Chronic DiseasesChronic DiseasesTreatments but no simple cure,Treatments but no simple cure,

persisting for a long timepersisting for a long time

• DiabetesDiabetes• EpilepsyEpilepsy• AsthmaAsthma• HypertensionHypertension• AddictionAddiction

Acute Diseases Cure, no residualPneumoniaAppendicitis

Resultant of interacting variablesResultant of interacting variables

Agent (Drug)Agent (Drug)

HostHost

EnvironmentEnvironment

+

-+

-

-

Outcomes:No useNo use

Use Use AbuseAbuse

AddictionAddiction+

Risk of AddictionRisk of Addiction

Source: Anthony et al, 1994Source: Anthony et al, 1994..

Ever Used Ever Used (%)(%)

Addiction (%)Addiction (%) Risk Risk (%)(%)

TobaccoTobacco 75.675.6 24.124.1 31.931.9

CocaineCocaine 16.216.2 2.72.7 16.716.7

HeroinHeroin 1.51.5 0.40.4 23.123.1

AlcoholAlcohol 91.591.5 14.114.1 15.415.4

CannabisCannabis 46.346.3 4.24.2 9.19.1

Rat model Addiction – 20% of exposed

1. Continue bar pressing long after

drug terminated – stopping difficult

2. High motivation – break point

3. Continue despite punishment

““Unseen” Unseen” Reward Reward

CuesCues

activateactivate

amygdala amygdala

v. striatumv. striatum

v. pallidum v. pallidum

InsulaInsula

Types of Genetic Studies

FamilyTwinAdoptionLarge population: COGACandidate gene studies

ASTHMA (adult only) .35 - .70

DIABETES (insulin dep) .70 - .95 (males)

HYPERTENSION .25 - .50 (males)

Heritability EstimatesTwin Studies

ALCOHOL (dependence) .55 - .65 (males)

OPIATE (dependence) .35 - .50 (males)

Eye Color 1.00

The Alcohol Pyramid

In Spec Treatment – 1,800,000

Abuse/Dependent – 18,000,000

“Harmful Users” – ??,000,000

Results at 5-7 Years

Practicing Medicine

Completers 92%

Continuers 73%

Non-Completers 28%

Health care reform for addiction treatment

• Not limited to acute care• Early identification• Long term care• Medications when indicated

Level Of Response To Alcohol

• Observe less response when tested with alcohol• Self-report of more drinks for an effect• IV alcohol clamp to control level

Response• Genetically influenced (heritability 40%)

• Low LR in animals, twins, 1° relatives, 40% offspring of alcoholics

Low response Predicts Alcoholism 4-20 Years Later

• If response low at age 20• And FH positive• 60% men developed alcohol use disorder

by age 30

Frontal Inhibitory SystemsFrontal Inhibitory Systems

• Inability to resist craving

• Unable to “Just say NO!”

• Impulsive behavior

• Poor performance on frontal lobe

tests, e.g., gambling

• Possible DSM V spectrum Dx

OCD, ADHD, ASP, ?

PET O-15PET O-15

HypoactivityHypoactivity

ReducedReduced

Gray MatterGray Matter

Cocaine PatientsCocaine Patients

Peoples, 2002

Brain Reward System

PrefrontalCortex

Nucleus Accumbens

Arcuate Nucleus Ventral

TegmentalArea

Nestler and Malenka. The Addicted Brain. Scientific American. March, 2004.

Laboratory Studies of Drug Craving

• Videos

• Imagery

• Odors

Naturally conditioned responses

Amygdala Nature Video Cocaine Video

Anterior Cingulate1.5

0

.5

1.0

2.0

2.5

Pt. 30023Childress ‘97

Pt. Op_1.1

Nature Video Opiate Video

Anterior Cingulate1.5

0

.5

1.0

2.0

2.5

Orbitofrontal

Pt. SX_4

Amygdala Nature Video Sexual Video

Anterior Cingulate

0

0.5

1

1.5

2

NeutralCocaine-Cues

Dist

ribut

ion

Volu

me

*

0

0.05

0.1

0.15

0.2

Caud

ate

Putam

en

Vent

ral S

triatu

m

Cere

bellu

m

K1

Bm

ax/K

d

Co

cain

e C

ravi

ng

30 20 10 0 -10 -20 -30 -40 30 20 10 0 -10 -20 -30 -40

2.5

2.0

1.5

1.0

0.50

0.0

-0.50

2.5

2.0

1.5

1.0

0.50

0.0

-0.50Ch

an

ge

in

Cra

vin

g (

Po

st-

Pre

)

