The Burden of Opioid-Related Mortality in the United States

IMPORTANCE Opioid prescribing and overdose are leading public health problems in North America, yet the precise public health burden has not been quantified. OBJECTIVE To examine the burden of opioid-related mortality across the United States over time. DESIGN, SETTING, AND PARTICIPANTS This study used a serial cross-sectional design in which cross sections were examined at different time points to investigate deaths from opioid-related causes in the United States between January 1, 2001, and December 31, 2016. MAIN OUTCOMES AND MEASURES Opioid-related deaths, defined as those in which a prescription or illicit opioid contributed substantially to an individual’s cause of death as determined by death certificates. We compared the percentage of deaths attributable to opioids and the associated person-years of life lost by age group. RESULTS Between 2001 and 2016, the number of opioid-related deaths in the United States increased by 345%, from 9489 to 42 245 deaths (33.3 to 130.7 deaths per million population). By 2016, men accounted for 67.5% of all opioid-related deaths, and the median (interquartile range) age at death was 40 (30-52) years. The percentage of deaths attributable to opioids increased in a similar fashion. In 2001, 0.4% of deaths (1 in 255) were opioid related, rising to 1.5% of deaths (1 in 65) by 2016, an increase of 292%. This burden was highest among adults aged 24 to 35 years. In this age group, 20.0% of deaths were attributable to opioids in 2016. Among those aged 15 to 24 years, 12.4% of deaths were attributable to opioids in 2016. Overall, opioid-related deaths resulted in 1 681 359 years of life lost (5.2 per 1000 population) in the United States in 2016, most of which (1 125 711 years of life lost) were among men. Adults aged 25 to 34 years had 12.9 years of life lost per 1000 population, and those aged 35 to 44 years had 9.9 years of life lost per 1000 population. CONCLUSIONS AND RELEVANCE Premature death from opioid-related causes imposes an enormous public health burden across the United States. The recent increase in deaths attributable to opioids among those aged 15 to 34 years highlights a need for targeted programs and policies that focus on improved addiction care and harm reduction measures in this high-risk population. JAMA Network Open. 2018;1(2):e180217. doi:10.1001/jamanetworkopen.2018.0217


Introduction
Increased rates of opioid prescribing and the associated negative health consequences have emerged as leading public health problems in North America, 1 particularly among young and middleaged adults. 2 By 2014, Canada and the United States had the highest per capita opioid consumption in the world, 3 and deaths related to opioid use have increased dramatically in both countries. 2,4,5 Importantly, opioid-related death rates are increasing most quickly among adults aged 25 to 44 years

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in the United States. 2 Consequently, the public health burden resulting from early loss of life is substantial.
Despite this, there is little recent information on the burden of opioid-related deaths in the United States. One study measuring the burden of opioid addiction globally in 2010 found that in North America, opioid dependence was responsible for nearly 1 million disability-adjusted life-years annually. 6 This study also found that more than half of disability-adjusted life-years were attributable to years of life lost (YLL), 6 indicating the important role that early loss of life has when quantifying the burden of opioid-related harm. In the United States, prescription opioid overdose contributed to 830 652 YLL among people younger than 65 years in 2008 7 ; however, this estimate was based on crude estimates of burden. Given the rapidly rising rate of opioid-related death across the United States, as well as the dramatically increasing role of fentanyl and other illicit opioids, more recent estimates of this burden are required. We therefore sought to quantify the burden of opioid-related death in the United States, and to compare this burden over time and by age and sex.

