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B. Kapur: Frequently Asked Questions: Opiate Dependency and Methadone Maintenance Treatment program follow-up Frequently Asked Questions: Opiate Dependency and Methadone Maintenance Treatment program follow-up Dr. Bhushan M. Kapur Associate Professor Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON CPSO 15nov13 Tables Table 1: Impact of half-life Start st End of 1 half-life nd End of 2 half-life rd End of 3 half-life th End of 4 half-life th End of 5 half-life th End of 6 half-life th End of 7 half-life Amount of drug left in the body Amount of drug eliminated 100% 0% 50.0% 25.0% 12.5% 6.25% 3.125% 1.56% 0.78% 50.0% 75.0% 87.5% 93.75% 96.87% 98.44% 99.22% Caution: Half-life can often be misleading. The duration of detection is dependent on amount taken – larger the amount taken longer is the detection period going to be. Sensitivity of the analytical method – more sensitive the method the longer is the detection period. Table 2: Poppy seed Bagel and Immunoassay Seven volunteers ate poppy seed covered bagel (one each). Urine was collected and tested for opiates by using immunoassay (CEDIA) method on a Hitachi 717 analyser followed by Remedi-HS HPLC. Before bagel 2 hours post 6-8 h post Bedtime 12h post First morning void 24h post Following morning 48 h post Male, 30, 140lbs 57 1888 1924 951 192 M, 40, 200lbs 54 499 905 292 359 M, 50, 160 lbs. 51 >5000 3345 NA 564 M, 40, 165 lbs. 62 1170 2081 NA Na F, 40, 125 lbs. 54 5906 3119 911 191 F, 25, 105 lbs. 38 2198 2858 1332 1101 F, 35, 135 lbs. 0 1888 1723 301 885 317 107 439 99 46 84 943 * ng/mL. Positive >300 ng/mL. Three of the highest concentrations were subjected to HPLC screen and were negative for any opioids. © 1997 - 2013 Bhushan Kapur All rights reserved 1 B. Kapur: Frequently Asked Questions: Opiate Dependency and Methadone Maintenance Treatment program follow-up Table 3: Descriptive Statistics for reference ranges1. pH Cr mmol/L Na Cl n 5464 5477 5474 5474 mean 5.9 11.6 115 130 min 5.0 0 6 7 max 9.0 50.2 353 374 Std dev 0.92 6.5 56 62 95% reference range >2 20-230 15-250 1 Bhushan Kapur et al.: Urine Fingerprinting - Detection of Sample Tampering in an Opiate Dependency Program, Ther Drug Mon, 21: 243-250, (1999). Table 4: Effects on EIA including CEDIA procedures. Summary of adulteration studies in Literature and our Lab. Amp Barb Benz Coc Opi PCP THC Marker Bicarbonate Bleach 1% - + - + - - + pH, Na Na, Cl, Bleach 10% ++ ++ ++ ++ ++ ++ ++ smell Detergent - ++ ++ ++ ++ ++ ++ pH Drano 0.1% Drano 20% ++ ++ ++ ++ ++ ++ ++ ++ pH Golden seal tea - - - - - - ++ Lemon Juice - + + + + - + Salt - - - - - - - Na, Cl, SpGr Vinegar - - - + - - + pH Visine - + + + - - ++ ? Water loading* (in-vivo) ± ± ± ± ± ± ± Cr, SpGr Liquid soap dark color pH cloudy ++ = strong interference; + = weak interference; - = no interference Although these interferences have been reported in literature, they are dependent on the amount added to the urine. *Water loading or in-vivo dilution is the most common form of adulteration. © 1997 - 2013 Bhushan Kapur All rights reserved 2 B. Kapur: Frequently Asked Questions: Opiate Dependency and Methadone Maintenance Treatment program follow-up Table 5: Drug half-lives and approximate urine detection periods DRUG Methamphetamine Half-life* (t½) 12 to 34 hours Amphetamine (metabolite of methamphetamine) 7 - 34 hours Methyenedioxymethamphe tamine (MDMA) (aka Ecstasy) 7.6 hours Opiates *** Morphine 1.3 to 6.7 hours (morphine) (metabolite of Heroin, Codeine, Hydromorphone, hydrocodone) Detection period** 2 - 3 days 2 to 3 days Opiates positive for 2-4 days (EIA)*** Comments 1) If Enzyme Immunoassay (EIA) is positive, confirmation by chromatography is required because of high incidence of false positives; 2) EIA cross-reacts with phenylpropanolamine, ephedrine, pseudoephedrine, bromphenriamine, bupropion, tradazone, chlorpromazine, promethazine, ranitidine etc.; (see tables 6 & 6a) 3) MDMA, MDA will be positive with the new generation Ecstasy EIA assay but will also cross-react with amphetamine derivatives as in (2). 4) Chromatography required in differentiating amphetamine derivatives such as MDA and MDMA. 1) EIA does not differentiate between opiates, and has a poor sensitivity for oxycodone, meperidine 2) Chromatography required in identifying specific opiates (codeine, oxycodone, hydrocodone etc 3) Hydromorphone requires sample extraction modification. 4) Even one poppy seed bagel will be detected on EIA ( see table 5 below). 5) a small amount of morphine is biotransformed into hydromorphone but not to Oxymorphone About 10% of codeine is transferred to morphine in normal metobolizers. False positive reported in literature: quinolones © 1997 - 2013 Bhushan Kapur All rights reserved 3 B. Kapur: Frequently Asked Questions: Opiate Dependency and Methadone Maintenance Treatment program follow-up DRUG Oxycodone Fentanyl Heroin 6-Mono-acetyl-morphine (MAM) Phencyclidine (PCP) Cocaine Benzoylecgonine (metabolite of cocaine) 9 δ -Tetrahydrocannabinol (THC) 9 δ -Tetrahydrocannabinoic acid (marijuana metabolite in urine) i) Benzodiazepines Diazepam Half-life* (t½) Detection period** 4 to 6 hours Not detected by opiate immunoassay – specific assay required (now available) IV=2.5min, Intranasal=6.5min Transdermal 7h (312h) Not detected by opiate immunoassay. 