Essentials for physicians and health care professionals ordering and interpreting urinary

screens for drugs of abuse.

Dr. Edward Randell

Disclosure of Potential for Conflict of Interest

FINANCIAL DISCLOSURE Grants/Research Support: CIHR and others. Speakers Bureau/Honoraria: None Consulting Fees: None Other: Employee of Memorial University

Learning Objectives

• Describe why urine is the preferred sample for drug of abuse screening

• Describe common interfering substances • Identify factors to consider when interpreting

positive and negative drug screens • Describe the strengths and limitations of

common techniques used for urine drug screening

Why are UDS important to clinical practice?

• Can identify more non-adherent patients than monitoring behavior and self-reporting alone

• Identify new or recurrent drug misuse • Support clinical decisions • Assist diagnosis • Deterrent and provide objective evidence of

abstinence in high risk patients

Why is interpreting UDS correctly important?

• UDS screen interpretation carries significant potential for harm if done incorrectly

• False accusations of drug abuse or diversion based on misinterpretation of UDS results carry potential medicolegal consequences.

Health care professionals who effectively employ UDS have a good understanding of the pharmacology of commonly encountered drugs and work closely with lab professionals when ordering and interpreting these tests

Drug Screens

Common Drug of Abuse

Amphetamines and Methamphetamine

Opiates

Benzodiazepines

Cocaine

Barbiturates

Methadone

Phencyclidine

Marijuana

Oxycodone

Introduction

Check out discuss of similar case at: http://paindr.com/two-puffs-too-bad-demystifying-marijuana-urine-testing/

A 40 years old female receiving Oxycodone, presents to a pain clinic for routine follow-up visit. A random urine drug screen is done by immunoassay and she tests positive for Marijuana (cannabinoids positive). When asked, she admits “I only smoked two puffs five days ago”. Fact or Myth?

Quiz: 7 UDS questions What is detected in the urine following:

1. Acetaminophen/Codeine administration 2. Morphine administration 3. Heroine use 4. Poppy seed consumption 5. 2nd hand exposure to Marijuana smoke

6. Explain a negative drug screen result for a patient on chronic opioid therapy… 7. On receiving a negative result on an opiate screen for a patient you prescribed hydromorphone you would…

• To determine level of UDS interpretative knowledge of physicians who use UDS to monitor adherence on chronic opioid therapy

• 7 question survey given to 114 physicians • 77 who use UDS regularly • 37 who didn’t

Reisfield, G. M., Bertholf, R., Barkin, R. L., Webb, F., & Wilson, G. (2006). Urine drug test interpretation: what do physicians know?. Journal of opioid management, 3(2), 80-86.

Reisfield, G. M., Bertholf, R., Barkin, R. L., Webb, F., & Wilson, G. (2006). Urine drug test interpretation: what do physicians know?. Journal of opioid management, 3(2), 80-86.

Reisfield, G. M., Bertholf, R., Barkin, R. L., Webb, F., & Wilson, G. (2006). Urine drug test interpretation: what do physicians know?. Journal of opioid management, 3(2), 80-86.

• 99 internal medicine residents • Compared personal confidence with

interpreting drug screens vs. measured performance.

Starrels, J. L., Fox, A. D., Kunins, H. V., & Cunningham, C. O. (2012). They don’t know what they don’t know: Internal medicine residents’ knowledge and confidence in urine drug test interpretation for patients with chronic pain. Journal of general internal medicine, 27(11), 1521-1527.

Starrels, J. L., Fox, A. D., Kunins, H. V., & Cunningham, C. O. (2012). They don’t know what they don’t know: Internal medicine residents’ knowledge and confidence in urine drug test interpretation for patients with chronic pain. Journal of general internal medicine, 27(11), 1521-1527.

There was no significant differences in interpreting drug screens among medical residents stating confidence in their ability versus those acknowledging lack of confidence.

Brief History of Drug screening 1950’s blood “tox screens”

1960’s TLC 1970’s IA and

POC testing

1980’s IA + GC-MS

21st Century LC-MS/MS

1950’s Emergency Rooms and Death

investigations

1970’s: Addiction treatment & criminal justice

1970’s Methadone maintenance/Opioid

Treatment/Military Workplace/Industry/Govt.

