Dr. Nora Volkow It's NOT What the Doctor Ordered National Rx Drug Abuse Summit 4-11-12

1. Dr. Nora D. Volkow, MD,
Director, National Institute on
Drug Abuse (NIDA) National
Institute of Health

2. Prescription Drug Abuse:
It s Not What the Doctor Ordered
April 10-12, 2012
Walt Disney World Swan Resort
Nora D. Volkow, M.D.
Director
National Institute on Drug Abuse

3. Learning Objectives
Attendance at this presentation will give participants
a better understanding of:
• Recent increasing trends in the misuse and abuse of
prescription drugs as well as the growing number of opioid
and stimulant prescriptions being dispensed by retail
pharmacies in the U.S.
• The ways in which the most commonly abused prescription
drug classes affect the brain and body and the possible
deleterious consequences that can result from such use
and abuse.
• Strategies being developed and implemented that will increase
awareness of the growing problem, and research aimed at
identifying tools and interventions to most effectively
prevent and treat prescription drug abuse.

4. Disclosure Statement
Presenter has nothing to disclose

5. Pharmaceutical Drug Abuse is a
Major Problem in the US
Past Month Use
(Among Persons Aged 12 or Older) in Millions
Source: 2010 National Survey on Drug Use and Health, SAMHSA, 2011.

6. 2011 Monitoring the Future Study
Prevalence of Past Year Drug Use Among 12th graders
Drug Prev. Drug Prev.
Alcohol 63.5 OxyContin* 4.9
Marijuana/Hashish 36.4 Sedatives* 4.3
Synthetic Marijuana 11.4 Hall other than LSD 4.3
Amphetamines* 8.2 Inhalants 3.2
Vicodin* 8.1 Cocaine (any form) 2.9
Adderall* 6.5 LSD 2.7
Salvia 5.9 Ritalin* 2.6
Tranquilizers* 5.6 Ketamine 1.7
Cough Medicine* 5.3 Provigil 1.5
MDMA (Ecstasy) 5.3 GHB 1.4
Hallucinogens 5.2 Methamphetamine 1.4
* Nonmedical use Categories not mutually exclusive

7. Past Year Initiates of Specific Illicit Drugs
Among Persons Aged 12 or Older: 2010
Numbers in Thousands
Source: 2010 National Survey on Drug Use and Health, SAMHSA, 2011.

8. Number of Opioid Prescriptions Dispensed by
U.S. Retail Pharmacies, Years 1991-2011
250 Opioids Hydrocodone Oxycodone
219
210
Prescriptions (millions)
201 202
200 192
180
169
158
151
150 139 144
131
120
109
96 100
100 80
86 91
76 78
50
0
91
92
93
94
95
96
98
99
2000
01
02
03
04
05
06
08
09
10
11
97
07
IMS’s Source Prescription Audit (SPA) & Vector One®: National
(VONA)

9. Dentists and Emergency Medicine Physicians were the
main prescribers for patients 5-29 years of age
5.5
million
prescrip8ons
were
prescribed
to
children
and
teens
(19
years
and
under)
in
2009
900
800
700
600
Rate
per
10,000
persons
GP/FM/DO
500
IM
400
DENT
ORTH
SURG
300
EM
200
100
0
0-­‐4
5-­‐9
10-­‐14
15-­‐19
20-­‐24
25-­‐29
30-­‐39
40-­‐59
60+
Age
Group

10. Eight-Fold Deaths
from Drug Overdoses 1971-2007
Source: CDC, Unintentional Drug Poisoning in
the US, National Vital Statistics System, 2010

11. Trends in ED Visits Involving the Nonmedical
Use of Narcotic Pain Relievers
Number of ED Visits
Source: 2008 (8/2009 update) SAMHSA DAWN

12. Number of Stimulant Prescriptions Dispensed by
U.S. Retail Pharmacies, Years 1991-2011

13. The use of stimulant
medications among
healthy individuals
for cognitive
enhancement is
increasing,
raising questions
not only about safety
but also its efficacy
across cognitive tasks
and individuals

14. Source of Prescription Drugs
(how they obtained the drugs they most recently used nonmedically)
Rates averaged across 2009 and 2010
Percent
Source: 2010 National Survey on Drug Use and Health, SAMHSA 2011.

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

16. Drugs of Abuse Act on the Reward & Ancillary Circuits
Through Different Mechanisms…But All Lead to
Similar Dopaminergic Effects in the VTA & NAc
Nicotine
+
Opiates
Alcohol
Opioid
Glutamate inputs
- Peptides
(e.g., from cortex)
Opiates
Alcohol
VTA
GABA
?
Interneuron
- PCP
Alcohol
` -
? Stimulants
+
Nicotine
+ DA
DA
Glutamate
+ Cannabinoids
-
inputs
(e.g., from
amygdala
PPT/LDT)
Adapted from Nestler 2005.

