General Session: Realities of Rx Drug Abuse -

1. Realities of Rx Drug Abuse
Nora D. Volkow, M.D.
Director

2. Nora Volkow has no financial relationships
with proprietary entities that produce
health care goods and services.

3. 1. Investigate recent increasing trends in the
misuse and abuse of Rx drugs.
2. Demonstrate the ways in which the most commonly
abused Rx drug classes affect the brain and body.
3. Outline strategies being developed and implemented
that will increase awareness of the growing problem.
Learning Objectives

4. Numbers in Millions
Prescription Drug Misuse/Abuse is a
Major Problem in the US
Source: SAMHSA, 2012 National Survey on Drug Use and Health, 2013.
4.7
4.9
5.1 5
4.8 4.9 4.8
4.3
4.8
2.1 2.2 2.1 2.1 2
2.2 2.2
2
2.3
1.2 1.1
1.4
1.2 1.1 1.2 1.1 1
1.3
0.3 0.3 0.4 0.3 0.2 0.3 0.4
0.2 0.2
0
1
2
3
4
5
6
2004200520062007200820092010 2011 2012
Current Drug Use Rates in
Persons Ages 12+
Percent
Past Year Nonmedical Use of Types
of Psychotherapeutic Drugs among
Persons Aged 12 or Older: 2002-2012

5. 0
100
200
300
400
500
600
700
800
900
1000
1100
0 1 2 3 4 5 hr
Time After Amphetamine
%ofBasalRelease
AMPHETAMINE
0
50
100
150
200
0 60 120 180
Time (min)
%ofBasalRelease
Empty
Box Feeding
Di Chiara et al.
FOOD
VTA/SN
nucleus
accumbens
frontal
cortex
These prescription drugs, like other
drugs of abuse (cocaine, heroin,
marijuana) raise brain
dopamine levels
Dopamine
Neurotransmission
Why Do People Abuse Prescription Drugs?
Di Chiara et al.

6. Opioids: Examples: OxyContin, Vicodin
Attach to opioid receptors in the
brain and spinal cord, blocking the
transmission of pain messages and
causing an increase in the activity
of dopamine
How They Work…
• Postsurgical pain relief
• Management of acute or chronic pain
• Relief of coughs and diarrhea
Opioids are Generally Prescribed for:
Amydala
(reward)
NAc
(reward)
Thalamus
(pain)

7. • Expectation of Drug Effects
Expectation of clinical benefits vs euphoria high
• Context of Administration
School, clinic, home vs bar, discotheque
• Dose and Frequency of Dosing
Lower, fixed regimes vs higher, escalating use
• Route of Administration
Oral vs injection, smoking, snorting
What is the Difference Between
Therapeutic Use and Abuse?

8. Rewarding Effects of Drugs Depend on
How Fast they Get into the Brain
Reward
Reward
0
20
40
60
80
100
0
20
40
60
80
100
0 10 20 30 40 50 60 70 80
%Peak
[11C]Cocaine in brain
Time (min)
[11C]Ritalin in brain
0 10 20 30 40 50 60 70 80
0
0.01
0.02
0.03
0.04
0.05
0.06
0 20 40 60 80 100 120
Time (minutes)
0
0.01
0.02
0.03
0.04
0.05
0.06
UptakeinStriatum(%/cc)
0
0.0005
0.001
0.0015
0.002
0.0025
0.003
0.0035
0 20 40 60 80 100 120
UptakeinStriatum(nCi/cc)
Time (minutes)
iv cocaine iv Ritalin oral Ritalin
0 20 40 60 80 100 120
Time (minutes)
Fast!!"Fast!!" Slow!!"
Cocaine (iv) and
Ritalin (iv) are
rewarding but
Ritalin (oral) is
not.
The slow brain
uptake of oral
Ritalin allows
treatment without
reward
Solanto MV. Behav Brain Res
1998; 94:127–152.
Fowler JS et al., Nuc Med Bio
2001; 28(5): 561-572.
Volkow ND and Swanson JM. Am J Psychiatry 2003;160: 1909-1918.

9. Source: SAMHSA Treatment Episode Data Set
(TEDS), 2000-2010
28,326
37,649
45,882
52,664
60,824
71,048
82,359
98,386
122,185
142,124
157,171
0
20,000
40,000
60,000
80,000
100,000
120,000
140,000
160,000
180,000
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
12
10
8
6
4
2
0
1990 1992 1994 1996 1998 2000 2002 2004 2006 2008
*Deaths
are
those
for
which
poisoning
by
drugs
(illicit,
prescrip9on,
and
over-­‐the-­‐counter)
was
the
underlying
cause.
National Vital Statistics System.
Drug Overdose Death Rates by State 2008.
100 people die from drug
overdoses every day in the US
CDC Vital Signs, July 2013.

