Patterns of Opioid Use (Codeine, Morphine Or Meperidine)

BMJ Open: first published as 10.1136/bmjopen-2019-029613 on 24 July 2019. Downloaded from PEER REVIEW HISTORY

BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to complete a checklist review form (http://bmjopen.bmj.com/site/about/resources/checklist.pdf) and are provided with free text boxes to elaborate on their assessment. These free text comments are reproduced below.

ARTICLE DETAILS

TITLE (PROVISIONAL) Patterns of opioid use (codeine, morphine, or meperidine) in the Canadian population over time: analysis of the Longitudinal National Population Health Survey 1994-2011. AUTHORS Canizares, Mayilee; Power, J. Denise; Rampersaud, Y. Raja; Badley, Elizabeth

VERSION 1 – REVIEW

REVIEWER Brian J Piper, PhD MS Department of Medical Education Geisinger Commonwealth School of Medicine Scranton, PA, USA REVIEW RETURNED 04-Oct-2018

GENERAL COMMENTS The manuscript “Patterns of opioid use in the Canadian population over time: are recent generations at greater risk?” by Canizares and colleagues is well-powered and carefully analyzed. General Concerns A) The primary dependent measure “In the past month, did you take codeine, Demerol or morphine?”, as the authors

acknowledge, is not worded very well. It doesn’t ask about opioids http://bmjopen.bmj.com/ (or opiates) as a group, unlike anti-depressants or tranquilizers. Of the scores of opioids and different formulations, Demerol is an odd choice because use has been decreasing rapidly. Dobbins, EH. Where has all the meperidine gone? Nursing 2010: 40(1): 65–66. doi: 10.1097/01.NURSE.0000365924.16631.a4 Based on the title “Patterns of opioids” the reader might wonder about methadone or others. This discussion should discuss any on September 23, 2021 by guest. Protected copyright. changes in these three agents (codeine, morphine, meperidine) over time. Perhaps a more specific title “Patterns of opioid (codeine, meperidine, morphine) use in the Canadian population over time: Are recent generations at greater risk?” could offset, albeit slightly, against this major methodological deficiency. B) There is an extensive literature about the risks of co-use of opioids and benzodiazepines. The intro should also devote at least a few sentences to this topic to better set the stage. This is an important finding. If the dataset is of sufficient size, even as a supplementary analysis, did this co-use change by period, age, or cohort? C) If it is not inconsistent with journal or NPHS policies, consider inclusion of the survey as a supplemental material. This would provide much greater methodological transparency. Minor Points Page 2, Line 15: insert comma in 12,542. Same convention should be used throughout (17,276; 1,020; 2,733; 1,361). Page 8, Ln 22-29: Perhaps the conditions could be listed in alphabetical order?

BMJ Open: first published as 10.1136/bmjopen-2019-029613 on 24 July 2019. Downloaded from Page 8, Ln 45: In these models Page 9, Ln 29: differs Page 14, Ln 22: “The study survey asked participants about opioid use in general.” Based on A (above), this appears inaccurate. A question for opioid use in general would be “In the past month, did you take prescription opioids (for example, codeine or morphine)?”

References: Please double-check the reference formatting consistency (article titles).

REVIEWER Ricky Bluthenthal Keck School of Medicine, University of Southern California, USA REVIEW RETURNED 22-Oct-2018

GENERAL COMMENTS BMJ review 2018 Overall Considering age, period, and cohort effects on drug use patterns is of growing interest. The submitted paper contributes to this by using a national data set from Canada. The paper is clearly written and the analyses appear to be appropriate. Nonetheless, one important limitation requires additional discussion. First, the study only asks about codeine, Demerol and morphine use and thus misses large categories of opioids (hydromorphone, hydrocodone, oxycodone, street heroin, and fentanyl) that are commonly used and are driving the current opioid crisis. Given the limitations (understandable though they are) of the existing data set, the authors need to provide better justification for using this sample to consider birth cohort trends in Canada. The issue should be raised in the introduction and justification for the sample should be provided in this section. Page 5, lines 16-18, many of the poisoning deaths are occurring among people who inject drugs and use or believe they are using heroin, not prescription opioids and certainly not just codeine, http://bmjopen.bmj.com/ Demerol, and morphine. The relevance of the data set used here to deaths that are driven by other opioids needs to be addressed in the introduction. Page 5, lines 27-29, the authors might want to just note that prescribing long acting opioids for acute and chronic pain was the key, rather than cancer and non-cancer. Non-cancer is probably too broad and misses the point about differences in prescribing due

