Transcript Current and Upcoming Approaches to Medically Supervised

Genetics,
Medical Consequences,
and Pharmacotherapy
of Addiction
Andrew J. Saxon, M.D.
Psychiatry & Behavioral Sciences
Addiction Treatment Center,
VA Puget Sound Health Care System
Addictions are Complex Disorders
The genetic contribution to vulnerability for addiction
(generally, or to a specific substance) is hypothesized
to involve multiple polymorphisms, including single
nucleotide polymorphisms (SNPs) in different genes.
Factors Contributing to Vulnerability
to Develop a Specific Addiction
use of the drug of abuse essential (100%)
Genetic
(25-60%)
Environmental
(very high)
• DNA
• SNPs
• other
polymorphisms
• prenatal
• postnatal
• contemporary
• cues
• comorbidity
• stress-responsivity
• mRNA levels
• peptides
• proteomics
• neurochemistry
• synaptogenesis
• behaviors
Drug-Induced Effects
(very high)
Kreek et al., 2000; 2005
Phenotyping in Addiction
No blood, tissue, radiologic test to make firm Dx
Gold Standard for Dx=structured interview using
DSM-IV criteria
BUT DSM-IV criteria expert consensus, not
scientifically validated; ongoing controversy over
criteria
Conflicting evidence on whether inheritance is
substance specific
Understanding Genetic and Environmental
Influences Using Twin Studies
MZ Twins
100% genes
100% home environment
DZ Twins
50% genes
100% home environment
If MZs > DZs → Additive Genetic Influence (A)
If DZs = MZs → Common Environmental Influence (C)
If MZs < 1 → Unique Environmental Influence (E)
Selected Twin Studies
Author
Year
Heath
True
Subs.
N (Twin
Pairs)
%Herita 95% CI
bility
1997 ETOH
5889
64%
32-73%
1999 Nicotine
3356
60.3%
55-65%
Lynskey 2002 Cannabis 6265
44%
15-72%
Kendler 2000 Cocaine
79%
59-90%
1198
Schuckit et al., 1994
Potential Alcohol Dependence Genes
Alcohol Dehydrogenase
Aldehyde Dehydrogenase
CYP450 2E1
Dopamine D1, D2, D3 Receptors
Dopamine Transporter
Serotonin Transporter
GABA Receptor Subunits
-,-, -Opioid Receptors
Cholinergic, Muscarinic Receptor Subunit (CHMR2)
Potential Tobacco Dependence Genes
CYP450 2A6
CYP450 2D6
CYP450 2E1
Dopamine D1, D2, D3 Receptors
Dopamine Transporter
GABA Receptor Subunits
Nicotinic Cholinergic Receptor Subunits 2 and 3
Src homology 2 domain-containing transforming protein C3 (SHC3)
Beta-arrestins 1 and 2
Catechol-O Methyl Transferase
Monoamine Oxidase
Potential Opioid Dependence Genes
CYP450 2D6
Dopamine D2, D4 Receptors
Dopamine Transporter
Proenkephalin
-,-Opioid Receptors
Catechol-O Methyl Transferase
Potential Cocaine Dependence Genes
Dopamine D2, D3 Receptors
Dopamine β-hydroxylase (cocaine paranoia)
Dopamine Transporter
Prodynorphin
Cannabinoid CB1 receptor
Chronic Alcohol Dependence
Causes Disease
Primary Diseases
Alcoholic health disease
(cardiomyopathy)
Alcoholic gastritis
Alcoholic liver cirrhosis
Alcoholic nerve disease
(polyneuropathy)
Alcoholic psychoses
Sources: NIAAA (1993); Stinson (1993); NHTSA (2002)
Secondary Diseases
Cancer (lip, mouth,
pharynx, esophagus,
larynx, liver, stomach)
