PONE-D-21-33076Opioid prescribing in out-of-hours primary care in Flanders and the Netherlands: a retrospective observational studyPLOS ONE

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[AvN, HDL, HP, KH, RV, TB, WM have declared that no competing interests exist. 

LvD received funding for a project not related to this study from TEVA.] 

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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

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

Reviewer #1: Yes

Reviewer #2: Yes

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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

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Reviewer #1: Yes

Reviewer #2: 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: The authors present a retrospective observational study examining data from routine electronic health records (EMRs) of patients in the Flanders and the Netherlands from 2015 to 2019. They analyzed the number of contacts in which GPs prescribed an opioid and the type of opioids that were prescribed. The opioid crisis in the United States has increased concerns about appropriate opioid prescribing and the significance of clearly defining the benefits and risks of utilizing opioid analgesics in patients suffering from pain. Evaluating real-world prescribing patterns can provide better insight into the creation of national guidelines.

The manuscript is engaging, timely, impactful, and interesting. The described manuscript format is appropriate, and there are ethical issues noted. The manuscript is referenced and structured correctly, and the results support the conclusions. The authors described the study's limitations which might question the generalizability of the data and therefore should suggest that further studies are needed.

Reviewer #2: Thank you for the opportunity to review this retrospective cross-sectional study that examines out-of-hours primary care opioid prescribing in the Netherlands and Flanders. The paper examines an often overlooked source of opioid prescriptions and utilizes two data sources that provide sufficient generalizability for their study areas. The scope is somewhat limited to health systems and countries that have similar models, but that is true of many studies and is hardly a criticism. I think the strength of the study is in their comprehensive data source and straight forward design. I do think the attempts to compare the two regions came up short; there weren't any statistical analyses comparing the two regions. However the authors do an admirable job of explaining why the regions differ in the rates/types of opioid prescribed, interpreting the results within the context of the local environment, and provide the non-European reader (Me) an understanding of the healthcare environment in those two countries/regions. I strongly question the decision to remove the weekday visits from the Netherlands analysis. I can appreciated that this was done to provide a more direct comparison between the two regions. But since there were no analyses done, you've just removed a large number of contacts (visits?) (2 million per year!!!!) and severely biases your study. I would think that by including these visits the reader would gain a much more complete understanding of the role of OOH-PCSs in opioid prescribing, which I believe to be the true benefit of the study (not the regional comparison). In the event that you want to statistically compare the regions, these can be removed.

Specific Comments:

Abstract

Background, Page 2, line 37-38: delete "that differ in the way..." as it is very confusing to read and is not necessary for the abstract

Methods: need to provide more info- study is a retrospective cross sectional study; what is the primary outcome (mean yearly rate of opioid prescriptions per 1000 visits); what are strong v weak opioids; define GP. Also, if you aren't doing a statistical analyses of the yearly rate, you shouldn't use the term "trend". I think it would be very easy to do a piece-wise linear regression using 2017 as a midpoint.

Results, Page 2, line 44-48: Would rewrite the description of the opioid prescribing rates in Flanders to read more like the Netherlands description (rates went from xx to y between 2015 - 2017 and then increased to zzz in 2019.

Page 2, line 48-49: "...OOH-contacts concerning an opioid prescription". I'm assuming that you mean that strong opioids were prescribed 8% of the time WHERE an opioid was prescribed. I would just clarify as it is a little confusing as written.

Conclusion, Page 2, line 55-56: I would rewrite this to something of the effect of "Measures to ensure judicious and evidenced-based prescribing of opioids need to be tailored to the local healthcare system organization".

Introduction

Page 3, line 64: "...benefits outweigh the risk of developing opioid dependence, opioid use disorder, overdose..."

Page 3, line 74-75: "Acute and chronic pain..." this line is out of place in context with the preceding paragraph

Page 3, line 76: I would provide the "definition" of Flanders earlier in the manuscript

Page 3, line 82-84: I would provide an actual number describing the risk of persistent opioid use after prescription (could use Shah A, Hayes CJ, Martin BC. Characteristics of Initial Prescription Episodes and Likelihood of Long-Term Opioid Use - United States, 2006-2015. MMWR Morb Mortal Wkly Rep. 2017;66(10):265-269)

Page 3, line 91: "...with each 80 to 160 GPs" Is this the number of GPs per OOH?