10. Primary Substance of Abuse
(Other Than Alcohol**) at Admission
to U.S. State Licensed or Certified
Substance Abuse Treatment Facilities,
Ages 12 and Older
Adapted by CESAR from OAS, SAMHSA,
Treatment Episode Dataset (TEDS) Highlights—2011,
National Admissions to Substance Abuse Treatment Services, 2013.
PercentageofAllAdmissions
20
16
12
8
4
0
1992
1994
1996
1998
2000
2002
2004
2006
2008
2010
Prevalence Of Narcotics
Involvement In Drivers Who
Died Within 1 Hour Of A Crash
Fatality Analysis Reporting System,
Selected States, 1999–2010
Brady JE and Li G
Am. J. Epidemiol. 2014.
PositiveforNarcotics,%
12
10
8
6
4
2
0
1.8%
5.4%
P<0.0001
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
1999

11. Past
Month
&Past
Year
Heroin
Use
Among
Persons
Aged
12
or
Older:
2002-­‐2012
Source:
SAMHSA,
2012
Na2onal
Survey
on
Drug
Use
and
Health,
2013.
404
314
398
379
560
373
455
582
621
620
669
166
119
166
136
339
161
213
193
239
281
335
0
100
200
300
400
500
600
700
800
Numbers
in
Thousands
Past
Year
Past
Month
HepaHHs
C
Virus
Among
Adolescents
&Young
Adults
Has
Increased
in
Recent
Years
Incidence
of
acute
hepaHHs
C
by
age
group
–
U.S.,
2000-­‐2011
0
0.5
1
1.5
2
2.5
3
Reportedcases/100,000population
0–19 yrs
20–29 yrs
30–39 yrs
40–49 yrs
50–59 yrs
≥60 yrs
Source: National Notifiable Diseases
Surveillance System (NNDSS), CDC
YEAR

12. Opioid Prescriptions
Dispensed by U.S. Retail
Pharmacies, 1991-2012
0
1
2
3
4
5
6
7
8
199920002001200220032004200520062007200820092010
Rate
Year
Opioid Sales KG/10,000
Opioid Deaths/100,000
Opioid Treatment Admissions/10,000
CDC National Vital Statistics System,
SAMHSA Treatment Episode Data Set,
DEA’s Automation of Reports and
Consolidated Orders System.)
Opioid sales increases in US
parallel increases in
opioid OD & Tx admission
IMS Health, Vector One: National , Years 1991 to 2011,
Data Extracted 2012
IMS Health, National Prescription Audit,
Years 2012 & 2013, Data Extracted 2014

13. Source of Prescription
Narcotics Among Those who
Used in the Past Year, 12th Grade*
0
20
40
60
80
100
*Categories not mutually exclusive
SOURCE: University of Michigan,
2013 Monitoring the Future Study
Internet Other
Took
from
friend/
relative
Bought
from
dealer/
stranger
Given
by
friend/
relative
Rx Bought
from
friend/
relative
Source of Prescription Drugs Among
Past Year Users Aged 12 or Older
(how they obtained the drugs they most recently
used nonmedically)
Source: 2012 National Survey on
Drug Use and Health, SAMHSA 2013.
2011 to 2012

14. Opioid Prescriptions by Age
2
6
19
30
159
-
20
40
60
80
100
120
140
160
180
-
5
10
15
20
25
30
35
2002 2006 2009 2012
No.ofPrescriptions,Age40+(millions)
No.ofPrescriptions(millions)
0 to 9 10 to 19 20 to 29 30 to 39 40+
IMS Health, Vector One® National
Opioids Overdose Death
by Age Group, US, 2008
Rateper100,000
Paulozzi LJ, J Safety Res 2012;
43(4): 283-289.

15. Jones, CM et al. JAMA, February 20, 2013; 309(7): 657-659.
PERCENT
Drug Involvement in Pharmaceutical Overdose Deaths
Opioid Analgesic Involvement in Deaths for Specific Drugs
Specific Drug Involvement in
Pharmaceutical Overdose Deaths USA, 2010
75.2
7.8
29.4
1.3
17.6
6.1
0.1
100
65.5
77.2
50
57.6 58
54.2
0
20
40
60
80
100
120
Opioid Analgesics Antiepileptic &
Antiparkinsonism
Drugs
Benzodiazepines Barbiturates Antidepressants Antipsychotic &
Neuroleptic Drugs
Other
Psychotropic
Drugs

16. 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.

17. Opioid Agonist Treatments Decreased
Heroin Overdose Deaths
Baltimore, Maryland, 1995-2009
Schwartz RP et al., Am J Public Health 2013;1 03: 917-922.
OverdoseDeaths,No.
PatientsTreated,No.
Heroin overdoses
Buprenorphine patients
Methadone patients

18. Retention In Methadone
Maintenance Drug Tx
NS after adjusting for demographics,
treatment agencies, other drug use,
public assistance type, medical,
psychiatric, social, legal
and familial factors.
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
PTOP Heroin
Treatment for Addiction to Opioid Medications
Prescription Opioid Abusers can be treated
at MMT facilities at least as effectively as
heroin users in terms of treatment retention.
ODDSRATIO
6.6
49.2
8.6
0
10
20
30
40
50
60
Phase 1 Phase 2 After Taper
%ofPatientsWithSuccessfulOutcomes
Brief and Extended
Buprenorphine-Naloxone Tx
for Rx Opioid Dependence
(Brief) (Extended)
Weiss RD et al., Arch Gen Psych 2011;
68(12): 1238-1246.
Banta-Green CJ et al., Addiction 2009;
104(5): 775-783.

19. Additional Challenge…
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
TOO FEW ARE TREATED
Knudsen et al, 2011, J Addict Med; 5:21-27.

20. How Can Research Help?
• Medications
PAIN: Develop less abusable analgesics
OD: User Friendly Naloxone
ADDICTION: New Medications
• mHealth Applications
• Non pharmacological interventions

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

22. Naloxone Nasal Spray
OD: User Friendly Naloxone
• AntiOp, single-dose,disposable naloxone nasal
spray that combines a nasal spray device with a
stable, concentrated naloxone solution
• Investigational New Drug (IND) filed in 2012
• Product could be on the market in about 18 months
• Lightlake Therapeutics, biopharmaceutical
company conducting clinical trials with intranasal
naloxone for binge eating disorder is applying it
towards the treatment of opioid overdose
• Clinical trials began last fall

23. mHealth for Preventing OD
Wireless SENSORS
Respiration
Oxymeter
Arrythmias
ALARM
Set up delivery
Alert Patient
Alert Third Party
NALOXONE
DELIVERY
Automatic
Patient
Third party

24. ADDICTION Treatment
• Develop better,
more targeted treatments
• Develop effective vaccines

25. Binding Site
Capillary
Blood Flow
Brain
Antibodies
VACCINE
Antibodies Can Reduce Brain Concentrations
Immunotherapies for Addiction Treatment
(i.e., Vaccines)
Capillary
Blood Flow
Brain
Targeting the drugs,
not the receptors

26. Technologies For Invasive & Non-invasive Neuromodulation
Transcranial Direct
Current Simulation (tDCS)
passes direct current though
two electrodes on the scalp
High-Definition transcranial
Direct Current Stimulation (HD-tDCS)
uses arrays of scalp electrode to
guide current to brain structures
Adapted from: Morena-Duarte I et al., Neuroimage 2014; 85(3): 1003-1013.
Non-Medication Strategies
For the Treatment of PAIN and ADDICTION
Motor Cortex Stimulation
uses electrodes
positioned on the cortex
Left sensory thalamusLeft periventricular gray
Gray AM et al., J Pain
2014; 15(3): 283-292.
Deep Brain Stimulation (DBS)
Stereotaxtic implantation of
electrodes that emit
electrical stimulation
to a targeted
neuronal region
Transcranial Magnetic
Stimulation (TMS)
uses magnets to non-invasively
induce current in the brain

27. • Responsible Prescribing and Management
of Chronic Pain
• Mandatory Addiction Education in Medical,
Nursing and Pharmacy Schools
• Availability of Naloxone
• Parity Tracking and Implementation
• Websites on Location and Quality of
Addiction Treatment Programs
Strategies that can Help Address the Dangers
of Opioid Overdose and Addiction in the US

28. Mezei, L and Murinson, BB., J Pain, 12, 1199 -1208, 2011.
Education on Pain in Medical Schools
Number of Hours of Pain Education
NumberofSchools
USA (median: 7 hours)
Canada (median: 14 hours)
Veterinarian schools:
75 hours on pain
0-5 5-10 10-15 15-20 20-25 25-30 >30

29. • Centers of Excellence in Pain Education (12 CoEPE)
• Consensus Workshop on
Opioids for Chronic Pain
ICs Involved:
ORWH NIA
OBSSR NINR
NIDA NICHD
NIDCR NIAMS
NINDS NCCAM