Diabetes
GI disease
Heart disease
(hypertension, stroke)
Liver disease
Pancreatitis (acute,
chronic)
Pneumonia/influenza
Tuberculosis
Antecubital Fossa
Injection Drug Abuse
MEDICAL COMPLICATIONS OF
DRUG ADDICTION
FROM UNSTERILE NEEDLE USE AND SHARING
HIV
Hepatitis
Sepsis
FROM SMOKING
Decreased diffusing capacity
Bronchospasm
FROM LIFESTYLE
STDs
TB
Substance Use and Mortality
Total U.S. Mortality 1995=2,312,132
Illicit Drugs
2%
Tobacco
19%
ETOH
5%
Other
Causes
74%
McGinnis & Foege, 1999
Outpatient Care & Subsequent
Hospitalization of Illicit Drug Users
Retrospective cohort study of 58,243 illicit drug
users covered by NY State Medicaid Program
Laine et al., JAMA, 2001
55.6% of HIV-positive, 37.5 of HIV-negative hospitalized
VA Costs per Subject
Onsite (n=358)
Mean
Total Costs
Total
Medical/Surgical
Costs
Total Mental
Health Costs
Outpatient
Laboratory
Costs
Outpatient
Pharmacy Costs
SD
Referral (n=362)
Mean
SD
15,194.27 16,123.63 16,035.04 18,869.39
p-value
ns
2,309.79
4,473.49
2,835.47
7,963.29
ns
6,798.10
7,368.62
6,570.24
6,620.10
ns
674.38
685.02
699.24
737.91
ns
1,003.69
1,485.77
904.10
1,396.11
ns
Medications for
Alcohol Dependence
• Disulfiram (Antabuse)
• Naltrexone (ReVia)
• Acamprosate (Campral)
Disulfiram
H5C2
C2H5
N
H5C2
C
S
S
S
C
S
N
C2H5
Tetraethylthiuram - Synthesized by Danish scientists in the
1930’s as an antihelminthic; a non-specific inhibitor of
sulfhydryl-containing enzymes
Disulfiram
Disulfiram-Alcohol Reaction
•
•
•
•
•
•
•
•
Related to acetaldehyde buildup
Flushing
Sweating
Nausea and Vomiting
Headache
Tachycardia
Sometimes hypotension
Sometimes dyspnea
Possible Medication
for Cocaine Dependence
Disulfiram
– FDA approved for ETOH dependence
– 80% of cocaine dependent patients have ETOH
dependence. Can disulfiram  in ETOH use  cocaine
use?
– Inhibits dopamine -hydroxylase, enzyme which
catalyzes the rate limiting step in conversion of
dopamine to norepinephrine
– In the human laboratory disulfiram elevates cocaine
plasma levels through an unknown mechanism
Disulfiram
Disulfiram and Cognitive Behavior
Therapy in Cocaine-Dependent
Outpatients
Carroll et al., 2004
• 121 cocaine dependent subjects randomized to
–
–
–
–
Disulfiram + Cognitive Behavioral Tx
Disulfiram + Interpersonal Psychotherapy
Placebo + Cognitive Behavioral Tx
Placebo + Interpersonal Psychotherapy
Carroll et al., 2004
Heinz et al., 2005
Meta-Analysis Oral Naltrexone vs. Placebo:
Relapse to Heavy Drinking
Srisurapanont & Jarusuraisin, 2006
A+118G (Asn40Asp)
Asparagine asn – amide (neutral)
H2N-CO-CH2-CH(NH2)-COOH
Aspartic acid asp – (negatively charged)
HOOC-CH2-CH(NH2)-COOH
 Asp40 allele frequency of 13-20% (24.3 –
36% of European Americans have at least
one copy)
Pharmacogenetics of Naltrexone
Alcohol-Induced "High"
"High"
Score
6
4
AA
2
AG/GG
0
BAC=.02
BAC=.04
BAC=.06
Breath Alcohol Concentration
Analyses indicated that carriers of the G allele reported greater increases in
alcohol-induced “High” across rising levels of BrAC, F(2,76)=4.30, p<.05.