17. Similarities Between Illicit & Prescription Drugs

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

19. Similarities Between Illicit & Prescription Drugs
Adderall
Methamphetamine

20. Stimulants
Example: Ritalin
How They Work…
Enhance brain activity by increasing the activity of brain
excitatory chemical messengers, such as norepinephrine
and dopamine, leading to mental stimulation
Stimulants Are Generally Prescribed For:
• ADHD
• Narcolepsy
• Depression that does not
respond to other treatments
• Asthma that does not
respond to other treatment

21. CNS Depressants
Examples: Valium, Xanax
How They Work…
Cause an increase in gamma-aminobutyric acid
(GABA), an inhibitory chemical messenger leading
to a decrease in brain activity
CNS Depressants are Generally Prescribed for:
• Anxiety
• Tension
• Panic attacks
• Acute stress reactions
• Sleep disorders
• Anesthesia (at high doses)

22. Sedatives
Examples: Valium, Xanax, Librium
Activate the Same Receptor as Alcohol
Brain areas where activity is increased by
sedative drugs and by alcohol
Sedative Drug Alcohol

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

24. Psychostimulant Drugs
cocaine d-methamphetamine MDMA
*
methylphenidate modafinil amphetamine

25. Pharmacokinetics in Human Brain
[11C]Cocaine
[11C]Methylphenidate

26. Effects Depend on the Drug Pharmacokinetics—
How fast it gets into the Brain
[11C]Cocaine [11C]Methylphenidate
100 100
80 80
% Peak
60 60
40 40
20 20
"High"
"High"
0 0
0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60 70 80
Time (min)

27. When Used Therapeutically Drugs are Given Orally which
Results in Slow Brain Uptake When Abused Drugs are
Snorted or Injected which Results n Fast Brain Uptake
oral Ritalin
0.0035
0.003
0.0025
0.002
0.0015
Slow!!!
0.001
0.0005
00 20 40 60 80 100 120
Time (minutes)
0.06
iv Ritalin
Uptake in Striatum (nCi/cc)
Uptake in Striatum (%/cc)
0.05
0.04
0.03
0.02 Fast!!!
0.01
0
0 20 40 60 80 100 120
Time (minutes)

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

29. Glucose Metabolism Was Greatly Increased
By the Expectation of the Drug
30
25
% Change
20
Unexpected MP 15
70
10
5
0
Expected MP
Unexpected
Expected MP
Got Placebo
Expected
MP
MP
Increases in Metabolism Were About
0
50% Larger When MP Was
µmol/100g/min Expected Than Unexpected
Source: Volkow, ND et al., Journal of Neuroscience,
23, pp. 11461-11468, December 2003.

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

31. MP ability to increase DA is affected by the
rate of DA release; which makes its effects
Context Dependent
20
P < 0.05
MP-induced change in DA
15
10
low DA cell firing! high DA cell firing!
5
DA"
0
MP MP
Neutral Salient
DAT"
MP" Context Context
DA D2-R"
signal! signal!

32. Four-Fold Substance Use Disorder TX Admissions
Pain Relievers: 1998-2008
Source: SAMHSA Treatment Episode Data Set
(TEDS), 1998 and 2008.

33. Treatment of Prescription Medications

34. Full and Partial Agonists vs Antagonists
Treatment Strategies for Opioid Addiction
antagonist
agonist
Full Agonist
(Methadone)
Opioid Effect
no effect
Partial Agonist
(Buprenorphine)
an antagonist drug is close
effect
enough in shape to bind to
the receptor but not close
an agonist drug has an
enough to produce an
active site of similar shape
effect. It also takes up Antagonist
to the endogenous ligand
receptor space and so (Naloxone)
so binds to the receptor
prevents the endogenous
and produces the same ligand from binding
Log Dose
effect

35. Buprenorphine for the Treatment of
Addiction to Opioid Medication
Subutex® -- Monotherapy product
Suboxone® -- Buprenorphine/Naloxone
Currently 19,000 physicians
are certified to prescribe buprenorphine
Related toCSAT Buprenorphine Information Center)
(Source: morphine (partial agonist)
Uses same receptors as morphine but does not
produce the same high
Can be abused, but combining with naloxone decreases
abuse potential
Long-lasting, less likely to cause respiratory depression

36. Medications to Treat Those Addicted
Specific Binding
Specific Binding
[18F]cyclofoxy (µ ligand)
[11C]carfentail (µ ligand)
Normal Control
Methadone Maintained Patient
27-47 % occupancy for 2mg Bup
30-35 % receptor occupancy for 85-92% occupancy for 16 mg Bup
methadone doses > 80 mg a day 94-98% occupancy for 32 mg Bup
Source: Kling et al., JPET, 2000.
Greenwald, MK et al., Neuropsychoph, 2003.

37. Need for New Medications
• Develop medications with lower abuse
Uptake in Striatum (nCi/cc)
0.0035
0.003
potential including drugs that don’t 0.0025
0.002
0.0015
Slow!
cross BBB (i.e., CbR2 agonist) 0.001
0.0005 !!
00 20 40 60 80 100 120
Time (minutes)
• Develop slow release formulations
(low dose and long duration)
• Develop novel formulations to reduce
abuse liability including mixture
formulations (e.g., naloxone
and buprenorphine)

38. How to Minimize the Diversion and
Abuse of Prescription Medications

39. Prevention Strategies - Training & Education
• Enhance clinical training for
physicians, nurses, dentists and
pharmacists in the areas of pain
management, opioid pharmacology
and abuse and addiction

40. Prevention Strategies – Public Education
• Increase patient, lay public, and
policy makers’ awareness of the
potential risks for abuse inherent
in all opioid analgesics

41. Take Back Programs
Maine model
– Postage paid medicine return
envelopes distributed across the state
– Disposal in compliance with state and
federal laws and sound environmental
practices
– 3850 envelopes returned (85%
prescription drugs)
– Psychotherapeutics made up 31%
of returns for individuals ages 50
and under

42. Prescription Monitoring Programs
• Statewide electronic database collects data on
substances dispensed in the state.
• Through the database, physicians and
pharmacies can identify patients who are
seeking multiple prescriptions.
• As of the summer of 2010, 34 states
had operational programs.

43. www.drugabuse.gov
Revised Jan 2012
Revised Dec 2011
Published Dec 2011 Revised Oct 2011