THE STAKE : 10 MIO POTENTIAL CUSTOMERS IN EUROPE

Population of Western Europe ± 325 Mio

Number of Number of withdrawals/ yearwithdrawals/ year (±4%)(±4%)

Number of alcoholNumber of alcoholdependent ± 10 Miodependent ± 10 Mio

Abstinent at 1 year (±18%)Abstinent at 1 year (±18%)

Abstinent Abstinent at 5 years (±6%)at 5 years (±6%)

STATES OF CHANGE - REVOLVING DOOR MODEL

(Di Clemente et Prochaska, 1982)

Précontemplation

Contemplation

PréparationAction

Maintenance

Relapse

Décision

TYPES OF CRAVING: DEFINITIONS

Psychological craving: Strong desire for drinking alcohol Strong, almost overpowering urge for alcohol during acute

withdrawal Strong desire or sense of compulsion to take alcohol (ICD-

10) Persistent desire or unsuccessful efforts to cut down or

control alcohol use (DSM-IV) Physical craving:

Elevated heart rate, Sweeting, Nausea, Anxiety

MANY STIMULI PRECEDE THE ARRIVAL OF ALCOHOL INSIDE THE BRAIN

BARSights and soundsof the environment

Smell of alcohol etc.

Taste of alcohol

Each cue initiates adaptation inside the brain

HOW CONDITIONED STIMULI BECOMESCUES FOR RELAPSE?

BAR

BAR

This is our patient, he/she hasbeen detoxified and has turnedhis/her back on alcohol and all theassociated stimuli.

Unfortunately, in our alcohol-based society it is impossible to avoid allthese stimuli for long.

HOW CONDITIONED STIMULI BECOME CUES FOR RELAPSE

BAR

BAR

Any of these stimuli induce adaptationwhich produces feelings opposite to those of alcohol eg anxiety, dysphoria.These feelings can be self-medicated withalcohol but the decision to do so intensifiesall the cues.

BAR

alcohol

In order to balance the increasingly severe "pseudo-withdrawal producedby the conditioned adaptation the patient relapses into heavy drinking

PAVLOVIAN CONDITIONING AND THE EFFECTS OF ALCOHOL

BAR Associatedstimuli

As the associatedstimuli repeatedlyprecede the arrivalof alcohol in the brain"conditioning" occurs

ALCOHOLUnconditioned

stimulus

BAR

Conditionedstimuli

BAR Once the stimuli havebecome conditioned theyelicit the response (eg feelings of relaxation) evenbefore the alcohol arrivesin the brain

ResponseBAR

EACH TIME THE ALCOHOL ARRIVES THE BRAIN INITIATES INCREASINGLY EFFECTIVE CHEMICAL ADAPTATIONS WHICH

OPPOSE THE DRUG AND CAUSE TOLERANCE

BAR BAR BAR BAR

BAR BAR

But every time the adaptation is preceded by the associated stimuli and so these become conditioned stimuli capable of eliciting the adaptation even before the alcohol arrives

ONE CONSEQUENCE ISTHAT TOLERANCE ISUSUALLY GREATER IN AFAMILIAR ENVIRONMENTBECAUSE THE "CUES"HELP INITIATE THEADAPTATION TO ALCOHOL INSIDE THEBRAIN

From: Heather (1995)

Source: Institute of Medicine (1990)

None

MildModerate

Substantial

Severe

Briefintervention

Primaryprevention

Specializedtreatment

ALCOHOL

PROBLEMS

RELATIONSHIP BETWEEN THE SEVERITY OF ALCOHOLPROBLEMS AND THE TYPE OF INTERVENTION NEEDED

Motivational interviewing

Cognitive - behaviour theory

Relapse prevention

Community reinforcement

EFFECTIVE PSYCHOLOGICAL TREATMENT FOR DRINKING PROBLEMS

% B

asel

ine

leve

l

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Ref: De Witte Progress in Neurobiology. 2000, 343-362

