Download Fatality Involving the Ingestion of Phenazepam and Poppy Seed Tea Case Report

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Case Report
Fatality Involving the Ingestion of Phenazepam
and Poppy Seed Tea
Kristen Bailey, Lauren Richards-Waugh, David Clay, Myron Gebhardt, Hamada Mahmoud, and James C. Kraner
Office of the Chief Medical Examiner, Charleston, West Virginia
Abstract
Phenazepam is a benzodiazepine derivative that has been in
clinical use in Russia since 1978 and is not available by
prescription in the United States; however, it is attainable through
various internet websites, sold either as tablets or as a referencegrade crystalline powder. Presented here is the case of a 42-yearold Caucasian male who died as the result of combined
phenazepam, morphine, codeine, and thebaine intoxication.
A vial of white powder labeled “Phenazepam, Purity 99%, CAS
No. 51753-57-2, Research Sample”, a short straw, and several
poppy seed pods were found on the scene. Investigation revealed
that the decedent had a history of ordering medications over the
internet and that he had consumed poppy seed tea prior to his
death. Phenazepam, morphine, codeine, and thebaine were
present in the blood at 386, 116, 85, and 72 ng/mL, respectively.
Introduction
The internet provides virtually unlimited access to medical
information and a forum for discussion of numerous health-related topics to over one billion people globally (1). Unfortunately, it also facilitates the dissemination of potentially hazardous substances by providing an alternative source of illicit
and prescription drugs (1,2). Furthermore, not only can drugs
be obtained through the internet, but also instructions, advice,
and first-person accounts of drug abuse practices (1,3).
Phenazepam (fenazepam) [7-bromo-5-(2-chlorophenyl)-1,3dihydro-2H-1,4-benzodiazepin-2-one] is a benzodiazepine
derivative which was first synthesized in 1975 through the
joint efforts of pharmacologists from the Academy of Medical
Sciences of the USSR and chemists from I.I. Mechnikov Odessa
National University in Ukraine (4,5). Its clinical use has been
widespread in the former Soviet Union since 1978, where it is
one of the most extensively prescribed benzodiazepines (5–7).
Structurally, phenazepam is similar to clonazepam (Figure 1).
Like other benzodiazepines, phenazepam is a therapeutically
useful anxiolytic with anticonvulsive and hypnotic activity.
Some report that it is comparable to lorazepam in regard to its
dose and therapeutic action (8), but others report that it has a
higher median lethal dose (LD50) in rats than benzodiazepines
such as chlordiazepoxide and diazepam (5).
In the United States, phenazepam is not currently approved
for prescription use and is not listed under the Controlled
Substances Act. Accordingly, distribution of the drug remains
uncontrolled. Phenazepam is, however, making its way into the
United States (9,10) and infiltrating illicit drug markets in
Sweden and Finland (8,11,12). Many internet websites provide potential global access to this drug with little difficulty,
and available preparations include tablets and reference-grade
crystalline powders.
As a fairly comprehensive information resource, the internet
provides a great deal of information concerning the use of
poppy seed tea (PST) to individuals hoping to achieve opiateinduced euphoria or control pain. Additional interest in PST is
sparked by the claim by some users that the consumption of
PST mitigates the severity of withdrawal symptoms from opiates (13). Several websites advertise the sale of seed pods, and
Figure 1. Structure of phenazepam.
Reproduction (photocopying) of editorial content of this journal is prohibited without publisher’s permission.
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seeds can be purchased in bulk from supermarkets or health
food stores at a relatively low cost. Detailed instructions for
preparation of PST, as well as anonymous forums for discussion
of its use are easily found following a web search for “poppy
seed tea.” A widely used method for the preparation of PST involves washing or soaking generous quantities of dried seeds in
water containing lemon juice. The resultant liquid is then
consumed. With this method, significant amounts of morphine, codeine, and other opiate alkaloids are extracted from
the residual coating and capsular debris of the seeds (13).
