Forensic Science International 257 (2015) 172176

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Forensic Science International

journal homepage: www.elsevier.com/locate/forsciint

Methadone-related deaths. A ten year overview

Claudia Vignali *, Cristiana Stramesi, Luca Morini, Fulvia Pozzi, Angelo Groppi
Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Via Forlanini, 12, 27100 Pavia, Italy

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 6 May 2015
Received in revised form 17 August 2015
Accepted 23 August 2015
Available online 31 August 2015

Over the last 10 years we have registered in our district (about 500,000 inhabitants) 36 cases of fatal
methadone poisoning, involving both patients on treatment and naive subjects: this is a signicant
increase of deaths due to methadone use, misuse or abuse compared with previous years.
Twenty-four patients (66.7%) were on methadone maintenance programs for heroin detoxication,
while 12 (33.3%) were taking the drug without a medical prescription. The average blood concentration
of methadone in patients undergoing a maintenance program was 1.06 mg/L (0.213.37 mg/L), against
0.79 mg/L (0.23.15 mg/L) in those taking the non-prescribed drug. Since 111 heroin-related deaths
were recorded in our district in the same period, the fact that there appear to be many methadone deaths
(about a third of heroin-related deaths) cannot be overlooked. The aim of this work is to understand the
possible reasons for such a large number of methadone-related deaths. On this subject, we have noticed
that risks associated with methadone intake are often underestimated by clinicians prescribing the drug:
sometimes methadone is prescribed without taking into account patients tolerance to opiates, and a
large number of subjects enrolled in methadone maintenance programs in Italy, have also been given
take-home doses, thus increasing the risk of abuse and diversion.
2015 Elsevier Ireland Ltd. All rights reserved.

Keywords:
Methadone
Blood levels
Death
Maintenance

1. Introduction
Methadone has been used in maintenance programs for heroin
addicts in Italy since the early 1980s. The correct dosage must be
careful calculated according to the patients tolerance to opiates,
also taking into account the pharmacological properties of this
compound. Methadone is highly toxic to those who are not
physically tolerant to opiates: indeed most cases of methadone
poisoning occur in persons not included in maintenance programs
[1,2]. The risk of death is highest during the rst 2 weeks of
maintenance therapy (induction period): accumulation of methadone is likely to occur because of the long elimination half-life of
the drug (mean 55 h after a single dose and 2225 h during chronic
dosages) [3]. As there we have observed a notable increase in
methadone-related deaths in our area over the last few years, we
have tried to study the possible reasons behind such an increase:
for example increased methadone use without medical prescription, incorrect use of the drug when take-home doses were
prescribed, simultaneous intake of alcohol or drugs as well as an
inappropriate methadone dosage during induction to methadone
treatment.

* Corresponding author. Tel.: +39 0382 987800; fax: +39 0382528025.

E-mail address: claudia.vignali@unipv.it (C. Vignali).
http://dx.doi.org/10.1016/j.forsciint.2015.08.017
0379-0738/ 2015 Elsevier Ireland Ltd. All rights reserved.

This work aims to examine these cases using the results of

toxicological analyses as a starting point and, when possible,
evaluating medical records and circumstantial evidence, to draw
attention to a problem which has already been documented in
other countries [46].
2. Materials and methods
The following toxicological analyses were carried out on
peripheral blood, urine and hair samples, when available, from
the 36 autopsy cases: quantitative determination of ethanol in
blood was performed using head space gas-chromatography (HSGC); systematic toxicological analysis (STA) in blood specimens
was carried out by gas chromatographymass spectrometry (GC
MS) using the method detailed in previously published studies
[7,8]. This method is able to identify acidic, neutral and basic drugs
of forensic interest at therapeutic and toxic levels. Quantitative
analyses of methadone in blood and urine were carried out using a
gas chromatograph equipped with a nitrogen phosphorus detector
(GC-NPD) according to the method routinely used in our
laboratory. Quantitative determinations of psychoactive compounds and their metabolites detected by STA in blood, were
carried out by GCMS or liquid chromatographytandem mass
spectrometry (LCMS/MS). When hair samples were available,
methadone and morphine concentration was determined by

