THE OPIOID EPIDEMIC & IMPORTANCE OF

TOXICOLOGY TESTING

Dr. Patrick Rainey, Chief Operating Officer

Dr. Zhiyi Qiang, Director of Advanced Clinical technology

Select Laboratory Partners

http://www.cnbc.com/2016/04/27/americans-consume-almost-all-of-the-global-opioid-supply.html

http://www.nytimes.com/interactive/2016/01/07/us/drug-overdose-deaths-in-the-us.html?_r=0

Where can it be used?

• Pain Management• Primary Care• Psychiatry• Substance Abuse Monitoring (Rehab)

Benefits of use:• Identify substance use that affects medical decisions• Identify potential adulteration or adverse drug interactions• Identify illicits or nonprescription drugs• Medication compliance/diversion• Abstinence monitoring• Fetal & neonate risk assessment

UTILIZING DRUG TESTING IN CLINICAL PRACTICE

• Employment drug screening• DUI• Newborn screening• Forensics

Negative for Any Drug (Including Prescribed Drug, 25%

Negative for Prescribed Drug and

Positive for Other Drug,

15%

Positive for Prescribed Drug and Positive for

Other Drug, 20%

Positive for Prescribed Drug and

Negative for Other Drug,

40%

Percentage of UDT Positives and Negatives (Quest Diagnostics, 2012, n=151,405)

Pain Clinic Studies of UDT

http://www.cesar.umd.edu/cesar/cesarfax/vol22/22-22.pdfhttp://ccoe.rbhs.rutgers.edu/online/ARCHIVE/endurings/09MC07.pdf

Screen – Determines presence or absence of a drug (Qualitative).

Immunoassay – a biochemical test that measures the presence and concentration of a drug through the use of an antibody/antigen binding model (typically only semi-quantitative).

Confirmation – Determines presence or absence of a drug, the identity of the drug and the amount of the drug present (Quantitative).

A Few Definitions…

Cup Screening

Typically performed in physician office

Rapid results, but only qualitative (positive or negative) & drug class

False positives and negatives are typical

Depending on patient risk stratification, sample is sent for further testing

Immunoassay for rapid qualitative detection

High throughput

Cutoffs for detection high relative to LCMS or GCMS confirmation

Biggest issue - Low Specificity, both false positives and negatives

Theory based on human immune system: Drug is antigen; antibody in solution binds to drug and is detected.

Immunoassay Testing

Johnson-Davis KL et al. J Anal Toxicol. 2016; 40(2):97-107

Summary results from immunoassay screens and confirmatory

testing (ARUP Laboratories)

False positive rate can be easily affected by :

Reagents/antibodies offered by the manufacture Medications that can interfere with the targeted analytes The dose of the medications and the concentrations excreted in

urine Characteristics of the studied populations

Reports of false-positive results of urine drug screens for

selected formulary agents.

Brahm NC et al. Am J Health Syst Pharm. 2010; 67(16):1344-50.

Now most common MS technique used

Specific & Quantitative over wide dynamic range

Large test menu

Metabolite confirmation

LC-MS/MS Confirmation

MS PLATFORM COMPARISONS

M. Sargent (Ed.), Guide to achieving reliable quantitative LC-MS measurements, RSC Analytical Methods Committee, 2013. ISBN 978-0-948926-27-3.

QQQ Ion Trap TOF qTOF

Selectivity High High High High

Sensitivity High High Lower Lower

Matrix considerations (sample prep)

Minimum More More More

Duty Cycle (speed) Fast Slower Moderate Moderate

Dynamic Range High Lower Lower Lower

The available MS platforms all have unique benefits for specific purposes. The comparisonsin the table are with regard to drug confirmations in urine or oral fluids.

LC-MS/MS Confirmation

Rules to call positive on LC-MS/MS:

1. Retention time2. Two unique transitions3. Transition ratio4. Deuterium labeled Internal standard5. Peak signal intensity

Doxepin on LC/MS (ng/mL)

Desmethyldoxepin on LC/MS (ng/mL)

Benzodiazepine on screening (qualitative number)

Collection date

120996 4068 1723 Positive (1733) 3/15/2016

121873 1643 298 Positive (421) 3/18/2016

122391 3704 1232 Positive (619) 3/22/2016

123985 7938 3492 Positive (2704) 3/29/2016

Case study: False positive of Benzodiazepine screening due to TCAs

Doxepin (Deptran or Sinequan)

Benzodiazepines

Patient GS, a 50 year old female, no prescription on Benzos but tested positive for Benzos on screening for 4 visits and the patient had an impending court. This patient has been on very good behavior so the result was surprising. The confirmation panels of Alkaloid, Amphetamines, Benzos, Illicits, Opioids, Sleep aids/Relaxants were ordered. But no TCAs or SSRIs.

Urine Testing

Advantages Disadvantages

Long history of use Collection Monitoring

Established Cutoffs Adulteration

Metabolite Detection Shy bladder syndrome

Adequate sample volume No established dose-responserelationship

Oral Fluid Testing

Advantages Disadvantages

Collection Monitoring Opiate induced “dry-mouth”

Adulteration unlikely Few metabolites

Can correlate to serum “Depot” effect/pill crushing

Provides prescribing physician with flexibility

Drug Class Analyte/Metabolite Brand/Common Name(s)

