Recent Developments in the Pharmacotherapy of Alcoholism
Henry R. Kranzler, M.D.
Alcohol Research CenterUniv. of CT School of Medicine
Potential Conflicts of InterestPotential Conflicts of Interest
Consulting and Research Support:
Ortho-McNeil Pharmaceuticals (current study)
Bristol-Myers Squibb Co. (recent study)
Forest Pharmaceuticals (consulting, support for lectures)
Alkermes, Inc. (consulting, support for lectures)
DrugAbuse Sciences (consulting)
ObjectivesObjectives
Learn about:
• The medications currently approved in the US to treat alcohol dependence
Candidate medications that are currently in development for that indication
The neurotransmitter systems that underlie alcohol’s effects, which are relevant to future developments in this therapeutic area
Prevalence of Alcohol Use DisordersPrevalence of Alcohol Use Disorders
Alcohol DependenceAlcohol Dependence 7.9 million (3.8%)7.9 million (3.8%)
Alcohol AbuseAlcohol Abuse 9.7 million (4.7%)9.7 million (4.7%)
NIAAA= National Institute on Alcohol Abuse and AlcoholismGrant BF, et al. Arch Gen Psychiatry. 2004;61:807-816.
Any Alcohol Use DisorderAny Alcohol Use Disorder17.6 million (8.5%)17.6 million (8.5%)
NIAAA – National Epidemiologic Survey onNIAAA – National Epidemiologic Survey onAlcohol and Related Conditions (NESARC)Alcohol and Related Conditions (NESARC)
Unmet Treatment NeedsUnmet Treatment Needs
NESARC data indicate that only about a quarter of adults with alcohol abuse or dependence ever receive treatment: Self-help groups Psychotherapy Pharmacological treatments
What is the Goal of Alcohol Treatment?What is the Goal of Alcohol Treatment?
• Primary goal of alcohol treatment has traditionally been the initiation and maintenance of abstinence
• Reduced drinking may be a suitable alternative for some patients; unclear as to how such patients can be identified a priori
Medications Approved in the US for Medications Approved in the US for Treatment of Alcohol DependenceTreatment of Alcohol Dependence
Disulfiram (Antabuse): 1949
Naltrexone (ReVia): 1994
Acamprosate (Campral): 2004
Long-Acting Naltrexone (Vivitrol): 2006
Medications Approved in the US for Medications Approved in the US for Treatment of Other DisordersTreatment of Other Disorders
Selective Serotonin Reuptake Inhibitors (SSRIs)
Ondansetron (Zofran)
Topiramate (Topamax)
These medication are not FDA-approved for treatment of alcohol dependence
DRUMS TRUMPETS CLARINETS HARP VIOLIN FLUTE
INDIVIDUAL FACTORS influencing the reward symphony Genetics Age Hormones Environment
ALCOHOL THE CONDUCTOR
( J.A. Engel, 1994 )
[ Muscle relax.] CNS stim. Euphoria [ ] [ ] Preference][ [Anxiolysis ] [Sedation ]
The Brain Symphony Orchestra#
4/4 .
Medications for Alcohol RehabilitationMedications for Alcohol Rehabilitation
Disulfiram
Naltrexone
Acamprosate
Serotonin Reuptake Inhibitors
Ondansetron
Topiramate
Disulfiram (Antabuse)Disulfiram (Antabuse)
• An alcohol-sensitizing medication that produces an unpleasant reaction when alcohol is ingested; it is used to deter alcoholics from drinking
• Interferes with the breakdown of acetaldehyde, a toxic metabolite of alcohol
Ethanol Acetaldehyde Acetate
l
Disulfiram and Abstinence Rates (VA Cooperative Study)Disulfiram and Abstinence Rates (VA Cooperative Study)
Noncompliant (80%) Compliant (20%)0
10
20
30
40
50
Per
cen
t R
emai
nin
g A
bst
inen
t
Fuller RK et al. JAMA. 1986; 256:1449-1455
Disulfiram 250 mg (N=202 men)Disulfiram 250 mg (N=202 men)
Disulfiram 1 mg (N=204 men)Disulfiram 1 mg (N=204 men)
Placebo (N = 199 men)Placebo (N = 199 men)
Drinking Days Among Those Who DrankDrinking Days Among Those Who Drank
Fuller RK et al. JAMA. 1986; 256:1449-1455
0
20
40
60
80
100
Treatment Group
Disulfiram 250 mg
Disulfiram 1 mg
Placebo
*p < .05
SummarySummary
• Although not efficacious for maintenance of abstinence, disulfiram may reduce harm by reducing drinking days among those who relapse.
