Journal of Analytical Toxicology 2012;36:12 –18
doi:10.1093/jat/bkr013
Blood Methadone Concentrations in Living and Deceased Persons: Variations Over Time,
Subject Demographics, and Relevance of Coingested Drugs
A.W. Jones*, Anita Holmgren and Johan Ahlner
Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Artillerigatan 12,
SE-587 58 Linköping, Sweden
*Author to whom correspondence should be addressed. email: wayne.jones@rmv.se.
Concentrations of d,l-methadone were determined in blood samples
from people arrested for driving under the influence of drugs
(DUID), users of illicit drugs, and methadone-related deaths. In
drug overdose deaths (N 5 346), mean (median) and highest con-
centrations of methadone in femoral blood were 0.53 mg/L
(0.40 mg/L) and 6.7 mg/L, compared with 0.46 mg/L (0.30 mg/L)
and 3.7 mg/L in non-poisoning deaths (N 5 157) ( p < 0.05). In
DUID suspects and users of illicit drugs (N 5 909), the blood-
methadone concentrations were much lower, 0.23 mg/L (0.20 mg/L)
and 1.1 mg/L ( p < 0.001). The median concentration of methadone
in blood decreased as the number of coingested drugs increased
in the overdose deaths: 0.5 mg/L with methadone the only drug
compared with 0.2 mg/L with 6 –9 other drugs present ( p <
0.001). These coingested drugs were mainly benzodiazepines
(diazepam, alprazolam, flunitrazepam) and amphetamines; THC and
morphine (from heroin) were the major illicit drugs. The overlap in
blood-methadone concentrations in living cases and autopsy cases
makes it difficult to conclude that methadone overdose was the
cause of death. Adverse drug-drug interactions and varying
degrees of tolerance to opiates complicate the interpretation.
Introduction
Methadone was synthesized in the early 1940s in Germany,
although this narcotic analgesic did not hit the headlines inter-
nationally until 1965 when Dole and Nyswander (1) described
the use of methadone maintenance treatment (MMT) for the
rehabilitation of heroin addicts (1, 2). MMT represented a para-
digm shift in pharmacotherapy for heroin addiction and substi-
tution programs began to spread around the world and are
prominent still today (3). The strategy of substituting a licit drug
(methadone) for an illicit drug (heroin) marked a turning point
in the rehabilitation of heroin addicts, many of whom were able
to live normal lives, albeit with daily intake of methadone (4, 5).
Like morphine, methadone is an agonist at the m-opiate
receptor, but its longer elimination half-life and improved oral
bioavailability make it an attractive alternative for pain medica-
tion as well as MMT programs (6, 7). Although supervised
intake of methadone was once the norm for use in treating
heroin addicts, the recent popularity of methadone as a pain
medication has led to people taking the medication home for
self-administration (7, 8). The less restrictive prescribing of
methadone for pain management has had negative conse-
quences, such as diversion from legitimate use to recreational
use and abuse (9– 11). Admission to hospital for treatment of
methadone poisoning has increased appreciably along with a
high prevalence of methadone-related overdose deaths in many
nations (12 –14).
# The Author [2012]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com
Article
The aim of the present study was to compare and contrast
the concentrations of d,l-methadone in femoral blood in
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methadone-related deaths with the concentrations determined
in venous blood from apprehended drivers (DUID) and people
arrested on the streets for use of illicit drugs. In addition, the
demographics of people using methadone, the prevalence and
concentrations of various coingested drugs were also evaluated
in the living and the dead.
Materials and Methods
Forensic toxicology in Sweden
Forensic toxicology in Sweden ( population 9.3 million) is cen-
tralized to a single accredited laboratory that receives biological
specimens for analysis from the living and the dead. Forensic
autopsies are performed at six university teaching hospitals
located in Lund, Gothenburg, Uppsala, Stockholm, Linköping,
and Umeå. The local police authorities request a forensic
autopsy whenever an unnatural or suspicious out-of-hospital
death is investigated. Blood and urine samples from people
arrested by the police suspected of driving under the influence
of alcohol or drugs or for using illicit drugs are also sent to the
same central toxicology laboratory.
This retrospective study was done with the help of an
in-house database (TOXBASE) that we searched for forensic
cases in which methadone was verified present in peripheral
blood samples. The period studied was 2000 –2010 because
over this time, the method used for qualitative and quantitative
analysis of methadone in blood has remained unchanged. We
recorded information about the age and sex of those taking
methadone, the concentrations in blood, the types and concen-
trations of co-administered drugs, the manner of death accord-
ing to the medical examiner reports, and whether drug
poisoning or other (trauma, natural) was also related to the
concentration of methadone in blood.
Biological specimens
Forensic pathologists in Sweden are required, whenever pos-
sible, to submit femoral blood for toxicological analysis after
adding potassium fluoride (1 –2%) as a preservative. If circum-
stances of the death precluded obtaining femoral blood (e.g.,
because of extensive trauma or if the body was decomposed),
these cases were omitted from the present study. In appre-
hended drivers and also in people arrested for use of illicit
drugs, venous blood is taken from a cubital vein into evacuated
grey-stopper tubes containing a mixture of potassium oxalate
and sodium fluoride (1%) as preservatives.
The material for this study comprised N ¼ 503 autopsy cases
involving methadone-related deaths, N ¼ 594 individuals
 Table I
Age, Sex, and Concentrations of Methadone in Blood in Methadone-Related Deaths, Traffic
Cases (DUID), and Users of Illicit Drugs*

