Richard C. Dart, MD, PhD Executive Director, RADARS System Denver Health and Hospital Authority

RADARS System 12 th Annual Scientific Meeting 95 Registrants Government 26 Academic 14 Industry/Pharma 28 Other 28 International Pre-Symposium International Landscape of Prescription Medication Misuse Betsy Nugent 2

RADARS System Scientific Advisory Board Principal Investigators Theodore J. Cicero, PhD Washington University in St Louis Steven P. Kurtz, PhD Nova Southeastern University Mark W. Parrino, MPA American Association for the Treatment of Drug Dependence Richard C. Dart, MD, PhD Rocky Mountain Poison & Drug Center, Denver Health Substance Abuse Experts Herbert D. Kleber, MD Columbia University Sidney Schnoll, MD, PhD PinneyAssociates George Woody, MD University of Pennsylvania Epidemiology/Biostatistics Nabarun Dasgupta, MPH Rocky Mountain Poison & Drug Center, Denver Health Law Enforcement John Burke Pharmaceutical Diversion Education, Inc.; International Health Facility Diversion Association 3

Petty died at 66 of "cardiopulmonary arrest due to: fentanyl, oxycodone, temazepam, alprazolam, citalopram, acetylfentanyl, and despropionyl fentanyl." Artist: Jason Mecier 4

ARS Question Which of these celebrities died from fentanyl contained in a counterfeit medication? Heath Ledger Michael Jackson Tom Petty Whitney Houston 5

Artist: Jason Mecier 6

What Happened in 2017? 8

2016 RADARS System Annual Meeting Deaths from Opioid Analgesics are Decreasing Natural & Semisynthetic Opioids, 2003 to 2015 NVSS Deaths per 100,000 population 6.5 5.5 4.5 3.5 2.5 1.5 0.5-0.5 Poison Center NVSS 2003 2004 2005 2006 2007 2008 2009 2010 2011 R=0.67 2012 2013 2014 2015 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 RADARS System Poison Center Program Deaths per 1,000,000 population Year **T40.2 Natural and semisynthetic opioids: oxycodone, morphine, hydromorphone, oxymorphone, others **RADARS System opioids: oxycodone, hydrocodone, morphine, hydromorphone, and oxymorphone. Deaths include cases followed to a known medical outcome whose death was related to the reported 9

Opioid Prescribing Declining Since 2010 80,000,000 Opioid Prescriptions Morphine Milligram Equivalents 80,000,000,000 70,000,000 70,000,000,000 60,000,000 60,000,000,000 Number of prescriptions 50,000,000 40,000,000 30,000,000 20,000,000 50,000,000,000 40,000,000,000 30,000,000,000 20,000,000,000 MMEs 10,000,000 10,000,000,000 0 0 Source: IQVIA National Prescription Audit, data extracted 2016-2018 10

National Vital Statistics Program, 2006-2016 10 9 8 NVSS Synthetic NVSS Deaths Per 100,000 population 7 6 5 4 3 2 1 NVSS Nat/Semi NVSS Nat/Semi w/o Heroin/Fent 0 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 11

Deaths from Prescription Opioids are Decreasing Substantially NVSS Deaths Per 100,000 population 10 9 8 7 6 5 4 3 2 1 0.16 0.14 NVSS Heroin T40.1 + Synth T40.4 0.12 0.1 0.08 NVSS Nat/Semi 0.06 NVSS Nat/Semi w/o Fent-Heroin 0.04 PC - Nat/Semi 0.02 PC Deaths Per 100,000 population 0 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 0 12

NEWS FROM RADARS SYSTEM 13

Mosaic Surveillance of Prescription Drug Abuse Acute Health Events 50 Poison centers 48 states 616,410 opioid cases 664,943 opioid mentions Non-Medical Use General population 30,522 adults; 50 states 3,693 cases with 38,996 opioid Mentions Entering Treatment Opioid Tx Program 115 programs; 37 states 79,299 respondents 266,082 Rx opioid mentions Drug Transactions Criminal Justice 664 agencies; 50 states 12,881 unique surveys >199,000 cases 171,179 opioid mentions StreetRx.com Entering Treatment SKIP 310 practices, 49 states 19,247 respondents 107,518 Rx opioid mentions Illicit Market Price StreetRx.com Users/Buyers, 50 states 90,396 price entries for an opioid Advanced Users/Targeted Studies RAPID Customized surveys to address special topics with patients who have sought treatment Web Monitoring > 150 million sites monitored > 197,000 posts coded for analysis 14 14

