PONE-D-24-19288

Impact of Vitamin C on the Reduction of Opioid Consumption for Acute Musculoskeletal Pain: A Double-Blind Randomized Control Pilot Study

PLOS ONE

Dear Dr. Daoust,

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:

The authors conducted a double-blind randomized pilot study to evaluate the effect of vitamin C on reducing opioid consumption in patients treated in the emergency department for acute musculoskeletal pain. They compared a group receiving 1 g of vitamin C twice daily for 14 days to a placebo group, both with a standardized opioid prescription. The results show that while the median morphine consumption was similar between the two groups, the naproxen consumption was significantly lower in the vitamin C group. 

The manuscript is well-written, and the authors have appropriately acknowledged the limitations resulting from the small sample size.

1) I suggest authors to integrate the study rationale into the introduction section of the manuscript ; 

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Axel Benhamed, M.D, MSc

Academic Editor

PLOS ONE

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 [This research was supported by the « Fonds Alma Mater et Chaire Docteur Sadok Besrour de l’Université de Montréal », the « Association des spécialistes en médecine d’urgence du Québec » and the « Fonds des Urgentistes de l’Hôpital du Sacré-Cœur de Montréal ».].  

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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?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: I Don't Know

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: As the statistical reviewer I will focus on methods and reporting. All looks reasonable but I was confused because the outcome for the future trial was not covered. one of the major aims of feasibility outcomes is to assess the outcome of interest for the future trial, obtain estimates of variability and reasonable effectiveness levels - that does not seem to be the case here or I have missed it. A section is needed on the next steps and what information could be used for the future trial, ideally a power calculation towards that.

Reviewer #2: General comments: This article presents a clinical trial evaluating the value of vitamin C in reducing morphine consumption in musculoskeletal pain. Patients are recruited for the study from the emergency departments in which they present. This article should be seen in the context of the "opioid crisis", which is affecting the USA in the main, but also Canada and to a lesser extent European countries.

The authors present this clinical trial as a feasibility study. It should make it possible to collect data on opioid and analgesic consumption in the study population after a visit to the emergency department for musculoskeletal trauma. It will also specify the pain scores of these patients over the fortnight following the emergency visit.

The study is monocentric. These quality criteria include prior publication of the protocol (reference 36) and adherence to CONSORT recommendations. Consecutive patients were recruited during the day on weekdays. There is no reason why this limitation of the inclusion period to the day should lead to a substantial bias in the results.

The authors' conclusions are correct for a feasibility study, identifying weaknesses in recruitment that need to be addressed. However, the authors should develop their hypothesis at greater length to explain the difference between per-protocol analysis and intention-to-treat analysis, which is theoretically the most appropriate method for analyzing a clinical trial. However, the intention-to-treat analysis, which shows a higher consumption of morphine in the vitamin C group, "in theory", does not really go in the direction intended by the authors. A lack of power cannot be invoked, since the inclusion of additional patients has methodologically no reason to change the direction of the difference. The authors therefore need to explain why they believe that the intention-to-treat analysis of this small feasibility study (which, it is true, is not designed to conclude on the efficacy of the treatment) is not predictive of a result in a future clinical trial.

Specific comments:

The authors' assertion associated with reference 25 that vitamin C is a drug with very low toxicity, even if globally acceptable, could be tempered by a recent article on vitamin C and sepsis in intensive care, which was associated in this clinical trial with excess mortality in the vitamin C group.

It seems to me that one piece of information is missing from the study's rationale: what is the percentage of opioid prescriptions in musculoskeletal trauma patients in the authors' department where this clinical trial is taking place, based on retrospective data, and what other therapeutic classes are used? These figures could be compared with, if available, similar data from other publications in Canada, the USA or Europe.

In the paragraph on vitamin C on page 6, the authors could indicate that the doses delivered are far in excess of physiological vitamin C requirements.

The authors indicate a median consent rate of 72% and a median retention rate of 88%. Could they clarify the definition of these two rates, as I don't understand why the retention rate is higher than the consent rate, unless the 88% is itself related to patients who have already consented.

In Table 2, the authors note several important differences between the vitamin C group and the placebo group (sex ratio, paracetamol, etc.). Would it be possible to have a column with the "p's" (as requested for the other tables)? If I've understood correctly, the authors attribute these differences to chance, due to the small number of patients compared?

