10/16/2017

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Drug Testing Interpretation in Addiction Care

Brandi Puet, Pharm.D.

Objectives

• Describe the difference between immunoassay and confirmatory testing.

• List explanations for unexpected negative or positive drug testing results.

• Demonstrate the ability to interpret urine drug testing results through case studies.

Background

• Clinical Scientist and Fellowship Director at a healthcare toxicology laboratory

• Doctor of Pharmacy – Auburn University• Postgraduate Training

– PGY-1 Pharmacy Practice at VA Tennessee Valley Healthcare System (Nashville)

– PGY-2 Medication Use Safety at Hospital Corporation of America (Nashville)

Patient A Patient B Patient C

Rx: none Rx: Suboxone Rx:Methadone

EtG: 36,800 ng/mL

EtS: None detected

Buprenorphine:69,007 ng/mL

Norbuprenorphine: 48 ng/mL

Methadone: 209 ng/mL

EDDP: <200 ng/mL

Which is Nonadherent?

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Purpose of Drug Testing Unexpected Negatives

Testing Considerations

• Collection/Specimen Validity?• Laboratory method used?• Appropriate test ordered?• Appropriate threshold?• Appropriate markers tested?• Drug Stability?

ImmunoassayScreening, Point-of-Care Testing (POCT)

Ability to detect a compound depends on cross-reactivity

Advantages: RapidLess expensive

Considerations:Results not confirmedIdentifies classes of drugsQualitativeConcerns with false (-) and false (+)

ConfirmatoryGC/MS, LC/MS/MS

Identifies compound based on its unique molecular fingerprint

Advantages: Identifies specific drugRules out false positivesIdentifies drugs/metabolites missed by screenQuantitative

Considerations:Testing takes time to completeMore training/expertise neededCost

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Testing Considerations:Immunoassay

Methadone

Methadone:5-50%

EDDP: 3-25%

Baselt, 11th ed.; Manchikanti, et al. Pain Physician. 2011.; Kirsh, et al. J Opioid Manag. 2015.;Mikel, et al. Ther Drug Monit. 2009. ; Pesce, et al. Pain Physician. 2010. ;Snyder, et al. Pain Physician. 2017. 

False (-) rates reported in literature: 4-60%

Clinical Considerations

• Disease states?• Concomitant medications?• Dose/dosing schedule?• Route of administration?• Specimen type?

Age         Weight         Medical Conditions         Diet         Concomitant Medications     

Urine pH       Nutrition        Tim

e of last dose

Genetics     Drug formulation       Environment        Hydration        Specimen Storage

Time of last  vo

id        Freq

uen

cy of u

se

Unexpected Positives

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Unexpected Positives

• Drug ingested• Unexpected

metabolite• Contamination

• Cross-reactivity

Immunoassay Confirmatory

• Drug impurity

• Minor metabolite

Immunoassay False Positive RatesAmphetamines 14-53%

Benzodiazepines 0.4-11%

Cocaine 0-12%

Marijuana 0.9-39%

MDMA/Methamphetamine 86-100%

Methadone 0-45%

Opiates 4-34%

Oxycodone 2-41%

PCP 100%

Manchikanti, et al. Pain Physician 2011; 14(2): 175‐87.; Johnson‐Davis, et al. 2016; 40: 97‐107.; Kirsh, et al. J Opioid Manage. 2015; 11(1): 61‐8.

Unexpected Positives: Cross-reactivity

Immunoassay False Positives

Amphetamines Amantadine AripiprazoleBrompheniramineBupropion ChloroquineChlorpromazine Ciprofloxacin DesipramineDoxepinEphedrineFluorescein

Fluoxetine Ginkgo Labetalol MDPVMetformin Methylphenidate Metronidazole OfloxacinPhenterminePhenylephrine Promethazine

Propranolol Pseudoephedrine Ranitidine SelegilineThioridazineTrazodoneTrimethobenzamideTrimipramineTyramine

