How: or, Behind the Curtain.

Transcription

1 How: or, Behind the Curtain.

2 A peek into laboratory testing

3 Collection is Key! No coats, purses, etc in bathroom Turn off water at sink Use colored (blue, green) disinfectants in toilets Use collection containers with temperature indicators (AND READ THEM) Observed collection NOT foolproof FOLLOW PROTOCOLS for hair and oral fluid NEVER, NEVER EVER encourage fluid intake!!!!!!!!!!!!!!!!

4 Moving from Collection To Testing. SCREENING Report Toxicology Urine toxicology screen Opiates: <300 ng/ml Opiate Confirmation Oxycodone: 425 ng/ml C O N F I R M A T I O N DEFINITIVE

5 Analysis SCREENING Most are immunoassaybased Movement to mass spectrometry Targets range from specific compounds to broad classes Selected to give good window of detection DEFINITIVE METHODS Currently, mass spectrometry Gas chromatography/mass spectrometry (GC/MS) Liquid chromatography/tandem mass spectrometry (LCMSMS, UPLCMS) Very specific Greater sensitivity hours p ingestion

6 What do we mean by specificity? CH 3 N CH 3 N HO O OH CH 3 O O OH MORPHINE CODEINE CH 3 N HO CH 3 O O OXYCODONE O Cocaine assays Opiate assays

7 Comparison of Several IAs Amount of drug needed to trigger a positive response LAB IA 1 LAB IA2 POCT 1 POCT 2 Calibrator lormetazepam oxazepam glucuronide Cut off 300 ng/ml oxazepam oxazepam CLONAZEPAM NORDIAZEPAM OXAZEPAM LORAZEPAM

8 Cut-offs The lowest concentration of a drug considered to be positive. Example: THC immunoassay 20 ng/ml; mass spec 3 ng/ml Concentration depends on method and setting. Clinical: Manufacturer or lab determined based on analytical ability. Work place drug testing, etc: Defined by federal or state statutes, or agency (DOT, DOD, IOC, NFL, etc).

9 Examples of Cut-offs Class target C/O (IA) C/O (GC/MS) Amphetamines d-amphetamine/ d- methamphetamine /50/200/ 500 Barbiturates secobarbital Benzodiazepines diazapam/ lormetazepam /100 Cannabinoids 9 COOH-THC 20 3/15 Cocaine benzoylecgonine /100 Methadone methadone Opiates morphine 2000/ Phencyclidine PCP 25 25

10 Time to result IA vs MS In-lab IA POCT IA MS Minutes to hours Minutes Complexity Moderate Waived to moderate (to high) Specificity (what is detected) Sensitivity (how much) Low to moderate ng/ml (qualitative) Low ng/ml (qualitative) When to use Screening Screening Time sensitive Appropriate staff and CLIA Hours to days High High pg/ml (quantitative) Screening and confirming Disputed screen Screening results unexpected Known inability of screen to detect drug NOTE: NO test or method is error free. Most errors occur before analysis (at time of collection!)

11 Comprehensive Testing Reserve for very, selected patients $$$$, 1-2 week tat May need both blood and urine Usually multiple screens followed by definitive Examples: Hallucinogen panel: hallucinogens, amphetamines, LSD, MDMD, methedrone, mescaline, PCP, belladonna alkaloids, tryptamines, salvinorins, phenethylamines Profiles to detect OTCs and prescriptives (>200 drugs)

12 Validity Testing ph Creatinine Specific gravity Common added adulterants (same old list): H2O; detergents, bleach, salt, ammonia, acids Glutaraldehyde Nitrites Chromates Peroxide and peroxidase

13 Interpretations Result below c/o Drug absent Drug present, but below designated cut-off Assay does not detect drug Result at or above c/o Screen: detected drugs belonging to the indicated class or another similar substance that cross-reacts with antibody in assay Confirmation or definitive: drug is present The result does not tell you the route, time of, or amount of ingestion.

14 Oh, NO! Unexpected Results... What does the metabolic profile look like? pharmacokinetics Was drug administered correctly, etc? Ex: frequency of fentanyl patch replacement What other drugs are used/prescribed, including CAMs? Use of grapefruit, etc? Pharmacogenetics Cross-reactivity with similar compounds (or contamination) Have any issues been reported with generics? Where is the prescription being filled?

15 Oh, NO! Unexpected Results... Were there any issues during collection? Human error? Office or Laboratory? re-test if there is any doubt and talk to the laboratory!

16 Talk to YOUR LAB An expert is often available to help with interpretations Some can be tricky even we scratch our heads Many manufacturers of screening assays Many versions of confirmation methods No two are the same DON T use web based info We are part of the health care team and here to work with you!

