ATALANTA 28-31 MARZO 2016 | 1. Rx Drug Abuse and Heroin Where is Science Leading Us? Nora D. Volkow, M.D. Director @NIDAnews National Institute on Drug Abuse 2. Numbers in Millions Prescription Drug Misuse/Abuse is a Major Problem in the US Source: SAMHSA, 2014 National Survey on Drug Use and Health ...

1. Rx Drug Abuse and Heroin
Where is Science Leading Us?
Nora D. Volkow, M.D.
Director
@NIDAnews
National Institute
on Drug Abuse

2. 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.
4.7
4.9
5.1 5
4.8 4.9 4.8
4.3
4.8
4.2
3.9
2.1 2.2 2.1 2.1 2
2.2 2.2
2
2.3
2 2
1.2 1.1
1.4
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
0
1
2
3
4
5
6
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
Current Drug Use Rates in
Persons Ages 12+
Past Year Nonmedical Use of
Psychotherapeutic Drugs
Persons Ages 12+
Opioid Abuse
0.4
0.5
1.1
1.5
6.5
22.2
27
0 10 20 30
Heroin
Inhalants
Hallucinogens
Cocaine
Psychotherapeutics
Marijuana
Any Illicit Drug

3. Past Month & Past Year Heroin Use Persons Aged 12 or Older
SAMHSA, 2014 National Survey on Drug Use and Health, 2015.
404
314
398 379
560
373
455
582
621 620
669 681
914
166
119
166
136
339
161
213 193
239
281
335
289
435
0
100
200
300
400
500
600
700
800
900
1000
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
NumbersinThousands
Abuse of Opioid Medications has led to a
Rise in Heroin Abuse
Past Year
Past Month
YEAR
Thousands

4. 4,030
4,400
5,528
7,456
8,517
9,857
10,928
13,723
14,408
14,800
15,597
16,651
16,917
16,007
16,235
18,893
Opioid Analgesic Overdose
Deaths in the USA
1,9601,8421,779
2,0892,0801,8782,0092,088
2,399
3,041
3,278
3,036
4,397
5,925
8,257
10574
0
2,000
4,000
6,000
8,000
10,000
12,000
Heroin Overdose Deaths
in 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)

5. Analgesic Mechanisms of Mu Opiate Drugs
(Heroin, Vicodin, Morphine)
Pain
Ascending
input
Descending
modulation
Dorsal
horn
Dorsal root
ganglion
Peripheral
nerve
Spinothalmic
Tract
Peripheral nociceptors
Trauma
Opioids
Alpha2 agonists
Local anesthetics
Anti-inflammatory
drugs
Local anesthetics
Opioids
Alpha2 agonists
Local anesthetics Thalamus
(pain)
ACC
(pain)
PAG
(pain)
Accumbens
(reward)

6. How Can Research Help?
• PAIN: Develop Less Abusable Analgesics
& Alternative Therapeutics
• OVERDOSES: User Friendly Naloxone
•ADDICTION: New Medications & Immunotherapies
• Pharmacogenomics (Precision Medicine)
• Implementation Science

7. Opioid deterrent formulations
Development of Safer Analgesics
Pro-drugs
Tamper resistant
formulation
Drug combinations
with adverse effects
if injected
Non-Opioid based analgesics
Cannabinoids;
Inflammatory mediators;
Ion channel blockers
Non-pharmacological
mechanisms and treatments
Surgical interventions for pain;
Neural stimulation technologies
for chronic pain; Spinal cord
stimulation

8. Abuse-Resistant Opioid Prodrug
(i.e., Signature Therapeutics)
PAIN: Less Abusable Analgesics

9. BIOMARKERS OF PAIN
PBR28 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

10. 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 Cord
Stimulation (SCS)
Minimally invasive
procedure placing
SCS leads into the
epidural space
Lamer TJ et al., Mayo Clinic Proceedings 2016; 91: 246-258.
Leung et al., Pain Physician 2016;19: E347-353.

11. Precision Medicine
CYP2B6 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 elimination
Genetic testing might help identify individuals at risk for methadone overdose
and could be useful in guiding methadone dosing
R-methadone S-methadone

12. 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

13. OVERDOSES: User Friendly Naloxone
Naloxone Nasal Spray Development
Needle-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?

14. 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 deaths
Rando et al., Am J Emerg Med 2015.

15. Medications for Opioid Addiction
effect
no effect
agonist antagonist
an agonist drug has an
active site of similar shape
to the endogenous ligand
so binds to the receptor
and produces the same effect
an antagonist drug is close
enough 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
OpioidEffect
Full Agonist
(Methadone)
Partial Agonist
(Buprenorphine)
Antagonist
(Naloxone)
Log Dose
Source: SAMHSA, 2012 National Survey on Drug Use and Health, 2013.

16. Opioid Agonist Treatments
Decreased Heroin OD Deaths
Baltimore, Maryland, 1995-2009
Heroin overdoses
Buprenorphine patients
Methadone patients
Challenge: Compliance with daily intake
Solution: Develop long acting medications
Schwartz RP et al., Am J Public Health 2013.
How Can Research Help?
565
143
2900
25000
49000
55000
60000
0
10000
20000
30000
40000
50000
60000
70000
0
100
200
300
400
500
600
1995 1996 1997 1998 1999
#onBuprenorphineTreatment
#ofOpioidODDeaths
# of Opioid Deaths
Ling et al. J Subst Abuse Tx 2002;23:87-92.
Auriacombe et al. JAMA 2001;285:45.
Buprenorphine Reduced OD
Opioid OD declined 75% after
buprenorphine introduced in France
ADDICTION: New Medications & Immunotherapies

17. 0 0 0 0 0 0
Percent
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, Both
Fatal and Non-fatal, Occurred In the Control Group
No overdoses occurred in the
naltrexone group, even after
discontinuation of XR-NTX

18. NEW THERAPEUTICS for Opioid Use Disorder
Extended 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
%ofPatientsFailingtoExceed
EachPossibleCriterionofSuccess
Buprenorphine Implants

19. 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

20. 78%
37% 45%
0
20
40
60
80
100
Buprenorphine Referral Brief Intervention
%engagedinTX
30thdaypost
randomization
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
5.4 5.4 5.6
0.9
2.3 2.4
0
1
2
3
4
5
6
Buprenorphine Referral Brief Intervention
Baseline
DaysofSelf-Reported
IllicitOpioidUseinthe
Past7Days
Implementation Science: Expanding MAT
How Can Research Help?

21. 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)

22. 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 after
an overdose.

23. PAIN: Develop Less Abusable Analgesics and
Alternative Therapeutics
National Pain Strategy
”HHS Secretary
should develop a
comprehensive,
population
health-level
strategy for
pain prevention,
treatment,
management,
education,
reimbursement
and research ..."
ORWH
OBSSR
NIDA
NIDCR
NINDS
NIA
NINR
NICHD
NIAMS
NCCIH
NIH Pain Consortium Centers
of Excellence in Pain Education
Goal:
Improve pain
treatment through education
How Can Research Help?

24. • 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

25. THE APPALACHIAN REGION
The 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, 2016
ARC 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.

26. Antibodies reduce amount of drug in the brain
Capillary Blood Flow
Brain
Targets drugs,
not receptors
Capillary Blood Flow
Brain
Antibodies
Vaccine
Binding
sites
ADDICTION: New Medications & Immunotherapies
How Can Research Help?