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Thank you for your revised manuscript. Both reviewers were pleased with how you had addressed their comments and suggestions.
The authors have replied and addressed all my comments in the text.
The authors have replied and addressed all my comments in the text.
Thank you for the opportunity to review this new version of the manuscript. The authors have replied and addressed all my comments. I believe the manuscript meets the Peer J criteria and is appropriate for publication.
The authors have done an excellent job in improving the quality and readability of this article even further. Suggestions for minor improvements are included below at the authors’ discretion:
Lines 79-80: The authors may consider changing the sentence into the following: ‘opioid dependence within 12 months after EMPPR use starts.’
Line 263: Possibly a word is missing in this sentence?
Lines 298-299: The authors may wish to include a reference to highlight differences in prescription opioid misuse between the US and, for example, Europe. See e.g.: Weisberg, D. F., Becker, W. C., Fiellin, D. A., & Stannard, C. (2014). Prescription opioid misuse in the United States and the United Kingdom: Cautionary lessons. International Journal of Drug Policy, 25(6), 1124–1130.
Both reviewers note that this is a paper of current interest to the field. Please address all the minor revisions noted, particularly the consistent use of terms and provision of clear definitions where needed. We look forward to receiving your revised version.
Strengths of the paper
1) Given the prescription opioids epidemic of recent years the paper tackles a subject of great current interest and concern. Using an interesting approach the authors estimate the incidence of non-medical use of prescription opioids and of making a fast transition and becoming a case of prescription opioids dependent syndrome.
2) The authors carefully note the limitations of the study.
References in line 48 should be change so the author name (e.g. institution) appears in the text and not “United States”
Line 223: The following part of the sentence can be removed: “Some readers may not appreciate that”.
I would appreciate the author's comments on:
The trends in onset of PPR and in rapid transition to PPR dependence; the trends for both outcomes seem to be going in opposite directions for most age groups (as observed in supplemental figure S3).
Discussion and conclusions:
In the limitations the authors could add something on what is described in Appendix B.4.3 of the 2012 NSDUH report: "the person-level weights in NSDUH were calibrated to population estimates (or control totals) obtained from the U.S. Census Bureau. For the weights in 2002 through 2010, annually updated control totals based on the 2000 census were used. Beginning with the 2011 weights, however, the control totals from the Census Bureau were based on the 2010 census. As a result, there was a possibility that the change from the 2000 to the 2010 census as the basis for updating NSDUH control totals could result in demographic and geographic shifts in the U.S. population that were not accounted for in population estimates that were made during the period between the censuses (i.e., in the annually updated 2000 census based control totals provided by the Census Bureau for the years 2002 to 2010)… With this estimation method, the postcensal estimates made for the years immediately following a census are likely to be more accurate (e.g., 2002 postcensal estimates) than those for years that are farther from the last census (e.g., 2009 postcensal estimates)." “...Caution would be advised in interpreting trends in substance use estimates from 2011 onward with estimates from prior years.”
Reference: Substance Abuse and Mental Health Services Administration, Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013. See Appendix B.4.3
This article deals with an important area of drug use (misuse of medicines), presenting new challenges to public health in the US and elsewhere. It provides valuable insights into a subgroup of prescription opioid users in the US as well as to the problem at large. The discussion of the limitations of the study is interesting, thorough and reads well. The authors do an excellent job in linking their findings to the need for (novel) health interventions and policy. However, some work is recommend, mainly to enhance the clarity and readability of the manuscript.
Key issues and suggestions (at the authors’ discretion) are listed below:
1.Terms such as ‘fast’ (line 25), ‘soon after’ (line 240) and ‘rapid’ (line 135, line 292), used to account for the period from initial use to dependence, are vague and open to interpretation. A definition of this specific time period should be provided from the beginning of the article. From Table 3, it appears that ‘fast transition’ is ‘no longer than 12 months’. Given that some pharmaceutical opioids can induce dependence in a period shorter than 12 months (resting on use patterns and product, of course), can ‘up to 12 months’ really be considered ‘fast’? Providing a specific time period minimizes this potential for interpretation.
2.One major problem in research into medicine misuse is variation in terminology and definition, e.g. ‘misuse’, ‘abuse’ and, in this case, ‘extra-medical’ use. The variation in definition often reduces comparability between studies. A clear and exhaustive definition of ‘extra-medical’ use should be provided therefore to prevent any misunderstanding (lines 40-41). This is very important as lines 303-305 reveal that NSDUH data excludes dependence following use within appropriate medical guidelines. Further clarification in this respect could also be achieved by answering the following questions: Why is the term ‘extra-medical’ used, say on behalf of FDA’s definition of misuse? How does it relate to the question posed, and definition used, in the NSDUH? (see also comment 8) What might 'other reasons outside...the prescribers' intent' be?
3.As the article appears to cover only opioid prescription drugs (lines 66-67) the term ‘prescription pain reliever’ is somewhat redundant and could be replaced by opioid prescription (OP).
4.‘Opioid-type drug dependence’, ‘opioid dependence’, and ‘opioid dependence syndrome’ are used interchangeably throughout the manuscript. Perhaps it might be better to only use one of these and provide a definition/reference?
5.Lines 51-52: A number of studies cast light on the multi-level factors influencing the misuse of opioid medicines. Some of these factors should be introduced to the reader. See references below.
6.Line 54: Opioid dependence could also lead to misuse. Indeed there is sufficient date to highlight that the relationship between use, misuse and dependence on medicines is highly complex and fluent over time. This should be noted (this is linked to points raised in comment 2).
7.The Methods section could be reduced in length to increase readability (NSDUH sampling and data is accounted for elsewhere), or parts of it could be added to the supplementary data.
8.Line 106: Would it be possible to provide a definition of ‘analgesic drug products’ to understand which medicines this involves?
9.The Result section reads more as a form of guidance for interpretation of tables, rather than an unambiguous presentation of main findings. See for example, ‘the meta-analysis forest plots...’ (lines 208-209), and ‘Table 2, Panel B, presents 95%...’ (lines 202-203). In many cases this information is already explained in the table legends. This section should present, in clear language, the main findings of the study and simply referred to tables in brackets inserted in the text, e.g. (Table 1). At least this is the opinion of this reviewer.
10.Line 236. These results are also important to policy-makers, regulatory bodies and health professionals.
11.Line 241: ‘Treatment services’ might be too broad a term to use here. Surely someone who is dependent on a mild opioid might benefit from advice and monitoring by a GP to begin with, whereas someone who is dependent on multiple and strong opioids might need actual substance use treatment.
12.Lines 326-327: What is meant by ‘opioids-attributable problems’?
Okie, S. A flood of opioids, a rising tide of deaths. New England Journal of Medicine 363, 1981–1985 (2010).
Dart, R. C. et al. Trends in Opioid Analgesic Abuse and Mortality in the United States. New England Journal of Medicine 372, 241–248 (2015).
Mars, S. G. et al. ‘Every “Never” I Ever Said Came True’: Transitions from opioid pills to heroin injecting. International Journal of Drug Policy 25, 257–266 (2014).
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