Campral® AND GLUTAMATE

Time (hr) after withdrawal p < 0.001

WITHDRAWALM

oti

lity

/ R

at /

12h

0

500

1000

1500

2000

2500

Control Campral (400 mg/kg/day)Ref: De Witte

P < 0.05

ACAMPROSATE

No effect on non-alcohol-preferring and non-dependent animals

Abolishes the alcohol dependence in dependent animals

Abolishes the alcohol withdrawal

Keeps dependent animals alive during multiple successive withdrawals

Ref: De Witte presentation

MATERIAL

Combined Data Analysis

• 11 Double blind, placebo controlled multicentre studies

• 8 European countries

• 3 338 alcohol dependent patients

Mean Age 42.8 years ± 9.3Sex: female 19%Mean MAST score 31.8 ± 10.9Mean CAGE score 3.5 ± 0.76

METHODOLOGY 1

• Data of all 11 trials were reasonably comparable for criteria which included: demographic variables clinical histories the major efficacy outcome criteria

• Safety data were readily comparable for 9 studies

• Treatment Duration: 3 months in one trial, 6 months in 5 trials and 12 months in 5 trials

• Medication free follow-up periods varied from 4 weeks to 12 months

• Assessment intervals during treatment differedCommon data were identified at days 0, 30, 90, 180, 270, 360

METHODOLOGY 2

Comparability

• All placebo controlled trials, performed under naturalistic conditions

• Two treatment groups (acamprosate and placebo) in 9 trials; three treatment groups (two acamprosate groups at different dosages and one placebo group) in 2 trials. 4-6 tablets per day

• All patients were started on study medication after the period of acute detoxification: 10 trials immediately after acute withdrawal therapy, all patients

abstinent at start of treatment 1 trial within 6 weeks of termination of acute withdrawal therapy,

60% patients abstinent

METHODOLOGY 3

• To follow a CORE PROTOCOL± adaptations according countries’ requests

• Studies carried out in accordance with theEUROPEAN GOOD CLINICAL PRACTICE

• To use CENTRAL LABORATORY FACILITIES (PRAMA, UKMAS) or to standardise the laboratory values

• PRIMARY OUTCOME CRITERION: Drinking behaviour1- Abstinence/Relapse/Missing assessment at each visit2- Time to first relapse (survival analysis)3- Cumulative Abstinence Duration (a mathematical sum of all

abstinent periods)

OUTCOME CRITERIANumber of dry days: cumulative abstinence duration (CAD)Number of dry days: cumulative abstinence duration (CAD)

If exact data were available: cumulate directly

Time to First Relapse = 30 daysCumulative Abstinence Duration = 75 days

CAD

Relapses

Cumulative Abstinence Duration = 60 days

CAD

Relapses

If exact data were not available: consider total period between visits

D0 D30 D60 D90 D120 D150 D180

Visit 1 2 3 4 5 6 7

OUTCOME CRITERIA

• At each visit: drinking or not?• Time to first drink

D0 D30 D60 D90 D120 D150 D180

A A R R RA A

A = abstinence R = relapse

Alcoholconsumption(quantity)

Assessment visits

0

5

10

15

20

25

30

35

40

45

50

%/Y

ea

rs

females%

age

GENDER / AGE

EUROPEAN TRIALS: RATE OF TOTAL ABSTINENCE (%)

0

0,25

0,5

0,75

Placebo Acamprosate

2 way ANOVA - treatment: p<0.001, study: p<0.001, interact: NS

RESULTS: ABSTINENT RATE

100

54

3120

14 12

63

43

3125 22

100

0102030405060708090

100

0 30 60 150 270 360

Placebo Acamprosate

Days

Survival analysisSurvival analysis

%A

bs

tin

en

ce

ra

te(n

o a

lco

ho

l c

on

su

mp

tio

n)

It measures:• time to first relapse• absolute abstinenceComment: this method does not take subsequent abstinent periodsinto consideration, but is a conservative measure to assess outcome

%

Mantel Cox: p<0.001

RESULTS: PROPORTION OF ATTENDING PATIENTS

0102030405060708090

0 30 90 180 270 360

Acamprosate Placebo

Differential attrition between treatment groupsDifferential attrition between treatment groupsComment: drop-out rate in naturalistic trials could be an objectiveoutcome measure of efficacy

DaysAtt

end

ance

rat

e (%

)

