Comments on Albrecht et al. reviews. A reply

We thank Beloeil et al. for their thoughtful comments and reflections on our two recently published meta-analyses exploring the paradigm of intra-operative opioid administration 1, 2. Their letter raises a number of methodological questions and explores the relevance of our conclusions. Beloeil et al. felt that two included articles may be outdated relative to modern practice, and were concerned that the patients in both groups would have received opioids. Although these two articles were indeed published more than 20 years ago, we respectfully disagree that the practice described is outdated and we let the reader judge, for example, whether a total dose of 1 μg.kg−1 fentanyl in the opioid-inclusive group for electrocautery tubal ligation is a practice that corresponds to many modern centres 3. Perhaps more importantly, we respectfully disagree that patients in the opioid-free group received opioids, as the trial's methodology reports that ‘[patients] receive either fentanyl 1 μg.kg−1 or saline, which was given intravenously in a blinded fashion at the time of induction.’ Although our literature search strategy was designed to be broadly inclusive, we do recognise that there are inherent limitations to any search strategy. We believe that the search return of more than 4500 references for both meta-analyses was broad enough to appropriately capture articles of interest. However, we appreciate the writers drawing attention to an additional publication from the Journal of Clinical Anesthesia and Pain Medicine. Our primary search would indeed not return this publication as the source is currently not indexed. Although we cast a broader net with Google ScholarTM in order to locate similar articles, the timing of our search failed to identify this source. We encourage readers to include the results of this publication in their broader reading around opioid-free anaesthesia. We recognise, as well, the potential for publication bias and included Duval and Tweedie's trim and fill test to evaluate this concern and reduce this risk of blindly missing important data. Our colleagues comment that current opioid-free anaesthesia practice involves the administration of many non-opioid analgesic drugs intra-operatively. In the absence of a widely accepted definition, and given the paucity of trials investigating opioid-free anaesthesia with or without multimodal analgesia, we again respectfully disagree and believe that this assertion reflects more the opinion of the authors than a widely accepted fact. However, we agree that the analgesic benefit of intra-operative multimodal analgesia in an opioid-free context should be properly investigated as it seems likely to represent a beneficial approach. The writers also draw attention to the primary outcomes defined in the included trials. Although it is likely that including only trials that explored the same primary outcome would reduce heterogeneity in the results, we are surprised by this comment. Considerable data would be excluded by this limited approach and we argue that the value of including a wide range of available data is in line with the writers call for inclusivity in trial selection. Furthermore, we contend that our approach is a well-established approach for investigations of this type. Regarding the inclusion or exclusion of intra-operative neuraxial anaesthesia or analgesia for one of the two meta-analyses 1, we thank our colleagues for providing this opportunity to clarify that only patients under general anaesthesia, without neuraxial anaesthesia or analgesia were included. In addition, contrary to the writer's assertion, the quality of evidence was rated down by one level due to concern regarding inconsistency in one of the meta-analyses 2. Moreover, we believe that the tables entitled ‘Summary of findings’, together with the footnotes, give all the necessary detail for the reader to understand the reasons behind our assessments, based on the Recommendation, Assessment, Development, and Evaluation Working Group system 4. Finally, we agree that a pain NRS difference of 0.7 out of 10 at two postoperative hours might not be clinically relevant. However, as specified in the Discussion, the absence of analgesic benefit in the immediate postoperative period in the remifentanil group, along with fewer episodes of hypotension, shivering and postoperative nausea and vomiting in the dexmedetomidine group, is a reasonable argument in favour of the latter. In conclusion, we appreciate that any methodology is prone to limitations and might be improved. However, we contend that the advantages of our approach are its reproducibility and robust foundation across numerous other publications within this journal 5-9. We agree with Beloeil et al. that caution is warranted when moving from one paradigm to another and that the contribution of multi-modal analgesia in opioid-free anaesthesia requires further high-quality investigation.

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