Citation

Giovanni ND, Fucci N. Forensic Toxicol. 2013; 31(2): 347-350.

Copyright

(Copyright © 2013, Holtzbrinck Springer Nature Publishing Group)

DOI

10.1007/s11419-013-0180-y

PMID

unavailable

Abstract

Conventional opioid drugs, such as heroin [1] and morphine [2], pose a constant threat to society through their abuse and links to the criminal underworld. Methadone is a synthetic diphenylpropylamine, similar in structure to acetylmethadol and propoxyphene [3]; although it is chemically different from morphine, it has similar clinical actions and analgesic effects [4, 5]. For this reason, it is employed in the treatment of opioid-dependent persons such as chronic heroin users [6, 7]. The use of methadone in therapeutic treatment is widespread, but it is also recognized that the goal of predictable and reproducible dosing is confounded by considerable variability in methadone pharmacokinetics [8]. After oral administration, methadone appears in the blood stream within 30 min with a bioavailability ranging from 70 to 90 %. It takes about 2-4 h to reach peak plasma concentration and it has a long but variable plasma half-life (15-55 h). It is widely distributed amongst tissues, highly bound to tissue proteins, primarily metabolized in the liver by N-demethylation and cyclization to the main metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), and is finally eliminated unconjugated [4]. Despite evidence supporting the benefits of methadone maintenance treatment, methadone itself has been associated with drug-related deaths [9, 10]. Literature data show that the blood methadone range in therapeutically treated persons is 30-1240 ng/ml, while methadone has also been found in people not in a maintenance program in a range of 30-990 ng/ml [9]. According to The International Association of Forensic Toxicologists (TIAFT) the therapeutic blood concentration of methadone is usually in the range 50-500 ng/ml but users often show values higher than 750 ng/ml. The acute intoxication however can be reached with concentrations ranging from 200 to 1000 ng/ml (http://www.tiaft.org). The lowest postmortem concentrations given as fatal in various studies have ranged from 60 to 320 ng/ml [3, 11]. These studies indicated that there is an overlap between the therapeutic concentration and those recorded in some methadone fatalities. Deaths caused by methadone intoxication primarily in combination with other drugs are becoming more frequent [9, 12]. In recent years, a number of reports have indicated an increase in methadone-related deaths, although the role of methadone in lethal intoxications has not been completely clarified [13, 14].
The authors performed a retrospective study of violent deaths that occurred in Rome from 2000 to 2010. In the period considered, about 4000 corpses were submitted for autopsy and 680 of them (17 %) were submitted for toxicological analysis to detect possible drug consumption as requested by the court. Routinely, we employ the systematic toxicological analysis procedure (STA) as recommended by TIAFT guidelines (http://www.tiaft.org). For our study, we considered 47 cases in which methadone was detected in blood (alone or together with other drugs) by postmortem drug testing. For each case, we obtained circumstantial and demographic data to assist in the interpretation of toxicological findings. Based on the toxicological identification of drugs, we classified the deaths into one of five categories as specified in Table 1. Only 40 cases were considered as true methadone-related deaths, because 7 deaths were related to other violent events. According to literature data [9, 15], we noted an overlap of blood concentrations of methadone both in methadone-related deaths and in other violent deaths; in addition, multidrug intoxications showed similar blood concentrations of methadone.

Language: en