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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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People who abuse or are dependent on

prescription opioids are 40x more likely to

be abusing or dependent on heroin.

From: Frieden, T. Heroin: The Epidemic That Knows No Boundaries; Medscape CDC Expert Commentary.

July 27, 2015. See: www.medscape.com/viewarticle/848294

From: http://www.agencymeddirectors.wa.gov/Files/2015AMDGOpioidGuideline.pdf

Over 60% of patients taking opioids for

at least 3 months are still on opioids five

years later.

Source of Prescription Drugs for Nonmedical Use

5

Free from

friend/relative

53 %Bought/took from

friend/relative

15 %

Other

5%

Rx from one

doctor

21 %

Drug Dealer

4 %Internet

0.1%

Source (2014): The National Survey on Drug Use and Health 2013

www.samhsa.gov/data/NSDUH/2013SummNatFindDetTables/NationalFindings/NSDUHresults2013.htm

Sources Where Users Obtained

Pain-Relievers for Nonmedical Use

The purpose of urine drug testing:

� Identify undisclosed drug use and/or abuse

� Identify aberrant behavior

� Verify compliance with treatment

Source: Washington State Agency Medical Directors’ Group. Interagency Guideline on

Prescribing Opioids for Pain. 3rd edition, June 2015.

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Urine drug testing can not do…..

There is no scientifically validated relationship

between the amount of drug taken and urine drug

concentration.

Therefore, a urine drug test cannot indicate the

amount of drug taken, when the last dose was

administered, or the source of that drug.

Source: Douglas L. Gourlay, MD, Yale H. Caplan, Ph.D., and Howard A. Heit, MD. Urine Drug

Testing in Clinical Practice, 4th Edition, 2010

Nationally Recognized Guidelines & Recommendations

• American Academy of Family Practitioners

• Centers for Disease Control & Prevention

• Washington State Agency Medical Directors’ Group

• Institute for Clinical Systems Improvement (ICSI)

• American Academy of Pain Medicine & American Pain Society in Opioid Treatment Guidelines

• Department of Veteran’s Affairs

• Center for Medicare & Medicaid Services (CMS)

• Physicians for Responsible Opioid Prescribing

All of the above organizations endorse periodic patient assessment with urine drug testing.

Updated Guidelines:

June 2015

http://www.agencymeddirectors.wa.gov/Files/2015AMDGOpioidGuideline.pdf

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Questions Confronting Providers

“Is my patient taking the medications I did prescribe ?”

� Adherence, non-adherence, diversion

“Is my patient taking drugs I did not prescribe ?”

� Non-medical use of scheduled prescriptions

� Scheduled prescriptions from other providers

� Illicit drug use

“What is the reliability of a urine drug test ?”

� How accurate are the tests

� Potential for misinterpretation

� How often should a patient be tested

Adherence vs. Non-adherence

� Retrospective study of 470 non-cancer COT patients.

� Urine drug tests included confirmation.

� Drug test results compared to Rx records:

From: Michna, E., et al., Clin J Pain 23:173-179, Feb 2007

54%

10%

14%

20%

2% Expected opioid present

(Normal)

Missing prescribed opioid

Unexpected drug present

Illicit drug

Adulterated specimen

Incidence of Aberrant UDT Results

StudyCOT patients with

aberrant UDT results

Cook RF, 1995 50%

Fishbain DA, 1999 46.5%

Hariharin J, 2007 38%

Ives TJ, 2006 32%

Berndt S, 1993 32%

Katz NP, 2003 29%

Michna E, 2007 45%

West R, 2010 9-33%

Manchikanti L, 2006 16%

From: Owen, Graves T., et al. Urine Drug Testing: Current Recommendations and Best Practices, Pain Physician 2012.

15:ES119-ES133, ISSN 2150-1149

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Recommendation for Frequency of UDT (1)

Risk Category (by ORT) UDT Frequency

• Low Risk 1 per year

• Moderate Risk 2 per year

• High Risk or Opioid dose > 120 mg

MED/d)

3 - 4 per year

• Aberrant Behavior(Lost Rx, multiple requests for early refill, opioids

from multiple providers, unauthorized dose

escalation, apparent intoxication, etc.)

At time of visit(Address aberrant behaviors in person,

not by telephone.)

Source: Washington State Agency Medical Directors’ Group. Interagency Guideline on Prescribing Opioids for

Pain. 3rd edition, June 2015.

