Dear Dr. Wonte,

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.

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ACADEMIC EDITOR:

Report details on how informed consent for the research was obtained (or explain why consent was not obtained).

NRS and VAS are reported. These outcome measures are not interchangeable. Please explain which was used to measure pain intensity and how this effected the outcome.

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==============================

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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: Yes

Reviewer #2: No

Reviewer #3: Yes

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2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: As the statistical reviewer I will focus on methods and reporting. Overall the trial is well described and the methods are appropriate.

1) the power calculation section needs some clarity. clarify the analgesic consumption in the two groups (what unit of measurement) and the power level and alpha at the start - then report the numbers needed to pick up the hypothesised difference (is it 60?). then add the 10% for loss to follow up. I dont' follow how you start with 30+30, then add 10% and end up with 60.

2) the repeated measures approach is appropriate but the section was a bit confusing. it seems like a single repeated measures mixed linear regression model was used? clarify the specifics of the model e.g. clustered errors?

3) There is no information on missing data. were the data complete for all patients in both groups? please state so. if not, would multiple imputation approaches be relevant here?b

Reviewer #2: Mesay Milkias Wonte and colleagues should be congratulated for carrying out a study which aims to alleviate pain in women after Caesarean Delivery.

The authors aim to compare the effect of wound infiltration (WI) with tramadol and bupivacaine versus bupivacaine on its own on pain in women after CSection. They write that previous studies assessed wound infiltration with bupivacaine and tramadol with conflicting results. They cite: (1) Sarwar A TS. Effectiveness of Local Bupivacaine Wound Infiltration in Post Operative Pain Relief After Caesarean Section. J Soc Obstet Gynaecol Pak. 2016;6(3):125-8 and (2) Haliloglu et al . Analgesic efficacy of wound infiltration with tramadol after cesarean delivery under general anesthesia: Randomized trial. J Obstet Gynaecol Res. 2016 Jul;42(7):816-21

I reviewed the abstracts of both papers VERY briefly – they both seem to have found that WI with tramadol effective. I am, therefore, not sure where the results are in conflict with each other. The authors might expand on this point.

This study seems to be a replication of the study carried out by ref 18 : Sachidanandaet at al. Comparison of Analgesic Efficacy of Wound Infiltration with Bupivacaine Versus Mixture of Bupivacaine and Tramadol for Postoperative Pain Relief in Caesarean Section Under Spinal Anaesthesia: A Double-Blind Randomized Trial. Journal of Obstetric Anaesthesia and Critical Care 7(2):p 85-89, Jul–Dec 2017.

It’s a replication in terms of the dose of tramadol that was infiltrated into the wound; size of cohort, method of anesthesia (spinal).

Replicating another study is certainly ethical, but this should be clearly indicated when describing the aims of the study in the Introduction.

Introduction

Third paragraph – I suggest that caring for pain after CSection is complex for the reasons that the authors list but probably a major factor is that mothers, wishing to breastfeed their newborns, and medical and nursing staff are not well acquainted with the medications which are safe vs less safe for lactation.

I suggest that the authors refer to the review by Patricia Lavand’homme Lavand'homme P. Postoperative cesarean pain: real but is it preventable? Curr Opin Anaesthesiol. 2018 Jun;31(3):262-267.

The authors could use information from this review to describe the complexity of caring for women post CSection, including addressing poor recovery and long long outcomes.

Tramadol.

According to Gesseck et al Neonatal Exposure to Tramadol through Mother's Breast Milk. J Anal Toxicol. 2021 Sep 17;45(8):840-846. , use of tramadol during pregnancy is generally avoided and may cause some reversible withdrawal effects in neonates, and its use during lactation is not licensed by the manufacturer.

I assume that if the tramadol is infiltrated to the incision, absorption to the blood stream will be less compared to when the medication is administered systemically. Later in the manuscript, the women seem to have received oral tramadol – and so this might not comply with the current recommendations for lactating women. The authors should address the issue of which opioids are recommended vs not for women after CSection and that there are warnings regarding use of tramadol.

I am aware that different guidelines, internationally, recommend different analgesics for lactating mothers.

I tried to look up international guidelines for recommendations as to which analgesic medications are safe for lactating women. I cite only a few examples here – as to this this thoroughly would require much more work , from the little I have seen, there is little standardization among the guidelines.

LactMed® database – recommend using tramadol for the shortest time possible.

