UNC HEALTH CARE SYSTEM
Best Practices in Urine
Toxicological Screening
Timothy J. Ives, Pharm.D., M.P.H., FCCP, CPP
Eshelman School of Pharmacy, and School of Medicine
The University of North Carolina at Chapel Hill
[email protected]
October 22, 20161
Disclosure
I have no relationships with
commercial interests related to the
content of my presentation.
Today’s Learning Objectives
1. Recognize the factors which enhance the
reliability and validity of the urine toxicology
screening process.
2. Identify the factors which constitute barriers to
successful testing.
3. Describe the clinical/biochemical testing
options.
To Begin, A Few Definitions
• Screen: A qualitative (positive/negative) test; usually
designed to detect many drug classes; confidence in
results may be poor, but depends on the assay
• Confirmation: A test designed for very high confidence
in identification of individual drugs/compounds; may
be qualitative or quantitative (reports the amount of
drug present)
• Cut-off: The concentration used to distinguish between
a positive and a negative result; defined by the product
manufacturer, or by the limit of quantification (LOQ)
Why Perform UTS?
• Helps to detect inappropriate drug use
• Identifies patients who are maintaining stability
• Test to confirm the history of current drug use
provided by patients
• Satisfies requirement for immediate results, but:
– Represents only a single point in time
– Compounds are usually found post-metabolism
– Results do not completely relate to patient’s current and
immediate presentation
Some Limitations to UTS
• Urine drug testing only indicates prior use
• Drug concentration in urine varies greatly, based on:
• Individual metabolism
• Body composition
• Time/Frequency of use
• Drug strength
• Current hydration status
• Not useful for determining:
• The time since the last use
• Extent/frequency of drug use
• Any additional use since the last positive test
• Current level of impairment
What Specimens to Test?
Urine: Current specimen of choice for initial testing; uses a
class-specific immunoassay
Blood: Common tests: BAC, acetaminophen, salicylate, TCAs
Saliva/Oral fluids: pH-dependent; collection device-dependent.
Need to measure specific parent compounds, within a short
turnaround time.
Sweat: High variability, due to added electrolytes, compounds
and a need for a sufficient volume
Hair: Greatest variability, due to length and rate of growth
Also, it is becoming more practical to explore unconventional
biological matrices such as fingernails or meconium.
Problems That Can Occur with Collection?
• Substitution: Fake urine or other yellow liquids (# 1)
• Adulteration:
• Detergents, bleach, salt, ammonia, acids
• Glutaraldehyde
• Nitrites
• Chromates
• Peroxide and peroxidase
• Dilution: Water!
At UNC: Up to 10% of confirmed samples are “suspicious”
How Do You Collect Samples?
• To reduce chances of sample dilution, adulteration, or
substitution:
• Do you do direct observation (aka visuals)?
• Do patients leave bags, bulky outdoor clothing, empty pockets
outside the collection room?
• Use a designated urine sample collection area, with “blued
toilet” and no access to tap water (unless cold only) until
sample is handed over
• If available, place a temperature strip on the specimen bottle.
If not available, is the sample warm (or is it cold, like water
out of the tap/toilet)?
• Un-witnessed urine collections are of little or no assessment
value, and also enhances denial.
2-Step Process: Screenings & Confirmations
Screenings:
• Test method = Enzyme Immunoassay (EIA)
• Designed to separate negative samples from
samples that are “presumptively” positive
• Easy to perform and cost-effective
• Specificity and cutoff concentrations vary
• Immunoassay technology is drug class-specific
• Does not identify individual drugs in each class,
and is not quantitative.
Second Step:
Confirmation:
• Test method = Gas Chromatography/Mass
Spectrometry (GC/MS)
• A follow-up procedure designed to validate positive
screening test results
• Most drugs are eliminated as metabolites
• GC/MS is more sensitive and specific than
screening, with identification and quantification of
both parent drug and its metabolite(s)
• Cutoffs are often lower than screens
What are Cut-offs (c/o)?
