Drug Abuse and Addiction in America: Challenges and Opportunities

Kurt Rasmussen, Ph.D. Director Division of Therapeutics and Medical Consequences National Institute on Drug Abuse Disclosures • No disclosures 2003

+

2017

• SOURCE: National Center for Health Statistics, National Vital Statistics System, mortality data (http://www.cdc.gov/nchs/deaths.htm). • SUGGESTED CITATION: Rossen LM, Bastian B, Warner M, Khan D, Chong Y. Drug poisoning mortality: United States, 2003–2017. National Center for Health Statistics. 2019. (Available from: https://www.cdc.gov/nchs/data- visualization/drug-poisoning-mortality/). Prescriptions: Waves Opioid Crisis: 1991-2011 Overdose Fatalities

250 35000 219 210 201202 200 192 30000 180 Other Synthetic 169 , 158 151 25000 31,335 150 139144 131 120 109 20000 , 14,996 96 100 100 86 91 Prescriptions (millions) Prescriptions 78 80 76 15000

50 10000 Natural and Semi-Synthetic

0 5000 Opioids, 12,552

91 92 93 94 95 96 97 98 99 01 02 03 04 05 06 07 08 09 10 11

2000 0

IMS’s Source Prescription Audit (SPA) &

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 Vector One®: National (VONA) 1999 SM HELPING to END ADDICTION LONG-TERM (HEAL) Initiative

ENHANCING MANAGEMENT Advance Effective Accelerate Treatments For Discovery And Pain Through Development Of Clinical Research Pain Treatments IMPROVING TREATMENTS Expand Enhance Therapeutic FOR MISUSE AND Treatments for Options ADDICTION Infants with NAS/NOWS Develop New and Improved Optimize Prevention & Effective Treatment Treatments Strategies NIH HEAL Initiative Improving Prevention and Treatment for Opioid Misuse, OUD and Overdoses

Expand Therapeutic Prevention Options

Implementation Knowledge Gaps Science

t Full

Medications c

e (: Daily Dosing)

f f

for Opioid Use E Partial Agonist

d i

o (: 3-4X week) i

Disorder p Antagonist O (MOUD) Log Dose (: ER 1 month) Extended Release (ER) Formulations Facilitate Use in Health Care & Justice Settings and Improve Compliance

Mu Antagonist: NALTREXONE Mu Partial Agonist: BUPRENORPHINE

SUBLOCADE™ Vivitrol® (Buprenorphine ER), Once-Month Injectable Once-month Injection FDA Approval 11.30.2017

Median % Opioid-Negative Urines for 24 weeks 100% CAM2038 Subcutaneous 80% Buprenorphine ER: 60% Once-Week Injection 40% Once-Month Injection

20%

0% PROBUPHINE® Percent of Weekly Urine Tests Urine Weekly of Percent PLACEBO ER-NTX 6 months implant Placebo: N=124 ER-NTX: N=126 Krupitzky et al., Lancet 2011 OUD pipeline BEFORE HEAL

Early Preclinical Late Preclinical Phase I Phase Ib Phase II Phase III New Formulation Time to Launch: >12 yrs 10-12 yrs 6-10 yrs 5-9 yrs 4-6 yrs 3-5 yrs <3 yrs ANS6637 Guanfacine ALDH2 inhibitor a2 adren agonist C4X3256 OX-1 antagonist NMDA antagonist Mor, Her, Oxy, Semiglutide Hydro vaccine GLP-1R agonist Oxy/ Lorcaserin nano-vaccine 5HT2c agonist Fentanyl Heroin Vaccine Tradipitant vaccine NK-1 VDCC blocker antagonist Heroin/Fent vaccine Hi-dose nasal spray Fentanyl mAb

