To present 11-year results from DRAMES (“Décès en Relation avec l’Abus de Médicaments Et de Substances” or Deaths in Relation with the Abuse of Drugs and Substances) study and provide new insights into deaths at therapeutic concentration for two opioid substitution treatments (OSTs): methadone (MTD) and buprenorphine (BUP).

DRAMES study is an ANSM nationwide study initiated in 2005 in France. It is based on spontaneous declarations by forensic toxicologists and medical examiners of drugs of abuse related deaths in order to identify dangerous substances, assess their toxicity and monitor trends in fatalities. This database may be useful to better understand toxicity of MTD and BUP and therefore help forensic toxicologists in interpreting postmortem blood concentrations.

The study included data from 2010 to 2020, from 27 laboratories in France.

Drug imputability was determined cross-blinded by a forensic toxicologist and an addicto-vigilant pharmacist. A causality score from level 1 (high) to 4 (low) is assigned to each substance in connection with the occurrence of death according to the blood concentration and also making it possible to prioritize the molecules between them among those who are involved and those who are only identified. For level 1, depending on the number of molecules involved, the score breaks down into 1.0 (1 single substance), 1.1 (1 predominant substance), 1.2 (2 co-dominant substances) or 1.3 (at least 3 co-dominant substances). Monointoxication groups included 1.0 and 1.1 fatalities and polyintoxication group included 1.2 and 1.3 fatalities. Therapeutic concentrations were inferior to 200ng/mL and inferior to 10ng/mL for MTD and BUP, respectively. Non-parametric Mann-Whitney U tests were used to compare median concentrations between the different groups.

The study included 1519 MTD-related deaths and 423 BUP-related deaths. Among those, 334 and 319 deaths were within the therapeutic range for MTD and BUP, respectively.

For MTD at therapeutic concentrations, higher concentrations were observed in the monointoxication group than in the polyintoxication group (149 vs. 119ng/mL; P<.001). But there was no difference between the naive and treated with OST groups (143 vs. 142ng/mL; P=0.461). Nor age, gender, association with cocaine or QTc-interval prolongation inducing drugs had a statistically significant effect on MTD concentrations.

For BUP, at therapeutic concentrations, higher concentrations were observed in the monointoxication group than in the polyintoxication group (2.8 vs. 2.2ng/mL; P=0.048). BUP concentrations were also higher in treated with OST group than in naive ones (2.4 vs. 1.1ng/mL; P=0.005).

This study identified different pattern for MTD and BUP fatalities at therapeutic concentration. Interestingly and contrary to BUP, at therapeutic concentrations, MTD concentrations did not differ in people under treatment and the naive ones. It has been showed that MTD induces more QTc-interval prolongation than BUP. Interindividual differences in susceptibility to cardiac toxicity could be an explanation for the deaths that could not be explained by therapeutic concentration or drug combination alone.

This study identified a different pattern for BUP and MTD fatalities at therapeutic concentration, suggesting a different toxicity mechanistic for the two OSTs at these concentrations.