Ch

an

ge

in

Cra

vin

g (

Po

st-

Pre

)

% Change Bmax/kd

Caudate

% Change Bmax/kd

Putamen

*

** **

Dopamine D2 Receptors are Lower in Addiction

DA

D2

Rec

epto

r A

vaila

bilit

yD

A D

2 R

ecep

tor

Ava

ilabi

lity

CocaineCocaine

AlcoholAlcohol

DA

DA

DA

DA DA DA

DA

Reward Circuits

DA DA DA DA

DA

Reward Circuits

DA

DA

DA

DA DA

DA

Drug Abuser

Non-Drug Abuser

HeroinHeroin

MethMeth

controlcontrol addictedaddicted

Adapted from Volkow et al., Neurobiology of Learning and

Memory 78:610-624, 2002.

Volkow ND and Wise RA: How can drug addiction help us understand obesity? Nature Neuroscience, May 2005

Alcohol: desired drinkAlcohol: desired drink

• Humans since recorded historyHumans since recorded history

• Animals from insects to elephantsAnimals from insects to elephantspopular literaturepopular literaturemonkeys engage in spontaneousmonkeys engage in spontaneous

alcohol-seekingalcohol-seekingAnimal models are predictive of human Animal models are predictive of human drug taking drug taking

Ethanol: Ethanol: a drug with complex effects on a drug with complex effects on

multiple neurotransmitter systemsmultiple neurotransmitter systems

Alcohol rewardAlcohol reward

Partial list• GABA• Serotonin• AMPA, Glu-rec• NMDA• Neuropeptide Y• Glycine• Opioid- µ, k, ∂

Alcohol rewardAlcohol reward

Sedating drug, facilitates GABAergic meds, no specific receptor

“dirty” drug- affects numerous receptor systems, directly or indirectly

FDA Approved MedicationsFDA Approved Medications

• Disulfiram (Antabuse)• Naltrexone (generic)• Acamprosate (Campral)• Depot Naltrexone (Vivitrol)

Arguments against medicationsArguments against medications

• They are just a “crutch”• You have to work the program yourself –

no chemical aids• They get in the way of the 12 steps• I’ve been sober for 10 years and I never

took medication• They have side effects• You’ll become addicted to them• Etc…

True Translational Story:True Translational Story:Naltrexone for AlcoholismNaltrexone for Alcoholism

• Animal labto

• Randomized clinical trialsto

• FDA approval for clinical practiceto

?? Standard practice

Endogenous Opioid SystemEndogenous Opioid System

Opiate Receptors

Simon 1973

Pert & Snyder 1973

Terenius 1973

Enkephalin 1975 ∂

B-Endorphin µ

Dynorphin k

Nociceptin OFQ/NOC 1990s

-60-50-40-30-20-10

010203040

1 to 5 5 to 10 10 to 15

Naltrexone 1.0 mg/kg

Naltrexone 3.0 mg/kg

Naltrexone 5.0 mg/kg

Naltrexone decreases Alcohol preference*Naltrexone decreases Alcohol preference*

Days NaltrexoneDays Naltrexone* Altshuler 1980* Altshuler 1980

% C

han

ge

fro

m S

alin

e P

retr

eatm

ent

% C

han

ge

fro

m S

alin

e P

retr

eatm

ent

Res

po

nse

Lev

els

(10

day

mea

n)

Res

po

nse

Lev

els

(10

day

mea

n)

Post-Shock DrinkingC

han

ge

in %

Eth

ano

l C

on

sum

pti

on

0

5

10

15

20

25

Placebo

Naltrexone

-51-2 3-4 5-6

Days Post-ShockDays Post-Shock

0

10

20

30

40

50

60

70

80

0 5 10 15 20 25 300

10

20

30

40

50

60

70

80

0 5 10 15 20 25 30

BaselinePost-Deprivation (Day 1)Post-Deprivation (Day 2)

SalineSaline .25 mg/kg Naltrexone.25 mg/kg NaltrexoneE

than

ol R

esp

on

ses

Eth

ano

l Res

po

nse

s

Time (min)Time (min) Time (min)Time (min)

Variable response to alcoholVariable response to alcohol

Alcohol seeking10 of 22 Rhesus (Altshuler)15% Vervets10-15% H. sapiens

Less variable in rodentsµ receptor knock outs will not self administer

alcohol

Assumption: alcohol releases Assumption: alcohol releases endogenous opioidsendogenous opioids

