Advancing Addiction Science to

Address the Opioid Crisis

National Institute on Drug Abuse
Bringing the full power of science to bear on drug abuse and addiction
Nora D. Volkow, M.D.
Director
National Institute on Drug Abuse

Science = Solutions

Wilson M. Compton, M.D., M.P.E.

Deputy Director
Advancing Addiction Science National Institute on Drug Abuse
 Overdose Deaths Increased Markedly in 2016

70,000
63,632
60,000

50,000 52,404
47,055
40,000

30,000

20,000 16,849

10,000

Source: Data Brief 294. NCHS, National Vital Statistics System, Mortality
 Virtually All of the U.S. Have Increased Drug Overdoses:
Estimated Age-adjusted Death Rates per 100,000 for Drug Poisoning by County

1999 2016
Source: https://www.cdc.gov/nchs/data-visualization/drug-
poisoning-mortality/index.htm
 Evolution of the Opioid OD Crisis:
Analgesics Heroin Fentanyl
45,000
40,000 42,249 Any
35,000 Opioid
30,000
25,000 19,413 “Fentanyl”
20,000
17,087 Rx
15,000
10,000 15,469 Heroin
5,000
0

Any Opioid Source: NCHS WONDER, NCHS Data Brief 294

Commonly Prescribed Opioids (natural & semisynthetics and methadone)
Heroin
Synthetic Opioids Other Than Methadone (i.e. Fentanyl and Related)
1. Over prescription of opioid medications led to
misuse
2. Addiction to prescription opioids led to heroin
3. Emergence of fentanyl(s), with higher potency
and greater profitability in the black market
than heroin.
 ENVIRONMENTAL AVAILABILITY: Current Opioid
Crisis Originated with Prescribing Increases
250

Opioid prescriptions 200

Opioid Prescriptions in MILLIONS

Tripled to MORE THAN 200
MILLION prescriptions in 150

recent years
100

50

0
People Misusing Analgesics Obtain them Directly &
Indirectly by Prescription

Source where pain relievers obtained for most recent misuse

Prescription 36% Friend/ Their

Relative Prescription
87%
54% 10%
10% Other Their Friend/Relative

Other 3%
Source: Han, Compton, et al. Annals of Internal Medicine 2017;167(5):293-301
Morphine-equivalent (mg/patient in need of care), and
estimated percentage of need that is met
Knaul FM Lancet 2017

Over reliance on opioids for pain management

 Analgesic Mechanisms of Mu Opiate Drugs
(Heroin, Vicodin, Morphine)

Anterior Cingulate
Cortex (ACC)
(pain) Periaqueductal
Grey (PAG)
Accumbens (pain)
(reward) Thalamus
(pain)
 Rx Opioid Misuse has been a Risk Factor for Heroin Use

% Heroin Treatment Admissions that Used Heroin or

Rx Opioid First

Most current heroin

users started opioid
use with prescription
opioids.

Decade of First Opioid Use (No. of Abusers)

Source: Cicero et al. JAMA Psychiatry. 2014;71(7):821-826.
 Most Heroin Users Report Previous Non-Medical Use of
Prescription Opioids,
BUT Only a Small Proportion of Non-Medical Users Progress
to Heroin

National General Population:

• Within 5 years, 3.6% of non-medical users of opioids progressed to
heroin within 5 years (i.e. less than 1% per year) (Muhuri, Gfroerer, Davies. 2013)
Local Longitudinal Study of Non-medical users:
• Within 3 years, 7.5% progressed to heroin (i.e. 2.8% per year) (Carlson,
Nahhas, martins, Daniulaityte. 2015)
 ECONOMICS: Heroin Increases Due to Lower
Price and Greater Availability
"Retail" Price Per Pure Gram
$3,500

$3,000

$2,500

$2,000

$1,500

$1,000

$500

$-

National Drug Control Strategy--Data Supplement 2014.

https://www.whitehouse.gov/sites/default/files/ondcp/policy-and-research/ndcs_data_supplement_2014.pdf
More than double of the drugs Heroin Contaminated with
seized by DEA tested positive Fentanyl Dramatically
for fentanyl from 2015 to 2016 Enhances Brain Hypoxia

National Forensic Laboratory Information

System (NFLIS). Fentanyl ORANGE
Fentanyl analogues RED Solis et al., 2017, eNeuro

Fentanyl’s higher potency contributes to its lethality and when

combined with heroin this might enhance their toxicity
2016 Fentanyl-Related Deaths Surpassed Heroin or
Rx

Graphs from NY Times Article

based on CDC MMWR Report
2017
Fentanyl and Counterfeit Products Broaden At-Risk Population

Source: Jones CM, et al. AJPH 2017, Mar;107(3):430-432.