to acute (or terminally ill) and chronic (much larger population with on September 23, 2021 by guest. Protected copyright. ongoing need for pain relief). Page 6, line 8. The authors might just want to add that “in national studies” cohort and period effects have not been considered. If they go this route then they should consider, and perhaps cite the following: Wall, M., Cheslack-Postava, K., Hu, M. C., Feng, T., Griesler, P., & Kandel, D. B. (2018). Nonmedical prescription opioids and pathways of drug involvement in the US: Generational differences. Drug Alcohol Depend, 182, 103-111. doi:10.1016/j.drugalcdep.2017.10.013

Local studies that have examined cohort differences in drug use patterns related to the opioid crisis include the following. The authors do not need to reference these studies but if they listed if they are interested. Austic, E., McCabe, S. E., Stoddard, S. A., Ngo, Q. E., & Boyd, C. (2015). Age and Cohort Patterns of Medical and Nonmedical Use of Controlled Medication Among Adolescents. J Addict Med, 9(5), 376-382. doi:10.1097/adm.0000000000000142

BMJ Open: first published as 10.1136/bmjopen-2019-029613 on 24 July 2019. Downloaded from Bluthenthal, R. N., Wenger, L., Chu, D., Bourgois, P., & Kral, A. H. (2017). Drug use generations and patterns of injection drug use: Birth cohort differences among people who inject drugs in Los Angeles and San Francisco, California. Drug and Alcohol Dependence, 175, 210-218. doi:http://doi.org/10.1016/j.drugalcdep.2017.04.001 Novak, S. P., Bluthenthal, R., Wenger, L., Chu, D., & Kral, A. H. (2016). Initiation of Heroin and Prescription Opioid Pain Relievers by Birth Cohort. Am J Public Health, 106(2), 298-300. doi:10.2105/AJPH.2015.302972 Pollini, R. A., Banta-Green, C. J., Cuevas-Mota, J., Metzner, M., Teshale, E., & Garfein, R. S. (2011). Problematic use of prescription-type opioids prior to heroin use among young heroin injectors. Subst Abuse Rehabil, 2, 173-180.

Page 8, line 3. I was surprised that Native Canadians were not included as a demographic group. Some justification for this exclusion is necessary.

REVIEWER Pauline Norris University of Otago, New Zealand REVIEW RETURNED 01-Nov-2018

GENERAL COMMENTS This is a really interesting paper which attempts to untangle age, period and cohort effects in the use of opioids in Canada. This has the potential to contribute to understanding the dimensions of the opioid epidemic. The authors locate their research well within existing literature and provide a good justification for the study. The introduction also provides a nice definition and explanation of age, period and cohort effects.

I have one significant concern about the study and otherwise only minor comments. http://bmjopen.bmj.com/

presumably Canada). This is a significant limitation which on September 23, 2021 by guest. Protected copyright. compromises the validity of the study. For example, it is hard to interpret the findings about total opioid use when very commonly used drugs are excluded. Unless there is data that shows that users of morphine, codeine and Demerol are a consistent percentage of users of opioids over time, and that users of newer drugs are similar to the users of morphine, codeine and Demerol, the findings presented here are very difficult to interpret.

Abstract Objectives: “risk factors” should be “risk factors for use” Population: the “aged 10-69 years in 1994/5” seems odd without explanation. Adding “the time of the first wave of the study” would be helpful Also, the cohorts do not seem to match those in the Results (page 10) “post World War I” has been missed Strengths and Weaknesses of the study Point 3: “opioid use in general”: it would be clearer to say “opioid use, regardless of source”

BMJ Open: first published as 10.1136/bmjopen-2019-029613 on 24 July 2019. Downloaded from

Results In general the results are clearly described but the phrase “there was a trend of greater opioid use from Gen Xers to the post-World war 1 cohort” could be more clearly expressed.

