Addiction Toxicology in C-L Psychiatry: A Broad Topic with Deep Implications
Filza Hussain MD – Stanford University JJ Rasimas MD PhD FACLP – Hennepin County Medical Center Akhil Shenoy MD MPH – Columbia University G. Scott Winder MD MSc – University of Michigan
ACADEMY OF CONSULTATION-LIAISON PSYCHIATRY Psychiatrists Providing Collaborative Care Bridging Physical and Mental Health CLP 2018 Disclosure: Filza Hussain MD JJ Rasimas MD PhD FACLP Akhil Shenoy MD MPH Gerald Scott Winder MD MSc
With respect to the following presentation, there has been no relevant (direct or indirect) financial relationship between the party listed above (and/or spouse/partner) and any for-profit company which could be considered a conflict of interest. Outline
• Brief introduction & technical orientation • Alcohol biomarkers • Designer drugs • Nicotine & tobacco • Common drugs of abuse • Integrating toxicology into clinical care Introduction & Orientation
G. Scott Winder MD MSc University of Michigan
Introduction
• “Tox screen” – various techniques to isolate and identify substances
• Findings ≠ diagnoses
• Only ~2% of labs are comprehensive
Goldfrank's Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015 Utility
• Early detection prognosis, medical decision-making
• Earlier samples are better (peak concentrations)
• Point-of-care devices rapidly detect drugs of abuse
• Adherence, abstinence, diversion
• New, candid, therapeutic pt encounters
Goldfrank's Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015 False positives & negatives
(+) (-) • Device failure, operator error • Body metabolized, cleared • Detection thresholds set high to substance limit cross-reactivity, incidental • Variability in urine production exposure • Wrong test is ordered • Detected substance unrelated to clinical problem
Goldfrank's Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015 Are the tests valid?
• Your laboratory is the best place for up-to-date and valid data • Multiple manufacturers of drug tests • Unique performance characteristics • Caution • Literature out-of-date • Reported problem has been fixed • Specs don’t apply to your facility’s equipment/procedure
Goldfrank's Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015 Immunoassays
• Screening • specificity in detecting concentration analytes • Reactions (color/light, particle capture) used for detection • Cross-reactivity is minimized (false positives) or exploited (drug class, metabolite detection) • Intentional confounding by adulterants • High-stakes decisions confirmatory testing
Goldfrank's Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015 Immunoassays
Enzyme-multiplied immunoassay technique Magnetic microparticle chemiluminescent assay Microparticle capture assay
color light
capture
Goldfrank's Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015 Chromatography
• Physical separation and light absorption
• Stationary phase: fine, layered particles in a column
• Mobile phase: liquid or gas flows through column, analytes absorb
• Analyte velocities are known, vary, identified
• Limits of detection false negative
• Similar velocities/absorption further testing
Goldfrank's Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015 Chromatography
www.thermofisher.com Goldfrank's Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015 What to sample?
• Urine = non-invasive
• analyte concentrations than serum
• Hair, indirect biomarkers
• sensitivity to remote exposure
• Less commonly used
Goldfrank's Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015 Limitations of toxicology
• Stigma • Newer agents, “designer drugs” are invisible • Wide variation between regions, institutions • Time delay on results (esp. send-outs) • Toxicologist consultation only at major medical centers • Metabolite detection ≠ acute events (red herring?) • i.e. phenobarbital on GC-MS from a patient taking primidone
Goldfrank's Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015 Alcohol Biomarkers
G. Scott Winder MD MSc University of Michigan Case example
61yo female w/ decompensated cirrhosis (EtOH, NASH) listed for liver transplant in Feb 2017. Neg uEtG and UDS x 4 at listing. Case example
• June 2017: (+) external uEtG, uEtS. Placed on hold. Routine tox labs scheduled. Pt denied drinking— “swabbing my face daily with alcohol due to a skin condition.” AST:ALT 2:1. tBili 3.45.2. MELD 19.
• July 2017: Multiple neg OSH uEtG. LFTs improved. Case example
• Aug 2017: LFTs. AST:ALT 2:1. Pt missed scheduled labs.
