Download Comparison of the Various Opiate Alkaloid Contaminants and Their

Journal of Analytical Toxicology,Vol. 30, May 2006
Comparison of the Various Opiate Alkaloid
Contaminants and Their Metabolites Found
in Illicit Heroin with 6-Monoacetyl Morphine
as Indicators of Heroin Ingestion
Sue Paterson* and RosaCordero
Toxicology Unit, Imperial College London, St. Dunstan's Road, London W6 8RP, United Kingdom
t Abstract
In this study the use of the various opiate alkaloid contaminants as
potential markers for illicit heroin ingestion were investigated.
Urine samples (n = 227) taken from prisoners for routine drug
screen, which were positive for opiates by immunoassay screening,
were analyzed for contaminants in illicit heroin. A previously
described method was used for the analysis; urines were extracted
using mixed-mode solid-phase extraction; the extracts were
derivatized using N-methyl-bistrifluoroacetamide and N-methyi-Ntrimethylsilyltrifluoroactamide/trimethylchlorosilane. The
derivatized extracts were subjected to electron impact gas
chromatography-mass spectrometry. The extracts were injected in
full scan mode followed by selected ion monitoring mode for target
opiate alkaloids found as contaminants in illicit heroin. The opiate
alkaloids and their metabolites specifically targeted included
meconine, desmethylmeconine, hydrocotarnine, acetylcodeine,
codeine, morphine, 6-monacetylmorphine (6-mare), papaverine,
hydroxypapaverine, and dihydroxypapaverine. Of the 227 samples
positive for opiates by immunoassay, using a cut-off of 300 ng/mL,
199 were confirmed positive for morphine and using a cut-off of 10
ng/mL, 28 were confirmed positive for 6-mam. Using the screening
method described in the study, the following numbers of positives
were found: 199 for morphine, 103 for codeine, 5 for meconine, 46
for desmethylmeconine, 18 for 6-mare, 136 for hydroxypapaverine,
and 139 for dihydroxypapaverine. Acetylcodeine, hydrocotarnine,
and papaverine were not detected in any of the samples. The
results of this study show that analysis for papaverine metabolites
is more sensitive than 6-mare as a way of demonstrating illicit
heroin use.
Introduction
Heroin or diacetylmorphine is metabolizedto 6-monoacetylmorphine (6-mare),which is then further metabolized to morphine. If morphine is detected in urine, 6-roam must be
* Author to whom all correspondenceshould be addressed. E-mail: [email protected].
detected in order to prove that it is the result of heroin ingestion. 6-Mare is only detectable in urine for 2--8 h compared with
morphine, which is detectable for 1-2 days (1). Because of this
difference in detection window, it is often not possible to
demonstrate that morphine detected in the urine is because of
heroin ingestion.
Screening urine for drugs of abuse is routinely performed on
the prison population of England and Wales. During this
screening, morphine is sometimes detected and it is possible
that the morphine could be due to the ingestion of illicit heroin,
but unless 6-mare is found, it cannot be proven.
Codeine containing preparations can be available for use as
analgesics in the prison population, and as codeine is metabolized to morphine, the morphine could be due to the ingestion
of codeine. Illicit heroin contains small amounts of acetylcodeine, which is metabolized to codeine. After ingestion of illicit heroin, the amount of morphine detected in urine is always
much greater than the amount of codeine. After ingestion of
codeine, the relative proportion of codeine and morphine varies
between individuals and as a function of time (2). Morphine is
eliminated more slowly than codeine, and depending on the
cut-offs used for the assays, it is possible to detect morphine
only after codeine ingestion (2). Therefore, the ratio of codeine
to morphine can suggest whether codeine or illicit morphine
has been ingested, but when morphine is present in small
amounts usually no codeine is detected.
In addition to morphine, street heroin contains various alkaloids extracted from the opium poppy,Papaversomniferum,
including codeine, thebaine, noscapine, and papaverine (3).
