Rx Drug Abuse and Heroin Where is Science Leading Us?

Nora D. Volkow, M.D.Director

@NIDAnews

National Institute on Drug Abuse

Numbers in Millions

Prescription Drug Misuse/Abuse is a Major Problem in the US

Source: SAMHSA, 2014 National Survey on Drug Use and Health, 2015.

2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 20140

1

2

3

4

5

6

4.7 4.9 5.1 5 4.8 4.9 4.84.3

4.84.2

3.9

2.1 2.2 2.1 2.1 2 2.2 2.2 22.3

2 2

1.2 1.11.4 1.2 1.1 1.2 1.1 1

1.3 1.3 1.4

0.3 0.3 0.4 0.3 0.2 0.3 0.4 0.2 0.2 0.2 0.3

Current Drug Use Rates in Persons Ages 12+

Pain Relievers

Tranquilizers

Stimulants

Sedatives

Past Year Nonmedical Use of Psychotherapeutic Drugs

Persons Ages 12+

Opioid Abuse

Heroin

Inhalants

Hallucinogens

Cocaine

Psychotherapeutics

Marijuana

Any Illicit Drug

0 5 10 15 20 25 30

0.4

0.5

1.1

1.5

6.5

22.2

27

Past Month & Past Year Heroin Use Persons Aged 12 or Older

SAMHSA, 2014 National Survey on Drug Use and Health, 2015.

2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 20140

100

200

300

400

500

600

700

800

900

1000

404

314398 379

560

373455

582621 620

669 681

914

166119

166 136

339

161213 193

239281

335289

435

Num

bers

in T

hous

ands

Abuse of Opioid Medications has led to a Rise in Heroin Abuse

Past Year

Past Month

YEAR

Tho

usan

ds

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

05,0

0010

,000

15,00

020

,000

4,0304,400

5,528

7,456

8,517

9,85710,928

13,72314,408

14,80015,597

16,65116,917

16,00716,235

18,893

Opioid Analgesic Overdose Deaths in the USA

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

0

2,000

4,000

6,000

8,000

10,000

12,000

1,9601,8421,7792,0892,0801,8782,0092,088

2,3993,0413,2783,036

4,397

5,925

8,257

10,574

Heroin Overdose Deathsin the USA

Centers for Disease Control and Prevention. Wide-ranging Online Data for Epidemiologic Research (WONDER), Multiple-Cause-of-Death file, 2000–2014. 2015 (http://www .cdc .gov/ nchs/ data/health_policy/ AADR_ drug_ poisoning_involving_OA_Heroin_US_2000-2014 .pdf)

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

Pain

Ascendinginput

Descending modulation

Dorsalhorn

Dorsal rootganglion

Peripheralnerve

SpinothalmicTract

Peripheral nociceptors

Trauma

OpioidsAlpha2 agonists

Local anestheticsAnti-inflammatorydrugs

Local anestheticsOpioidsAlpha2 agonists

Local anesthetics Thalamus(pain)

ACC(pain) PAG

(pain)Accumbens(reward)

How Can Research Help?

• PAIN: Develop Less Abusable Analgesics & Alternative Therapeutics

• OVERDOSES: User Friendly Naloxone

• ADDICTION: New Medications & Immunotherapies

• Pharmacogenomics (Precision Medicine)

• Implementation Science

Opioid deterrent formulations

Development of Safer Analgesics

Pro-drugs

Tamper resistant formulation

Drug combinations with adverse effectsif injected

Non-Opioid based analgesicsCannabinoids;Inflammatory mediators; Ion channel blockers Non-pharmacological mechanisms and treatmentsSurgical interventions for pain; Neural stimulation technologies for chronic pain; Spinal cord stimulation

Abuse-Resistant Opioid Prodrug (i.e., Signature Therapeutics)

PAIN: Less Abusable Analgesics

BIOMARKERS OF PAINPBR28 Binding is Increased in Thalamus of Patients with Low Back Pain

Marco L. Loggia et al. Brain 2015;138:604-615.Thalamic PBR28 binding was inversely correlated with perception of pain

How Can Research Help?Non-Medication Strategies For the Treatment of PAIN and ADDICTION

Transcranial Magnetic Stimulation (TMS)Magnets induce current

in the brain

Examples: Neuronavigation Guided (Stereotaxic) rTMS used in treating Mild Traumatic Brain Injury-Related

Headaches (MTBI-HA)

Spinal CordStimulation (SCS)

Minimally invasive procedure placing SCS leads into the

epidural spaceLamer TJ et al., Mayo Clinic Proceedings 2016; 91: 246-258.

