Motivations, perceived risk, and tampering of XTAMPZA ER and abuse-deterrent opioid drugs

Hannah L. Burkett; Richard C. Dart; Joshua C. Black

doi:10.1371/journal.pone.0332574

Peer Review History

Original SubmissionAugust 14, 2024
17 Dec 2024 Decision Letter - Amisha Raikar, Editor Dear Dr. Burkett, 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. ============================== COMMENTS OF ACADEMIC EDITOR: ============================== Please submit your revised manuscript by Jan 31 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, Amisha Raikar, Guest Editor PLOS ONE Journal requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section. 3. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section. 4. Your abstract cannot contain citations. Please only include citations in the body text of the manuscript, and ensure that they remain in ascending numerical order on first mention. 5. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. Additional Editor Comments : 1. Revise the objective to succinctly state the purpose and method of the study in more accessible terms. 2. Provide a brief background on ADFs and their purpose before moving to specific examples like XTAMPZA ER. 3. While the DAST-10 threshold for substance use disorder is mentioned, include a brief justification for using this specific tool and how it contributes to the study outcomes. 4. Some sentences are very long and packed with multiple pieces of information. Break them into shorter, clearer sentences to improve readability. 5. Consider defining terms like "RADARS System" and "DAST-10" for readers who may not be familiar with these methodologies. 6. In the discussion section, the ideas are densely packed and occasionally jump between topics (e.g., tampering behaviors, prescribing practices, and study strengths). Consider organizing the discussion into distinct paragraphs for each main topic (e.g., prevalence of NMU, tampering motivations, prescribing practices, study strengths, and limitations). 6. Expand on the implications of using real-world evidence (RWE) in post-market surveillance and how this study aligns with FDA guidance. Consider tying this to broader trends in RWE uses for regulatory decision-making [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? Reviewer #1: No Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: No Reviewer #2: No ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: Thank you for giving me the opportunity to review the manuscript. I read it with interest. This study addresses an important public health problem in the U.S. regarding the prevention of misuse and harmful outcomes associated with non-medical use of opioids. The authors attempt to explore the usefulness of XTAMPZA ER through a survey-based approach. The Abuse-deterrent formulations (ADF) encouraged by the FDA could be effective in preventing the inappropriate use of opioids. The ADF can protect against the unintentional use of opioids to achieve a feeling of euphoria; it will avoid a sharp increase in blood opioid concentration level. As a consequence, the ADF would be considered to reduce the incidence of opioid abuse and acute poisoning. Examining the effectiveness of the ADF is crucial for national institutes developing policies against the opioid crisis, citizens exposed to the danger of harm from opioids, and the ADF opioid manufacturers. While the evidence of the ADF is sought, it is challenging to study the cases of non-medical use of opioids in the community, as the authors wrote. The authors conducted an online survey using the RADARS System. However, I think this survey could not achieve the authors' aim because of the issue of the online panel. The respondents of this survey are limited to non-medical use opioid survivors. And vice versa, people who had died or experienced severe harm by the non-medical use of opioids could not answer this survey. Thus, I think that this study could not show the actual effect of ADF on non-medical use of opioids. Moreover, the result that only 628 of 9158 respondents answered the follow-up survey suggests that the respondents might be biased toward those with high literacy. People who do not have high literacy may use and tamper more than respondents. In the results section, the authors indicated that responders can endorse more than one drug. In other words, each drug group includes concomitant use of other formula opioids. Therefore, I assume that these results could not show the actual number of regarding characteristics, tampering, and other items in only XTAMPZA ER use. I am also wondering why the authors did not consider the consumption of XTAMPZA ER and the opioids used as a comparator in this study. For these reasons, I'm afraid I have to disagree with the author's conclusion: "Among similar drugs, XTAMPZA ER was not the drug of choice for non-medical use, and popular methods of tampering may not involve increased risk of harmful outcomes." To better address the research objectives, I suggest that authors consider combining the results of several surveys derived from different data sources in future studies. Consider Mortality Records, Emergency Department