VERSION 1 – AUTHOR RESPONSE

Reviewer: 1 Reviewer Name: Brian J Piper, PhD MS Institution and Country: Department of Medical Education, Geisinger Commonwealth School of Medicine, Scranton, PA, USA Please state any competing interests or state ‘None declared’: None declared.

The manuscript “Patterns of opioid use in the Canadian population over time: are recent generations at greater risk?” by Canizares and colleagues is well-powered and carefully analyzed.

General Concerns A) The primary dependent measure “In the past month, did you take codeine, Demerol or morphine?”, as the authors acknowledge, is not worded very well. It doesn’t ask about opioids (or opiates) as a group, unlike anti-depressants or tranquilizers. Of the scores of opioids and different formulations, Demerol is an odd choice because use has been decreasing rapidly. Dobbins, EH. Where has all the meperidine gone? Nursing 2010: 40(1): 65–66. doi: 10.1097/01.NURSE.0000365924.16631.a4 Based on the title “Patterns of opioids” the reader might wonder about methadone or others. This discussion should discuss any changes in these three agents (codeine, morphine, meperidine) over time. Perhaps a more specific title “Patterns of opioid (codeine, meperidine, morphine) use in the Canadian population over time: Are recent generations at greater risk?” could offset, albeit slightly, against this major methodological deficiency. http://bmjopen.bmj.com/ Response: Thank you for your comments. We were inadvertently more ambiguous than we intended in describing the outcome variable. We have explicitly included the three agents in the title as suggested as well as through the paper to remind the reader that our study did not look at opioid use in general.

Although we agree with the reviewer that examining a restricted list of opioids could be seen as a methodological deficiency, it is worth noticing that for comparing birth cohorts using longitudinal panel on September 23, 2021 by guest. Protected copyright. data is ideal. This type of design allows disentangling the effects of age and period from birth cohort particularly as we can compare cohorts at overlapping ages. Also, since with this design allows to follow the health experience of same people over time, we could examine how changes on risk factors affected changes in opioid use. However, a drawback of the design is that the question on opioids is restricted to a list of agents chosen at the beginning of the survey in 1994/95. A reflection of the timeframe of the survey is that it asked about use of opioids that were commonly used in the 1990s: morphine, codeine and meperidine (Demerol). Although this could be seen to limit the relevance of the study, between 1991 and 2007, codeine was the most frequently prescribed opioid in Ontario —largest province accounting for 40% of the population of Canada. [1] Furthermore, another study show that in 1991, codeine and morphine together accounted for almost all opioid-related deaths in Ontario; while the number of deaths associated with these drugs remained fairly constant between 1991 and 2015. [2] In 2010, at the peak of the fentanyl epidemic, there were more deaths from these two drugs combined than those attributed to fentanyl. Therefore, examining the temporal patterns of these three agents is informative and adds to the literature in this topic. We have added a new paragraph with this information in the Introduction (page # 6).

BMJ Open: first published as 10.1136/bmjopen-2019-029613 on 24 July 2019. Downloaded from B) There is an extensive literature about the risks of co-use of opioids and benzodiazepines. The intro should also devote at least a few sentences to this topic to better set the stage. This is an important finding. If the dataset is of sufficient size, even as a supplementary analysis, did this co-use change by period, age, or cohort?

Response: Thank you for the suggestion. We have added a paragraph in the introduction where we briefly discuss risk factors for opioid use, including the co-use of opioids and Benzodiazepine (page # 5). Unfortunately, the dataset does not have sufficient sample size to be able to fit the models for the co-use of these drugs.

C) If it is not inconsistent with journal or NPHS policies, consider inclusion of the survey as a supplemental material. This would provide much greater methodological transparency.

Response: We have added the direct link to the survey documentation which includes the questionnaire as well as the general methodology.

D) Minor Points Page 2, Line 15: insert comma in 12,542. Same convention should be used throughout (17,276; 1,020; 2,733; 1,361).

Response: Changes were made.

Page 8, Ln 22-29: Perhaps the conditions could be listed in alphabetical order?