Highway safety

The Technology used for UDS

How are DOAs screened?

Immunoassay GC-MS (Gas Chromatography coupled to Mass

Spectrometry) LC-MS (Liquid Chromatography coupled to Mass

Spectrometry)

Actually the following list is more accurate Method Common Abbreviation

Cloned enzyme donor immunoassay CDIA

Enzyme-linked immunosorbent assay ELISA

Enzyme-multiplied immunoassay technique EMIT

Fluorescence polarization immunoassay FPIA

Radioimmunoassay RIA

Point of care testing methods POCT

Gas Chromatography Mass Spectrometry GC-MS

Liquid Chromatography Ultraviolet Detection HPLC-UV

Liquid Chromatography High Resolution Mass spectrometry LC-hrMS

Liquid Chromatography tandem mass spectrometry LC-MS/MS

Liquid Chromatography time-of-flight mass spectrometry LC-TOF

Thin Layer Chromatography TLC

Immunoassay Urine Drug Screens (UDS) • Uses antibodies specific for drug or common

metabolite target • Detection of a drug depends on antibody

specificity, cut-off, and drug concentration. • Immunoassay-based Lab Methods

• Automated on laboratory analyzers

• Immunoassay-based POCT devices • Presence of band indicates a positive result

GC-MS

Barbosa, S. S., Leal, F. D., Padilha, M. C., Silva, R. S., Pereira, H. M. G., Aquino Neto, F. R., & Silva Júnior, A. I. D. (2012). Specificity and selectivity improvement in doping analysis using comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry. Química Nova, 35(5), 982-987.

LC-MS/MS

20 Eichhorst, J. C., Etter, M. L., Rousseaux, N., & Lehotay, D. C. (2009). Drugs of abuse testing by tandem mass spectrometry: a rapid, simple method to replace immunoassays. Clinical biochemistry, 42(15), 1531-1542.

UDS techniques are targeted or untargeted

Targeted drug screens - identify specific drugs to screen excluding most others.

• Most common: Immunoassay & LC-MS/MS • All UDS commonly used in NL are targeted. Untargeted drug screens – are broad drug

screens without exclusion. • GC-MS and LC-hrMS methods are untargeted.

Comparison of UDS techniques Screening Screening/Confirmatory

Analysis Immunoassay GC-MS or LC-MS/MS

Ability to detect drug class (Sensitivity)

Low to nil for synthetic opioids but fair for others

High

Ability to discriminate drug from similar compounds (Specificity)

Variable-false positives and false negatives

High

Use Qualitative screen Quantitative confirmation

Cost Variable Variable

TAT rapid Many days

Application Works best for screening drug-free population; may be less useful in pain-management.

Definitive & Legally defensible

Interpretation Complex Complex

Why urine?

Why is urine the most used sample?

• Easy to obtain • Minimal preparation • Most drugs of interest & their metabolites

concentrate in urine • Good sensitivity and specificity for recent use • Wider window of detection compared to blood

Positivity in urine indicates exposure ...But

• Does not correlate with clinical status • Can miss very recent exposure • Positivity means different things depending on

the screening method used.

Interpreting urine drug screens

Urine Drug Test Positive Negative

Patie

nt re

port

s ta

king

the

drug

Yes

True Positive 1. Patient is taking the drug as

reported. 2. Test detects the substance

reported

False Negative 1. Patient may be mistaken about

taking the drug. 2. Last dose too low or too long ago to

be detected.

No

False Positive 1. Interfering substance 2. Unreported self-

administration of a cross-reacting substance

True Negative 1. Patient is not taking the drug as

reported. 2. UDS does not detect the substance.