Patient Risk Status/ Profile Frequency of Opioid Monitoring

• Stable opioid treatment

• Low risk for adverse outcome* Once every 3-6 months

• History of addictive disorder

• Occupation requiring high mental activity

• Older adults

• Unstable/dysfunctional social environment

• Psychiatric or medical comorbidities

More frequent after treatment

initiation; changes in opioid dose

• Very high risk for adverse outcome* Once weekly

Source: Chou R, Fanciullo GJ, Fine PG, et al; American Pain Society-American Academy of Pain Medicine Opioids

Guidelines Panel. Clinical guidelines for the use of opioid therapy in chronic noncancer pain. J Pain. 2009;10(2):113-130.

*Undesirable effects associated with opioid use (misuse, abuse, addiction or diversion).

Recommendation for Frequency of UDT (2)

Drug/ Drug Class to Test

• Prescribing drug (if not listed)

• Amphetamines

• Opioids

• Cocaine

• Benzodiazepines

• Alcohol

• Barbiturates

• Oxycodone

• Methadone

• Fentanyl

• Marijuana

Source: Washington State Agency Medical Directors’ Group. Interagency Guideline on

Prescribing Opioids for Pain. 3rd edition, page 63. June 2015. .

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Laboratory Analysis in Pain Management

• Drug screen (“initial test”, “UDS”)• Immunoassays (Emit, ELISA, others)

• Specimen Validity Test

– pH, creatinine, specific gravity, oxidants, etc.

– Check for dilution, interference, adulterants

• Confirmation Testing (mass spectrometry)• GC-MS

• LC-MS/MS

• LC-TOF/MS

• Directed (mass spectrometry)• LC-MS/MS or GC/MS

16From: Clinical Toxicology, A Guide for Laboratory Professionals. CAP Press (2012)

Screen vs. Confirmation Tests

• Screen test: – Detect drugs or drug classes

– Qualitative: positive or negative result

– Result confidence � variable

– Lab-based multichannel instrument or Instant-test (POC)

• Confirmation test: – Chromatography with mass spectrometry methods

– Result confidence � very high

– Highly sensitive and specific

– Quantitative or qualitative

Note:

Repeating an immunoassay on the same or another urine specimen is not an acceptable confirmation strategy.

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Analytical Requirements

• Drugs of Abuse– Commercial reagents on automated immunassay analyzer

• Confirmation using GC-MS

• Pain Management Analgesics – Commercial immunoassay reagents are generally not sensitive

enough to detect opioids at lower concentrations

– GC-MS or LC-MS-MS

• LC-MS-MS required for lower cutoffs– Lower cutoffs are required for pain management

• Negative result is a red flag

Lab immunoassay Screen

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Point-of-Care Drug Test (POC)

� POC testing in clinical practice:

� Detects some pain medications and many illicit drugs

� Convenient, rapid turn-around-time

� Adjunct to clinical laboratory testing

� Device must be CLIA waived

� Allows provider-patient discussions

� Confirmation of positive (and negative) tests

� Disadvantages:� False-positive results (cross-reactivity)

� False-negative results (fails to detect)

� Subjective interpretation

� Non-specific drug classes (opiates, amphetamines, benzodiazepines)

� Not Detected: alcohol, oxymorphone, hydrocodone (+/-), hydromorphone, buprenorphine, fentanyl, carisoprodol, tapentadol and tramadol.

Question:

Which of the following might explain a positive

opiate screen (unconfirmed)?

(a) codeine use

(b) heroin use

(c) morphine use

(d) poppy-seed ingestion

(e) hydrocodone use (variable cross-reactivity)

(f) all the above

Caution: Opiate Immunoassay Screen Test

� Situation: Patients may be dismissed from the practice based on a negative drug test result for a prescribed medication.

� Background: Opiate Screen is designed to detect morphine

� Assessment: Opiate screen does not detect:

� Oxycodone� Methadone� Fentanyl� Hydrocodone (+/- ?) � Hydromorphone � Oxymorphone� Tramadol, buprenorphine, carisoprodol

� Recommendation:

Be aware most prescription opioid analgesics are not “opiates” and will test negative on an Opiates Screen.

http://www.painphysicianjournal.com/2008/march/2008;11;S155-S180.pdf

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Immunoassay: Potential for False-Negative

Does Opiate Screen detect Hydrocodone or

Hydromorphone?

Using 112 urine specimens from patients prescribed HC or HM

where all urines had negative Opiate Screens by immunoassay:

� 81 specimens (71%) were positive for hydrocodone /

hydromorphone by mass spectrometry.

From: R Bertholf, et al: Journal of Analytical Toxicology (2015);39:24-28

Immunoassay: Potential for False-Negative (continued)

Hydromorphone detection problems with Opiates Screen?

69% of specimens found positive for hydromorphone by mass spec

were negative with Opiate Screen immunoassay.

From: Mikel et al. LC-MS/MS Extends the Range of Drug Analysis in Pain Patients. Ther Drug

Monit., 2009 December; Volume 31, Number 6.