WHO guidelines for lactating mothers BREASTFEEDING AND MATERNAL MEDICATION Recommendations for Drugs in the Eleventh WHO Model List of Essential Drug – the most recent version seems to be from 2002. They do not mention tramadol among the opioids

Roofthooft et al PROSPECT Working Group of the European Society of Regional Anaesthesia and Pain Therapy. PROSPECT guideline for elective caesarean section: an update. Anaesthesia. 2023 Sep;78(9):1170-1171.– recommend wound infiltration but with a local anesthetic alone.

The authors write that tramadol has local anesthetic properties when it is injected into peripheral nerves, citing REFS 13 and 14

I looked up these references. Reference 14 - Subedi et al . An overview of tramadol and its usage in pain management and future perspective. Biomed Pharmacother. 2019 Mar;111:443-451 – states in the Introduction … that use of tramadol is … restricted in pregnant women as well as breast feeding mothers as it may cause birth defects and harm the foetus and to the nursing babies. Tramadol is rated as Category C in the pregnancy risk drug by American Food and Drug Administration. Due to these effects, physicians hould avoid prescribing tramadol to pregnant women and nursing mothers .

This citation does certainly not advocate using tramadol in lactating mothers. Citing it for this statement was probably unintentional.

The second reference seems correct for this statement:

Kaki AM, Al Marakbi W. Post-herniorrhapy infiltration of tramadol versus bupivacaine for postoperative pain relief: a randomized study. Annals of Saudi medicine. 2008;28(3):165-8. 14.

Methods

Why did the authors use both VAS and NRS for assessing pain?

Was pain assessed at rest or movement-related?

Which medication was injected into the spinal catheter?

What do the authors intend to say when they write

….At the 6th hour postoperatively, the time the uterus stayed outside the abdomen and pain severity was statistically significant (8.22±1.767), (P=0.027)

The authors provide summarized results of the pain readings comparing the two groups. They should include a table in which the raw pain scores for each of the assessment time points, for both groups.

Or a graph of the pain scores as a function of time.

Rather than calculate means - which can be misleading - the authors could evaluate the proportion of women who reported scores of eg 3/10 and less at the different time points

I cannot find figure 2.

It will be easier to assess the outcomes related to pain - once the authors address the issues above.

Under Analgesic consumption , page 10 - it seems that patients received systemic tramadol in addition to the infiltration – is this correct? If so - then this seems to contradict recommendations and then it is dubious whether publishing the findings from this study is ethical without extensive discussion of the pros and cons of using tramadol in this population.

Discussion

Page 14 – the authors write

Tramadol may prove predominantly useful in patients with limited cardiopulmonary function, including the aged, the obese, and smokers, in patients with impaired liver or renal function, and in patients in whom non-steroidal anti-inflammatory drugs are not suggested or need to be used with caution (26).

However these patient groups are not included in the current study which focuses on CSection and according to several sources tramadol – at least systemic – is not recommended for women who are breast feeding.

As I wrote above - this is an issue that should be discussed at some length if this manuscript is to be accepted for publication.

Reviewer #3: In the introduction section, I recommend including the prevalence of caesarean sections in Ethiopia, as the study was conducted there and highlights the burden of pain management in caesarean sections and the limited access to opioid analgesics and epidural analgesia in low-resource settings.

Similarly, the authors include, “Research has revealed that tramadol has certain local anesthetic properties when it is injected into peripheral nerves (13, 14).” However, the fact is that wound infiltration, or local infiltration analgesia, involves injecting local anesthetic directly into the tissues surrounding the wound, not the nerves themselves. Therefore, please include references that show the effect of tramadol on wound infiltration if possible. Otherwise, paraphrase the statement if there is a lack of evidence in this regard.

Use a consistent term throughout the documents, either "pregnant" or "parturient." Additionally, use the same abbreviation to describe the two groups (bupivacaine versus a comparison of bupivacaine and tramadol) consistently throughout the documents.

In method sections

Authors mentioned that they used a visual analogue scale and a numeric rating scale to measure pain severity. What is the importance of using two pain assessment scales for a homogenous population?

Redefine total analgesic consumption in the operational definitions as you are using mean tramadol consumption quantity instead of saying analgesic drugs in milligrams.

You mentioned that the anaesthetist in charge, who was not part of the study, prepared the medications. Would you write the details of the person who performed the infiltration procedures? Is it the same obstetrician? Include details of the anatomical locations and techniques where infiltration was performed.