Poppy seeds harvested in different years or from different regions of the world display a wide range of concentrations of
morphine (2–251 mg/kg seeds), codeine (0.4–57 mg/kg seeds)
(14), and compounds such as thebaine, papaverine, and
noscapine (narcotine). Accordingly, teas prepared from differing varieties of seeds will also exhibit variations in the concentrations of such compounds. PST prepared from “recipes”
provided by PST users has been shown to contain morphine in
concentrations ranging from 10 to 105 mg/kg seeds and
codeine concentrations ranging from 3 to 11 mg/kg seeds (13).
Figure 2. Poppy seed pods.
It has been demonstrated that approximately 50% of the morphine and codeine in poppy seeds can be extracted by soaking
seeds in water for 5 min with constant agitation (15). Users of
PST report that the onset of effects usually occurs within 15
min of ingestion and that these effects can be felt for up to
24 h, depending on the amount of tea consumed (13).
Here, a fatality involving concurrent use of phenazepam
and PST is presented.
Case History
A 42-year-old Caucasian male was found unresponsive in bed
by his wife when she returned home from nursing school. She
called 911, and EMS responded to the scene where he was pronounced dead. The woman reported that her husband was an alcoholic, had a history of drug abuse, and visited his doctor five
months earlier for treatment of insomnia and asthma. She also
stated that he had been unemployed for an extended period of
time and spent his days at home accessing the internet, through
which he had previously purchased medications. A search of the
decedent’s bedroom yielded a short straw, several poppy seed
pods (Figure 2), a plastic measuring cup containing several
lemon slices, and a small glass vial labeled “Phenazepam, Purity
99%, CAS No. 51753-57-2, Research Sample”. The vial contained a small amount of white powder (Figure 3). When later
questioned about the seed pods, the decedent’s wife indicated
that they were “opium poppy seed pods” that her husband used
to make tea.
A complete autopsy was performed, revealing marked obesity
(body mass index = 37), cardiomegaly (660 g), and pulmonary
findings consistent with bronchial asthma. Marked pulmonary
edema, diffuse visceral congestion, and moderate cerebral
edema were also documented. Samples submitted to the toxicology laboratory included blood from the subclavian vein,
urine, gastric contents, liver, and vitreous humor. Powder from
the glass vial was submitted at a later date by law enforcement.
Materials and Methods
Figure 3. Vial containing white powder.
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Subclavian blood was analyzed for volatiles using direct injection and gas chromatography–flame-ionization detection
(GC–FID) with t-butanol employed as the internal standard.
Preparation of the sample involved the addition of 2 mL t-butanol to 1 mL subclavian blood and vortex mixing prior to
manual injection of approximately 0.5 µL onto an HP 6890 series GC with an FID. Subclavian blood (precipitated with acetone and reconstituted in 0.1 M, pH 6.5 phosphate buffer)
and urine were screened for a panel of drugs by enzyme immunoassay on a MGC 240 analyzer using DRI® reagent kits
purchased from the manufacturer (Microgenics, Fremont,
CA). An alkaline drug screen on urine was performed using
Toxi-Lab® Toxi-Tubes® A (Varian, Palo Alto, CA) and GC–mass
spectrometry (MS). A minute amount of powder from the
glass vial was dissolved in methanol and analyzed by GC–MS.
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Mass spectral data from analysis of the powder was compared
with that of a phenazepam standard (Lipomed, Cambridge,
MA).
Next, benzodiazepine and opiate confirmations were performed. Negative serum was purchased from Sigma Aldrich
(St. Louis, MO). Codeine, codeine-d6, morphine, and morphine-d6 were obtained from Cerilliant (Round Rock, TX).
Methanol and formic acid were purchased from EMD Chemicals (Gibbstown, NJ), and acetonitrile was from JT Baker
(Phillipsburg, NJ). Deionized water was prepared using a MilliQ system (Millipore, Bedford, MA).
