3/17/2019 Direct biomarkers of alcohol consumption in professionals health programs Scott Teitelbaum, FAAP, DFASAM Pottash Professor in Psychiatry and Neuroscience Department of Psychiatry University of Florida Division Chief of Addiction Medicine Medical Director, Florida Recovery Center Special Thanks to Colleagues Dr. Gary Reisfield and Dr. Shannon Large Objectives • Name three direct biomarkers of alcohol consumption. • Describe the temporal windows of detection for alcohol and its direct biomarkers. • Identify the sources of clinical false positive and clinical false negative results in alcohol biomarker testing. • Identify the most commonly observed direct alcohol biomarker in participants and new evaluees in Florida’s professionals health programs. 1 3/17/2019 09/23/15 AlcoholUnchanged inmetabolism breath, urine, sweat ≤5% Ethanol ≥95% Alcohol dehydrogenase (ADH) Acetaldehyde Aldehyde dehydrogenase (ALDH) Acetate Adapted from: Karch S. Drug Abuse Handbook, 2007 BrAC monitoring 2 3/17/2019 BrAC and zero order kinetics .08 After 1 h .065 After 2 h .050 After 3 h .035 After 4 h .020 After 5 h .005 TAC Monit oring 3 3/17/2019 Unchanged in breath, urine, sweat ≤5% ≤0.1% Ethyl glucuronide (EtG) ≤0.1% Ethanol Ethyl sulfate ≥95% Alcohol dehydrogenase (EtS) (ADH) Acetaldehyde Aldehyde dehydrogenase (ALDH) Acetate Adapted from: Karch S. Drug Abuse Handbook, 2007 Urinary EtG/EtS limitations: 1 EtG EtS 1. Incidental exposures 1. Incidental exposures “Clinical false 2. UTI: E. coli * positive” 1. Dilution 1. Dilution “Clinical false 2. UTI: E. coli (with β-glucuronidase) negative” C. sordellii (with β-glucuronidase) 3. UGT 1A1 polymorphism (?) *In presence of alcohol (i.e., alcohol in urine or yeast (e.g., Candida albicans) + glucose) 4 3/17/2019 EtG/EtS limitations: 2 Alcohol dose group Low ( n=18) Medium ( n=18) High ( n=17) Target BAC (g/dL) 0.02 0.08 0.12 EtOH dose, mean (g) 26.3 57.8 78.8 Number of standard drinks 2 4 6 Peak BAC (g/dL) 0.03 0.09 0.14 89K 200K 11K ng/mL ng/mL ng/mL Alcohol dose group Low ( n=18) Medium ( n=18) High ( n=17) EtG , mean time (hrs) to final 22 ± 5 32 ± 10 37 ± 12 positive @ 100 ng/mL EtG , mean time (hrs) to final 12 ± 5 23 ± 3 26 ± 7 positive @ 500 ng/mL Jatlow PI, et al. Alcohol Clin Exp Res 2014;38:2056-2065 5 3/17/2019 Suggested EtS cut-off concentrations to detect any alcohol consumption [EtG] 4 Suggested EtG cut-off concentrations to detect any alcohol consumption • Anton (2014): • 100 ng/mL for clinical applications • 500 ng/mL for forensic applications • Jatlow (2014): 100 ng/mL or 200 ng/mL for clinical trials • Lowe (2015): 200 ng/mL for clinical and research purposes • McDonell (2015): • 100 ng/mL for clinical and research purposes • 200 ng/mL for when “minimizing false positive results is essential” • SAMHSA (2012): • 100 ng/mL for confirmation of total abstinence • 100-1,000 ng/mL indicates ethanol consumption or incidental exposures • >1,000 ng/mL confirms ethanol consumption Unchanged in breath, urine, sweat ≤5% ≤0.1% Ethyl glucuronide (EtG) ? ≤0.1% Phospholipase D (PLD) Phosphatidylethanol Ethanol (PEth) Ethyl sulfate ≥95% Alcohol dehydrogenase (EtS) (ADH) Acetaldehyde Aldehyde dehydrogenase (ALDH) Acetate Adapted from: Karch S. Drug Abuse Handbook, 2007 6 3/17/2019 Phosphatidylcholine choline water ethanol PLD choline choline ethanol Phosphatidic acid Phosphatidylethanol (PEth) Adapted from: Isaksson A, et al. Drug Testing and Analysis 2011; 3:195-200 PEth 16:0/18:1 Phosphatidyl ethanol 7 3/17/2019 Daily alcohol consumption n=44 Grams/day Drinks/day Women 16-16.5 1.15 Men 32-33 2.3 n=23 n=21 14 (<3.5-183) ng/mL <3.5 (<3.5-25) ng/mL 13 (<3.5-84) ng/mL 16 (5-120) ng/mL Kechagias S, et al. Alcohol and Alcoholism 2015;50:399-406 100 ng/mL 35 ng/mL 20 ng/mL Kechagias