1. THE STAKE : 10 MIO POTENTIAL CUSTOMERS IN EUROPE
Population of Western Europe ± 325 Mio
Number of alcohol
dependent ± 10 Mio
Number of
withdrawals/ year
(±4%)
4% represents the percentage of alcohol dependent patient undergoing detoxification. Only 18% of those are abstinent after one year.
Abstinent
at 5 years (±6%)
Abstinent at 1 year (±18%)

2. STATES OF CHANGE - REVOLVING DOOR MODEL (Di Clemente et Prochaska, 1982)
Précontemplation
Relapse
Contemplation
Maintenance
This representation is more complete and fits better with the next one.
Préparation
Action
Décision

3. 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
I don’t have references available for this slide. These definitions were collected from various papers.
See for review: T. Wetterling et al Eur. How to assess craving for alcohol Addict Res 1997;

4. MANY STIMULI PRECEDE THE ARRIVAL OF ALCOHOL INSIDE THE BRAIN
Sights and sounds
of the environment
Smell of alcohol etc.
Taste of alcohol
BAR
From J. Littleton’s presentation

5. HOW CONDITIONED STIMULI BECOMES CUES FOR RELAPSE?
This is our patient, he/she has
been detoxified and has turned
his/her back on alcohol and all the
associated stimuli.
Unfortunately, in our alcohol-based
society it is impossible to avoid all
these stimuli for long.
BAR
Each cue initiates adaptation inside the brain
BAR
From J. Littleton’s presentation

6. HOW CONDITIONED STIMULI BECOME CUES FOR RELAPSE
Any of these stimuli induce adaptation
which produces feelings opposite to
those of alcohol eg anxiety, dysphoria.
These feelings can be self-medicated with
alcohol but the decision to do so intensifies
all the cues.
BAR
BAR
BAR
alcohol
From J. Littleton’s presentation
In order to balance the increasingly severe "pseudo-withdrawal produced
by the conditioned adaptation the patient relapses into heavy drinking

7. PAVLOVIAN CONDITIONING AND THE EFFECTS OF ALCOHOL
BAR
ALCOHOL
Unconditioned
stimulus
Associated
stimuli
BAR
As the associated
stimuli repeatedly
precede the arrival
of alcohol in the brain
"conditioning" occurs
BAR
Conditioned
stimuli
Once the stimuli have
become conditioned they
elicit the response (eg
feelings of relaxation) even
before the alcohol arrives
in the brain
Response
BAR
From J. Littleton’s presentation

8. EACH TIME THE ALCOHOL ARRIVES THE BRAIN INITIATES INCREASINGLY EFFECTIVE CHEMICAL ADAPTATIONS WHICH OPPOSE THE DRUG AND CAUSE TOLERANCE
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
BAR
BAR
ONE CONSEQUENCE IS
THAT TOLERANCE IS
USUALLY GREATER IN A
FAMILIAR ENVIRONMENT
BECAUSE THE "CUES"
HELP INITIATE THE
ADAPTATION TO
ALCOHOL INSIDE THE
BRAIN
From J. Littleton’s presentation

9. RELATIONSHIP BETWEEN THE SEVERITY OF ALCOHOL
PROBLEMS AND THE TYPE OF INTERVENTION NEEDED
None
Mild
Moderate
Substantial
Severe
ALCOHOL
PROBLEMS
Specialized
treatment
Brief
intervention
Primary
prevention
From: Heather (1995)
Source: Institute of Medicine (1990)

10. EFFECTIVE PSYCHOLOGICAL TREATMENT FOR DRINKING PROBLEMS
Motivational interviewing
Cognitive - behaviour theory
Relapse prevention
Community reinforcement

11. Ref: De Witte Progress in Neurobiology. 2000, 343-362
Campral® AND GLUTAMATE
% Baseline level
Time (hr) after withdrawal p < 0.001
Ref: De Witte Progress in Neurobiology. 2000,

12. WITHDRAWAL P < 0.05 Motility / Rat / 12h
The motility is associated with withdrawal. The two horizontal lines stand for normal range ( )
Ref: De Witte

13. 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

14. Combined Data Analysis
MATERIAL
Combined Data Analysis
11 Double blind, placebo controlled multicentre studies
8 European countries
3 338 alcohol dependent patients
Mean Age 42.8 years ± 9.3
Sex: female 19%
Mean MAST score 31.8 ± 10.9
Mean CAGE score 3.5 ± 0.76
Names of the 11 studies concerned by the pooled analysis. Pelc II, Barrias, Poldrugo, Tempesta, Paille, Geerlings, Prama, Ladewig, Besson, Chick, Withworth

15. METHODOLOGY 1 demographic variables clinical histories
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 differed
Common data were identified at days 0, 30, 90, 180, 270, 360

16. 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

17. METHODOLOGY 3 To follow a CORE PROTOCOL
± adaptations according countries’ requests
Studies carried out in accordance with the
EUROPEAN GOOD CLINICAL PRACTICE
To use CENTRAL LABORATORY FACILITIES (PRAMA, UKMAS)
or to standardise the laboratory values
PRIMARY OUTCOME CRITERION: Drinking behaviour
1- Abstinence/Relapse/Missing assessment at each visit
2- Time to first relapse (survival analysis)
3- Cumulative Abstinence Duration (a mathematical sum of all abstinent periods)

18. OUTCOME CRITERIA
Number of dry days: cumulative abstinence duration (CAD)
If exact data were available: cumulate directly
Time to First Relapse = 30 days
Cumulative Abstinence Duration = 75 days
Relapses
CAD D0
D30
D60
D90
D120
D150
D180
If exact data were not available: consider total period between visits
Cumulative Abstinence Duration = 60 days
Relapses
CAD
Visit 1 2 3 4 5 6 7