Benzodiazepine calibrators consisted of negative serum fortified with phenazepam, diazepam, nordiazepam, clonazepam,
7-aminoclonazepam, temazepam, oxazepam, alprazolam, lorazepam, midazolam, demoxepam, chlordiazepoxide, and
norchlordiazepoxide at concentrations of 5, 10, 25, 50, 100,
250, 500, and 1000 ng/mL. Controls at concentrations of 20,
200, and 650 ng/mL were prepared independently. Blank
Table I. Instrument Parameters
Source temperature (°C)
Desolvation temperature (°C)
Desolvation gas (L/h)
Cone gas (L/h)
Column temperature (°C)
Phenazepam
Morphine and
Codeine
150
350
850
30
40
150
450
850
50
40
Table II. MRM Transitions and Conditions
Precursor
Ion
(m/z)
Product
Ions
(m/z)
Cone
Voltage
(V)
Collision
Energy
(eV)
Phenazepam
349
184*
104
206
40
40
40
54
30
32
Diazepam-d5
290
154*
198
50
50
30
34
Morphine
286
165*
153
201
55
55
55
42
42
26
Morphine-d6
292
64*
153
55
55
26
46
Codeine
300
58*
165
153
50
50
50
28
38
44
Codeine-d6
306
61*
153
50
50
34
54
* Denotes MRM transition used for quantitation.
serum was extracted and included in the analysis. Sample
preparation was performed using a modification of a method
described by Karinen et al. (16). Two-hundred microliters of
calibrators, controls, and samples were added to 2.0-mL
polypropylene microcentrifuge tubes, and 10 ng diazepamd5 was added as internal standard to each tube. Protein precipitation was achieved through the addition of 1.0 mL cold
acetonitrile/methanol (85:15). Each tube was vortex mixed
briefly and centrifuged at 32,000 × g at 2°C for 15 min. Supernatants were transferred to 12 × 75-mm glass culture
tubes and dried at 45°C under a stream of nitrogen. Residues
were reconstituted in 150 µL initial mobile phase (0.1%
formic acid/acetonitrile with 0.1% formic acid, 72:28) and
placed into microcentrifuge tubes, centrifuged a second time,
and transferred to autosampler vials for analysis.
Opiate calibrators consisted of negative serum spiked with
morphine, codeine, oxycodone, oxymorphone, hydrocodone,
dihydrocodeine, hydromorphone, and 6-acetylmorphine at
concentrations of 2.5, 5, 10, 20, 50, 100, 500, and 1000 ng/mL.
Controls at concentrations of 7.5, 200, and 650 ng/mL were
prepared and included in the analysis, along with a blank
serum. Sample preparation was performed as described, with
10 ng morphine-d6 and codeine-d6 added to each tube as internal standards for morphine and codeine. Again, residues
were reconstituted in 150 µL initial mobile phase (0.1%
formic acid/acetonitrile with 0.1% formic acid, 99:1) and
placed into microcentrifuge tubes for a second centrifugation prior to analysis.
All chromatography was performed using a Waters Acquity
ultra-performance liquid chromatograph (UPLC®) with separation achieved on an Acquity UPLC BEH C18 2.1- × 100-mm
(1.7 μm) column (Waters, Milford, MA). For each analysis,
column temperature was maintained at 40°C. All chromatographic runs were performed using linear gradients where
solvent A was 0.1% formic acid and solvent B consisted of
acetonitrile with 0.1% formic acid. For phenazepam, the initial conditions of solvent A/solvent B (72:28) were maintained
for 0.1 min. Solvent A was then decreased to 58% over 2.2 min
and maintained until 2.7 min. It was then reduced to 50% at
3 min and to 5% at 3.5 min, where it was held until 4.5 min.
The system was returned to initial conditions and held for 1
min prior to the next injection. For morphine and codeine,
solvent A was decreased from 99% to 0% over 5.0 min. At 5.5
min, initial starting conditions were restored and maintained
for 1 min until the subsequent injection. Average retention
times (in minutes) observed under these chromatographic
conditions were 3.22 for phenazepam, 3.34 for diazepam-d5,
1.90 for morphine and morphine-d6, and 3.47 for codeine and
codeine-d6.