30. Education for Healthcare Providers
CME Courses developed by NIDA & Medscape Education, funded by ONDCP
Safe Prescribing for Pain
Managing Pain Patients
Who Abuse Rx Drugs
Skills and tools clinicians can use
to screen for and prevent abuse in
patients with pain
Learn symptoms of opioid addiction &
dependence in patients with chronic
pain, & how to screen for, prevent,
& treat such conditions

31. • Responsible Prescribing and Management
of Chronic Pain
• Mandatory Addiction Education in Medical,
Nursing and Pharmacy Schools
• Availability of Naloxone
• Parity Tracking and Implementation
• Websites on Location and Quality of
Addiction Treatment Programs
Strategies that can Help Address the Dangers
of Opioid Overdose and Addiction in the US

32. • NIDA CoEs were established in 2007
to help fill gaps in current medical
education curricula related to both
illicit drugs and Rx drug abuse
• Working with NIDA, medical school
faculty at the CoEs have developed
a diverse portfolio of innovative
curriculum resources about how to
identify and treat patients struggling
with drug abuse and addiction
NIDA
Resources for Medical Students,
Resident Physicians & Faculty
Centers of Excellence
for
Physician Information

33. Percent of Students
Reporting Nonmedical Use
of Vicodin in Past Year
0
5
10
15
20
02 03 04 05 06 07 08 09 10 11 12 13
Denotes significant difference between 2012 and 2013
SOURCE: University of Michigan, 2013 Monitoring the Future Study
0
5
10
15
20
02 03 04 05 06 07 08 09 10 11 12 13
Percent of Students
Reporting Nonmedical Use
of OxyContin in Past Year
8th Grade 10th Grade 12th Grade
PREVENTION WORKS

35. Increases in Heroin Abuse as Access to
Prescription Pain Relievers is Decreased
Cicero TJ et al. N Engl J Med 2012;367:187-189.
Growing evidence suggests that abusers of prescription
opioids are shifting to heroin as prescription drugs become
less available or harder to abuse
For example, a
recent increase in
heroin use accompanied
a downward trend in
OxyContin abuse
following the introduction
of an abuse-deterrent
formulation
of that medication.
Cicero T et al., NEJM 2013.

36. Bateman BT et al, Anesthesiology, February 2014.
Prevalence of Opioid Dispensing
During Pregnancy by State
Opioid Use During
Pregnancy (%)
6.5 -- 11.0
11.1 -- 14.0
14.1 -- 16.5
16.6 -- 20.5
20.6 -- 26.3
(Overall) and By Trimester
ProportionofPregnancies
16
14
12
10
8
6
4
2
0
2005 2006 2007 2008 2009 2010 2011
Anytime in Pregnancy
First Trimester
Second Trimester
Third Trimester
Temporal Trends in
Opioid Dispensing
During Pregnancy

37. Ling, W. et al. JAMA 2010;304:1576-1583.
IMPLANTABLE
Buprenorphine – Probuphine™
Retention of Patients Through the Trial
Delivers
Buprenorphine for 6
Months
120
100
80
60
40
20
0
NumberofPatients
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Week
Buprenorphine
Placebo
66%
31%
Titan Pharmaceuticals
New Medications For Addictions To
Opioid Prescriptions

38. ##p<0.01, ###p<0.001, significant reduction of analgesia
vs. Control/KLH group, ### p<0.001, significant
reduction of analgesia vs. Control/KLH group
Heroin
1
mg/kg,
s.c.
30
min
Hot Plate Test
The Vaccine(s)
New Heroin Vaccine(s)
K.D. Janda & G.F. Koob Laboratories at TSRI

39. FDA NEWS RELEASE -- For Immediate Release: Sept. 10, 2013
The U.S. Food and Drug Administration today announced class-wide safety labeling changes
and new postmarket study requirements for all extended-release and long-acting (ER/LA)
opioid analgesics intended to treat pain.
Safety Labeling Changes & New Postmarket Study
Requirements For All Extended-Release &
Long-acting (ER/LA) Opioid Analgesics
• The class-wide labeling changes include important new language to
help health care professionals tailor their prescribing decisions based
on a patient’s individual needs
• Based on a review of relevant literature, FDA has concluded that more
data are needed regarding the serious risks of misuse, abuse,
hyperalgesia, addiction, overdose, and death associated with the
long-term use of ER/LA opioid analgesics and is thus requiring
ER/LA opioid analgesic drug sponsors to conduct
post-marketing studies and a clinical trial to assess these risks.

40. Prediction of Pain on the Basis of Data from Other Participants in Study 1.
Wager TD et al. N Engl J Med 2013;368:1388-1397.
Pain Signature Map, voxels in which activity reliably predicted pain
fMRI-Based Neurologic Signature of Physical Pain