Prevalence of Alcohol Use Prevalence of Alcohol Use DisordersDisorders

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)

Epidemiology of Use and AbstentionEpidemiology of Use and Abstention

0

10

20

30

40

50

60

70

80

18-24 25-44 45-64 > 64

Drank past year

Lifetime abstainer

P

erce

nt

Epidemiology of Heavy UseEpidemiology of Heavy Use

0

2

4

6

8

10

12

14

16

18-24 25-44 45-64 > 64

Heavy Use

Women: > 1 drink / day Men: > 2 drinks / day

Per

cen

t

0

5

10

15

20

25

18-29 30-44 45-64 65+ 18-29 30-44 56-64 65+

Pe

rce

nt

Abuse Dependence

Men Women

12-mo. Prevalence of DSM-IV AUD Diagnoses

Medications Approved in the Medications Approved in the US for Treatment of Alcohol US for Treatment of Alcohol

DependenceDependence

Disulfiram (Antabuse): 1949Disulfiram (Antabuse): 1949 Naltrexone (ReVia): 1994Naltrexone (ReVia): 1994 Acamprosate (Campral): 2004Acamprosate (Campral): 2004 Long-Acting Naltrexone (Vivitrol): Long-Acting Naltrexone (Vivitrol):

20062006

NaltrexoneNaltrexone

Non-specific opioid receptor antagonistNon-specific opioid receptor antagonist Dose dependent binding to Dose dependent binding to , , and and

opioid receptorsopioid receptors FDA approved as adjunctive FDA approved as adjunctive

pharmacotherapy for the treatment of pharmacotherapy for the treatment of alcoholism alcoholism

OpioidsOpioids Acute alcohol increases plasma Acute alcohol increases plasma -Endorphin -Endorphin

levels levels

OpioidsOpioids Opioid antagonists reduce alcohol drinkingOpioid antagonists reduce alcohol drinking

Clinical trialsClinical trials

Naltrexone has been shown to Naltrexone has been shown to Increase percentage of days abstinent from Increase percentage of days abstinent from

alcoholalcohol Reduce number of drinks/drinking dayReduce number of drinks/drinking day Increase time to relapseIncrease time to relapse Decrease craving for alcoholDecrease craving for alcohol

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

Cum

ulat

ive

Pro

port

ion

with

No

Rel

apse

Naltrexone (N=35)

Placebo (N=35)

Volpicelli et al., Arch Gen Psychiatry, 1992

Effect of Long-Acting Naltrexone on Effect of Long-Acting Naltrexone on Maintenance of AbstinenceMaintenance of Abstinence

0102030405060708090

100

Per

cent

with

out 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

COMBINE COMBINE (Anton et al., 2006)(Anton et al., 2006)

ASAM, 2007

VA cooperative studyVA cooperative study

From Krystal et al 2001

Cochrane review Cochrane review (Srisurapanont and Jarusuraisin 2002)(Srisurapanont and Jarusuraisin 2002)

NTX treatment can decrease the chance of NTX treatment can decrease the chance of alcohol relapse for 36% as compared to placebo alcohol relapse for 36% as compared to placebo treatment. In addition, the treatment is likely to treatment. In addition, the treatment is likely to reduce the chance of returning to drinking for 13%.reduce the chance of returning to drinking for 13%.

Short-term treatment of NTX for alcoholism gives Short-term treatment of NTX for alcoholism gives a meaningful benefit in preventing a relapse. a meaningful benefit in preventing a relapse.

Small to Modest efficacy!Small to Modest efficacy!

