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United Kingdom Multicentre Acamprosate Study (UKMAS): A 6-Month Prospective Study Of Acamprosate Versus Placebo In Preventing Relapse After Withdrawal From Alcohol
by J.
Chick*,
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ABSTRACT |
A 6-month randomized controlled study of acamprosate versus
placebo in preventing relapse following withdrawal from alcohol
was undertaken in 20 centres throughout the UK. Patients diagnosed
as alcohol-dependent and detoxified within the preceding 5 weeks
were randomly assigned to treatment with either acamprosate
(A) 666 mg three times/day or identical placebo (P). A total of 664
patients were screened; 581 were entered into the treatment phase.
One-third were episodic drinkers, 84% were male, 44% were unmarried
and 48% were unemployed. Medication was first taken on average 24
days after the start of detoxification; 32% of patients had already
relapsed by this time. The 6-month study period was completed by
35% of patients; adverse events led to withdrawal of a further 14%
(A) and 9% (P) respectively. Compliance was poor in that, by the
end of the second week, only 57% of patients were judged to be
taking at least 90% of their tablets. The mean total of abstinent
days achieved was 77 (A) and 81 (P). Complete abstinence for 6
months was achieved by 12% (A) and 11% (P); drinking remained
within controlled limits in a further 3% (A) and 6% (P). An effect
of acamprosate on consumption was not seen when subgroups,
including those defined by the Lesch typology, were analysed
separately. However, the mean percentage reduction in craving for
alcohol measured on a visual analogue scale was greater in the
acamprosate, than placebo, patients at week 2 and week 4 (P
< 0.001) and the mean decrease in the Hamilton Anxiety score at the
4th week was greater in the acamprosate than placebo patients (P
= 0.017). In comparison with other published trials of acamprosate,
patients started study medication after a longer time following
detoxification, had more often recommenced drinking before
medication was started and had a higher drop-out rate, and this
might have contributed to the lack of a treatment effect in this
study.
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INTRODUCTION |
The rapidity of relapse in alcohol-dependent patients who have
sought assistance to withdraw from alcohol is a cause for concern.
Admissions of patients diagnosed as alcohol-dependent is placing
an increasing burden on acute medical services (Chick, 1997
).
Advances in understanding the neuropharmacology of alcohol dependence
and the rapid reinstatement of the syndrome after abstinence
have supported hopes that pharmacotherapy may aid recovery (Chick
and Erickson, 1996).
There is evidence that acamprosate, calcium acetyl
homotaurinate, can lengthen time to relapse, reduce drinking days,
and increase the percentage attaining complete abstinence among
alcohol-dependent patients who have accepted treatment for their
condition (see e.g. Sass et al., 1996; Whitworth et al.,
1996; Geerlings et al., 1997; Pelc et al., 1997;
Poldrugo, 1997). Homotaurinate is a naturally occurring structural
analogue of
-aminobutyric
acid (GABA); acamprosate is a synthetic derivative. This compound
crosses the blood–brain barrier, modulates GABA transmission
(Daoust et al., 1992),
decreases postsynaptic potentials in the neocortex, perhaps by
affecting excitatory amino acid (N-methyl-d-aspartate: NMDA)
receptors (Zeise et al., 1993),
and diminishes voluntary alcohol intake in alcohol-preferring rats
(Boismare et al., 1984;
Le Magnen et al., 1987a;
Gewiss et al., 1991).
Evidence by Lamblin et al. (1993), Rassnick et al.
(1992) and other studies reviewed by Tsai et al. (1995)
implicates glutamate neurotransmission, and NMDA modulation
thereof, in the GABA system in alcohol-seeking behaviour. Tsai
et al. (1998) assessed glutamatergic neurotransmission and
oxidative status in alcohol-dependent patients after acute alcohol
withdrawal and 4 weeks later and found persistent abnormalities in
cerebrospinal fluid. Littleton (1995) has proposed that one of
acamprosate's actions, mediated by its effects on calcium channels
as well as on the NMDA receptors in the glutamate system, is to
suppress conditioned alcohol withdrawal craving.
Acamprosate administration to animals does not give rise to
a dependence syndrome (Grant and Woolverton, 1989),
nor does it exacerbate either acute or chronic ethanol toxicity in
rats (Le Magnen, 1987b). When alcohol-dependent patients who
have been abstinent while taking acamprosate cease taking the drug
they do not experience a rebound of craving or alcohol misuse
(Whitworth et al., 1996).