Ray & Hutchison, 2007
Cumulative Survival (time to relapse)
Genetic Polymorphisms and Alcohol
Treatment
Naltrexone /
Asp40 Allele (A/G, G/G)
Naltrexone
Asn40 Allele (A/A)
Placebo /
Asp40 Allele (A/G, G/G)
Placebo /
Asn40 Allele (A/A)
Days
Oslin DW, et. al. 2003
COMBINE Study
Good Clinical Outcome (%)
Asn40/Asn40
Asp40
Naltrexone
73
96
Placebo
63
51
Asn40/Asn40
Asp40
Naltrexone
21
4
Placebo
29
12
Relapsed (%)
Acamprosate
Acamprosate Pre-clinical Effects
• Boismaire et al., 1984
– Acamprosate reduces rodent alcohol consumption
– This effect blocked by bicucilline (GABAA Antagonist)
• Grant & Woolverton, 1989
– Acamprosate does not substitute for alcohol or
pentobarital in animals trained to self-administer them
– Animals will not self-administer acamprosate
• Zeise et al., 1993
– Acamprosate attenuates post-synaptic responses
induced by Excitatory Amino Acid agonists thereby
decreasing generalized neuronal excitability
Acamprosate for Maintaining Abstinence
Mann et al., 2004
Medications for Opioid Dependence
• Naltrexone
• Methadone
• Buprenorphine
Naltrexone for
Opioid Dependence
 Most ideal pharmacologic treatment
 Requires detoxification before initiation
or severe withdrawal will be precipitated
 Requires Naloxone challenge test
 Risk of OD if medication stopped
 In general poor patient compliance but
superb treatment for selected patients
Depot Naltrexone to Block Heroin Effect
Comer et al., 2002
Methadone Pharmacology
 Rapidly absorbed orally
 Peak Levels in 4 hours
 Half-life=24 hours
 Metabolized in liver
 Doses should be individualized but
higher doses generally more effective
Kyle et al., 1999
Swedish Methadone Study
Experimental Group
(Methadone)
Gunne & Gronbladh, 1981
Before
Control Group
(No Methadone)
Swedish Methadone Study
Experimental Group
(Methadone)
After 2 Years
Control Group
(No Methadone)
a
b
c
d
d
d
Gunne & Gronbladh, 1981
a
b
c
d
Sepsis
Sepsis and Endocarditis
Leg Amputation
In Prison
Buprenorphine
45
Partial Agonist Activity Levels
100
Full Agonist (e.g. heroin)
90
80
At higher doses, even when
partial agonist drug completely
binds all mu receptors
70
60
%
Mu Receptor 50
Intrinsic
40
Activity
Maximum opioid agonist effect
is never achieved
Partial Agonist (e.g. buprenorphine)
30
20
Like full agonists, partial agonist drugs
produce increasing mu opioid receptor
specific activity at lower doses
10
0
no drug
low dose
DRUG DOSE
high dose
Fentanyl vs. Buprenorphine: Effect of Increasing
doses on respiration; n=5-8 per dose group*; drugs infused
over 90 sec.
*n=1 for highest fentanyl dose
Dahan, 2006
Zubieta et al., 2000
Buprenorphine, Methadone, LAAM:
Opioid Urine Results
100
All Subjects
Mean % Negative
80
LAAM
49%
60
Bup
Hi Meth
40%
40
39%
20
Lo Meth
19%
0
1
3
5
7
9
11
Study Week
13
15
17
Adapted from Johnson, et al., 2000
Nicotine Replacement
for Smoking Cessation
All forms OR 1.77 (95%CI 1.66-1.88)*
Gum
OR 1.66 (95%CI 1.52-1.81)
Patches
OR 1.81 (95%CI 1.63-2.02)
Spray
OR 2.35 (95%CI 1.63-3.38)
Inhaler
OR 2.14 (95%CI 1.44-3.18)
Lozenge OR 2.05 (95%CI 1.62-2.59)
*17% vs. 10% 1 year quit rates
Antidepressants
for Smoking Cessation
Bupropion
OR 2.06 (95%CI 1.77-2.40)
Nortriptyline
OR 2.79 (95%CI 1.70-4.59)
Pharmacogenetics of Smoking Cessation
Lerman et al., 2006
Varenicline – A Designer Drug



New molecular entity
Selective partial agonist of 42 nicotinic
receptor
Effects


Partial receptor activation (up to 60%) mimics
dopamine agonist effects of nicotine, reduces
post-cessation craving and nicotine withdrawal
sx
Blocks nicotine binding and therefore effects of
nicotine if smoking – reduces reinforcing
effects of nicotine
Nicotine Receptors





Each receptor composed of 5 subunits
Functional properties are determined by subunit
composition – 3 main types
42 concentration related to nicotine
dependence
Repeated nicotine exposure  functional
nicotine receptors in the brain leads to 
dopamine activation
Withdrawal sx relate to up-regulated nAChRs
w/o nicotine
Effects of Varenicline on Dopamine Release
Coe et al., 2005
Continuous Abstinence Rates
Gonzales, D. et al. JAMA 2006;296:47-55.
Copyright restrictions may apply.
Jorenby, D. E. et al. JAMA 2006;296:56-63.
Genetics, Medical Consequences,
Pharmacotherapy Conclusions
• We have started the search for the
genetics of addiction, but we are a long
way from the answer
• The medical consequences of addiction
are extreme
• We need a wider range of better
pharmacotherapies, and neurobiology and
genetics may help us find them