Leung et al., Pain Physician 2016;19: E347-353.

Precision MedicineCYP2B6 is the main determinant of methadone elimination; its gene CYP2B6 is highly polymorphic. Most significant variant is CYP2B6*6, which has reduced expression and activity and occurs commonly in Africans, Asians, and Hispanics.

Kharasch et al., Anesthesiology. 2015;123(5):1142-1153.

Individuals with CYP2B6*6 had higher blood concentrations of R- and S-methadone after one oral dose (11 mg); due to reduced eliminationGenetic testing might help identify individuals at risk for methadone overdose and could be useful in guiding methadone dosing

R-methadone S-methadone

AA, compared with G carriers, had greater MOR in anterior cingulate (ACC), accumbens (NAc), and thalamus (THA)

Peciña M et al., Neuropsychopharmacology 2015.

• A118G SNP at OPRM1, is functional: it affects receptor levels in brain

• 118G as well as other variants have been associated with increased risk for addiction to opiates and with worse clinical severity for overdoses.

The Target Of Opioids Is the µ Opioid Receptor and the Gene That Encodes (OPRM1) Is Polymorphic

Hancock et al., Biol Psychiatry. 2015. Manini et al., J Med Toxicol. 2013.

G carrier AA

OVERDOSES: User Friendly Naloxone

Naloxone Nasal Spray DevelopmentNeedle-free, unit-dose, ready-to-use opioid overdose antidote

Adapt Pharma NARCAN nasal spray APPROVED BY FDA, November 18, 2015

Image courtesy of ADAPT Pharma, Inc.

$37.50 per 4mg NARCAN Nasal Spray device

How Can Research Help?

Opioid OD Death were Reduced In Communities that Implemented

Nasal Naloxone Distribution Program

Unadjusted Unintentional Opioid-Related

Overdose Death Rates

Unadjusted Opioid-Related Acute Care Hospital Utilization Rates

Walley AY et al., BMJ 2013.

Intranasal Naloxone Administration By Police First Responders In Ohio

Intranasal naloxone administration by police first responders is

associated with decreased OD deathsRando et al., Am J Emerg Med 2015.

Medications for Opioid Addiction

effectno effect

agonist antagonist

an agonist drug has anactive site of similar shapeto the endogenous ligandso binds to the receptor

and produces the same effect

an antagonist drug is closeenough in shape to bind to the

receptor but not close enough to produce an effect. It also takes

up receptor space and so prevents the endogenous ligand

from binding

Opi

oid

Eff

ect

Full Agonist(Methadone)

Partial Agonist(Buprenorphine)

Antagonist(Naloxone)

Log Dose

Source: SAMHSA, 2012 National Survey on Drug Use and Health, 2013.

Opioid Agonist Treatments Decreased Heroin OD Deaths Baltimore, Maryland, 1995-2009

Heroin overdoses Buprenorphine patientsMethadone patients

Challenge: Compliance with daily intakeSolution: Develop long acting medications

Schwartz RP et al., Am J Public Health 2013.

How Can Research Help?

1995 1996 1997 1998 19990

100

200

300

400

500

600

0

10000

20000

30000

40000

50000

60000

70000565

1432900

25000

4900055000

60000

# of

Opi

oid

OD

Dea

ths

# on

Bup

reno

rphi

ne T

reat

men

t

Ling et al. J Subst Abuse Tx 2002;23:87-92.Auriacombe et al. JAMA 2001;285:45.

Buprenorphine Reduced ODOpioid OD declined 75% after

buprenorphine introduced in France

ADDICTION: New Medications & Immunotherapies

0 0 0 0 0 0

Perc

ent

Source: O’Brien CP et al., Poster presentation at the Annual Meeting of the College on Problems of Drug Dependence, June 2015.

