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B. Kapur: Frequently Asked Questions: Opiate Dependency and Methadone Maintenance Treatment program follow-up
Frequently Asked Questions: Opiate Dependency and
Methadone Maintenance Treatment program follow-up
Dr. Bhushan M. Kapur
Associate Professor Department of Laboratory Medicine and Pathobiology,
Faculty of Medicine, University of Toronto,
Toronto, ON
CPSO 15nov13
Tables
Table 1: Impact of half-life
Start
st
End of 1 half-life
nd
End of 2 half-life
rd
End of 3 half-life
th
End of 4 half-life
th
End of 5 half-life
th
End of 6 half-life
th
End of 7 half-life
Amount of drug left in the body
Amount of drug eliminated
100%
0%
50.0%
25.0%
12.5%
6.25%
3.125%
1.56%
0.78%
50.0%
75.0%
87.5%
93.75%
96.87%
98.44%
99.22%
Caution: Half-life can often be misleading. The duration of detection is dependent on amount taken – larger the
amount taken longer is the detection period going to be. Sensitivity of the analytical method – more sensitive the
method the longer is the detection period.
Table 2: Poppy seed Bagel and Immunoassay
Seven volunteers ate poppy seed covered bagel (one each). Urine was collected and tested for opiates by using
immunoassay (CEDIA) method on a Hitachi 717 analyser followed by Remedi-HS HPLC.
Before bagel
2 hours post
6-8 h post
Bedtime 12h post
First morning void
24h post
Following morning
48 h post
Male, 30,
140lbs
57
1888
1924
951
192
M, 40,
200lbs
54
499
905
292
359
M, 50,
160 lbs.
51
>5000
3345
NA
564
M, 40,
165 lbs.
62
1170
2081
NA
Na
F, 40, 125
lbs.
54
5906
3119
911
191
F, 25, 105
lbs.
38
2198
2858
1332
1101
F, 35,
135 lbs.
0
1888
1723
301
885
317
107
439
99
46
84
943
* ng/mL. Positive >300 ng/mL.
Three of the highest concentrations were subjected to HPLC screen and were negative for any opioids.
© 1997 - 2013 Bhushan Kapur All rights reserved
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B. Kapur: Frequently Asked Questions: Opiate Dependency and Methadone Maintenance Treatment program follow-up
Table 3: Descriptive Statistics for reference ranges1.
pH
Cr mmol/L
Na
Cl
n
5464
5477
5474
5474
mean
5.9
11.6
115
130
min
5.0
0
6
7
max
9.0
50.2
353
374
Std dev
0.92
6.5
56
62
95% reference range
>2
20-230
15-250
1
Bhushan Kapur et al.: Urine Fingerprinting - Detection of Sample Tampering in an Opiate Dependency Program,
Ther Drug Mon, 21: 243-250, (1999).
Table 4: Effects on EIA including CEDIA procedures.
Summary of adulteration studies in Literature and our Lab.
Amp
Barb
Benz
Coc
Opi
PCP
THC
Marker
Bicarbonate
Bleach 1%
-
+
-
+
-
-
+
pH, Na
Na, Cl,
Bleach 10%
++
++
++
++
++
++
++
smell
Detergent
-
++
++
++
++
++
++
pH
Drano 0.1%
Drano 20%
++
++
++
++
++
++
++
++
pH
Golden seal tea
-
-
-
-
-
-
++
Lemon Juice
-
+
+
+
+
-
+
Salt
-
-
-
-
-
-
-
Na, Cl,
SpGr
Vinegar
-
-
-
+
-
-
+
pH
Visine
-
+
+
+
-
-
++
?
Water loading*
(in-vivo)
±
±
±
±
±
±
±
Cr, SpGr
Liquid soap
dark
color
pH
cloudy
++ = strong interference; + = weak interference; - = no interference
Although these interferences have been reported in literature, they are dependent on the
amount added to the urine.
*Water loading or in-vivo dilution is the most common form of adulteration.
