10/12/2015 1 Interpreting: Urine Drug Test Results in Chronic Opioid Therapy and Drugs of Abuse Grant D. Beardsley, M.S., MT(ASCP) Clinical Toxicologist, Grant Beardsley, MS, MT(ASCP) • I have nothing to disclose. • I work for PeaceHealth Laboratories and will share some of our processes, but I have no commercial interest. What Americans Believe • 70% of opioid users do not know sharing painkillers is a felony • 90% of opioid users are unconcerned about addiction • Only 20% Americans consider prescription pain medication to be a serious safety threat. From: 2015 National Safety Council –Opioid Painkiller Media Briefing (n=427) http://www.nsc.org/NewsDocuments/031115-Public-Opinion-Poll.pdf
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Transcript
10/12/2015
1
Interpreting:
Urine Drug Test Results in
Chronic Opioid Therapy
and Drugs of Abuse
Grant D. Beardsley, M.S., MT(ASCP)
Clinical Toxicologist,
Grant Beardsley, MS, MT(ASCP)
• I have nothing to disclose.
• I work for PeaceHealth Laboratories and
will share some of our processes, but I
have no commercial interest.
What Americans Believe
• 70% of opioid users do not know sharing
painkillers is a felony
• 90% of opioid users are unconcerned about
addiction
• Only 20% Americans consider prescription
pain medication to be a serious safety threat.
From: 2015 National Safety Council – Opioid Painkiller Media Briefing (n=427)
Gourlay, DL, Heit, HA. Patient Centered Approach to UDT in the Chronic Pain Patient. PainWeek, Las Vegas, NV; Sept 9, 2011.
The Laboratory’s Challenge:
Specimen Matrix
Biological specimens are mostly
made of what we are not
interested in measuring.
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� A mixture of 95 drug standards injected into LC-MS/MS (top).
� Patient specimen (bottom).
Chromatography (LC-MS/MS)
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SECOND: Multiple Reaction Monitoring
170 210 250 290
210
222
268 280165
Spectrum with
background ions
Q1 lets only
drug ion 210
pass through
190 210
210
Q2 Collision Cell
breaks ion 210
apart
150 170 190 210
210158
191
Q3 filters specified
product ions 158 and
191 from precursor
ion 210 to detector.
160
158
190
191
no chemical background
Ions
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Interpretation of Opiate/Opioid Test Results
� Understanding opiate-opioid metabolism is essential for
interpretation of test results.
� Historical knowledge of metabolism is data based on standard
opiate-opioid doses.
� New findings in high dose pain medication challenges historical
knowledge.
Oxycodone 5 mg tablet Oxycodone 80 mg tablet
Pharmacokinetics
Major and Minor Metabolic Pathways for Opiates & Opioids
MorphineCodeine 6-Monoacetylmorphine
Poppy Seeds and Morphine Drugs
Minor Metabolism
(high dose codeine)Minor Metabolism
(high dose morphine)
Hydrocodone Hydromorphone Heroin
Norhydrocodone (CYP3A4)
SB Karch. Pathology of Drug Abuse. CRC Press, 4th Ed. (2009)
Clinical Toxicology, A Guide for Laboratory Professionals. CAP Press (2012)
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Major and Minor Metabolic Pathways Opioids (cont.)
Methadone Methadone Metabolite (EDDP)
Buprenorphine Norbuprenorphine
Tramadol O-desmethyl tramadol
Oxycodone Oxymorphone
Oxycodone Noroxycodone (CYP3A4)
SB Karch. Pathology of Drug Abuse. CRC Press, 4th Ed. (2009)
Clinical Toxicology, A Guide for Laboratory Professionals. CAP Press (2012)
Benzodiazepines
• Complicated metabolism for many benzodiazepines
• Parent benzodiazepine frequently not found in urine
– Immunoassays may target the parent medication and have poor cross-reactivity to the metabolites
• Patients may be taking more than one benzodiazepine
• Significant patient safety issue when taken with opiate/opioids
Benzodiazepine Metabolism & Elimination
Clorazepate (Tranxene)
Diazapam (Valium) Temazepam (Restoril)
Nordiazepam Oxazepam (Serax)Halazepam (Paxipam)
Chlordiazepaxide (Librium)
Flurazepam (Dalmane) N-hydroxyethylflurazepam
7-aminoclonazepam
α-hydroxyalprazolamAlprazolam (Xanax)
Lorazepam (Ativan)
Clonazepam (Klonopin)
Glu
cu
ron
ida
tio
n
Flunitrazepam (Rohypnol)
Source: Clinical Toxicology Testing; CAP Press (2012)
7-Aminoflunitrazepam
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Example:
Rx - Clonazepam
Benzodiazepines Screen - Positive by instant cup test
Is confirmation test necessary?
