We read with interest three recently published articles in which opioid-free anesthesia was discussed.1–3  However, we would like to address several concerns regarding the scientific discussion of these publications.

Beloeil et al.1  hypothesize that opioid-free anesthesia balanced with dexmedetomidine reduces postoperative opioid-related adverse events compared with balanced anesthetic with remifentanil. The results of this trial showed a greater incidence of serious adverse events, especially hypoxemia and bradycardia, in the dexmedetomidine group. However, the trial just compared remifentanil with dexmedetomidine, with ketamine and intravenous lidocaine in both groups. The use of locoregional analgesia or nonsteroidal anti-inflammatory drugs was excluded. Furthermore, the protocol mentioned that dexmedetomidine dosage should be in the range of 0.4 to 1.4 µg·kg−1·h−1 and dose adjustments were based on heart rates of the patients and monitored by analgesia nociception index. However, the reported doses of dexmedetomidine were 1.2 ± 2 µg·kg−1·h−1 (mean ± SD). Besides the fact that the absence of loading doses of dexmedetomidine may have led to a slow installation of its effect, and that a continuous infusion till the end of the surgery of a sedative agent with a half-life of more than one hour is debatable, we would like to discuss the validity of conducting a trial on high doses of dexmedetomidine. Looking at the dose distribution, some simulations done by us suggest that as many as 21% of subjects may have received more than the allowable maximum dose according to the study protocol, which may be considered a protocol violation because the drug may have dose-dependent side effects (fig. 1). If true, such a frequent protocol violation denotes, at least, a suboptimal study design precluding any extrapolation to a cautious use of the medication, and at the maximum, an earlier interruption of the trial because of hazardous design. The authors argue that high doses are described in other trials, but the only trial they mention to justify this design (high doses without a bolus) is a trial that used a bolus and infused in total 0.6 ± 0.6 µg·kg−1·h−1 (including the bolus dose).4  Furthermore, the patients were monitored with analgesia nociception index, but the authors never showed results of this monitoring. Therefore, the Postoperative and Opioid-free Anesthesia (POFA) trial uses a nonsupported drug dosage and may have exposed a significant proportion of their participants to protocol violations. Finally, the trial merely reconfirmed the well-known side effects of high doses of dexmedetomidine. The authors are credited for conducting this trial, but it doesn’t reflect responsible opioid-free anesthesia practice and just makes the scientific discussion on opioid-free anesthesia more controversial.2,3  They have only demonstrated the already well-known side effects of high-dose dexmedetomidine rather than opioid-free anesthesia risk–benefit ratio.

Fig. 1.

Dexmedetomidine dose distribution according to a Monte Carlo simulation of a fictive trial with similar data to those of the Postoperative and Opioid-free Anesthesia (POFA) trial with n = 1,000, asymmetric normal distribution, mean ± SD = 1.02 ± 2.0, skewness = 0.89, curtosis = 0.75, dose range: 0.15 to 2.85, patients with a dose greater than 1.4: n = 209.

Fig. 1.

Dexmedetomidine dose distribution according to a Monte Carlo simulation of a fictive trial with similar data to those of the Postoperative and Opioid-free Anesthesia (POFA) trial with n = 1,000, asymmetric normal distribution, mean ± SD = 1.02 ± 2.0, skewness = 0.89, curtosis = 0.75, dose range: 0.15 to 2.85, patients with a dose greater than 1.4: n = 209.