• Sept 2017 – Psychiatry consultation: (+) fear of transplant. Pt knew about fatty liver dz for years. Avid drinker (~2/day) since her 30’s. ongoing cravings since last drink in 2015. insight: “never been a problem.” Repeated rubbing alcohol (+) uEtG. Husband found out that morning about (+) uEtG. Husband: “you are barking up the wrong tree—she’s not drinking.” Discussed PEth specs with pt and husband. No drinking disclosure. Case example
• Sept 2017 – Hepatology visit (1 hour after psych eval): Disclosed to female hepatologist that she had found husband’s bottle of whiskey hidden in the garage. Drinking for weeks. Continued to minimize her drinking and had little concern. Txp eval closed. Referred for AUD tx.
• Oct 2017 – present: PEth 1938 ng/mL. Weekly counseling with local agency, continues but now bi-monthly. (-) PEth in Jan 2018. Neg monthly uEtG. MELD 13. Eval remains closed. Alcohol Metabolism
www.wardelab.com Litten, R. Z., et al. (2010). Alcoholism: Clinical and Experimental Research 34(6): 955-967 Serum ethanol
• Widely used, available
• Limited detection window (5-8 hrs)
• Most helpful in acute presentations, active drinking
• Potential false (+) bacterial fermentation in serum sample
100 mg% is the legal level of intoxication in most states 50 mg% is the level at which deterioration of driving skills begins
pubs.niaaa.nih.gov Borucki, K., et al. (2007). Alcoholism: Clinical and Experimental Research 31(3): 423-42 Aspartate aminotransferase (AST) & Alananine aminotransferase (ALT)
• Enzymes involved in amino acid metabolism • Cheap, widely available screening test • AST:ALT>2.0 90% of cases 2/2 alcohol • Many false (+) that raise levels: • Obesity, weight gain, liver disease, antibiotics, antiepileptics, statins, NSAIDs, strenuous exercise, muscle disorders • False (-) • Levels drop during cirrhosis • Insensitive to EtOH use in persons <30yo
Conigrave et al Addiction. 2003 Dec;98:31-43. Serum γ-glutamyltransferase (GGT) • Membrane-bound glycoprotein on most cells • Inexpensive, indirect screening marker • Many false (+) • drugs, diseases, infections, ischemia • barbiturates, phenytoin, phenazone, dextropropoxyphene, MAOI, TCA, warfarin, thiazides, anabolic steroids • biliary tract disease, severe heart & kidney diseases, trauma, hyperthyroidism, obesity • 34-85% sensitivity, 11-95% specificity, 2-3 week detection window • sensitive in moderate drinkers since GGT after heavy use • Adjusted thresholds recent drinking in liver dz
Hannuksela, M. L., et al. (2007). Clinical Chemical Laboratory Medicine 45(8): 953-96 Whitfield, J. B., et al. (2018). Alcohol 66: 1-7 Litten, R. Z., et al. (2010). Alcoholism: Clinical and Experimental Research 34(6): 955-967 Serum carbohydrate-deficient transferrin (%CDT)
• 50-80g ethanol/day x2 weeks transferrin alteration • %CDT = percent altered compared to the overall transferrin • False (+): primary biliary cirrhosis, end-stage liver disease • 39-94% sensitivity, 82-100% specificity • 2-3 week detection window • Thresholds influenced by gender (45 U/L female, 64 U/L male) • Low cost screening test
Nguyen, V. L., et al. (2018) Alcoholism: Clinical and Experimental Research 42(2): 238-243 Hannuksela, M. L., et al. (2007). Clinical Chemical Laboratory Medicine 45(8): 953-96 Kollmann, D., et al. (2016). Transplant International 29(5): 559-567 Litten, R. Z., et al. (2010). Alcoholism: Clinical and Experimental Research 34(6): 955-967 Serum mean corpuscular volume (MCV)
• 90% of AUD pts have macrocytosis • Inexpensive screening test for heavy drinking • Several-month detection window • Numerous false (+) • Liver diseases, vitamin B12/folate deficiency, hematological disease, reticulocytosis, hypothyroidism • Slow return to normal, poor for relapse detection
Girard et al (1987) Hematol Oncol Clin North Am. Jun;1(2):321-34 Hannuksela, M. L., et al. (2007). Clinical Chemical Laboratory Medicine 45(8): 953-96 Litten, R. Z., et al. (2010). Alcoholism: Clinical and Experimental Research 34(6): 955-967 http://www.wardelab.com/19-3.html Fatty acid ethyl esters (FAEE)