Response: Changes were made.

Page 8, Ln 45: In these models Page 9, Ln 29: differs

Response: Changes were made. http://bmjopen.bmj.com/ Page 14, Ln 22: “The study survey asked participants about opioid use in general.” Based on A (above), this appears inaccurate. A question for opioid use in general would be “In the past month, did you take prescription opioids (for example, codeine or morphine)?”

Response: We have re-worded that section. The sentence was replaced with the following “A major limitation of the study is that the survey question asked only about three opioid agents: morphine, codeine and Demerol (meperidine).” on September 23, 2021 by guest. Protected copyright.

References: Please double-check the reference formatting consistency (article titles).

Response: We have downloaded the BMJ style for EndNote and hope that the references are now properly formatted.

Reviewer: 2 Reviewer Name: Ricky Bluthenthal Institution and Country: Keck School of Medicine, University of Southern California, USA Please state any competing interests or state ‘None declared’: None declared

Overall A) Considering age, period, and cohort effects on drug use patterns is of growing interest. The submitted paper contributes to this by using a national data set from Canada. The paper is clearly written and the analyses appear to be appropriate. Nonetheless, one important limitation requires additional discussion. First, the study only asks about codeine, Demerol and morphine use and thus

BMJ Open: first published as 10.1136/bmjopen-2019-029613 on 24 July 2019. Downloaded from misses large categories of opioids (hydromorphone, hydrocodone, oxycodone, street heroin, and fentanyl) that are commonly used and are driving the current opioid crisis. Given the limitations (understandable though they are) of the existing data set, the authors need to provide better justification for using this sample to consider birth cohort trends in Canada. The issue should be raised in the introduction and justification for the sample should be provided in this section.

Response: Thank you for the suggestion. We have added a discussion in the introduction about the limitations of the data source (page # 6). As noted in the response to Reviewer #1 point A, Canadian data show that codeine and morphine account for a substantial portion of the opioids prescribed and opioid-related deaths, thus we think that the analysis of these data is informative for the public and policy makers.

B) Page 5, lines 16-18, many of the poisoning deaths are occurring among people who inject drugs and use or believe they are using heroin, not prescription opioids and certainly not just codeine, Demerol, and morphine. The relevance of the data set used here to deaths that are driven by other opioids needs to be addressed in the introduction. Response: We have deleted these 2 sentences as in our paper we are not focusing on deaths. However, as we have mentioned previously Canadian data show that codeine and morphine are associated with a substantial portion of opioid-related deaths, even at the peak of the fentanyl epidemic. [2]

C) Page 5, lines 27-29, the authors might want to just note that prescribing long acting opioids for acute and chronic pain was the key, rather than cancer and non-cancer. Non-cancer is probably too broad and misses the point about differences in prescribing due to acute (or terminally ill) and chronic (much larger population with ongoing need for pain relief).

Response: We have modified the introduction and made the appropriate changes.

D) Page 6, line 8. The authors might just want to add that “in national studies” cohort and period http://bmjopen.bmj.com/ effects have not been considered. If they go this route then they should consider, and perhaps cite the following: Wall, M., Cheslack-Postava, K., Hu, M. C., Feng, T., Griesler, P., & Kandel, D. B. (2018). Nonmedical prescription opioids and pathways of drug involvement in the US: Generational differences. Drug Alcohol Depend, 182, 103-111. doi:10.1016/j.drugalcdep.2017.10.013 Local studies that have examined cohort differences in drug use patterns related to the opioid crisis include the following. The authors do not need to reference these studies but if they listed if they are on September 23, 2021 by guest. Protected copyright. interested. Austic, E., McCabe, S. E., Stoddard, S. A., Ngo, Q. E., & Boyd, C. (2015). Age and Cohort Patterns of Medical and Nonmedical Use of Controlled Medication Among Adolescents. J Addict Med, 9(5), 376- 382. doi:10.1097/adm.0000000000000142 Bluthenthal, R. N., Wenger, L., Chu, D., Bourgois, P., & Kral, A. H. (2017). Drug use generations and patterns of injection drug use: Birth cohort differences among people who inject drugs in Los Angeles and San Francisco, California. Drug and Alcohol Dependence, 175, 210-218. doi:http://doi.org/10.1016/j.drugalcdep.2017.04.001 Novak, S. P., Bluthenthal, R., Wenger, L., Chu, D., & Kral, A. H. (2016). Initiation of Heroin and Prescription Opioid Pain Relievers by Birth Cohort. Am J Public Health, 106(2), 298-300. doi:10.2105/AJPH.2015.302972 Pollini, R. A., Banta-Green, C. J., Cuevas-Mota, J., Metzner, M., Teshale, E., & Garfein, R. S. (2011). Problematic use of prescription-type opioids prior to heroin use among young heroin injectors. Subst Abuse Rehabil, 2, 173-180.