The authors mentioned that patients received IV tramadol at a dose of 0.5 mg/kg if they had a shivering grade of three or above. Does this affect your outcome variables? Intraoperative tramadol may prolong the duration of postoperative analgesia and reduce the mean consumption of postoperative analgesics. At the very least, please acknowledge this point in the limitations section. This might be the reason for the discrepancy with other studies that you have been mentioning in the discussion sections, especially with Sachidananda et al. on the severity of pain scores at different points in time.

Under the Anesthetic Management and Surgery section, you mentioned that a numeric rating scale was used to assess the severity of postoperative pain for 24 hours at T2, T6, T12, T18, and T24 hours, where T represents time. However, in the abstract section, you refer to both a visual analogue scale and a numeric rating scale to measure pain severity, and you also operationalize the definitions of both pain assessment tools. Please clarify which assessment tool you used in the manuscript; probably, you have used NRS.

Please clarify in the outcome section when you evaluated the incidence of shivering during the postoperative period, as the current statement does not specify whether it refers to the intraoperative or postoperative phase.

In the results section, the previous caesarean section scar was an indication for caesarean delivery. Do you think having a CS scar affects your study outcomes, and do you consider it a limitation?

In the intraoperative characteristics, you mentioned that “At the 6th hour postoperatively, the time the uterus stayed outside the abdomen and pain severity was statistically significant (8.22±1.767), (P=0.027).” This information should not be included here. Please either change the heading to "perioperative characteristics" or move this information to another section.

In the discussion section, the authors mentioned that “Similar to the findings of Sachidananda et al., our study showed a statistically significant difference (p = 0.0484) between the mean (±SD) postoperative pain score of the treatment group at 6 and 12 hours after surgery (2.60 ± 0.97) and that of the control group. However, the mean (±SD) postoperative pain score at 18 and 24 hours was 2.07 ± 0.64 and 2.07 ± 0.37 in the groups receiving bupivacaine and those receiving a combination of bupivacaine and tramadol, respectively, with P = 0.8825(18). The possible explanation for these discrepancies may be the differences in the study population.” However, there is no discrepancy in the study populations; both are pregnant women who underwent caesarean delivery and received similar pain management. The only difference is the study location. Please provide other plausible evidence if there is a difference in preoperative analgesics used, doses, and postoperative pain management practices.

Again, the authors noted that “According to another study by Gebremedhin et al., which involved 120 patients undergoing lower abdominal surgery, the median (IQR) pain severity (NRS) score was 0.0 (0-0) until 12 hours, and 1 (0–5) and 3 (1–5) at 18 and 24 hours in the local wound infiltration (LWI) groups with bupivacaine and tramadol (BT) compared to LWI bupivacaine alone (B) in the post-anesthesia care unit and ward. There was a notable difference in pain severity between the BT and B groups at the twelve-, eighteen-, and twenty-four-hour marks (p < 0.001) (44). However, in our study, there was also a significant difference at 2hr. The discrepancies may be due to the difference in study population, study design, and other confounding variables.” In addition to mentioned reasons, include type of surgery as main factor for discrepancy.

I would recommend to paraphrase the limitation as follows:

This study was of high quality due to its double-blinded design; however, it has some limitations. These include a lack of control over confounding variables such as incision size, the study being monocentric, the timing of uterine exteriorization, and a shorter duration of postoperative follow-up. Another limitation is that different obstetricians performed the wound infiltrations, which may have resulted in variations in the procedure of wound infiltration technique.

Please ensure the text is concise and engaging. You don't need to justify every difference; just focus on the pertinent points. Additionally, please proofread the language and grammar throughout the document. Otherwise, well done.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes:  Dereje Zewdu Assefa

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Dear Dr. Wonte,

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.

=ACADEMIC EDITOR:

Please submit your revised manuscript by Aug 08 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,

Regina (Rianne) L.M. van Boekel

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

Reviewer #3: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

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3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: I Don't Know

Reviewer #3: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: I am satisfied with the authors' responses and the resulting changes to the paper.........................

Reviewer #2: Mesay Milkias Wonte and colleagues addressed some of the points I raised but not others in my original review. Studies such as this one with vulnerable populations such as women who have given birth and have a responsibility to another person – their baby - have an ethical and medical responsibility to be as medically flawless as possible as other clinicians are liable to emulate their findings. This is one objective of studies. I am referring specifically to what seem to be controversies related to administering tramadol to women who have given birth and that the authors do not address this topic.