• Esterification of fatty acids + ethanol • Detection windows • Serum: 24 hours, up to 99 hours in heavy drinkers • Hair: 2 months • Unclear sensitivity • More research needed on individual variability • Hair less available and less acceptable to patients • Forensic use • False (+) with alcohol-based hair products
Auwärter, V., et al. (2001). Clinical chemistry 47(12): 2114-2123 Borucki, K., et al. (2007). Alcoholism: Clinical and Experimental Research 31(3): 423-42 Doyle, K. M., et al. (1994). Journal of Lipid Research 35(3): 428-437 Litten, R. Z., et al. (2010). Alcoholism: Clinical and Experimental Research 34(6): 955-967 Pragst, F., et al. (2001). Forensic Science International 121(1-2): 76-88 Urinary 5-hydroxytryptophol (5-HTOL) and 5-hydroxyindole acetic acid (5-HIAA)
• Serotonin metabolites whose ratio is altered by EtOH • 5-HTOL and 5-HIAA as alcohol • Technically demanding and no accepted standards • 10-hour detection window • False (+): serotonin-rich foods, bananas, pineapples, disulfiram, cyanamide • May be useful for monitoring recent, low levels of EtOH (sobriety)
Stephanson, N., et al. (2005). Journal of Chromatography B 816(1): 107-112. Borucki, K., et al. (2007). Alcoholism: Clinical and Experimental Research 31(3): 423-42 www.wardelab.com Urinary ethyl glucuronide and ethyl sulfate
• Formed in different pathways • Concurrent use increases sensitivity • Highly correlated (Spearman’s r=0.84)
Wurst, F. M., et al. (2006). Addiction 101(2): 204-211 Ethyl glucuronide
• Alcohol metabolite, well-characterized, widely used • Positive in urine within hours • Detection window = 5 days • Fast, inexpensive, available
• Sensitivity 76%, specificity 93% (Stewart ACER 2013) • Bacteria in urine false (+) and false (-) • Household and food products false (+) • renal function detection time • Detectable in hair for about 90 days • Not widely used or available • Less acceptable to patients
Borucki, K., et al. (2007). Alcoholism: Clinical and Experimental Research 31(3): 423-42 Høiseth, G., et al. (2012). Alcoholism: Clinical and Experimental Research 36(7): 1148-1151 Sterneck, M., et al. (2014). Liver International 34(3): 469-476 Walsham, N. E. and R. A. Sherwood (2012). Annals of clinical biochemistry 49(2): 110-117 Walsham, N. E. and R. A. Sherwood (2014). Advances in Clinical Chemistry Volume 67: 47-71 Urinary ethyl glucuronide
• Staufer et al 2011
• 141 txp candidates & recips
• 308 clinical encounters
• “Urinary EtG was the best independent predictor of alcohol consumption in univariate and multivariate analysis” Urinary ethyl sulfate
• Minor metabolite • Unaffected by bacterial contamination • availability than uEtG • renal function (GFR<60) detection time
• Sensitivity 82%, specificity 86% (Stewart ACER 2013) • Some false (+) • mouthwash use (unlikely with routine use), hand sanitizer gels • 1-2 day detection window
Høiseth, G., et al. (2012). Alcoholism: Clinical and Experimental Research 36(7): 1148-1151 Walsham, N. E. et al (2014). Advances in Clinical Chemistry. 67: 47-71 Wurst, F. M., et al. (2006). Addiction 101(2): 204-211 Phosphatidylethanol
• Accumulating lipid species only when EtOH in serum • PEth 16:0/18:1 • Whole or dried blood samples (mild discrepancies, Spearman’s r=0.9) • Highly sensitive (97-99%) and specific (100%) • Long detection window (up to 28 days) • Low consumption detectable for up to 12 days • Moderate-to-heavy consumption detectable up to 3 weeks • Validated in liver disease • Quantitative values may be correlated with different EtOH quantities
Nguyen, V. L., et al. (2018). Alcoholism: Clinical and Experimental Research 42(2): 238-243 Fleming, M. F., et al. (2017). Alcohol Clin Exp Res 41(4): 857-862 Piano, M. R., et al. (2015). Alcohol and Alcoholism 50(5): 519-525 Schröck, A., et al. (2017). Drug and Alcohol Dependence 178: 80-86 Phosphatidylethanol
• Detection ability for varying levels of chronic alcohol consumption • Cutoffs of 20 ng/mL vs 200 ng/mL (green dashed line: excessive drinking) • Men and women vary in peak PEth and duration (men: blue, women: pink)
Simon TW et al Reg Toxicology & Pharmac 2018 (94) No misuse Moderate Severe by AUDIT misuse misuse “But doctor, I didn’t drink!”
