Review Reports - Intraoperative Methadone in Adult and Pediatric Cardiac Surgery: A Narrative Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is an excellent review manuscript that will be interesting to readers. There are couple of structural suggestions that would improve the comprehension:

Present manuscript search strategy not in the Results but in the Methods section.
Present main results of manuscripts' review not in the Discussion but it the Results section.

Author Response

This is an excellent review manuscript that will be interesting to readers. There are couple of structural suggestions that would improve the comprehension:

Present manuscript search strategy not in the Results but in the Methods section.
Present main results of manuscripts' review not in the Discussion but it the Results section.

First, we would like to express our immense gratitude for the time spent reviewing our manuscript. Although it is not a systematic review and does not follow the PRISMA framework, the structure of a narrative review is flexible, focused on a qualitative and interpretive analysis of the literature, ideal for describing the state of the art of a topic which is the case of our manuscript. Despite this, we used the same structure as a systematic review in order to logically organize the content, where the search strategy is presented in the methods section and the search results are summarized in the results section. For the description and discussion of our findings, we used the discussion section.

Reviewer 2 Report

Comments and Suggestions for Authors

Major comments

Methods transparency is insufficient even for a narrative review.
Please expand the Methods section to improve reproducibility: provide the complete search strings for each database, specify the screening workflow (title/abstract/full-text), report explicit inclusion/exclusion criteria, clarify how duplicates were handled, define the data-extraction items, and indicate whether any quality appraisal (risk of bias) was performed or not. A PRISMA-style flow and an exclusion-reason summary would substantially strengthen credibility.
Quantitative claims are overconfident given heterogeneous evidence.
Statements such as “30–70% reduction in opioid requirements,” “20–30% improvement in satisfaction,” and “up to $6,355 savings” should be contextualized by study design (RCT vs retrospective), intervention type (methadone alone vs multimodal protocols), surgical procedure, and baseline analgesic regimens. Please tone down causal/definitive wording and clearly indicate when estimates come from specific studies or highly selected settings.

3. Separate adult vs pediatric evidence and align conclusion strength with evidence level.
Pediatric evidence is predominantly retrospective with variable dosing and mixed findings (e.g., prolonged hospital stay in younger children in an adjusted analysis). The current conclusion that methadone is “robust and safe… including pediatric cases” is too strong. Please present adult and pediatric evidence separately and provide graded conclusions (e.g., stronger for adult RCTs; cautious/conditional for pediatrics).
CPB pharmacokinetics and the ‘supplemental dose’ proposal need a balanced clinical framework.
The manuscript highlights a substantial concentration drop during CPB (e.g., 48%), while other data suggest concentrations may remain above the minimum effective threshold for ~24 hours with standard dosing. Please provide a structured discussion that reconciles these findings and offers practical guidance (when supplemental dosing might be considered, and when it may be unnecessary), including assumptions behind the proposed therapeutic range.
Safety discussion should include clearer dose–response guidance, especially delirium and QTc.
The association between higher dosing (>0.25 mg/kg) and delirium risk is clinically important. Please expand on delirium definitions, patient risk factors, and provide a practical dosing/monitoring recommendation (e.g., suggested dose ranges by risk profile). For QTc, consider adding perioperative monitoring considerations and common interacting medications in cardiac surgery.

Minor comments

Please standardize Tables 1–2 to include: procedure type, methadone dose/timing, comparator, key outcomes (pain scores, OME, extubation time, QTc, delirium), and study limitations. Distinguish methadone-only vs multimodal protocols.
The English is generally understandable, but several sentences are overly assertive. Please revise to reflect observational uncertainty and heterogeneity.

Author Response

Methods transparency is insufficient even for a narrative review.
Please expand the Methods section to improve reproducibility: provide the complete search strings for each database, specify the screening workflow (title/abstract/full-text), report explicit inclusion/exclusion criteria, clarify how duplicates were handled, define the data-extraction items, and indicate whether any quality appraisal (risk of bias) was performed or not. A PRISMA-style flow and an exclusion-reason summary would substantially strengthen credibility.

First, we would like to express our immense gratitude for the time spent reviewing our manuscript. The screening workflow was added in methods section and is highlighted in yellow.

Quantitative claims are overconfident given heterogeneous evidence.

Statements such as “30–70% reduction in opioid requirements,” “20–30% improvement in satisfaction,” and “up to $6,355 savings” should be contextualized by study design (RCT vs retrospective), intervention type (methadone alone vs multimodal protocols), surgical procedure, and baseline analgesic regimens. Please tone down causal/definitive wording and clearly indicate when estimates come from specific studies or highly selected settings.