The level of pain intensity above 7 confirms that this is severe pain, for which the recommendations are indeed to obtain a morphine prescription. However, pain intensity at admission cannot prejudge pain intensity at discharge from the emergency department, especially in patients with immobilization, which is itself highly analgesic. It would therefore be interesting to have the discharge VAS from Table 1.

Concerning pain intensity, as shown in figure 3, it can be seen that on average, both in per-protocol analysis and even more so in intention-to-treat analysis, pain was greater by between half and one VAS point each day in the vitamin C group. What was the statistical test used to compare these two series in figure 3? It seems to me that they can be treated as Kaplan-Meier curves.

Reviewer #3: Dear authors,

Thank you for the opportunity to review this article. The aim of this pilot study was to assess the feasibility of conducting a randomized, placebo-controlled trial to determine the opioid-sparing and analgesic effects of vitamin C compared to placebo(lactose) over a two-week follow-up period in ED-discharged patients with acute musculoskeletal (MSK) injuries.

Minor comments :

Some texts in the introduction seem to repeat themselves with slight nuances. For example, on page 3:

"Currently, the main strategy employed to reduce opioid consumption is to limit the rate and quantity of opioids prescribed for acute pain.[12-15] However, most interventions reduce opioid prescription rates, but not the quantity of prescribed opioids.[16]"

These two sentences should be combined to avoid repetition. Please review the flow of the introduction to eliminate this type of redundancy.

Methods :

* Patient and Public Involvement : please note the reference of ethic comitee.

Discussion :

Results should only appear in the results section. For example :

* "The main barriers were the high refusal rate (41%) by eligible patients, mainly because they lacked interest for the study, were in too much pain and did not have enough time to participate" OR "Our median (IQR) retention rate of 75% is lower than the 88% (80%-97%) reported in the same review"

Major comment :

To enhance the comprehensiveness of the article, I recommend incorporating a more detailed discussion of the pathophysiology, either in the introduction or the discussion section. This will provide a better understanding of the mechanisms by which vitamin C exerts its effects in this context.

Reviewer #4: I would like to thank the authors for giving me the opportunity to review this article.

The aim of this study was to assess the feasibility of conducting a randomized, placebo- controlled trial to determine the opioid-sparing and analgesic effects of vitamin C over a two-week follow-up period in ED-discharged patients with acute musculoskeletal injuries. So, the main outcome for feasibility was the recruitment rate. This work is very clearly presented and the article is well constructed. However, I fail to understand its purpose and the importance of the main result. Especially as the expected number of patients was not reached, with a high rate of loss to follow-up (25%), giving the opposite impression to that suggested by the authors. In this context, I find it very difficult to have an opinion on the scientific interest of such a publication.

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Reviewer #1: No

Reviewer #2: Yes: JOLY Luc-Marie, Univ Rouen Normandy, Universitary Hospital of Rouen, Emergency Medicine Department, F-76000 Rouen, France

Reviewer #3: No

Reviewer #4: No

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Impact of Vitamin C on the Reduction of Opioid Consumption for Acute Musculoskeletal Pain: A Double-Blind Randomized Control Pilot Study

PONE-D-24-19288R1

Dear Dr. Raoul Daoust

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.

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Kind regards,

Axel Benhamed, M.D, MSc

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Dear Authors,

Thank you for submitting the revised version of your manuscript to PLOS ONE and for the effort you have dedicated to addressing the reviewers’ comments.

After a thorough review of your revisions, I am pleased to note that you have adequately and thoughtfully addressed the concerns raised during the initial assessment. Your responses are well-reasoned, detailed, and enhance the overall quality and clarity of the manuscript.

I am therefore delighted to inform you that your article has been accepted for publication in PLOS ONE.

Congratulations on your work, and thank you for choosing PLOS ONE as the platform to share your research. We look forward to seeing the impact of your findings within the scientific community.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #5: All comments have been addressed

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #5: Yes

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

Reviewer #1: Yes

Reviewer #5: I Don't Know

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: (No Response)

Reviewer #5: Yes

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #5: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

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

Reviewer #5: Thanks for the opportunity to review this revised manuscript. I have read through the comments from previous reviewers and the revised manuscript and agree that all comments have been addressed. I am not as concerned as the previous reviewers about the clinical outcomes being reported as per protocol versus intention-to-treat analysis, as this is not the primary concern of a pilot trial. I would encourage the authors to report the main trial as intention-to-treat, unless they have a very well justified reason to use per-protocol. I look forward to seeing further investigation on this interesting topic.

Best wishes,

Caitlin

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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 #5: Yes: Caitlin Jones

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