• Vanilla, almond, or lemon extracts can be 70- to 160-proof • Rubbing alcohol (isopropyl): 60-75% • Perfume, cologne: 50-99%
www.wardelab.com Take home points
• Biomarkers do not make diagnoses or replace thoughtful clinical examination and reasoning
• Serum markers of alcohol’s effects (AST:ALT, GGT, etc.) are non-specific but can aid in identifying drinking patterns
• Alcohol metabolites (EtG) perform well as markers of recent drinking and are widely available
• As a send-out, PEth is an emerging indirect marker querying more remote and chronic alcohol exposure Designer Drugs
G. Scott Winder MD MSc University of Michigan Clinical case
33yo male veteran with history of depression and OUD presenting to ER with paranoia and agitation.
Medical workup: mild HTN, normal thyroid, NSR on EKG, elevated CPK (363 U/L), normal UDS, neg serum EtOH, LFTs normal. Received Haldol 5mg and Ativan 2mg.
Psychiatry consultation: pt appears agitated, frightened, and tremulous. No evident AH/VH. Low participation in interview. No collateral available. Admitted to inpatient service. Background & definitions
• Undetected in comprehensive tox screens
• Detection needs authentic material but new drugs quickly supplant the last
• Sparse literature
• Will be an ongoing problem
• Manufacturers want to evade detection
Goldfrank's Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015 Past media attention
Sunday, May. 29, 2011 'Bath Salts': Evil Lurking at Your Corner Store By Mehmet Oz
I checked my disguise in the mirror: a ski hat and sunglasses did a good job of concealing my identity, even if I did look absurd. Normally I would have shared a laugh with my staff about this, but what we were doing that day was hardly funny. A few blocks away, at a tobacco shop, I spent $80 to buy several packages of drugs that when snorted have a similar effect as ecstasy but are much more toxic. There was no back-alley drug dealer; there were no lowered voices or code words — just a small-business owner making a sale. I am telling you today, first as a father and then as a doctor, that the ease of that transaction chilled me. Kids everywhere are in danger from this substance, and the threat is legal, cheap and very deadly.
Bath salts (also nicknamed plant food) is slang for a group of products that contain methylenedioxypyrovalerone (MDPV) or mephedrone — stimulant hallucinogens that prevent the reuptake of norepinephrine, dopamine and serotonin. Keeping your brain drenched in these feel-good chemicals can lead to euphoria — but also to seizures, tachycardia, paranoia, hallucinations, violence and death. A precursor to MDPV was developed in the 1960s as an antifatigue medication, but it was too dangerous for Synthetic cathinones – “bath salts”
Amphetamine Cathinone
Bupropion
Mephedrone MDPV Synthetic cathinones – “bath salts”
• Structurally similar to amphetamine
• High potency = concentrations below detection cutoffs
• No current medical indication (Schedule I)
• Highly inconsistent content
• Contaminants
Winder, GS et al. Journal of substance abuse treatment 44.1 (2013): 42-45. Synthetic cathinones – “bath salts”
• “Bath salts” panels are send-outs • Delayed results • GC-MS and LC-MS • MDPV (dimethylenyl-methyl-MDPV) • Mephedrone (4-methylmethcathinone) • 3-bromomethcathinone (3-BMC) • Fluphedrone (3-fluoromethcathinone) • Identified in hair samples, blood, urine, stomach contents • Clinical meaning of drug levels is unknown • Cathinone users frequently have other drugs in their system
Winder, GS et al. Journal of substance abuse treatment 44.1 (2013): 42-45. Synthetic cannabinoids – “spice, K2” Synthetic cannabinoids – “spice, K2”
• >100 artificial CB agonists Tetrahydrocannabinol • “legal highs” • Inert plant matter sprayed with drug
• Not commonly detected on urine JWH-018 cannabinoid screens • low concentrations (high potency) • low assay cross-reactivity HU-210
Winder, GS et al. Federal pract 31.11 (2014): 22-27 Images from wikipedia.com Example of ARUP send-out results Take home points
• Individual designer drugs (DD) will change but the concept is here to stay