Page 3-4, line 90-106: This explanation of the differences in the care models of the Netherlands and Flanders is excellent and completely necessary to interpret the findings of the study. However it needs to be condensed and moved to the discussion. You can introduce a very brief explanation in the intro to justify why you are comparing the two regions, but the bulk of the description should be reserved for the discussion

Methods

Page 4, line 113: I would think this is a retrospective cross sectional study

Page 4, line 116 and line 121: Does iCAREdata cover 10% or 66% of the Flemish population?

Page 6, line 146-148: I think it is unwise to exclude these data. The comparison between the regions seems like a secondary aim. You are excluding 2 million contacts per year...that's a lot. I would strongly encourage you to include these visits in your yearly descriptions and in the event you go back and perform a statistical analyses comparing the regions, you can then remove them. Trying to describe this very narrow subset of weekend contacts that result in an prescription is just not nearly as helpful.

Page 6, line 150: ALL means need to have 95% CI

Results

All values that represent mean need 95% CI. And please be consistent with the number of significant figures you are using.

Page 6, line 171-172: Would re-write first sentence "Between 2015-2019, XXX (2.5%) OOH-contacts resulted in an opioid prescription (Figure 1, Table S1)"

Page 6-7, line 173-177: I am not following your % decrease calculation; going from 24 --> 21% is an absolute reduction of 3%. 1-(21/24) = 12.5% relative reduction. If my math is incorrect please let me know

Page 7, line 178-179: I would continue to present the mean (with 95% CI) values instead of switching to range.

Page 7, line 188: Give % for each opioid

Discussion

I would encourage you to include some discussion on how these results compare to other studies that describe opioid prescribing, particularly those that examine sources of opioid prescribing. Listed are references that I am familiar with as a US-based provider (Temporal Trends in Opioid Prescribing Practices in Children, Adolescents, and Younger Adults in the US From 2006 to 2018, JAMA Pediatr

. 2021 Oct 1;175(10):1043-1052. doi: 10.1001/jamapediatrics.2021.1832. Opioid Prescribing to US Children and Young Adults in 2019, Pediatrics

. 2021 Sep;148(3):e2021051539. doi: 10.1542/peds.2021-051539. Epub 2021 Aug 16. Variation in Adult Outpatient Opioid Prescription Dispensing by Age and Sex — United States, 2008–2018, MMWR Morb Mortal Wkly Rep. 2020 Mar 20;69(11):298-302. doi: 10.15585/mmwr.mm6911a5.).

Page 8, line 217-218: "Overall we did...nor in the Netherlands." Were you expecting to see a large increase? Was that your hypothesis? Seems odd to state this here, would delete.

Page 8, line 223-225: Are you saying that the overall trend of decreasing opioid prescribing is secondary to the increased knowledge of the dangers of opioids?

It is confusing as this sentence just follows your statement that prescribing of strong opioids increased between 2015-2019 so it makes it seem like you are saying the attention being paid to prescribing has lead to increased strong opioid prescribing

Page 9, line 254: Please provide a reference

Page 9-10: Given the high prevalence of tramadol in your sample, I would include some discussion on the recent paper that showed increased mortality with tramadol (Association of Tramadol vs Codeine Prescription Dispensation With Mortality and Other Adverse Clinical Outcomes, JAMA. 2021 Oct 19;326(15):1504-1515. doi: 10.1001/jama.2021.15255.)

Limitations: IF you are going to continue to exclude the weekday contacts in the Netherlands, it needs to be listed in the limitations as this is excluding the majority of contacts from the Netherlands and significantly biases the results. As stated previously, would strongly encourage you to include these results and perform trend analysis.

Tables and Figures

Try to use "." or "," as decimal points...you go back and forth in the supplemental material

Figure 1: Year should be on the X-axis

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Reviewer #1: Yes: Joseph V Pergolizzi, MD

Reviewer #2: No

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Opioid prescribing in out-of-hours primary care in Flanders and the Netherlands: a retrospective cross-sectional study

PONE-D-21-33076R1

Dear Dr. Hek,

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,

Vijayaprakash Suppiah, PhD

Academic Editor

PLOS ONE

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

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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 #2: Yes

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

Reviewer #2: Yes

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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 #2: 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 #2: 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 #2: Thank you for your thoughtful revisions. I commend you for your hard work. All comments have been addressed.

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Reviewer #2: No