19. OUTCOME CRITERIA At each visit: drinking or not? Time to first drink
Alcohol
consumption
(quantity) D0
D30
D60
D90
D120
D150
D180
Assessment
visits A A R R A A R
A = abstinence R = relapse

20. GENDER / AGE

21. EUROPEAN TRIALS: RATE OF TOTAL ABSTINENCE (%)
2 way ANOVA - treatment: p<0.001, study: p<0.001, interact: NS

22. RESULTS: ABSTINENT RATE
Survival analysis %
Mantel Cox: p<0.001
(no alcohol consumption)
%Abstinence rate
Days
It concerns the pooling of 11 trials representing 3338 patients : Withworth, Pelc II, Geerlings, Paille, Prama, Poldrugo, Tempesta, Barrias, Besson, Ladewig and Chick
It measures:
time to first relapse
absolute abstinence
Comment: this method does not take subsequent abstinent periods
into consideration, but is a conservative measure to assess outcome

23. RESULTS: PROPORTION OF ATTENDING PATIENTS* * * *
Attendance rate (%)
Days
This concerns the same 11 studies mentioned before
Differential attrition between treatment groups
Comment: drop-out rate in naturalistic trials could be an objective
outcome measure of efficacy

24. RESULTS: ABSTINENCE RATE PER VISIT*
Abstinence rate (%) * * * *
This graph shows the results of the combined efficacy analysis.
After 180 days of treatment, 35% of patients on Campral were abstinent compared with 25% of patients on placebo.
After 360 days, abstinence rates were 33% for patients on Campral and 21% for patients on Placebo. The time points were at 30, 90, 180, 270, and 360 days
Days

25. SF 36 QoL SCORES BEFORE AND AFTER PFPhysical Functioning BPBodily pain
CAMPRAL TREATMENT
Before Treatment
After Campral®
Treatment
Ref: Pooled Neat studies
After checking we changed PH for PF. These data has not been published yet. However they were presented in different congresses.
Physical Component
Mental Component
PFPhysical Functioning BPBodily pain
RPRole Physical
GHGeneral Health
MHMental Health
SFSocial Funtioning
RERole Emotional
VTVitality
HTHealth Transition

26. 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

27. RESULTS: ADVERSE EVENTS
Adverse events of statistical significance with a frequency of more
than 5% were:
Gastro-intestinal
irritation
15% in the first 30
days, 8% d31-90
4-8% more than
placebo
Sex drive changes
9% in the first
30 days
3% more than
placebo
Difficulty in falling
asleep
7% between days
181 and 270
3% more than
placebo
The figures are correct.
Regarding diarrhoea, there is a difference of 8% between acamprosate (15%) and placebo (7.1%)in the first 30 days. For days a significant difference (4%) is still found between the two treatments
GOOD SAFETY PROFILE

28. 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

29. CAD

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

31. MICADO STUDY (Netherlands)
De Wildt et al
3 Treatment Groups
a) Campral only:
6 weekly ~ 10 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

32. MICADO STUDY (Netherlands)
De Wildt et al

33. 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.

34. ACAMPROSATE AND QUALITY OF LIFE
HRQoL secondary analysis of the European NEAT Programme
Synthesis from 5 countries: Austria, Belgium, Portugal,
Switzerland and the United Kingdom
F. Poldrugo, Department of Psychiatry, University of Trieste, Italy
P. Lehert, Catholic University of Mons, Belgium
Main Investigators:
C. Ansoms, F. Fisher, W.J. Fuchs, M. Morgan, I. Pelc
and A.J. Pires Preto

35. CAPRISO STUDY 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

36. 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

37. 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 ranks
A priori Power: n = 2*50 /  =.05  =.2  = 25% 2 - sided

38. Population (N = 100) - Exclusion Criteria
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

39. Population (N = 100) - Inclusion Criteria
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

40. Baseline data per type of follow up
CAPRISO STUDY
Baseline data per type of follow up

41. Population (N = 100) - Demographic Data
CAPRISO STUDY
Population (N = 100) - Demographic Data
Age (years)  8.2
Gender female (%) 22
Marital status (%)
Education status (%)
Family history (%) 63
Smoking (%) 82
Employement (%)

42. CAPRISO STUDY Influence of baseline variables on CAD % Cont’d
No evident effect observed with
Initial Severity
Living status
Smoking habits
Drinking pattern
Number of previous withdrawal

43. Clinical Global Impression
CAPRISO STUDY
Clinical Global Impression
2: p = 0.011

44. CAPRISO STUDY Conclusion
1. 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

45. CAPRISO STUDY I. PELC, M.D., Ph.D. Collaborators
P. Verbanck M.D, Ph. D.
O. Le BON M.D. Psychiatrists
C. Hanak M.D.
J. Tecco M.D.
A. Vandenborre Chief Nurse
D. Montag, S. Minet Social Workers
M. Streel, X. Noël B.Sc. Psychologists
C. Houtain, I. Baert Social Nurse Researchers Université Libre de Bruxelles
Clinical Department and Laboratory of Psychological Medecine, Alcohology and Drug Dependence
and General Practitioners of the Brussels’ Region
Dr F. Deckers Merck - Lipha - Bruxelles
Dr F. Landron Merck - Lipha - Lyon
Prof. P. Lehert University of Mons (Belgium) and University of Melbourne (Australia) Statistical Analysis