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AlcoholismAlcoholismAlcoholismAlcoholism
David W. Oslin, MD
Associate ProfessorUniversity of Pennsylvania, School of Medicine
And
Philadelphia, VAMC
Hazelden Research Co-Chair on Late Life Addictions
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Introduction Introduction Alcoholism costs the nation $150 Billion / annum
in the US. As such it is the most expensive addictive disorder.
Alcoholism leads to increased mortality and morbidity
Alcoholism is common with about 7 million Americans afflicted
Worldwide alcoholism is the 7th leading cause of disability
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Alcohol UseAlcohol Use
AbstinenceModerate Use
Binge Use
Problems / AbusiveDrinking
Dependent
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Undertreatment of Alcohol Use DisordersUndertreatment of Alcohol Use Disorders
Grant BF et al. Arch Gen Psychiatry. 2004;61:807-816.SAMHSA, Office of Applied Studies. Substance Dependence, Abuse and Treatment Tables; 2003IMS - MAT March 2006
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Defining Alcohol DependenceDefining Alcohol Dependence
a person's maladaptive pattern of alcohol use leads to clinically important distress or impairment
3 of the following in a 12-month period Tolerance Withdrawal More time or larger amounts than desired Desire or effort to cut down Time spent obtaining or recovering Social, occupational or recreational effects Drinking despite consequences
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Alcoholism: A Chronic DiseaseAlcoholism: A Chronic Disease
Alcoholism is often compared to traditional illnesses
Asthma, diabetes, heart disease and arthritis Progressive, relapsing disease Genetic factors are important Symptoms show with advanced disease Treatment requires lifestyle changes
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Clinical ComponentsClinical Components
Withdrawal (acute and subacute)
Tolerance
Social devastation
Medical consequences CNS – depression, cognition Non-CNS – liver, heart, renal, PNS, pancreas, etc
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Risks vs. BenefitsRisks vs. Benefits
Risks Benefits
Abstinence Cardiovascular Social
Moderate Medication interactions Social
Cardiovascular
At-Risk Psychological distress
Suicide risk
Fractures
Adherence
Social
Abuse Social
Legal
None
Dependence All aspects of health / functioning
None
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Barriers to Recognition and TreatmentBarriers to Recognition and Treatment
Patient factors
Health professional factors
Healthcare system factors
Society factors
Treatment factors
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Treatment OptionsTreatment Options
Brief therapies Self-help groups (AA, ACOA, etc.) Individual therapy Family therapy Psychoeducational activities Hypnosis Activities therapy Group therapy (elder specific) Psychopharmacology
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Caveats About TreatmentCaveats About Treatment
Addiction treatment is not one size fits all. There are many options—use them
Compliance with treatment is important. Continually support treatment
Treatment is not a “carve out” available only in select settings
While abstinence is often the goal, it is not the only goal
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How does Alcohol work at the cellular level?How does Alcohol work at the cellular level?
Older hypotheses suggesting that ethanol has very generalized, non-specific actions on many neuronal systems seem unlikely
At intoxicating concentrations, ethanol has some very specific actions on a number of membrane proteins
Certain kinds of ligand-gated ion channels (i.e., postsynaptic receptors) appear to be an important target for ethanol action
Experimental strategies need to be developed to determine which actions of ethanol are relevant to specific behavioral effects
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I-RISA Model of Addiction I-RISA Model of Addiction Volkow (2004)Volkow (2004)
Salience
Control
Memory Memory
Control
Drive Salience DriveSTOP GO
Non-Addicted Brain Addicted Brain
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Pharmacological InterventionsPharmacological Interventions
Detection Threshold Disinhibition
Salience Cue-Reactivity Craving Relapse
Conflict Registration
Repeated Reward
Antagonists
Anti-CravingDrugs
CognitiveEnhancers
Agonists
Antagonist Anti-Craving DrugCognitive Enhancer Agonist
NaltrexoneAcamprosateModafinilMethadone
Opioid dependenceAlcohol dependenceCocaine dependenceOpioid dependence
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Pharmacotherapy for AddictionPharmacotherapy for Addiction
Alcohol dependence Naltrexone Acamprosate Antabuse
Opioids Buprenorphine Methadone
Cocaine ?
Nicotine Nicotine replacement Bupropion Verenicline
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Opioid antagonists - basic science Opioid antagonists - basic science
Alcohol consumption affects the production, release, and activity of opioid peptides (Herz, 1997)
Opioid peptides mediate some of alcohol’s rewarding effects by enhancing midbrain dopamine release
Opioid antagonists suppress alcohol-induced reward (Swift,1999) and general consummatory behaviors (Boyle et al. 1998)
Genetic high-risk / FH+ individuals have an exaggerated alcohol-induced rise in -endorphin level, and are more responsive to naltrexone treatment (Gianoulakis et al. 1996; King et al. 1997)
Embellished from Gianoulakis 1998
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NaltrexoneNaltrexone
Functions as an opioid receptor antagonist (mu >> delta or kappa)
Development was an example of bench to bedside translational science (opioid effects on reward pathways)
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Studies supporting efficacy Studies not supporting efficacy
Study # Ss Notes Study # Ss Notes
Volpicelli et al 1992 70 None Oslin et al 1997 44 Older
O’Malley et al 1992 97 None Kranzler et al 2000 183 None
Volpicelli et al 1997 97 None Krystal et al 2001 627 VA only
Kranzler et al 1998 20 Depot Lee et al 2001 (Singapore) 53 None
Anton et al 1999 131 None Gastpar et al 2002 (Germ.) 171 None
Chick et al 2000 (UK) 169 Adherence Kranzler et al 2004 315 Depot
Monterosso et al 2001 183 None Killeen et al 2004 145 None
Morris et al 2001 (Australia) 111 None Oslin et al in press 240 None
Heinala et al 2001 (Finland) 121 Nonabst.
Latt et al 2002 (Australia) 107 None
Ahmadi and Ahmadi 2002 (Iran) 116 None
Guardia et al 2002 (Spain) 202 None
Balldin 2003 118 None
Kiefer et al 2003 (Germany) 160 None
Kranzler et al 2003 153 None
Kranzler et al 2004 315 For drinking not relapse
Anton et al 2004 270 None
Garbutt et al 2005 627 Depot / males
Randomized Placebo Controlled Naltrexone TrialsRandomized Placebo Controlled Naltrexone TrialsRandomized Placebo Controlled Naltrexone TrialsRandomized Placebo Controlled Naltrexone Trials
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Naltrexone in the Treatment of Alcohol Naltrexone in the Treatment of Alcohol DependenceDependence
Volpicelli et al, Arch Gen Psychiatry, 1992; 49: 876-880
Cumulative Relapse Rate
No. of Weeks Receiving Medication
10 2 3 4 5 6 7 8 9 10 11 120.00.10.2
0.40.50.60.70.80.91.0
0.3
Cum
altiv
e P
ropo
rtio
n W
ith N
o R
elap
se
Naltrexone HCL (N=35)Placebo (N=35)
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Long-Acting Naltrexone Results: Long-Acting Naltrexone Results: Median Heavy Drinking DaysMedian Heavy Drinking Days
BaselinePlaceboL-A Ntx 190 mgL-A Ntx 380 mg
Median Heavy DrinkingDays per Month
0
5
10
15
20
25
30
n = 624
19.3
3.1
6.04.5
48%
p < 0.005
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P value
Acamprosate 0.23
Naltrexone 0.02
CBI 0.16(n=607) (N=619)
423 (69.7) 433 (70.0)
No CBI CBI
(N=618) (N=608)433 (70.1) 423 (69.6)
(N=612) (N=614)437 (71.4) 419 (68.2)
Placebo Acamprosate
Placebo Naltrexone
Mean (SD)Control Intervention
Main Effects
Results: Percent of Participants Relapsed (one or more heavy Results: Percent of Participants Relapsed (one or more heavy drinking day)drinking day)
Participants who received Naltrexone were less likely to relapse than participants who did not receive Naltrexone.
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For Whom?For Whom?
Under what conditions and for which patients will naltrexone have the greatest impact?
Treatment variance is common Adherence Gender / Race Pharmacokinetics Pharmacodynamics
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0
2
4
6
8
10
12
14
16
Low Density Medium Density High Density
NaltrexonePlacebo
% D
ays
of H
eavy
Dri
nkin
g
Monterosso et al 2001
Effects of Family History on Naltrexone Response
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Human Mu Opioid Receptor GeneHuman 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 SNPs
1 INTRON
3 SNP 1 3’UTR
SNPOPRM1 gene is estimated to span at least 90 kb in the chromosome 6q24-25 region. Four coding exons are separated by 3 introns.
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A+118G (Asn40Asp) A+118G (Asn40Asp)
Asp40 allele frequency of 13-20% (24.3 – 36% of European Americans have at least one copy)
Functional Significance: Asp40 variant binds beta-endorphin and activates G-
protein coupled protein potassium ion channels with 3 times greater potency
Naloxone challenge alters CRF secretion in those with the Asp40 variant
Asp40 variant appears to be transcribed less efficiently than Asn40
Asp40 increases pain sensitivity
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OPRM1 A118G EFFECTOPRM1 A118G EFFECTON TRANSCRIPTIONON TRANSCRIPTION
Zhang et al, JBC, 2005
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OPRM1 A118G EFFECTOPRM1 A118G EFFECTON TRANSLATIONON TRANSLATION
Zhang et al, JBC, 2005
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in vivo in vivo A118G Effects in Response to a mu A118G Effects in Response to a mu Opioid Receptor AgonistOpioid Receptor Agonist
05
1015202530354045
AA AG GG
OPRM1 GENOTYPE
% meiosis45 +/- 8
33 +/- 6*
24 +/- 7*
•p<0.001AA vs AG/GGLotsch et al,2006
(8) (3)(40)(n)
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Lotsch et al, 2006
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G Allele Carriers Hyporesponsive to mu Opioid G Allele Carriers Hyporesponsive to mu Opioid Receptor AgonistsReceptor Agonists
Romberg et al. Polymorphism of mu-opioid receptor gene (OPRM1:c.118AG) does not protect against opioid-induced respiratory depression despite reduced analgesic response. Anesthesiology 2005;102:522-30.
