Cannabinoids versus placebo for pain: A systematic review with meta-analysis and Trial Sequential Analysis

Jehad Barakji; Steven Kwasi Korang; Joshua Feinberg; Mathias Maagaard; Ole Mathiesen; Christian Gluud; Janus Christian Jakobsen

doi:10.1371/journal.pone.0267420

Peer Review History

Original SubmissionApril 7, 2022
16 Jun 2022 Decision Letter - Tariq Jamal Siddiqi, Editor PONE-D-22-10156Cannabinoids versus placebo for pain: a systematic review with meta-analysis and Trial Sequential AnalysisPLOS ONE Dear Dr. Barakji, 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 Jul 31 2022 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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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. Please ensure that you refer to Figures 2-5 in your text as, if accepted, production will need this reference to link the reader to the figure. 3. Please include your tables as part of your main manuscript and remove the individual files. Please note that supplementary tables (should remain/ be uploaded) as separate "supporting information" files. 4. 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. 5. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed: - https://bmjopen.bmj.com/content/9/10/e031574 In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed. [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? 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 ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 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 ****** 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: No ****** 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: 1. Don’t use short forms like TSA directly in the abstract. 2. Introduction: Please improve upon the Introduction. There should be use of a variety of sentence structures, if possible. Importantly, the gaps in current literature and consequently the rationale for this review remain unclear and should be elaborated upon further in the Introduction. Secondly, please discuss both acute and chronic pain while briefly outlining the comparison of cannabinoids with other relevant treatment therapies for pain. Thirdly, briefly outline the please discuss current guideline recommendations, if any. You may find the following paper useful: https://www.cadth.ca/sites/default/files/pdf/htis/2019/RC1153%20Cannabis%20Chronic%20Pain%20Final.pdf 3. Methods: Please cite “visual analogue scale (VAS) or numerical rating scale (NRS)”. Additionally, please elaborate upon the use of 95% and 98% confidence intervals for dichotomous outcomes – “We calculated risk ratios (RRs) with 95% and 98% confidence intervals (CIs) for our dichotomous outcomes”. 4. Results: The detailed analysis of the data at hand is commendable. Please state an insignificant p value as there being no difference between the cannabinoid and placebo groups, for instance for “Meta-analysis indicated that cannabinoids increased the risk of serious adverse events (RR 1.18; 98% CI 0.95 to 1.45; P = 0.07; low certainty of evidence; Supplementary figure 27).” 5. Use the short form for “Trial Sequential Analysis” as TSA after mentioning the full-form once initially. Also, state the full form of GRADE. 6. Discussion: Please discuss, compare, and contrast findings of other studies with your findings instead of merely stating “Our findings are in contrast to the majority of previous reviews which have indicated an adequate analgesic effect of cannabinoids and supported the use of cannabinoids for the treatment of chronic pain. 20-23 111 112 Our findings suggest that cannabinoids reduced chronic pain when compared with placebo, however, whether this effect is clinically important seems questionable. Our findings regarding cancer pain and acute pain are in line with previous reviews on this topic.113- 115”. Also, improve upon the structure and quality of the Discussion section in general. 7. References: Avoid the use of references more than 10 years old. ****** 6. PLOS authors have the option to publish the peer review history of their article (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: Yes: Warda Ahmed ******** [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.0267420.r001
Revision 1
14 Jul 2022 Author Response 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. This has been addressed. We have changed the reference style. The headings have been changed according to the PLOS ONE requirements. Figure and table caption have been inserted directly after they have been cited in the text. 2. Please ensure that you refer to Figures 2-5 in your text as, if accepted, production will need this reference to link the reader to the figure. Figures 2-5 are now referred to in the text. 3. Please include your tables as part of your main manuscript and remove the individual files. Please note that supplementary tables (should remain/ be uploaded) as separate "supporting information" files. We have now included the “Table 1: Table of included studies” in our manuscript. 4. 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. We have now included a paragraph of our supporting information files at the end of the manuscript. This includes captions of all the supplemental files. 5. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed: - https://bmjopen.bmj.com/content/9/10/e031574 We have now rephrased and changes the sentence structure of the introduction section in order to avoid overlapping text with the above mentioned publication. In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed. We have carefully checked that all sources are cited and that there is no duplicated text outside the methods section. Reviewer response: 1.Don’t use short forms like TSA directly in the abstract. We have changed this accordingly 2. Introduction: Please improve upon the Introduction. There should be use of a variety of sentence structures, if possible. Importantly, the gaps in current literature and consequently the rationale for this review remain unclear and should be elaborated upon further in the Introduction. Secondly, please discuss both acute and chronic pain while briefly outlining the comparison of cannabinoids with other relevant treatment therapies for pain. Thirdly, briefly outline the please discuss current guideline recommendations, if any. You may find the following paper useful: https://www.cadth.ca/sites/default/files/pdf/htis/2019/RC1153%20Cannabis%20Chronic%20Pain%20Final.pdf The introduction has now been revised and separated into different sections to provide a better overview. We have tried to describe the difference between acute pain, chronic pain and cancer pain more in depth while trying to included current guideline recommendations. We thank the reviewer for this suggestion. We have also tried to clarify the rational for this systematic review further in the end of the introduction section. 3. Methods: Please cite “visual analogue scale (VAS) or numerical rating scale (NRS)”. Additionally, please elaborate upon the use of 95% and 98% confidence intervals for dichotomous outcomes – “We calculated risk ratios (RRs) with 95% and 98% confidence intervals (CIs) for our dichotomous outcomes”. We have now cited the visual analogue scale (VAS) or numerical rating scale (NRS) in the methods section. We have also elaborated upon the use of two different confidence intervals. This rationale has also been described in the section “Assessment of statistical and clinical significance" previously, therefore we have also referred to this section. 4. Results: The detailed analysis of the data at hand is commendable. Please state an insignificant p value as there being no difference between the cannabinoid and placebo groups, for instance for “Meta-analysis indicated that cannabinoids increased the risk of serious adverse events (RR 1.18; 98% CI 0.95 to 1.45; P = 0.07; low certainty of evidence; Supplementary figure 27).” We have changed this to “Meta-analysis showed no evidence of a difference between cannabinoids versus placebo (RR 1.18; 98% CI 0.95 to 1.45; P = 0.07; low certainty of evidence; Fig 3, Supplementary figure 27)”. 5. Use the short form for “Trial Sequential Analysis” as TSA after mentioning the full-form once initially. Also, state the full form of GRADE. We have changed this accordingly. 6. Discussion: Please discuss, compare, and contrast findings of other studies with your findings instead of merely stating “Our findings are in contrast to the majority of previous reviews which have indicated an adequate analgesic effect of cannabinoids and supported the use of cannabinoids for the treatment of chronic pain. 20-23 111 112 Our findings suggest that cannabinoids reduced chronic pain when compared with placebo, however, whether this effect is clinically important seems questionable. Our findings regarding cancer pain and acute pain are in line with previous reviews on this topic.113- 115”. Also, improve upon the structure and quality of the Discussion section in general. We have included the position paper of the IASP and compared our results to the findings of the IASP. Further, we have divided the discussion section into several parts to improve the structure. Therefore the following sections appear in the discussion section: “Strengths”, “Limitations” and “Minimal important difference”. 7. References: Avoid the use of references more than 10 years old. We thank the peer reviewer for this advice. This has been taken into consideration. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0267420.r002
17 Aug 2022 Decision Letter - Tariq Jamal Siddiqi, Editor Cannabinoids versus placebo for pain: a systematic review with meta-analysis and Trial Sequential Analysis PONE-D-22-10156R1 Dear Dr. Barakji, 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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. 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, Tariq Jamal Siddiqi Academic Editor PLOS ONE Additional Editor Comments (optional): 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 #2: All comments have been addressed ******** 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 #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: Yes ****** 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 #2: Yes ****** 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 #2: Yes ****** 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 #2: (No Response) ****** 7. PLOS authors have the option to publish the peer review history of their article (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 #2: No ******** https://doi.org/10.1371/journal.pone.0267420.r003
Formally Accepted
19 Aug 2022 Acceptance Letter - Tariq Jamal Siddiqi, Editor PONE-D-22-10156R1 Cannabinoids versus placebo for pain: a systematic review with meta-analysis and Trial Sequential Analysis Dear Dr. Barakji: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. 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. If we can help with anything else, please email us at plosone@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. Tariq Jamal Siddiqi Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0267420.r004

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