Identifying predictors of robust Identifying predictors of robust treatment response to naltrexone treatment response to naltrexone

could improve clinical practice could improve clinical practice

Potential predictors of naltrexone Potential predictors of naltrexone responseresponse

Family history of alcoholism Family history of alcoholism Monterosso et al., 2001; Rubio et al., 2005Monterosso et al., 2001; Rubio et al., 2005

OPRM1 OPRM1 opioid receptor gene polymorphisms opioid receptor gene polymorphisms Oslin et al., 2003Oslin et al., 2003

Age of onset of alcohol abuse Age of onset of alcohol abuse Rubio et al., 2005Rubio et al., 2005

Antisocial traits and heavier drinkersAntisocial traits and heavier drinkers Rohsenow et al., 2007Rohsenow et al., 2007

Higher level of alcohol craving Higher level of alcohol craving Volpicelli et al., 1995Volpicelli et al., 1995

Consistent drinking patterns Consistent drinking patterns Gueorguieva et al 2007Gueorguieva et al 2007

Laboratory modelsLaboratory models Human clinical laboratory paradigms can Human clinical laboratory paradigms can

be used to model a variety of behaviors in be used to model a variety of behaviors in controlled conditions. controlled conditions. Careful experimental manipulations to Careful experimental manipulations to

understand the mechanisms underlying a understand the mechanisms underlying a behavior. behavior.

Can be used to evaluate medication signals Can be used to evaluate medication signals following a shorter treatment periodfollowing a shorter treatment period

Laboratory models-Alcohol Laboratory models-Alcohol In the field of alcohol research, controlled In the field of alcohol research, controlled

human laboratory studies have been human laboratory studies have been used to study used to study different populations of drinkers different populations of drinkers

• (e.g., social drinkers, dependent drinkers, women, (e.g., social drinkers, dependent drinkers, women, high-risk individuals), high-risk individuals),

different types of cues different types of cues • (e.g., stress, social drinking, solitary drinking, (e.g., stress, social drinking, solitary drinking,

peer influences), peer influences), different types and schedules of alcohol different types and schedules of alcohol

• (e.g., beer, wine, hard liquor, IV alcohol; fixed (e.g., beer, wine, hard liquor, IV alcohol; fixed doses, scheduled administration, ad-lib drinking). doses, scheduled administration, ad-lib drinking).

Laboratory models to study alcohol-Laboratory models to study alcohol-naltrexone interactionsnaltrexone interactions

Human laboratory-based paradigms have Human laboratory-based paradigms have been used to evaluate naltrexone’s been used to evaluate naltrexone’s effects ineffects in Social drinkers Social drinkers

• e.g. Swift et al 1994, King et al 1997 e.g. Swift et al 1994, King et al 1997 Non-treatment seeking alcohol dependent Non-treatment seeking alcohol dependent

drinkers drinkers • e.g. Anton et al 2004; Drobes et al 2004, e.g. Anton et al 2004; Drobes et al 2004,

Krishnan-Sarin et al 2007, O’Malley et al 2002 Krishnan-Sarin et al 2007, O’Malley et al 2002 Importantly, effects observed in laboratory Importantly, effects observed in laboratory

studies similar to those seen in clinical trialsstudies similar to those seen in clinical trials

Alcohol Self-Administration Model (O’Malley, Krishnan-Sarin et al., 2002)

4 pm

Choice Block #1

5:00 pm

OutpatientTreatment

Priming Drink

Alcohol Reactivity

• craving

Ad-Lib Period

•4 drinks per choice period (.015 g/dl)

•$12 tab per choice period

(.03 g/dl)

Naltrexone pretreatment

Choice Block #2

6:00 pm 7 pm

Day 0

Day 6 Day 7

MET Intervention Discharge

Figure 1

Naltrexone Dose

# of

dri

nks

+ S

E

0

2

4

6

FH +FH -

0

2

4

6 C: Females only

B: Males only

N=3 N=3N=4

N=5

N=3N=4

N=16

N=18 N=10N=7

N=9

N=10

# of

dri

nks

+ S

E

0

2

4

6

# of

dri

nks

+ S

E

A: Males and Females

N=12

N=19

N=12

N=21

N=14

N=14

0 mg 50 mg 100 mg

From Krishnan-Sarin et al., 2007

Naltrexone and FH of alcoholism