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? 1 BMJ Open: first published as 10.1136/bmjopen-2019-029613 on 24 July 2019. Downloaded from Page 8, Ln 45: In these models<insert comma> 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 2 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/ 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 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” 3 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.