C. Vignali et al. / Forensic Science International 257 (2015) 172176

GCMS as described in a previously published method [9] on 2 cm

strands of hair closest to the scalp. Cut-off values in hair analysis
were 0.2 ng/mg both for morphine and methadone as recommended by the Society of Hair Testing (SOHT) guidelines for drug
testing in hair [10].
3. Results
3.1. Toxicological ndings
Between 2004 and 2013, we observed 36 cases of fatal
poisoning related to methadone intake, 25 of which in the last
5 years. Twenty-seven of the 36 deceased were males and nine
females. Average age was 33 (min 2max 54 years). Two-thirds of
these subjects were undergoing methadone therapy and one-third
had purchased the drug on the black market.
Research into the subjects medical histories revealed that four
of the deceased had been on methadone therapy for a few days,
while 20 were following a methadone maintenance program. Nine
of these were receiving take-home doses, 11 were undergoing
supervised intake at an Addiction Treatment Center (Fig. 1).
Methadone was the only psychotropic compound detected in
blood in eight cases. In the remaining 28 cases drugs of abuse/
metabolites or psychoactive pharmaceutical drugs were also
found. As regards average blood methadone concentrations, we
found the highest level (1.06 mg/L) in subjects who were taking
prescribed methadone. The lowest average concentrations were
found in subjects who took diverted or illegally obtained doses
(0.79 mg/L) and in patients who had just started methadone
treatment (0.78 mg/L).
Benzodiazepines, antidepressants and antipsychotics were
found in blood in 17 cases, and in ve of these exceeded
therapeutic ranges (cases n. 3, 20, 24, 28, 34). Drugs of abuse
were detected in nine cases: both morphine and cocaine in one
case, cocaine and metabolites in two other cases, benzoylecgonine
alone in another six cases. Lastly, ethanol >0.5 g/L was measured in
12 cases. Table 1 lists all the compounds detected in blood samples
and their levels; concentrations of psychoactive drugs are
highlighted whenever they exceed therapeutic ranges [11,12].
Hair samples were available in 17 cases only: analyses were
negative for methadone in six cases, two of whom were given takehome doses (n. 18 and n. 21); methadone concentrations in hair
ranged from 0.27 ng/mg to 24.3 ng/mg; morphine was detected
only in two cases: n. 18 and n. 20.
3.2. Grouping of death cases
The cases were divided into three groups: (1) induction phase
deaths (11%); (2) diverted/illegally obtained methadone deaths
(33%); (3) prescribed methadone deaths post-induction phase
(56%). Almost half the subjects in the third group (45%) had takehome doses; the other half (55%) underwent supervised intake of
the drug at an Addiction Treatment Center. Overall, 24 subjects
were on methadone maintenance therapy and 12 were not.

Fig. 1. Grouping of the deaths.

173

3.2.1. First group: induction phase deaths

The medical records of the four subjects who had just started
methadone therapy (cases n. 14), showed that three of them had
just been transferred from prison to a rehabilitation center.
Methadone treatment had been discontinued while in custody:
clinical records clearly reported methadone down titration until
discontinuation during imprisonment, but therapy was resumed
after admission to the rehabilitation center. In two cases,
methadone treatment was resumed at the patients request, due
to a persistent craving for opiates.
In all four cases death occurred 2 or 3 days after initiating
therapy. Case n. 4 is particularly signicant: despite successful
completion of a methadone maintenance program, the patient was
given 30 mg + 50 mg + 70 mg methadone during the rst 3 days of
treatment. On the third day, the man felt sick after lunch and went
to bed; in the afternoon he was found lifeless. Post-mortem blood
concentration of methadone was 1.08 mg/L; hair sample analysis
was negative for morphine and methadone.
Patient n. 3 (a former heroin addict who had spent a year in
prison) was given 40 + 40 mg of methadone in 2 days: on the
second day the man overdosed on methadone, was hospitalized
and naloxone was administered. Despite the overdose the day
before, on the third day he was given 40 mg of methadone again:
the man was found dead the next morning.
3.2.2. Second group: diverted/illegally obtained methadone deaths
The second group (Cases n. 516) included 12 subjects who were
not on methadone therapy: hair analysis discovered three nave
subjects, and others who had probably purchased methadone on
the black market. Cocaine and benzoylecgonine were also found in
the blood of one of these 12 cases, and benzoylecgonine alone was
detected in two cases. In another two cases, pharmaceutical drugs
were detected in blood samples (venlafaxine and quetiapine in
case n. 6; mirtazapine in case n. 14). In another case (n. 10), the
only compound detected, besides methadone, was a high
concentration of ethanol (2.24 g/L). In four cases (n. 5, 11,
12 and 13) methadone had been taken while partying, probably
hoping for a psychoactive effect: three men 22, 29 and 38 years old
and a 16-year-old girl, were found dead the next morning by casual
acquaintances, whom they had met the same night.
Cases n. 7 and n. 16 involved toddlers who had drunk their
fathers drug. In case n. 16, the parents were suspected of having
deliberately administered methadone to their child on more than
one occasion. To prove this, the corpse was exhumed 4 months
after death to collect some hair strands. Hair analysis conrmed
the presence of methadone, but results were very difcult to
interpret: two hair segments (each 2 cm long) were examined and
methadone was found in both segments (washings were negative).
Post-mortem contamination from sweat produced close to the
time of the death might also explain this, as could body uids it
being an exhumed corpse. Thus, we analyzed the results of the two
hair segments according to Kintz et al. [13] and found that
methadone concentration was not the same along all the entire
hair shaft: 3.1 ng/mg methadone were found in the proximal
segment, and 4.9 ng/mg in distal segment. These results would
point to the intake of repeated doses of methadone, even though it
is difcult to distinguish with any certainty between long-term
intake or a single acute exposure to methadone due to the decay of
the corpse.
Subjects not undergoing therapy, could be divided into addicts
who usually bought methadone on the black market and nave
subjects who took the drug believing it would have psychotropic
effects; young subjects are often looking to get high, without
knowing the properties of methadone: in this respect, we observed
that the average age of nave subjects was 25.7 years, and the
average age of patients undergoing methadone therapy was 38.

C. Vignali et al. / Forensic Science International 257 (2015) 172176

174

Table 1
Age, sex, methadone daily doses and toxicological ndings.
Sample

Age/sex

Daily dose (mg)

First group (induction phase deaths)

1
39 M
40; 50; 50
2
27 M
40; 40; 40
39 F
3

Methadone

Ethanol (g/L)

Other drugs in blood (mg/L)

Blood (mg/L)

Urine (mg/L)

Hair (ng/mg)

0.47
0.21
1.38

4.7
1.38
n.a.

n.a.
n.a.
n.a.

neg
neg
0.17

1.08

3.9

neg

neg

Delorazepam (0.03)
Diazepam (0.05); nordazepam (0.16)
Venlafaxine (0.35); 7-aminoclonazepam (0.39); lorazepam
(0.08)
Citalopram (0.14)

Second group (diverted/illegally obtained methadone deaths)

5
22 M
0.52
0.87
6
40 F
0.49
1.76
7
2F
0.2
2.46
8
33 M
0.21
0.12
9
32 M
0.62
12.7
10
28 M
0.39
2.56
11
38 M
3.15
13.6
12
29 M
1.46
0.72
13
16 F
0.69
13.8
14
41 M
0.64
2.37
26 M
0.52
4.45
15
16
2M
0.63
5.25

neg
neg
n.a.
0.27
n.a.
n.a.
n.a.
neg
n.a.
n.a.
n.a.
3.14.9

neg
0.62
neg
0.92
neg
2.24
neg
0.4
neg
neg
neg
neg

Cocaine (0.06); benzoylecgonine (1.11)

Venlafaxine (0.73); quetiapine (0.26)
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
Benzoylecgonine (0.21)
Mirtazapine (0.17)
Benzoylecgonine (0.87)
n.d.

Third group (prescribed methadone deaths post-induction

17
39 F
0.98
18
39 M
40
0.34
19
36 M
13
0.48
20
43 M
1.3
21
24 M
40
0.5
22
54 F
80
0.98
23
49 F
40
3.37
24
42 M
40
1.06
25
33 M
0.97
26
34 M
0.92
27
26 M
0.59
28
30 M
0.63
29
42 M
80
0.38

phase)
n.a.
23
n.a.
9.5
9.52
n.a.
n.a.
n.a.
12.1
n.a.
0.9
0.34
5.54

n.a.
neg
2.4
8.7
neg
n.a.
13.3
2.3
n.a.
n.a.
n.a.
0.51
1.82

neg
neg
1.2
0.63
0.56
neg
0.65
1.2
neg
0.84
2.06
2.36
neg

1.3
n.a.
7.42
n.a.
5.12
3.63
13.9

n.a.
1.28
1.52
n.a.
n.a.
n.a.
24.3

0.82
neg
neg
neg
0.49
neg
neg

Lorazepam (0.02)
n.d.
n.d.
Citalopram (0.49); levomepromazine (0.4)
Benzoylecgonine (0.19)
n.d.
Desalkylurazepam (0.1)
Promazine (0.81)
n.d.
Cocaine (0.5); benzoylecgonine (1.13); citalopram (0.31)
Morphine (0.02); cocaine (0.03); benzoylecgonine (0.18)
Venlafaxine (0.98)
Prometazine (0.07); levomepromazine (0.25); nordazepam;
(0.04) delorazepam (0.04)
Benzoylecgonine (0.11)
n.d.
Citalopram (0.35)
Benzoylecgonine (1.16); lidocaine, paracetamol, levamisole
Sertraline (2)
Diazepam (0.15); nordazepam (0.18); paracetamol
Benzoylecgonine (0.48); levomepromazine (0.09)

30
31
32
33
34
35
36

25 M

29
40
44
43
45
45
33

M
F
M
M
M
F
M

30; 50; 70

30

0.13
1.09
1.19
1.5
2.05
1.27
1.38

n.d. not detected.

n.a. not available.

3.2.3. Third group: prescribed methadone deaths post-induction

phase
The third group (cases n. 1736) included 20 patients enrolled
in methadone maintenance treatment for opiate addiction, nine of
them receiving take-home doses of the drug, and 11 who were
taking methadone doses every day at an Addiction Treatment
Center. Interestingly, two of them had negative hair analyses for
methadone, but many empty methadone bottles had been found in
their homes, so these subjects are likely to have sold their doses. On
occasions, take-home doses had been misused: in the blood sample
of a woman who was supposed to take 40 mg methadone a day
(case n. 23) we found a very high methadone concentration:
3.37 mg/L. It was proven that the woman was not a poor
metabolizer (CYP2D6 and CYP2B6 activities were evaluated), so
she is likely to have voluntarily taken too high a dose of
methadone.
Drugs of abuse and ethanol were found more frequently in
blood samples of patients taking methadone at an Addiction
Treatment Center (cases 2636) than in the other cases: we found
cocaine and/or metabolites in ve cases; morphine in one case and
ethanol >0.8 g/L in four cases. On the basis of these results, it is
likely that the decision not to provide methadone take-home doses

to these subjects was taken considering the high risk of polydrug

and ethanol abuse. Hair samples were available for ve of these
cases, and methadone was constantly higher than 0.5 ng/mg.
4. Discussion
In Italy, take-home doses are widely prescribed and include up
to 75% of patients on maintenance therapy with methadone or
buprenorphine under medical prescription, depending on the
different choices of Addiction Treatment Centers [14]. The number
of patients receiving take-home doses has been increasing over the
last few years, the main reason being the daily frequency of
methadone intake which often hinders the patients working life.
As regards the risk of methadone diversion, a study carried out by
Davis et al. [15], revealed cause for concern: 60% of subjects on
methadone maintenance in New York City used to sell their doses.
Methadone diversion does not seem to be very common in Italy,
but no real data regarding the extent of the phenomenon is
available. On the other hand, soon after the introduction of takehome doses, with the undeniable advantage of better compliance,
several disadvantages emerged: rstly the risk of diversion and
abuse. Sometimes patients do not take the drug regularly or sell

C. Vignali et al. / Forensic Science International 257 (2015) 172176

their doses, taking methadone only when heroin is not available.

Furthermore, take-home doses could be dangerous if children are
living in the house and the drug is not safely stored: the American
Association of Poison Control Centers reported over 30,000 cases of
exposure to methadone in the United States between January
2000 and December 2008; 2186 subjects were under 6 years of age
and 20 of these died [16]. For this reason, when there are children
living at home, mandatory use of a lockable container to store the
drug should be recommended.
In subjects who had just started treatment, we should underline
the superciality of some clinicians who had prescribed methadone, for not assessing patients tolerance and not taking into
account the risks related to the administration of this drug,
characterized by a long half-life. Due to its long half-life, it is also
crucial to manage overdose cases properly: overdose symptoms
often regress after a naloxone injection, but can represent a few
hours later, after hospital discharge, with a high risk of death.
An effective tool in helping to diagnose fatal methadone
poisoning could be hair analysis: establishing abstinence in the
weeks (or months) prior to death provides supporting evidence of a
lack of tolerance to the drugs implicated in the cause of death. For
this reason it is very important to analyze a strand of hair collected
during autopsy: if hair analyses are negative for both methadone
and morphine, tolerance to opiates can be excluded, and a low
blood concentration of methadone may be enough to explain the
cause of death, even if ethanol or other psychoactive drugs are not
found. An assessment of the results of hair analyses found that six
out of 17 subjects had certainly abstained from methadone for at
least 2 months, thus greatly increasing the risk of death when
taking this drug; in another case methadone concentration in hair
was very low (0.27 ng/mg), suggesting low or occasional intake
over the last 2 months of life.
Although hair analysis is not useful for proving a lethal
intoxication, it provides a source of information related to drug use
in the months prior to death: it is effective to highlight reduced
tolerance, resolving the question of whether or not drug use was
chronic [17]. However, some limitations of hair analysis need to be
considered: biological variables including differences in hair
growth and mechanism of drug incorporation; external diffusion
from sweat and sebum that may lead to false positive results;
deleterious effect due to aggressive cosmetic treatments (i.e.
bleaching and dyeing) that may reduce drug concentration in hair
[10].
The 2014 Annual Report to the Italian Parliament on addiction
and drug use in Italy, conrms that Addiction Treatment Centers
treated 164.993 patients in Italy during 2013, 31% of whom were
over 39 years of age (the highest percentage in Europe); heroin was
the primary drug of use among these patients (71.5%); 50% were
pharmacologically treated, the others received psychological
treatment only. Heroin-related deaths were 42.4% in 2013, while
this report claims that methadone-related deaths were only 3.8%
[18]. These data are surprising and do not match ours: some
methadone deaths are likely to have been miscalculated maybe
due to incomplete or inaccurate post-mortem toxicological
analyses. Instead, our ndings are similar to those of Wikner
et al. [19]: their study revealed 776 heroin deaths from 2003 to
2010 and 342 methadone deaths in the same period in Sweden. A
large number of methadone deaths has been observed in other
countries too: Handley et al. [20] found that the number of deaths
involving heroin and morphine decreased in England and Wales
during 20002011, whereas methadone-related deaths increased.
In the United States, deaths from too high an incoming dose or
too rapid an increase in dosages during methadone induction, as
well as interactions with other drugs are increasing. Greater
attention during methadone induction and stabilization, better
patient education and increased clinical vigilance are essential: for

175

this reason a group of experts have drawn up a consensus

statement on methadone induction and stabilization, to reduce the
risk of overdose or death related to methadone maintenance
treatment of addiction [21].
In some cases, people at risk of death are not mainly heroin
addicts: according to an American study, the proportion of
methadone-related deaths increased by 300% from 2001 to
2006 in Vermont, particularly among those who had taken
methadone for chronic pain and those obtaining diverted
methadone; instead subjects taking methadone for heroin
dependence accounted for an insignicant number of methadone-related deaths [22]. The authors also emphasized that
improved education of clinicians about the pharmacokinetics of
methadone and its potential abuse and diversion, as well as an
awareness of the increasing number of methadone-related deaths,
may help to reduce the number of fatalities from this drug.
5. Conclusion
An evaluation of our results, led us to draw the following
conclusions: 11% of the subjects considered died during induction
into methadone treatment due to the administration of excessively
high starting doses; when take-home doses are prescribed, some
patients tend to use the drug irregularly, subsequently increasing
the risk of overdose (this has been documented by ndings of
unopened syrup bottles in the patients home and/or the results of
hair analysis); moreover, in two cases, take-home methadone
doses had indirectly led to the death of two toddlers who drank the
syrup left unattended by their parents. Subjects undergoing
supervised methadone intake often drank alcohol or took
psychotropic drugs simultaneously, increasing the risk of death.
We observed that abuse of illegally obtained methadone, often by
patients who were allowed to take it home, is rather common. In
this respect, special caution has to be exercised when prescribing
take-home doses, together with a more careful evaluation during
induction into methadone treatment when tolerance to opiates is
unknown.
Conict of interest
The authors declare that they have no conict of interest.
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