In vivo evidence: only indirect evidence in brain, direct evidence in plasma

In vitro evidence: direct measures in lymphocyte cultures, HIV effects of alcohol blocked by naltrexone.Wen Ze Ho et al, 2006

Molecular mechanism unknown

Naltrexone Concurrently Antagonizes EtOH-Induced Accumbal DA Release and EtOH Self-Administration

Gonzales & Weiss (2002) J Neurosci 18:10663-10671

Assumption: alcohol causes the Assumption: alcohol causes the release of endogenous opioids release of endogenous opioids

which are “required” for DA which are “required” for DA release in response to alcohol?release in response to alcohol?

Brain Reward System

PrefrontalCortex

Nucleus Accumbens

Arcuate Nucleus Ventral

TegmentalArea

Nestler and Malenka. The Addicted Brain. Scientific American. March, 2004.

–

GABA

Ventral Tegmental AreaArcuate Nucleus

Dopamine

-Endorphin Neuron

Long Loop

Nucleus Accumbens

Dopamine

–

Alcohol

Gianoulakis. Alcohol-Seeking Behavior: The Roles of the Hypothalamic-Pituitary-Adrenal Axis and the Endogenous Opioid System. Alcohol Health and Research World. 1998;22(3).

DopamineOpioid Antagonism

–

GABA

Ventral Tegmental AreaArcuate Nucleus

-Endorphin Neuron

Nucleus Accumbens

–

Alcohol

Dopamine

Gianoulakis. Alcohol-Seeking Behavior: The Roles of the Hypothalamic-Pituitary-Adrenal Axis and the Endogenous Opioid System. Alcohol Health and Research World. 1998;22(3).

Alcohol effects become conditioned to environmental cues

Naltrexone blocks cue induced relapse better than stress induced

70

80

90

100

110

120

130

140

150

10 20 30 40 50 60 70

Time (minutes)

Do

pa

min

e (

% b

as

eli

ne)

Saline, N=13

Naltrexone, N=16

Pre-AlcoholPre-Alcohol “Craving”“Craving”

Alcohol - Beverage Condition

Insula

Cingulate

Nucleus Accumbens

Z=1.645 Ex .05

Alcoholics (n=10) Controls (n=10)

Ventral Tegmental Area

Cingulate

Z=1.645 Ex .05

Alcohol - Beverage Condition

Alcoholics (n=10) Controls (n=10)

Propose an RCT of an opiate antagonist in human alcoholics

because of animal data ??

IND 1983Begin open studies

50 mg dose based on experience with heroin

Philadelphia VA Hospital

Post-SynapticNeuron

KappaKappa Mu Mu Delta Delta

Affinity for Opiate ReceptorAffinity for Opiate Receptor

TXTX

TXTX

TXTX

Opiate ReceptorsOpiate Receptors

KappaKappa MuMu DeltaDelta

NaltrexoneNaltrexone 406 406 108 108 54 54 MorphineMorphine 1 1 1 1 1 1

MORMOR

MORMOR

MORMOR

MO

RM

OR

..

..

..

..

NOCNOC

NN

Double blind design

• 70 chronic alcoholics

• All received intensive day hospital, AA, psychotherapy

• Half received Naltrexone 50 mg/day

• Half received identical placebo

• Weekly craving scores

• “slips” measured (not a relapse)

• Relapse defined

Pharmacological Treatments for Pharmacological Treatments for AlcoholismAlcoholism

Mea

n (

SE

M)

Cra

vin

g S

c ore

(0-

9)M

ean

(S

EM

) C

ravi

ng

Sco

re (

0 -9)

0

1

2

3

4

5

Placebo

Naltrexone

0 1 2 3 4 5 6 7 8 9 10 11 120 1 2 3 4 5 6 7 8 9 10 11 12

Weeks on MedicationWeeks on Medication

Craving Scores by WeekCraving Scores by Week

Cue-induced increases in DA were associated with cravingCue-induced increases in DA were associated with craving

P < 0.002

% Change Bmax/Kd

-0.50

0.0

0.50

1.0

1.5

2.0

2.5

-40-30-20-100102030

Putamen

Ch

an

ge

in C

rav

ing

(Pre

- P

os

t)

Relationship between Cue-Induced Decreases in [11C]raclopride Binding and Cocaine Craving