Klepstad et al. The 118 A G polymorphism in the human mu-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiol Scand 2004;48:1232-9
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Alcohol Induced StimulationAlcohol Induced Stimulation
01020304050
0.02 0.04 0.06
AA Allele
AG Allele
Ray and Hutchinson, 2004
Breath Alcohol Concentration
Subj
ectiv
e In
toxi
catio
n/H
igh
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Does Genotype influence Treatment Does Genotype influence Treatment Response with opioid receptor Response with opioid receptor
antagonism?antagonism?
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Data Supporting Genetic InfluencesData Supporting Genetic Influences
4-fold increased risk in close relatives (e.g. children, siblings)
Identical vs fraternal twins
Adopted away children still have a 4-fold increase in risk
Work with genetic animal models
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Genetic Polymorphisms and Alcohol Genetic Polymorphisms and Alcohol TreatmentTreatment
Naltrexone /Asp40 Allele (A/G, G/G)
Naltrexone Asn40 Allele (A/A)
Placebo /Asp40 Allele (A/G, G/G)
Placebo /Asn40 Allele (A/A)
Cu
mu
lati
ve S
urv
ival
(ti
me
to r
elap
se)
Days Oslin DW, et. al. 2003
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COMBINE StudyCOMBINE Study
Good Clinical Outcome (%)
Asp40Asn40/Asn40
Naltrexone 73 96
Placebo 63 51
Relapsed (%)
Asn40/Asn40 Asp40
Naltrexone 21 4
Placebo 29 12
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Naltrexone Should Be Used for Naltrexone Should Be Used for Patients With:Patients With:
Prior treatment failure
High level of interest in biomedical therapies
Low level of interest in traditional psychosocial therapies
Cognitive impairment
In most alcohol-dependent patients
Consider depot formulation for added adherence
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Glutamate antagonist: acamprosate - basic science Glutamate antagonist: acamprosate - basic science
Excitatory neurotransmitter
N-methyl-D-Aspartate (NMDA) contributes to alcohol’s intoxicating, cognitive, and dependence-forming effects
NMDA antagonist, acamprosate, reduces the intensity of post-cessation alcohol craving on exposure to high-risk drinking situations (Spanagel & Zieglgansberger, 1997)
Embellished from Spanagel & Zieglgansberger, 1997
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Glutamate antagonist: acamprosate - Glutamate antagonist: acamprosate - clinical science - 1clinical science - 1
Pooled data from a series of double-blind studies involving
> 3,000 individuals support acamprosate’s (1.3 g - 2 g / day) efficacy for treating alcoholism
Twice as many patients who received acamprosate vs. placebo remained abstinent at 1-year follow-up
Acamprosate’s treatment effect size is small to medium
From Whitworth et al. 1996
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SSRI’s and other serotonergic agentsSSRI’s and other serotonergic agents
By all accounts serotonin is important in addictions
But results from treatment trials? Some say yes, some say no, others
maybe.
Does the target audience matter?
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SertralineSertraline
0
5
10
15
20
25
Type A Type B
SertralinePlacebo
Per
cent
Day
s D
rink
ing
Type A – Low risk/severity Type B – High risk/severity
Pettinati, 2000
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ConclusionsConclusions
Alcoholism is a major public health problem associated with medical,
psychiatric, and economic consequences
Alcoholism is a Brain Disorder
Activates & dysregulates reward-related circuits
Important genetic basis
Responds to Pharmacotherapy
Stigma prevents its proper diagnosis and treatment
Understanding the biological basis of alcoholism will reduce its stigma and
improve its prognosis
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What Are the Terms?What Are the Terms?
Generally defined as drinking no more than 2 drinks per day No binge drinking Modified for women (1 drinks per day) Modified for older adults (1 drinks per day)
Social/Moderate DrinkerSocial/Moderate Drinker
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What is a Drink?What is a Drink?
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Factors Modifying the Factors Modifying the Ethanol Elimination RateEthanol Elimination Rate
There is a 3-4 fold variability in the rate of ethanol elimination by humans because of genetic and environmental factors, including
Sex / genetic factors Age Race Food biological rhythms Exercise Alcoholism Drugs / medications
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U.S. Total = 2.18U.S. Total = 2.181.99 or below 2.00 to 2.24 2.25 to 2.49 2.50 or over
Know Your State’s ConsumptionKnow Your State’s Consumption
DC