Objective of the study: As I wrote in my original review, the authors still do not describe their study as a replication study and validation of infiltrating the CSection incision with a mixture of tramadol and bupivacaine to their setting in Ethiopia. This seems to me a perfectly adequate aim. Though – as I wrote above - am not confident that administering tramadol in this population is medically justified.

Page 10 The authors still do not address the issue of which opioids are recommended vs not for women after C-Section and that there are warnings regarding use of tramadol. The authors assume that when the tramadol is infiltrated into the incision, absorption into the blood is probably not clinically significant. Is this assumption correct in pregnancy when vasculature is more extensive? However, even if this assumption is correct, after surgery, the tramadol was administered systemically. Whether orally or IV is not stated – this should be stated. I, therefore, suggest that the authors cannot avoid addressing the controversies related to tramadol.

Furthermore, it is possible that had they added an opioid to the spinal injection – rather than use a local anaesthesic only and administered other multi-modal treatments, eg 1-2 non-opioid groups round the clock - onset of pain may have been later and pain scores lower. I appreciate that this is a topic for a different study.

Methods

Rather than calculate means - which can be misleading , particularly in studies where pain is assessed - the authors should add the proportion of women who reported scores of ≥3/10 at all the time points assessed. This is missing and the authors compared their findings of pain with the Kumar et al. who assessed the proportion of women who reported scores of >4 at rest and movement-related and did not find differences between the study groups.

The authors did not correct for age – the age range of the sample is large (15 to 49 years) and some underwent at least one CSection. A child of 15 years old who has a CSection will not respond to pain in the same way as a women who is 49 and this is her second or more CSection. I appreciate that the groups are balanced, at least statistically, this respect.

Results

Minor Analgesic consumption – the units – mgs – is missing for average difference of tramadol between the groups. And for diclofenac.

For tramadol - is a mean difference of 10 mg between the groups clinically significant ?

The units of time are also missing under the mean difference for First Analgesia Request Time.

Again – is a mean of 15 minutes difference between the groups, clinically significant?

There is no need to write time at an accuracy of 3 digits after the decimal.

Discussion

Under limitations: that authors should add that assessment of pain after surgery was not multi-modal, it included only assessing pain at rest.

Minor - there is generally no need to repeat the actual findings in terms of data in the Discussion. This is the purpose of the Results section.

Last but one paragraph on page 12 – the authors are probably referring to the systemic doses (IV? Oral?) of the tramadol and diclofenac. Again – no need to include the actual data – this was reported in the Results section.

Reviewer #3: My comments are fully addressed; so, I endorse the acceptance of this paper at this stage as it adds knowledge to the existing literature.

**********

what does this mean? ). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: Yes:  Ruth Zaslansky, DSc

Reviewer #3: Yes:  Dereje Zewdu Assefa

**********

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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.

Dear Dr. Wonte,

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 11 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 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,

Dereje Zewdu Assefa, BSc, MSc

Academic Editor

PLOS ONE

Journal Requirements:

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. 

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

The manuscript has improved during the second round of revisions. However, the second reviewers raised critical questions that the authors need to address.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

Reviewer #3: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

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3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: N/A

Reviewer #3: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: (No Response)

Reviewer #3: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: No further comments..........................................................................................

Reviewer #2: The authors continue to avoid addressing the controversies related to tramadol in women who are pregnant and plan to breastfeed. The studies cited by the authors as indicating that tramadol is safe were not powered to detect side effects. The authors should be transparent about the use of tramadol in this cohort of women. Particularly if they wish that this form of treatment is to be employed by other clinicians.

In their reply the authors write:

>Even though tramadol is not recommended in pregnant mothers and lactating mothers, there are multitudes of studies >which are conducted in this area including the systematic review but none of >them reported any critical fetomaternal >incidents associated with the tramadol infiltration at the >wound site in normal healthy fit partuirents.

The authors admit that tramadol is not recommended in pregnant women and lactating mothers.

The study has now been carried out and if the editors of this journal wish to publish it – it does not seem ethical to me to avoid addressing the complexities of administering tramadol in this cohort of women even when the medication is infiltrated to the surgical incision. Availability of other published studies – not powered to detect side effects – is not justification to continue along these lines.