Ca

uda

teC

au

date

Pu

tam

en

Pu

tam

en2.002.00

2.502.50

3.003.00

3.503.50

NeutralNeutralCocaine-CuesCocaine-Cues

Bm

ax/

Kd

Bm

ax/

Kd

P < 0.05P < 0.05

P < 0.01P < 0.01

Volkow et al J Neuroscience 2006

Subjective “high” in Naltrexone and Subjective “high” in Naltrexone and Placebo SubjectsPlacebo Subjects

Naltrexone PlaceboNaltrexone Placebo

mea

n

“hig

h”

rati

ng

mea

n

“hig

h”

rati

ng

0.1

0

- 0.1

- 0.2

- 0.3

- 0.4

- 0.5 **

* p<.05* p<.05

A.A. coming to treatment appointment coming to treatment appointment with a blood alcohol concentration with a blood alcohol concentration

> 100 mg%> 100 mg%oror

B.B. self report of drinking five or more self report of drinking five or more days within one weekdays within one week

oror

C.C. self report of five or more drinks during self report of five or more drinks during one drinking occasionone drinking occasion

Alcohol RelapseAlcohol Relapse

Non-relapse “Survival”Non-relapse “Survival”

Volpicelli et al, Arch Gen Psychiatry, 1992; 49: 876-880Volpicelli et al, Arch Gen Psychiatry, 1992; 49: 876-880

No. of Weeks Receiving MedicationNo. of Weeks Receiving Medication

10 2 3 4 5 6 7 8 9 10 11 12

0.0

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.3Naltrexone HCL (N=35)Naltrexone HCL (N=35)

Placebo (N=35)Placebo (N=35)

Cu

mm

ula

tive

Pro

po

rtio

n w

ith

No

Rel

apse

Cu

mm

ula

tive

Pro

po

rtio

n w

ith

No

Rel

apse

Rates of Never Relapsing According to Treatment Group Rates of Never Relapsing According to Treatment Group (n=97)(n=97)

O’Malley et al, Arch of Gen Psychiatry, Vol 49, Nov 1992

Naltrexone/coping skillsNaltrexone/supportive therapyPlacebo/coping skillsPlacebo/supportive therapy

Days

0

20

40

60

80

100

n=97

Per

cent

With

out R

elap

se

0 20 40 80 60

Alcohol “PRIMING” in human, non-treatment seeking Alcoholics

O’Malley et al

From the animal laboratory back to the clinic

0

0.02

0.04

0.06

0.08

0.1

0 10 20 30 40 80 110 150 180

Placebo, n = 8

Naltrexone, n = 10B

loo

d A

lco

ho

lB

loo

d A

lco

ho

l lev

els

(g/d

l)le

vels

(g

/dl)

0

5

10

15

20

25

30

35

40

0 10 20 30 40 80 110 150 180

Placebo, n = 7

Naltrexone, n = 9

Cra

vin

gC

rav i

ng

Priming Dose First Choice Second Block

Addiction Therapy may be related to activation of Frontal Cortex

(Boettiger, et.al. 2009)(Crews and Boettiger et.al. 2009)

Possible mechanisms of naltrexone effects

1. Block reward via endogenous opioid system - alcohol activates E.O. - Extinction of alcohol self-administration

2. Reduction in craving does not require extinction

some treated alcoholics do not test by drinking

3. Direct effect of naltrexone on frontal executive fxInc activity in r.lat.orbital gyrus during decision making (delay of reward) & decreased selection of immediate reward. (Boettiger et al 2009)

Studies supporting efficacyStudies supporting efficacy Studies not supporting efficacyStudy # Ss Notes Study # Ss Notes

Volpicelli, et al 1992 70 None Kranzler, et al 1999

183 None

O’Malley, et al 1992 97 None Krystal, et al 2002 627 None

Mason, et al 1994 [Nalmefene]

21 None

Oslin, et al 1997 44 Elderly

Volpicelli, et al 1997 97 None

Mason, et al 1999 [Nalmefene]

105 None

Kranzler, et al 1998 20 Depot

Anton, et al 2000 131 None

Chick, et al 2000 (UK) 169 Adherence

Monterosso, et al 2001 183 None

Morris, et al 2001 (Australia)

111 None

Heinala, et al 2001 (Finland)

121 Nonabstinent

Lee, et al 2001 (Singapore)

Kiefer et al 2003 (Germany)

53

160

None

None

Studies supporting efficacy Studies not supporting efficacy

Study # Ss Notes Study # Ss Notes

Latt et al 2002 107 Family Prac

Balldin et al 2003 118 None

Feeney et al 2001 50 Hist. cont

Rubio et al 2001 157 v. Acamp.