Lowest concentration of a drug considered to be positive
by screening or confirmation; thus distinguishing between a
negative and a positive sample = a therapeutic “threshold”
Cutoffs provide important safeguards:
• Legal protections (evidentiary admissibility)
• Measured in ng/mL = ppb; concentration used depends
upon the setting
• Work place drug testing, etc: Defined by federal or state
statutes, DOT, DOD, IOC, NFL, etc.
• Most labs report results below the c/o as “negative”, and
results above the c/o as “positive”
Cut-Off Levels (ng/mL)
Screening
amphetamines
500
barbiturates
200
benzodiazepines
200
cannabinoids
20
cocaine (benzoyl ecognine)
150
opiates
300
heroin/6-monoacetyl morphine 10
phencyclidine (PCP)
25
alcohol
20
Confirmation
25-200
100
50
3
50
50
20
25
10
NB: Testing Methods and Cutoffs are regulated by SAMHSA (Substance Abuse and Mental
Health Services Administration) – Why is this important?
Pharmacology: Opioids (& metabolites)
Medication
What’s seen in the UTS
Codeine
Norcodeine, morphine (metabolites)
Hydrocodone
Hydrocodone, hydromorphone
(primary metabolite), codeine, morphine
Morphine
Morphine, hydromorphone (with use of
higher doses of morphine)
Heroin
6-acetylmorphine (metabolite), morphine
Oxycodone*
Oxycodone, oxymorphone (metabolite)
* Not commonly noted as an opiate on UTS due to low sensitivity,
except with higher doses; confirmation is necessary
Oyler JM, et al. Identification of hydrocodone in human urine following controlled codeine
administration. J Anal Toxicol. 2000; 24: 530-5.
What are Target Analytes (in UTS)?
• Immunoassay screenings typically target the metabolites that
are primarily excreted over a reasonable time period.
• GC/MS confirmations are more specific, and center on only
one specific metabolite.
Immunoassay Target Analytes (highest sensitivity to lowest):
• Cannabinoid (marijuana): 11-nor-Δ9-THC > 11-nor-Δ8-THC
• Opiates: morphine > codeine > 6-acetylmorphine (from heroin) >
hydromorphone > hydrocodone > oxycodone > oxymorphone
• Benzodiazepines: 6-nordiazepam > oxazepam > 7-aminoclonazepam
• Cocaine: benzoyl ecgonine
• Amphetamine: methamphetamine > amphetamine
Example of Screening vs. Confirmation
Screening:
• Amphetamine <500 ng/mL
• Benzodiazepine <200 ng/mL
• Cannabinoid >20 ng/mL
• Cocaine >150 ng/mL
• Methadone <300 ng/mL
• Opiate >300 ng/mL
+
+
+
Confirmation:
• Benzoyl ecgonine = 4,623 ng/mL
• (11- nor-)9-THC = 222 ng/mL
• Hydrocodone = 1,322 ng/mL
• Hydromorphone = negative (i.e., it is still < 50 - 100 ng/mL)
UTS, Window of Detection, & Cut-Offs
Class
Amphetamines
Barbiturates
Benzodiazepines
Cannabinoids
Cocaine
Methadone
Opiates
Target Drug
WOD
C-O (IA)
C-O (GC/MS)
d-amphetamine
2 – 4 days
(pH dependent)
500
25- 200
secobarbital
1 - 21 days
200
100
nor-diazepam
~72 hours
200
50
9-THC
1 - 30 days
20
3
benzoyl ecgonine
12 - 72 hours
150
50
methadone
72 hours
300
100
morphine
2 - 4 days
300
100
What could cause a positive drug test?
• Indicates that a legitimate drug(s), or the metabolites tested
for, was detected in the screened sample
• Drug presence is above the “cut-off” level
• Patient was previously prescribed the drug, or admitted past
use, but disease (e.g., CKD) or time of specimen collection
since drug discontinuation is insufficient for elimination
•
•
•
•
Prescription obtained from another clinic
Incorrect prescription was filled
Laboratory error
Drug detected is from an unprescribed or illegal drug
What could cause a negative drug test?