Response: Thank you for the suggestions. We have made changes and incorporated some of the suggested literature.

BMJ Open: first published as 10.1136/bmjopen-2019-029613 on 24 July 2019. Downloaded from E) Page 8, line 3. I was surprised that Native Canadians were not included as a demographic group. Some justification for this exclusion is necessary.

Response: According to Statistics Canada 1196 census data, [3] indigenous people accounted about 3% of the Canadian population. Furthermore, given the timeframe of the survey the majority of participants were white. We have added this information in the methods section (page #8, sociodemographic characteristics).

Reviewer: 3 Reviewer Name: Pauline Norris Institution and Country: University of Otago, New Zealand Please state any competing interests or state ‘None declared’: None declared

A) This is a really interesting paper which attempts to untangle age, period and cohort effects in the use of opioids in Canada. This has the potential to contribute to understanding the dimensions of the opioid epidemic. The authors locate their research well within existing literature and provide a good justification for the study. The introduction also provides a nice definition and explanation of age, period and cohort effects.

I have one significant concern about the study and otherwise only minor comments.

As noted by the authors in their discussion of the study limitations, the survey question asked only about morphine, codeine and Demerol. This may have been a good list of opioids at the time of the baseline survey in 1994/5, but does not include drugs like oxycodone and fentanyl which now account for significant proportions of opioid use and deaths in other countries (and presumably Canada). This is a significant limitation which compromises the validity of the study. For example, it is hard to interpret the findings about total opioid use when very commonly used drugs are excluded. Unless there is data that shows that users of morphine, codeine and Demerol are a consistent percentage of

users of opioids over time, and that users of newer drugs are similar to the users of morphine, http://bmjopen.bmj.com/ codeine and Demerol, the findings presented here are very difficult to interpret.

Response: Thank you for the comments. This issue has been raised by the previous reviewers. We have added a discussion in the introduction about the limitations of the data source (page # 6). Please see our more detailed response to Reviewer #1 point A. Briefly, Canadian data show that codeine and morphine account for a substantial portion of the opioids prescribed and opioid-related deaths, thus we think that the analysis of these data is informative for the public and policy makers. on September 23, 2021 by guest. Protected copyright.

B) Abstract Objectives: “risk factors” should be “risk factors for use” Population: the “aged 10-69 years in 1994/5” seems odd without explanation. Adding “the time of the first wave of the study” would be helpful Also, the cohorts do not seem to match those in the Results (page 10) “post World War I” has been missed Strengths and Weaknesses of the study Point 3: “opioid use in general”: it would be clearer to say “opioid use, regardless of source”

Response: Thank you. We have made the changes.

Results In general the results are clearly described but the phrase “there was a trend of greater opioid use from Gen Xers to the post-World war 1 cohort” could be more clearly expressed.

Response: We have changed the sentence with the hope of improving clarity.

BMJ Open: first published as 10.1136/bmjopen-2019-029613 on 24 July 2019. Downloaded from References

1. Dhalla IA, Mamdani MM, Sivilotti MLA, et al. Prescribing of opioid analgesics and related mortality before and after the introduction of long-acting oxycodone. Canadian Medical Association Journal 2009;181(12):891.

