Opioid-sparing anesthesia versus opioid-free anesthesia for postoperative recovery quality in breast cancer surgery patients: A systematic review and Bayesian network meta-analysis

JingWang Liu; JiaXin Liu; MingJie Wang; XiuLi Wang

doi:10.1371/journal.pone.0334614

Peer Review History

Original SubmissionJune 20, 2025
24 Jul 2025 Decision Letter - Benjamin Benzon, Editor Dear Dr. Wang, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. ============================== Please submit your revised manuscript by Sep 07 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols . We look forward to receiving your revised manuscript. Kind regards, Benjamin Benzon, Ph.D., M.D. Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. When completing the data availability statement of the submission form, you indicated that you will make your data available on acceptance. We strongly recommend all authors decide on a data sharing plan before acceptance, as the process can be lengthy and hold up publication timelines. Please note that, though access restrictions are acceptable now, your entire data will need to be made freely accessible if your manuscript is accepted for publication. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If you are unable to adhere to our open data policy, please kindly revise your statement to explain your reasoning and we will seek the editor's input on an exemption. Please be assured that, once you have provided your new statement, the assessment of your exemption will not hold up the peer review process. 3. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. 4. Please upload a copy of Figure 1-7, to which you refer in your text on page 7, 8, 11, 14 and 15. If the figure is no longer to be included as part of the submission please remove all reference to it within the text. 5. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. 6. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. Additional Editor Comments: The reviewers made some comments, I am looking forward to you response. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? Reviewer #1: Partly Reviewer #2: Yes Reviewer #3: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** Reviewer #1: I am concerned regarding QoR. Although QoR-40 and QoR-15 are evaluating self reported quality of recovery in the last 24 days the instrument are not same. The QoR-40 is having 40 items thet are sorted in five dimensions. Although there are five dimensions in QoR-40, the QoR-15 does not have five dimensions. The QoR-15 was developed from 16 items from QoR-40, and items have different likerrt scale (11) and QoR-40 is having 5. Although there are both used, it is not clear is better shorter and more simple QoR-15 or more comprehensive but time consuming QoR-40. I think both instruments are great way for evaluation QoR but they are not comparable. Can you explain to readers why did you decide to compare different but related QoR instruments in this study and why is it not good. Reviewer #2: Dear Authors, I really enjoyed reading your review. I don't completely agree with the notion presented in line 388 that alpha 2 antagonist could induce hypothermia. I believe that contribution to hypothermia is minor (reducing body temp by 0.5 degrees) and does not contribute to significant postoperative hypothermia (although it is not very enjoyable after an hour or more in cold OR). Also, I believe that it is not the same for the postoperative outcome and quality of recovery if we used OSA or OFA for the axillary node extraction and radical mastectomy. That might need further explanation and/or analysis. Reviewer #3: It would be great if author compare different techniques of both opioid sparing anaesthesia and opioid free anaesthesia and give a reader an recommendation which one to use. And in opioid based anaesthesia did the patients received only opioid for analgesia or combination with other analgesic agents? ****** what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy Reviewer #1: No Reviewer #2: No Reviewer #3: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0334614.r001
Revision 1
29 Jul 2025 Author Response Dear Dr. Benzon, Thanks for providing us with this great opportunity to submit a revised version of our manuscript. In the manuscript revision, we have indicated the removed sections using red text and strikethrough, while the added sections are highlighted in blue. Additionally, we have addressed each of the journal’s requirements as follows: 1. The manuscript has been revised according to the PLOS ONE formatting guidelines. 2. We agree to the data availability policy. As this meta-analysis is a secondary study, no new raw data were generated. All data were derived from previously published studies. Upon acceptance of the manuscript, we will either send the original data from the included studies to you or upload them to GitHub(https://github.com/whenthereis/away.git). 3. The corresponding author’s ORCID has been verified in the submission system. 4. Figures 1–7 have been uploaded to the system in accordance with the journal's requirements. 5. The supplementary materials have been included in the Supporting Information section at the end of the manuscript, and appropriate citations have been added in the main text. 6. No specific references were requested by the other reviewers. We hope this revised manuscript has addressed your concerns, and look forward to hearing from you. Sincerely, The Authors Reply to Reviewer #1 Dear Reviewers, Thank you very much for your time involved in reviewing the manuscript. Your concerns are valid; if the correlation between the scales is low, mixed comparisons could indeed affect the reliability of the results. However, according to the original literature on the QoR-15 scale (Development and Psychometric Evaluation of a Postoperative Quality of Recovery Score The QoR-15, DOI: 10.1097/ALN.0b013e318289b84b), the variance explained between the total scores of QoR-15 and QoR-40 is as high as 97%, and the five dimensions of QoR-15 are entirely derived from QoR-40. The clinical discriminative power of each dimension is similar, indicating that the two scales are highly correlated. Therefore, we used a linear transformation method to eliminate the scale differences and confirmed the robustness of the conclusions through sensitivity analysis (SMD method).Additionally, several meta-analyses on postoperative recovery quality have combined the QoR-15 and QoR-40 scales for comparison (Opioid-free anaesthesia and postoperative quality of recovery: a systematic review and meta-analysis with trial sequential analysis, DOI: 10.1016/j.accpm.2024.101453). This includes studies published in top anesthesiology journals such as BJA (The impact of perioperative ketamine