and often include relatively small cohorts. Their protocols may not reflect optimal daily practice. In contrast, retrospective analyses include all procedures, capture larger populations, and are better suited to evaluate safety and rare adverse events. This meta-analysis included 42 RCTs with 4666 patients, whereas a single retrospective bariatric cohort from our group already included 9246 patients at one center and demonstrated fewer adverse events with OFA [4].

Tripodi et al.’s findings confirm that while postoperative pain at 24 h did not differ significantly, OFA, especially combinations including ketamine, alpha-2 agonists, and lidocaine was associated with reduced PONV, decreased postoperative opioid requirements, and a lower incidence of intraoperative hypotension. If intraoperative opioids offer no benefit for postoperative pain control yet clearly increase the risk of side effects, their continued routine use in multimodal anesthesia is difficult to justify.

Furthermore, the discussion of OFA should not be confined to symptoms such as pain or nausea. During surgery, the systemic stress response is attenuated, but not abolished, by regional anesthesia [5, 6], and inflammatory activation persists. Consequently, large comparative studies often show little or no difference in major postoperative outcomes between regional and general anesthesia [7, 8]. This suggests that excessive inflammation remains an unmet need. OFA protocols including intravenous lidocaine and dexmedetomidine achieve the most substantial reductions in inflammatory markers, outperforming either drug alone as well as opioid-based regimens [9].

As Kehlet noted as early as 1985, “stress-free anesthesia does not exist, whatever dose of opioids you give” [10]. Indeed, opioids have never been shown to attenuate systemic inflammation. By contrast, lidocaine and alpha-2 agonists are potent anti-inflammatory agents, and their judicious intraoperative use may finally bring us closer to the long-sought goal of stress- and inflammation-free anesthesia.

Correct dosing, however, is critical. Several published studies overdosed (e.g. the POFA trial by Beloeil et al. [11], as we highlighted in a previous Letter to the Editor [12]), while others underdosed, possibly due to the absence of nociception monitoring. Nociception monitoring addresses only part of the perioperative stress response. Given the interindividual variability in drug needs, physiological stress monitoring remains promising but unvalidated in OFA and warrants further refinement. [13].

The implications extend well beyond pain control and hemodynamic stability. Preserving immune function is critical for preventing postoperative infection and supporting tissue repair. Avoiding immune suppression during anesthesia may also mitigate long-term complications increasingly linked to inflammatory pathways, including postoperative cognitive dysfunction (POCD) [14] and ventilator-induced lung injury (VILI) [15].

For these reasons, it seems premature to conclude, as Tripodi et al. do, that OFA has “no advantage.” On the contrary, the absence of inferiority in analgesia, combined with a more favorable side-effect profile, stronger preservation of immune function, and retrospective evidence of safety, strongly support further development and wider clinical implementation of opioid-free strategies. We agree that large, well-designed multicenter RCTs are needed to evaluate the role of OFA within multimodal anesthesia. Such trials should be preceded by structured education and training in OFA techniques [16], and supported by improved monitoring and protocol implementation, enabling precise, individualized titration of non-opioid agents. If intraoperative opioids offer no demonstrable benefit, the unavoidable question might also be: why continue to use them today?

If the current evidence for OFA still suffers from protocol-related variability in drug dosing, we expect that patient-centered, multicenter, and pragmatic implementation studies will clarify its true perioperative impact.

Authors’ contributions

“JPM wrote the first draft of the manuscript. All authors reviewed the manuscript and contributed with their specific expertise.”

Funding

No author got funding for this project.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no financial competing interests that could be perceived as influencing the results or discussion of this paper. J.P. Mulier contributed to the early development of opioid-free anesthesia in collaboration with Marc Dekock; these activities were academic and non-commercial, and all related information has been shared openly.