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B. Kapur: Frequently Asked Questions: Opiate Dependency and Methadone Maintenance Treatment program follow-up
Table 5: Drug half-lives and approximate urine detection periods
DRUG
Methamphetamine
Half-life* (t½)
12 to 34 hours
Amphetamine (metabolite
of methamphetamine)
7 - 34 hours
Methyenedioxymethamphe
tamine (MDMA) (aka
Ecstasy)
7.6 hours
Opiates ***
Morphine
1.3 to 6.7 hours
(morphine)
(metabolite of Heroin,
Codeine, Hydromorphone,
hydrocodone)
Detection period**
2 - 3 days
2 to 3 days
Opiates positive for 2-4
days (EIA)***
Comments
1) If Enzyme Immunoassay
(EIA) is positive, confirmation
by chromatography is required
because of high incidence of
false positives;
2) EIA cross-reacts with
phenylpropanolamine,
ephedrine, pseudoephedrine,
bromphenriamine, bupropion,
tradazone, chlorpromazine,
promethazine, ranitidine etc.;
(see tables 6 & 6a)
3) MDMA, MDA will be positive
with the new generation
Ecstasy EIA assay but will also
cross-react with amphetamine
derivatives as in (2).
4) Chromatography required in
differentiating amphetamine
derivatives such as MDA and
MDMA.
1) EIA does not differentiate
between opiates, and has a
poor sensitivity for oxycodone,
meperidine
2) Chromatography required in
identifying specific opiates
(codeine, oxycodone,
hydrocodone etc
3) Hydromorphone requires
sample extraction
modification.
4) Even one poppy seed bagel
will be detected on EIA ( see
table 5 below).
5) a small amount of morphine
is biotransformed into
hydromorphone but not to
Oxymorphone
About 10% of codeine is
transferred to morphine in
normal metobolizers.
False positive reported in
literature: quinolones
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B. Kapur: Frequently Asked Questions: Opiate Dependency and Methadone Maintenance Treatment program follow-up
DRUG
Oxycodone
Fentanyl
Heroin
6-Mono-acetyl-morphine
(MAM)
Phencyclidine (PCP)
Cocaine
Benzoylecgonine
(metabolite of cocaine)
9
δ -Tetrahydrocannabinol
(THC)
9
δ -Tetrahydrocannabinoic
acid (marijuana metabolite
in urine)
i) Benzodiazepines
Diazepam
Half-life* (t½)
Detection period**
4 to 6 hours
Not detected by opiate
immunoassay – specific
assay required (now
available)
IV=2.5min,
Intranasal=6.5min
Transdermal 7h (312h)
Not detected by opiate
immunoassay.
60 to 90 minutes
Specific immunoassay
recently introduced
minutes
Comments
1) 33-66% of single dose
eliminated in 24 hours.
2) Chromatography will identify
Oxycodone and or its
metabolites
Large amount will give positive
on some opiate immunoassays.
Immunoassay recently
introduced
Chromatography will identify
both fentanyl and nor-fentanyl
Fentanyl is 80% to 85% protein
bound
Not detected in urine. Positive
for opiate (morphine) is
indicative of probable Heroin
use.
MAM: Detected by
chromatography Specific
immunoassay is available
30 minutes
few hours
7 to16 hours
2 to 3 days
Positive incidences are very rare.
0.5 to 1.5 hours
few hours
Cocaine not detected by EIA
detected by chromatography
Benzoylecgonine detected by
EIA, chromatography.
5 to 7 hours
3 to 5 days
14 to 38 hours
90% fall in 1 hour
(blood)
Parent drug not detected in urine
Detected as “Cannabinoids” by
EIA. False positive reported
NAIDS naproxen and ibuprofen
much longer (60h) in
chronic heavy users
few hours to days
15 to 40 hours
Few days to many
weeks depending on
chronicity of use
days -weeks (depending
on half-life)
2 weeks or more after
last chronic use of
diazepam
i) EIA does not differentiate
between different
benzodiazepines. Some short
acting agents have poor
sensitivity.
- Oxaprozin (Daypro) can cause a
false positive.