During the production of heroin, morphine is acetylated to diacetylmorphine. Codeine, which is also present in the extract,
is acetylated to form acetylcodeine. Therefore, detection of
acetylcodeine in urine proves ingestion of illicit heroin (4), but
the study by O'Neal and Poklis in 1997 (5) concluded that
acetylcodeine was found in fewer specimens and at lower concentrations than 6-mare, and their study in 1998 (6) concluded
that acetylcodeinewas not a reliable biomarker of illicit heroin
use because of the low concentrations present in urine. Acetyl-
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267
Journal of Analytical Toxicology, Vol. 30, May 2006
1% trimethylchlorosilane (TMCS) was from Perbio (Cramlington, U.K.). 4-Hydroxypapaverine (97.8%), 3-hydroxypapaverine (97.9%), and 3,4-dihydroxypapaverine hydrobromide
(96.9%) were custom synthesized by Edinburgh Pharmaceuticals (Edinburgh, U.K.). Ammonium hydroxide, chemicals, and
all other drug standards were purchased from Sigma-Aldrich
(Poole, U.K.). The DB-5 capillary column was from Crawford
Scientific (Strathaven, Scotland). Drugs of abuse controls were
obtained from DPC (Llanberis, U.K.).
codeine has a similar half-life to 6-mare; neither remains detectable in urine for as long as morphine following heroin use
(7,8). McLachlan-Troup et al. (9) investigated the potential to
distinguish between the use of street heroin and pharmaceutical diamorphine through the detection in urine of various
opiate alkaloids originating in the opium poppy. They concluded that detection in the urine of the metabolites of
noscapine and metabolites of papaverine were useful for this
purpose (9). Detection of these metabolites in urine also has the
potential to show that morphine detected in urine has been derived through the use of street heroin rather than codeine.
The aims of the study were to investigate whether any of the
various opiate alkaloids or their metabolites originating from
the opium poppy, present as contaminants of illicit heroin,
could be used to show if morphine in the urine of prisoners was
because of consumption of illicit heroin and to determine if any
of the opiate alkaloids or their metabolites were better indicators of heroin use than 6-mare.
Samples
Two hundred and twenty seven urine samples of those submitted for routine screening for drugs of abuse and found positive for opiates at 300 ng/mL using the Cedia| immunoassay
technique had the opiates (morphine, 6-roam, codeine, and dihydrocodeine) confirmed as normal by gas chromatography-mass spectrometry (GC-MS) in the laboratory carrying
out this work on behalf of the Prison Service. The remaining
sample was then forwarded to the ToxicologyUnit at Imperial
College London for analysis for the various opiate alkaloids
and their metabolites. The staff of the Toxicology Unit was
blinded to the confirmation results. Among the samples submitted to the ToxicologyUnit were two control samples, and the
ToxicologyUnit was also blinded to this.
Materials and Methods
The samples used for this study were taken as part of the routine screening carried out by the Prison Service. All samples
were anonymized, and there were no consequences for the
prisoners as a result of this study.
Method of analysis
The urines were analyzed by mixed-mode solid-phase extraction (SPE) followedby GC-MS using a previously described
procedure (10). In summary, after addition of internal standard
Materials
(1.5 mL, 0.67 mg/L MDA-d~in 1Macetate buffer pH 5), urines
All solvents were analytical grade and were purchased from
(4 mL) were incubated overnight with 13-glucuronidase(Helix
VWR (Poole, U.K.). Methylenedioxamphetamine-ds (MDA-ds)
pomatia, 50 IJL) at 60~ After cooling, the sample was adwas obtained from Promochem (Welwyn Garden City, U.K.).