Poison Center Program All Opioids, Intentional Abuse, 2006-2017 0.8 0.7 0.6 Per 100,000 population 0.5 0.4 0.3 0.2 0.1 0 oxycodone, hydrocodone, hydromorphone, fentanyl, morphine, tramadol 15

Drug Diversion Program All Opioids, Diversion, 2006-2017 4 3.5 Per 100,000 population 3 2.5 2 1.5 1 0.5 0 20061 20063 20071 20073 20081 20083 20091 20093 20101 20103 20111 20113 20121 20123 20131 20133 20141 20143 20151 20153 20161 20163 20171 20173 oxycodone, hydrocodone, hydromorphone, fentanyl, morphine, tramadol 16

Treatment Center Programs Combined All Opioids, Abuse, 2006-2017 9 8 7 Per 100,000 population 6 5 4 3 2 1 0 20061 20063 20071 20073 20081 20083 20091 20093 20101 20103 20111 20113 20121 20123 20131 20133 20141 20143 20151 20153 20161 20163 20171 20173 oxycodone, hydrocodone, hydromorphone, fentanyl, morphine, tramadol 17

Poison Center Program API, 2006-2017 0.25 HC Per 100,000 population 0.2 0.15 0.1 Methadone 0.05 0 Oxycodone Fentanyl Hydrocodone Hydromorphone Morphine Oxymorphone Methadone Buprenorphine Bup Tramadol Tapentadol 18

Drug Diversion Program API, 2006-2017 1.8 HC Per 100,000 population 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 Methadone 0 Oxycodone Fentanyl Hydrocodone Hydromorphone Morphine Oxymorphone Methadone Buprenorphine Tramadol Tapentadol 19

Treatment Center Programs Combined API, 2006-2017 Per 100,000 population 3 2.5 2 1.5 Methadone 1 0.5 HC Oxycodone Fentanyl Hydrocodone Hydromorphone Morphine Oxymorphone Methadone Buprenorphine Tramadol Tapentadol 0 20

Changes in Prescription Drug Abuse, 2017 After substantial improvement from 2010 to 2016, abuse and diversion seem to have plateaued. Buprenorphine a concern? Generally safer than methadone Rescheduling of hydrocodone effective although seems to have affected oxycodone abuse Lots of room for improvement How do we do that without compromising the care of pain patients? 21

Poison Center Program Prescription Stimulant Rates, 2007-2017 0.14 0.12 Per 100,000 population 0.1 0.08 Methylphenidate Amphetamine 0.06 0.04 0.02 0 22

Drug Diversion Program Prescription Stimulant Rates, 2007-2016 0.4 0.35 Per 100,000 population 0.3 0.25 0.2 Methylphenidate Amphetamine 0.15 0.1 0.05 0 23