Visit and Hospitalization data, Poison Center data, etc. While the study addresses an important issue, the limitations in the methodology significantly constrain its ability to answer the research question. For these reasons, I recommend rejecting the manuscript in its current form. However, the study topic remains important, and I encourage the authors to consider revising their approach to better align with their research objectives. Reviewer #2: The authors present an interesting study that warrants discussion. Given the ongoing opioid epidemic, the public health implications that studies of this nature explore are noteworthy. While the present study raises important questions regarding a public health crisis, I do have a few questions and suggestions. There are multiple sentences that are confusing (e.g., sentence starting on line 73). Introduction • ER is clarified as “extended-release” in the first paragraph and does not need to be re-clarified again (e.g., start of the third paragraph). • See previous comment for immediate release (IR). • What is the nationally representative survey participants were recruited from? Methods • I am confused about what survey participants were pulled from. You mention RADARS and NMURx, but it is not clear how both surveys were utilized in this study. • The first paragraph needs to be split into two. • The description of each of the focal variables is difficult to discern since everything is mentioned in a single paragraph. There is no mention of the sociodemographic variables (mentioned in the results section). Results • I think there is a formatting issue with the sub-header lines for “Figure 1…” and for “Figure 2…” Discussion • You do not clarify what the abbreviation of FDA refers to, even though it is a commonly discussed agency in the US. You mention the agency’s full name earlier in the paper, but do not include the abbreviation. ****** what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy Reviewer #1: No Reviewer #2: No ******** [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. Attachments Attachment Submitted filename: PLOS ONE_XTAMPZA ER.docx https://doi.org/10.1371/journal.pone.0332574.r001
Revision 1
28 Jan 2025 Author Response To the editors: Thank you for your interest and the opportunity to revise our manuscript. We have responded to the reviewer comments below and uploaded a modified manuscript for consideration. We have also updated manuscript formatting based on the PLOS One style guide. Editor Comment 1: Revise the objective to succinctly state the purpose and method of the study in more accessible terms. AUTHOR RESPONSE EDITOR COMMENT 1: We have revised the objective and stated it plainly beginning on line 107. Editor Comment 2: Provide a brief background on ADFs and their purpose before moving to specific examples like XTAMPZA ER. AUTHOR RESPONSE EDITOR COMMENT 2: We added a sentence describing that ADF’s are an intervention to reduce the risks of ER opioid misuse by creating physical barriers to tampering beginning on line 56. Editor Comment 3: While the DAST-10 threshold for substance use disorder is mentioned, include a brief justification for using this specific tool and how it contributes to the study outcomes. AUTHOR RESPONSE EDITOR COMMENT 3: We added description of why we characterized the sample in terms of problematic drug use behavior beginning on line 110 and a description of the DAST-10 validated instrument beginning on line 153. Editor Comment 4: Some sentences are very long and packed with multiple pieces of information. Break them into shorter, clearer sentences to improve readability. AUTHOR RESPONSE EDITOR COMMENT 4: We edited the full manuscript and broke up sentences and paragraphs where necessary to improve readability. Editor Comment 5: Consider defining terms like "RADARS System" and "DAST-10" for readers who may not be familiar with these methodologies. AUTHOR RESPONSE EDITOR COMMENT 5: We removed mention of the RADARS System and added a description of the DAST-10 beginning on line 153. We reviewed the manuscript for additional terms which were possibly not well defined and added more complete definitions. Editor Comment 6: In the discussion section, the ideas are densely packed and occasionally jump between topics (e.g., tampering behaviors, prescribing practices, and study strengths). Consider organizing the discussion into distinct paragraphs for each main topic (e.g., prevalence of NMU, tampering motivations, prescribing practices, study strengths, and limitations). AUTHOR RESPONSE EDITOR COMMENT 6: We have reorganized the discussion section by main topics, ensuring multiple topics do not appear within the same paragraph. Editor Comment 7: Expand on the implications of using real-world evidence (RWE) in post-market surveillance and how this study aligns with FDA guidance. Consider tying this to broader trends in RWE uses for regulatory decision-making AUTHOR RESPONSE EDITOR COMMENT 7: We added a deeper discussion of the need for real-world evidence in post-marketing surveillance as well as a description of how our study meets those needs beginning on line 267. Reviewer #1 Comment 1: The authors conducted