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

Institute of Health

April 10-12, 2012 Walt Disney World Swan Resort

Prescription Drug Abuse: It’s Not What the Doctor Ordered

Nora D. Volkow, M.D. Director

National Institute on Drug Abuse

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.

Disclosure Statement

Presenter has nothing to disclose

 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.

Prevalence of Past Year Drug Use Among 12th graders 2011 Monitoring the Future Study

* Nonmedical use

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

Categories not mutually exclusive

Past Year Initiates of Specific Illicit Drugs Among Persons Aged 12 or Older: 2010

Num

bers

in T

hous

ands

Source: 2010 National Survey on Drug Use and Health, SAMHSA, 2011.

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

76 78 80 86 91 96 100 109

120 131

139 144 151 158

169 180

192 201 202

210 219

0

50

100

150

200

250 91

92

93

94

95

96

97

98

99

20

00

01

02

03

04

05

06

07

08

09

10

11

Pres

crip

tions

(mill

ions

)

IMS’s Source Prescription Audit (SPA) & Vector One®: National (VONA)

Opioids Hydrocodone Oxycodone

Dentists and Emergency Medicine Physicians were the main prescribers for patients 5-29 years of age

0  

100  

200  

300  

400  

500  

600  

700  

800  

900  

0-­‐4                 5-­‐9                 10-­‐14             15-­‐19             20-­‐24             25-­‐29             30-­‐39   40-­‐59   60+  

Rate  per  10,000  pe

rson

s  

Age  Group  

GP/FM/DO  

IM  

DENT  

ORTH  SURG  

EM  

5.5  million  prescrip8ons  were  prescribed  to  children  and  teens  (19  years  and  under)  in  2009  

Eight-Fold Deaths from Drug Overdoses 1971-2007

Source: CDC, Unintentional Drug Poisoning in the US, National Vital Statistics System, 2010

Trends in ED Visits Involving the Nonmedical Use of Narcotic Pain Relievers

Num

ber o

f ED

Visi

ts

Source: 2008 (8/2009 update) SAMHSA DAWN

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

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

Source: 2010 National Survey on Drug Use and Health, SAMHSA 2011.

Source of Prescription Drugs (how they obtained the drugs they most recently used nonmedically)

Rates averaged across 2009 and 2010

Perc

ent

0 100 200 300 400 500 600 700 800 900

1000 1100

0 1 2 3 4 5 hr Time After Amphetamine

% o

f Bas

al R

elea

se

AMPHETAMINE

0

50

100

150

200

0 60 120 180 Time (min)

% o

f Bas

al R

elea

se

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?

BUT dopamine is also elevated by natural reinforcers

Opioid Peptides

Nicotine Alcohol Opiates

VTA Interneuron

Alcohol

DA

Glutamate inputs (e.g., from cortex)

+

?

DA

GABA

-

?

+

Stimulants

Cannabinoids

Opiates -

-

-

Alcohol PCP

+

Nicotine

Glutamate inputs (e.g., from amygdala PPT/LDT)

Drugs of Abuse Act on the Reward & Ancillary Circuits Through Different Mechanisms…But All Lead to Similar Dopaminergic Effects in the VTA & NAc

Adapted from Nestler 2005.

`

+

Similarities Between Illicit & Prescription Drugs

Opioids

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

Examples: OxyContin, Vicodin How They Work…

•  Postsurgical pain relief •  Management of acute or chronic pain •  Relief of coughs and diarrhea

Opioids are Generally Prescribed for:

Activate Opiate Receptors, which Modulate Pain & Reward

Opiate Receptors Activate Dopamine Cells

Amydala (reward)

NAc (reward)

Thalamus (pain)

Methamphetamine

Adderall

Similarities Between Illicit & Prescription Drugs

Stimulants

Enhance brain activity by increasing the activity of brain excitatory chemical messengers, such as norepinephrine and dopamine, leading to mental stimulation

Example: Ritalin How They Work…

•  ADHD •  Narcolepsy •  Depression that does not

respond to other treatments •  Asthma that does not

respond to other treatment

Stimulants Are Generally Prescribed For:

CNS Depressants

Cause an increase in gamma-aminobutyric acid (GABA), an inhibitory chemical messenger leading

to a decrease in brain activity

Examples: Valium, Xanax How They Work…

CNS Depressants are Generally Prescribed for: •  Anxiety •  Tension •  Panic attacks •  Acute stress reactions •  Sleep disorders •  Anesthesia (at high doses)

Sedatives

Activate the Same Receptor as Alcohol Brain areas where activity is increased by

sedative drugs and by alcohol

Sedative Drug Alcohol

Examples: Valium, Xanax, Librium

•  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?