Sex, N (%) Mean Percentiles

Age (Median)
†
Forensic Cases N Mean + SD Male Female (mg/L) 90th 95th 97.5th
‡
Autopsy cases (all) 503 38 + 12.3 418 (83) 85 (17) 0.51 (0.30) 1.1 1.5 1.9
Drug poisoning 346 36 + 11.5 282 (82) 64 (18) 0.53 (0.40)‡ 1.1 1.6 2.0
Other causes 157 41 + 13.3§ 136 (87) 21 (13) 0.46 (0.30)‡ 1.0 1.4 1.8
Living cases (all) 909 36 + 8.7 813 (89) 96 (11) 0.23 (0.20) 0.4 0.5 0.6
Traffic (DUID) 594 38 + 8.5 532 (90) 62 (10) 0.23 (0.20) 0.4 0.6 0.7
Use of illicit drugs 315 34 + 8.6# 281 (89) 34 (11) 0.22 (0.20) 0.4 0.5 0.6

* The mean, median, standard deviation, and upper percentiles of the frequency distributions
were used as descriptive statistics.
†
Predominance of males in the autopsy cases and the living cases (p , 0.001).

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Figure 1. Rise in annual numbers of forensic cases positive for methadone from
2000 to 2010, representing autopsy, impaired drivers (DUID), and people arrested for
use of illicit drugs.
suspected for driving under the influence of drugs, and N ¼
315 people suspected for use of illicit drugs.
‡
Significantly higher median concentration of methadone in autopsy materials compared with all
living cases (p , 0.001) and in other causes of death compared with drug poisoning deaths
(p , 0.05).
§
Other causes of death were older than poisoning deaths and all living cases (p , 0.001).
#
Users of illicit drugs were younger than DUID suspects and autopsy cases (p , 0.001).