Poison Center Program Route of Administration, 3Q 2017 % Int. Abuse Cases 24

RADARS System Publications 2017-2018 1. Trends in intentional abuse or misuse of benzodiazepines and opioid analgesics and the associated mortality reported to poison centers across the United States from 2000 to 2014. 2. Comparative rates of mortality and serious adverse effects among commonly prescribed opioid analgesics. Drug Saf. 3. Racial/ethnic differences in prevalence trends for heroin use and non-medical use of prescription opioids among entrants to Opioid Treatment Programs, 2005-2016. Subst Use Misuse 4. Assessment of tapentadol API abuse liability with the RADARS System. J Pain. 5. Changes in misuse and abuse of prescription opioids following implementation of Extended-Release and Long-Acting Opioid Analgesic Risk Evaluation and Mitigation Strategy. Pharmacoepidemiol Drug Saf. 6. Understanding abuse of buprenorphine/naloxone film versus tablet products using data from ASI-MV substance use disorder treatment centers and RADARS System Poison Centers. J Subst Abuse Treat. 7. Law enforcement-derived data on gabapentin diversion and misuse, 2002-2015. Pharmacoepidemiol Drug Saf. 8. The demand side of the prescription opioid epidemic: does the initial source of opioids matter? Drug Alcohol Depend. 9. Increased use of heroin as an initiating opioid of abuse. Addict Behav. 10. Increases in self-reported fentanyl use among a population entering drug treatment. Drug Alcohol Depend. 11. Psychoactive substance use prior to the development of iatrogenic opioid abuse: analysis of opioid abusers. Addict Behav. 12. Relative preferences in the abuse of IR vs.er opioids in treatment-seeking opioid abusers. Pharmacoepidemiol Drug Saf. 13. Do abuse deterrent opioids work? J Opioid Manag. 14. Patterns of prescription drug use/misuse in Spain: The European Opioid Treatment Patient Survey. Heroin Addict Relat Clin Probl. 15. Medical outcomes associated with prescription opioid abuse via oral and non-oral routes of administration. Drug Alcohol Depend. 16. Changes in drug use patterns reported on the web after the introduction of ADF OxyContin: findings from the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System Web Monitoring Program. Pharmacoepidemiol Drug Saf. 25

National Poison Data System (NPDS) 2007-2014 Generic Code Intentional Abuse Benzodiazepines 51275 Dextromethorphan 18182 Amphetamines 13833 Carisoprodol 8633 Atypical Antipsychotics 8556 Other Sedative/Hypnotic/Anti-Anxiety or Anti-Psychotic 8150 Diphenhydramine 5927 Other SSRI 5185 Other Antihistamines 5155 Methylphenidate 3662 Other Antidepressant 3173 Trazodone 3124 Other Muscle Relaxant 2989 Cyclobenzaprine 2948 Gabapentin 1373 Phenothiazines 1288 Amitriptyline 1271 Clonidine 1159 26

Drug Diversion Program Gabapentin, 2012-2015 Buttram ME, Kurtz SP, Dart RC, Margolin ZR. Law enforcement-derived data on gabapentin diversion and misuse, 2002-2015. Pharmacoepidemiol Drug Saf 27

New Fentanyl Cases are Due to Illicit Fentanyl Identified Fentanyl UN-identified Fentanyl Cicero TJ, Ellis MS, Kasper ZA. Increases in self-reported fentanyl use among a population entering drug treatment: the need for systematic surveillance of illicitly manufactured opioids. Drug Alcohol Depend. 28 28

Summary 1. Abuse of prescription stimulants and other non-opioid drugs may be increasing 2. Non-oral routes of abuse surprisingly high for prescription stimulants Abuse of other drugs is on the rise Illicit fentanyl is our biggest challenge 29

Survey of Non-Medical Use of Rx Drugs (NMURx) Coverage UK: 3Q14 Singapore: 3Q15 US, Canada: 3Q16 France, Italy: 2Q17 Germany, Spain: 4Q17 30

Survey of Non-Medical Use of Prescription Drugs (NMURx) An online, cross-sectional survey that assesses prescription drug use in the general adult population 10,000-30,000 unique individuals twice annually Same survey Canada United Kingdom Germany France Spain Italy 31

Survey of Non-Medical Use of Prescription Drugs (NMURx) and National Survey of Drug Use and Health (NSDUH) NMURx 2016 NSDUH 2015 Weighted N=247,773,709 Weighted N=242,801,072 Characteristic % (95% CI) % (95% CI) 18-25 yrs 13.9 (13.4-14.4) 14.4 (14.1-14.7) 26-34 16.5 (16.1-16.9) 15.8 (15.4-16.2) 35-49 24.4 (23.9-24.9) 24.9 (24.3-25.4) 50-64 25.9 (25.4-26.4) 25.7 (25.0-26.4) 65+ 19.3 (18.8-19.7) 19.2 (18.6-19.9) Gender - Female 51.3 (50.7-51.9) 51.8 (51.1-52.5) Race/Ethnicity Non-Hispanic White 77.1 (76.6-77.7) 64.7 (64.1-65.4) Non-Hispanic Black 7.2 (6.8-7.5) 11.8 (11.4-12.2) American Indian/Alaskan Native 0.6 (0.5-0.7) 0.5 (0.4-0.6) Non-Hispanic Asian 3.6 (3.4-3.8) 5.5 (5.1-5.9) Hispanic 8.9 (8.5-9.2) 15.6 (15.1-16.1) Unknown 5.9 (5.6-6.2) NA Student enrollment is defined by NMURx as attending any type of college or university in the past 3 months; it is defined by NSUDH as any respondents currently enrolled in a college or university. Substance abuse treatment is defined by NMURx as ever sought professional help for substance abuse; it is defined by NSDUH as ever received treatment or counseling designed to help reduce or stop alcohol or drug use (respondents not asked question due to skip logic were classified as no treatment). 32 32

