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Opioids and Dose-Related Deaths—Association or Causation?—Reply

Opioids and Dose-Related Deaths—Association or Causation?—Reply In reply We believe Dr Williamson has misinterpreted some aspects of the methodology of our study and its findings. Dr Williamson states that an unadjusted analysis reveals no association between higher opioid dose categories and opioid-related mortality. This is incorrect. Although not reported in our published article,1 the association between dose and opioid-related mortality was consistent in our unadjusted conditional logistic regression model for the primary outcome (odds ratio, 2.32, 2.97, and 3.69 among those prescribed 50-99 mg of morphine equivalents per day [ME/d], 100-199 mg of ME/d, and ≥200 mg of ME/d, respectively, compared with the 1-19 mg of ME/d group; P < .001 for all comparisons). Although the 95% confidence intervals overlap between high and moderate dose categories, a clear and significant association between higher doses of opioids and opioid-related mortality is apparent in both unadjusted and adjusted models. Dr Williamson further states that we had difficulty matching cases to controls in our article and that there was a significant decrease in the number of matched controls with increasing dose. We did not report the proportion of cases in each dose group that were successfully matched in our original article, but in fact the proportion of cases fully matched to 4 controls did not differ substantially among groups (range, 81.1% to 84.1%, including 83.2% among people prescribed ≥200 mg of ME/d). Dr Williamson correctly suggests that our observational study cannot elucidate a causal relationship between opioid dose and related mortality. However, a randomized controlled trial assessing the relationship between opioid-related mortality and dose is neither feasible nor ethical. We must therefore rely on well-designed observational studies1-3 to shed light on this important drug safety issue. Finally, we agree with Dr Williamson that chronic pain may be so severe that it increases the risk of suicide. However, given the absence of evidence that high-dose opioid therapy reduces the risk of suicide and the presence of evidence that many individuals commit suicide with opioids,4 the risk of suicide is yet another reason to prescribe opioids particularly cautiously to individuals with chronic nonmalignant pain. Back to top Article Information Correspondence: Ms Gomes, Ontario Drug Policy Research Network, Institute for Clinical Evaluative Sciences (ICES), 2075 Bayview Ave, G-Wing, Toronto, ON M4N 3M5, Canada (tara.gomes@ices.on.ca). Financial Disclosure: Dr Dhalla receives salary support in the form of a postdoctoral fellowship from the Canadian Institutes of Health Research. Disclaimer: The opinions, results and conclusions reported in this letter are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. References 1. Gomes T, Mamdani MM, Dhalla IA, Paterson JM, Juurlink DN. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med. 2011;171(7):686-69121482846PubMedGoogle ScholarCrossref 2. Dunn KM, Saunders KW, Rutter CM, et al. Opioid prescriptions for chronic pain and overdose: a cohort study. Ann Intern Med. 2010;152(2):85-9220083827PubMedGoogle Scholar 3. Bohnert AS, Valenstein M, Bair MJ, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011;305(13):1315-132121467284PubMedGoogle ScholarCrossref 4. Dhalla IA, Mamdani MM, Sivilotti ML, Kopp A, Qureshi O, Juurlink DN. Prescribing of opioid analgesics and related mortality before and after the introduction of long-acting oxycodone. CMAJ. 2009;181(12):891-89619969578PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

Opioids and Dose-Related Deaths—Association or Causation?—Reply

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Publisher
American Medical Association
Copyright
Copyright © 2011 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinternmed.2011.453
Publisher site
See Article on Publisher Site

Abstract

In reply We believe Dr Williamson has misinterpreted some aspects of the methodology of our study and its findings. Dr Williamson states that an unadjusted analysis reveals no association between higher opioid dose categories and opioid-related mortality. This is incorrect. Although not reported in our published article,1 the association between dose and opioid-related mortality was consistent in our unadjusted conditional logistic regression model for the primary outcome (odds ratio, 2.32, 2.97, and 3.69 among those prescribed 50-99 mg of morphine equivalents per day [ME/d], 100-199 mg of ME/d, and ≥200 mg of ME/d, respectively, compared with the 1-19 mg of ME/d group; P < .001 for all comparisons). Although the 95% confidence intervals overlap between high and moderate dose categories, a clear and significant association between higher doses of opioids and opioid-related mortality is apparent in both unadjusted and adjusted models. Dr Williamson further states that we had difficulty matching cases to controls in our article and that there was a significant decrease in the number of matched controls with increasing dose. We did not report the proportion of cases in each dose group that were successfully matched in our original article, but in fact the proportion of cases fully matched to 4 controls did not differ substantially among groups (range, 81.1% to 84.1%, including 83.2% among people prescribed ≥200 mg of ME/d). Dr Williamson correctly suggests that our observational study cannot elucidate a causal relationship between opioid dose and related mortality. However, a randomized controlled trial assessing the relationship between opioid-related mortality and dose is neither feasible nor ethical. We must therefore rely on well-designed observational studies1-3 to shed light on this important drug safety issue. Finally, we agree with Dr Williamson that chronic pain may be so severe that it increases the risk of suicide. However, given the absence of evidence that high-dose opioid therapy reduces the risk of suicide and the presence of evidence that many individuals commit suicide with opioids,4 the risk of suicide is yet another reason to prescribe opioids particularly cautiously to individuals with chronic nonmalignant pain. Back to top Article Information Correspondence: Ms Gomes, Ontario Drug Policy Research Network, Institute for Clinical Evaluative Sciences (ICES), 2075 Bayview Ave, G-Wing, Toronto, ON M4N 3M5, Canada (tara.gomes@ices.on.ca). Financial Disclosure: Dr Dhalla receives salary support in the form of a postdoctoral fellowship from the Canadian Institutes of Health Research. Disclaimer: The opinions, results and conclusions reported in this letter are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. References 1. Gomes T, Mamdani MM, Dhalla IA, Paterson JM, Juurlink DN. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med. 2011;171(7):686-69121482846PubMedGoogle ScholarCrossref 2. Dunn KM, Saunders KW, Rutter CM, et al. Opioid prescriptions for chronic pain and overdose: a cohort study. Ann Intern Med. 2010;152(2):85-9220083827PubMedGoogle Scholar 3. Bohnert AS, Valenstein M, Bair MJ, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011;305(13):1315-132121467284PubMedGoogle ScholarCrossref 4. Dhalla IA, Mamdani MM, Sivilotti ML, Kopp A, Qureshi O, Juurlink DN. Prescribing of opioid analgesics and related mortality before and after the introduction of long-acting oxycodone. CMAJ. 2009;181(12):891-89619969578PubMedGoogle ScholarCrossref

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Oct 10, 2011

Keywords: opioids

References