justed to pH 8 and then subjected to SPE using Bakerbond
Bakerbond Narc-2 mixed-phase cartridges were from Trichema
narc-2 columns. These are mixed-mode columns and allowed
(Warrington, U.K.). Derivatizing reagent N-methyl-bis trifluothe simultaneous extraction of acidic, basic, and neutral comroacetamide (MBTFA)was from Sigma-Aldrich (Poole, U.K.),
pounds. After conditioning the columns with methanol (2 mL),
and N-methyJ-N-trimethylsilyltrifluoroacetamide (MSTFA) +
followed by distilled water (2 mL), followedby
0.1M phosphate buffer pH 6 (2 mL), the
Table I. Retention Times (tR) and Mass Spectral Data for Target Opiate
sample was applied.After the column had been
Alkaloids
washed with distilled water (2 mL), 0.01M
Ions(m/z)
acetic acid (250 1JL) was applied. ChloroIon
form/isopropanol (80:20) (2 x 1.5 mL) was
Drug
tR Target Qualifier Qualifier
Ratio
then used to extract the acidic/neutral drugs
(min)
Ion
1
2
followed by chloroform/isopropanol/ammonium hydroxide (80:20:3) (2 x 1.5 mL) to ex11.30 165
194
176
100:80:40
Meconine
11.55 193
237
222
100:92:50
Desmethylmeconine-TMS
tract the basic drugs. The extracts were
100:70:55
Hydrocotarnine
11.80 220
221
178
combined, MBTFA(25 IJL)was added, and they
15.45 371
178
234
100:45:30
Codeine-TMS
were dried down under nitrogen at 90~ The
15,75 236
196
414
100:70:50
Morphine-2TMS
extracts were further derivatized with
15.85 341
282
229
100:70:35
Acetylcodeine
MSTFA/TCMS(50 IJL) followedby MBTFA(25
100:70:50
16.20 399
340
287
6-Mam-TMS
tJL). An aliquot of the sample (1.0 IJL)was in17.35 396
382
366
100:97:20
Hydroxypapaverine-TMS
peak1
jected
onto the GC-MS.
17.40 396
382
366
100:41:35
peak 2
peak 3
peak 4
Dihydroxypapaverine-2TMS peak1
peak 2
Papaverine
268
17.50
17.57
17.30
17.45
17.55
396
396
454
454
338
382
382
440
440
324
366
366
424
424
308
100:39:9
100:65:31
100:46:33
100:79:32
100:90:22
Instrumentation
A Hewlett-Packard (HP) 6890 series GC
fitted with a split-splitless injector with an
HP7683 automatic liquid sampler interfaced
with an HP5973 mass selective detector were
Journal of Analytical Toxicology, Vol. 30, May 2006
used (Agilent, Stockport, U.K.). The analytical column was a
DB-5 (crosslinked5% phenyl methyl siloxane, 30 m x 0.25-mm
i.d., 0.25-1Jm film thickness) fitted with a retention gap (uncoated, deactivated silica) (1 m x 0.25-mm i.d.). Temperature
conditions were as follows: initial temperature of 80~ for
2 min, increased to 310~ at 16~
held for 5 min, giving
a total run time of 21 min. The flow of the carrier gas (helium)
was maintained at 1.0 mL/min in constant flow mode. The
injector port was set at 280~ The GC-MSwas programmed to
perform a 1.0-pL splitless injection. The samples were analyzed using full scan (55-550 ainu). The samples were then
re-injected and analyzed using a selected ion monitoring (SIM)
program to monitor the target opiate alkaloids listed in Table I.
Control material
A control was run with each batch of samples to check
retention times and performance of the assay. The control
material was diluted with blank urine to give the following
concentrations in rag/L: amphetamine-d, 1.25; benzoylecgonine, 0.375; codeine, 0.75; methadone, 0.25; metamphetamined, 1.25; morphine, 0.075; morphine-3-glucuronide, 1.325;
oxazepam, 0.25; secobarbital, 0.5; and tetrahydrocannabinoic
acid, 0.0625.
