Realities of Rx Drug Abuse

Nora D. Volkow, M.D. Director

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

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

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

2004 2005 2006 2007 2008 2009 2010 2011 2012

 Current Drug Use Rates in  Persons Ages 12+

Perc

ent

Past Year Nonmedical Use of Types of Psychotherapeutic Drugs among

Persons Aged 12 or Older: 2002-2012

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?

Di Chiara et al.

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)

•  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?

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

% P

eak

[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

Upt

ake

in S

tria

tum

(%/c

c)

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)

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.

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.

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.

Perc

enta

ge o

f All

Adm

issi

ons

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.

Posit

ive

for N

arco

tics,

%

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

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  

Num

bers  in  Tho

usan

ds  

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

Rep

orte

d ca

ses/

100,

000

popu

latio

n

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  

Opioid Prescriptions Dispensed by U.S. Retail Pharmacies, 1991-2012

0

1

2

3

4

5

6

7

8

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

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

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

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.

of P

resc

ript

ions

, Age

40+

(mill

ions

)

No.

of P

resc

ript

ions

(mill

ions

)

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

Rat

e pe

r 100

,000

Paulozzi LJ, J Safety Res 2012; 43(4): 283-289.

Jones, CM et al. JAMA, February 20, 2013; 309(7): 657-659.

PER

CE

NT

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

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

Opi

oid

Effe

ct

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 Overdose Deaths Baltimore, Maryland, 1995-2009

Schwartz RP et al., Am J Public Health 2013;1 03: 917-922.

Ove

rdos

e D

eath

s, N

o.

Patie

nts T

reat

ed, N

o.

Heroin overdoses Buprenorphine patients Methadone patients

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.

OD

DS

RAT

IO

6.6

49.2

8.6

0

10

20

30

40

50

60

Phase 1 Phase 2 After Taper

% o

f Pat

ient

s With

Suc

cess

ful O

utco

mes

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.

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.

How Can Research Help?

• Medications PAIN: Develop less abusable analgesics OD: User Friendly Naloxone ADDICTION: New Medications • mHealth Applications • Non pharmacological interventions

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

PAIN: Less Abusable Analgesics

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

mHealth for Preventing OD

Wireless SENSORS

Respiration Oxymeter

Arrythmias

ALARM

Set up delivery Alert Patient

Alert Third Party

NALOXONE DELIVERY

Automatic Patient

Third party

ADDICTION Treatment

•  Develop better, more targeted treatments

•  Develop effective vaccines

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

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 thalamus Left 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

•  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

Mezei, L and Murinson, BB., J Pain, 12, 1199 -1208, 2011.

Education on Pain in Medical Schools

Number of Hours of Pain Education

Num

ber

of S

choo

ls

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

•  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

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

•  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

•  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

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

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.

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 Prop

ortio

n of

Pre

gnan

cies

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

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

Num

ber o

f Pat

ient

s

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

##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

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.

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