Methadone and concomitant drugs in Methadone-Related Deaths – possible mechanisms of interactions

V Mijatovic1, I Samojlik1, S Petkovic0,2, N Ajdukovic0,2. 1Faculty of Medicine, University of Novi Sad, Department of Pharmacology, Toxicology and Clinical Pharmacology, 21000, Serbia, 2Faculty of Medicine, University of Novi Sad, Department of Forensic Medicine, 21000, Serbia

Methadone is an effective analgesic and it is widely used to suppress withdrawal symptoms from other opiates. Its consumption is usually associated with concomitant drug use in heroin addicts, and this combination is the possible risk factor for lethal outcome. The aim of this study was to analyze characteristics of methadone related deaths (MRDs), and to evaluate the concomitant use of the drugs that can contribute to methadone toxicity.

To investigate MRDs, 10 year retrospective study was carried out (January 2001 - December 2010) at the Institute of Forensic Medicine in Novi Sad, Clinical Centre of Vojvodina, Serbia. These data included age and sex of subjects, and drugs detected in post-mortem samples of blood and urine. Toxicological screening and quantification of drugs were carried out in blood and urine using gas chromatography-mass spectrometry. Methadone concentration in blood was defined to be lower than 200 µg/l, 200-1000 µg/l, and higher than 1000 µg/l.

The total number of 40 MRDs was identified – 19.05% of all deaths associated with fatal opiate-related poisoning. The median age of victims at the time of death was 31, whereas the majority of them (80%) were male. The concentration of methadone in blood and urine samples was quantified in 11 cases and in 9 of them it was lower than 200 µg/l (mean concentration 79.45 µg/l). In one case it was 245 µg/l, whereas in the other one methadone was detected only in urine in concentration of 1209 µg/l. In 7 cases only methadone was found (17.5 % of MRDs); 47.5% of MRDs was associated with other drugs - the average number of associated drugs was 3.5, while in blood samples of 35% of MRDs different illicit drugs were identified. The most frequent concomitants were one or more benzodiazepines (67.5% of MRDs), followed by antipsychotics (15%), tramadol (15%) and antidepressants (12.5%). The most commonly identified benzodiazepine was diazepam.

In MRDs the low methadone level combined with other drugs was most frequently noted. The mechanism of deaths can not be attributed to particular pathway. The most detected concomitants were well known inhibitors, inducers or metabolic substrates of CYP3A4 and CYP2D6 involved in metabolism of methadone. Moreover, they can increase the risk of torsades de pointes and respiratory depressant effect of methadone. Further studies could clarify the possible mechanism of death where methadone is used in combination with benzodiazepnes in order to prevent them.