*

* * *

RESULTS: ABSTINENCE RATE PER VISIT

0102030405060708090

100

0 30 90 120 150 180 210 240 270 300 330 360

Acamprosate Placebo

Days

Ab

stin

ence

rat

e (%

)

*

****

*: p<0,001

SF 36 QoL SCORES BEFORE AND AFTER CAMPRAL TREATMENT

0102030405060708090

100

PF BP RP GH MH SF RE VT HT

Before Treatment

After Campral®

Treatment

MHMental HealthSFSocial FuntioningRERole Emotional

VTVitalityHTHealth Transition

PFPhysical Functioning BPBodily painRPRole Physical

GHGeneral Health

Physical ComponentPhysical Component Mental ComponentMental Component

CONCLUSIONS FROM Campral® CLINICAL STUDIES

• Double the abstinence rates compared with placebo

• Used within a programme of psychosocial support, Campral® can significantly improve abstinence rates following alcohol withdrawal

• Campral® is equally effective with a range of psychosocial support strategies

RESULTS: ADVERSE EVENTS

Adverse events of statistical significance with a frequency of moreAdverse events of statistical significance with a frequency of morethan 5% were:than 5% were:

Gastro-intestinalirritation

Sex drive changes

Difficulty in fallingasleep

15% in the first 30 days, 8% d31-90

9% in the first30 days

7% between days181 and 270

3% more thanplacebo

3% more thanplacebo

4-8% more thanplacebo

GOOD SAFETY PROFILE

Campral®: A MAJOR ADVANCE IN THE TREATMENT OF CHRONIC ALCOHOLISM

• A novel and unique non-aversive therapeutic agent

• Abstinence rates twice that with placebo achieved when used in conjunction with psycho-social support measures

• Good tolerability established

• No significant dependence potential

CAD

248 Patients

28 weeks Campral treatment for all patients

(4-6 tablets / day)

3 Treatment Groups with different levels of

counselling

Manual driven

Session recordings

MICADO STUDY (Netherlands)De Wildt et al (submitted for publication)

MICADO STUDY (Netherlands)De Wildt et al

3 Treatment Groups

a) Campral only:• 6 weekly min medical visits. Collect drinking data, evaluate vital signs• no reinforcement, motivation, high risk situation discussions.

– b) Campral with Minimal Intervention (MI) a plus:• 3 x 20 min weekly visits (W 2, 3, 4)

– discuss cost benefit drinking– discuss drinking situations– review motivation

– c) Campral with Brief Psycho-Social Intervention (PSI) a plus:• 7 x 60 min weekly visits (W 2, 3, 4, 5, 6, 7, 8)• Increase coping skills (Monti, Abrams et al 89, MATCH-Kadden 92,

Schippers 94)• significant other, good and bad moments, problem solving, cognitive

restructuring

MICADO STUDY (Netherlands)De Wildt et al

0

10

20

30

40

50

60

70

A A + MI A + PSI

AbstinenceRelapseMissing

CONCLUSIONS

14 out of 17 studies confirmed that acamprosate reduces relapse in alcohol dependence.

Treatment over 12 months suggests continued abstinence after termination of medication.

Adverse events are rare and minor.

Early evidence suggests that acamprosate without particular psycho-social support may be as effective as acamprosate combined with minimal or brief intervention. Further investigation is necessary.

ACAMPROSATE AND QUALITY OF LIFE

HRQoL secondary analysis of the European NEAT ProgrammeSynthesis from 5 countries: Austria, Belgium, Portugal,Switzerland and the United Kingdom

F. Poldrugo, Department of Psychiatry, University of Trieste, ItalyP. Lehert, Catholic University of Mons, Belgium

Main Investigators:C. Ansoms, F. Fisher, W.J. Fuchs, M. Morgan, I. Pelc and A.J. Pires Preto

Study design Primary objectives:

– Comparison of the efficacy of acamprosate with or without a – follow-up by a social nurse after detoxification

Study design:

– The patients were hospitalized for 3 weeks and randomized to one of the 2 treatment groups

• Group 1: The patient sees his/her GP whenever necessary. However, the follow-up is monitored by a nurse

• Group 2: The patient is seen by his/her GP

Treatment duration: – 26 weeks

CAPRISO STUDY

Methods (1)