Data acquisition
The software used for data acquisition was HP Enhanced
Chemstation G1701BAversion B.01.00. In addition to the 61
drugs routinely looked for in the drug treatment patients, various opiate alkaloids were specifically targeted. An additional
macro was written in-house for this software, which performed
target compound analysis for the specific opiate alkaloids. The
followingopioids were available as pure standards and were put
through the analytical procedure producing the following
derivatives: codeine, hydroxypapaverine, and 6-mare formed
TMS derivatives;morphine and dihydroxypapaverine,the 2TMS
derivatives; papaverine and acetylcodeine did not derivatise;
thebaine was not detected; and noscapine broke down to give
meconine and hydrocotarnine. Pure standards for meconine
and hydrocotarnine were not available, but as these compounds
did not derivatise,they were matched with spectra in a standard
reference library (11). Pure standard desmethylmeconinewas
not available, so this compound was identified by matching
the retention time and spectra obtained from the elucidation of
this metabolite derivative as reported previouslyby McLachlanTroup et al. (9). Desmethylmeconine had previously been synthesized on a micro scale to allow confirmation of the structure
of this urine metabolite. Neither desmethylmeconine,hydroxypapaverine, nor dihydroxypapaverine were available in sufficient quantities to allow for any quantitation. The GC retention
time, target ions, qualifier ions, and ion ratios used for the
target opiate alkaloids are shown in Table I. The limit of detection using scan was taken as a signal equal to or greater than
10 times the baseline noise; the limit of detection using SIM
was taken as a signal equal to or greater than three times the
baseline noise. Using scan the limit of detection was 50 ng/mL
for morphine and 200 ng/mL for 6-mam, and using SIM the
limit of detection was 20 ng/mL for morphine and 25 ng/mL for
6-mare. To identify a positive, the retention time had to be
within 1% of the standard for those compounds where a standard was available. For a full scan spectrum match there had to
be at least an 80% match with the ions in the standard spectrum. Using SIM three ions were used, and the ratio of these
ions had to be within 10% of the ratio for these ions in the standard spectrum. The opiate alkaloids were first matched using
the scan trace. If the signal to noise was less than 10 then the
SIM trace was used.
Results and Discussion
Figure i shows the main metabolic pathways for papaverine
and noscapine. Papaverine is metabolized by being demethylated to form four different hydroxylated metabolites and a dihydroxy metabolite (12), though noscapine is metabolized by a
C-C bond cleavage to meconine, which is then demethylated to
form desmethylmeconine (13). Figure 2 shows typical extracted
ion chromatograms, and Figure 3 shows the ion spectra for
desmethylmeconine-TMS, hyroxypapaverine-TMS, and dihydroxypapaverine-2TMS.A standard for desmethylmeconine was
not available; however, McLachlan-Troupet al. had synthesized
A
CH30
~
v
CH30
3'-Hydroxypapaverine
c'~o,,~w~.
"-'~
~
7-Hydroxpapaverine
3
= c.3o,,~,.~N
"-~
o.,o
Papaverine
4'-Hydroxypapaverine
l
CH3 0 - ~ . ~ . . ~ . N
1
"--~.
I,
.oxJj.r
6-Hydroxypapaverine
4',6-Dihydroxypapaverine
B
H3C~
"'H ~1~
O
Noscapine
H3CO
OCH3
/
Meconine
Ho o
OCM3
Desmethylmeconine
Figure 1. The main metabolic pathway for papavrine (A) and the main
metabolic pathway for noscapine (B).
269
Journal of Analytical Toxicology, Vol. 30, May 2006
this metabolite on a micro-scale to confirm the structure of the
postulated TMS derivative (9). The hydroxypapaverinewindow
shows four peaks, each peak has the ion spectra for hydroxypapaverine-TMS, suggesting the four peaks correspond to TMS
derivatives of the four different species of hydroxy metabolites;
when four peaks are seen, the peak height ratios vary, though
peak 1 is invariablythe largest. The dihydroxpapaverinewindow
shows two peaks, both peaks have the ion spectra of dihydroxypapaverine-2TMS; two peaks are always seen, but the peak
height ratio of the two peaks varies slightly. It has been postulated that there is one dihydroxy metabolite of papaverine (12),
but our findings suggest that there are two major dihydroxypapaverine metabolites corresponding to the characteristic two
peaks shown on GC-MS.