an online survey using the RADARS System. However, I think this survey could not achieve the authors' aim because of the issue of the online panel. The respondents of this survey are limited to non-medical use opioid survivors. And vice versa, people who had died or experienced severe harm by the non-medical use of opioids could not answer this survey. Thus, I think that this study could not show the actual effect of ADF on non-medical use of opioids. AUTHOR RESPONSE 1: Survivor bias is a limitation of this study as it would be with any data source that uses retrospective self-reported individual level data. I have added this as a limitation to the current study beginning on line 320. Comment 2: Moreover, the result that only 628 of 9158 respondents answered the follow-up survey suggests that the respondents might be biased toward those with high literacy. People who do not have high literacy may use and tamper more than respondents. AUTHOR RESPONSE 2: Of the 9,158 respondents who were invited to initiate the follow-up survey, 2,186 initiated the follow up survey, but only 738 were eligible to complete the survey based on past year reported NMU. This information is clarified beginning on line 189. Comment 3: In the results section, the authors indicated that responders can endorse more than one drug. In other words, each drug group includes concomitant use of other formula opioids. Therefore, I assume that these results could not show the actual number of regarding characteristics, tampering, and other items in only XTAMPZA ER use. AUTHOR RESPONSE 3: Respondents who endorsed more than one product were asked all relevant follow up questions separately in regards to each product. All reported metrics are specific to the products in each drug group presented. Comment 4: I am also wondering why the authors did not consider the consumption of XTAMPZA ER and the opioids used as a comparator in this study. AUTHOR RESPONSE 4: Consumption of XTAMPZA ER by several routes was considered and described in Table 2. Comment 5: For these reasons, I'm afraid I have to disagree with the author's conclusion: "Among similar drugs, XTAMPZA ER was not the drug of choice for non-medical use, and popular methods of tampering may not involve increased risk of harmful outcomes." AUTHOR RESPONSE 5: Among adults that reported NMU of a qualifying product, less than 3% reported XTAMPZA ER as their preferred drug. We have added clarification in the results and discussion sections that all conclusions are specific to the sample of adults reporting NMU. Comment 6: To better address the research objectives, I suggest that authors consider combining the results of several surveys derived from different data sources in future studies. Consider Mortality Records, Emergency Department Visit and Hospitalization data, Poison Center data, etc. AUTHOR RESPONSE 6: The objective of this work is to characterize how adults who report NMU of ADF products and their comparators use and tamper with these products in a community setting. This requires self-reported data sampled from the general population to capture adults who do not interact with the healthcare system. The goal of this work is to compliment the clinical studies that have been conducted. Such a study using clinical data has already been published by our group: https://doi.org/10.1093/pm/pnaa272. This work expands upon the past work by adding information from those in a community setting. Comment 7: While the study addresses an important issue, the limitations in the methodology significantly constrain its ability to answer the research question. For these reasons, I recommend rejecting the manuscript in its current form. However, the study topic remains important, and I encourage the authors to consider revising their approach to better align with their research objectives. AUTHOR RESPONSE 7: The research objective has been more clearly stated beginning on line 101. The manuscript has been reframed to more directly meet those objectives. Reviewer #2 Comment 1: There are multiple sentences that are confusing (e.g., sentence starting on line 73). AUTHOR RESPONSE 1: We have edited the full manuscript and updated any sentences that were confusing. Comment 2: ER is clarified as “extended-release” in the first paragraph and does not need to be re-clarified again (e.g., start of the third paragraph). AUTHOR RESPONSE 2: We removed the clarification. Comment 3: See previous comment for immediate release (IR). AUTHOR RESPONSE 3: We removed the clarification. Comment 4: What is the nationally representative survey participants were recruited from? AUTHOR RESPONSE 4: The nationally representative survey is the Survey of Non-Medical Use of Prescription Drugs (NMURx) routine survey. We added this clarification beginning on line 117. Comment 5: I am confused about what survey participants were pulled from. You mention RADARS and NMURx, but it is not clear how both surveys were utilized in this study. AUTHOR RESPONSE 5: Survey participants for the follow-up survey were recruited from the NMURx routine survey which is launched 2 times annually as part of the RADARS system. We have removed reference