17 Drug testing results Should always be used in context with other patient data eg, medical record, med lists (inc old), assessment and monitoring data, behavioral observation, anecdotal remarks from family Are NOT indicative of every therapeutic compliance scenario. Expert knowledge of drug metabolism and sometimes collaboration with laboratory is essential to an accurate interpretation

18 Guidelines In current review National Academy of Clinical Biochemistry with American Academy of Pain Management, evidenced based Clinical Laboratory Standards Institute consensus based Let me know if you are interested in reviewing

19 Outline History and use of drug testing in the clinical setting Who, what, when, where, how, and why Behind the curtain testing What s in this urine? Your conundrums: audience submits cases

20 What s in This Urine?

21 Case 1 A 32 yo female with past medical history of ADHD, anxiety, and hypothyroidism is seen for follow-up treatment of chronic back pain of 3 years duration. Medication list includes Adderall XL 30 mg po, daily Xanax 0.5 mg po, bid Levothyroxine 100 mcg po, daily Percocet 5/325 mg po, 1-2 q 6 h What do you expect to find in her urine?

22 Case 1 What do you expect to find in her urine? Adderall amphetamine Xanax alprazolam (extensive metabolism) Percocet oxycodone (oxymorphone) with acetaminophen Levothyroxine thyroxine, not monitored in urine Urine Drug Screens: Amphetamines c/o 500 ng/ml; broad specificity w amphetamine/methamphetamine + many sympathomimetic amines Benzodiazepines c/o 200 ng/ml; moderate specificity across class, but excellent w alprazolam and metabolites Opiate c/o 300 ng/ml; poor specificity to oxycodone (<1%)

23 Case 1 What do you expect to find in her urine? Urine Drug Screen: Amphetamines 500 ng/ml Benzodiazepines 200 ng/ml Opiate 300 ng/ml Do these results make sense analytically? Are these results appropriate to prescribed medications?

24 Amphetamine and Methamphetamine Methamphetamine amphetamine norephedrine Optical isomers (d- and l-) Illicit methamphetamine is either d- or a racemic mixture Drugs containing amphetamine or methamphetamine Amfetamine, Adderal, benzedrine, Dexedrine, Desoxyn, Methedrine, Vick s inhaler Compounds metabolized to amphetamine or methamphetamine Amphetaminil, benzphetamine, clobenzorex, dimethylamphetamine, ethylamphetamine, famprofazone, fencamine, fenethylline, fenproporex, furfenorex, mefenorex, prenylamine, selegiline Methylphenidate (Ritalin) differs and often NOT detected by amphetamine immunoassays. Isomers not distinguished by most routine methods! Special chromatography needed Look at prescribed amph/methamph (what is isomer composition?) > 20% d-methamphetamine is suspicious

25 Metabolic Profile of Opiates OXYMORPHONE OXYCODONE HEROIN HYDROMORPHONE 6-ACETYLMORPHINE HYDROCODONE MORPHINE CODEINE NORMORPHINE MORPHINE 3-GLUCURONIDE NORCODEINE CODEINE GLUCURONIDE NORMORPHINE GLUCURONIDE NORCODEINE GLUCURONIDE

26 Metabolic Profile of Opiates OXYMORPHONE OXYCODONE HEROIN HYDROMORPHONE 6-ACETYLMORPHINE HYDROCODONE MORPHINE CODEINE MORPHINE NORMORPHINE 3-GLUCURONIDE NORCODEINE CODEINE GLUCURONIDE NORMORPHINE GLUCURONIDE NORCODEINE GLUCURONIDE

27 Metabolic Profiles of Benzodiazepines Alprazolam -OH alprazolam + 4-OH alprazolam Chlordiazepoxide nordiazepam + oxazepam Clonazepam 7-aminoclonazepam Diazepam temazepam + nordiazepam + oxazepam Flurazepam N-OH ethyl glucuronide Flunitrazepam 7-aminoflunitrazepam Lorazepam lorazepam glucuronide Oxazepam oxazepam glucuronide Temazepam oxazepam

28 Case 1 What do you expect to find in her urine? Urine Drug Screen: Amphetamines 500 ng/ml Benzodiazepines 200 ng/ml Opiate 300 ng/ml Amph screen appropriate w analytical expectations and prescribed medications. Results may be appropriate. Benzo screen has excellent cross-reactivity with aprazolam and its primary metabolites. Results may be appropriate. Opiate screen used has poor cross-reactivity with oxycodone. Results suspect.