or esketamine on the subjective quality of recovery after surgery: a meta-analysis of randomised controlled trials, DOI: 10.1016/j.bja.2024.03.012). These pieces of evidence support the scientific reliability of combining the two scales for comparison. Sincerely, The Authors Reply to Reviewer #2 Dear Reviewers, Thank you very much for your time involved in reviewing the manuscript and your very encouraging comments on the merits. We had previously overstated the impact of α2 receptor antagonists on temperature reduction, so We have revised the wording to avoid any absolute statements. Regarding your second question about the influence of surgical method differences on postoperative recovery quality, We acknowledge that such differences will certainly affect the results. We will add a discussion on this limitation in the study. However, since the surgical methods included are relatively fixed—being either breast-conserving surgery or total mastectomy with sentinel lymph node biopsy or axillary lymph node dissection (modified radical mastectomy = total mastectomy with axillary lymph node dissection)—excluding studies that involve multiple surgical approaches would render it impossible to form a closed-loop network for analysis. This would also prevent subgroup analysis. Moreover, if surgical method differences had a significant impact on the results, it would theoretically increase the heterogeneity of the study. However, the primary outcome of our study shows very low heterogeneity. Therefore, we believe that within the range of surgical methods included, variations in surgical approaches do not affect the robustness of our study’s results. Sincerely, The Authors Reply to Reviewer #3 Dear Reviewers, Thanks for your great suggestion on our manuscript. Your suggestions are highly valuable and offer important clinical insights. We had previously conducted a network meta-analysis exploring the impact of various non-opioid anesthesia strategies on postoperative recovery quality, aiming to identify the optimal non-opioid anesthesia regimen. However, due to the refinement and complexity of the anesthesia strategies, the number of subgroups increased significantly. To ensure sufficient evidence for comparison, We had to broaden the inclusion criteria by expanding the range of surgical procedures. This ultimately resulted in high heterogeneity and low evidence quality. Therefore, we believe that current evidence is insufficient to support a detailed comparison of specific anesthesia strategies in a meta-analysis. Nonetheless, this is a promising direction, and we plan to conduct further analyses once more robust evidence becomes available. Regarding your second question, with the advancement of modern anesthetic concepts, perioperative analgesic protocols relying solely on opioids have become increasingly uncommon. In our study, most trials categorized under the opioid-based anesthesia group adopted a strategy of "opioid-dominant analgesia supplemented with non-opioid agents" during surgery. Only a small number of studies employed opioids as the sole intraoperative analgesic. If the intra-group variability within the opioid-based anesthesia group had a significant influence on the outcomes, it would theoretically increase the heterogeneity across studies. However, our primary outcomes demonstrated very low heterogeneity, suggesting that this variability did not compromise the robustness of our findings. Sincerely, The Authors Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0334614.r002
1 Oct 2025 Decision Letter - Benjamin Benzon, Editor Opioid-sparing anesthesia versus opioid-free anesthesia for postoperative recovery quality in breast cancer surgery patients: A systematic review and Bayesian network meta-analysis PONE-D-25-33203R1 Dear Dr. Wang, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Benjamin Benzon, Ph.D., M.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #1: All comments have been addressed Reviewer #3: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #1: Partly Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: No Reviewer #3: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #3: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #3: Yes ****** Reviewer #1: Thank you for your answers . My intention was that you explain readers why is ok to combine similar but different questioners. Can you explain and discuss your response in a work, not just to me. Although questioners QoR-40 and QoR-15 are correlated and collinear it is not proof that they are similar. Correlation and covariance are not evidence of similarity. Can you use Bland Altman statistic to show how 2 instruments are similar. What is with normality and homoscedasticity of QoR-40 and QoR15 score ? Dear Reviewers, Thank you very much for your time involved in reviewing the manuscript. Your concerns are valid; if the correlation between the scales is low, mixed comparisons could indeed affect the reliability of the results. However, according to the original literature on the QoR-15 scale (Development and Psychometric Evaluation of a Postoperative Quality of Recovery Score The QoR-15, DOI: 10.1097/ALN.0b013e318289b84b), the variance explained between the total scores of QoR-15 and QoR-40 is as high as 97%, and the five dimensions of QoR-15 are entirely derived from QoR-40. The clinical discriminative power of each dimension is similar, indicating that the two scales are highly correlated. Therefore, we used a linear transformation method to eliminate the scale differences and confirmed the robustness of the conclusions through sensitivity analysis (SMD method).Additionally, several meta-analyses on postoperative recovery quality have combined the QoR-15 and QoR-40 scales for comparison (Opioid-free anaesthesia and postoperative quality of recovery: a systematic review and meta-analysis with trial sequential analysis, DOI: 10.1016/j.accpm.2024.101453). This includes studies published in top anesthesiology journals such as BJA (The impact of perioperative ketamine or esketamine on the subjective quality of recovery after surgery: a meta-analysis of randomised controlled trials, DOI: 10.1016/j.bja.2024.03.012). These pieces of evidence support the scientific reliability of combining the two scales for comparison Reviewer #3: (No Response) ****** what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy Reviewer #1: No Reviewer #3: No ******** https://doi.org/10.1371/journal.pone.0334614.r003
Formally Accepted
Acceptance Letter - Benjamin Benzon, Editor PONE-D-25-33203R1 PLOS ONE Dear Dr. Wang, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Benjamin Benzon Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0334614.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .