Drug Screening: Things You Need to Know

Transcription

1 Drug Screening: Things You Need to Know (a view inside the clinical laboratory) Gary L. Horowitz, MD Director, Clinical Chemistry, Beth Israel Deaconess Medical Center Associate Professor of Pathology, Harvard Medical School

2 Case Scenario Dr. Goldstein prescribes oxycodone for one of his patients. To check that the patient is taking the drug (and not selling it), he orders periodic urine opiate screens. When the test is positive, he s reassured. When it s negative, he concludes his patient is not taking the drug as prescribed. Sounds reasonable, doesn t it?

3 Drug Screening immunoassays fast turnaround time on automated platforms allow for rapid treatment/disposition of ED patients extremely cost-effective far from perfect, though false negatives false positives how can we avoid misleading clinicians?

4 Reasons to Test Urine some (most) methods are approved only for urine concentrations in urine are usually higher, making it more likely that, with any method, you ll detect drugs in serum, peak values occur very transiently, typical levels can be exceedingly low in contrast, in urine, one gets the effect of integration over time (detection limit = 300 ng/ml) Morphine (0.125 mg/kg IM) Morphine (other source) [Serum] (Peak ~15 min) [Serum] (~2 hrs) [Urine] Baselt RC. Disposition of Toxic Drugs and Chemicals in Man. 7 th Edition (2004).

5 Take Home Message #1 negative does not mean no drug present negative means less than an arbitrary threshold thankfully, few samples occur near thresholds ways to get below threshold: time hydration poor cross-reactivity

6 Will We Detect Oxycodone? semisynthetic narcotic analgesic derived from codeine indicated for relief of severe pain can be taken orally high abuse potential morphine codeine oxycodone methadone

7 Take Home Message #2 cross-reactivity can really confuse things for example, opiate screening assays detect not only morphine but also other opiates otherwise, you d have to run an assay for each drug even if each drug s cross-reactivity were 100%, (i.e., they reacted exactly like morphine), package insert data can be misleading: presented analytically not physiologically that is, on a mg/l to mg/l basis whether or not such concentrations are ever seen in patients!

8 Morphine Codeine Oxycodone Hydrocodone Meperidine Tramadol Fentanyl Methadone Buprenorphine

9 Selected Cross-Reactivities Different Manufacturers extracted from Magnani B. Concentrations of compounds that produce positive results. In: Shaw LM, Kwong TC, eds. The Clinical Toxicology Laboratory

10 Will We Detect Oxycodone? typical concentrations serum: 20 ng/ml urine: ng/ml amount to yield positive result Oxycodone 75,000 ng/ml Roche Diagnostics package insert (6/8/2007) If screen is positive, it s something other than oxycodone If screen is negative, oxycodone could easily be present Dr. Goldstein is 180 o wrong!

11 Fentanyl, Too? 100 ug/hr patch 2.5 ng/ml blood concentration typical urine concentrations not given 125,000 ng/ml required to look like 300 ng/ml morphine... will NOT detect even supraphysiologic concentrations of fentanyl

12 Clinical Judgment A Real Case urine positive for opiates and for cocaine Rx percocet (= oxycodone + acetaminophen)

13 Issues of Concern (Percocet Case) 1) cocaine screen positive 2) opiate screen positive: not oxycodone 3) don t yet know if oxycodone is present GC/MS Assay proved: morphine present oxycodone absent

14 On to False Positives... How about poppy seeds? Do they really cause a false positive opiate screen? No! They represent a true positive! Poppy seeds contain real morphine!

15 Urine Morphine Concentrations Following Ingestion of Poppy Seed Crackers McCutcheon JR, Wood PG. Clinical Chemistry 1995; 41:

16 A Real False Positive Example not every positive is a true positive only way to be 100% sure is to check by 2 different methods typically, immunoassay screen + mass spectroscopy confirmation usually unnecessary as immunoassay >99% accuracy, except: forensics pre-employment testing and drug abuse compliance clinically wrong Adapted from Baden LR, Horowitz GL, et al. JAMA 2001;286:3115

17 Summary some false positives are true positives poppy seeds do contain morphine % cross-reactivity can be misleading eg, naloxone high % cross-reactivity but one never achieves those levels in practice need to know physiologic concentrations even with extensive testing, there can be surprises fluoroquinolones (levofloxacin) false positive opiate definitive testing (LC/MS/MS) not practical for all samples turnaround time (TAT) cost