Toxicological analysis
The analytical toxicology starts with an initial screening ana-
lysis for drugs of abuse using a specimen of urine if available,
and using blood after protein precipitation if not. Immunoassay
(EMIT or CEDIA) serves to select presumptive positive cases
that are then verified by more specific chromatographic
methods. Ethanol was determined in blood by headspace gas
chromatography (GC) with a well-established method, and
results were reported positive if the concentration exceeded
an analytical cutoff of 0.2 g/L (0.02 g/100 mL).
Illicit drugs are analyzed by gas chromatography –mass spec-
trometry (GC –MS) with deuterium-labeled internal standards.
Prescription drugs (e.g., benzodiazepines) and methadone
were analyzed in whole blood after solvent extraction and ca-
pillary column GC with a nitrogen-phosphorus detector. This
analytical method allowed quantitative analysis of about 200
different weakly acidic, neutral, and basic drugs as well as many
metabolites. The analytical limit of quantitation for reporting
presence of methadone in blood was 0.05 mg/L for samples
from the living and 0.1 mg/L for autopsy specimens.
Statistical analysis
Means, medians, standard deviations (SD), and upper 90th,
95th, and 97.5th percentiles were used as descriptive statistics.
Two mean values (e.g., mean age in men and women) were
compared by Student’s independent t-test. Two medians were
compared by Mann-Whitney test for unpaired data, and propor-
tions of males to females were compared by a chi-squared test.
Results were considered statistically significant if p , 0.05.
Results
Development in methadone cases
Figure 1 shows the increases in number of forensic cases
(living and dead) in which methadone was verified present in
blood samples submitted for forensic toxicology over an
Figure 2. Relative frequency distributions of the age of victims of methadone-related
deaths in Sweden compared with people arrested for DUID or for the use of illicit
drugs.
11-year period. The increase in number of methadone cases
was most apparent in the methadone-related deaths.
Age, sex, and concentration of methadone in blood
The proportion of male to female methadone users was 90%
versus 10% in DUID suspects and users of illicit drugs, com-
pared to 83% versus 17% in autopsy cases (Table I). The
average age of methadone users was about the same in men
and women ( p . 0.05), whereas the overall age of methadone
users was 37 + 10 years. Table I shows that victims of a
methadone-related poisoning death were younger (36 + 11.5 y,
N ¼ 346) compared with other causes of death in methadone
users (41 + 13.3 y, N ¼ 157) (p , 0.001).
Figure 2 compares the relative frequency distributions of age
of methadone users in autopsy cases and living cases (DUID
suspects and users of illicit drugs). The ages spanned from ,20
years to .75 years, and the vast majority was between 25 and
45 years.
The median concentration of methadone in blood was
higher in poisoning deaths (0.4 mg/L) compared with other
causes of death in methadone users (0.3 mg/L), and the
autopsy material had higher concentrations than the DUID sus-
pects and the users of illicit drugs (0.2 mg/L) (Table I).

Blood Methadone Concentrations in Living and Deceased Persons: Variations Over Time, Subject Demographics, and Relevance of Coingested Drugs 13

Figure 3. Box and whiskers plots showing concentration distributions of methadone
in femoral blood in drug-related deaths compared with traffic cases (DUID) and users
of illicit drugs.
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Figure 5. Relative frequency distribution of the concentration of d,l-methadone in
blood from the apprehended drivers and users of illicit drugs (living cases) and drug
poisoning deaths with methadone as one of the drugs identified. Note that N ¼ 7
autopsy cases (2%) with blood-methadone . 2.0 mg/L are not plotted for clarity.

Table II
Age, Sex, and Median Concentrations of Methadone in Femoral Blood in Methadone-Related
Deaths in Relation to the Number of Other Drugs Identified in Addition to Methadone

# Cause of Death
Number Age + SD Males Females Median Poisoning Other
of Drugs N† (years) N ‡ (%) N (%) (mg/L) (%) (%)
0* 33 42 + 12.4 28 (85) 5 (15) 0.5 17 (52) 16 (48)
1 99 39 + 13.6 81 (82) 18 (18) 0.4 62 (63) 37 (37)
2 99 36 + 11.3 92 (93) 7 (7) 0.3§ 66 (67) 34 (33)
3 124 36 + 11.9 98 (79) 26 (21) 0.3§ 90 (73) 34 (27)
4 80 37 + 12.7 66 (83) 14 (17) 0.3§ 58 (72) 22 (28)
5 41 37 + 11.6 32 (78) 9 (22) 0.3§ 33 (80) 8 (20)
6–9 27 39 + 11.3 21 (78) 6 (22) 0.2§ 20 (74) 7 (26)

Figure 4. Year-by-year changes in median concentrations of methadone in
peripheral blood in DUID suspects and users of illicit drugs (living cases) and drug
poisoning deaths.
The box and whiskers plot in Figure 3 indicates good agree-
ment between the concentration distributions of methadone in
DUID suspects and users of illicit drug, whereas means and
medians were significantly higher in autopsy cases, the latter
also having more extreme outlying values.
Fluctuations in median concentrations of methadone over
the 11-year study period can be seen from Figure 4, which
shows all living cases (N ¼ 909) and autopsy cases (N ¼ 346)
when drug poisoning was given on the death certificate. The
medians were always higher in the autopsy cases except for
one year (2005) when they were the same (Figure 4).
Relative frequency distributions of blood-methadone concen-
trations in living cases and poisoning deaths are compared in
Figure 5. Use of a higher cutoff concentration for reporting
methadone positive results in autopsy cases explains the
absence of a bar under 0.1 mg/L. The concentration of metha-
done in blood exceeded 1.0 mg/L in only 2 living cases (0.2%)
compared with 46 (13%) autopsy cases. Furthermore, there
were 41% of autopsy cases with blood methadone .0.50 mg/L
compared with 9.7% of the living cases (p , 0.001).
Drugs coingested with methadone in autopsy cases
Table II presents mean age, proportion of men to women and
the median concentrations of methadone in blood in the
* Methadone was the only drug present.
†
Number of instances.
‡
Predominance of males over females (p , 0.001).
§
Significantly lower median concentrations of methadone compared with methadone-only
deaths.
autopsy cases in relation to the number of other drugs identi-
fied in the blood samples. The median concentration of metha-
done decreased from 0.5 mg/L (mono-drug deaths) to 0.2 mg/
L (6 –9 drugs), which is a statistically significant difference
( p , 0.001).
Table II also shows the proportion of deaths classified by
medical examiners as a drug poisoning or some other cause
(e.g., trauma, natural) in relation to number of coingested
drugs. In the mono-drug deaths (methadone only), 52% were
poisonings and 48% were attributed to other causes
( p . 0.05). As the number of coingested drugs increased,
about 70 –80% of the deaths were attributed to poisoning,
whereas only 20 –30% were ascribed to other causes
( p , 0.001).
The drugs most often identified in blood along with metha-
done are listed in Table III showing a predominance of benzo-
diazepines (diazepam, alprazolam, and clonazepam) and the
major illicit drugs were cannabis, amphetamine, and morphine
(mainly from heroin). The median concentration of methadone
in blood varied from 0.3 to 0.5 mg/L depending on the types of
coingested drugs.

14 Jones et al.
Table III number of coingested drugs in DUID suspects or people
Rank Ordering of the Drugs Identified in Blood in Methadone-Related Deaths, Number of arrested for use of illicit drugs. This table shows a trend
Instances (N), the Median Concentration of the Drug, and the Median Concentration of towards a decreasing median concentration of methadone with
Methadone increasing number of coingested drugs from 0.2 to 0.1 mg/L.
Median Drug Median Methadone The types and rank ordering of the coingested drugs were
Drug Present in Blood N Concentration (mg/L) Concentration (mg/L) slightly different in the living cases (Table V). Benzodiazepines
Diazepam 132 0.1 0.3 were still highly prevalent, especially alprazolam, diazepam, and
THC 122 0.001 0.3 flunitrazepam; cannabis, amphetamine, and morphine (from
Amphetamines* 96 0.21 0.3
Ethanol 89 1000 0.3
heroin) were the major illicit drugs. The median concentration
Morphine† 70 0.045 0.3 of methadone in blood varied from 0.1 to 0.3 mg/L depending
Alprazolam 68 0.06 0.4 on the types of other drugs identified in blood.
7-Aminoclonazepam 68 0.2 0.4
Acetaminophen 67 5.0 0.3
Zopiclone 57 0.11 0.5
Alimemazine 50 0.2 0.5 Discussion

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Codeine 49 0.03 0.3
Tramadol 40 0.7 0.3 The use of methadone as pharmacotherapy for rehabilitation
of heroin addicts has had many proponents and critics since the
* Amphetamine and/or methamphetamine. seminal publications by Dole and Nyswander (15, 16).
†
In 15 cases, 6-MAM was present in blood (heroin use); the concentration of free-morphine
was 0.24 mg/L (median), and blood methadone was 0.3 mg/L. In 55 cases, 6-MAM was
Methadone is a synthetic opioid, both historically and structural-
negative in blood; median concentration of free-morphine was 0.02 mg/L, and blood methadone ly related to pethidine, with both substances possessing anal-
was 0.3 mg/L. gesic and spasmolytic properties (17). These drugs have
potential for abuse and have been implicated in many overdose
deaths and admissions to hospital emergency departments for
Table IV
Age, Sex, and Median Concentrations of Methadone in Blood in Traffic Cases (DUID Suspects)
life-saving treatment (8, 18). Many of the methadone-related
and Individuals Arrested for Use of Illicit Drugs in Relation to the Number of Other Drugs fatalities in our study were previously registered for drug-related
Identified in Addition to Methadone offences; 69% (N ¼ 346) among poisoning deaths compared
with 59% (N ¼ 157) when some other cause of death was given
Median Blood
Number of Drugs N* Age + SD Males N ‡ (%) Females N (%) Methadone (mg/L) by the medical examiner.
Care is needed when methadone is prescribed for the first
0† 113 36 + 8.6 108 (96) 5 (4) 0.2
1 220 37 + 8.7 187 (85) 33 (15) 0.2 time to opiate-naive individuals for MMT and in pain manage-
2 305 36 + 8.6 272 (89) 33 (11) 0.2 ment programs (19, 20). The potential for diversion and abuse
3 168 37 + 9.2 153 (91) 15 (9) 0.2
4 68 35 + 8.5 61 (90) 7 (10) 0.1
of methadone is lower if the drug is administered under supervi-
5-7 35 35 + 7.7 32 (91) 3 (9) 0.1 sion, such as was often done at outpatient clinics (21). The
upsurge of take-home methadone for MMT and pain manage-
* Number of instances.
†
ment has had negative consequences, including diversion from
Methadone was only drug present.
‡
Predominance of males over females (p , 0.001).
the licit to the illicit drug market and this is considered a key
factor in many methadone-related deaths and drug overdose
treatment (9).
Table V
The method of analysis used in our laboratory cannot distin-
Rank Ordering of Drugs Identified Together with Methadone in Traffic Cases (DUID) and Users of
Illicit Drugs, Number of Instances (N), Median Concentration of the Coingested Drug, and the guish between the two optical isomers of methadone, so
Median Concentration of Methadone the concentrations reported here are for the racemate d,l-
methadone. Some laboratories analyze the R- and S-forms of
Median Drug Median Methadone
Drug Present in Blood N Concentration (mg/L) Concentration (mg/L) methadone separately, because these isomers have a different
pharmacokinetic profile, including half-life and volume of dis-
Alprazolam 228 0.08 0.2
Diazepam 210 0.2 0.2 tribution (22, 23). The analgesic effect of methadone resides in
Morphine* 202 0.03 0.1 the R-form, whereas the S-form has been incriminated in po-
Flunitrazepam 181 0.014 0.2 tentially fatal cardiovascular events by prolonging the so-called
Amphetamines† 155 0.3 0.1
THC 135 0.001 0.1 QT-interval (24, 25). Prescribing a pharmaceutical product con-
Codeine 126 0.01 0.1 sisting essentially of the R-isomer of methadone (e.g., for pain
Clonazepam 117 0.05 0.2
Zopiclone 86 0.08 0.3
management or for MMT) might reduce mortality associated
Nitrazepam 40 0.05 0.2 with the S-isomer (26). Others have suggested that polymorph-
Ethanol 38 780 0.2 ism in the enzymes responsible for hepatic metabolism of
Paracetamol 33 5.0 0.2
methadone CYP3A4, CYP2B6, or CYP2D6 may play a role in
* In 30 cases, 6-MAM (heroin use) was present in blood, and morphine concentration was methadone toxicity and methadone-related deaths (27 –29).
0.08 mg/L (median) and methadone 0.10 mg/L. In 172 cases, 6-MAM was negative in blood, In an autopsy study involving the analysis of methadone in
and morphine concentration was 0.03 mg/L (median) and blood methadone 0.10 mg/L. blood from left and right femoral veins, Linnet et al. (30)
†
Amphetamine and/or methamphetamine.
demonstrated that analytical variation was negligible compared
with sampling site variation. This suggests that more efforts are
Drugs coingested with methadone in living cases needed to reduce sources of pre-analytical variation in post-
Table IV presents mean age, proportion of men to women, and mortem toxicology. Methadone is a drug with a fairly large
the median concentrations of methadone in relation to the volume of distribution (3.6 –5 L/kg), which makes it prone to

Blood Methadone Concentrations in Living and Deceased Persons: Variations Over Time, Subject Demographics, and Relevance of Coingested Drugs 15
Table VI noted for the concentrations of methadone determined in
Compilation of Blood Methadone Concentrations in Methadone-Related Deaths from the blood from peripheral and central sampling sites. This under-
Literature Compared with the Concentrations Reported in the Present Study scores the need to report blood-sampling site when post-
Investigators (reference) N* Blood Methadone (mg/L) Mean, (median), Highest
mortem drug concentrations are compared and contrasted.
Seymour et al. (33) reported a higher median concentrations in
Danielson et al. (42) 46 0.39 (0.32) 0.89
Worm et al. (43) 59 0.43 (0.28) 3.09
single-drug methadone deaths (median 0.7 mg/L) compared
Milroy and Forrest (32) 50 0.58 (0.44) 2.7 with mixed-drug deaths (median 0.3 mg/L). In many of the
Clark et al. (44) 18 0.56 (0.44) 1.9 drug poisoning deaths, an elevated concentration of metha-
Capelhorn and Drummer (45) 56 0.53 (0.40) 5.5
Drummer et al. (20) 10 0.65 (0.39) 2.5 done was simply an incidental finding and the coingested drugs
Chugh et al. (46) 22† 0.48 (0.50) 0.90 were primarily responsible for the death. In cases when metha-
Buchard et al. (47) 90 0.93 (0.62) 8.0 done was the only drug identified in blood (median concentra-
Laberke and Bartsche (12) 146‡ 1.3 (0.7) 14.0
114§ 0.73 (0.5) 4.5 tion 0.5 mg/L) 52% of deaths were classified as drug poisoning
Shields et al. (13) 176 0.54 (– ) 4.0 whereas 48% had other causes ( p . 0.05).
Albion et al. (14) 11# 0.41 (0.72) 3.0
In a Norwegian study of DUID suspects (34), the median