Rubio et al 2002 30 Cont. Drink.

Gastpar et al 2002 105 Neg. in self report

Pos. GGT

Gastpar et al 2002 105 Neg. in self

report

Pos. GGT

Guardia et al 2002 202 Relapse

Kranzler et al 2003 153 Heavy drinkers

O’Malley et al 2002 18 Human lab

Anton et al 2006 1383 RCT, depot

Results: Heavy Drinking Days

Baseline

Placebo

Vivitrex 190 mg

Vivitrex 380 mg

75th Percentile

25th Percentile

Med

ian

Hea

vy

Dri

nki

ng

Da

ys p

er M

on

th

0

5

10

15

20

25

30

Overall Male Female

19.3

7.05.6

4.94.0

2.1

5.4

19.3

3.1

5.94.4

21.5

Why do many alcoholics respond to naltrexone, but others show no response?

% D

ays

Hea

vy D

rin

kin

g

(PACS < 5) (PACS 6-15) (PACS > 15)

0

2

4

6

8

10

12

14

16

Low Crave Mod Crave High Crave

NTX

PLAn = 44

n = 72

n = 57

PACS = Penn Alcohol Craving Scale

Baseline Craving Scores

Family History and Naltrexone EfficacyFamily History and Naltrexone Efficacy%

Day

s H

eavy

Dri

nki

ng

% D

ays

Hea

vy D

rin

kin

g

0

2

4

6

8

10

12

14

16

NXTPLA

< 25% Alc Problem 25%-50% Alc Problem > 50% Alc Problem

Density of Familial Alcohol Problems

n = 77 n = 73

n = 29

Baseline b-Baseline b-Endorphin Levels in Low- and Levels in Low- and High-Risk, and Abstinent Alcoholic PatientsHigh-Risk, and Abstinent Alcoholic Patients

0

10

20

30

40

50

Low Risk High Risk Abstinent

Pla

sma

Pla

sma

-E

nd

orp

hin

Lev

els

(pg

/ml

-En

do

rph

in L

evel

s (p

g/m

l)

Gianoulakis. Gianoulakis. Eur J Pharmacol.Eur J Pharmacol. 1990;180:21-29 1990;180:21-29.

0

20

40

60

80

100

120

140

160

180

0 20 40 60 80 100 120

High Risk

Low Risk

Minutes after alcohol consumptionMinutes after alcohol consumption

% c

han

ge

in p

lasm

a b

-en

do

rph

in le

vels

% c

han

ge

in p

lasm

a b

-en

do

rph

in le

vels

Change in b- Endorphin Levels after Alcohol Change in b- Endorphin Levels after Alcohol

ConsumptionConsumption

0

5

10

15

20

25

FH+

FH-

0

5

10

15

20

25

BAES Stimulation Scores BAES Stimulation Scores Among FH+ and FH SubjectsAmong FH+ and FH Subjects

PlaceboPlacebo NaltrexoneNaltrexone

Base 2 30 min 60 min 120 minBase 2 30 min 60 min 120 min Base 2 30 min 60 min 120 minBase 2 30 min 60 min 120 min

Possible Families of Risk Factors• Level of response (LR)• P3/disinhibition/ASPD/type 2/B• Independent axis II disorders• Endogenous Opioid System• Alcohol metabolizing enzymes

Key effect: Sensitivity of Endogenous Opioid system to alcohol

One source of individual variability in response to ethyl alcohol

OPRM1 PROTEIN STRUCTURE

LIGAND BINDING

EXTRACELLULARNH2 TERMINUS

A118G

COOH TERMINUS

N40D, N is anN-glycosylation site

Human Mu Opioid Receptor Gene

PROMOTOR 5’UTR EXON 1 EXON 2 EXON 3 EXON 4 3’UTR

10 variants

4 5’UTR

SNPs

2 SNPs 1 SNP

6 INTRON 2 SNPs6 INTRON 2 SNPs

1 INTRON 1 INTRON

3 SNP3 SNP1 3’UTR

SNP6.6 kb of OPRM1 gene sequence was determined in ~200 persons; 25 variants occurred at a frequency >1%.

The 118 A>G exon 1 SNP increases OPRM1 affinity for beta-endorphin. The functional significance of other variants remains unknown.