Immunoassay: Potential for False-Negative (continued)

In a study where 77,881 urine specimens were positive for opioids using LC-MS/MS:

• 59% were opioid negative by point of care (POC) test

• 23% opioids missed by routine tests used in many clinical, hospital and reference laboratories

Evans M, Kriger S, Gunn J, Schwilke G. (2009) Effective monitoring of opiates in chronic pain patients.

Practical Pain Management. (6):32-33.

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Immunoassay: Potential for False-Negative (continued)

Benzodiazepines and instant POC tests ……..

• Point of Care (POC) tests showed 24% false-negative rate in urine from patients taking benzodiazepines.

• 10% false-positive rate in patients not taking benzodiazepines.

Manchikanti,L, et al. Comparative Evaluation of the Accuracy of Benzodiazepine Testing in Chronic

Pain Patients Utilizing LC/MS/MS of Urine Drug Testing. Pain Physician (2011);14:259-270.

Instant POC tests ……..

The simplicity of use and access to rapid results of the on-site drug testing can lead to serious medical or social consequences if unexpected

results are not confirmed by secondary analysis.

Chia-Ni Lin, et al. Evaluation of the NexScreen and DrugCheck Waive RT Urine Drug Detection Cups.

J Anal Toxicol (2013) 37 (1): 30-36.

Immunoassay Limitations

“Drug screening by immunoassay does not allow

for complete adherence-monitoring in those

patients who are prescribed drugs that are not

detected by common immunoassay screens.”

J. Dickerson, et al. Improved detection of opioid use in chronic pain patients through monitoring of opioid

glucuronides in urine. Journal of Analytical Toxicology. 36:541-547 (2012).

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Confirmation Testing

Because of cross-reactivity and different sensitivity

and specificity between immunoassays, a second

confirmatory test is required unless a screen result is

expected or the patient has disclosed drug use.

Confirmation Testing:

� Confirm a positive drug/ drug group

� Confirm a negative drug/ drug group

Source: Washington State Agency Medical Directors’ Group. Interagency Guideline on Prescribing Opioids for

Pain. 3rd edition, June 2015.

.

GC/MS Confirmation

LC-MS/MS

Tandem Mass Spectrometer

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Liquid

Chromatography

Tandem Mass

Spectrometer

Direct Testing of Opiates & Opioids by LC-MS/MS (Tandem Mass Spectrometry)

Quantitative Analysis � Codeine� Morphine� Hydrocodone� Hydromorphone� Oxycodone� Oxymorphone� Meperidine� Fentanyl� Norfentanyl� 6-Monoacetyl morphine

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

What is the interpretation?

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Interpretation Urine Drug Test Results

Morphine 8250 ng/mLHydromorphone 325 ng/mL Oxymorphone 110 ng/mL

Ethanol 0.077 g/dL

� Morphine consistent with use of prescribed morphine.

� Hydromorphone source from metabolism of morphine and is consistent with use of prescribed morphine.

� Oxymorphone positive result ���� discrepant, unexpected.

� Beverage alcohol used within 14 hours of urine sample collection.

Follow-up:

Patient admits occasionally taking a relative’s oxymorphone;

also regularly drinks wine with dinner.

Actions:

� Patient informed about the danger from taking non-prescribed medicines; discontinue oxymorphone use immediately.

� Reduce or even eliminate alcohol intake.

� The aberrant UDT escalates patient to high-risk status.

�Add unannounced monthly UDT to monitor adherence.

Amphetamine

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Amphetamine confirmed positive test:

What are the sources of amphetamine in urine?

Prescription brand names:

� Adderall® - racemic of amphetamine salts

� Dexedrine®, Dextrostat®

� Vyvanse® is l-Lysine-d-amphetamine (lisdexamfetamine), a prodrug metabolized to amphetamine.

� NOT Methylphenidate (Ritalin®, Concerta®)

Methylphenidate and metabolite (ritanilic acid) are not detected by immunoassay screens and routine GC/MS confirmation tests.

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Methamphetamine

Methamphetamine confirmed positive test:

What are the sources of methamphetamine in urine?

Amphetamine is a metabolite of methamphetamine, after methamphetamine use both are often found in urine.

� D-Methamphetamine sources:

� illicit methamphetamine

� Desoxyn® (methamphetamine HCl)

� Didrex® (benzphetamine) metabolite

� L-Methamphetamine sources:

� Selegiline metabolite (Eldepryl®, Emsam®, Zelapar®)

� Vick’s Vapor-Inhaler® (desoxyephedrine, levo-methamphetamine)

� D/L-Methamphetamine sources:

� illicit methamphetamine

� 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

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