Furthermore, it is possible that women received tramadol systemically after the surgery. This is still unclear to me. Needs to be clarified. See below.

The authors write that

>None of the patients received tramadol orally or intravenously.

How was the tramadol (and diclofenac) after surgery administered? I cannot find that this is addressed in the Methods but it is in the Results, the authors write.

>Analgesia consumption

>The mean tramadol consumption was lower in a mixture of tramadol and bupivacaine group (BT) (140.00+48.06 mg) >than bupivacaine group (175.00+34.11 mg) with a statistically significant mean difference(MD) of 10.76 (95% CI, 13.45 >to 56.54), t (58) = 3.25, P= 0.002, (d=0.84). There was no significant difference in mean diclofenac consumption >between the two groups in a combination of tramadol and bupivacaine group (52.50+48.84 mg) than bupivacaine alone >group (57.50+46.95 mg), (P=0.69), (d=0.10).

How was this tramadol administered ?

In the discussion the authors write

>The efficacy of tramadol for the management of moderate to severe postoperative pain has been revealed in both >inpatients and day surgery patients. Most importantly, contrasting with other opioids, tramadol has no clinically >significant effects on respiratory or cardiovascular parameters. Tramadol may prove predominantly useful in patients >with limited cardiopulmonary function, including the aged, the obese, and smokers; in patients with impaired liver or >renal function; and in >patients in whom non-steroidal anti-inflammatory drugs are not suggested or need to be used with >caution (37).

This paragraph bears little relevance to women who have given birth.

The proportion of patients who report scores of 4/10 and above

I suggest that the authors create a table with the % of women in both groups whose scores are 4/10, displaying this information over time. This is a simple analysis to carry out and should not be expected of readers.

To compare the pain scores, they might use Mann-Whitney U test and correct for multiple comparisons.

The table can be included in the appendix as this is not the primary analysis.

In the Discussion, the authors cite the study carried out by Kumar M, Batra YK, Panda NB, Rajeev S, Nagi ON. Tramadol added to bupivacaine does not prolong analgesia of continuous psoas compartment block . Pain Pract. 2009;9(1):43-50.

These were patients undergoing total hip replacement and received a different block - and so I am not sure how this citation is relevant for discussion of the findings in the current study, unless the authors intend to review different procedures where bupivacaine and tramadol are used for infusion. Please clarify.

Minor.

Replication study. The authors address the strengths of a replication study in their reply to the editor but do not address this in their manuscript. Women undergoing CSection in many countries in the world, would benefit from improved treatment and so it is laudable that the authors are seeking better care for women in Ethiopia.

Reviewer #3: My comments are fully addressed. Given that this study adds knowledge to the existing literature, especially in resource-limited settings, I fully endorse the acceptance of this manuscript.

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Reviewer #1: No

Reviewer #2: Yes:  Do you want your identity to be public for this peer review? My identity can be public, for the sake of transparency. I am not seeking the recognition.

Reviewer #3: Yes:  Dereje Zewdu Assefa

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Dear Dr. Wonte,

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 Oct 25 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.

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We look forward to receiving your revised manuscript.

Kind regards,

Dereje Zewdu Assefa, BSc, MSc

Academic Editor

PLOS ONE

Journal Requirements:

1. 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. 

2. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments :

The manuscript has notably improved following the third round of revisions, and the authors have addressed several previous concerns with greater clarity. However, Reviewer 2 has raised important and critical points that still require your attention prior to acceptance.

In particular, the safety of tramadol use in breastfeeding mothers remains insufficiently addressed. Please provide a clear, transparent, and evidence-based discussion on the potential risks associated with tramadol exposure in neonates through breast milk. This should include documented effects such as respiratory depression or central nervous system depression, supported by relevant and current literature. Ensure that this safety consideration is prominently discussed in both the manuscript and any clinical recommendations derived from your findings.

Additionally, please upload the supplementary table as referenced in your response letter or manuscript, as it is currently missing from the submission.

We look forward to receiving a revised version that adequately addresses these final points.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #2: No

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #2: N/A

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #2: Yes

**********

Reviewer #2: Reply to the third revision

There is an ongoing to and fro with the authors about the safely of administering tramadol for lactating women.

As studies suggest that a significant proportion of people in Ethiopia may be CYP2D6 ultra-rapid metabolizers, medications such as tramadol and codeine increase the risk of adverse effects, especially in breastfeeding infants.