• No drugs or metabolites were detected in the sample
• Patient is not taking the medication, or ran out early
(i.e., outside the period of detection)
• Drug was not absorbed, or very poorly absorbed
• Drug was taken incorrectly: only PRN instead of on
a standard regimen, less than prescribed, less
frequently than prescribed, or not at all (diversion?))
• Accelerated metabolism/elimination
• Urine was dilute and concentrations were below
detection limits of analytical method
• Inappropriate specimen handling, laboratory error
Interpreting UTS Results
• Screening result at or above the c/o
• Detected drugs belonging to the indicated class
(true positive), or another similar substance that
cross-reacts with antibody in the immunoassay
(false positive)
• Screening result below the c/o
• Drug is absent (true negative)
• Drug is present, but below designated c/o
• Assay does not detect drug (false negative)
Some Excuses & Limitations with UTS
• “I can’t pee” or “I just went”
• “I haven’t used since the last appointment, but I took a
Tylenol #3 for a headache yesterday”
• The urine is cold: Did they bring it with them? Did they
dilute it?
• Benzodiazepines & cannabinoids persist for several weeks
• All other drugs only test positive for a few days
• Often, oxycodone IR or OxyContin does not test positive
in most opiate immunoassay tests (sensitivity = ~70%)
• No reliable commercial test for fentanyl or tramadol (yet)
• Clonazepam & alprazolam test negative on immunoassay for
benzodiazepines – Why?
Other Interpretation Cautions
• Hydromorphone: minor metabolite in patients receiving
chronic morphine (via alternate pathway)
• Hydrocodone: minor metabolite detectable in patients
taking high amounts of codeine.
• With a longer t1/2 than oxycodone; a patient prescribed
oxycodone may only have oxymorphone detected in urine.
• Heroin is metabolized to morphine, which may be
detectable after its use.
• The drug dose that was taken cannot be extrapolated
from drug screen results, even with a confirmation.
The Strongest UTS Results are when:
• Confirmed by GC/MS method
• Both parent drug and drug metabolites are identified
• More than one sample is tested at two separate times
(pattern of results)
• More than one specimen source/type (i.e., urine,
blood, meconium, hair, etc.) is tested
• A chain of custody is maintained
• Results come from a certified laboratory
Cook JD, et al. The characterization of human urine for specimen validity determination in
workplace drug testing: a review. J Analytical Toxicol. 2000; 24: 579-88.
How Do You Know That It’s Urine?
Substitution, Adulteration, and Dilution
•
•
•
•
Visual examination: Color, froth?
Olfactory examination: Does it smell like urine?
Tactile examination: Is it warm?
Chemical evaluation:
• Most common form of specimen tampering: sample dilution
• If suspected, test the sample provided for a urine creatinine level to
rule out intentional dilution.
• Normal limit = 18 – 200 mg/dL
• < 20 mg/dL is diagnostic for dilution (or for water intoxication, diabetes
insipidus) – most sensitive indicator of dilution
• < 5 mg/dL isn’t physiologically possible
• Specific gravity: determine if urine creatinine is < 20 mg/dL
Concerning level is < 1.003
• Urine pH: Range = 6.5 – 8.0
Substitution: Synthetic Urine
Mimics normal human urine:
• Creatinine
• Electrolytes (Na ,K, Cl, Ca, Mg)
• Urea, Phosphate
• Difficult to detect by standard testing
Non-Human Urine:
• Difficult to Detect
Substitution: Synthetic/Fake Urine
Substitution is more prevalent than adulteration
Interference? Another Myth
• Drinking vinegar or cranberry juice will produce a
“negative” urine drug test.
• Theory: To cause a “pH shift”, making the urine
sample acidic - altering the chemistry of immunoassay
tests
• Reality: The body buffers the weak acid, and dilutes it
to physiological pH
Equipment: Urinator or Whizzinator?