9 OUD pipeline AFTER HEAL

Early Preclinical Late Preclinical Phase I Phase Ib Phase II Phase III New Formulation Time to Launch: >12 yrs 10-12 yrs 6-10 yrs 5-9 yrs 4-6 yrs 3-5 yrs <3 yrs DM24 SBI-553 ITI-333 KLS13019 ANS6637 Guanfacine Pregab + Lofex Olani LAAM MOR/DOR het NT-1 biased MOR PA/5HT2a CBD analogue ALDH2 inhibitor a2 adren VDCC inh/a2 6 mo naltr Oral, re-intro antagonist PAM antagonist agonist agonist implant PZM21 NAN/NAQ PF5190457 C4X3256 Ketamine BICX102 Naltrexone MOR biased MOR implant GHS1aR antag OX-1 antagonist NMDA 3 mo naltr 1 yr implant agonist modulator MOR antag antagonist implant MOR biased GPR151 N0RS-033 Mor, Her, Oxy, Semiglutide Suvorexant OPNT003 Brixadi agonist antagonist Nalmefene Hydro vaccine GLP-1R agonist OX-1/2 Nasal Bupr 1 wk/1 prodrug antagonist nalmefene mo inj Oxy/Fentanyl AT-121 LYN-014 NYX-783 Cannabidiol Lorcaserin Bupren/Nalox AP003 nano-vaccine NOP/MOR Long acting NMDA 5HT2c agonist Oral, long Mlt-dose nlx partial agonist methadone modulator acting nasal spray Fentanyl PTPRD KNX100 Heroin Vaccine Tradipitant Gabapentin Naltrexone AP004 vaccine inhibitor Unknown NK-1 VDCC blocker 2 mo injection Nlx prefilled mechanism antagonist syringe Heroin/Fent R-methadone AP007 NP10697 AZD4041 ASP8062 Naltrexone Naloxone vaccine prodrug Extd-release GluN2B OX-1 antagonist GABA-B PAM 6 mo implant Hi-dose nasal nalmefene antagonist spray Fentanyl Muscarinic M5 Nalmefene mAb NAM Transmucosal

Metho- cinnamox MOR antag

10

• Vaccines (fentanyl and analogues), heroin/ • Reduced drug reaching brain • Protection against overdose Ultimately, we anticipate multiple medications, integrated with devices and psychosocial interventions, employed in an EndOUD GameEnd Game orchestrated fashion, will be needed to achieve truly effective treatments tailored for maximal efficacy for induvial patients. Implementing MOUD in Healthcare Settings

Primary Care: Low Threshold Office-Based Buprenorphine Emergency department-initiated Treatment Unobserved induction, buprenorphine At most weekly visits, • Reduced self-reported illicit opioid use No psychosocial treatment. • Increased engagement in treatment • Decreased use of inpatient services Self-Reported Illicit Opioid Use in the Past 7 Days 6 Baseline 30 days 5 5.4 5.4 5.6 4

3 Days

2 2.3 2.4 • Treatment retention at 38 weeks 1 0.9 0 equivalent to office-based opioid Buprenorphine Referral Brief Intervention treatment. D’Onofrio G et al., JAMA April 28, 2015. Bhatraju EP et al., Addict Sci Clin Pract. 2017 CTN Node Expansion

• Optimizing Retention, Duration and Appalachian Node – Discontinuation MOUD Univ. of Pittsburgh & WV Univ. Great Lakes Node – • Subthreshold OUD Trial Rush University • ED-Initiated Buprenorphine Greater Intermountain Node – • MOUD for OUD Expecting Mothers Univ. of Utah Greater Southern CA Node – • Rural Expansion MOUD UCLA • Hospital Initiation MOUD Southwest Node – Univ. of New Mexico Justice Community Opioid Innovation Network

Coordination and Translation Center: George Mason University Methodology and Advanced Analytics Resource Center: University of Chicago

13 Hubs Novel Studies Each 5+ Communities STATE POLICY ROLLOUTS LEVERAGING TECHNOLOGY Cascade of Care Focus 18 States + Puerto Rico PEER NAVIGATION SUPPORT 88 communities Justice & Treatment Partner INTER ORGANIZATIONAL LINKAGES >25,000 justice-involved Diversity of Justice Setting, MOUD COMPARATIVE individuals Geography, and Intervention EFFECTIVENESS The HEALing Communities Study: Integrating Evidence Based interventions across Settings