• Suspect DD in a patient with compelling history, known substance use, neg tox, and inconclusive medical workup
• DD testing is unlikely to be helpful for acute management but obtaining it can be another data point in long term care Nicotine & Metabolites Filza Hussain MD Stanford University Case
• 46 year old Vietnamese man with HCV cirrhosis • undergoing LTE • On initial labs Urine Cotinine of 2800 ng/ml • Patient counselled for smoking cessation • Prescribed NRT patches • 3 months later Random urine drug test • Urine Cotinine of 1213 ng/ml • Patient avers he has stopped smoking but his friends all smoke around him Nicotine& metabolites
Smoking: Why do we care? Nicotine Delivery Systems • A preventative cause of cardiovascular, pulmonary, oncological and perioperative complications. • Ill effects of nicotine and tobacco have been well established • Surgical programs have guidelines for periods of abstinence for improved outcomes • Greater implications in the transplant population with increased risk of perioperative problems such as sepsis and prolonged hospital stay. • Later complications are varied and include graft dysfunction and possible graft loss • The lungs, hearts, and kidneys from donors who have smoked are associated with worse recipient survival and increased morbidity
Corbett, C., Armstrong, M. J., & Neuberger, J. (2012). Tobacco Smoking and Solid Organ Transplantation. Transplantation Journal, 94(10), 979-987 Vaping and e-cigarettes
• Electronic Nicotine Delivery Systems ( ENDS) • Battery-powered electronic nicotine delivery systems that simulate smoking by vaporizing nicotine-containing solutions • Adjusted national sales increased from $11.6 million in 2010 to $751.2 million in 2016 • Tobacco industry brands entered the market and eventually captured 87.8% of share by 2016 • Considered by consumers to be safer than combustible cigarettes • Aerosols contain nicotine in variable amounts • Increase in the number of calls to poison control • Harmful nanoparticles, carbonyls, and toxic volatile organic compounds such as benzene and toluene • Knowledge of the long-term toxicological and immunological effects of e-cigarette (e-cig) aerosols remains elusive due to the relatively short existence of vaping • prolonged exposure to some constituents of e-cig aerosols might result in respiratory complications such as asthma, chronic obstructive pulmonary disease and inflammation
Cantrell, J. et. al (2018). History and Current Trends in the Electronic Nicotine Delivery Systems Retail Marketplace in the United States: 2010–2016. Kaur, G., Pinkston, R., Mclemore, B., Dorsey, W. C., & Batra, S. (2018). Immunological and toxicological risk assessment of e-cigarettes Nicotine and its Metabolites
• eCO and thiocyanate are products of combustion- not applicable for detecting smokeless tobacco use • Nicotine and cotinine are nearly optically pure S-isomers • Cotinine will be positive in patients on NRT • Substances that are present in tobacco, measurable in biological fluids, but not derived metabolically from nicotine would be valuable for validating tobacco abstinence in persons undergoing NRT • Tobacco contains 4–45% R-isomers of the minor alkaloids nornicotine, anabasine, and anatabine Nicotine and its Metabolites: Detection
Detection Method Comments Self-report of smoking limited utility due to compromised accuracy Expired air carbon monoxide (eCO) objective measure, but short half-life detection window of less than 24 hours. Only provides an indication of recent smoking exposure
Thiocyanate (a metabolite of hydrogen cyanide) less specific due to confounding by dietary and carboxyhemoglobin environmental sources Cotinine measured in saliva, plasma, urine, and hair Immunoassay, test strips a quantitative, daily measure of exposure to tobacco non-Hispanic blacks metabolize cotinine more slowly than do non-Hispanic whites Benowitz et al., 1999; Perez-Stable et al., 1998 Nicotine Detection: Cotinine Cut off levels Metabolite Specimen Detection Window Comments Nicotine Urine <24 hours Dependent on Urine pH Cotinine Blood Up to 7 days after nicotine use Invasive but can be obtained with other tests 10–20 ng/mL Cotinine Urine 4-7 days after last use Upto 20ng/ml in SHS