We acknowledge that the sentences were too vague in the abstract, so we rewrote it according to the new abstract attached in the revised file. Furthermore, in the respective subsections of the manuscript's discussion section, we included the improvements requested by the reviewer. Additionally, we toned down the conclusive tone regarding the benefits of methadone in pediatric cardiac surgery in the abstract's conclusion. In subsection "4.10. Methadone in Pediatric Cardiac Surgery," the last and penultimate paragraphs emphasize the limitations of the evidence in the pediatric population.

3. Separate adult vs pediatric evidence and align conclusion strength with evidence level.

Pediatric evidence is predominantly retrospective with variable dosing and mixed findings (e.g., prolonged hospital stay in younger children in an adjusted analysis). The current conclusion that methadone is “robust and safe… including pediatric cases” is too strong. Please present adult and pediatric evidence separately and provide graded conclusions (e.g., stronger for adult RCTs; cautious/conditional for pediatrics).

The paragraphs outlining the limitations in pediatric cardiac surgery are highlighted in yellow in subsection 4.10, emphasizing the absence of clinical trials to date and citing the ongoing clinical trial registered at ClinicalTrials.gov.

Reviewer 3 Report

Comments and Suggestions for Authors

This appears to be a well-conducted study.
This manuscript requires revisions.
1- There is a discrepancy between the title of the document “Intraoperative Methadone in Adult and Pediatric Cardiac Surgery: A Narrative Review” and the title uploaded to the system. Authors are advised to recheck this. (“Intraoperative methadone in adult and pediatric cardiac surgery: a scoping review”)
2- Authors are advised to interpret the current findings more critically and compare them with vertical integration.

Author Response

1- There is a discrepancy between the title of the document “Intraoperative Methadone in Adult and Pediatric Cardiac Surgery: A Narrative Review” and the title uploaded to the system. Authors are advised to recheck this. (“Intraoperative methadone in adult and pediatric cardiac surgery: a scoping review”)

There was indeed an error in the translation, and the manuscript is a narrative revision, not a scoping revision. This change had already been made in the original manuscript version; however, the Susy platform did not allow editing of the original title and abstract submitted the first time. The correction will be made. Thank you once again for your time dedicated to reviewing this manuscript.

Reviewer 4 Report

Comments and Suggestions for Authors

The authors performed a systematic narrative of the effect of use of intra-op methadone in pediatric and adult cardiac patients and its impact on intra-op and post-op opioid requirements, pain scores, patients' satisfaction, PONV, respiratory depression and mechanical ventilation.

Background: There has been increased interest clinically in the administration of methadone intra-operatively for achieving adequate pain control and reducing intra-op and post-op opioid requirement and better pain control. Several studies have been published confirming the efficacy of methadone. Previously methadone was initially used for maintenance in opioid addiction due to its long active nature and there was a debate clinically when to stop pre-operatively since there was a concern due to its long-acting nature intra-operative opioids wouldn't be effective. However, there was shift in paradigm when methadone has been shown to reduce intra-op opioid requirements by 20% and recommended to continue in the pre-op period.

Scientific soundness: The manuscript is well written, and the authors performed a systematic review on the effect of intra-op cardiac patients in adult and pediatric. In cardiac patients, especially CABG patients especially undergoing sternotomy pain control intra-op and post-op is challenging traditionally using high dose of fentanyl and dilaudid intra-op and post op period affective hemodynamic and delaying extubation and increasing PONV. Methadone has the advantage of providing better hemodynamic profile and minimizing opioid requirement and PONV and facilitate early extubation.

Limitations of study that needs to be addressed:

Materials and Methods: The authors need to follow PRISMA guidelines while performing a systematic review and present the results in the PRISMA chart.

1.They need to provide detail how the systematic review was performed

2. How many duplicate articles were removed

3. what are the keywords used

4. How did they decide if there was conflict in including the articles

5. What age was used as a cut off for pediatric studies

6. Whether there was any overlap in adult studies with pediatric studies.

Results:

By performing the meta-analysis, the authors can provide more insight to the readers about the impact of methadone in intra-op and post-op opioid requirement
Does the presented articles have any adverse outcomes due to methadone administration such as QT prolongation. What percent of patients have QT prolongation
what would be the authors recommendations for baseline QT interval for not administering methadone in both male and female cardiac patients
is there any impact of the effect of methadone in intra-op and post-op opioid requirements if the methadone just administered intra-operatively rather than continuing from the pre-op. If so, what are the dose adjustments from the study

It interesting and appreciate the authors for reporting the plasma dilution of methadone during and post cardiopulmonary by pass

Author Response

Limitations of study that needs to be addressed:

Materials and Methods: The authors need to follow PRISMA guidelines while performing a systematic review and present the results in the PRISMA chart.

