Characterizing post-mortem blood concentrations in methadone-related deaths

Methadone is a widely used opioid agonist in maintenance therapy for opioid addiction; however, its global diversion is increasing. Determining methadone's role in drug-related deaths is often challenging due to its pharmacological properties, such as tolerance, and the co-consumption of psychotropic substances. This study aims to identify the demographic, clinical, and therapeutic characteristics of methadone-related deaths to support forensic interpretation. A systematic literature review was conducted to retrieve and analyze publications on methadone-related deaths that included post-mortem toxicological analyses. The data were integrated with methadone-related death cases examined at the Institute of Forensic Medicine in Bologna. The literature review identified 58 articles for data extraction. Aggregated data were available in 29 papers, while individual-level data were reported in 30 studies (with one paper providing both). The aggregated data comprised 3,148 cases, with a median of 80 cases per study (interquartile range, IQR 32-129). A total of 240 individual cases were retrieved from the literature (n = 204) and Bologna's Forensic Medicine records (n = 36). Among these, 27 were children, 190 were adults, and 23 had no reported age. The median blood methadone concentration was 300 ng/mL (IQR 195-600 ng/mL) in children and 503 ng/mL (IQR 300-933 ng/mL) in adults, overlapping with levels observed in living patients undergoing methadone maintenance therapy. Statistically significant differences in methadone blood concentrations were found between deaths attributed solely to methadone and those involving multidrug intoxication, with higher concentrations observed in the former group (p < 0.001). This review confirms previous findings on the overlap between therapeutic and toxic methadone blood concentrations, highlighting the increasing risk of multidrug intoxications. The extensive number of cases collected and reviewed serves as a valuable resource to assists forensic pathologists in interpreting post-mortem methadone concentrations in relation to the cause of death.