Study Setting and Population
This study used a serial cross-sectional design in which repeated cross sections were examined over

Opioid-Related Deaths
We obtained population-based estimates of all deaths related to prescribed or illicit (eg, heroin and fentanyl derivatives) opioids in the United States using the CDC WONDER database. Consistent with the CDC, 9 we defined opioid-related deaths as those with an underlying cause of death related to

Burden of Opioid-Related Deaths
To explore the burden of opioid-related deaths by age, we stratified patients into 7 age groups at the time of death: 0 to 14 years, 15 to 24 years, 25 to 34 years, 35 to 44 years, 45 to 54 years, 55 to 64 years, and 65 years or older. We quantified the burden of opioid-related death in 2 ways. First, we identified the proportion of all deaths in each age group that were opioid related using age-specific all-cause mortality estimates as the denominator. Second, we calculated the YLL due to opioidrelated death using methods adapted from the Global Burden of Disease study. 10 We calculated YLL using standard 5-year life expectancy tables developed by the World Health Organization and did not apply discounting or age weights to align with the organization's most recent guidance. 10 We calculated YLL for men and women by multiplying the number of deaths by the standard life expectancy and adjusting for the average age at death within each 5-year age group. The YLL were aggregated into 10-year age groups overall and stratified by sex.

JAMA Network Open | Substance Use and Addiction
The Burden of Opioid-Related Mortality in the United States, 2001-2016

Statistical Analysis
We used descriptive statistics to summarize demographic characteristics of opioid-related deaths over the study period (numbers and percentages for binary variables, and median and interquartile range for continuous variables). In our analysis of the age-specific proportion of deaths attributable to opioids, we compared percentages in the years 2001, 2006, 2011, and 2016 using the Cochran-Armitage test for trend for each age group. All analyses used a 2-sided type I error rate of .05 as the threshold for statistical significance.

Results
Over  (Table); however, this varied by age and sex. In particular, when stratified by age, adults aged 25 to 34 years and those aged 35 to 44 years experienced the highest burden from opioid-related deaths (12.9 YLL per 1000 population and 9.9 YLL per 1000 population, respectively). We also found that the burden of opioid-related death was higher among men (1 125   The proportion of deaths in each age group that involved an opioid was calculated using opioid-related death data and all-cause mortality data. Death data were obtained from the Centers for Disease Control and Prevention WONDER online database. This analysis was performed at four 5-year time intervals between 2001 and 2016.

Discussion
In this population-based study of the burden of opioid-related deaths in the United States, we found that 1 in 65 deaths was opioid related in 2016, representing an enormous toll in YLL. Indeed, in the United States, the YLL from opioid-related deaths exceed those attributable to hypertension, HIV/AIDS, and pneumonia and amount to approximately one-tenth of the YLL due to cancer. 11,12 Furthermore, this burden is highest among adults aged 25 to 34 years; in this age group, 1 in 5 deaths in the United States is opioid related.

Limitations
This study uses regularly collected population-based data from death certificates of US residents over a 15-year study period to generate population-based estimates of the current and changing burden of opioid-related deaths. One limitation that merits emphasis is the validity of our outcome definition. Death investigations are managed at the state level and generally consist of a medical examiner system, coroner system, or a combination of the two. 14 These systems may lead to differential ascertainment of opioid-related deaths across the country because the determination of opioid involvement relies on the quality of the death investigation, including whether autopsy and postmortem toxicology results are obtained. Therefore, because the absence of postmortem toxicology results could inappropriately misclassify some deaths as not opioid related, it is likely that our results underestimate the true burden of opioid-related death across the country. Despite this, the definition used in this study is consistent with reporting of opioid-related deaths that is regularly conducted by the CDC, 9 and these findings are therefore comparable with other regularly reported national statistics.

Conclusions
Premature death from opioid-related causes imposes an enormous and growing public health burden across the United States. The recent increase in the proportion of deaths attributable to opioids among adolescents and young adults and the accompanying estimates of YLL are alarming, particularly among men. Furthermore, the aging population of people with opioid use disorder requires attention, as the burden of opioid overdose among adults aged 55 to 64 years is growing at a concerning rate. These trends highlight a need for tailored programs and policies that focus on both appropriate prescribing and harm reduction in these demographics.
Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer:
The opinions, results, and conclusions reported in this article are those of the authors and are independent from the funding sources. No endorsement by the Institute for Clinical Evaluative Sciences, the Strategy for Patient-Oriented Research Unit of the Canadian Institutes of Health Research, or the Ontario Ministry of Health and Long-Term Care is intended or should be inferred.