2. Gomes T. Latest trends in opioid-related deaths in ontario: 1991 to 2015: Ontario Drug Policy Research Network 2017.

3. https://www12.statcan.gc.ca/nhs-enm/2011/as-sa/99-011-x/99-011-x2011001-eng.cfm

VERSION 2 – REVIEW

REVIEWER Brian Piper, Assistant Professor of Neuroscience Department of Medical Education, Geisinger Commonwealth School of Medicine, Scranton, Pennsylvania, USA. REVIEW RETURNED 07-Feb-2019

GENERAL COMMENTS The manuscript “Patterns of opioid use (codeine, morphine, and meperidine) in the Canadian population over time: are recent generations at greater risk?” by Canizares and colleagues is well- powered and carefully analyzed.

General Concern

The primary dependent measure “In the past month, did you take codeine, Demerol or morphine?”, as the authors acknowledge, is not worded very well. Please read, carefully consider, and cite:

Fischer et al. The effect of an educational intervention on http://bmjopen.bmj.com/ meperidine use in Nova Scotia, Canada: a time series analysis. Pharmacoepidemiol Drug Saf 2012; 21(2):177-83.

Dobbins, EH. Where has all the meperidine gone? Nursing 2010: 40(1): 65–66.

Friesen et al. REGIONAL PRESCRIBING PATTERNS IN THE

ASSESSMENT OF THE RESPONSE TO SAFETY WARNINGS on September 23, 2021 by guest. Protected copyright. FOR MEPERIDINE. J Popul Ther Clin Pharmacol 22 (2):e237- e244.

Meperidine prescribing dropped substantially in the first decade of the 2000s in Canada. As such, asking about three opioids simultaneously produces temporal data patterns that are, at best, borderline uninterpretable, and at worst, frankly, a waste of the reader’s time.

Perhaps it might be possible to run some additional models that just focus on the period before meperidine dropped off to determine if some of the same patterns held up? Just a light suggestion.

Information about overdoses in the current limitation paragraph is irrelevant as this is a study about use. Delete. The discussion should be explicit that this question wording produces data that is of questionable value for addressing cohort and age effects.

BMJ Open: first published as 10.1136/bmjopen-2019-029613 on 24 July 2019. Downloaded from Somewhere (introduction?), inclusion of the pattern of each of these agents, individually, in Canada from other data sources (like ref 29) would be very informative.

Minor Points

Abstract: pick a format for the cohorts (Baby Boom or baby boom) and be consistent

Abstract: It is odd to single out one formulation (Demerol) in the outcome. Delete.

Intro, p. 5, line 5: benzodiazepine should be in lower-case

Results: p. 13, line 20-34: This paper doesn’t report on “opioid use”, only this trio. Please be consistent with the terminology of “studied opioids”.

References: Please double-check the reference formatting consistency (countries capitalized, volumes and pages listed, journal titles following a uniform format).

REVIEWER Pauline Norris University of Otago, New Zealand REVIEW RETURNED 25-Feb-2019

GENERAL COMMENTS The authors have made a good attempt to address the key concern of all the reviewers: that the data only related to three specific opioids. This remains a substantial limitation of the study, but is now explicitly addressed in the paper. The abstract and the conclusion still need to be revised so that it is clear the paper is about three opioids. The term “opioid use” is misleading, and should be replaced by something like “the three specific opioids” http://bmjopen.bmj.com/ or “the opioids studied” or “these opioids”.

On page 6, the statement: “Furthermore, another study show that in 1991, codeine and morphine together accounted for almost all opioid-related deaths in Ontario; while the number of deaths associated with these drugs remained fairly constant between 1991 and 2015. [30]” is a little misleading. The important point is

that deaths from codeine and morphine are likely to be a changing on September 23, 2021 by guest. Protected copyright. proportion of opioid deaths between 1991 and 2015. This should be clarified so that readers are not misled.

VERSION 2 – AUTHOR RESPONSE

Reviewer: 1 Reviewer Name: Brian Piper, Assistant Professor of Neuroscience Institution and Country: Department of Medical Education, Geisinger Commonwealth School of Medicine, Scranton, Pennsylvania, USA. Please state any competing interests or state ‘None declared’: None declared.