60 to 90 minutes Specific immunoassay recently introduced minutes Comments 1) 33-66% of single dose eliminated in 24 hours. 2) Chromatography will identify Oxycodone and or its metabolites Large amount will give positive on some opiate immunoassays. Immunoassay recently introduced Chromatography will identify both fentanyl and nor-fentanyl Fentanyl is 80% to 85% protein bound Not detected in urine. Positive for opiate (morphine) is indicative of probable Heroin use. MAM: Detected by chromatography Specific immunoassay is available 30 minutes few hours 7 to16 hours 2 to 3 days Positive incidences are very rare. 0.5 to 1.5 hours few hours Cocaine not detected by EIA detected by chromatography Benzoylecgonine detected by EIA, chromatography. 5 to 7 hours 3 to 5 days 14 to 38 hours 90% fall in 1 hour (blood) Parent drug not detected in urine Detected as “Cannabinoids” by EIA. False positive reported NAIDS naproxen and ibuprofen much longer (60h) in chronic heavy users few hours to days 15 to 40 hours Few days to many weeks depending on chronicity of use days -weeks (depending on half-life) 2 weeks or more after last chronic use of diazepam i) EIA does not differentiate between different benzodiazepines. Some short acting agents have poor sensitivity. - Oxaprozin (Daypro) can cause a false positive. - Gravol can cause false positive - sertraline can cause false positive © 1997 - 2013 Bhushan Kapur All rights reserved 4 B. Kapur: Frequently Asked Questions: Opiate Dependency and Methadone Maintenance Treatment program follow-up Half-life* (t½) Detection period** Comments ii) Clonazepam 19 to 60 hours Poor – to not detected iii) Flunitrazepam (date rape drug Rohypnol)**** 9 to 25 hours Not differentiated by immunoassay ii)Extensive bio transformed, less than 0.5% excreted in urine over 24 hours –sometime visible on hydrolysis and GCMS if chronic dosing is involved iii) Need to test for the amino derivative of Flunitrazepam by chromatography. iv) Extensive metabolized. 2% excreted unchanged in urine DRUG iv) Bromazepam 10-20 hours Poor v) Lorazepam 9-16 hours 122% cross reactivity but dosage very low Methadone 15 to 40 hours. (Lit) 1 to 4 days. In chronic users urine should always be positive In chronic users halflife 27+8h (BK studies) EDDP (Methadone metabolite) Barbiturate (Phenobarbital) Alcohol (Ethanol) Half-life similar to methadone 35 to120 hours 1 to 2 weeks after last use (Phenobarbital) Blood levels fall by an average of 3.2 to 3.9 mmol/L/hour Or 15 to18 mg/100 ml/hour in social drinkers. Can be much higher in heavy drinkers. Can be 30mg/100mL/hr (BK data) 1.5 > 12 hours depending on the peak blood level. Urine typically positive for 1 to 2 hours after BAC is zero. © 1997 - 2013 Bhushan Kapur All rights reserved v) hydrolyzed urine: GCMS can differentiate between diazepam, nordiazepam, oxazepam and lorazepam At alkaline pH methadone is reabsorbed in the kidney. Chromatography or specific EIA required to distinguish methadone from its metabolite EDDP False positive reported: Diphenhydramine, Phenylpropanolamine, clomipramine, chlorpromazine, quetiapine and thioridazine, verapamil EDDP not affected by urine pH (better marker for compliance monitoring) Chromatography required to differentiate between various barbiturates False positive reported NAIDS naproxen and ibuprofen 1. During absorption phase urine level lags behind blood level i.e. BAC is higher than UAlc. 2. During elimination phase blood levels lags behind urine level i.e. UAlc is higher than BAC 5 B. Kapur: Frequently Asked Questions: Opiate Dependency and Methadone Maintenance Treatment program follow-up DRUG Ethyl Glucuronide Gamma-Hydroxybutyrate (GHB) (date rape drug) # * ** *** **** Half-life* (t½) Detection period** 2 to 3 hours Depends on use. Lit. reports up to 120h if LCMSMS (0.1mg/L) is used. 25- 30 h (by EIA BK data) Less than 12 hours 0.3 to 1.0 hour Comments 0.02% of ethanol is excreted as ETG. Chromatography required. Detected as GHB lactone EIA Enzyme immunoassay R.C. Baselt: Disposition of Toxic Drugs and Chemicals in Man, Fifth Edition 2000 The detection period is very much dose and half-life dependent. The larger the dose, the longer the period the drug/metabolite can be detected in the urine. Opiates may be positive for up to 2 weeks after last use with slow release opiates. Flunitrazepam (Rohypnol) is usually not detected with the generic EIA benzodiazepine procedure. Use chromatography to detect Amino-Flunitrazepam © 1997 - 2013 Bhushan Kapur All rights reserved 6 B. Kapur: Frequently Asked Questions: Opiate Dependency and Methadone Maintenance Treatment program follow-up Figure 6: Specific Gravity - Ur Creatinine Figure 7: Urine Temperature 37 36.5 36 35.5 35 34.5 34 0 5 10 15 20 25 30 35 40 45 50 Seconds Kapur 1989 Temperature © 1997 - 2013 Bhushan Kapur All rights reserved Regression 7