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25** 1.2 (0.59) 6.0
Levine et al. (31) 15†† 0.72 (0.55) 2.7 (and range) of blood-methadone concentrations was 0.46 mg/L
15‡‡ 0.57 (0.56) 1.5 (0.19–0.65 mg/L) when methadone was the only drug identi-
Seymour et al. (33) 52# 0.80 (0.7) 2.63
135§§ 0.40 (0.3) 3.84 fied in blood in 10 cases, compared with 0.28 mg/L (range
Madden and Shapiro (48) 76 0.46 (– ) 3.79 0.06– 1.24 mg/L) in poly-drug users (N ¼ 625). These values
Present study 346## 0.53 (0.4) 6.7 compare with a median of 0.20 mg/L (range 0.05 –1.1 mg/L) in
157*** 0.46 (0.3) 3.7
the present study of DUID suspects (N ¼ 594). In both Norway
* N ¼ number of cases. and Sweden, the most common coingested drugs in methadone
†
Sudden cardiac death. users were benzodiazepines (alprazolam, flunitrazepam, and di-
‡
Time period 1998 –2007.
§ azepam). The traffic delinquents in Norway were mainly men
Time period 1989 –1997.
#
Methadone was only drug present. (87%) aged 30 –40 years, and there was no gender difference
** Mixed-drug deaths. in the median concentration of methadone in blood (34). Each
††
Heart blood. DUID suspect was examined by a physician, who looked for
‡‡
Alternative blood sample (e.g., subclavian). signs and symptoms of drug influence, although there was no
§§
Methadone-related mixed drug deaths.
##
Drug poisoning deaths.
significant correlation between the concentration of metha-
*** Other causes of death in methadone users. done in blood and the conclusion from the clinical examin-
ation (impaired or not impaired). Neither the Norwegian study
nor the present study could be used to tell how many
redistribute from tissue compartments into central blood after DUID suspects, if any, required medical intervention for
death. In one study, the mean (median) concentration in heart drug overdose.
blood was 0.57 mg/L (0.56 mg/L) compared with 0.72 mg/L The daily dose of methadone for effective relief of pain or to
(0.55 mg/L) for an alternative sampling site, mainly subclavian counteract withdrawal in heroin addicts seems to differ widely
blood (31). Femoral blood is the preferred specimen for analysis between different patients, making it important to titrate the
in postmortem toxicology because redistribution artifacts are dose to the required clinical effect (35, 36). In this connection,
minimized, making results somewhat easier to interpret. the starting dose should be carefully selected to avoid adverse
In the present study, median concentration of methadone effects such as acute opiate toxicity (37). A very high daily
was significantly higher ( p , 0.001) in autopsy cases compared dose of methadone was necessary to achieve a clinical effect in
with living cases, although there was a considerable overlap in a person exhibiting polymorphism in the CYP450 enzyme and
the frequency distributions (Figure 5). There were also more who was genotyped as an ultra rapid metabolizer (38). In MMT
extreme values in the autopsy material, as expected in drug programs, the plasma concentrations of methadone usually
overdose deaths, with 41% above 0.50 mg/L compared with range from about 0.25 mg/L to 0.50 mg/L and accordingly are
only 9.7% above this concentration in the living cases. Table VI close to the median values observed in methadone-related
presents the results of a literature search into the concentra- deaths shown in Table VI (39, 40). As emphasized elsewhere
tions of methadone reported in postmortem blood under dif- (41), in postmortem toxicology, valid and relevant information
ferent circumstances. Because of the skewed concentration for the pathologists would be to report whether the concentra-
distributions it is more valid to compare and contrast medians tion of a certain drug was low, average, or high compared with
rather than means. When an article presented methadone con- past experiences from the same laboratory and the same type
centrations in individual cases, the mean and median values of blood sample with the same analytical method.
were calculated by us. Unfortunately, in some articles, the site In conclusion, this study demonstrates an appreciable
used to sample blood was not mentioned, so the concentra- overlap in the concentrations of d,l-methadone in peripheral
tions reported in Table VI probably reflect both central and blood from the living and the dead. This complicates the inter-
peripheral blood compartments. pretation of blood-methadone concentrations in autopsy cases
Milroy and Forrest (32) reported that, in 50 adult poisoning because knowledge about the individual’s tolerance to opiates
deaths involving methadone, the median concentration was is mostly lacking. Moreover, a high prevalence of poly-drug use
0.435 mg/L, compared with 0.294 mg/L when the death was in methadone users increases the potential for an adverse drug-
ascribed to a combination of methadone and other drugs (N ¼ drug interaction and at the same time heightening the risk of
56). In the same study, large differences, up to 100%, were acute toxicity.

16 Jones et al.
Acknowledgment
There was no external funding for preparing this article, and
none of the authors consider that they have a conflict of inter-
est in publishing this work.
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