UDS Interpretation

Factors Affecting UDS interpretation

Time since ingestion

Duration of use

Administration Route Urine volume Hydration

Status

Amount of drug ingested

Diet

Urine pH

Concurrent Medications

Urinary frequency

Testing Method

Dosage Intervals

Disease State Body Weight

Individual metabolism

Interpreting UDS

• Unexpected interferences • Target Compounds • Cut-offs • Windows of Detection • Importance of considering drug metabolism

Common Immunoassay Interferences Target Drugs Interfering Drugs

Amphetamines Diet Pills, Vicks inhaler (US), Trazodone, Aripiprazole, Promethazine and Phentermine

Marijuana Efavirenz (Antiretroviral), baby shampoo and soap, pantoprazole and possibly other proton pump inhibitors

Hydromorphone Hydrocodone

Methadone Quetiapine

Fentanyl Trazodone

TCAs Quetiapine

Opiates/Morphine Poppy Seeds, Quinolone antibiotics

Benzodiazepines Sertraline

PCP Venlafaxine

Agents that can cause positive results on amphetamine immunoassay.

Moeller, K. E., Lee, K. C., & Kissack, J. C. (2008, January). Urine drug screening: practical guide for clinicians. In Mayo Clinic Proceedings (Vol. 83, No. 1, pp. 66-76). Elsevier

Cross-reactivity is a common problem for UDS relying on immunoassay technique.

Moeller K E et al. Mayo Clin Proc. 2008;83:66-76

Different methods have different targets

Drug/Class Immunoassay Screen Mass Spectrometry Benzodiazepines Oxazepam Specific Drugs: Diazepam,

Oxazepam, Loraxepam, Temazepam, Alprazolam, Clonazepam…

Opiates Morphine Specific Drugs: Morphine, Codeine, Oxycodone, Fentanyl, Hydromorphone….

Cocaine Cocaine Metabolite Cocaine and Benzoeconine Marijuana THC metabolite THC and THC-COOH Amphetamine & Methamphetamine

Amphetamine & Methamphetamine

Specific Drugs: Amphetamine, MDA, MDMA, metamphetamine…

Some Mass Spectrometry methods are non-targeted – meaning that they detect “everything” and both suspected and unsuspected can be explored.

Moeller K E et al. Mayo Clin Proc. 2008;83:66-76

For both Morphine and Codeine

Different methods have different cutoffs.

Cutoffs determine the drug concentration at which a positive result is reported. This is not the same as a detection limit.

For how will a UDS remain positive?

Most- 1 to 3 days Some (marijuana, diazepam, ketamine, PCP) may

be detected for a week or more Depends of urine concentration of drug and assay

cutoff

Excretion pattern of Cocaine

0

2000

4000

6000

8000

10000

12000

0 10 20 30 40 50 60

Cocaine (base) 42 mg smoked BenzoyleconineEcgonine Methyl esterCocaine

Cone, E. J., Sampson-Cone, A. H., Darwin, W. D., Huestis, M. A., & Oyler, J. M. (2003). Urine testing for cocaine abuse: metabolic and excretion patterns following different routes of administration and methods for detection of false-negative results. Journal of analytical toxicology, 27(7), 386-401

Detected by immunoassay (300 µg/L)

Marijuana (Heavy use) (Moderate use)

Benzodiazepines (Long acting)

Barbiturate (long acting)

Window of detection in urine

2 days 4 days 6 days 1 week 2 weeks

(Short acting)

(Short)

(Single use)

Amphetamine & Metamphetamine

Alcohol and Phencyclidine

Moeller K E et al. Mayo Clin Proc. 2008;83:66-76

Cocaine

Meperidine

Window of detection in urine

1 days 2 days 3 days

Methadone

Oxycodone

Morphine from Heroine

Morphine

Moeller K E et al. Mayo Clin Proc. 2008;83:66-76

Codeine

4 days

Up to 6 days if metabolite tested

Heroine only a few hours

Often missed

Often missed

Window of detection based on sample type.

Minutes Hours Days Weeks Months Years

Blood

Saliva

Urine

Sweat

Hair

Drug Metabolism must be considered

Benzodiazepine assays are prone to false negatives.

Drug metabolism must be considered.

Implication of cutoffs and cross-reactivity to immunoassay.

Smith, M. L., Shimomura, E. T., Summers, J., Paul, B. D., Nichols, D., Shippee, R., ... & Cone, E. J. (2000). Detection times and analytical performance of commercial urine opiate immunoassays following heroin administration. Journal of Analytical Toxicology, 24(7), 522-529.