Functional AlleleFunctional Allele

Increase

and

Decrease

05

101520253035404550

0.02 0.04 0.06

AA alleleAG allele

Se

lf-r

e po

rte

d S

tim

ula

t io

n (

SH

AS

)

Breath Alcohol ConcentrationBreath Alcohol Concentration

Alcohol effects by genotypeAlcohol effects by genotype

Wand et al, Neuropsychopharm 26:106–114, 2002

Ethnicity & A118G Allele Frequency

• Based on multiple studies, allele frequencies differ markedly across ethnicities for the A118G SNP in the mu opioid receptor gene. It arose after the out-of-Africa migration.

• Crowley et al, 2003• Gelernter et al,

1999• Tan et al, 2003• Bart et al, 2004

African 1% Koreans 31%

African-

American

3% Chinese 35%

Swedish 17% Malaysian 45%

European-

origin US

15% Indian 47%

ETHNICITY f(G) ETHNICITY f(G)

05

101520253035404550

0.02 0.04 0.06

AA alleleAG allele

Se

lf-r

e po

rte

d S

tim

ula

t io

n (

SH

AS

)

Breath Alcohol ConcentrationBreath Alcohol Concentration

Alcohol effects by genotypeAlcohol effects by genotype

Subjective “high” in Naltrexone and Subjective “high” in Naltrexone and Placebo SubjectsPlacebo Subjects

Naltrexone PlaceboNaltrexone Placebo

mea

n “

hig

h”

rati

ng

mea

n “

hig

h”

rati

ng

0.1

0

- 0.1

- 0.2

- 0.3

- 0.4

- 0.5 **

* p<.05* p<.05

OPRM1 A118G and Opioid DependenceOPRM1 A118G and Opioid Dependence

Bart et al (Mol Psychiatry 9:547, 2004) studied opioid addicts in

Sweden for A118G.

0

20

40

60

80

100

120

140

160

controls opioidaddicts

A/A

A/G, G/G

There was a significant (Chi squared = 13, p = 0.00025)increase in A/G, G/G genotypeamong opioid addicts. The attributable

risk for the G allele is ~ 18%, suggesting

that ~ 18% of Swedish opioid addicts have disease in part due to the G allele.

OPRM1 A118G and AlcoholismOPRM1 A118G and Alcoholism

Bart et al (Neuropsychopharmacol, 2005) studied alcoholics in Sweden for the A118G.

0

50

100

150

200

250

300

controls alcoholics

A/A

A/G, G/G

There was a significant (Chi squared = 7.2, p = 0.007)increase in A/G, G/G genotypeamong alcoholics. In this study the attributable risk for the G

allele is ~ 11%, suggesting that

~ 11% of Swedish alcoholics have disease in part due to the G allele.

Relapse Rate by GenotypeRelapse Rate by Genotype

8470564228140

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

Naltrexone /Asp40 Allele (A/G, G/G)

Naltrexone Asn40 Allele (A/A)

Placebo /Asp40 Allele (A/G, G/G)

Placebo /Asn40 Allele (A/Al)

847070564228140

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

Naltrexone /Asp40 Allele (A/G, G/G)

Naltrexone Asn40 Allele (A/A)

Placebo /Asp40 Allele (A/G, G/G)

Placebo /Asn40 Allele (A/Al)

8484565642422828141400

1.01.0

.9.9

.8.8

.7.7

.6.6

.5.5

.4.4

.3.3

.2.2

.1.1

0.00.0

Naltrexone /Naltrexone /Asp40 Allele (A/G, G/G)Asp40 Allele (A/G, G/G)

Naltrexone Naltrexone Asn40 Allele (A/A)Asn40 Allele (A/A)

Placebo /Placebo /Asp40 Allele (A/G, G/G)Asp40 Allele (A/G, G/G)

Placebo /Placebo /Asn40 Allele (A/Al)Asn40 Allele (A/Al)

Pro

po

rtio

n N

on

rela

pse

dP

rop

ort

ion

No

nre

lap

sed

DaysDays

COMBINE Study

• N = 1383; 9 randomized groups– MM + Placebo

– MM + Naltrexone

– MM + Acamprosate

– MM + Naltrexone + Acamprosate• CBI only

• At least 4 days abstinence at baseline• Endpoints

– Percent days abstinent

– Time to first heavy drinking day

+/- CBI

CBI = cognitive behavioral intervention;MM = medical managementAnton et al. JAMA. 2006;295:2003.