- Gravol can cause false positive
- sertraline can cause false
positive
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B. Kapur: Frequently Asked Questions: Opiate Dependency and Methadone Maintenance Treatment program follow-up
Half-life* (t½)
Detection period**
Comments
ii) Clonazepam
19 to 60 hours
Poor – to not detected
iii) Flunitrazepam (date
rape drug Rohypnol)****
9 to 25 hours
Not differentiated by
immunoassay
ii)Extensive bio transformed, less
than 0.5% excreted in urine over
24 hours –sometime visible on
hydrolysis and GCMS if chronic
dosing is involved
iii) Need to test for the amino
derivative of Flunitrazepam by
chromatography.
iv) Extensive metabolized. 2%
excreted unchanged in urine
DRUG
iv) Bromazepam
10-20 hours
Poor
v) Lorazepam
9-16 hours
122% cross reactivity
but dosage very low
Methadone
15 to 40 hours. (Lit)
1 to 4 days.
In chronic users urine
should always be
positive
In chronic users halflife 27+8h (BK studies)
EDDP (Methadone
metabolite)
Barbiturate (Phenobarbital)
Alcohol (Ethanol)
Half-life similar to
methadone
35 to120 hours
1 to 2 weeks after last
use (Phenobarbital)
Blood levels fall by an
average of
3.2 to 3.9
mmol/L/hour
Or
15 to18 mg/100
ml/hour in social
drinkers. Can be much
higher in heavy
drinkers. Can be
30mg/100mL/hr (BK
data)
1.5 > 12 hours
depending on the peak
blood level.
Urine typically positive
for 1 to 2 hours after
BAC is zero.
© 1997 - 2013 Bhushan Kapur All rights reserved
v) hydrolyzed urine: GCMS can
differentiate between diazepam,
nordiazepam, oxazepam and
lorazepam
At alkaline pH methadone is
reabsorbed in the kidney.
Chromatography or specific EIA
required to distinguish
methadone from its metabolite
EDDP
False positive reported:
Diphenhydramine,
Phenylpropanolamine,
clomipramine, chlorpromazine,
quetiapine and thioridazine,
verapamil
EDDP not affected by urine pH
(better marker for compliance
monitoring)
Chromatography required to
differentiate between various
barbiturates
False positive reported NAIDS
naproxen and ibuprofen
1. During absorption phase urine
level lags behind blood level i.e.
BAC is higher than UAlc.
2. During elimination phase
blood levels lags behind urine
level i.e. UAlc is higher than BAC
5
B. Kapur: Frequently Asked Questions: Opiate Dependency and Methadone Maintenance Treatment program follow-up
DRUG
Ethyl Glucuronide
Gamma-Hydroxybutyrate
(GHB) (date rape drug)
#
*
**
***
****
Half-life* (t½)
Detection period**
2 to 3 hours
Depends on use.
Lit. reports up to 120h if
LCMSMS (0.1mg/L) is
used. 25- 30 h (by EIA BK data)
Less than 12 hours
0.3 to 1.0 hour
Comments
0.02% of ethanol is excreted as
ETG.
Chromatography required.
Detected as GHB lactone
EIA Enzyme immunoassay
R.C. Baselt: Disposition of Toxic Drugs and Chemicals in Man, Fifth Edition 2000
The detection period is very much dose and half-life dependent. The larger the dose, the longer
the period the drug/metabolite can be detected in the urine.
Opiates may be positive for up to 2 weeks after last use with slow release opiates.
Flunitrazepam (Rohypnol) is usually not detected with the generic EIA benzodiazepine
procedure. Use chromatography to detect Amino-Flunitrazepam
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6
B. Kapur: Frequently Asked Questions: Opiate Dependency and Methadone Maintenance Treatment program follow-up
Figure 6: Specific Gravity - Ur Creatinine
Figure 7: Urine Temperature
37
36.5
36
35.5
35
34.5
34
0
5
10
15
20
25
30
35
40
45
50
Seconds
Kapur 1989
Temperature
© 1997 - 2013 Bhushan Kapur All rights reserved
Regression
7