Unexpected Positives: Cross-reactivity

Immunoassay False PositivesBenzodiazepines Chlorpromazine

EfavirenzFenoprofen

FlurbiprofenIndomethacinKetoprofen

OxaprozinSertralineTolmetin

Buprenorphine CodeineDihydrocodeine

MorphineMethadone

Tramadol

Marijuana AspirinBaby washEfavirenz

Hemp productsNSAIDsPPIs

RifampinTolmetin

Unexpected Positives: Cross-reactivity

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IA False PositiveMethadone Chlorpromazine

ClomipramineDiphenhydramine

DoxylamineOlanzapineQuetiapine

TapentadolThioridazineVerapamil

Opiates Dextromethorphan Diphenhydramine DoxylamineNaloxone

PentazocineQuinine QuinolonesRanitidine

Rifampin TolmetinVerapamil

Phencyclidine DextromethorphanDiphenhydramineDoxylamineIbuprofenImipramine

Ketamine LamotrigineMDPV MeperidineThioridazine

Tramadol VenlafaxineO-desmethylvenlafaxine

Unexpected Positives: Cross-reactivity

Norcodeine Codeine Morphine

NorhydrocodoneHydrocodone Hydromorphone

Dihydrocodeine

Oxycodone OxymorphoneNoroxycodone

(minor) (minor)

3A4

3A4

3A4

2D6

2D6

2D6

Unexpected Positives: Metabolism

Unexpected Positives: Pharmaceutical Impurities

Prescription DrugPharmaceutical 

ImpuritiesAllowable Limit (%) Typical Observed (%)

Codeine Morphine 0.15 0.01‐0.1

Hydrocodone Codeine 0.15 0‐0.1

HydromorphoneMorphine

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

OxymorphoneHydromorphone

Oxycodone

0.15

0.5

0.03‐0.1

0.05‐0.4

Haddox et al. Poster: American Academy of Pain Medicine; February 2010; San Antonio, TX.

Unexpected Positives: Pharmaceutical Impurities

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Heroin Positives Benzodiazepine Interpretation

Benzodiazepine Interpretation Methamphetamine Interpretation

No• Amphetamine (Adderall®)

• Dextroamphetamine (Dexedrine®)

• Lisdexamfetamine (Vyvanse®)

• Phentermine (Adipex-P®, Qsymia®)

• Pseudoephedrine (Sudafed®)

Yes• Methamphetamine (Desoxyn®)

• Benzphetamine

• Selegiline (Eldepryl®, EMSAM®)

• OTC LevmetamfetamineVapoinhaler

• Illicit Methamphetamine

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Methamphetamine: “Illegal in the Mirror”

• D-methamphetamine: Stimulant, more commonly abused

• L-methamphetamine: Less stimulant, not as commonly abused

Image source: http://scienceblogs.com/moleculeoftheday/2006/10/27/lmethamphetamine-would-you-bel/

D-Predominant• Methamphetamine (Desoxyn®)

– 95-100% D (aka 0-5% L)

– C-II for treatment of ADHD, obesity

• Benzphetamine

– 95-100% D (aka 0-5% L)

– C-III for treatment of obesity, metabolizes to d-methamphetamine

• Illicit Methamphetamine (common)

– 0-100% D

L-Predominant• Selegiline (Eldepryl®, EMSAM®)

– 0-5% D (aka 95-100% L)

– Rx for treatment of Parkinson disease or major depression

– Metabolizes to l-methamphetamine

• Levmetamfetamine (OTC vapoinhaler)

– 0-5% D (aka 95-100% L)

– OTC for congestion

• Illicit Methamphetamine (rare)

– 0-100% D

D/L Isomer Interpretation

0% 5% 95% 100%

1. Selegiline2. OTC Vapoinhaler3. Illicit Meth (rare)

1. Methamphetamine Rx2. Benzphetamine3. Illicit Meth

1. Illicit Meth 2. Selegiline or OTC vapoinhaler

ANDMethamphetamine Rx or Benzphetamine

D-Isomer Percentage

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Unexpected Positives:

Drug Present(Confirm)

Unexpected Sources

Amphetamine • Dextroamphetamine (Dexedrine®)• Lisdexamfetamine (Vyvanse®)

