The current opioid crisis began as an influential campaign by pharmaceutical companies. New, potent opioids such as oxycodone were marketed as a less addictive and safer way to treat chronic pain. ¹ With this emergence of widespread opioid prescriptions that began in 1999 came a surge in opioid-related overdose deaths. Over the next decade, the opioid-related mortality rate in the United States more than doubled from 2.9 to 6.9 per 100,000 from 1999 to 2010. ² The second and third waves of the opioid crisis were attributed primarily to a rise in popularity of heroin and fentanyl, respectively. In 2021, this rate soared to 21.4 deaths per 100,000 people, with a record 80,816 deaths that year. ³ Starting in 2016 with the Comprehensive Addiction and Recovery Act, the federal government began enacting multiple pieces of legislation aiming to expand access to care for those suffering from addiction, curtail the overprescription of opioids, and bolster prohibitions and sanctions relating to the import of narcotics into the country. ²

The COVID-19 pandemic put significant strain on the American healthcare system and inhibited routine access to all forms of healthcare, including addiction treatment and rehabilitation services. Epidemiological evidence suggests a disproportionate impact of the opioid crisis across varying regions, ethnicities, races, and socioeconomic groups. ⁴ Our study expands on the existing literature regarding opioid-related mortality by focusing on regional differences in opioid use, the impact of COVID-19, and various epidemiological factors. Analyzing regional disparities in opioid-related mortality may elucidate underlying issues and reveal insights to facilitate the development of more effective treatment solutions for regions experiencing elevated mortality rates. Furthermore, previous studies are limited to pre-pandemic data and thus do not analyze the effect of COVID-19 on opioid abuse across the country. We aim to use the Centers for Disease Control and Prevention’s WONDER database to improve our understanding of the impact that the COVID-19 pandemic and its various social and economic consequences have had on the number of opioid-related deaths in the United States across race, gender, and region.

The Centers for Disease Control and Prevention’s Wide-ranging Online Data for Epidemiologic Research was utilized to track opioid-related deaths in the United States over time. ⁵ We analyzed records from the Multiple Cause-of-Death Public Use Record and the CDC WONDER database to assess the presence of opioid-related causes of death listed as contributing factors on nationwide death certificates. This database has been employed in various studies to examine mortality trends related to different diseases, including drug overdose. ^{6– 8} Data was obtained by selecting current final multiple causes of death and the year ranges of 1999-2020 and 2018-2022. Opioid-related mortality was identified using the International Classification of Diseases, 10th Revision, Clinical Modification codes T40.0-T40.4 for individuals aged 15 and older. This age range was selected because opioid-related deaths are rare among individuals under 15. The results from all states were chosen and split up by region and by state level data. Institutional review board approval was not required for this study, as the CDC WONDER database provides anonymized and publicly accessible data.

We extracted data on opioid-related deaths and population sizes from 1999 to 2023, including demographic and regional information such as gender, race/ethnicity, age, region, and state-level information. Racial/ethnic groups were defined as non-Hispanic (NH) White, NH Black, NH American Indian/Alaskan Native, NH Asian/Pacific Islander, and Hispanic people as identified on death certificates. Regions were classified into Northeast, Midwest, South, and West according to the Census Bureau definitions. ⁹

We calculated both crude and age-adjusted mortality rates (AAMR) for opioid-related deaths. We then used the Joinpoint Regression Program (Joinpoint version 4.9.0.0 available open access from National Cancer Institute, Bethesda, Maryland https://surveillance.cancer.gov/joinpoint/) to determine trends in mortality within the study period. ^{6– 8} This software employs Joinpoint regression to identify significant shifts in annual mortality patterns by fitting models with linear segments to periods of notable temporal change. The annual percentage change (APC) in age-adjusted mortality rates (AAMRs), along with 95% confidence intervals (CIs), was calculated for each segment defined by a Joinpoint using the Monte Carlo permutation test. To summarize the overall mortality trend across the study period, the weighted average of the APCs was presented as average annual percentage changes (AAPCs), along with their corresponding 95% CIs. An APC or AAPC was classified as increasing or decreasing if the slope representing the change in mortality over the interval significantly differed from zero, determined using a two-tailed t-test. Statistical significance was set at p ≤ 0.05, denoted by an asterisk (*) in the results and figures.

Opioid use disorders (OUD) place a significant strain on healthcare systems and come with substantial financial costs to society, estimated at $7.3 billion annually in the U.S. ^{8, 10– 12} Despite this considerable spending, our study shows that OUD-related mortality continues to rise across all regions of the country. We observed an increase in the overall crude mortality rate from 1999 to 2023 in both the Midwest and the entire U.S. This study highlights several key trends in opioid use-related mortality.