• Given the potential for serious adverse events (i.e., the disulfiram-ethanol reaction), disulfiram is probably not suitable for use as a primary harm reduction strategy
Medications for Alcohol RehabilitationMedications for Alcohol Rehabilitation
Disulfiram
Naltrexone
Acamprosate
Serotonin reuptake inhibitors
Ondansetron
Topiramate
Pharmacology of NaltrexonePharmacology of Naltrexone
• Orally bioavailable antagonist of mu, delta, and kappa opioid receptors
• Appears to reduce dopamine release associated with alcohol expectancies and consumption
• FDA-approved oral dosage: 50 mg/day
Naltrexone (Revia) in the Treatment of Naltrexone (Revia) in the Treatment of Alcohol DependenceAlcohol Dependence
Number of Weeks Receiving Medication
10 2 3 4 5 6 7 8 9 10 11 120.00.1
0.2
0.40.50.60.70.80.9
1.0
0.3
Cu
mu
lati
ve P
rop
ort
ion
w
ith
No
Rel
apse
Naltrexone (N=35)
Placebo (N=35)
Volpicelli et al., Arch Gen Psychiatry, 1992
Oral Naltrexone Studies in Alcohol Oral Naltrexone Studies in Alcohol DependenceDependence
Meta-analysis of 14 published studies involving more than 2000 patients revealed:
Clear effect of naltrexone on risk of relapse to heavy drinking [OR: 0.62 (0.52, 0.75), P<0.001]
Borderline effect of naltrexone on abstinence rate [OR: 1.26 (0.97,1.64), P=0.08].
Bouza et al., Addiction, 2004
Vivitrex (Alkermes, Inc.)Vivitrex (Alkermes, Inc.)
Common biodegradable medical polymer that is used for sutures, extended release pharmaceuticals
Metabolized to CO2 and H20
Dry Powder Microspheres Diluent
Microsphere Suspension
Hypodermic Needle
IM
Once Monthly Dosing
+
Time (Days)0 5 10 15 20 25 30
Na
ltre
xon
e (
ng
/mL
)
0
5
10
15
20
25
30
35
40
Mean Steady State Naltrexone Concentration Following Mean Steady State Naltrexone Concentration Following VivitrexVivitrex®® 380 mg Compared to Daily Oral Dosing 380 mg Compared to Daily Oral Dosing
380 mg IM Mean ± SD
50 mg Oral Mean ± SD
Results: Heavy Drinking DaysResults: Heavy Drinking Days
PretreatmentPlaceboVivitrex 190 mgVivitrex 380 mg
75th Percentile25th Percentile
Median Heavy Drinking Days per Month
0
5
10
15
20
25
30
n = 624
19.3
3.1
6.04.5
Garbutt et al., 2005
Effect of Long-Acting Naltrexone on Effect of Long-Acting Naltrexone on Maintenance of AbstinenceMaintenance of Abstinence
0102030405060708090
100
Per
cen
t w
ith
ou
t R
elap
se
p < 0.025
Placebo (n = 28) Vivitrex (n = 28)
Subjects with 4-day lead-in abstinence
1 2 3 54 6 7 8 109 11 12 13 1514 16 17 18 2019 21 22 23 2524 26 27 28 3029 31
Weeks
Targeted Naltrexone for Problem DrinkersTargeted Naltrexone for Problem Drinkers
• 8-week study of oral naltrexone • 150 subjects, whose goal was to reduce or
stop drinking• Targeted medication: one tablet/day for the
first week, reduced by one tablet/week; subjects urged to use medication 2 hr in anticipation of a situation self-identified as high risk for drinking
Kranzler et al., J Clin Psychopharmacol, 2003
Daily vs. Targeted Naltrexone: Daily vs. Targeted Naltrexone: Effects on Heavy DrinkingEffects on Heavy Drinking
0.1
0.15
0.2
0.25
1 2 3 4 5 6 7 8
Study Week
He
av
y D
rin
kin
g D
ay
s
Daily Placebo
TargetedPlacebo
DailyNaltrexone
TargetedNaltrexone
Kranzler et al., J Clin Psychopharmacol, 2003
Med: p = .092, 19.0% reduction; Med X Sched X Time: p = .001
SummarySummary
There is not consistent evidence of the efficacy of naltrexone for maintenance of abstinence; effects may depend on study design (i.e., initial abstinence requirement).