Drugs detected by opioid screens using mass spectrometry

Drug Mass Spectrometry

Heroine 6 monoacetyl morphine Morphine

Codeine Codeine Morphine Hydrocodone

Oxycodone Oxycodone Oxymorphone Hydrocodone

Poppy Seeds Morphine

Hydrocodone Hydrocodone Hydromorphone

Fentanyl Fentanyl Norfentanyl

Most drug screens identify opiates not opioids

Opioid • Chemicals that work by

binding opioid receptors • Opiates + semisynthetic • Heroin, hydrocodone,

Hydromorphone, oxycodone, Fentanyl, Meperidine,…

Opiate • Natural alkaloids derived

from opium poppy • Codeine and Morphine

Many Opioids and Benzodiazepines are missed by routine immunoassay UDS.

Interpretation

Negative for prescribed medication

Diversion

Patient run out of medication

Patient not taking full amount

Sample tampering

Immunoassay testing (false negative)

Interpretation

Positive for un-prescribed medication

Drug Abuse

Testing error: False Positive (poppy seeds)

Laboratory error: testing or clerical

Variability: within and between patients

Immunoassay testing

Open communication with lab is required…

1. The clinical value of UDS depends on the level of interaction between the ordering physician and testing lab.

2. Appropriate lab use requires consideration of: 1. The purpose of the UDS 2. Why, who, and when the test is done 3. The limits of the lab results 4. What is meant in lab reporting terminology 5. The significance of screening cutoffs

How people beat drug tests

1. Substitution with synthetic urine or “purchased” drug free urine

2. Flush out with commercially available product 3. Adulteration by adding reactive or masking

substance to the urine 1. Visine eye drops, Salt, Oxidizing agents, Potassium

Nitrite, glutaraldehyde.

Finding Cheats: A few simple tests

Sample Temperature • 90 to 100 for first 4 minutes

pH • Should be 4.5 to 8

Creatinine • Should be >3 mmol/L

Nitrite • Negative

Conclusions

Quiz: 7 UDS questions What is detected in the urine following:

1. Acetaminophen/Codeine administration 2. Morphine administration 3. Heroine Use 4. Poppy seed consumption 5. 2nd hand exposure to Marijuana smoke

6. Explain a negative drug screen result for a patient on chronic opioid therapy. 7. On receiving a negative result on an opiate screen for a patient you prescribed hydromorphone you would…

(Codeine & Morphine)

(Morphine)

(6 monoaceylmorphine & Morphine)

(Morphine)

(Nothing)

(Which opioid? Screen may not measure.)

(Most screens do not measure hydromorphone. Request confirmatory procedure)

Effective UDS use depends on:

Good relationship with Lab

Know which test lab is using

Insure screening results are

confirmed before serious action

Choose testing strategy based on purpose of testing

Know recent medication history

Insure proper collection and

labelling

References Dowell, D., Haegerich, T. M., & Chou, R. (2016). CDC guideline for prescribing opioids for chronic pain—United

States, 2016. JAMA, 315(15), 1624-1645. Moeller, K. E., Lee, K. C., & Kissack, J. C. (2008). Urine drug screening: practical guide for clinicians. In Mayo Clinic

Proceedings (Vol. 83, No. 1, pp. 66-76). Elsevier Hammett-Stabler, C.A., Weber, L.R. (2008) A Clinical Guide to Urine Drug Testing. CME monograph available at

http://ccoe.rbhs.rutgers.edu/online/ARCHIVE/endurings/09MC07.pdf Reisfield, G. M., Bertholf, R., Barkin, R. L., Webb, F., & Wilson, G. (2006). Urine drug test interpretation: what do

physicians know?. Journal of opioid management, 3(2), 80-86. Starrels, J. L., Fox, A. D., Kunins, H. V., & Cunningham, C. O. (2012). They don’t know what they don’t know: Internal

medicine residents’ knowledge and confidence in urine drug test interpretation for patients with chronic pain. Journal of general internal medicine, 27(11), 1521-1527.

Pesce, A., West, C., Egan-City, K., & Clarke, W. (2012). Diagnostic accuracy and interpretation of urine drug testing for pain patients: an evidence-based approach. In Toxicity and drug testing.