Combine: NIAAACombine: NIAAAGood OutcomeGood Outcome

NaltNalt A/G, GG A/G, GG 95%95% N = 28N = 28

Nalt Nalt A/A A/A 73%73% N = 86N = 86

Plac.Plac. A/G, GG A/G, GG 63%63% N = 60N = 60

Plac.Plac. A/A A/A 65%65% N = 205N = 205

Odds ratio, nalt good regs, GVA = 10.25 (95% CI 1.31 - 80.0 P= .03)Odds ratio, nalt good regs, GVA = 10.25 (95% CI 1.31 - 80.0 P= .03)

*VA multi-site study: sample size with G allele small*VA multi-site study: sample size with G allele small

Rhesus model

Ortholog of A118G allele in humans(OPRM1C77G)

increased sensitivity to alcohol

increased alcohol preference

greater effect in males (Barr et al)

Sub-sample of VA coop. study

Those who gave blood for DNA

Naltrexone sig. better than placebo, but no genetic

association.

Finnish study with Nalmefene- Naltrexone superior to

placebo, but no genetic association

PROSPECTIVE study in progress

Slow release version of naltrexone

Genetic Variables

Risk Increase DecreaseLow LR +

High LR -

ASP +

ALDH2 -

G-Allele-µ op. (Stimulation)

+

Environment + -

genome scans - Phenotype association

Genotype - Behavior, (DSM IV)

1940s categories

- Endophenotype –

biological-alcohol response, imaging

EndophenotypeEndophenotypeEndorphin Dependent AlcoholismEndorphin Dependent Alcoholism

• AlcoholAlcohol Endogenous Opioids Endogenous Opioids

• Euphoria/StimulationEuphoria/Stimulation

• Sensitive µ ReceptorsSensitive µ Receptors

• Family HistoryFamily History

• Alcohol CravingAlcohol Craving

Best TreatmentBest Treatment

• Medications

Plus

• Psychosocial Intervention

Penn/VA Center TeamPenn/VA Center Team

Joe Volpicelli James McKayWade Berrettini A. Thomas McLellanJohn Cacciola David MetzgerAnna Rose Childress David OslinJames Cornish Helen PettinatiCharles Dackis Michael StrombergRonald Ehrman Elmer YuTeresa Franklin George WoodyKyle Kampman Arthur Alterman

FOR MORE INFORMATIONFOR MORE INFORMATION

http://www.med.upenn.edu/csa/http://www.med.upenn.edu/csa/or or

obrien@mail.trc.upenn.eduobrien@mail.trc.upenn.edu

Possible Gender Effect

Males more responsive in only study with large number of women

MedicationsMedications• Nicotine

Nicotine patch, gum, nasal sprayBupropionVareniclineRimonabant*

• OpiatesMethadoneBuprenorphineNaltrexone

• StimulantsModafinilTopiramateBaclofenDisulfiramPropranololVigabatrin (clinical trials)

• AlcoholDisulfiram

Naltrexone Acamprosate Topiramate

0100200300400500600700800900

10001100

0 1 2 3 4 5 hrTime After Amphetamine

% o

f B

asal

Rel

ease

DADOPACHVA

AccumbensAMPHETAMINEAMPHETAMINE

0

100

200

300

400

0 1 2 3 4 5 hrTime After Cocaine

% o

f B

asal

Rel

ease

DADOPACHVA

AccumbensCOCAINECOCAINE

0

100

150

200

250

0 1 2 3 4 5hrTime After Morphine

% o

f B

asal

Rel

ease Accumbens

0.51.02.510

Dose (mg/kg)

MORPHINEMORPHINE

0

100

150

200

250

0 1 2 3 hrTime After Nicotine

% o

f B

asal

Rel

ease

AccumbensCaudate

NICOTINENICOTINE

Effects of Drugs on Dopamine Levels

Source: Di Chiara and Imperato

Learning Objectives

• Describe the data supporting a new

subtype or endophenotype of

alcoholism.

• Describe the relative merits of the

various medications available for

the treatment of alcoholism.

• Describe the range of specific

psychosocial treatments for

alcoholism.

Dependence (Addiction)Dependence (Addiction)

• ToleranceTolerance• WithdrawalWithdrawal• More use than intendedMore use than intended• Unsuccessful efforts to cut downUnsuccessful efforts to cut down• Spends excessive time in Spends excessive time in

acquisitionacquisition• Activities given up because of useActivities given up because of use• Uses despite negative effectsUses despite negative effects

DSM-IV

Possible ChangesPossible Changes

• Addiction instead of Dependence?Addiction instead of Dependence?