All Recorded Overdose Events, BothFatal and Non-fatal, Occurred In the Control Group

No overdoses occurred in the naltrexone group, even after discontinuation of XR-NTX

NEW THERAPEUTICS for Opioid Use DisorderExtended release medications (improve compliance)

IMPLANTABLE Buprenorphine Probuphine™ (6 months)EVA

polymer Probuphine®

26 mm long,2.5mm

diameter

Buprenorphine

FDA’s Final Decision Initially Expected Feb 27, 2016

Delayed 3 months Rosenthal RN et al., Addiction 2013;105: 2141-2149.

% of Urines Negative (out of 72) for Opioids Across Weeks 1 to 24

Placebo

Sublingual Buprenorphine

…………………….........Probuphine is designed to release sustained therapeutic drug levels in patients with opioid addiction for up to six months%

of P

atie

nts F

ailin

g to

Exc

eed

Eac

h Po

ssib

le C

rite

rion

of S

ucce

ss

Buprenorphine Implants

Lack of uptake of medication-assisted treatment

Addiction Specialty Programs Offering

Services

As % of all programs surveyed (N=345)

Within adopting programs, % of eligible

patients receiving Rx

Opioid Tx Meds:

Methadone 7.8 41.3

Buprenorphine 20.9 37.3

Tablet naltrexone 22.0 10.9

Knudsen et al, 2011, J Addict Med; 5:21-27.

TOO FEW ARE TREATED

Implementation Science: Expanding MAT

Buprenorphine Referral Brief Intervention0

20

40

60

80

100

78%

37% 45%

% e

ngag

ed in

TX

30

thda

y po

st

rand

omiz

atio

n

D’Onofrio JAMA. 2015.

ED-initiated Buprenorphine Increased Engagement In Addiction Tx, Reduced Self-reported Illicit Opioid Use & Decreased Use Of Inpatient Addiction Tx Services

Buprenorphine Referral Brief Intervention0

1

2

3

4

5

6

5.4 5.4 5.6

0.92.3 2.4

Baseline

Day

s of S

elf-

Rep

orte

d Il

licit

Opi

oid

Use

in th

e Pa

st 7

Day

s

Implementation Science: Expanding MATHow Can Research Help?

HHS Strategy To Address Opioid-Drug Related Overdose, Death and Dependence

• Providing training and educational resources, including updated prescriber guidelines, to assist health professionals in making informed prescribing decisions

• Increasing use of naloxone

• Expanding the use of Medication-Assisted Treatment (MAT)

Opioid Prescribing After a Nonfatal OD:Association With Repeated Overdose

Ann Intern Med. 2016.

Repeated OD

Despite the fact that opioid discontinuation after overdose is associated with lower risk for repeated overdose, almost all patients continue to receive prescription opioids afteran overdose.

PAIN: Develop Less Abusable Analgesics and Alternative TherapeuticsNational Pain Strategy

”HHS Secretary should develop a comprehensive, populationhealth-level strategy for pain prevention, treatment, management, education, reimbursement and research ..."

ORWHOBSSRNIDANIDCRNINDS

NIANINRNICHDNIAMSNCCIH

NIH Pain Consortium Centers of Excellence in Pain Education

Goal: Improve pain treatment through education

How Can Research Help?

• NIDA CoEs established in 2007 to help fill gaps in medical education curricula related to both illicit drugs and Rx drug abuse

• Medical schools at CoEs have developed a diverse portfolio of innovative curriculum resources about how to identify and treat patients struggling with SUD

Resources for Medical Students, Resident Physicians & Faculty

NIDA

THE APPALACHIAN REGIONThe Appalachian Region includes all of West Virginia and parts of Alabama, Georgia, Kentucky, Maryland, Mississippi, New York, North Carolina, Ohio, Pennsylvania, South Carolina, Tennessee, & Virginia. The Region is home to more than 25 million people and covers 420 counties & almost 205,000 square miles.

February 25, 2016ARC Partners with NIDA to Improve Opioid Intervention Services in Appalachia

• With ARC support, NIDA will provide one-year research grants to address the dramatic increase in adverse outcomes of opioid injection drug use in Appalachia.

• Findings will help build a foundation for improved intervention programs and larger-scale research efforts to provide services addressing this growing public health threat.

• Applications are due April 28.  

Antibodies reduce amount of drug in the brain

Capillary Blood Flow

Brain

Targets drugs, not receptors

Capillary Blood Flow

Brain

AntibodiesVaccine

Binding sites

ADDICTION: New Medications & Immunotherapies

How Can Research Help?