Results:

By performing the meta-analysis, the authors can provide more insight to the readers about the impact of methadone in intra-op and post-op opioid requirement

We are planning to conduct a systematic review with meta-analysis after this narrative review to increase the robustness of the results. The objective of this manuscript is to synthesize, in a qualitative and descriptive manner, all the findings to date from studies involving methadone in cardiac surgery.

2. Does the presented articles have any adverse outcomes due to methadone administration such as QT prolongation. What percent of patients have QT prolongation

Section 4.7 covers the two articles to date that have evaluated the QTc interval in cardiac surgery patients who received methadone. No cases of Torsades de Pointes were reported in the articles that evaluated the QTc interval. Furthermore, as cited in our manuscript, all patients in both the control group and the methadone group experienced a transient increase in QTc in the first 24 postoperative hours with no difference in the incidence of arrhythmias between the groups.

3. what would be the authors recommendations for baseline QT interval for not administering methadone in both male and female cardiac patients

In section 4.7, we added the QTc interval (highlighted in yellow), which is considered a contraindication for intraoperative methadone administration, as suggested by the study by McClain et al.

4. is there any impact of the effect of methadone in intra-op and post-op opioid requirements if the methadone just administered intra-operatively rather than continuing from the pre-op.

We cannot confirm this impact since most studies used intraoperative methadone. Only one pilot study (Bolton et al) used preoperative methadone; however, the dose was administered orally upon admission to the surgical center.

Reviewer 5 Report

Comments and Suggestions for Authors

The presented work is a narrative analysis of the use of intraoperative methadone in adult and pediatric cardiac surgery. The topic is clinically relevant, and the authors present a wide range of data. However, the methodology needs to be clarified and reinforced to ensure full transparency and credibility of the review.

The authors declare that the work is a narrative review, which in itself allows for greater flexibility in the selection and interpretation of data. Nevertheless, with such a wide range of topics and a large number of studies included (41), it would be advisable to use at least partial elements of a systematic methodology to reduce the risk of bias.

For m.in, there is a lack of an assessment of the quality of the included studies, an analysis of the risk of bias, a clear justification for the inclusion of studies with a very different structure (RCTs, retrospective cohorts, case series), information on whether the review was recorded (e.g. PROSPERO).

The authors give basic criteria, but they are too broad and imprecise:

included "all studies evaluating the use of intraoperative methadone", regardless of age, type of surgery, type of study or methodological quality,
Only conference abstracts, case reports and non-English papers were excluded.

Such broad criteria result in a wide variation in the quality of evidence, the risk of excessive influence of retrospective research, and the difficulty in drawing unambiguous conclusions.

There is also a lack of information on whether the selection was carried out according to an established protocol and whether quality assessment tools were used. The paper presents numerous numerical data, but the methodology of their acquisition has not been described. It is not known whether the data extraction was performed by two reviewers, it is not stated what variables were collected, and the method of dealing with data gaps is not described.

The synthesis is narrative in nature, which is consistent with the declared type of review, but no structure for assessing the strength of evidence is presented, no distinction is made between RCT results and retrospective studies, and no heterogeneity analysis is performed.

Author Response

Dear reviewer, on behalf of the other authors, I would like to thank you for your time in reading and reviewing this manuscript. As another reviewer pointed out, we compiled all studies involving intraoperative methadone in cardiac surgery, aiming to be as comprehensive as possible. The main objective of a narrative review is to provide a comprehensive and interpretive synthesis of the existing literature on a given topic, allowing for the organization of current knowledge and a theoretical discussion of the "state of the art." It seeks to contextualize subjects, explore under-researched topics, and identify gaps, without the need for rigid search protocols. We intend to soon begin a systematic review with meta-analysis to address this topic. This future work will be properly registered in PROSPERO and will follow all PRISMA guidelines.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The review methodology is not sufficiently rigorous for the strength of the conclusions. It is labeled a narrative review, yet it uses a quasi-systematic search/reporting style without protocol registration, formal risk-of-bias assessment, or clearly described full-text eligibility review. Screening is described as title and abstract based, and duplicates were removed manually.
The evidence base is heterogeneous and partly non-primary. Randomized trials, observational studies, editorials, review articles, and consensus papers are all included, which risks overinterpretation and indirect support for conclusions.
Several claims are too definitive. The abstract states that safety is “confirmed,” opioid reduction reaches 70%, and methadone is cost-effective, despite substantial reliance on retrospective data and mixed findings.
The manuscript makes practice recommendations that exceed the evidence. It proposes a new 0.05 mg/kg post-CPB dose even while acknowledging conflicting pharmacokinetic findings and that the issue remains contentious.
The pediatric section is overstated. The manuscript itself admits there are no pediatric cardiac RCTs, most studies are retrospective/small, regimens vary, and one study found longer hospital stay in younger children.