Cotinine Saliva 1-2 days after last use In expensive, Non Invasive Cut off for active smoking 10–25 ng/mL
Cotinine Hair 30-90 days Non Invasive, specimen tampering not possible No quick results Expensive
Anabasine Urine Identify Tobacco use rather than NRT
Nornicotine Urine Identify Tobacco use rather than NRT
An optimal cotinine cutoff value for distinguishing true smokers from true nonsmokers shows a lack of standardization among studies. Kim, S. (2016). Overview of Cotinine Cutoff Values for Smoking Status Classification Nicotine and its Metabolites: Analyzing Results
Metabolites in Urine Nontobacco user with Nontobacco user with Tobacco User (ng/ml) no passive exposure passive exposure
Nicotine <5 <20 1000-5000
Cotinine <5 <20 1000-8000
Anabasine <2 <2 10-500
Nornicotine <2 <2 10-900 Urine Toxicology for Common Drugs of Abuse Akhil Shenoy MD MPH Columbia University Medical Center Where do we place the extra armor? False Negatives and False Positives
Sensitivity Cut off Levels Concentration Windows of detection Specificity Cross-reactivity
Urine screen availability (standard vs. add on) Confirmation, Liquid Chromatography/Mass Spectroscopy (LC/MS) CNS Stimulants Hallucinogenics Cocaine CNS Cannabinoids Amphetamines DMT (Ayahuasca) MDMA Depressants DXM Inhalants Cathinones (“bath salts”) Opiates Ketamine Caffeine Powder Synthetic Opioids LSD DXM or PCP Barbiturates Mescaline (Peyote) Benzodiazepines PCP (Rohypnol) Psilocybin (mushrooms) Salvia GHB Synthetic Cannabinoids SAHMSA 5 or NIDA 5
Initial test cutoff Confirmatory test Confirmatory test cutoff Initial test analyte concentration analyte concentration
Marijuana metabolites 50 ng/mL THC 15 ng/mL
Cocaine metabolites 150 ng/mL Benzoylecgonine 100 ng/mL Codeine/Morphine Morphine 2000 ng/mL 2000 ng/mL Opiate metabolites Codeine 2000 ng/mL Heroin metabolite 10 ng/mL 6-Acetylmorphine 10 ng/mL Phencyclidine 25 ng/mL Phencyclidine 25 ng/mL Amphetamines Amphetamine 250 ng/mL 500 ng/mL AMP/MAMP Methamphetamine 250 ng/mL MDMA 250 ng/mL MDMA 500 ng/mL MDA 250 ng/mL MDEA 250 ng/mL Point of Care Testing(POCT) Cocaine Assay Tests cocaine’s main metabolite: benzoylecgonine
Detection: 1-3 days
False Negatives: N/A
False Positives: Teas and foods made with coca plant leaves 1/8th of an Second hand smoke in children ounce Amphetamine Assay
Tests for Amphetamine and Methamphetamine
Detection: 2-4 days
False Negatives: N/A False Positive l-Methamphetamine (Vick’s inhaler), l-Deprenyl, Amantadine, Aripiprazole, Atomoxetine, Benzphetamine, Bupropion, Chlorpromazine, Chloroquine, Clobenzorex, Desipramine, Dextroamphetamine, Dimethylamylamine, Ephedrine, Fenfluramine, Fenproporex, Isometheptene, Isoxsuprine, Labetalol, Metformin, Methylphenidate, Methamphetamine, Mexiletine, MDMA, Phentermine, Procainmide, Promethazine, Pseudoephedrine, Phenylephrine Phenylpropanolamine, Quinacrine, Ranitidine, Ritodrine, Selegiline, Thioridazine, Trazodone, Trimipramine, Trimethobenzamide, Tyramine MDMA – add on assay Tests for methylenedioxymethamphetamine
Detection: 1-3 days False Negatives: N/A
False Positives: N/A Other Psychostimulants – No Assay
Cathines Cathinones and Substituted Cathinones
Khat “Bath Salts”
DXM Dextromethorphan “Robo-Trip” alpha PVP “flakka” Case 1 53 yo male, married, former welder, with HCV and alcohol liver disease. Cirrhosis since 2000s Daily beer (6-pack) 2005-2017. In remission since Jan 2017 hospitalization for decompensated cirrhosis and new AKI presenting for outpatient evaluation for liver transplant Alcohol use disorder, severe, in early remission.
IV heroin, remote. opioid use disorder, in sustained remission http://ww w.eventscr ibe.net/ars _test/ARS/ pollingPPT Meds: amlodipine, furosemide, labetalol, spironolactone, diazepam prn ?Key=QTBJ H
MSE: calm, pleasant, open. Motivated to live for his wife and 12 yo daughter, getting remarried next year. He acknowledged he had a problem that we described as severe alcohol use disorder.
Urine EtG was negative. Question 1
What is your clinical suspicion about the positive urinary toxicology?
