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6:Methadone related deaths: identifying the vulnerable patients
Mariarosaria Aromatarioa, Paola Antonella Fiorea, Simone Cappellettia, Edoardo Bottonia, Costantino Ciallellaa,*
aDepartment of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences 
�Sapienza� University of Rome
Viale Regina Elena, 336 � 00161 Rome, Italy

*Corresponding author:
Costantino Ciallella
Phone: 00390649912618
Fax: 0039064455335
e-mail:  HYPERLINK "mailto:costantino.ciallella@uniroma1.it" costantino.ciallella@uniroma1.it 
Viale Regina Elena, 336 � 00161 Rome, Italy

Abstract
Methadone has been used in opioid dependence treatment since the 1960s and is now prescribed also as a chronic pain treatment. Even though its effectiveness has been worldwide assessed, literature reports several cases of death associated with the assumption of this drug. Risk factors are still uncertain and the frequent combination with other substances of abuse makes it even more difficult to determine the exact role of methadone in the pathogenesis of lethal events. In this paper the authors want to present the autoptic findings in an extremely restricted sample of deaths characterized by blood being positive for the sole methadone. The aim of this work is to point out those preexistent pathologic conditions that seem to increase the risk of death in methadone treatment, in order to achieve a better selection of the patients prior to treatment.

Introduction
Methadone is a full �-opioid agonist that inhibits monoamine reuptake and N-methyl-D-aspartate receptors. It is metabolized in the liver by the P450, CYP3A4; it is a weak inhibitor of the C3A4 system and a minor weak substrate of 2C89, 2C19 and 2D6 [1-2]. Since the 1960s it has been used to treat heroin addiction.[3]. Several studies have shown Methadone Maintenance Treatment (MMT) to reduce crime, HIV seroconversion and risk of death when compared to illegal heroin abuse, though in recent years its increased use not only in MMT but also in chronic pain management has evidenced methadone�s negative aspects, such as adverse effects and related deaths. The worldwide diffusion of the substance justifies its frequent retrieval during the routine toxicological analysis performed on urine and blood samples collected during forensic autopsies, but establishing whether its assumption is involved in the pathogenesis of death or not, is far more complicated [4-12]. Where multiple substances are detected, it may not be possible to identify which substance was the principal cause of poisoning, and hence, mentions of methadone on the death certificate may be incidental [13].
Unlike other drugs, the lethal concentration in blood is uncertain as the range varies from 0.4 to 4.07 �g/ml, with a median concentration of 1.0 �g/ml (see Figure 1); it appears to be influenced by several individual factors such as age, enzymatic asset (perhaps related to the genetic polymorphisms of the C3A4 system), liver and kidney function, while the way of assumption (oral or i.v) doesn�t seem to make any difference. Moreover most of the times methadone is detected together with multiple substances (e.g.: alcohol, benzodiazepines, amphetamines, other opioids.).
In order to overcome the lack of knowledge about the lethal effect of methadone alone and with the aim of highlighting the influence of individual risk factors, such as preexistent conditions, in increasing the risk of death during methadone assumption, we decided to concentrate on the cases in which the post mortem toxicological analysis detected methadone alone. 
Even though such eventuality isn�t common among all the cases in which methadone can be found, its study may provide a valuable contribution in understanding the role of methadone in the causation of death. The importance of such acknowledgement is easier to understand considering that now, more than ever, the increased diffusion of methadone on medical prescription determines a growing responsibility of the doctor when adverse events occur.
Figure 1

Materials and Methods
A routine screening test for blood alcohol using headspace gas chromatography and the search of a broad spectrum of drugs on urine samples (including methadone, benzodiazepines, cocaine, amphetamines/methamphetamines, opioids, barbiturates, tetrahydrocannabinol, tricyclic antidepressants) using the ASCENDTM Multi-immuno-assay kit (TriageTM8 - Merk�) were performed on all the suspect drug-related deaths during one year (2011); the results of those who were positive for the presence of methadone were confirmed by Gas Chromatography - Mass Spectrometry (GC-MS).
Among all the cases positive for methadone (n. 51), only the ones that resulted negative for any other searched substance were included in this work.
Autopsy was performed in every case and was completed by collecting specimens of the organs for histological analysis. Where there was no macroscopic evidence of organ lesion requiring special observation, the specimens were collected according to the following scheme: 1 from the brain, 4 from the heart (right anterior ventricular wall, free ventricular wall, left ventricular wall, septum)1 from each pulmonary lobe, 1 from the liver, 1 from the pancreas, 1 from each kidney, 1 from the spleen. A routine microscopic histopathological study was performed on specimens fixed by using buffered formalin 10%, embedded in paraffin and stained with hematoxylin/eosin. All specimens were examined with a light microscope (DMLB 100T Leica, Wetzlar). 
In each case, information about the circumstances of death and the clinical history, with particular referral to the drug abuse habits, was collected. 
It was not possible to get the details of the methadone maintenance treatment that the subjects were following prior to death. 
Results
The cases respecting our inclusion criteria were 8 (15,7%), 6 male and 2 female; the mean age was 34.8 years old (range 21-45 years old); at the time of death they all were being treated for heroin addiction with MMT. 3 died out in the street, 2 died in a private home, 1 died in a car and 2 died in prison.
In each case both the autoptic and histological findings demonstrated preexistent conditions affecting the heart and lungs and/or the liver.
In particular evidence of hypetrophic or dilatative cardiomyopathy and early signs of myocardial ischaemia such as contraction bands and ondulation of the fibers could be seen while observing the heart specimens. 
Evidence of flogosis was often observed in the lungs as the expression of pathological patterns going from isolated inflammatory foci to  HYPERLINK "http://www.google.it/url?sa=t&rct=j&q=pulmonar%20flogosis%20bronchopneumonia&source=web&cd=2&cad=rja&ved=0CDcQFjAB&url=http%3A%2F%2Fen.wikipedia.org%2Fwiki%2FBronchopneumonia&ei=CXMkUbmHPMqu4ASVsYCQCA&usg=AFQjCNFFKoeoaWiWxy72zPjx_avD6j4YxA&bvm=bv.42661473,d.bGE" bronchopneumonia. 
Chronic active flogosis of the porto-biliary spaces was almost constantly present variously associated with aspects of steatosis or of severe macronodular cirrhosis.
Figure 2
The blood concentration of methadone was in a range between 0.5 and 0.9 which is consistent with assumption for therapeutic purposes during MMT. Among the 8 cases observed only in one the methadone concentration (17 �g/ml) highly exceeded the therapeutic dose and was compatible with an acute intoxication; in this particular case (case 1, Figure 2) the analysis of the circumstantial data evidenced that the deceased had received the methadone for a complete month of treatment a few days earlier.