Table II shows the number of samples positive for the target
opiate alkaloids. Of the 227 samples received, 199 were positive
for morphine. Acetylcodeine, hydrocotarnine, and papaverine
were not detected in any of the samples. Acetylcodeine has a
Ion 193.00 (192.70
A
200000 !on 2{ '~91236.70
]mn z;~ ~(221.70
= ls~176176176 I~
==
500001
~
110:;0" ..............11.66
Time (rain)
Ion 396.00 (395.70 to 396.70): 2575.D
800000]1r 382.00 (361. 0 to 382.70): 2575.D
!ton 365.00 (365 0 to 366.70): 2575.0
=
6oc~oo2
B
1
4~
4~oooi
.,.e
17~20
17.40
17.60
Time (min)
Ion 454.00 (453.70 to 454.70): 25
400000 Ion 440.00 (439,70 to 440.70]: 25
lion 424.00 (423.70 to ~?.4.70): 25
3oooooI
~
C
jr 2
r
i
17.20
17.40
17.60
Time (min)
Figure 2. Typical extracted ion chromatographs of desmethylmeconineTMS (100:100:60) (A), hydroxypapaverine-TMS (100:90:25) showing
the characteristic 4-peak pattern (B), and dihydroxypapaverine-2TMS
(100:75:30) showing the characteristic 2-peak pattern (C).
270
retention time very close to morphine (retention times of 15.85
and 15.75 for acetylcodeine and morphine, respectively)and has
common ions. The ions used for monitoring morphine (429,
414, and 236) are not present in acetylcodeine,but the ions used
for monitoring acetylcodeine (341,282, and 229) are present in
morphine. The GC-MS conditions were not modified to allow
for better separation of morphine and acetylcodeine,as previous
studies had shown that acetylcodeine was not suitable for confirmation of street heroin ingestion (5,6).
Noscapine broke down during the analytical procedure to
form meconine and hydrocotarnine; noscapine is also metabolized to meconine. Meconine was detected in five urine samples,
but hydrocotarnine was not detected at all. This indicates that
the meconine detected was the metabolic product of noscapine
rather than the analytical breakdown product and that the
amount of unchanged noscapine excreted was too low to be detected. The amount of unchanged papaverine was probably also
too low to be detected. It is known that less than 1% of a dose
is excreted unchanged (12).
Compound analgesics containing codeine are used in the
prison population, and 103 samples were positive for codeine.
There were two samples positive for codeine but negative for
morphine and a further 32 samples where the peak area was
greater for codeine than morphine. No contaminants of street
heroin or papaverine/noscapine metabolites were detected in
any of these 34 samples. In these 34 cases the codeine is most
probably due to ingestion of codeine rather than illicit heroin.
In the remaining 69 samples the codeine could have been due
to metabolism of acetylcodeine, which is present in all samples
of illicit heroin, although it is possible that there could have
been ingestion of both codeine and illicit heroin.
One hundred and thirty six samples were positive for hydroxypapaverine, and 139 were positive for dihydroxypapaverine, and all samples, which were positive for
hydroxypapaverine,were also positive for dihydroxypapaverine;
only 3 samples were positive for dihydroxpapaverine alone. As
the amounts of the papaverine metabolites present were very
small, we concluded that a sample should only be reported positive if both hydroxy and dihydroxypapaverine were present.
For both metabolites, a positive was determined by first
checking the scan spectra; if the retention time matched, the
spectra matched using the stated criteria, and the signal-tonoise ratio was greater than 10, then a positive was reported; if
the signal-to-noise was less than 10, then SIM was used. Again,
if the retention time and the target ion ratios matched and the
signal to noise was greater than 3, then a positive was reported.
One hundred and thirty six of the 199 (68%) samples positive
for morphine were positive for papaverine metabolites.
Of the samples testing positive for morphine, 18 were positive
for 6-mare and 136 were positive for papaverine metabolites. All
samples, which tested positive for 6-mare, were also positive for
papaverine metabolites. The SPE GC-MS method described
here had a cut-off for 6-mare of 200 ng/mL using scan or 25
ng/mL using SIM. This method is used in scan for routine
screening of drug treatment patients. This allows the detection
of unknown as well as targeted drugs. In drug treatment patients, finding morphine alone is considered indicative of heroin
ingestion.