ECONOMICS:
CHEAP
Fentanyl
Precursor
Chemicals
 Increasing Prenatal Exposure
Increasing Admissions for Increasing Costs for Neonatal
Newborn Withdrawal Exposure
Syndromes (Number per
1000 Admissions)

Source: Winkelman TNA, Villapiano N, Kozhimannil KB,

Davis MM, Patrick SM.. Pediatrics. 2018;141(4):e20173520
Source: Tolia VN, Patrick SW, et al. NEJM 2015;372:2118-2126
Buprenorphine may have Advantages in Treating Neonatal
Opioid Withdrawal (if medications are required)
Duration of treatment (Panel A) and length of hospital stay (Panel B)
were shorter for buprenorphine group than for morphine group

Kraft WK et al., N Engl J Med 2017 May 4;376:2341-2348.

 Counties Deemed Highly Vulnerable to
Rising rates of HCV Rapid Dissemination of HCV or HIV

Suryaprasad et al. Clin Infect Dis. 2014

HIV (and Hepatitis C) Outbreak

Source: Van Handel et al, JAIDS 2016
Linked to Oxymorphone Injection
Use in Indiana, 2015
Peters et al.
The New England Journal of Medicine
2016;375:229-239
Science = Solutions: Using Research to Improve
HIV and Hepatitis C in Rural Areas
NIH is partnering with the CDC, SAMHSA and the Appalachian
Regional Commission (ARC) to conduct research to address
increased opioid injection drug use and resulting overdose, HIV
and Hepatitis C infection.
• Improve understanding problem’s
scope; contributing health trends
• Identify resources, obstacles
• Develop intervention approaches
to address these health threats
 Overlap of Benzodiazepines and Opioids
Opioid Analgesic ED Visits and OD Deaths Involving Benzodiazepines &
Benzodiazepine ED Visits and OD Deaths Involving Opioids
90 2004 2005 2006 2007 2008 2009 2010 2011

80 AAPC = 1.5% (95% CI 0.8%-2.2%)

70
Percent

60

50

40 AAPC = 8.4% (95% CI 7.1%-9.7%)

30

20

10

0
Opioid Analgesic Deaths Involving Benzodiazepines Benzodiazepine Deaths Involving Opioid Analgesics
Opioid Analgesics Benzodiazepines
Source: CM Jones, JK McAninch. American Journal of Preventive Medicine 2015;49:493-501. Science = Solutions
U.S. Department of Health and Human Services
OPIOID STRATEGY
 Advancing the practice of pain management
 Targeting availability and distribution of
overdose-reversing drugs
 Improving access to prevention, treatment,
and recovery services
 Strengthening timely public health data
and reporting
 Supporting cutting-edge research
 Inadequate Pain Treatment as a Driver?
91.8 million adults used prescription opioids (37.8% of
the U.S. adult population) 7.2
12.0
1.9 million adults
11.5 million adults 48.7
had prescription
misused prescription 7.0
opioid use disorders
opioids (4.7% of the
(0.8% of the U.S.
U.S. adult population) 16.2
adult population)

4.6 2.4 0.9 0.6 1.0 relieve physical pain 8.9

relax or relieve tension
experiment
10.8
2.2 get high or feel good
help with sleep
11.2
help with emotions or feelings
66.3 increase/decrease effects of other drugs
hooked or have to misuse Source: Han, Compton, et al. Annals of Internal
Medicine 2017 (epub Aug 1, 2017)
other reason
 Doctors Continue to Prescribe Opioids for
Ninety-one Percent of Overdose Patients
In a 2-year follow-up of 2848 commercially insured patients who had a
nonfatal opioid overdose during long-term opioid therapy :
10%
14%
63% of high-
17%
dose opioid pts of high- dose
13% still on high patients
dose 31-90 overdosed
days after again within
OD two years
high dose moderate dose
low dose none
33-39% of those with active opioid prescriptions during follow-up also
were prescribed benzodiazepines. Source: Larochelle et al. Ann Intern Med. 2016;164(1):1-9.
Recent Landscape for Guidelines:
 Small Number
 Outdated
 Not Conflict Free
Solution…. Opioid Prescribing
Guidelines
 Intended for primary care providers
 Applies to patients >18 years old in chronic pain
outside of end-of-life care
 Builds on joint CDC, NIDA, ONC, SAMHSA summary
on “Common Elements in Guidelines for Prescribing
Opioids for Chronic Pain” and the NIH Pathways to
Prevention for Opioids in Treating Chronic Pain
 PUBLISHED MARCH 15, 2016
 Opioid Education
Resources for Medical Students,
Resident Physicians & Faculty