Discussion 
Aside from the great enthusiasm for the effectiveness of MMT in the treatment of opioid dependence � as in several Cochrane reviews - and the World Health Organization�s proposal to include methadone as an essential medicine, lethal events related to blood tests positive for methadone are always more often cited in literature [6; 14-15]. In the majority of the reported cases, methadone is detected together with other substances which are known to have a depressant effect on the respiratory system (e.g. benzodiazepines, opioids and alcohol), therefore its role in the pathogenesis of death cannot be clearly determined [12]. In literature there are only few referrals to the mortality rate in cases in which methadone is detected alone and the reported percentages appear to be way below the 15.7% we found our experience [12, 16].
However, due to its variable pharmacokinetics and its known association with electrocardiographic QT complex (QTc) prolongation and the subsequent increased risk of the onset of a fatal arrhythmia, known as Torsade de Pointes (TdP), methadone can be considered a possible cause of death itself or, at least, a potential risk factor for vulnerable patients [17-18].
In order to identify useful signs to promptly recognize the vulnerable patients we decided to focus on macro and microscopic peculiar aspects in patients who died after the sole assumption of methadone at therapeutic dose.
In this discussion we are going to exclude the one case of acute intoxication (case 1. Figure 2).
The 7 remaining cases in our experience were characterized by evidence of preexistent conditions affecting the lungs, the heart and the liver which can be considered to be in strict relationship with the lethal effects of methadone.
The frequent evidence of pulmonary flogosis, especially when it is massive, is for itself a possible risk factor for respiratory depression. Drug abusers, because of their irregular lifestyle, frequent poor nutrition and immune-depression, are more susceptible to respiratory infections; moreover opioids in general and methadone in particular increase the risk of ab ingestis pneumonia as, not only they have a pro-emetic effect, but they also inhibit the cough reflex [19]. 
The pathological alterations that were observed in the heart tissue recall the aspect of sudden cardiac death with signs of acute myocardial ischaemia. According to the latest studies methadone would be responsible for a QTc prolongation, which, in some patients, evolves in a lethal arrhythmia known as TdP. No dose relation has yet been found between methadone and QTc prolongation, nor the risk factors for TdP have been ascertained. At the present moment, high daily doses of methadone, medications that cause QTc prolongation, or inhibit CYP3A4, hypomagnesemia, hypokaliemia, a history of unexplained syncope or seizures should be considered risk factors for TdP and evaluated in risk benefit analysis before starting MMT [20-21].
As far as the liver abnormalities we described in �Results� are concerned, it is important to consider that they deeply influence the metabolism of the methadone slowing it down. Preexistent conditions affecting the liver therefore represent another important risk factor in patients in MMT, especially during the induction period which is already for itself characterized by low elimination, long half life and tendency to accumulate of the methadone.
Defining the role of methadone in the pathogenesis of death of patients in MMT or in chronic pain treatment is often a hard challenge for the forensic pathologists as the underlying causes that lead to an increased susceptibility may be superimposed by the toxicity of the methadone itself. In the lack of guidelines for the therapeutic use of methadone it is our strong believe that our study can be a starting point in identifying potential vulnerable patients prior to treatment in order to achieve a better risk-benefit rate and, in the end, reduce the mortality rate in patients in MMT, which appears to be significantly higher in comparison with the same age groups in the general population [22]. 
According to our study, the frequent evidence of heart, lung and liver conditions in MMT related deaths, suggests an accurate screening focused on these organs should be performed on the patients prior to the beginning of treatment. A strict and targeted follow up should also be scheduled in order to promptly identify signs and symptoms associated to the onset of those clinical conditions that may increase the patient�s vulnerability to methadone assumption.

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