*

cocaine d-methamphetamine MDMA

methylphenidate modafinil amphetamine

Psychostimulant Drugs

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

"High" "High" 0

20

40

60

80

100

0

20

40

60

80

100

0 10 20 30 40 50 60 70 80

% P

eak

[11C]Cocaine

Time (min)

[11C]Methylphenidate

0 10 20 30 40 50 60 70 80

Effects Depend on the Drug Pharmacokinetics— How fast it gets into the Brain

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

0 0.01 0.02 0.03 0.04 0.05 0.06

0 20 40 60 80 100 120 Upt

ake

in S

tria

tum

(%/c

c)

Time (minutes)

Upt

ake

in S

tria

tum

(nC

i/cc) iv Ritalin

Fast!!!

0

0.0005

0.001

0.0015

0.002

0.0025

0.003

0.0035

0 20 40 60 80 100 120 Time (minutes)

oral Ritalin

Slow!!!

•  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?

Source: Volkow, ND et al., Journal of Neuroscience, 23, pp. 11461-11468, December 2003.

Glucose Metabolism Was Greatly Increased By the Expectation of the Drug

Unexpected MP 70

0 µmol/100g/min

Expected MP

Increases in Metabolism Were About 50% Larger When MP Was Expected Than Unexpected

0 5

10 15 20 25 30

% C

hang

e

Une

xpec

ted

MP

Expe

cted

MP

Expe

cted

MP

Got

Pla

cebo

•  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?

signal! signal!

low DA cell firing! high DA cell firing!

DA"

DAT"

DA D2-R"

MP"

MP ability to increase DA is affected by the rate of DA release; which makes its effects

Context Dependent

0

5

10

15

20

MP Neutral Context

MP Salient Context

MP-

indu

ced

chan

ge in

DA

P < 0.05

Four-Fold Substance Use Disorder TX Admissions Pain Relievers: 1998-2008

Source: SAMHSA Treatment Episode Data Set (TEDS), 1998 and 2008.

Treatment of Prescription Medications

Full and Partial Agonists vs Antagonists Treatment Strategies 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

Opi

oid

Effe

ct

Full Agonist (Methadone)

Partial Agonist (Buprenorphine)

Antagonist (Naloxone)

Log Dose

Subutex® -- Monotherapy product Suboxone® -- Buprenorphine/Naloxone

Buprenorphine for the Treatment of Addiction to Opioid Medication

Currently 19,000 physicians are certified to prescribe buprenorphine (Source: CSAT Buprenorphine Information Center) Related to morphine (partial agonist)

Uses same receptors as morphine but does not produce the same high

Long-lasting, less likely to cause respiratory depression

Can be abused, but combining with naloxone decreases abuse potential

Normal Control

Methadone Maintained Patient

Source: Kling et al., JPET, 2000.

Specific Binding [18F]cyclofoxy (µ ligand)

30-35 % receptor occupancy for methadone doses > 80 mg a day

Specific Binding [11C]carfentail (µ ligand)

Greenwald, MK et al., Neuropsychoph, 2003.

Medications to Treat Those Addicted

27-47 % occupancy for 2mg Bup 85-92% occupancy for 16 mg Bup 94-98% occupancy for 32 mg Bup

Need for New Medications

•  Develop medications with lower abuse potential including drugs that don’t cross BBB (i.e., CbR2 agonist)

•  Develop slow release formulations (low dose and long duration)

•  Develop novel formulations to reduce abuse liability including mixture formulations (e.g., naloxone and buprenorphine)

0 0.0005 0.001 0.0015 0.002

0.0025 0.003

0.0035

0 20 40 60 80 100 120

Upt

ake

in S

tria

tum

(nC

i/cc)

Time (minutes) Slow!!!

How to Minimize the Diversion and Abuse of Prescription Medications

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

Prevention Strategies – Public Education

•  Increase patient, lay public, and policy makers’ awareness of the potential risks for abuse inherent in all opioid analgesics

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

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.

Revised Dec 2011

Revised Jan 2012

Published Dec 2011 Revised Oct 2011

www.drugabuse.gov