Ohio State University Columbia University PI: Rebecca Jackson PI: Nabila El-Bassel Healthcare Criminal Justice Community

• Primary care • Jails • Families • Emergency • Prisons • Schools departments • Parole/Probation • Police and fire • Inpatient • Drug courts departments hospital care • Faith-based Boston Medical Center University of Kentucky • Behavioral organizations PI: Jeffrey Samet PI: Sharon Walsh health • Local industry

Rural Communities Urban Communities OD Deaths: Provisional Data 3/ 2018 – 2/ 2019 35000 Source: CDC National Vital Statistics System, September 12, 2019 SYNTHETIC OPIOIDS 30000 Other Synthetic Narcotics, 31,335 25000 Heroin, 14,996 20000 , 14,666 15000

Natural and Semi- 10000 Synthetic Opioids, PSYCHOSTIMULANTS 12,552 5000 Methamphetamine, 12,676

0

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

OVERDOSE MORTALITY BY CLASS OF DRUG ADAPTED FROM NCHS STATISTICS CDC National Vital Statistics System, January 15,18 2020 NAT & SEMI – SYNTHETIC OTHER PSYCHO- HEROIN METHADONE COCAINE Centers for Disease Control and PreventionSYNTHETIC OPIOIDS STIMULANTS

JUNE 2018 * 15,408 13,703 3,226 30,817 15,408 11,667

JUNE 2019 * 14,973 12,275 2,883 33,752 15,391 14,687

Change -2.82% -10.42% -10.63% 9.52% -0.11% 25.88% * Number of predicted deaths for the 12 months ending in June of the indicated yea`r PRESENTATION TITLE Intersection between Opioid crisis and COVID-19 COVID-19: Potential Implications for People with SUD • SUD-related lung impairment may increase risk for serious effects from COVID-19 (smoking/vaping, opioids, methamphetamine) • Stress on health systems may be a barrier to care for those with SUD • Populations experiencing homelessness or incarceration at higher risk for SUD; may have increased exposure to COVID-19 • Difficulties in accessing medications (including methadone clinics) • Restriction of community support system like syringe exchange programs • Challenges of stress and social isolation to sustain recovery COVID-19: Potential Implications for SUD Research • Lab closures • IRB closures • Halted recruitment/enrollment/patient interaction in clinical trials • Healthcare system overwhelmed with clinical needs and research delayes • Public health partners for HEALing Communities overwhelmed • Researchers not permitted into correctional facilities Notice of Special Interest (NOSI) regarding the Availability of Administrative Supplements and Urgent Competitive Revisions for Research on the 2019 Novel Coronavirus Notice Number: NOT-DA-20-047 • Key Dates Release Date: March 19, 2020 First Available Due Date: March 19, 2020 Expiration Date: March 31, 2021 • Related Announcements PA-18-935Urgent Competitive Revision to Existing NIH Grants and Cooperative Agreements (Urgent Supplement - Clinical Trial Optional) PA-18-591 Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional) • Issued by National Institute on Drug Abuse (NIDA) • Purpose • NIDA is issuing this Notice of Special Interest (NOSI) to highlight the urgent need for research on the 2019 Novel Coronavirus (2019-nCoV, also known as COVID-19). NIDA is especially interested in research collecting and examining data on the risks and outcomes for COVID-19 infection in individuals suffering from SUD. & Reward Mechanisms of Mu Drugs (Heroin, Vicodin, Morphine)

ACC (pain) Accumbens Thalamus PAG (reward) (pain) (pain) Social Interaction Favored over Heroin Unless Social Interaction is Punished

Sliding door Partner chamber

Resident HEROIN self-administration chamber Drug lever Social lever

James Nachtwey. TIME Special Report

Venniro et al., Nature Neuroscience 2018 Plethora of new targets for pain therapy development

Ajay S et al Nature Reviews Drug Discovery 16, 545-564, 2017