1. The primary dependent measure “In the past month, did you take codeine, Demerol or morphine?”, as the authors acknowledge, is not worded very well. Please read, carefully consider, and cite: • Fischer et al. The effect of an educational intervention on meperidine use in Nova Scotia, Canada: a time series analysis. Pharmacoepidemiol Drug Saf 2012; 21(2):177-83.

BMJ Open: first published as 10.1136/bmjopen-2019-029613 on 24 July 2019. Downloaded from • Dobbins, EH. Where has all the meperidine gone? Nursing 2010: 40(1): 65–66. • Friesen et al. REGIONAL PRESCRIBING PATTERNS IN THE ASSESSMENT OF THE RESPONSE TO SAFETY WARNINGS FOR MEPERIDINE. J Popul Ther Clin Pharmacol 22 (2):e237- e244.

Response: Thank you for the suggestion. We have included this information in the Introduction, page 6.

2. Perhaps it might be possible to run some additional models that just focus on the period before meperidine dropped off to determine if some of the same patterns held up? Just a light suggestion.

Response: Thank you for the suggestion. However, we have opted not to run this analysis because one of the advantages of using the full range of years that the NPHS covers is that, while comparing birth cohorts, there are enough overlapping years which minimize the effect of confounding by age and period. By limiting the number of years, we would then introduce additional sources of confounding to the results.

3. Information about overdoses in the current limitation paragraph is irrelevant as this is a study about use. Delete. The discussion should be explicit that this question wording produces data that is of questionable value for addressing cohort and age effects.

Response: We have removed this information.

4. Somewhere (introduction?), inclusion of the pattern of each of these agents, individually, in Canada from other data sources (like ref 29) would be very informative.

Response: See point # 7 in response to the Associate Editor.

http://bmjopen.bmj.com/ 5. Abstract: pick a format for the cohorts (Baby Boom or baby boom) and be consistent

Response: Changes were made.

6. Abstract: It is odd to single out one formulation (Demerol) in the outcome. Delete.

Response: Changes were made. on September 23, 2021 by guest. Protected copyright.

7. Intro, p. 5, line 5: benzodiazepine should be in lower-case

Response: Changes were made.

8. Results: p. 13, line 20-34: This paper doesn’t report on “opioid use”, only this trio. Please be consistent with the terminology of “studied opioids”.

Response: We have made changes throughout the manuscript to specifically refer to the three opioids studied.

9. References: Please double-check the reference formatting consistency (countries capitalized, volumes and pages listed, journal titles following a uniform format).

Response: Changes were made.

BMJ Open: first published as 10.1136/bmjopen-2019-029613 on 24 July 2019. Downloaded from Reviewer: 2 Reviewer Name: Pauline Norris Institution and Country: University of Otago, New Zealand Please state any competing interests or state ‘None declared’: None declared

1. The authors have made a good attempt to address the key concern of all the reviewers: that the data only related to three specific opioids. This remains a substantial limitation of the study, but is now explicitly addressed in the paper. The abstract and the conclusion still need to be revised so that it is clear the paper is about three opioids. The term “opioid use” is misleading, and should be replaced by something like “the three specific opioids” or “the opioids studied” or “these opioids”.

Response: We have made changes throughout the manuscript to specifically refer to the three opioids studied.

2. On page 6, the statement: “Furthermore, another study show that in 1991, codeine and morphine together accounted for almost all opioid-related deaths in Ontario; while the number of deaths associated with these drugs remained fairly constant between 1991 and 2015. [30]” is a little misleading. The important point is that deaths from codeine and morphine are likely to be a changing *proportion* of opioid deaths between 1991 and 2015. This should be clarified so that readers are not misled.

Response: We have made changes with the hope of improving clarity. It now reads:

Furthermore, another study show that in 1991, codeine and morphine together accounted for almost all opioid-related deaths in Ontario; however, while the proportion of deaths accounted for these two agents have declined over time, the number of deaths associated with these drugs remained fairly constant between 1991 and 2015.

http://bmjopen.bmj.com/ VERSION 3 – REVIEW

REVIEWER Pauline Norris University of Otago, New Zealand REVIEW RETURNED 12-May-2019

GENERAL COMMENTS The authors have successfully addressed my concerns with the