What Americans Believe. Grant Beardsley, MS, MT(ASCP) 10/12/2015. Interpreting: Urine Drug Test Results in Chronic Opioid Therapy and Drugs of Abuse

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1 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) 1

2 Over 60% of patients taking opioids for at least 3 months are still on opioids five years later. From: 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, See: Sources Where Users Obtained Pain-Relievers for Nonmedical Use Source of Prescription Drugs for Nonmedical Use Drug Dealer 4 % Internet 0.1% Other 5% Bought/took from friend/relative 15 % Rx from one doctor 21 % Free from friend/relative 53 % Source (2014): The National Survey on Drug Use and Health 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.3 rd edition, June

3 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, 4 th 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

4 Questions Confronting Providers Is my patient taking the medications I did prescribe? Adherence, non-adherence, diversion Is my patient taking drugs I did notprescribe? 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: 14% 20% 10% 2% Expected opioid present (Normal) 54% Missing prescribed opioid Unexpected drug present Illicit drug From: Michna, E., et al., Clin J Pain 23: , Feb 2007 Adulterated specimen Incidence of Aberrant UDT Results Study COT patients with aberrant UDT results Cook RF, % Fishbain DA, % Hariharin J, % Ives TJ, % Berndt S, % Katz NP, % Michna E, % West R, % Manchikanti L, % From: Owen, Graves T., et al. Urine Drug Testing: Current Recommendations and Best Practices, Pain Physician :ES119-ES133, ISSN

5 Recommendation for Frequency of UDT (1) Risk Category (by ORT) Low Risk Moderate Risk High Risk oropioiddose > 120 mg MED/d) Aberrant Behavior (Lost Rx,multiple requests for early refill, opioids from multiple providers, unauthorized dose escalation, apparent intoxication, etc.) UDT Frequency 1 per year 2 per year 3-4 per year 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.3 rd edition, June Recommendation for Frequency of UDT (2) Patient Risk Status/ Profile Stable opioid treatment Low risk for adverse outcome * History of addictive disorder Occupation requiring high mental activity Older adults Unstable/dysfunctional social environment Psychiatric or medical comorbidities Very high risk for adverse outcome * Frequency of Opioid Monitoring Once every 3-6 months More frequent after treatment initiation; changes in opioid dose Once weekly * Undesirable effects associated with opioid use (misuse, abuse, addiction or diversion). Source: Chou R, FanciulloGJ, 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): 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.3 rd edition, page 63. June

6 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 From: Clinical Toxicology, A Guide for Laboratory Professionals. CAP Press (2012) 16 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. 17 Lab immunoassay Screen 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 6

7 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. 7

8 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 positivefor 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.TherDrug 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):

9 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: 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 DrugCheckWaive RT Urine Drug Detection Cups. J Anal Toxicol(2013) 37 (1): 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: (2012). 9

10 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.3 rd edition, June GC/MS Confirmation LC-MS/MS Tandem Mass Spectrometer 10

11 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, The Laboratory s Challenge: Specimen Matrix Biological specimens are mostly made of what we are not interested in measuring. 11

12 Chromatography (LC-MS/MS) A mixture of 95 drug standards injected into LC-MS/MS (top). Patient specimen (bottom). 12

13 SECOND: Multiple Reaction Monitoring Ions Spectrum with background ions Q1 lets only drug ion 210 pass through Q2 Collision Cell breaks ion 210 apart Q3 filters specified product ions 158 and 191 from precursor ion 210 to detector no chemical background 13

14 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 Poppy Seeds and Morphine Drugs Codeine Morphine 6-Monoacetylmorphine Minor Metabolism (high dose codeine) Minor Metabolism (high dose morphine) Hydrocodone Hydromorphone Heroin SB Karch. Pathology of Drug Abuse. CRC Press, 4 th Ed. (2009) Clinical Toxicology, A Guide for Laboratory Professionals. CAP Press (2012) Norhydrocodone (CYP3A4) 14

15 Major and Minor Metabolic Pathways Opioids (cont.) Oxycodone Oxycodone Oxymorphone Noroxycodone (CYP3A4) Methadone Methadone Metabolite (EDDP) Buprenorphine Norbuprenorphine Tramadol O-desmethyl tramadol SB Karch. Pathology of Drug Abuse. CRC Press, 4 th 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 Diazapam (Valium ) Temazepam (Restoril ) Clorazepate (Tranxene ) Halazepam (Paxipam ) Chlordiazepaxide (Librium ) Flurazepam (Dalmane ) Alprazolam (Xanax ) Clonazepam (Klonopin ) Lorazepam (Ativan ) Nordiazepam Oxazepam (Serax ) N-hydroxyethylflurazepam α-hydroxyalprazolam 7-aminoclonazepam Glucuronidation Flunitrazepam (Rohypnol ) 7-Aminoflunitrazepam Source: Clinical Toxicology Testing; CAP Press (2012) 15

16 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 Alprazolam Chlordiazepoxide Clonazepam Diazepam Flunitrazepam(not in US) Flurazepam Lorazepam Nordiazepam (not in US) Oxazepam Urine Metabolites Half-life, plasma (hr) α-hydroxyalprazolam Nordiazepam Oxazepam 7-Aminoclonazepam Nordiazepam Oxazepam Temazepam 7-Aminoflunitrazepam Hydroxyethylflurazepam Lorazepam Oxazepam Oxazepam Detection Time in Urine (d) 11 to 15 2 to 5 5 to 30 2 to 5 20 to 40 2 to 5 20 to 40 7 to 10 6 to 24 2 to 5 2 to 3 1 to 2 9 to 24 2 to 5 > 24 7 to 10 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 16

17 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 Acceptable Opioid Process Impurities in Commercial Drug Substances Commercial Active Pharmaceutical Ingredient Process Impurities Allowable Limit (%) Typical Observed (%) Codeine Morphine Hydrocodone Codeine Hydromorphone Morphine Hydrocodone Morphine Codeine Oxycodone Hydrocodone Oxymorphone Hydromorphone Oxycodone 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):

18 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 (T max ) 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 tidfor chronic pain requests an increase in dose. The physician orders a urine pain management drug test panel that shows: Urine Drug Test Results: Morphine Hydromorphone Oxymorphone Ethanol 8250 ng/ml 325 ng/ml 110 ng/ml g/dl What is the interpretation? 18

19 Interpretation Urine Drug Test Results Morphine Hydromorphone Oxymorphone Ethanol 8250 ng/ml 325 ng/ml 110 ng/ml 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 19

20 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 prodrugmetabolized to amphetamine. NOTMethylphenidate (Ritalin, Concerta ) Methylphenidate and metabolite (ritanilicacid) are not detected by immunoassay screens and routine GC/MS confirmation tests. 58 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 svapor-inhaler (desoxyephedrine, levo-methamphetamine) D/L-Methamphetamine sources: illicit methamphetamine NOTMethylphenidate (Ritalin, Concerta ) Methylphenidate and metabolite (ritanilicacid) are not detected by immunoassay screens and routine GC/MS confirmation tests

21 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 21

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