29 Case 1 Confirmations ordered Amphetamines Amphetamine 3900 ng/ml Others < c/o Benzodiazepines OH-alprazolam 1429 ng/ml Others < c/o Are these appropriate? Opiates Morphine 1152 ng/ml Others < c/o

30 Case 1 Amphetamine results are consistent with prescription Benzodiazepine results are consistent with prescription Opiate results are inconsistent with prescription She subsequently admits to selling her prescription and using heroin (last use was several days earlier).

31 Case 2 42 yo female Fentanyl Reports lack of pain control by day 3 UDS ordered All below cut-off Concerned provider calls to ask about fentanyl detection using screen, should confirmation be done? Resident explains fentanyl not detected by opiate screen and approves fentanyl confirmation Confirmation is also bdl Now what?

32 Case 2 Investigation Review of medications shows order for generic fentanyl patch with reapplication every 5 days. Fentanyl patch was prescribed to be changed every 5 d timing was too long. And at time of case, FDA recall for generic brand used. Recommended serum drug concentrations Serum fentanyl pre-application of patch shows no detectable fentanyl. Serum fentanyl 24 h later within therapeutic range.

33 Case 3 53 yo male, chronic back pain Prescription: MS Contin 30 mg 2/d What do you expect in the urine? UDS Amphetamines <500 ng/ml Barbiturates <200 ng/ml Benzodiazepines <200 ng/ml Cannabinoids 20 ng/ml Cocaine 150 ng/ml Opiates 300 ng/ml Methadone <300 ng/ml

34 Case 3 Prescription: MS Contin 30 mg 2/d What do you expect in the urine? UDS Amphetamines <500 ng/ml Barbiturates < 200 ng/ml Benzodiazepines < 200 ng/ml Cannabinoids 20 ng/ml Cocaine 150 ng/ml Opiates 300 ng/ml Methadone < 300 ng/ml Propoxyphene < 300 ng/ml Confirmation Opiates Morphine ng/ml Codeine <50 ng/ml Hydromorphone 237 ng/ml Hydrocodone <50 ng/ml Oxycodone <50 ng/ml Oxymorphone <50 ng/ml 6AM <15 ng/ml Cocaine Cocaine <50 ng/ml Benzoylecgonine 120 ng/ml Cannabinoids THC carb acid 72 ng/ml

35 Case 3 Prescription: morphine Confirmation Morphine ng/ml Hydromorphone 237 ng/ml Is this appropriate?

36 Case 3 Where s the cocaine? Cocaine Cocaine <50 ng/ml Benzoylecgonine 120 ng/ml ng/ml Excretion Pattern of Cocaine and metabolites time (h) BZE EME COC

37 Case 3 Is this passive inhalation? Cannabinoids THC carb acid 72 ng/ml

38 Case 4 39 yo male with chronic low back pain following a MVA in 2003 who returns to clinic for follow-up. Meds: Lioresal (baclofen) 10 mg/po tid Voltaren (diclofenac sodium) 1% gel topical 2-4 g 5x/d Docusate sodium 100 mg po prn Neurontin (gabapentin) 800 mg/po tid Dolophine (methadone) 10 mg/po 2 morning, 1 afternoon, 1 evening, 2 bedtime Roxicodone (oxycodone) 15 mg/po qid prn pain Tylenol (acetaminophen) 325 mg/po 2 tab q 8 h prn pain What do you expect to find in his urine?

39 Case 4 Screen Results Methadone 300 ng/ml Opiates < 300 ng/ml* Benzodiazepines < 200 ng/ml THC < 20 ng/ml * Remember most opiate screens do not cross-react well with oxycodone Confirmation Results Oxycodone < 50 ng/ml Oxymorphone < 50 ng/ml Are these results consistent or inconsistent with prescribed medications?

40 Case 4 Review past results Screening Opiates < 300 <300 <300 <300 Methadone Confirmation Oxycodone < 50 < 50 < 50 < 50 Now what? Oxymorphone < 50 < 50 < Methadone EDDP Adulterants unremarkable unremarkable unremarkable unremarkable

41 Could this patient have an altered metabolic profile? CYP P450s, esterases, others Ultra-rapid metabolizers metabolize drugs faster than normal Extensive metabolizers normal Intermediate metabolizers metabolize slower than normal Poor metabolizers metabolize much slower than normal Excretion patterns comparing Rapid v Poor metabolizer hours p ingestion

42 Case 4 CYP450 2D6 Two copies of CYP 2D6*4, poor metabolizer CYP2D6*4 has no activity CYP2D6: codeine (morphine*), hydrocodone (hydromorphone*), tramadol (o-desmethyl-tramadol), oxycodone (oxymorphone*) CYP3A4: codeine (norcodeine), hydrocodone (norhydrocodone), tramadol (N-desmethyl-tramadol), fentanyl (norfentanyl)*, methadone (EDDP), buprenorphine (norbuprenorphine) * fentanyl, oxymorphone, morphine, hydromorphone undergo significant 1 st pass metabolism Now, what do you think of his urine drug testing results?

