National Institute on Drug AbuseBringing the full power of science to bear on drug abuse and addictionNora D. Volkow, M.D.DirectorNational Institute on Drug Abuse

Advancing Addiction Science to Address the Opioid Crisis

Advancing Addiction Science

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

National Institute on Drug Abuse

Science = Solutions

16,849

47,055

52,404

63,632

0

10,000

20,000

30,000

40,000

50,000

60,000

70,000

199920002001200220032004200520062007200820092010201120122013201420152016

Overdose Deaths Increased Markedly in 2016

Virtually All of the U.S. Have Increased Drug Overdoses: Estimated Age-adjusted Death Rates for Drug Poisoning by County

20151999

https://www.cdc.gov/nchs/data-visualization/drug-poisoning-mortality/

Other Synthetic Opioids(e.g. fentanyl)

Commonly Prescribed Opioids(natural and semi-synthetic opioids and methadone)

Heroin

Methadone

Overdose Deaths Primarily from Opioids: Prescription Drugs, Heroin and Synthetics (i.e. Fentanyl and similar)

ENVIRONMENTAL AVAILABILITY: Current Opioid Crisis Originated with Prescribing Increases

Opioid prescriptions Tripled to MORE THAN 200 MILLION prescriptions in recent years

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Opio

id P

resc

riptio

ns in

MILL

IONS

People Misusing Analgesics Obtain them Directly & Indirectly by Prescription

Source where pain relievers obtained for most recent misuse

10%

36%87%

10%

3%

54%

Friend/Relative

Prescription

Other

Their Prescription

Their Friend/RelativeOther

Source: Han, Compton, et al. Annals of Internal Medicine 2017;167(5):293-301

Source where pain relievers obtained for most recent misuse

10%

36%87%

10%

3%

54%

Friend/Relative

Prescription

Other

Their Prescription

Their Friend/RelativeOther

Source: Han, Compton, et al. Annals of Internal Medicine 2017;167(5):293-301

Rates of U.S. Adults > 18 and Older Reporting Pain, 2015

CDC and NCHS, 2015

9.7

27.6

13.9

20.9

30.4

17.4

05

101520253035

Severeheadache or

migraine

Low back pain Neck pain

Men Women

Women suffer more pain in many categories and are prescribed more opioids

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100000000

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140000000

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Males Females

Opioid Prescriptions U.S. Retail Pharmacies, 2002-2013

Source: IMS Health, National Prescription Audit

Num

ber o

f `Pr

escr

iptio

n

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

Thalamus(pain)

ACC(pain)

PAG(pain)

Accumbens(reward)

Rx Opioid Misuse has been a Risk Factor for Heroin Use

% Heroin Treatment Admissions that Used Heroin or Rx Opioid First

Source: Cicero et al. JAMA Psychiatry. 2014;71(7):821-826.

Most current heroin users started opioid use with prescription opioids.

Decade of First Opioid Use (No. of Abusers)

Most Heroin Users Report Previous Non-Medical Use of Prescription Opioids,

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)

BUT Only a Small Proportion of Non-Medical Users Progress to Heroin

Heroin Users: First Opioid Now Likely to be Heroin

Source: Cicero T et al. Addictive Behaviors 2017;74:63-66

ECONOMICS: Heroin Increases Due to Lower Price and Greater Availability

$-

$500

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"Retail" Price Per Pure Gram

National Drug Control Strategy--Data Supplement 2014. https://www.whitehouse.gov/sites/default/files/ondcp/policy-and-research/ndcs_data_supplement_2014.pdf

Fentanyl and Counterfeit Products Broaden Risk Population

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

Graphs from NY Times Article based on CDC MMWR Report2017

2016 Fentanyl-Related Deaths Surpassed Heroin or Rx

ECONOMICS: CHEAP

Fentanyl Precursor Chemicals

Increasing Prenatal Exposure

Admissions for Newborn Withdrawal Syndromes

(Number per 1000 Admissions)

Source: Tolia VN, Patrick SW, et al. NEJM 2015;372:2118-2126 Science = Solutions

Counties Deemed Highly Vulnerable to Rapid Dissemination of HCV or HIV

Source: Van Handel et al, JAIDS 2016

Rising rates of HCV

Suryaprasad et al. Clin Infect Dis. 2014

HIV (and Hepatitis C) Outbreak Linked to Oxymorphone Injection

Use in Indiana, 2015Peters et al.