MS–MS analysis was carried out using a Waters TQ Detector with ionization in electrospray positive mode. Target
compounds were analyzed using multiple reaction monitoring
(MRM) with argon as the collision gas. Instrument parameters
for phenazepam, morphine, and codeine are given in Table I,
and details of the MRM transitions and conditions are shown
in Table II. One quantification transition and two target transitions were monitored for drugs of interest, whereas only a
quantification transition and a single target transition were
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monitored for deuterated internal standards.
The LOQ for benzodiazepine and opiate analysis was set to
that of the lowest calibrator, 5 ng/mL for benzodiazepines
and 2.5 ng/mL for opiates. Both assays were found to be linear
over the range of calibrators used, with r2 = 0.99 for each
drug of interest. Within-run precision was calculated at concentrations of 20, 200, and 650 ng/mL for phenazepam and
concentrations of 7.5, 200, and 650 ng/mL for morphine and
codeine (n = 3 for each concentration). For phenazepam, coefficients of variation (%CV) ranged from 0.68% to 7.5%; for
morphine, %CV ranged from 0.77% to 11.1%; and for codeine,
%CV ranged from 2.67% to 6.24%. To be acceptable, all ion ratios had to be within ± 20% of the average ion ratios for the
calibrators. Additionally, concentrations of positive controls
had to be within ± 20% of their expected concentrations.
Prior to analysis of case samples, blood controls were prepared, extracted, and quantified using serum curves. For each
drug, these controls met the acceptability parameters noted
above; therefore, serum curves were used for analysis. Matrix
effects were evaluated using post-column infusion of drugs of
interest with simultaneous injection of blank extracted matrix
(blood and serum) under desired chromatographic conditions. This assessment did not reveal any notable ion suppression or enhancement.
Results
No ethyl alcohol or other volatile compounds were detected
in subclavian blood by GC–FID. Both subclavian blood and
urine screened positive for benzodiazepines and opiates by
enzyme immunoassay. Preliminary data collected by our laboratory using spiked urine suggested that phenazepam
demonstrates significant cross-reactivity for the Microgenics
DRI Benzodiazepine Assay. The following compounds were
detected in the urine alkaline drug screen by GC–MS through
matches with NIST, AAFS, and in-house spectral libraries:
Figure 4. MRM chromatograms of extracted blank (A), 200 ng/mL control (B), and case (C) for phenazepam and diazepam-d5.
Figure 5. MRM chromatograms of extracted blank (A), 200 ng/mL control (B), and case (C) for morphine and morphine-d6.
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nicotine, cotinine, hydrocodone, codeine, and thebaine. Free
phenazepam was found in the blood at a concentration of 386
ng/mL. Unconjugated morphine and codeine were quantified
in the blood at 116 and 85 ng/mL, respectively, by LC–MS–MS.
MRM chromatograms of extracted blanks, 200 ng/mL controls, and case specimens for phenazepam, morphine, and
codeine are shown in Figures 4–6. Thebaine was quantified in
the blood by GC–MS at 72 ng/mL (NMS Labs, Willow Grove,
PA). Heroin use was excluded based on investigative findings
and the absence of 6-acetylmorphine and acetylcodeine in the
blood and urine (17,18). The powder in the vial was confirmed
to be phenazepam with no other drugs detected; however,
further study of purity of the phenazepam preparation was not
performed.
