Upload
dulcie-mosley
View
217
Download
0
Tags:
Embed Size (px)
Citation preview
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
[email protected]@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