Journal of Analytical Toxicology, Vol. 30, May 2006
Five samples were positive for meconine, and all of the samples that were positive for meconine were positive for
desmethylmeconine. Forty six of the 199 (23%) of the samples
positive for morphine were positive for desmethylmeconine.
All samples which were positive for meconine were positive for
hydroxy and dihydroxypapaverine. Only I sample, which was
positive for desmethylmeconine,was not positive for hydroxypapaverine/dihydroxypapaverine. This shows that using this
methodology, papaverine metabolites are better indicators of illicit heroin ingestion than noscapine metabolites.
The laboratory carrying out routine drug testing for the
Prison Service use criteria broadly based on the U.K. Workplace Drug Testing Forum criteria with cut off levels specific to
HM Prison Service for England and Wales,which are 300 ng/mL
for the irnmunoassayscreening for opiates; 300 ng/mL for mor-
phine, codeine, or dihydrocodeine confirmation; and 10 ng/mL
for 6-roam confirmation. Using these criteria, the laboratory
found the same number of samples positive for morphine, but
28 samples positive for 6-mam compared with 18 positive for 6mare when using a cut-off of 25 ng/mL.
The alkaloids thebaine, papaverine, and noscapine are present
in poppy seeds (14). Consumption of poppy seeds gives rise to
the presence of morphine and codeine in urine (15-18). Cassella
et al. (19) proposed thebaine as a direct marker for poppy seed
use although the work of Meadway et al. (17) found that the
elimination of thebaine varied widely between individuals, suggesting that its absence from a specimen was not necessarily indicative of opiate abuse. The presence of noscapine or
papaverine and their metabolites were not included in any of
these studies. Four volunteers (staff at the ToxicologyUnit) ate
a lunch of poppy seed rolls and cake. The urine
from these volunteers was collected at 2, 4,
A
and 24 h and analyzed using the same method
as for the analysis of prisoner's urine. Morphine was shown to be present, but not papaverine metabolites (unpublished data). As
both the country of origin and the preparation
of the seeds can influence the concentration of
the
various alkaloids (20), a more comprehen.<
sive study is proposed using poppy seeds from
different origins. Although papaverine is found
in poppy seeds, there is a need to establish
whether
or not consumption of papaverine....
I
1
containing
poppy seeds can produce metabom/z
lites in sufficient quantities to be detectable in
.........
~.
B
urine.
This study shows that the number of samples
where ingestion of street heroin was indicated
increased by a factor of five using detection of
papaverine metabolites rather than 6-mam.
There are two published papers concerning the
pharmacokinetics of papaverine (21,22); Belpaire et al. (21) concluded that excretion of papaverine metabolites was essentially complete
within 24 h, and Wilen et al. (22) concluded
that 80% of a given dose of papaverine was
excreted within 48 h. These are relatively old
m/z
C
studies using old technologies. Recent studies
im~.~*u)~
)tcrloH
with the National Addiction Centre, Institute of
Psychiatry, Kings College London suggest that
papaverine has a similar window of detection as
morphine (23). Further studies are proposed to
establish a more precise estimate of the detection window for papaverine metabolites in
~w
urine.
Papaverine is a smooth muscle relaxant and
vasodilator. It is not licensed for use in the U.K.
but it is available in other countries including
,
..,_~ I .....
l,
h.~a ..1.. ~, [ l ~ _,,~ ..
the USA, although it is only available on prescription. Papaverine is also an ingredient pam/z
paveretum, which is a preparation containing
Figure 3. Ion chromatograms of desmethylmeconine-TMS (A), hydroxypapaverine-TMS (B),
predominantly morphine but contains other
and dihydroxypapaverine-2TMS (C).