The New England Journal of Medicine2016;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

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Opioid Analgesic Deaths Involving Benzodiazepines Benzodiazepine Deaths Involving Opioid Analgesics

2004 2005 2006 2007 2008 2009 2010 2011Pe

rcen

t

Opioid Analgesics BenzodiazepinesSource: CM Jones, JK McAninch. American Journal of Preventive Medicine 2015;49:493-501.

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

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

Overlap of Benzodiazepines and OpioidsOpioid Analgesic ED Visits and OD Deaths Involving Benzodiazepines &

Benzodiazepine ED Visits and OD Deaths Involving Opioids

Science = Solutions

U.S. Department of Health and Human Services OPIOID STRATEGY

Improving access to prevention,

treatment, and recovery services

Targeting availability and distribution of

overdose-reversing drugs

Strengthening timely public health data

and reporting

Supporting cutting-edge

research

Advancing the practice of pain

management

ComprehensiveEvidence-based

Targets drivers of epidemic

Flexible to emerging threats

Inadequate Pain Treatment as a Driver?

1.9 million adults had prescription opioid use disorders(0.8% of the U.S. adult population)

91.8 million adults used prescription opioids (37.8% of the U.S. adult population)

11.5 million adults misused prescription opioids (4.7% of the U.S. adult population)

48.7

8.9

16.2

7.0

12.0

7.2

66.3

11.2

2.210.8

4.62.4 0.9 0.6 1.0 relieve physical pain

relax or relieve tensionexperimentget high or feel goodhelp with sleephelp with emotions or feelingsincrease/decrease effects of other drugshooked or have to misuseother reason

Source: Han, Compton, et al. Annals of Internal Medicine 2017 (epub Aug 1, 2017)

Limited Medical Education on Pain (and Addiction)

Mezei L, et al. Pain education in North American medical schools J Pain. 2011

Number of med schools teaching 0 to 5 hours, 5 to 10 hours, etc.. U.S. medical schools dark gray bars, Canadian schools light gray.

Pain Education in USA:

9 Mean Hours(range 1-31)

Doctors Continue to Prescribe Opioids for Ninety-one Percent of Overdose Patients

Source: Larochelle et al. Ann Intern Med. 2016;164(1):1-9.

high dose moderate doselow dose none

14%

13%

63% of high-dose opioid pts still on high dose 31-90 days after OD

17%of high- dose

patients overdosed

again within two years

In a 2-year follow-up of 2848 commercially insured patients who had a nonfatal opioid overdose during long-term opioid therapy :

Ø33-39% of those with active opioid prescriptions during follow-up also were prescribed benzodiazepines.

Opioid Prescribing Guidelines

Ø Intended for primary care providersØ Applies to patients >18 years old in chronic pain

outside of end-of-life careØ 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

Ø PUBLISHED MARCH 15, 2016

Ø Recent Landscape for Guidelines:§ Small Number§ Outdated§ Not Conflict Free

ØSolution….

Resources for Medical Students, Resident Physicians & Faculty

Web training on pain assessment and treatment

Archived NIDA CME Courses:

Safe Prescribing for PainManaging Pain Patients

Who Abuse Rx Drugs

Opioid Education

Upcoming NIDA CME Course:

Adolescent Substance Use (Prescription Opioid Module)

Bringing NIDA research to

clinical practice

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

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Opio

id M

ME

in B

ILLIO

NS

Opioid Morphine Milligram Equivalents Prescribed Declined 23.1% from

3rd quarter 2010 to 2nd quarter 2016

Recent Declines in Opioid Prescriptions

RESEARCH TARGET:

Safe, Effective Strategies for Pain Management

Soergel DG, et al., Pain 2014. Manglik A, et al., Nature 2016. DeWire SM, et al., JPET 2013. Bohn LM, et al., Science 1999

A Promising New Generation Of Pain Therapeutics

Science = Solutions

Biased Mu-Opioid Receptor Ligands

Research on the Neurobiology of Pain

• 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.

Males

Females

Gender Differences in Kappa Opioid Receptor Availability

Direct Overdose InterventionNaloxone Distribution for opioid overdose victims.

The potential for direct intervention to save lives.

Ø “Evzio” naloxone auto-injector APPROVED BY FDA, April 3, 2014

Science = Solutions

Ø “Narcan Nasal Spray” naloxone APPROVED BY FDA, November 18, 2015

Receptor occupancy by INTRANASAL equivalent to INTRAVENOUS Naloxone

Baseline

Phillip et al. J Pharmacol ExpTher 2016

Intranasal Intravenous

NALOXONE REQUIRES FAST AND EFFICIENT DELIVERY as achieved with iv injection but few know how to inject

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0 .4 m g IM

Intranasal Narcan

Injectable

Blo

od C

once

ntra

tion

Positive pharmacology of nasal naloxone: Rapid onset and high peak blood level

Retail Pharmacy Prescriptions for Naloxone Increase Markedly

• Retail prescriptions show an increase of 9520% from the 4th quarter of 2013 to 2nd quarter 2016.

• Outpatient prescribing of naloxone may complement community-based distribution and first responder access.

Sources: Jones CM, Lurie PG, Compton WM. Am J Public Health. 2016;106(4):689-690; IMS Health, published https://www.performance.gov/content/reduce-opioid-related-morbidity-and-mortality Science = Solutions

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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 AddictionFull Agonist: Methadone (daily dosing)

Partial Agonist: Buprenorphine (3-4X week, or implant)

Antagonists: Naltrexone (monthly extended release)

effect

no effect

agonist antagonist

Binds to the receptor and activates it;

Full agonists have maximal effect.

Partial agonist have intermediate effect.

Prevent Heroin from binding.

Binds to receptor but has no effect.

Prevents heroin from binding.

Op

ioid

Eff

ec

t

Full Agonist(Methadone)

Partial Agonist(Buprenorphine)

Antagonist(Naltrexone)

Log Dose

Science = Solutions

Medications are Underused

25%

75%

MAT No MAT

In 2014, only 25% of opioid admissions had treatment plans that included receiving medications.

Treatment Episode Data Set (TEDS): 2004-2014.

Jones C et al., Am J Public Health 2015.

In 48 states and D.C., Opioid Abuse and Dependence Rates Exceed Buprenorphine Treatment Capacity

• 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

Science Driven Solutions: Improving Addiction Treatment

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

and New Eng J Med 2016;374:1232-1242

Abstinence with Interim Buprenorphine

Sigmon SC et al. N Engl J Med 2016.

Antibodies and Vaccines to Treat OUD and Prevent Overdose

•Heroin vaccine validated in primate model in 2017

•First vaccine for fentanyl and fentanyl analogs reported in a mouse model in 2016

•Reduces drug reaching the brain

•Protect high-risk individuals against overdose Bremer et al, 2017;

Bremer et al, 2016; Janda and Treweek, 2012.

Non-Pharmacological Treatments for Addiction

Salling and Martinez, 2016.

Transcranial Direct Current Simulation (tDCS)

Deep Brain Stimulation (DBS)Implanted electrodes emit electrical stimulation to targeted brain region

Transcranial Magnetic Stimulation (TMS)

Using Research to End the Opioid CrisisNIH Opioid Research Initiative

PAIN MANAGEMENTSafe, effective, non-addictive strategies

OPIOID ADDICTION

TREATMENTNew, innovative medications and

technologies

OVERDOSE REVERSAL

Interventions to reduce mortality

and link to treatment

Non-Opioid Analgesics

Biomarkers For Pain

Opioid Vaccines

Nonpharmacological Treatments (e.g. TMS)

Respiratory Stimulation Devices

• Complex biological, developmental and social aspects of substance use and addiction suggest multipronged responses.• The severity of the opioid crisis demands

urgent action.

Summary:

Advancing Addiction Science

www.drugabuse.gov

Science = Solutions