S, et al. Alcohol and Alcoholism 2015;50:399-406 8 3/17/2019 Piano MR, et al. Alcohol Alcohol 2015;50:519-525 Classification Definitions Abstainers (n=23) ≤1 drink in past month M: ≤3 drinks, ≤ 2x/week Moderate drinkers ( n=22) F: ≤2 drinks, ≤ 2x/week M: ≥ 5 drinks, ≥ 2x/week Binge drinkers* ( n=58) F: ≥ 4 drinks, ≥ 2x/week *Average number of past month binges: 7.2 ± 4 Average number of drinks per last binge: 8.3 ± 2 (range: 4-13) 4.1 drinks/week 16.5 drinks/week Piano MR, et al. Alcohol Alcohol 2015;50:519-525 9 3/17/2019 Our conclusions based on extant literature • PEth 20 theoretically offers perfect specificity for alcohol consumption • There are large inter-individual variations in PEth kinetics • PEth 20 can theoretically be detected for >4 weeks after last use • One cannot determine time/quantity of last drink from PEth concentration • Negative PEth 20 ≠ proof of alcohol abstinence • Negative PEth 20 is compatible with: • Alcohol abstinence • Daily low-risk (1-2 drinks/day) alcohol consumption • Positive PEth 20 disproves abstinence • Positive triple-digit PEth indicates heavy alcohol consumption The roles of phosphatidylethanol (PEth), ethyl glucuronide (EtG), and ethyl sulfate (EtS) in identifying alcohol consumption among participants in professionals’ health programs Reisfield G, University of Florida, Psychiatry Teitelbaum S, University of Florida, Psychiatry Morrison D, University of Florida, Psychiatry Large S, University of Florida, Psychiatry Jones J, United States Drug Testing Laboratories Inc 1,040 IMEs • uEtG, uEtS, PEth measured • ≥1 positive results 57 194 On contract New evaluations 10 3/17/2019 Percentage of IMEs with positive results at PEth 20 and/or different EtG/EtS cutoff concentrations On contract New evaluations Mdn: 58 ng/mL Mdn: 83 ng/mL Mdn: 688/47 ng/mL Mdn: 1,842/218 ng/mL Mdn: 3,567 ng/mL 153 40 Mdn: 1,384 ng/mL 120 26 58 4 Evaluees with a single positive biomarker Mdn: 51 ng/mL Mdn: 41 ng/mL 31 73 12% Oncontract 19 EtS100 Percentage of PEth 20 - and EtGEtG 500100/EtS/EtS1 25 -positive participants according to00 reason for referral n=57 100% Mdn: 51 ng/mL Mdn: 69 ng/mL 90% 81% 80% 70% 65% 58% 60% 50% Mdn: 310/40 ng/mL Mdn: 687/62 ng/mL 40% 26% 30% 27% 20% 10% 3% Oncontract 0% Alcohol-related referral (n=31) Non-alcohol-related referral (n=26) PEth EtG100/EtS25EtG500/EtS100 11 3/17/2019 Percentage of PEth 20 - and EtGEtG 500100/EtS/EtS1 25 -positive participants according to alcohol00 use disorder history 100% Mdn: 55 ng/mL Mdn: 122 ng/mL n=57 90% 86% Mdn: 310/40 ng/mL Mdn: 541/41 ng/mL 80% 76% 70% 60% 50% 43% 40% 30% 28% 20% 14% 11% 10% 0% Oncontract History of alcohol use disorder (n=36) No history of alcohol use disorder (n=21) PEth EtG100/EtS25EtG500/EtS100 Role of PEth in the IME PEth providing essential information 100% 90% 80% 70% 60% 50% 6 10% 40% 30% 20% 27 47% 10% 0% Oncontract PEth (+) PEth (-) IMEs with hair EtG 20 testing On contract New evaluations 16 50 31 6 15 1 12 3/17/2019 Conclusions 1. There is no single ideal biomarker for measuring alcohol abstinence 2. For detecting any recent alcohol use, PEth was the single most important biomarker, but… 3. For detecting any recent alcohol use, PEth combined with EtG/EtS had the greatest yield. 4. With regard to urinary biomarkers, traditional EtG 500 -only screening would have left most very recent alcohol consumption undetected. The greatest yield necessitates EtS testing. 5. Based on very limited evidence, hair EtG 20 offered the lowest yield for detecting alcohol consumption. 6. Best use of biomarkers requires history (days), history (weeks), history (months)! Additional talking points • Roles of PEth • In PHP • Early after +EtG • Random • In treatment • Early • Role of mobile BrAC monitoring tools 13.