Discussion
The number of deaths resulting from the use of opioid compounds in combination with benzodiazepines has displayed
an alarming increase in recent years (19). When taken in excess, opioids can often elicit significant respiratory depression, and when used in conjuction with benzodiazepines, enhancement of opioid-mediated central nervous system
depression may be observed (20,21). In this case, assessing
the relative contributions to fatal toxicity of phenazepam and
the poppy seed derived compounds, as well as the extent of
their combined effects, was especially challenging. Another
factor to be considered was the assessment of the decedent’s
natural disease and associated respiratory insufficiency, which
may have left the decedent more vulnerable to fatal respiratory
depression in the presence of these compounds. Interpretation
of toxicity produced by opiate compounds is dependent on
several factors, particularly the extent to which the user has developed tolerance to the compounds. Studies indicate that
morphine and codeine at the concentrations found in the presented case are capable of producing toxicity in those who
lack tolerance to opioid medications (22). Although the decedent was reported to abuse drugs, the available information did
not specifically point to a history of ongoing opioid abuse, and
as such, it is not clear whether any level of opioid tolerance was
present. Had the decedent been using opioid drugs or PST for
a period of time, one would expect him to have developed
some degree of pharmacodynamic tolerance to the compounds
detected, and the concentrations observed may not have been
lethal. Although reliable information pertaining to the interpretation of blood thebaine concentrations is limited, the detection of thebaine in the urine and blood corroborates the
decedent’s reported consumption of PST (23,24).
Phenazepam intended for oral administration is supplied in
0.5–2-mg tablets, with the normal adult dose being 0.5 mg 2–
3 times daily for the treatment of anxiety (6). Kankaanpää et al.
(25) reported a pharmacologically relevant concentration of
phenazepam to be 300 ng/mL, although an effective therapeutic concentration range of 30–70 ng/mL for treatment of
neurosis has also been reported (8). Peak plasma concentrations from 8 to 15 ng/mL following a 2-mg oral dose have
been described (8), and single oral doses of the drug at 3 and 5
mg produced average blood concentrations of 24 and 38
ng/mL, respectively (6). Furthermore, blood phenazepam levels
in 20 subjects arrested for impaired driving ranged from 18 to
400 ng/mL (8).
In this case, the possibility that phenazepam alone contributed to severe cardio-pulmonary distress is likely, given
the suggested potency of the drug (8). However, information
pertaining to phenazepam in the scientific literature is limited
and somewhat contradictory; therefore, a reliable estimation of
its degree of toxicity is difficult. Mrozkowska et al. (12) report
a non-fatal case in which a 26-year-old male ordered
phenazepam over the internet and reported ingesting a significant quantity of the drug (400–600 mg). This resulted in an extremely high blood concentration (1.2 µg/g, or approximately
1200 ng/mL) seven days post-ingestion, though it should be
noted that this study did not identify whether this concentration referred to free or total phenazepam. The concentration of
Figure 6. MRM chromatograms of extracted blank (A), 200 ng/mL control (B), and case (C) for codeine and codeine-d6.
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phenazepam in the present case report suggests the consumption of an amount of phenazepam significantly in excess
of that which would be seen in a clinical setting and some
level of impairment and/or toxicity would be expected. On the
other hand, based on the non-fatal outcome highlighted in
the case presented by Mrozkowska et al. (12), ascribing fatal
toxicity to a phenazepam blood concentration of 386 ng/mL is
unwarranted.
Although it could not be ascertained whether the decedent
had previously used phenazepam, it would not be surprising if
death ensued after his first use of the drug. It seems likely
that the decedent may not have had full knowledge or appreciation of the purity of the drug he purchased via the internet.
Any prior personal experience or familiarity he had regarding
insufflation of a given amount of crushed tablets containing
pharmacologically inert ingredients and his naivety about the
potency of the “99% pure” drug purchased through the internet could have led to the inadvertent exposure to a significant and unintentionally large quantity of the drug.
Conclusions
To summarize, it was the opinion of the certifying pathologist that the cause of death was combined morphine, codeine,
thebaine, and phenazepam intoxication in the setting of recreational abuse of PST and non-prescribed phenazepam with
marked obesity acting as a contributory factor to death. This
case is unique in that 1. phenazepam and PST are rarely observed in postmortem investigations; 2. it is the only reported
fatality involving both phenazepam and PST; and 3. the
phenazepam and the instructions for use and preparation of
PST were apparently obtained by the user from the internet.
Furthermore, the fatal outcome in this case report underscores the potentially negative role played by the internet in facilitating access to illicit/uncontrolled substances and hazardous drug abuse practices.
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