Medical schools have developed innovative curriculum resources about how to identify and
treat patients with substance use disorders

Web training on pain assessment
and treatment
Archived NIDA CME Courses:
Safe Prescribing for Pain
Managing Pain Patients
Who Abuse Rx Drugs
Bringing NIDA
research to
clinical practice
Upcoming NIDA CME Course:
Adolescent Substance Use
(Prescription Opioid Module)
Recent Declines in Opioid Prescriptions
70
Opioid MME in BILLIONS

60

50

40
Opioid Morphine Milligram Equivalents Prescribed
30
Declined 23.1% from
3rd quarter 2010 to 2nd quarter 2016
20

10

0
 RESEARCH TARGET:

Safe, Effective Strategies for Pain

Management
 A Promising New Generation Of Pain Therapeutics
Biased Mu-Opioid Receptor Ligands

Soergel DG, et al., Pain 2014. Manglik A, et al., Nature 2016. DeWire SM, et al., JPET 2013. Bohn LM, et al., Science 1999
Science = Solutions
Research on the Neurobiology of Pain
Gender Differences in Kappa Opioid Receptor Availability

Males

Female
s

• Males had higher K opioid receptor availability than

females presumably from increased dynorphin.
• Could this help explain gender differences in pain
catastrophizing??

Vijay et al., Am J Nucl Med Mol Imaging. 2016 6(4):205-214.

 Direct Overdose Intervention
Naloxone Distribution for opioid overdose victims.
The potential for direct intervention to save lives.
 “Evzio” naloxone auto-injector
APPROVED BY FDA,
April 3, 2014
 “Narcan Nasal Spray” naloxone
APPROVED BY FDA,
November 18, 2015

Science = Solutions
 Retail Pharmacy Prescriptions for Naloxone Increase
Markedly
35000

• Retail prescriptions show an 30000

2016
increase of 9520% from the 4th 25000

quarter of 2013 to 2nd quarter 20000

15000
2016. 2014
2015
10000

• Outpatient prescribing of 5000

naloxone may complement 0

community-based distribution
and first responder access.
Sources: Jones CM, Lurie PG, Compton WM. Am J Public Health.
2016;106(4):689-690;

Science = Solutions
 Medications are Effective for Opioid Use Disorder

Medication Assisted Treatment

(MAT) can DECREASE:
• Opioid use
• Opioid-related overdose deaths
• Criminal activity
• Infectious disease transmission
And INCREASE
• Social functioning
• Retention in treatment Kakko J et al., The Lancet 2003.
 Effective Medications for Opioid Addiction
Full Agonist: Methadone (daily dosing)
Partial Agonist: Buprenorphine (3-4X week, or implant)
Antagonists: Naltrexone (monthly extended release)

agonist antagonist

Opioid Effect
Full Agonist
(Methadone)

no effect Partial Agonist

effect Binds to receptor but (Buprenorphine
has no effect.
Binds to the receptor and Prevents heroin from Antagonist
activates it; binding. (Naltrexone)
Full agonists have maximal Log Dose
effect.
Partial agonist have
intermediate effect.
Prevent Heroin from binding. Science = Solutions
 Medications are Underused
In 48 states and D.C., Opioid Use In 2014, only 25% of opioid admissions
Disorder Rates Exceed had treatment plans that included
Buprenorphine Treatment Capacity receiving medications.
100% 75%
90%
80% % Treatment Programs 25%
70%
60% Offering FDA-approved
50% SUD Medications MAT No MAT
40% Treatment Episode Data Set
30% 25% (TEDS): 2004-2014.
17% 16% 19%
20%
9% 9%
10%
Jones C et al., Am J Public Health 2015.
0%

Knudsen et al., J Addict Med 2011

Opioid Use Disorder Cascade of Care in USA

Williams AR, Nunes E, Olfson M. Health Affairs Blog, 2017

Science Driven Solutions: Improving Addiction Treatment
• Probuphine: buprenorphine implant; releases sustained dose for up to 6
months (FDA Approval May 26, 2016)
• Initiating buprenorphine treatment in the emergency department improves
treatment engagement and reduces illicit opioid use
• Extended release naltrexone initiated in criminal justice settings lowers
relapse rates and overdoses
• Abstinence from opioids over 12 Weeks with interim buprenorphine
Abstinence with
Interim Buprenorphine

