Cause-specific excess mortality in people who use opioids illicitly: systematic review and meta-analysis

Background: Illicit opioid use is associated with high levels of morbidity and mortality. A previous systematic review determined all-cause and cause-specific mortality rates, but did not provide measures of excess mortality for specific causes. Understanding excess mortality is crucial for quantifying disease burden attributable to illicit opioid use and identifying areas in need of intervention focus. We updated the previous review to determine all-cause and cause-specific mortality rates and excess mortality associate with illicit opioid use.

Method: We searched Medline, Embase, and PsycInfo for cohort studies reporting crude mortality rates (CMR) and standardised mortality ratios (SMR) among people who use illicit opioids published from 2009 to the present day. Data from studies prior to 2009 were extracted from the previous systematic review. Included cohorts were those of people who use or inject heroin or other illicit opioids, including extra-medical use of pharmaceutical opioids. Pooled CMRs and SMRs were estimated using Stata.

Results: In total, 102 cohorts including 1,234,621 people and 5,109,108 person-years (py) of follow-up were available for analysis. The all-cause CMR among people using illicit opioids was 1.7 per 100 py (95% CI: 1.5, 1.8); among people who injected opioids, the CMR was 2.9 per 100 py (95% CI: 2.0, 4.3). Globally, all-cause mortality was 12 times the expected rate (SMR 11.6; 95% CI: 9.5, 13.6), rising to 17 times the expected rate (SMR 17.2; 95% CI: 12.6, 21.8) for people who inject opioids. Using studies that defined drug-related deaths to include overdose and drug dependence, the CMR was 0.6 per 100 py (95% CI: 0.6, 0.7) and SMR 49.5 (95% CI: 28.0. 71.0); for those studies that included only poisonings under drug-related deaths, the CMR was 0.5 per 100 py (95% CI: 0.4, 0.6) and SMR 66.2 (95% CI: 28.5, 103.9). AIDS-related mortality rates were similarly high, at 0.5 per 100 py (95% CI: 0.4, 0.5), and elevated relative to the general population (SMR 25.0; 95% CI: 11.7, 38.2). Significant excess mortality was also observed for a range of other causes, including liver-related deaths (SMR 8.5; 95% CI: 5.0, 12.1), violence (SMR 7.7; 95% CI 5.1, 10.3), accidental injuries (SMR 7.4; 95% CI: 4.7, 10.2), and suicide (SMR 6.6; 95% CI 5.3, 7.8).

Conclusions: Drug-related and AIDS-related causes continue to be the leading causes of deaths in this group, but this meta-analysis highlights that liver disease and trauma – accidental, self-inflicted, and inflicted by others - contribute significantly to mortality. Many of these deaths are preventable through access to existing medicines, including naloxone, HIV antiretroviral therapies, and hepatitis C antiviral therapies. Mental health care, treatment for substance use disorders (including non-opioid disorders), and structural interventions that address causes of violence are needed to assist in reducing traumatic deaths.