Naltrexone reduces the risk of heavy drinking and may be the medication of choice for harm reduction.
Medications for Alcohol RehabilitationMedications for Alcohol Rehabilitation
Disulfiram
Naltrexone
Acamprosate
Serotonin reuptake inhibitors
Ondansetron
Topiramate
Pharmacology of Acamprosate (Campral)
Acamprosate has complex effects on glutamate-NMDA activity and is a GABA agonist; the normal balance between these systems is altered by chronic drinking.
In animals trained to drink alcohol, acamprosate reduces deprivation-induced drinking.
FDA-approved dosage is 1998 mg/day (divided in 3 doses)
Acamprosate (Campral) Acamprosate (Campral)
In 11 European clinical trials (> 3,300 patients), acamprosate :
• Significantly improved the abstinence rate [OR = 1.88 (1.57, 2.25), P < 0.001]
• Significantly improved treatment retention [OR = 1.29 (1.13,1.47), P < 0.001].
Bouza et al., Addiction, 2004
Sass et al. StudySass et al. Study%
of
Pat
ien
ts A
bst
inen
t 100
Weeks
80
60
40
20
00 24 48 72 96
Treatment Period* Follow-Up Period†
*p=0.001; †p=0.003 Sass et al., Sass et al., Arch Gen PsychiatryArch Gen Psychiatry, 1996, 1996
43%
21%
17%
37%
Placebo (N=136)
Acamprosate (N=136)
US Acamprosate Study: ITT AnalysisUS Acamprosate Study: ITT Analysis
020406080
100
Percent Days Abstinent
Placebo
ACA 2g
ACA 3g
Mason et al. 2006
ES = 0.036 ES = 0.129
ES = Effect Size
US Acamprosate Study: ITT US Acamprosate Study: ITT (Adjusted) Analysis*(Adjusted) Analysis*
25
45
65
Percent Days Abstinent
Placebo
ACA 2g
ACA 3g
Mason et al. 2006
Linear Dose Effect: p=0.01
*Adjusted for severity, readiness to change, psychological antecedents, ASI score, treatment exposure
SummarySummary
There is a small effect size for acamprosate in the maintenance of abstinence.
The lack of efficacy in the US study may be due to greater sample heterogeneity, confounding the small advantage shown in European studies.
NTX, ACA, and NTX/ACA for Relapse Prevention in NTX, ACA, and NTX/ACA for Relapse Prevention in Alcohol-Dependent PatientsAlcohol-Dependent Patients
Kiefer F et al. Arch Gen Psychiatry. 2003;60:92-99.