Anxiolytic -Benzodiazepines &

Non-benzodiazepines*

Alprazolam, a-OH alprazolam Xanax

Clonazepam (7-aminoclonazepam) Klonopin

Diazepam (Nordiazepam) Valium

Lorazepam Ativan

Oxazepam Serax

Temazepam Restoril

Zolpidem* (Zolpidem-COOH) Ambien

Zopiclone* Lunesta

Zaleplon* Sonata

AmphetaminesAmphetamine Adderal, Vyvanse

Methamphetamine Desoxyn, Vicks, Meth, etc

Methylenedioxyamphetamines

MDA Adam

MDEA Eve

MDMA Ectasy

BarbituratesButalbital Fioricet, Fiorinal

Phenobarbital Phenobarbital

Phenethylamine and Piperidine

Methylphenidate (Ritalinic acid) Ritalin

Drug Class Analyte Brand/Common Name(s)

GABA inhibitor (requires separate injection)

Gabapentin Neurontin

Pregabalin Lyrica

Analgesics/Opiates/ Opioid agonists/Opioid

antagonists

6-Acetylmorphine Heroin metaboliteCodeine Tylenol 3 and 4

Hydrocodone, Norhydrocodone Vicodin, LortabHydromorphone Dilaudid, Exalgo

Morphine Avinza, Kadian, MS ContinOxycodone, Noroxycodone Percocet, Oxycotin

Oxymorphone Opana

Buprenorphine, Norbuprenorphine Subutex

Fentanyl, Norfentanyl Actiq, Duragesic

Meperidine, Normeperidine DemerolTapentadol Nucynta

Tramadol, O-desmethyltramadol Ultram

Methadone, EDDP DolophineNaloxone Suboxone (Naloxone +Buprenorphine)

Pentazocine Talwin (Pentazocine +Naloxone)

Tricyclic antidepressants

Amitriptyline ElavilDoxepin, Desmethyldoxepin Aponal

Imipramine Tofranil

Clomipramine, Desmethylclomipramine AnafranilNortryptiline Pamelor

Drug Class Analyte Brand/Common Name(s)

Selective Serotonin Reuptake inhibitors

(SSRi)/Selective Neurepinephrine

Reuptake inhibitors (SNRi)*

Citalopram, Desmethylcitalopram Celexa, Lexapro

Fluoxetine, Norfluoxetine Prozac

Paroxetine Paxil

Sertraline Zoloft

Muscle relaxantCarisoprodol Soma

Meprobamate Equanil, Equagesic, Miltown

Illicits

THC-COOH Marijuana metabolite

Benzoylecgonine Cocaine metabolite

Mitragynine Kratom

Phencyclidine PCP, Angle dustMDMA Ecstasy, Molly

Spice/synthetic marijuana

JWH-018 5-pentanoic acid JWH-018 metabolite

JWH-073 4-butanoic acid JWH-073 metabolite

UR-144 5-pentanoic acid UR-144/XLR-11 metabolite

Bath SaltsMDPV Bath salt

Alpha-PVP Flakka

Spice/K2/Synthetic Cannabinoids

Different to THC

– Seizures– Hypertension– Nausea/vomiting– Agitation– Violent behavior– Coma– Death

Similar to THC

– Abnormally rapid heart rate– Reddened eyes– Anxiousness– Hallucinations– Memory deficits

National Forensic Laboratory Information System (NFLIS)--Miami, FL in 2014

http://ndews.umd.edu/publications/sentinel-community-site-scs-profiles-site

JWH-073

JWH-018

THC

UR-144

XLR-11

Prevalence of Spice/K2 constituents in 2010-2014

http://www.nmslabs.com/uploads/PDF/Designer_Drug_Trends_February_2014.pdf

How K2/Spice works:Synthetic cannabinoids, acting as THC agonists, bind CB1 and CB2 receptors much stronger and longer than natural THC.

Receptor Drug (agonist)

Forensic Sci Rev. 2014; 26(1):53-78. http://ok.gov/odmhsas/documents/B%26W%20OK%20Designer%20Drugs%206-20-14%20.ppt

Why change the key?

Prolong the effect of the drug

Increase the potency of the drug

“Select” the desired effect

Make the drug more difficult to detect

Make an illegal drug “legal”

Drug

JWH-073 metabolite

JWH-018 metabolite

UR-144/XLR-11 metabolite

K2/Spice doesn’t show positives on THC screenings!

Bath salts:MDPV (Methylenedioxypyrovalerone) - a psychoactive drug with powerful stimulant properties which acts as both a norepinephrine & dopamine reuptake inhibitor

Usually snorted like cocaine

Duration of effect 2-3 hours /adverse effect 6-8 hrs

MDPV - no history of FDA approved medical use

Sold as a “research chemical”

Cause self harm and even death

Flakka:It is a designer drug containing the chemical compound a-PVP (Alpha-pyrrolidinopentiophenone), a highly ADDICTIVE synthetic stimulant Chest pain Paranoia Hallucinations Breakdown of skeletal muscle tissue Kidney failure

Bath salt or Flakka doesn’t show positives on regular screenings!

1) In a patient prescribed Tylenol #3, which of the following is expected to be detectable in the urine? (29% correct)

a. Codeineb. Hydrocodonec. Morphined. Hydromorphonee. all of the above

2) In a patient abusing heroin, one would be likely to detect which of the following in the urine? (7% correct)

a. heroinb. 6-AMc. Morphined. b and ce. all of the above

Exam

J Opioid Manag. 2007 Mar-Apr;3(2):80-6.

3) A patient taking Oxycontin is given a urine drug test. He notifies you that he ate a poppy seed muffin for breakfast. What might reasonably be detected in the urine? (22% correct)

a. Oxycodoneb. Codeinec. Morphined. all of the above

4) Which of the following are plausible explanations for a negative urine opiate screen in a patient on chronic opioid therapy? (17% correct)

a. Patient ran out of opioid early and has not used any in a few daysb. Patient is a "fast metabolizer"c. Drug screen does not detect that particular opioidd. a, b and ce. a and c only

THANK YOU!