Confirmation shows patient taking lorazepam and alprazolam in
addition to clonazepam
Benzodiazepines in Urine
Drug Urine Metabolites Half-life, plasma (hr)
Detection Time in
Urine (d)
Alprazolamα-Hydroxyalprazolam
11 to 15 2 to 5
Chlordiazepoxide Nordiazepam
Oxazepam5 to 30 2 to 5
Clonazepam7-Aminoclonazepam
20 to 40 2 to 5
DiazepamNordiazepam
Oxazepam
Temazepam
20 to 40 7 to 10
Flunitrazepam (not in US)7-Aminoflunitrazepam
6 to 24 2 to 5
FlurazepamHydroxyethylflurazepam
2 to 3 1 to 2
LorazepamLorazepam
9 to 24 2 to 5
Nordiazepam (not in US)Oxazepam
> 24 7 to 10
OxazepamOxazepam
4 to 15 2 to 5
Clorazepate
(prodrug) Nordiazepam
Oxazepam
> 24 7 to 10
Source: Clinical Toxicology Testing; CAP Press (2012).
Negative result for a prescribed medication:
� Non-adherence, possible diversion
� Medication used incorrectly:
o Less than prescribed dose used
o Less frequently used than prescribed
� Variable drug delivery, or not well absorbed
� Rapid metabolism/elimination
� Dilute urine or adulterated urine specimen
� Immunoassay screen failed to detect drug concentration
� Clerical or analytical error
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Positive result for a drug not prescribed
� Drug was used:
� Previous prescription
� Illicit use (street purchase, theft)
� Prescription obtained from another provider
� Incorrect prescription was filled
� Non-medical use (“shared prescription”)
� Metabolite detected from a legitimate prescription
o Codeine (high dose) ⇒ hydrocodone
o Morphine (high dose) ⇒ hydromorphone
� Poor test method specificity (immunoassay)
� Prescription manufacturing impurity
Commercial Active Pharmaceutical
Ingredient
Process Impurities Allowable Limit (%) Typical Observed (%)
Codeine Morphine 0.15 0.01-0.1
Hydrocodone Codeine 0.15 0-0.1
Hydromorphone Morphine
Hydrocodone
0.15
0.1
0-0.025
0-0.025
Morphine Codeine 0.5 0.01-0.05
Oxycodone Hydrocodone 1.0 0.02-0.12
Oxymorphone Hydromorphone
Oxycodone
0.15
0.5
0.03-0.1
0.05-0.4
Acceptable Opioid Process Impurities in Commercial Drug Substances
NB: New methods eliminate these impurities for hydrocodone and hydromorphone; Both varieties are available. Information from API
Manufacturers’ Certificates of Analysis.
Ethanol Testing in Urine
From: JA Gudin, et al. Risks, management, & monitoring of combination opioid, benzodiazepines, and/or
alcohol use. Postgrad Med. July (2013) 125(4): 115-130.
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Testing for Methadone:
High inter-individual variability
• Absorption and metabolism make its clinical
effects and toxicity difficult to predict
– Oral bioavailability: 41 – 95%
– Peak plasma (Tmax) levels from 1 - 6 hours
– Prolonged elimination T½ : 7 – 65 hours
Testing for Methadone & Metabolite (EDDP)
• Immunoassay Screen (IA):
� Specific test needed to detect methadone
� Metabolite (EDDP) is not detected by IA
� Methadone excretion increased in acid urine
• Confirmation by mass spectrometry
� Methadone & EDDP targeted for analysis
� Confirm unexpected IA negative screens
� Suspect: methadone positive, EDDP negative
� Detection time after last dose: 3 – 11 days
Case study:
A patient receiving SR-morphine 30 mg tid for chronic pain requests an increase in dose. The physician orders a urine pain management drug test panel that shows:
Urine Drug Test Results: Morphine 8250 ng/mLHydromorphone 325 ng/mL Oxymorphone 110 ng/mLEthanol 0.077 g/dL
� NOT Methylphenidate (Ritalin®, Concerta®) Methylphenidate and metabolite (ritanilic acid) are not detected by immunoassay screens and routine GC/MS confirmation tests. 60
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Testing for Cocaine
35 – 54%
Testing for Cocaine
• Immunoassay Screen:
– Target cocaine metabolite, benzoylecgonine
– Very reliable, few false positive by IA
• Confirmation by Mass Spectrometry:
– Target cocaine metabolite, benzoylecgonine
– Detected for 1 to 5 days after use
– Positive result is not due to other “caines” (ex. lidocaine).
Testing for Marijuana (THC)
Immunoassay Screen:
• Carboxy-THC is detected but many other THC metabolites
cross-react with the test.
• False positives from pantoprazole (Protonix®), otherwise rare.
Confirmation by Mass Spectrometry:
• Threshold-cutoff set to avoid passive exposure (15 ng/mL)
• Single Use: positive for 1 to 3 days after last use
• Chronic Use: positive up to 30 days or longer after last use