to RADARS as it is not directly relevant and reworked the methods section to clearly describe the two NMURx surveys and how they were each used for this research. Past validation studies for the NMURx survey are cited. Comment 6: The first paragraph [of the methods] needs to be split into two. AUTHOR RESPONSE 6: We split the first paragraph of the methods into one paragraph describing the routine NMURx survey and a second paragraph describing the follow-up survey. Comment 7: The description of each of the focal variables is difficult to discern since everything is mentioned in a single paragraph. AUTHOR RESPONSE 7: We have reorganized the methods section to describe each of the variables one at a time split thoughtfully into 3 paragraphs. Comment 8: There is no mention of the sociodemographic variables (mentioned in the results section). AUTHOR RESPONSE 8: We added a description of the sociodemographic variables taken from the routine NMURx survey beginning on line 136. Comment 9: I think there is a formatting issue with the sub-header lines for “Figure 1…” and for “Figure 2…” AUTHOR RESPONSE 9: We have updated the sub-headers to both figures and addressed the formatting errors. Comment 9: You do not clarify what the abbreviation of FDA refers to, even though it is a commonly discussed agency in the US. You mention the agency’s full name earlier in the paper, but do not include the abbreviation. AUTHOR RESPONSE 9: We added a clarifying abbreviation following the first mention of the agency’s full name on line 91. Attachments Attachment Submitted filename: Author Response.docx https://doi.org/10.1371/journal.pone.0332574.r002
20 Mar 2025 Decision Letter - Amisha Raikar, Editor Dear Dr. Burkett, 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 May 04 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, Amisha Raikar, Master of Pharmaceutics Guest Editor PLOS ONE Journal Requirements: 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. Comments to the Author Reviewer #1: (No Response) Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #1: Partly Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: N/A Reviewer #2: Yes ****** 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: No ****** Reviewer #1: Thank you for answering my comments and revising your manuscript. I have additional comments to improve your manuscript to make it better. Abstract (1) Line 18: I could not understand the meaning of the term "drug use profiles" until I read the Discussion(line 227). I recommend that the authors add some explanation. (2) Line 20: I guess 16� is "non-"ADF ER. (3) Are decimal points in percentages rounded down? Is it rounded off? It does not seem to be consistent. Materials and Methods (1) Even if the authors wrote about the sponsor of this research in Acknowledgment, I think that it should also be written in Materials and Methods. (2) Line 106-� I understand the classification of comparable products, however, I could not know how the authors chose comparable products. Additionally, the list of products should be shown in a table. (3) Lines 30-43: The authors wrote the number of participants. It should also be shown as a flow diagram. (4) The questionnaire of this survey should be shown. Result (1) Table 2: In the "Reason for Tampering", "To increase the high feeling from the pill", "To improve the pain relief from the pill", and "To feel the effects of the pill more quickly" should be separate from other items. I think that "To swallow", "inject", "smoke or vape", and "snort" mean only change the route, do not mean the reasons. These are different concepts. (2) Table 2: In the "Risk Behaviors and Outcomes" should be distinguished from "Risk Behaviors" and "Outcomes". (3) Figures should be improved. I can imagine what the authors want to show in the Figures, however, it is unclear on what basis each point is placed in its respective position. I know the two X axes show "mean difficulty" and "mean perceived risk of tampering", respectively. The actual value of the respective means should also be specified somewhere. Discussion (1) Lines 214: The figures 33.8� and 7.7% are not shown in the Result section and Tables. It is unfriendly for readers. I recommend that the authors show these in the Results section. (2) The number of consumptions, the number of prescriptions dispensed, or the ratio of the products surveyed in this study in the US is required. If XTAMPZA is not commonly prescribed and distributed in the US, the number of participants who non-medically use XTAMPZA will also be small. Reviewer #2: I appreciate the author’s response to my comments. I have some additional suggestions listed below. Please double-check punctions and grammar. Introduction • There is an extra “.” On line 41. • Need to capitalize the start of the sentence on line 74. • Missing a period at the end of the sentence on line 76. • There is an extra “.” and “,” on line 80. • You explain what NMU stands for in line 95, but it needs to occur at the first usage of NMU (line 85). Results • This may be an oversight on my end, but I do not see where Figures 1 or 2 are supposed to be placed in the manuscript. Discussion • The limitations (starts on line 260) should be a separate paragraph. • Your last paragraph is a single sentence. Expanding this paragraph with a couple more sentences would help highlight the novelty and implications of this study. ****** what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy Reviewer #1: No Reviewer #2: No ******** [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 https://doi.org/10.1371/journal.pone.0332574.r003