• Abuse? necessaryAbuse? necessary

• Severity?Severity?

• Substance and non-substance addictionsSubstance and non-substance addictionsGambling addictionGambling addictionInternet gaming?Internet gaming?Food? Sex? Shopping?Food? Sex? Shopping?

DSM-V

Risk of AddictionRisk of Addiction

Source: Anthony et al, 1994.Source: Anthony et al, 1994.

Ever Used (%)Ever Used (%) Dependence (%)Dependence (%) Risk (%)Risk (%)

TobaccoTobacco 75.675.6 24.124.1 31.931.9

CocaineCocaine 16.216.2 2.72.7 16.716.7

HeroinHeroin 1.51.5 0.40.4 23.123.1

AlcoholAlcohol 91.591.5 14.114.1 15.415.4

CannabisCannabis 46.346.3 4.24.2 9.19.1

Drugs of Abuse all Drugs of Abuse all Activate Reward SystemActivate Reward System

• Cues associated with drugsCues associated with drugs become conditioned stimulibecome conditioned stimuli

From: Koob G, Everitt, B and Robbins T, Reward, motivation and addiction. In: Fundamental Neuroscience, in press.

Key Elements of the Neurocircuitry of Addiction

Key Elements of the Neurocircuitry of Addiction

From: Koob G, Everitt, B and Robbins T, Reward, motivation and addiction. In: Fundamental Neuroscience, in press.

[11C]Raclopride Binding In Cocaine Abusers (n=18) Viewing a Neutral and a Cocaine-Cue

Video

Viewing a video of cocaine scenes decreased specific binding of [11C]raclopride presumably from DA

increases

Neutral video

Volkow et al J Neuroscience 2006

Cue-induced increases in DA were associated with cravingCue-induced increases in DA were associated with craving

P < 0.002

% Change Bmax/Kd

-0.50

0.0

0.50

1.0

1.5

2.0

2.5

-40-30-20-100102030

Putamen

Ch

an

ge

in C

rav

ing

(Pre

- P

os

t)

Relationship between Cue-Induced Decreases in [11C]raclopride Binding and Cocaine Craving

Ca

uda

teC

au

date

Pu

tam

en

Pu

tam

en2.002.00

2.502.50

3.003.00

3.503.50

NeutralNeutralCocaine-CuesCocaine-Cues

Bm

ax/

Kd

Bm

ax/

Kd

P < 0.05P < 0.05

P < 0.01P < 0.01

Volkow et al J Neuroscience 2006

““Unseen” Unseen” Cue Cue

ParadigmParadigm

33 msec 33 msec targetstargets

467 msec 467 msec “masks”“masks”

““Unseen” Unseen” Reward Reward

CuesCues

activateactivate

amygdala amygdala

v. striatumv. striatum

v. pallidum v. pallidum

InsulaInsula

Alcoholism: FDA Approved MedicationsAlcoholism: FDA Approved Medications

• DisulfiramDisulfiram

• NaltrexoneNaltrexone• Depot naltrexoneDepot naltrexone• AcamprosateAcamprosate

Specific Meds can block rewardSpecific Meds can block reward

• GABA enhancersGABA enhancers

• Receptor antagonists Receptor antagonists

Baclofen blunts Amygdala Connectivity during 500 msec “SEEN” Cocaine Cues

Placebo Baclofen

Second half of the task [Drug 2; placebo n = 9; baclofen n =10]

70

80

90

100

110

120

130

140

150

10 20 30 40 50 60 70

Time (minutes)

Do

pa

min

e (

% b

as

eli

ne)

Saline, N=13

Naltrexone, N=16

Pre-AlcoholPre-Alcohol “Craving”“Craving”

What is Transducer?

• Alcohol releases Beta endorphin in

– Plasma (pituitary)

– Lymphocyte cultures (HIV infectivity blocked by naltrexone

– ? CNS

Post-DocsPost-Docs

Tom Aronson, MD

Joseph Volpicelli, MD, PhD

0

20

40

60

80

Any Alcohol DrinkingAny Alcohol Drinking

Naltrexone PlaceboNaltrexone Placebo

Per

cen

t o

f S

ub

ject

sP

erce

nt

of

Su

bje

cts

0.0

0.2

0.4

0.6

0.8

1.0

Days DrinkingDays Drinking

Naltrexone PlaceboNaltrexone Placebo

Ave

rag

e D

rin

kin

g D

ays

Ave

rag

e D

r in

kin

g D

ays

per

wee

kp

er w

eek