Author Response

The review methodology is not sufficiently rigorous for the strength of the conclusions. It is labeled a narrative review, yet it uses a quasi-systematic search/reporting style without protocol registration, formal risk-of-bias assessment, or clearly described full-text eligibility review. Screening is described as title and abstract based, and duplicates were removed manually

First, we would like to thank the reviewer for their valuable contribution. Again, we would like to reiterate that the main function of a narrative review is to provide a comprehensive analysis of the literature on a topic, contextualizing current knowledge, historical development, and highlighting gaps, without the need for rigorous search methods. It is ideal for updating, educational material, and theoretical grounding. Unlike a systematic review, a narrative review does not require a rigid protocol for study selection, focusing more on interpretation and narrative.

The evidence base is heterogeneous and partly non-primary. Randomized trials, observational studies, editorials, review articles, and consensus papers are all included, which risks overinterpretation and indirect support for conclusions

In the results tables and discussion, all selected articles had their observational/experimental nature duly cited, as well as the evidence generated by each study.

Several claims are too definitive. The abstract states that safety is “confirmed,” opioid reduction reaches 70%, and methadone is cost-effective, despite substantial reliance on retrospective data and mixed findings.

In fact, the effect of methadone in reducing opioid consumption by 69% on the third day of evaluation is a result from a clinical trial by Wong et al., used as a reference for this narrative review. This information was added to the discussion with the respective source and to the abstract in order to show the magnitude of effect that intraoperative methadone can achieve.

The manuscript makes practice recommendations that exceed the evidence. It proposes a new 0.05 mg/kg post-CPB dose even while acknowledging conflicting pharmacokinetic findings and that the issue remains contentious.

Since narrative reviews aim for the author's "interpretation" of the literature, we suggest the study by Salas et al. as one of the possibilities for post-CPB management. Currently, we have two studies on the pharmacokinetics of methadone in CPB. The study by Salas et al. suggests a bolus of 0.05 mg/kg, while the study by Wong et al. does not use a new bolus. The authors' experience follows the protocol used by Salas et al., which is why they suggest this approach. However, we make it clear in the text that this is still a controversial issue, since Wong et al. do not use a new dose after CPB. Thus, it is up to the reader to choose which strategy to use. The narrative review aims to provide both pieces of information.

The pediatric section is overstated. The manuscript itself admits there are no pediatric cardiac RCTs, most studies are retrospective/small, regimens vary, and one study found longer hospital stay in younger children.

All pediatric studies are indeed small and observational. Currently, the PRECISE trial is underway and will allow for a more robust answer regarding methadone in pediatric cardiac surgery. The authors made this limitation clear in the limitations section of "4.10. Methadone in Pediatric Cardiac Surgery." However, it is worth emphasizing that these are, to date, all the published articles on methadone in cardiac surgery. If we review them all, they show equivalence or superiority of the methadone group. All of them, to be published in excellent journals, passed through a Research Ethics Committee before publication. In fact, methadone was used in the pediatric age group, showed an effect in reducing opioid use, and without serious adverse events.

Reviewer 4 Report

Comments and Suggestions for Authors

The authors addressed few of my concerns, not all. Nevertheless, systematic review with meta-analysis rather than narrative review would add significance to the literature.

Author Response

The authors addressed few of my concerns, not all. Nevertheless, systematic review with meta-analysis rather than narrative review would add significance to the literature.

First, we would like to thank the reviewers for the time dedicated to the review process. We are currently working on a systematic review and meta-analysis on this topic. We believe that we will soon be able to submit the article for publication in this journal. The idea with this first paper was to create a robust theoretical foundation and serve as supplementary material for readers seeking a more didactic review.