43 Case 5 54 yo, male 4 d Hx: nausea, vomiting, dyspnea, mental status change Agitated, hallucinating PMH: cirrhosis, anemia, ETOH abuse, hepatitis C Medications: amitriptyline, promethazine, tramadol, hydrocodone /acetaminophen

44 Case 5 Resident calls laboratory: Can we send out a comprehensive tox screen to look for peyote, LDS, etc? She notes that the patient has a Combined respiratory alkalosis and metabolic acidosis with a prolonged PTT What additional test results would you want to see (first)?

45 Case 5 CHEM: Na 146 ( ) BUN 11 (7-21) PO ( ) K 3.5 ( ) CR 1 ( ) Mg 2.0 ( ) Cl 116 (98-107) glu 87 (65-110) AST 26 ( 19-55) HCO 3 9 (22-30) OSMO 309 ALT 22 (19-72) alk phos 107 (38-126) Ca 8.2 ( ) GGT 27 (13-126) bili 0.3 (0-1.2) NH 4 27 (15-45) UA: SG 1.005; ph 5.5 HEME: HCT 35.3 (37-51); PT 15 ( ); PTT 38.3 ( ); INR 1.65 ABG: ph 7.39 ( ); pco 2 17 (35-45); po (80-110) Tox: UDS neg, ETOH neg Referral Testing: Heavy Metals: As 20 g/d, Pb 12 g/d ANYTHING ELSE?

46 Case 5 How about a simple salicylate level?

47 Case 6 Interpret these results: Opiate Confirmation BUPRENORPHINE > ng/ml Norbuprenorphine < 5 ng/ml

48 Additional Resources Baselt. Disposition of Toxic Drugs and Chemicals in Man American Academy of Pain Medicine Relieving Pain in America Reisfield, Bertholf, et al. J Opioid Manag. 2007;3:80-6.; J Opioid Manag. 2007;3:333-7 Yang JM. Clin Lab Med. 2001;21: Hammett-Stabler C, et al. Clinica Chimica Acta. 2002;315: Cook JH, et al. J Anal Toxicol. 2000;24: Casavant MJ. Pediatr Clin N Am. 2002;49: Moeller K, et al. Mayo Clin Proc. 2008;83:66-76 Cone et al. J. Anal Toxicol 2006;30:1-5 Wasan et al Pain Medicine 2008; 9: Starrels, etc al. J Gen Intern Med 27: Radnovich, et al. Postgrad Med. 2014;126(4): McCarberg, et al. Curr Med Res Opin. 2013;29(5): Jannetto, et al. Expert Opin Drug Metab Toxicol. 2011;7(6): Sehgal, et al. Pain Physician. 2012;15(3 Suppl):ES67-92 Meldrum. JAMA. 2003; 12;290(18): Bonezzi, et al. Minerva Anestesiol. 2012;78(6): Kwon, et al. Pain Pract Nov 20. doi: /papr Hurley, et al. Curr Opin Anaesthesiol Aug 29. Mantyh. Curr Opin Support Palliat Care. 2014;8(2):

49 Outline History and use of drug testing in the clinical setting Who, what, when, where, how, and why Behind the curtain testing What s in this urine? Your conundrums: audience submits cases

50 Now for your questions

51 Drug Testing Case Studies <11% <2.5%

52 Drug Testing Case Studies

53 Adulterants, Substituted Specimen Your chronic pain patient, who is on methadone and Provigil, hands you a urine specimen that is less than 90 o F and has a specific gravity of <1.001 and a creatinine less than 2. What do you think about this specimen? What do you tell the patient?

54 Validity Testing Specific Gravity >1.001 and <1.030 Creatinine >2 mg/dl Temperature ph > 4.5 < 9 normal range ph absolute invalid <3 >11

55 Adulterants, Substituted Specimen Your chronic pain patient, who is on methadone and Provigil, hands you a urine specimen that is less than 90 o F and has a specific gravity of <1.001 and a creatinine less than 2. What do you think about this specimen? What do you tell the patient?

56 Drug Testing Case Studies Patient on Adderall for ADHD and temazepam (Restoril) tests positive for: Amphetamine and oxazepam (Serax) Are the results compatible with the legitimate prescriptions?

57

58 Office Based Urine Drug Screening J. Paul Martin, MD, FASAM Medical Review Officer