A) Both the amphetamine and benzodiazepine screen were Labetelol false positives B) The amphetamine screen was a false positive but benzodiazepine was a true positive C) Both the amphetamine and benzodiazepine screen were true positives Opiate Assay Tests codeine and morphine
False Negatives: Semi-synthetic and Synthetic Opioids False Positives: Fluoroquinolones (Levofloxacin, Ciprofloxacin) Semi-Synthetic and Synthetic Opioids – add on assays
Oxycodone/oxymorphone Fentanyl Detection Time: 2-4 days Detection Time: 1-3 days
Buprenorphine Detection Time: 3 days
Methadone Detection Time: 3 days False positives: Diphenhydramine, Doxylamine, Quetiapine, Verapamil Benzodiazepines Assay Tests oxazepam CNS Depressants Benzodiazepines False negatives: Lorazepam, Clonazepam, Alprazolam False positives: Sertraline, Efaviranz
Barbiturates – Add on phenobarbital False positives: Ibuprofen, Naproxen
GHB – No Assay available Case 2 61 yo female photographer w HCV cirrhosis HCV in FSR. Referred for 2nd opinion
10 years with a psychopharmacologist. Wishing to switch care. Psychiatric conditions included anxiety, ADD, OCD, and bipolar disorder. No encephalopathy
MEDS: Gabapentin, Clonazepam 1.5mg qhs, Methylphenidate 60mg qam, Lamotrigine, Quetiapine, Ambien, tincture of Opium Question 2 Is the Methadone true positive?
MEDS Gabapentin Methylphenidate 60mg qam Clonazepam 1.5mg qhs Ambien Quetiapine tincture of Opium Lamotrigine Cannabinoid Assay
Detection Time: Single use: 1-3 days Moderate use (4x/week) 5-7 days Daily use 10-15 days Long-term heavy use >30 days
False Negatives: Synthetic cannabinoids
False Positives: Efavirenz, Ibuprofen, Naproxen, CBD? PCP Assay
Detection Time: 8 - 14 days
False Negatives: N/A
False positives: Diphenydramine (Benadryl) Tramadol (Ultram) Dextromethorphan Chlorpromazine Methadone Venlafaxine, O-desmethylvenlafaxine Ibuprofen Lamotrigine Other Hallucinogens Ketamine – add on assay or LC/MS LSD – add on assay or LC/MS Psilocybin (Psilocin) – send out LC/MS
DMT (dimethyltryptamine) Synthetic cannabinoids Dimitri, Ayahuasca K2, Spice Case 3
24 yo man presents to the ED with altered sensorium. He exhibits erratic, dissociative behavior, including hallucinations.
On physical exam he was in hypertensive urgency with a blood pressure of 209/118 mm HG and was diaphoretic. He was euphoric, hyperalert and inappropriately laughing.
Urine toxicology is positive for phencyclidine (PCP) and cannabinoids Question 3
Is the PCP true positive?
DXM Dextromethorphan “Robo-Trip” Beyond Urine
or
Hair, Nails, and more Take Home Points
1. Start with clinical suspicion
2. Assays are not perfect and not diagnostic
3. Get the confirmation GC/MS or LC/MS when needed
4. Call your hospital or clinic chemistry lab to learn what additional tests you can run, the turnaround time, and the costs Integrating Toxicology Into Clinical Care
J.J. Rasimas, M.D., Ph.D., F.A.P.M., F.A.C.M.T. Associate Professor of Psychiatry & Emergency Medicine C-L Fellowship & Service Director / Medical Toxicology Hennepin County Medical Center – Minneapolis, MN Concluding Theme = Lessons from Real Estate Making Use of Toxicology Data
• Where was the sample gathered ? • Where is the patient being seen ? • Is the patient being seen? • Where is the patient currently being cared for? • ED • Inpatient Hospital • Clinic ✮ • Where is the patient going next ? • Will you see the patient (here / there) again ? The Sample
• Inpatient consultation for a patient with no prior medical history • 42 y/o♀presented agitated and delusional • Urine screening positive for cocaine and THC • Mass spectrometry shows cocaine, its metabolite, and lidocaine • Patient will not speak to you • Does not appear to be perceptually disturbed • Refuses to interact
• If you can answer the trivia question, it might also give you a way in… Practical / Ethical considerations
• Many patients with drug use histories have trauma histories predating and then running concurrent with addiction • Gathering samples • Invasive Reliable • Deception protects and obstructs • Severity of illness demands sensitivity • Also points to a need for more astute, organized treatment In, then out…
• 30 y/o homosexual ♂with h/o IV use of opioids and stimulants • Profound maltreatment in his youth • Extended inpatient stay for endocarditis • Buprenorphine initiated and maintained • Norbuprenorphine 360 ng/mg Cr during hospital stay • After discharge, doing well for 3 months • Attending AA • No use reported or obvious relapse events • A f/u drug screen is done as part of outpatient monitoring Nothing…or all Specimen Validity Testing (SVT)