Benzodiazepines • Designer benzos

Cocaine • Coca tea• Topical pharmaceutical cocaine (inpatient)

Codeine • Pharm impurity in morphine (up to 0.5%)• Schedule V cough suppressants• Poppy seeds (morphine more predominant)• Heroin (morphine more predominant)

Unexpected Positives:

Drug Present(Confirm)

Unexpected Sources

Cotinine • Nicotine replacement products

Ethyl Glucuronide/Ethyl Sulfate

• Post-collection fermentation (diabetes)• Alcohol-containing medications• Autobrewery syndrome (very rare)• Electronic cigarette use• Excessive hand sanitizer use• Ingestion of baker’s yeast with sugar• Ingestion of large amounts of grape juice• Ingestion of large amounts of nonalcoholic beer/wine

Fentanyl • Counterfeit pills sold on street (such as oxycodone)• Contaminant of heroin products

Audience Participation Unexpected Positives:

Drug Present(Confirm)

Unexpected Sources

Hydrocodone • Minor metabolite of codeine• Pharmaceutical impurity in oxycodone (up to 1%)• Prescription cough suppressants (e.g. Tussionex®)

Hydromorphone • Minor metabolite of morphine• Metabolite of hydrocodone

Marijuana • Dronabinol (Marinol®)• Hemp• Cannibidiol products

Morphine • Metabolite of codeine• Poppy seeds• Heroin

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Marijuana Period of Detection

Goodwin, et al. J Anal Toxicol. 2008; 32(8): 562-9.

Carboxy-THC Serial Excretion• Ratios

– 1.5 x

– 0.5 x• Schwilke study

Schwilke, et al. Addiction. 2011; 106(3): 499-506.

Case Studies Case Study #1 “No Metabolites”(Rx: Diazepam, Fentanyl, Oxycodone)

Oral Fluid

Urine

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Case Study #2: “Reuse?”

Date of Collection Carboxy-THC (ng/mL)

Cr

(mg/dL)

CTHC/Cr x 100 (ng/mg Cr)

Ratio

10/4/17 17 173 10 0.71

10/2/17 <20 77 N/A N/A

9/28/17 26 184 14 1.07

9/27/17 16 120 13 0.68

9/22/17 42 218 19 0.41

9/20/17 69 150 46 N/A

Case Study #2: “Reuse?”

0

5

10

15

20

25

30

35

40

45

50

Case Study #3: “Illicit or Not?”(Rx: Methadone)

Case Study #4: “Illicit or Not?”(Rx: Oxycodone PRN)

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Case Study #5: “How Many Drugs Ingested?”(Rx: Buprenorphine, Alprazolam)

Case Study #6: “Consistent Results?”(Rx: Alprazolam, Methadone)

Drug/Metabolite Concentration (ng/mL)

Codeine 256

Norcodeine 118

Morphine 61,100

Hydromorphone 636

Oxycodone 430

Oxymorphone 1,350

Noroxycodone 231

Case Study #7: “Drugs Ingested?”(Rx: Oxycodone)

Case Study #8: “Consistent Results?”(Rx: Amphetamine, Gabapentin, Suboxone)

Drug/Metabolite Concentration

Buprenorphine 179 ng/mL

Norbuprenorphine 359 ng/mL

Naloxone 222 ng/mL

Amphetamine 46,800 ng/mL

Gabapentin 198 mcg/mL

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Patient A Patient B Patient C

Rx: none Rx: Suboxone Rx:Methadone

EtG: 36,800 ng/mL

EtS: None detected

Buprenorphine:69,007 ng/mL

Norbuprenorphine: 48 ng/mL

Methadone: 209 ng/mL

EDDP: <200 ng/mL

Which is Nonadherent?Age         Weight         Medical Conditions         Diet         Concomitant Medications     

Urine pH       Nutrition        Tim

e of last dose

Genetics     Drug formulation       Environment        Hydration        Specimen Storage

Time of last  vo

id        Freq

uen

cy of u

se

Questions?

• Brandi Puet, Pharm.D. • brandi.puet@aegislabs.com• 615-760-2883