Close modal

Shanthanna et al.2  critically reviewed perioperative opioid use, especially in view of opioid-sparing versus opioid-free strategies. In fact, the authors did not explicitly distinguish between eliminating intraoperative opioids (opioid-free anesthesia) and postoperative opioids (opioid-free analgesia). This lack of distinction may confuse the reader into believing that opioid-free anesthesia may mean elimination of all opioids, including in the postoperative and postdischarge periods. Opioid-free anesthesia is, by definition, referring to anesthesia while the patient is asleep, and nociception has to be considered instead of “pain,” an experience that is always associated with consciousness. Consequently, at the end of the surgical procedure or at the recovery ward, opioids might be titrated to effect when indicated. Opioid-free anesthesia has emerged as a new stimulating research perspective and has gained in popularity as a way to enhance early recovery and to spare opioids for the postoperative period.5  Hence, the goal is not by any way an obligation to eliminate the postoperative opioids where these are useful but rather to improve the clinical outcomes. In randomized controlled trials, one meta-analysis and a large retrospective study, it was shown that opioid-free anesthesia strategies may improve different outcomes.6,7  In addition, the arguments in favor of the use of locoregional analgesia, but also of ketamine, are supported by a significant body of evidence.8  Shanthanna et al. state that opioid-free strategies, including opioid-free anesthesia, are noble in their cause, do not serve to decrease the risk of persistent opioid use, and distract us from optimizing pain and minimizing realistic long-term harms. This statement seems to be a bit biased or at least opinion based and not supported by any evidence.

In an accompanying editorial, Kharasch and Clark3  state that medical change is driven by concepts of effectiveness and safety and that these concepts should improve and refine as better data become available. We agree with this statement. However, we strongly disagree with their conclusion that the POFA trial clearly demonstrates that we can do more harm than good by opioid-free anesthesia. The authors never come with scientific data to critically discuss the use of opioids and are opposing opioid-free anesthesia by using the results of the POFA trial without discussing the many limitations of the POFA trial, which doesn’t represent proper opioid-free anesthesia practice. It is important to underline that opioid-free anesthesia is not an overreaction to the opioid crisis; opioid-free anesthesia existed before this crisis and started before in the European countries where opioids crisis was not a concern.5  If we respectfully disagree with the Kharasch and Clark’s statement that opioid-free anesthesia may appear neither logical nor beneficial to patients, opioid-free anesthesia could be misapplied in clinical practice. Thus, we do agree that a more critical look should be considered for further evaluation in the next future.

Are opioids really some of our most powerful drugs, as stated by Kharasch and Clark? There are many uncertainties about the pervasive effect of opioids and strong evidence for the existence of dose-dependent toxicity.9  There are strong arguments that intraoperative opioids, remifentanil in particular, may be associated with worse postoperative pain and worse outcomes, making their safety profile questionable. Moreover, intraoperatively used remifentanil showed unexpected unfavorable outcomes and was associated with a deterioration of pain levels and increased postoperative analgesic requirement.10  The potential benefits of remifentanil seem to be outweighed by its potential disadvantages, especially in surgical procedures in which high postoperative pain scores are expected.11  Furthermore, opioid-induced hyperalgesia is induced by higher doses of intraoperative opioids and associated with increased postoperative pain scores and higher morphine consumption.12  Therefore, for many reasons, opioids are not a holy grail in anesthesia, and their use should be carefully reconsidered.

We stress the importance of proper education regarding how to practice opioid-free anesthesia and how new ways of monitoring of antinociception may help implement opioid-free anesthesia. Furthermore, future well-designed trials that investigate the role of opioid-free techniques in multimodal anesthesia make sense only if they are part of a continuum where the development of patient-centered approaches is essential. The main goal in perioperative medicine is to enhance recovery, reduce complications, and improve outcome, not by focusing on using or not using of opioids (intraoperatively) only but also to broaden our scope in which research and development of opioid-free anesthesia strategy as part of multimodal anesthesia approaches deserves a place, rather than being excluded.

Dr. Mulier received personal fees, department grants, financial support, and nonfinancial support to organize scientific meetings from MSD Merck (Kenilworth, New Jersey), GE Healthcare (Chicago, Illinois), Medtronic (Dublin, Ireland), and Johnson & Johnson (New Brunswick, New Jersey) outside the submitted work. Dr. Lavand’homme was in the pharmacovigilance committee of the POFA trial and has no other conflict of interest. Dr. De Baerdemaeker has received departmental nonrestricted educational grants from GE and Medtronic. Dr. de Boer has received research grants from Merck and is member of the Executive Commitee and treasurer of the ERAS Society. The other authors declare no competing interests.

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