This study revealed significant regional trends in age-adjusted mortality rates (AAMR). The Midwest exhibited the highest AAMR from 1999 to 2021, followed by the Northeast, which aligns with findings from earlier regional studies. ^{13– 15} However, our research indicated that the Midwest’s mortality rates were higher than the average of other U.S. regions between 2014 and 2021. One potential reason for this elevated mortality is limited access to treatment. A study by Cummings et al. showed that the Midwest and Southern regions had the highest number of counties lacking substance use disorder treatment facilities. ¹⁶ This lack of access may contribute to a larger number of individuals struggling with severe addiction, thereby increasing the risk of relapse and mortality rates. In addition, other factors contributing to regional differences in opioid use-related mortality include regional drug market differences, differences in opioid use patterns, and overall substance use patterns that differ between regions. Understanding these disparities in opioid use-related mortality in the Midwest can help guide targeted interventions to enhance outcomes.

This study also examined AAMR for populations of all races in the United States. The American Indian and Native Alaskan populations experienced the highest AAMR from 1999 to 2023. The Black population experienced the second-highest AAMR from 1999 to 2023. Previous research has identified non-White race as a risk factor for opioid use disorder (OUD). ^{17, 18} A study by Quintero et al. found that non-White populations are more likely to transition into OUD, although the rates of disorders varied by drug type and age. ¹⁸ These groups may face a higher risk of developing OUD due to significantly lower rates of completing OUD treatment, compounded by various socioeconomic and structural disparities including poverty, social isolation, and treatment access disparities. ^{18, 19}

Our study also tracked trends before and during the COVID-19 pandemic. From 2006 to 2019, the mortality gap between American Indian and Native Alaskan populations and others narrowed; however, this gap widened again after the onset of COVID-19, reversing earlier progress. Research has shown that non-white communities were disproportionately affected by the pandemic, leading to increased stress for these families and communities. ^{20, 21} This heightened stress may have contributed to rising substance use and related mortality during this time. The tight-knit nature of these communities, due to their culture and family units may have served as a source of resilience and acted as protective factors before the pandemic. However, the fragmentation of families and communities during the pandemic has been theorized to have become risk factors for increased behavioral addictions such as gambling and drug use based on current trends. ²² Furthermore, studies have found that along with the social disruptions caused by the pandemic, historical trauma and socioeconomic challenges have also contributed to the increased risk of behavioral addictions in these populations. ²² Overall, our findings underscore the importance of recognizing demographic and socioeconomic disparities and highlighting the specific needs of American Indian and Native Alaskan populations in the United States.

From 1999 to 2023, both crude mortality rates and AAMR were higher for men than for women. Men also experienced an increase in APC at the beginning of the COVID-19 outbreak, while women did not show any significant changes in trends during that period. Our findings align with other studies that have identified male sex as a risk factor for substance use-related mortality. ^{3, 18, 19, 23}

This study identified several notable changes following the onset of COVID-19. Opioid-induced deaths in the U.S. increased significantly and remained elevated from March 2020 through the end of 2021. Both the Midwest and other regions experienced a statistically significant increase in APC from 2019 to 2021. Additionally, men, as well as Black American Indian and Native Alaskan populations from all regions, saw a marked rise in AAMR. This timing coincides with the initial COVID-19 surge in the U.S. The pandemic had a profound effect on mental health, leading to increased opioid and substance use. ^{22, 24– 28} A study by Friedman and Akre reported a rise in drug overdoses after the COVID-19 outbreak, peaking in May 2020. ¹⁴ Another factor may be the overall decline in visits and access to OUDT facilities in 2020. Research by Cantor et al. indicated that weekly visits to these facilities dropped compared to 2019, with the most significant declines occurring in counties experiencing higher COVID-19 burdens. ²⁸ Overall, our findings align with existing research on the impact of COVID-19 on OUD. ^{7, 28} To mitigate spikes in opioid-related deaths during future crises, the U.S. must find ways to maintain access to OUD treatment and address negative coping strategies involving substances.

Our study shows that the United States opioid crisis has escalated during the COVID-19 pandemic, resulting in significant increases in mortality across various demographic groups and regions. The Midwest, especially West Virginia, saw the highest mortality rates, while Hawaii experienced the smallest increase. Despite the overall rise in the Midwest, Nebraska’s lower increase suggests notable regional differences that require further investigation. Our study highlights ongoing demographic and regional disparities in opioid-related behaviors and mortality, with certain disadvantaged groups particularly affected since COVID-19. Addressing these disparities is essential to reducing substance use-related mortality effectively.