The authors write that they ‘We have added clarification in the manuscript to reflect this context and

referenced relevant safety guidelines’

Where are these citations? .

Recent guidelines such as the 2021 NICE guidelines: Caesarean birth [F] Opioids for pain relief after caesarean birth

https://www.nice.org.uk/guidance/ng192/evidence/f-opioids-for-pain-relief-after-caesarean-birth-pdf-9071941651

Opioid analgesia for women who have had a spinal/epidural anaesthesia: The committee noted that (in studies which used spinal anaesthesia) **** morphine was more effective than pethidine (also known as meperidine) for pain relief and had less impact on breastfeeding.**** Oral oxycodone was more effective than IV morphine or IV oxycodone at reducing the incidence of moderate and severe pain, with less nausea and vomiting. However, the committee discussed that the FDA and American Academy of Paediatrics advise that oxycodone (as well as codeine and tramadol) increases the risk of neonatal sedation and respiratory depression, and that oral morphine or the less commonly-used 18 Caesarean birth: evidence reviews for opioids as pain relief FINAL (March 2021) FINAL Opioids for pain relief hydromorphone may be suitable alternatives. In addition, the MHRA has issued a warning advising that codeine should not be taken by breastfeeding mothers. ****The committee noted that codeine and tramadol can be particularly problematic in up to 28% of women who are CYP2D6 ultra-rapid metabolisers and who convert these drugs to morphine rapidly, leading to high morphine levels in their breast milk.****

The FDA warn against use of tramadol

Codeine and Tramadol Medicines: Drug Safety Communication - Restricting Use in Children, Recommending Against Use in Breastfeeding Women | American Society of Anesthesiologists (ASA) April 27, 2017

• A strengthened Warning to mothers that breastfeeding is not recommended when taking codeine or tramadol medicines due to the risk of serious adverse reactions in breastfed infants. These can include excess sleepiness, difficulty breastfeeding, or serious breathing problems that could result in death.

Text such as the authors write in their reply to the reviewers should be included in the article itself. For example: Tramadol is not routinely recommended during breastfeeding due to potential neonatal risks (REFS), this is particularly relevant in CYP2D6 ultra-rapid metabolizers, however, we (the authors) suggest that these neonatal risks are minimized by minimizing the duration of drug exposure, reducing the dosage or administering lowest effective dose, and choosing the appropriate routes which have least absorption to breast milk are recommended’.

Details from the FDA Communication (April 20, 2017)

• Strengthened Warning: The FDA added a Contraindication to tramadol’s label, explicitly advising against its use during breastfeeding for safety reasons U.S. Food and Drug AdministrationASA.

• Explanation: Tramadol and its active metabolite (O desmethyltramadol) are present in breast milk. Mothers who are CYP2D6 ultra rapid metabolizers may convert tramadol more quickly to its active form, increasing the risk of infant overdose via breast milk U.S. Food and Drug Administration+1.

• FDA Recommendation: The agency urges both healthcare professionals and breastfeeding women to avoid codeine and tramadol and to consider safer alternative

How was the tramadol (and diclofenac) after surgery administered? I

cannot find that this is addressed in the Methods but it is in the Results, the authors

write. How was this tramadol administered.

According to the authors:

1. It was infiltrated into the wound

2. For shivering – not clear was tramadol or pethidine administered for shivering ?

3. After surgery – IV tramadol with IM diclofenac. Why is this not stated clearly in the methods?

The proportion of patients who report scores of 4/10 and above.

I have not been able to access the supplementary table.

**********

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Reviewer #2: Yes:  Ruth Zaslansky, DSc

**********

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Analgesic Effectiveness of Wound Infiltration with Bupivacaine versus a Mixture of Bupivacaine and Tramadol for Postoperative Pain Management among Parturients Undergoing Elective Cesarean Section under Spinal Anesthesia:A Randomized Controlled Trial

PONE-D-25-04955R4

Dear Dr. Wonte,

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.

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Kind regards,

Dereje Zewdu Assefa, BSc, MSc

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 #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: Yes

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: No

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

Reviewer #1: Again, there is nothing else for me to add. Again, there is nothing else for me to add. Again, there is nothing else for me to add.

Reviewer #2: This is the 4th round of revisions.

The editors have decided to accept this manuscript.

I have no further comments.

**********

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: Yes:  Ruth Zaslansky, DSc

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