• Substitution is submission of a specimen that is not human urine or is from another person (a “clean” specimen) • Temperature, creatinine and specific gravity help determine whether a specimen has been substituted • Adulteration is the addition of chemicals to a urine specimen • Mask or destroy drugs / metabolites • pH testing can be informative • “Fake positive” the presence of a compound that “should” be present • Dilution • Intentional (drinking large amounts of water before providing a specimen) • Physiologic (e.g. diabetes) • Specific gravity +/- creatinine can help with validity Substitution 101
• Use another person’s • Make sure friend is “clean” • Report “shy bladder” or h/o sexual trauma as a reason to avoid being observed • Synthetic urine • Expensive $$$ • Lacks IgG
樂 Substitution 301 & 420 Chemistry 101 & 202
• Adulteration • Nitrates / nitrites, acids, bases, oxidizing / reducing agents • “Spiking”
• Dilution • Auto-dilution: drinking water • External dilution: adding water directly to sample • “Blue” toilet water • No flowing water in bathroom sink Be the professor:
• Temperature outside range (> 100 or < 90 deg F within 4 minutes) • Urine Cr < 20 mg/dL • Specific Gravity > 1.045 or < 1.030 g/mL Practical considerations
• Addiction is powerful • So is shame • So is hunger • So are the elements • So is money • Relationship is powerful • Based on common ground • Based on real regard • Detailed knowledge ADDED to caring may be the start of dialogue Ethical / Legal considerations
• Consent is still consent • Acute hospital testing occurs without it • What is done with those results must not be taken lightly • And in most jurisdictions… • “No, I will not run a drug test on your child because you want to know if he’s using...” • “Yes, I will obtain and use drug testing results to impose on your autonomy if you’re pregnant…” • Clinical samples and tests on them are not, themselves, forensic data • Special procedures / chain of custody • Fail to hold to these principles, and all that stuff about relationship is: UP IN SMOKE Transparency
• Since you know that drug tests do not confirm: • Use • Addiction • Abstinence • Admit it out loud – to patients • Tell the courts while you’re at it… • Speak plainly about why they are important • Proper care (medications and treatment plans, both) • Safety • Patient • Public • Larger interests, if they apply (e.g. organ transplants, employer / court decisions Patient encounters
• Patients feel insulted / infantilized / disrespected • Note the parallel experience of those close to them in their lives • Be ready for projective identification • Be ready for projective countertransference • Sometimes from the first visit, but especially in a longitudinal relationship • Doctors (most folks) don’t enjoy being lied to • Expectation of it may pollute relationships from the start • Experience of it may find us very quickly acting in (and/or out) • We are cast in the role of detective / law enforcement • Figuring stuff out is fun • Makes losing sight of caregiving easy The “Gotcha” Continuum Consulting encounters
• We are identified with our patients • Stigma / negative countertransference of other services toward addicts • And to those who specialize in helping them • Two useful options: • Acknowledge the emotions and attitudes with genuine feeling • Just be sure to move from “joining” to shift focus to what should be humanely done • Modeling of poise and equanimity for whatever comes at you • Better for more direct, inflexible attackers • Teach about the tests, their limitations, and ours • A stance somewhere in the range of Columbo & Jessica Fletcher • (Try to) maintain practical consistency between patients and teams Summary
• Addicts need doctors who care about them (1st) and are smart (close 2nd) • Attend to relationship right from the start • Even in the technical realm of toxicology lab testing • Location frames the utility of testing and its impact on relationship • Roles with patients and consultees are and should be different • One can still be a tox-testing expert to both
Acknowledgments
Timothy J. Wiegand, MD, FACMT, FAACT, DFASAM Mark A. Rapp, MD Questions & Discussion
Filza Hussain MD – Stanford University JJ Rasimas MD PhD FACLP – Hennepin County Medical Center Akhil Shenoy MD MPH – Columbia University G. Scott Winder MD MSc – University of Michigan