Prospective evaluation during a 26 weeks follow-up period of alcoholic patients, after detoxification

Two randomized parallel groups with follow-up by a social nurse (F group, N = 50) or without follow-up (NF group, N = 50)

Evaluation visit at week 1, 2, 3, 4, 6, 10, 14, 18, 22, 26

Outpatient from week 4

Acamprosate for all patients

CAPRISO STUDY

Methods (2) Evaluation of efficacy:

For every visit, the patient is considered as abstainer, relapser or missing.Missing = relapser

Outcome criteria: Main endpoint: CAD (sum of complete abstinent days) * Second endpoints: CGI and compliance

Statistical analysis: Anova on ranks Explanatory analysis: GLM on ranksA priori Power: n = 2*50 / =.05 =.2 = 25% 2 - sided

CAPRISO STUDY

Population (N = 100) - Exclusion Criteria

Other dependencies except nicotine

An expected longer hospital stay more than 3 weeks for detoxification

Known renal insufficiency

Previous treatment with acamprosate

Having participated in another study in the last 30 days

Pregnancy or breast feeding in women of childbearing age

Legal incapacity

CAPRISO STUDY

Population (N = 100) - Inclusion Criteria

Men and women from 18 to 65 years old

DSM-IV criteria for alcohol dependence

Last alcohol consumption within the previous 7 days

Undergoing an inpatient detoxification planned for 3 weeks

Living in the region of Brussels

Having given written informed consent

CAPRISO STUDY

Baseline data per type of follow up

N.F: 50 patients F: 50 patients P

Age 43.5 8.8 43.1 7.2 NS

Gender F (%) 26.0 18.0 NS

DSM IV score 6.1 0.9 6.3 0.9 NS

Number of drinks per day 20.4 13.6 17.8 8.6 NS

Number of previous withdrawal 0.4 0.5 0.3 0.4 NS

Years of alcohol dependence 13.1 9.2 15.2 10.1 NS

Dose of Campral 6t/day (%) 76.0 84.0 NS

CAPRISO STUDY

Employed Jobless Retired or Sick

28 45 27

No Secondary University

32 44 24

Single Married Divorced Widowed

37 18 40 5

Population (N = 100) - Demographic DataAge (years) 43.3 8.2

Gender female (%) 22

Marital status (%)

Education status (%)

Family history (%) 63

Smoking (%) 82

Employement (%)

CAPRISO STUDY

Initial Severity

Living status

Smoking habits

Drinking pattern

Number of previous withdrawal

Influence of baseline variables on CAD % Cont’d

No evident effect observed with

CAPRISO STUDY

No FU FU

Markedimprovement

7 11

Slightimprovement

4 14

No change 11 13

Slightly worse 25 11

Much worse 3 1

Clinical Global Impression

2: p = 0.011

CAPRISO STUDY

Conclusion1. Significant differences in outcomes between the 2 treatment

conditions showing a strong influence of social nurse intervention during psycho-social follow-up

2. Success rate of the pharmacological active treatment (Acamprosate, I. Pelc, 1992) is positively or negatively influenced by a psycho-social support process

3. Significant influence of Age, Education, Marital status, Family History, Gender and Previous Attendance to SHG on CAD

4. No significant influence of Smoking, Drinking Pattern, Living Status, Number of Previous Detoxification and Initial Severity

5. Providing psycho-social support has to be relevant to patient’s specific needs

CAPRISO STUDY

I. PELC, M.D., Ph.D.Collaborators

P. Verbanck M.D, Ph. D.O. Le BON M.D. PsychiatristsC. Hanak M.D.J. Tecco M.D.

A. Vandenborre Chief NurseD. Montag, S. Minet Social WorkersM. Streel, X. Noël B.Sc. Psychologists

C. Houtain, I. Baert Social Nurse Researchers Université Libre de BruxellesClinical Department and Laboratory of Psychological Medecine, Alcohology and Drug Dependence

and General Practitioners of the Brussels’ Region

Dr F. Deckers Merck - Lipha - BruxellesDr F. Landron Merck - Lipha - LyonProf. P. Lehert University of Mons (Belgium) and

University of Melbourne (Australia) - Statistical Analysis

CAPRISO STUDY