Revision 2
2 May 2025 Author Response To the editors: Thank you for your interest and the opportunity to revise our manuscript. We have responded to the reviewer comments below and uploaded a modified manuscript for consideration. We have also updated manuscript formatting based on the PLOS One style guide. Reviewer #1 Comment 1: Line 18: I could not understand the meaning of the term "drug use profiles" until I read the Discussion(line 227). I recommend that the authors add some explanation. AUTHOR RESPONSE 1: We added an explanation for this term in the abstract beginning on line 18. Comment 2: Line 20: I guess 16� is "non-"ADF ER. AUTHOR RESPONSE 2: This has been updated to be more clear. Comment 3: Are decimal points in percentages rounded down? Is it rounded off? It does not seem to be consistent. AUTHOR RESPONSE 3: All percentages have been rounded to 1 decimal place. Materials and Methods Comment 4: Even if the authors wrote about the sponsor of this research in Acknowledgment, I think that it should also be written in Materials and Methods. AUTHOR RESPONSE 4: Funding disclosure added, beginning on line 137. Comment 5: Line 106: I understand the classification of comparable products, however, I could not know how the authors chose comparable products. Additionally, the list of products should be shown in a table. AUTHOR RESPONSE 5: Comparable products were selected based on having similar indication and forms to XTAMPZA ER. This has been clarified beginning on line 122 and a full list of products included in each group has been added as an appendix table. Comment 6: Lines 30-43: The authors wrote the number of participants. It should also be shown as a flow diagram. AUTHOR RESPONSE 6: Flow chart was added as figure 1 on line 163. Comment 7: The questionnaire of this survey should be shown. AUTHOR RESPONSE 7: Wording of the survey has been included as an appendix. Result Comment 8: Table 2: In the "Reason for Tampering", "To increase the high feeling from the pill", "To improve the pain relief from the pill", and "To feel the effects of the pill more quickly" should be separate from other items. I think that "To swallow", "inject", "smoke or vape", and "snort" mean only change the route, do not mean the reasons. These are different concepts. AUTHOR RESPONSE 8: The reasons described in the manuscript reflect the way the questions were asked on the survey (exact survey language added as supplemental). Because these products are not intended for non-oral use, use by other routes motivates tampering with the pills and that motivation was considered a reason in how the question was developed. This reasoning was added beginning on line 133. Comment 9: Table 2: In the "Risk Behaviors and Outcomes" should be distinguished from "Risk Behaviors" and "Outcomes". AUTHOR RESPONSE 9: This table has been updated to separate outcomes from risk behaviors. Comment 10: Figures should be improved. I can imagine what the authors want to show in the Figures, however, it is unclear on what basis each point is placed in its respective position. I know the two X axes show "mean difficulty" and "mean perceived risk of tampering", respectively. The actual value of the respective means should also be specified somewhere. AUTHOR RESPONSE 10: Actual means corresponding to each point have been added as captions to both figures. The methods have also been updated to include the numerical values of the Likert scale for better interpretability of the means. Discussion Comment 11: Lines 214: The figures 33.8� and 7.7% are not shown in the Result section and Tables. It is unfriendly for readers. I recommend that the authors show these in the Results section. AUTHOR RESPONSE 11: Comment 12: The number of consumptions, the number of prescriptions dispensed, or the ratio of the products surveyed in this study in the US is required. If XTAMPZA is not commonly prescribed and distributed in the US, the number of participants who non-medically use XTAMPZA will also be small. AUTHOR RESPONSE 12: The proportion of dispensing for each comparator group relative to XTAMPZA ER was added beginning on line 154. Reviewer #2 Comment 1: Please double-check punctions and grammar. AUTHOR RESPONSE 1: Both coauthors and myself have reviewed the manuscript for punctuation and grammar, making several corrections. Introduction Comment 2: There is an extra “.” On line 41. AUTHOR RESPONSE 2: Extra punctuation removed. Comment 3: Need to capitalize the start of the sentence on line 74. AUTHOR RESPONSE 3: “f” changed to “F”. Comment 4: Missing a period at the end of the sentence on line 76. AUTHOR RESPONSE 4: punctuation added. Comment 5: There is an extra “.” and “,” on line 80. AUTHOR RESPONSE 5: Extra punctuation removed