The drug thus has no abuse potential.
This paper reports the results of the first study into the
safety and efficacy of acamprosate in a sample of patients attending
specialized treatment centres in the UK. Its design differed
in some respects from previously reported trials, including its use
of a diary card on which patients were to record on a daily basis
any alcohol consumed instead of relying on memory at assessment
visits. Some preliminary data from this study were previously
published in Conference Proceedings (Soyka, 1996).
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PATIENTS AND METHODS |
Design
This work was undertaken in 20 UK clinics during 1991– 1993 as
a 6-month randomized controlled study of acamprosate versus an
identically presented placebo. The clinics were connected with
psychiatric services and a general hospital, including both
teaching hospitals and district general hospitals. It was intended
that the medication would be used as an adjunct, not an
alternative, to the clinic's usual psychosocial out-patient
treatment programme. No check on blindness of patients or assessors
was made; in other ways this study design followed criteria
recommended by Moncrieff and Drummond (1998) and the Plinius Maior
Society (1994).
A recruitment examination and assessment was conducted
within 5 weeks of the end of detoxification (defined as at least 5
days of abstinence). Detoxification may have been carried out
on an in-patient or an out-patient basis. The length of this
‘pre-baseline period’, up to 5 weeks, was chosen, because some
patients to be recruited would be undergoing in-patient treatment
of about 4 weeks duration. There was then a ‘wash-out’ period of 1
week, during which patients had to be free of benzodiazepines and
were instructed not to drink alcohol. Patients were then reassessed
and, using randomization in blocks of eight, allocated to treatment
with either active medication, acamprosate 1998 mg (two tablets of
333 mg each three times per day), or identically presented placebo
(also two tablets three times per day). Assessments were made after
1 week on medication, then at 2-weekly intervals, and later at
4-weekly intervals for a total of 24 weeks. Medication was stopped
and patients then reassessed 4 weeks later to monitor the effects
of the abrupt withdrawal of the study medication. In all, 11
assessments were planned (see Fig. 1).
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During the study, the protocol was amended to allow reduction
of the dosage to four tablets per day if gastrointestinal side-effects
were distressing. The study was approved by the local Ethics
of Research Committee at each UKMAS centre.
Treatment for detoxification when on medication during the study, even if hospital admission were required, was not a reason for withdrawal from the study, nor was the prescription of benzodiazepines for periods up to 7 days. Admission to hospital for reasons other than alcohol withdrawal was regarded as a serious adverse event and led to withdrawal from the study. Benzodiazepines were not permitted for other purposes, but the urine checks made did not systematically include a check for these or other drugs.
Inclusion and exclusion criteria
Patients were included if they were 18–65 years of age, weighed
>60 kg (later modified to 50 kg), fulfilled criteria for alcohol
dependence (DSM-III; American Psychiatric Association, 1980), had
at least a 12-month history of alcohol dependence, had undertaken
withdrawal from alcohol during the preceding 5 weeks, had been
abstinent for at least 5 days before enrolment to the study and
gave written informed consent.
Patients were excluded if they were receiving disulfiram or calcium carbimide, drugs known to induce hepatic enzymes with the exception of oral contraceptives, or tranquillizers on a regular basis. Patients were also excluded if they had abused drugs in the previous 12 months, had serious medical or psychiatric disorders, or were pregnant or at risk of becoming pregnant. During the study any patient given drugs known to induce hepatic enzymes or psychotropic medication, apart from hypnotics, were withdrawn from the study.
Baseline measures
At baseline, a drinking history was obtained, and the following
scales completed: the SADQ (Stockwell et al., 1983)
in which a score of 30 suggests severe dependence (range 0–60),
the MAST (Selzer, 1971)
in which a score of 5 indicates ‘alcoholic’ (range 0–52) and the
CAGE (Ewing, 1984)
in which a score of 2 indicates a probable alcohol problem (range
0–4).
Safety monitoring
Tolerance of the drug, concomitant diseases, concurrent medications,
and vital signs were recorded at every visit; physical examination
including ECG was conducted before and after the study, and
blood samples for measurement of haematological and biochemical
variables (analysed at a centralized laboratory) were taken at
entry and after 1 month, 3 months and at the end of the medication
period. At the visit immediately prior to starting medication, and
at 1, 3 and 6 months, the clinician rated the Hamilton Anxiety and
the Hamilton Depression scales (Hamilton, 1959, 1967 respectively).
Outcome variables
Indicators of alcohol consumption.
