Sex Differences in Opioid-Related Mortality Trends in the United States, 1999-2020: By Age, Race/Ethnicity, Region, and Opioid Type.

Background: Previous studies on opioid-related mortality in the United States have largely focused on burden estimation by sex, with limited analysis of temporal trends in sex-based differences in opioid-related overdose deaths. This study examines opioid overdose mortality trends by sex in the United States from 1999 through 2020. Methods: We retrospectively analyzed mortality data from the National Center for Health Statistics' Multiple Cause of Death Files, from 1999 to 2020. Using International Classification of Diseases (ICD)-10 codes (X40-X44, X60-X64, X85, and Y10-Y14 in underlying causes; T40.0-T40.4 and T40.6 in multiple causes), we identified opioid-related overdose deaths. Sex-based mortality trends were analyzed across age, race/ethnicity, region, and opioid type using piecewise linear regression. Annual percentage changes (APCs) and average annual percentage changes were calculated, with model selection based on weighted Bayesian information criteria, and confidence intervals (CIs) estimated via the empirical quantile method. Results: From 1999 to 2020, 564,418 opioid-related overdose deaths were recorded in the United States. Men experienced a significantly higher mortality burden than women (mortality rate ratio = 2.11; 95% CI: 2.09, 2.12). Mortality rates in men also increased at a higher rate (APC = 14.9; 95% CI: 11.4, 21.0) than in women (APC = 8.0; 95% CI: 7.0, 8.8) across most age, race/ethnicity, region, and opioid-type categories. However, among women under 45 years, women in the Northeastern region, and women who died from synthetic opioid overdoses, mortality trends are higher compared with men. Conclusions: Although men exhibit higher opioid-related mortality trends overall, certain subgroups of women, under 45 years, those in the Northeast, and those affected by synthetic opioids, are experiencing worsening trends than men in recent years. Targeted interventions are needed to address the broader impact on men and the emerging risks among vulnerable groups of women.