opiate alkaloids, the formula varying from
-T'-'
M
" .L
Jl
271
Journal of Analytical Toxicology, Vol. 30, May 2006
Table II. Number of Samples Positive for Target Opiate
Alkaloids
Drug
Morphine-2TMS
6-Mam-TMS
Codeine
Meconine
Desmethylmeconine-TMS
Hydroxypapaverine-TM8
Dihydroxypapaverine-2TMS
No positive
199
18
103
5
46
136
139
Acetylcodeine
Hydrocotarnine
0
0
Papaverine
0
country to country. Papaveretum is used to supplement anaesthesia in particular pre-operative medication, and it is combined
with salicylate to form a compound analgesic. It is unlikely
that papaverine metabolites found in urine of street heroin
users are due to the intake of prescribed papaverine medication,
although it is always a possibility.
Brenneisen and Hasler studied the pyrolysis products from diacetylmorphine and adulterants of street heroin samples (24).
They found that papaverine was heat stable but noscapine was
pyrolyzed to a greater extent. In the study with the National Addiction Centre, the route of administration of the street heroin
was included in the questionnaire completed by each volunteer.
Using this information, it was shown that papaverine metabolites were detected in the urine of subjects who injected or
smoked the street heroin (19).
The method is in routine use for analyzing samples from
drug treatment patients. Immunoassay screening is not used as
these samples are nearly all positive and positive for a number
of drugs. Routinely, scan only is used. This has the required sensitivity for routine clinical work, including the detection of papaverine metabolites, and the advantage of scan is that
unknowns can be detected. However, using scan the limit of detection for 6-mare is 200 ng/mL. This is acceptable for routine
clinical work (unlike work place drug testing) as detecting morphine is interpreted as indicating heroin/diamorphine ingestion.
For this study, SIM was used in order to increase the sensitivity
for 6-mare to 20 ng/mL. One of the clinics served by the Toxicology Unit is treating clients with injectable diamorphine. As
6-mare is a metabolite common to both diamorphine and illicit
heroin it cannot be used to distinguish between the two substances. In order to find out if these clients are using illicit
heroin, in addition to the prescribed diamorphine, the compounds routinely looked for using scan include desmethylmeconine, hydroxypapaverine, and dihydroxypapaverine.
The quantities of contaminants in illicit heroin vary depending on the country of origin of the opium poppy and the
method of production of the heroin. It is possible that some
batches of illicit heroin may contain little or no papaverine.
Therefore, although the presence of papaverine metabolites
can show ingestion of street heroin, it does not follow that the
absence of papaverine metabolites shows that illicit heroin has
not been used. Papaverine metabolites cannot be a definitive
272
marker for illicit heroin use, but this study does show papaverine metabolites are a more useful indicator of heroin use
than 6-roam. The samples screened in this study came from various prisons throughout England and Wales, suggesting the
heroin had been derived from a variety of sources.
Conclusion
During routine screening of urine samples using standard
procedures and cut-offs, 6-roam was detected in 28 out of a
batch of 199 morphine positive samples, showing that the morphine was due to heroin ingestion in 14% of the samples. Using
the method described in this paper, papaverine metabolites
were detected in 136 out of 199 morphine-positive samples,
showing that the morphine was due to heroin ingestion in 68%
of the samples. This shows that papaverine metabolites were five
times more effective as an indicator of heroin ingestion than
6-mam. Further studies, preferably quantitative, are needed
before detection of papaverine metabolites can be used routinely to confirm ingestion of illicit heroin. These studies include the need to establish the time window for the detection of
papaverine metabolites in urine after heroin ingestion and to establish if the ingestion of poppy seeds containing papaverine can
give rise to significant concentrations of the papaverine metabolites in urine. The data presented here shows that papaverine
metabolites are better than noscapine metabolites as indicators
of illicit heroin use.
Acknowledgments
The authors would like to thank The Drug Strategy Unit of
HM Prison Service for funding this study and for allowing the
data to be submitted for publication. The authors would also
like to thank Medscreen| for providing the samples and the data
from the routine screening of samples for HM Prison Service.
References
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testing for opiates: 1. Detection of 6-acetylmorphine in urine as an
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