•
•
•
•
•
•
Available in a variety of natural life-like skin tones
Fully adjustable latex belt
4 oz vinyl bag
One dehydrated, toxin-free urine specimen
Four organic heat pads
$150.00
Adulteration with Household Products
Adulterant
Drug Test Affected
Chlorine bleach
Liquid drain cleaner
(sodium hydroxide (Drano®)
Vinegar
Cannabinoid, morphine, amphetamine
Morphine, amphetamine
Amphetamine
Dubious Promotional Media (e.g., from the Internet)
Pyridinium chlorochromate
(Urine Luck®)
UR’n Kleen
Instant Clean and Stealth
Amphetamine, cocaine, morphine,
cannabinoid, PCP
All of the above, except amphetamine
Cannabinoid, PCP, cocaine
Wong R. The effect of adulterants on urine screen for drugs of abuse: detection by an on-site dipstick device.
Am Clin Lab. 2002; 21: 37-9.
Paul BD, et al. Effects of pyridinium chlorochromate adulterant (urine luck) on testing for drugs of abuse and a
method for quantitative detection of chromium (VI) in urine. J Anal Toxicol. 2000; 24: 233-7.
Dilution: Two Types with Urine Specimens
Pre-collection dilution:
• Consumption of large quantities of fluids (water loading,
flushing, hydrating, etc.) prior to collection
• Newer: Dilution with Adulteration: Flushing or
detoxifying products: Gold Seal, Instant Clean, Clean & Clear,
Test-Free, etc. No evidence of additional effect on drug
elimination.
Post-collection dilution:
• Adding fluid to specimen post collection
True medical causes for dilute urine:
Diabetes insipidus, muscle wasting syndromes, kidney disease,
diuretic use, pharmaceutical toxicity (e.g., lithium)
Some Principles of Drug Testing
• Place written UTS policies and procedures in your clinic
policy, and use them consistently.
• Add to your medication contract a phrase that permits
urine toxicological screening and confirmation.
• Perform a urine creatinine conc. to identify tampering.
• Perform confirmations on all positive screening results.
• Ensure that the sample collection process is effective:
• random/unannounced selection
• witnessed observation during sample collection
• know your cut-off levels and windows of detection
Principles of Drug Testing
• Outline a process in your clinic policy for managing patients
with an inappropriate UTS. Simple dismissal avoids
addressing the real problem.
• Place a dilute sample prohibition in your medication contract,
with sanctions for repeat offenses.
• When developing and administering your drug testing
program assume that the participants you are testing know
more about urine drug testing than you do (even if it comes
from the internet).
• Beware of “opioid-only” pain clinics & their questionable
UTS cut-off levels.
Your Final Exam!
• Patient AB is prescribed Tylenol #3. What do you
expect to find in the UTS, on screening & confirmation?
• Patient CD is prescribed MS-Contin. What do you
expect to find in the UTS, on screening & confirmation?
• Patient EF is suspected of heroin use. What do you
expect to find in the UTS, on screening & confirmation?
• Patient GH is prescribed Vicodin (hydrocodone &
acetaminophen) chronically, and is asked to provide a
random UTS. On confirmation: hydrocodone = 537
ng/mL, hydromorphone = undetectable. What is going
on here?
Reisfield GM, et al. Family physicians' proficiency in urine drug test interpretation. J Opioid Manag.
2007; 3(6): 333-7.
Time Permitting: Other Exam Questions
• Patient IJ tests positive for cannabinoids on a random urine
drug screen. She explains that her husband sometimes
smokes pot in the bedroom (aka “passive positive”).
Is this plausible?
• Patient KL received an injection of procaine (Novocain)
from a dentist. Will a UTS result be positive for cocaine
because of it? What about the following cases?
• “I tested positive for cocaine because I used Orajel or
Anbesol (benzocaine) for a toothache.”, or
• “I tested positive for cocaine because I got a bad
sunburn and applied Solarcaine® (lidocaine).”
Reisfield GM, et al. Family physicians' proficiency in urine drug test interpretation. J Opioid Manag. 2007; 3(6):
333-7.
Thank You
Any Questions?