Survey of Non-Medical Use of Prescription Drugs (NMURx) and National Survey of Drug Use and Health (NSDUH) Residential Region NMURx 2016 NSDUH 2015 Northeast 17.9 (17.4-18.4) NA Midwest 21.1 (20.6-21.6) NA South 37.5 (36.9-38.1) NA West 23.5 (23.0-24.0) NA Total Household Income < $20,000 12.4 (12.0-12.8) 17.9 (17.3-18.4) $20,000-49,999 29.5 (29.0-30.1) 30.0 (29.4-30.7) $50,000 52.2 (51.6-52.8) 52.1 (51.4-52.8) Unknown 5.9 (5.6-6.2) NA Student Enrollment 11.1 (10.7-11.6) 8.4 (8.1-8.7) Current Healthcare Professional 5.1 (4.9-5.4) NA Served in Armed Forces 10.6 (10.3-10.9) 9.1 (8.7-9.6) Lifetime Substance Abuse Treatment 6.3 (6.0-6.6) 6.2 (5.9-6.5) 34 34

Survey of Non-Medical Use of Prescription Drugs (NMURx) and National Survey of Drug Use and Health (NSDUH) 70 60 % Respondents 50 40 30 20 NMURx NSDUH 10 0 NA NA 35 35

NMURx: Opioids, BDZ, Stimulants, GABA, Illicit Drugs, 2017 Q3 80 70 60 % 50 40 30 20 10 0 36 36

Non-Medical Use Around the World, 2017 90 80 70 % Respondents 60 50 40 30 20 10 0 Pain Reliever Use Pain Reliever NMU 37

Non-Medical Use Around the World, 2017 12 10 % Respondents 8 6 4 Rx Stim Use Rx Stim NMU 2 0 38

2017 Program Effectiveness of ADFs in the Real World Richard C. Dart, MD, PhD Executive Director, RADARS System, Denver Health and Hospitals Professor, University of Colorado School of Medicine Abuse Deterrent Formulations of Prescription Opioid Analgesics Hon. Earl Buddy Carter U.S. Representative (R-GA, 1st District) 39

2017 Program Understanding Changes in the US Heroin Market: Notes from the Field Dan Ciccarone MD, MPH Professor of Family and Community Medicine, UCSF Principal Investigator, Heroin in Transition Study (NIH/NIDA) The Illicit Injection of Prescription Opioids Risks and Rewards Jon E. Zibbell, PhD Senior Public Health Scientist Behavioral Health, RTI International 40

2017 Program Getting to Category IV FDA s Current Approach to the Postmarket Evaluation of Opioid Analgesic Products with Properties Intended to Deter Abuse Tamra E. Meyer, PhD, MPH Lead Epidemiologist, Division of Epidemiology II, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, Food and Drug Administration A Causal Approach to Understanding Abuse in the Community Nabarun Dasgupta, MPH, PhD Senior Scientist RADARS System, Denver Health and Hospitals John Schwarz, PhD Director of Biostatistics RADARS System, Denver Health and Hospitals 41

2017 Program Thinking Outside the Opioid Box: Non-Opioid Pharmaceutical Abuse Janetta L. Iwanicki, MD Associate Medical Director Rocky Mountain Poison & Drug Center, Denver Health and Hospital Authority Panel Discussion and Summary 42

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