0 10 20 30 40 50 60 70 80
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Proportion ofSurvivors
(Nonrelapsing)
Time, d
PlaceboAcamprosateNaltrexone
Naltrexone plus acamprosate
Relapse to Heavy Drinking During TreatmentRelapse to Heavy Drinking During Treatment
Acamprosate Main Effect
Placebo (n=618)
Acamprosate (n=608)
P
Percent 70.1 69.6 0.23
Naltrexone Main Effect
Placebo (n=612)
Naltrexone (n=614)
P
Percent 71.4 68.2 0.02
CBI Main Effect
No CBI (n=607)
CBI (n=619)
P
Percent 69.7 70.0 0.16
The COMBINE STUDY, JAMA, 2006
Relapse to Heavy Drinking: Naltrexone x CBI Interaction
The COMBINE STUDY, JAMA, 2006
Composite Clinical Outcome* During Last 8 Weeks of Treatment
Naltrexone by CBI interaction, p=0.02
*No more than 2 daysheavy drinking over 8weeks, no more than 11 (women) or 14 (men) Drinks/week, and no alcohol problems
Medications for Alcohol RehabilitationMedications for Alcohol Rehabilitation
Disulfiram
Naltrexone
Acamprosate
Serotonin reuptake inhibitors
Ondansetron
Topiramate
0.0
0.10.2
0.30.4
0.50.6
0.70.8
0.91.0
0 1 2 3 4 5 6 7 8 9 10 11 12
Fluoxetine
Placebo
Fluoxetine and Relapse RatesFluoxetine and Relapse Rates
Weeks in Treatment
Pro
po
rtio
n A
bst
inen
t
Kranzler et al., Am J Psychiatry, 1995Kranzler et al., Am J Psychiatry, 1995
(N=101)
% Completely Abstinent During Treatment% Completely Abstinent During Treatment
0
10
20
30
40
50
60
70
Type B Type A
Sertraline
Placebo
Pettinati et al., Alcohol Clin Exp Res, 2000Pettinati et al., Alcohol Clin Exp Res, 2000
Per
cen
t (%
)p<0.0001*p<0.0001*
SummarySummary
Similar findings with fluoxetine and fluvoxamine indicate that SSRIs do not reduce drinking behavior in an unselected sample of alcoholics.
In subgroups of alcoholics, some SSRIs may increase the likelihood of abstinence. Prospective validation of these findings is needed.
Medications for Alcohol RehabilitationMedications for Alcohol Rehabilitation
Disulfiram
Naltrexone
Acamprosate
Serotonin reuptake inhibitors
Ondansetron
Topiramate
OndansetronOndansetron
Drinks / Day among EOA at StudyEnd
0 1 4 160
1
2
3
4
: p < : p 0.01
Ondansetron doses in g/ kg b.i.d
Mean
drin
ks /
day
Johnson et al., JAMA, 2000
SummarySummary
Ondansetron reduces drinking behavior only among early-onset alcoholics.
Independent replication of this finding is needed.
Medications for Alcohol RehabilitationMedications for Alcohol Rehabilitation
Disulfiram
Serotonin reuptake inhibitors
Ondansetron
Naltrexone
Acamprosate
Topiramate
Topiramate (Topamax): Mean Change from PretreatmentTopiramate (Topamax): Mean Change from Pretreatment
-80
-70
-60
-50
-40
-30
-20
-10
0
0 1 2 3 4 5 6 7 8 9 10 11 12
Key:
Placebo
Topiramate
Study Weeks
Per
cen
t H
eavy
Dri
nki
ng
Day
s
-60.34 9.89
-32.73 11.03
Pretreatment: 68.3% (topiramate) vs. 60.8% (placebo)
Johnson et al., Lancet 2003
P = 0.0004
-80
-60
-40
-20
0
20
40
60Placebo (N=48)
Topiramate (N=55)
Topiramate Treatment of Alcohol DependenceTopiramate Treatment of Alcohol Dependence
Percent Change From Baseline in Self-Reported Percent Change From Baseline in Self-Reported Drinking at Week 12Drinking at Week 12
Heavy Drinking Days Days Abstinent
P<.0004
P<.003
Johnson et al. Lancet. 2003;361:1677-1685.
ConclusionsConclusions
Psychosocial treatments for alcohol dependence, while efficacious, are not adequate for many patients.
A growing number of medications are useful in preventing relapse or promoting abstinence.
Additional research is needed to resolve conflicting findings and to guide clinical care.