Lee JD, et al., Addiction 2015;100:1005-1014

and New Eng J Med 2016;374:1232-1242 Sigmon SC et al. N Engl J Med 2016.
 Buprenorphine Treatment (BT) The “Massachusetts Model” of
Retention Improves Preventive Office Based Opioid Treatment
Primary Care Screenings (OBOT) with Buprenorphine
% entering BT that received primary care screenings Collaborative care between nurse care
100 91 managers and generalist physicians
90
80.1
76.3
80 71.4 72.9 ER Admissions per OBOT Enrollment
70
57.1 58.5 Prior 6 Months Future 6 Months Future 7-12 Months
60
49.3 48.7 1.53
50 44.4
40 1.24
28.6 1.17 1.17
30
20
10
0.69 0.65 0.62 0.67
0 0.58 0.54 0.61
0.55

Days
2008 2009 2010 2011
Integrating BT into primary care settings could
also improve co-morbid disease diagnosis and
Source: Office of Data Analytics and Decision Support, Bureau of
management of chronic diseases Substance Abuse Services, MA Department of Public Health. 2014.
Haddad MS et al., Bulletin of the New York Academy of Medicine 2015; 92(1):193–213.
 Opioid Medication Postincarceration OD Deaths After
Therapy (OMT) In Prison Implementing OMT Statewide in
Rhode Island Corrections
Mortality Post Release OD deaths in those incarcerated in
Survival Curve During the Year Following
Release (Drug-Poisoning Mortality) 2017 decreased by 60% compared
to 2016 (5.7% vs 14.5%)
Survival probability

Statewide OD Deaths 12.5%

decrease

Number OD Fatalities
250
OMT unexposed 200 179
OMT exposed
157
150
100
Days since prison release 50
0
75% reduction in OD deaths in the 1/1 to 6/30 1/1 to 6/30
first month post release with OMT 2016 2017

Marsden J et al., Addiction 2017; 112:1408-1418. Green TC, Clarke J, Brinkley-Rubenstein L, Marshall BDL, Alexander-
Scott N, Boss R, Rich JD. JAMA Psychiatry 2018;75(4):405-407.
 XR-Naltrexone and Buprenorphine-Nx Equally Safe and
Effective In Preventing Relapse (After Induced to Medication)
Relapse-free survival and treatment effect over time Opioid craving during the trial
for the XR-NTX and BUP-NX treatment groups

In this population it was more difficult to initiate patients to XR-NTX than

BUP-NX, and this negatively affected overall relapse. However, once
initiated, both medications were equally safe and effective. `
Lee JD et al., Lancet 2017, November 14 (E-pub ahead of print.)
New Targets: Medications to Decrease Withdrawal
 Non-Pharmacological Treatments for Addiction

Transcranial Magnetic Transcranial Direct Deep Brain Stimulation (DBS)

Stimulation (TMS) Current Simulation (tDCS) Implanted electrodes emit electrical
stimulation to targeted brain region

Salling and Martinez, 2016.

 Immunotherapies for Opioid Use Disorder

Vaccine Antibodies reduce amount of drug in the brain

Antibodies Targets drugs,
not receptors
Binding
Capillary Capillary
Blood Flow sites Blood Flow

Brain Brain

Hwang et al., Efficacious Vaccine against Heroin Contaminated with Fentanyl. ACS Chem. Neurosci. 2018
 NIH Opioid Research Initiative
Using Research to End the Opioid Crisis
PAIN MANAGEMENT
Safe, effective, non-addictive strategies

Nonpharmacological Biomarkers
Treatments (e.g. TMS) For Pain
OPIOID OVERDOSE
ADDICTION REVERSAL
Non-Opioid
TREATMENT Opioid Vaccines Analgesics Interventions to
New, innovative reduce mortality
Respiratory
medications and Stimulation and link to
technologies Devices treatment
What’s with pain? Analysis shows few investments, high
failure rate
John Carroll Endpoints news, Feb 12 2018.

Limited investment in development of safer analgesics

 NIH Public Private Partnership
To Address the Opioid Crisis
Focus Area A: Enhance the range of medication options to treat opioid use disorder and
prevent/reverse overdoses
• Develop new formulations and combinations of medications to treat opioid use
disorder and to prevent overdoses
• Develop more potent or longer lasting opioid antagonists to reverse overdoses from
fentanyl or its derivatives.
• Develop and validate alternative endpoint other than abstinence that are acceptable to FDA
for approval of OUD medications
Focus Area B: Pain
• Establish data sharing collaborative between industry groups
• NIH to serve as a neutral broker
• Determine objective measures to understand, predict responses to pain
• Biomarkers for pain – and a “Pain-ometer”
• Clinical trial network to accelerate trials on common and rare pain syndromes and
to evaluate biomarkers
 Summary:
• Complex biological, developmental and
social aspects of substance use and
addiction suggest multipronged responses.
• The severity of the opioid crisis demands
urgent action.
Science = Solutions
Advancing Addiction Science
www.drugabuse.gov