18 What You Should Do if you know what you re looking for, order it specifically oxycodone, fentanyl, buprenorphine inquire about sample type and turnaround time when screening, always submit urine indicate the drugs you suspect, if any be aware of false negatives and false positives, vary with from method to method (check with your lab) for pain clinic situations in particular consider confirming all positive results by a second method be aware, though, that this doesn t address false negatives ordering each drug specifically does take care of this problem, though if something doesn t make sense: don t send a new sample: investigate the current sample! contact Laboratory Director clinical judgment (yours) is still needed

19 From BIDMC OnLine Lab Manual Opiates (Urine) Immunoassay designed to detect opiates and related compounds Positive threshold corresponds to 100 ng/ml morphine Like most screening immunoassays, our opiate assay typicall detects only morphine, hydromorphone (Dilaudid), hydrocodone (Vicodin), and codeine Our opiate assay does NOT DETECT methadone. That is, a patient on methadone with a positive opiate screen has some other opiate-related drug in his/her system Our assay also does NOT RELIABLY DETECT naloxone (Narcan), meperidine (Demerol), buprenorphine (Suboxone), fentanyl, or oxycodone (Oxycontin/Percocet/Percodan). (At very high concentrations (10,000 ng/ml), oxycodone may be detected. More detailed information on opiate/opioid nomenclature, metabolism, and assay performance if available here.

20 Using Opiate Screening Immunoassays

21 Using Opiate Screening Immunoassays based in part on information from White RM, Black ML. Pain Management

22 Add Education to Final Report

23 Previous BIDMC Requisition Urine Drug Screening Tests Amphetamines Barbiturates Benzodiazepines Cocaine Methadone Opiates

24 Current BIDMC Requisition Urine Drug Tests Same Day Immunoassay Screen Mass Spec Send-Out 7-Day TAT Barbiturates Benzodiazepines Benzodiazepines will not reliably detect lorazepam includes lorazepam, clonazepam Cocaine Buprenorphine Methadone Fentanyl Opiates Tramadol detects morphine, codeine, hydrocodone will not detect buprenorphine, fentanyl, methadone, tramadol Oxycodone

25 Advantages of LC-MS/MS The gold standard: Two principles involved: LC separation by retention time (Identification #1) Mass Spec confirmation by fragmentation pattern (Identification #2) Multiple drugs identified in one assay eg, morphine, codeine, hydrocodone, oxycodone, etc can be designed to include metabolites, too The downsides (versus immunoassays) relatively expensive huge capital equipment costs expertise to set up methods and to run assays potentially long TAT

26 On-Line Monographs

27 Other Resources Chapter 15, Toxicology Screening for Opioids Gary L. Horowitz

28 Thank You for Your Attention

29 Additional Slides (Time Permitting)

30 Heroin versus Morphine heroin = diacetylmorphine 6-MAM is diagnostic of heroin if present, heroin must have been taken but, if absent, one can t prove heroin wasn t taken

31 Methadone versus Opiates opiate immunoassays do not detect methadone! Methadone Immunoassay Opiate Immunoassay Interpretation 1 Positive Positive 2 Positive Negative methadone present plus another opiate present methadone present no other opiate present* * oxycodone, mepiridine, etc., may still be present

32 More on Sample Types alternative sample types hair sweat oral fluid ( saliva ) urine concentrations even with creatinine correction, of limited utility metabolism, half-lives, timing, hydration

33 More on Saliva Bosker WM, Huestis MA. Clin Chem 2009;55: ssdkrc package insert: same company that supplies our urine opiate assay

34 Professional Practice in Clinical Chemistry April, 2013 Meeting two hospitals in same network in same city each offering Pain Management UDT, including an opiate screening assay #1 used an assay with threshold = 2000 ng/ml #2 used an assay with threshold = 300 ng/ml a sample could well be positive at one site, and negative at the other site Most point-of-care assays are 2000 ng/ml

35 Point-of-Care Testing for Drugs-of-Abuse Features CLIA waived Multiple drugs/drug classes Lower sensitivities e.g., morphine 300 vs 2000 Affordable ($5/cup) If confirmation desired, send cup to lab

36 A New Paradigm in Toxicology Testing? Current practice: screen with rapid, simple immunoassays confirm positives with LC-MS/MS e.g., opiate screen positive identify specific opiates with a targeted assay for ~8 drugs Newest LC-MS/MS methods: can identify 65+ drugs with a single assay! maybe POC for rapid feedback, with comprehensive drug screen to follow, detecting drugs suspected and unsuspected

37 A New Paradigm in Toxicology Testing? Note: overlap of peaks is not problematic This is LC-MS/MS, so overlapping peaks can be definitively resolved by mass fragmentation patterns