Prevalence of Alcohol Use
Disorders
NIAAA – National Epidemiologic Survey on
Alcohol and Related Conditions (NESARC)
Any Alcohol Use Disorder
17.6 million (8.5%)
Alcohol Abuse
9.7 million (4.7%)
Alcohol Dependence
7.9 million (3.8%)
NIAAA= National Institute on Alcohol Abuse and Alcoholism
Grant BF, et al. Arch Gen Psychiatry. 2004;61:807-816.
Epidemiology of Use and Abstention
Drank past year
Lifetime abstainer
80
Percent
70
60
50
40
30
20
10
0
18-24
25-44
45-64
> 64
Epidemiology of Heavy Use
Heavy Use
Women: > 1 drink / day
Men: > 2 drinks / day
16
14
Percent
12
10
8
6
4
2
0
18-24
25-44
45-64
> 64
12-mo. Prevalence of DSM-IV AUD Diagnoses
25
Abuse
Dependence
Percent
20
15
10
5
0
18-29 30-44 45-64
Men
65+
18-29 30-44 56-64
Women
65+
Medications Approved in the
US for Treatment of Alcohol
Dependence
 Disulfiram
(Antabuse): 1949
 Naltrexone (ReVia): 1994
 Acamprosate (Campral): 2004
 Long-Acting Naltrexone (Vivitrol):
2006
Naltrexone
 Non-specific
opioid receptor antagonist
 Dose dependent binding to m, d and k
opioid receptors
 FDA approved as adjunctive
pharmacotherapy for the treatment of
alcoholism
Opioids

Acute alcohol increases plasma b-Endorphin
levels
Opioids

Opioid antagonists reduce alcohol drinking
Clinical trials
 Naltrexone




has been shown to
Increase percentage of days abstinent from
alcohol
Reduce number of drinks/drinking day
Increase time to relapse
Decrease craving for alcohol
Cumulative Proportion
with No Relapse
Naltrexone (Revia) in the Treatment of
Alcohol Dependence
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Naltrexone (N=35)
Placebo (N=35)
0
1
2
3
4
5
6
7
8
9 10 11 12
Number of Weeks Receiving Medication
Volpicelli et al., Arch Gen Psychiatry, 1992
Effect of Long-Acting Naltrexone on
Maintenance of Abstinence
Percent without Relapse
Subjects with 4-day lead-in abstinence
100
90
80
70
60
50
40
30
20
10
0
p < 0.025
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
Weeks
Placebo (n = 28)
Vivitrex (n = 28)
COMBINE (Anton et al., 2006)
ASAM, 2007
VA cooperative study
From Krystal et al 2001
Cochrane review
(Srisurapanont and Jarusuraisin 2002)

NTX treatment can decrease the chance of
alcohol relapse for 36% as compared to
placebo treatment. In addition, the treatment
is likely to reduce the chance of returning to
drinking for 13%.

Short-term treatment of NTX for alcoholism
gives a meaningful benefit in preventing a
relapse.

Small to Modest efficacy!
Identifying predictors of robust
treatment response to naltrexone
could improve clinical practice
Potential predictors of naltrexone
response

Family history of alcoholism


OPRM1 m opioid receptor gene polymorphisms


Rohsenow et al., 2007
Higher level of alcohol craving


Rubio et al., 2005
Antisocial traits and heavier drinkers


Oslin et al., 2003
Age of onset of alcohol abuse


Monterosso et al., 2001; Rubio et al., 2005
Volpicelli et al., 1995
Consistent drinking patterns

Gueorguieva et al 2007
Laboratory models
 Human
clinical laboratory paradigms can
be used to model a variety of behaviors in
controlled conditions.


Careful experimental manipulations to
understand the mechanisms underlying a
behavior.
Can be used to evaluate medication signals
following a shorter treatment period
Laboratory models-Alcohol
 In
the field of alcohol research, controlled
human laboratory studies have been
used to study

different populations of drinkers
• (e.g., social drinkers, dependent drinkers, women,
high-risk individuals),

different types of cues
• (e.g., stress, social drinking, solitary drinking,
peer influences),

different types and schedules of alcohol
• (e.g., beer, wine, hard liquor, IV alcohol; fixed
doses, scheduled administration, ad-lib drinking).
Laboratory models to study
alcohol-naltrexone interactions
 Human
laboratory-based paradigms have
been used to evaluate naltrexone’s
effects in

Social drinkers
• e.g. Swift et al 1994, King et al 1997

Non-treatment seeking alcohol dependent
drinkers
• e.g. Anton et al 2004; Drobes et al 2004,
Krishnan-Sarin et al 2007, O’Malley et al 2002

Importantly, effects observed in laboratory
studies similar to those seen in clinical trials
Alcohol Self-Administration Model
(O’Malley, Krishnan-Sarin et al., 2002)
Day
0
Day 6
Day 7
4 pm
Outpatient
Treatment
Choice
Block #2
5:00 pm
6:00 pm
Alcohol
Reactivity
• craving
Naltrexone
pretreatment
Choice
Block #1
Priming
Drink
(.03 g/dl)
7 pm
Ad-Lib Period
•4 drinks per choice
period (.015 g/dl)
•$12 tab per choice
period
MET
Intervention
Discharge
Naltrexone and FH of alcoholism
F igure 1
# of drinks + S E
6
FH +
FH -
A : M ales an d F em ales
N = 12
N = 21
4
N = 14
N = 12
2
N = 14
N = 19
0
# of drinks + S E
6
B : M ales on ly
N=7
N = 18
N = 10
4
N=9
2
N = 16
N = 10
# of drinks + S E
0
6
C : F em ales on ly
4
N=5
N=3
N=4
2
N=3
N=3
N=4
0
0 mg
50 m g
100 m g
N altrexone D ose
From Krishnan-Sarin et al., 2007