Assessment of risk factors associated with methadone-induced deaths: A population study based on forensic autopsies...

Population-based study of methadone-induced deaths (2003-2022) and associated risk factors.

All deaths with blood presence of methadone and forensic autopsy performed in Biscay (Basque Country, Spain) were included. Comprehensive autopsies, clinical records, toxicological and histopathological studies were analyzed. Multiple logistic regression analysis identified risk factors associated with methadone-induced deaths, using methadone-incidental deaths as controls.

Methadone was detected in 369 individuals, mainly middle-aged men. Deaths were classified as methadone-induced (n = 261) or methadone-incidental (n = 108). Among methadone-induced deaths, 93 % had a substance use disorder, and 48 % were in methadone maintenance treatment programs. Chronic liver (51 %), pulmonary (39 %), and cardiac (23 %) diseases were common. Prescribed psychotropic drugs were detected in 93 % of subjects (benzodiazepines 91 %; psychotropics that prolong QT 46 %). Illicit drugs (cocaine [44 %], cannabis [32 %], heroin [26 %], and amphetamine [15 %]) were also frequent. Use of benzodiazepines (OR=5.03) or psychostimulants (OR=2.65) emerged as primary risk factors for methadone-induced deaths. Presence of another psychotropic drug in addition to methadone increased risk by 2.42 times, and two or more prescribed drugs by 3.45. Presence of > 2 illicit drugs enhanced risk by 2.83. Combination of 1-2 illicit and/or psychoactive substances increased the risk by 5.25, 3-4 substances by 9.56, and > 5 by 11.97.

This forensic study reveals that poly-drug use is a major contributor to methadone-related fatalities. Concomitant use of methadone with benzodiazepines or psychostimulants is particularly hazardous. Pharmacological interactions must be carefully assessed in methadone users. Our findings underscore the value of forensic data in identifying lethal drug combinations and supporting safer prescribing practices and public health strategies.