Comment 6: You explain what NMU stands for in line 95, but it needs to occur at the first usage of NMU (line 85). AUTHOR RESPONSE 6: definition of NMU abbreviation added to first instance on line 86 and removed from line 96. Results Comment 7: This may be an oversight on my end, but I do not see where Figures 1 or 2 are supposed to be placed in the manuscript. AUTHOR RESPONSE 7: Figure 1 has a title/caption beginning on line 196 and figure 2 has a title/caption beginning on line 212. Discussion Comment 8: The limitations (starts on line 260) should be a separate paragraph. AUTHOR RESPONSE 8: The limitations have been split into a paragraph separate from the strengths, beginning on line 274, with some added content. Comment 9: Your last paragraph is a single sentence. Expanding this paragraph with a couple more sentences would help highlight the novelty and implications of this study. AUTHOR RESPONSE 9: The concluding paragraph has been expanding to highlight the novelty and important results of this study. Attachments Attachment Submitted filename: Author_Response_auresp_2.docx https://doi.org/10.1371/journal.pone.0332574.r004
7 Jul 2025 Decision Letter - Hope Onohuean, Editor Dear Dr. Burkett, 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. Based on the revised manuscript and the authors' responses to reviewers, the paper is well-structured, data-rich, and addresses major reviewer concerns. However, a few key areas for further improvement remain that could enhance the manuscript’s clarity, rigor, and reader trust. Some part of the abstract and discussion are still wordy. This may hinder understanding for broader audiences. Perform a final language polish focusing on removing redundant phrases like in line 285-286. Simplifying overly long sentences, in the Abstract (line 18–19) and Discussion (line 287- 289). ============================== Please submit your revised manuscript by Aug 21 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, Hope Onohuean, PhD Academic Editor PLOS ONE Journal Requirements: 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. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #2: All comments have been addressed Reviewer #3: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #2: Yes Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #2: Yes Reviewer #3: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #2: Yes Reviewer #3: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #2: Yes Reviewer #3: Yes ****** Reviewer #2: All my concerns have been addressed. I applaud the authors for their dedicated efforts to develop this manuscript to its current form. Reviewer #3: Based on the revised manuscript and the authors' responses to reviewers, the paper is well-structured, data-rich, and addresses major reviewer concerns. However, a few key areas for further improvement remain that could enhance the manuscript’s clarity, rigor, and reader trust. Some part of the abstract and discussion are still wordy. This may hinder understanding for broader audiences. Perform a final language polish focusing on removing redundant phrases like in line 285-286. Simplifying overly long sentences, in the Abstract (line 18–19) and Discussion (line 287- 289). ****** 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 Reviewer #3: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org https://doi.org/10.1371/journal.pone.0332574.r005
Revision 3
20 Aug 2025 Author Response To the editors: Thank you for your interest and the opportunity to revise our manuscript. We have responded to the reviewer comments below and uploaded a modified manuscript for consideration. We have also updated manuscript formatting based on the PLOS One style guide. Reviewer #3 Comment 1: Reviewer #3: Based on the revised manuscript and the authors' responses to reviewers, the paper is well-structured, data-rich, and addresses major reviewer concerns. However, a few key areas for further improvement remain that could enhance the manuscript’s clarity, rigor, and reader trust. Some part of the abstract and discussion are still wordy. This may hinder understanding for broader audiences. Perform a final language polish focusing on removing redundant phrases like in line 285-286. Simplifying overly long sentences, in the Abstract (line 18–19) and Discussion (line 287- 289). AUTHOR RESPONSE 1: We performed a thorough round of editing, focusing on removing redundant text and simplifying long sentences. Attachments Attachment Submitted filename: Author_Response_auresp_3.docx https://doi.org/10.1371/journal.pone.0332574.r006
2 Sep 2025 Decision Letter - Hope Onohuean, Editor Motivations, perceived risk, and tampering of XTAMPZA ER and abuse-deterrent opioid drugs PONE-D-24-32479R3 Dear Dr. Burkett, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Hope Onohuean, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0332574.r007
Formally Accepted
Acceptance Letter - Hope Onohuean, Editor PONE-D-24-32479R3 PLOS ONE Dear Dr. Burkett, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Hope Onohuean Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0332574.r008

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