At each assessment, breath
alcohol was checked using an alcolmeter (Lion Laboratories, Ty
Verlon, Cardiff, UK); the patients rated their degree of craving on
a visual analogue scale 100 mm long [no desire for alcohol (0 mm)
to uncontrollable desire for alcohol (100 mm)]; a record card (Fig.
2)
was issued on which patients were asked to note on a daily basis
whether or not they drank and how much, and the previous period's
card was collected. At 1 month, 3 months and 6 months, mean red
blood corpuscular volume (MCV) and serum
-glutamyl
transferase (GGT) activity (Chick et al., 1981),
and also serum aspartate aminotransferase (AST) activity and
urinary ethanol concentration were all assessed. At the end of the
study, the Alcohol-Related Problems Questionnaire (Patience et
al., 1997)
was administered; this contains eleven questions about problems in
relationships with friends or family, or the areas of health, work
or the law. Attempts were made to contact patients who did not
attend by telephone and letter, in order to obtain missing data.
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At completion of the study, each patient was asked to rate
how effective his or her ‘control’ in abstaining from alcohol
had been during the study. Each investigator was asked to rate in a
similar way their patients' success in ‘control’.
Compliance. Returned tablets were counted. Failure to attend or to return the tablet bottle even at a subsequent visit, was recorded as ‘no data’. Some patients were permitted to reduce their daily dosage if they suffered unwanted side-effects. This was taken into account when assessing compliance.
Typology categorization.
A retrospective categorization of the patients enrolled in the
Edinburgh and London centres was undertaken using the Lesch
typology algorithm, which has been used to predict response to
acamprosate (Lesch and Walter, 1996).
Patients were traced through contact addresses, hospital and
primary care National Health Service Records, and the Register of
Deaths. The data necessary to classify a patient were obtained at
interview by a psychologist from the Lesch clinical group,
supplemented if necessary from clinical records, and the research
database. Classification was based on a computer-held algorithm.
Analysis was made of outcome in relation to typology.
Analysis
Power. For the primary efficacy variable of abstinence for 6 months,
based on previous reports of an expected placebo response of
25% and an expected response to acamprosate of 40% (Lhuintre et
al., 1985),
a sample of 512 would have a 95% power of detecting a difference
between treated and untreated patients using a 5% significance
level and a two-tailed test.
Efficacy.
Following the intention to treat (ITT) principle, any randomized
patient who took at least one dose of study medication was entered
into the analysis. It was assumed that all patients who terminated
treatment before the end of the study, including those experiencing
adverse events, were treatment failures. Primary efficacy variables
were pre-defined as: duration of continuous abstinence; duration of
continuous abstinence or controlled drinking. Abstinence was
defined as: diary card available and no reported drinking
and negative breath and/or urine alcohol levels. Controlled
drinking was defined as mean daily self-reported consumption of 5
units or below (men) or 3 units or below (women) and no single day
exceeding 8 units (men) or 6 units (women). A unit was that amount
of beverage containing 8 g of ethanol. Secondary outcome variables
were cumulative abstinence duration, and craving for alcohol.
Compliant subgroup. A subgroup of more compliant patients was identified post hoc as those who (1) met inclusion criteria; (2) did not take any prohibited medication during the first 14 days on study medication; (3) attended at least one of the scheduled visits in the first 2 weeks after starting medication; (4) took at least 50% of study medication according to tablet counts during the first 14 days. Excluded from this subgroup were 24 patients who had not met the initial inclusion criteria, but which had not been identified at the outset.
To examine predictors of outcome, subgroups were created
according to ratings on certain baseline characteristics (e.g.
gender) and the proportions of good responders in the two treatment
groups were compared either using
2
or two-tailed Fisher's exact probability tests, as appropriate.
Multiple regression analysis was used to examine the significance
of these relationships.
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RESULTS |
Recruitment to the study
An unspecified number of patients was considered or approached
without formal evaluation of eligibility. Staff were asked later
about their reasons for pre-recruitment exclusion; the commonest
were medical or psychiatric unfitness, patient's refusal, or
patient requesting disulfiram. A total of 664 patients were
formally examined for eligibility to enter the study. Of these, 83
did not go forward to randomization. These 83 comprised: 24 lost to
follow-up between assessment and randomization, 40 failed to meet
inclusion criteria, three showed worsening of their condition, 10
changed their minds about taking medication or otherwise withdrew
co-operation, and in the remaining six no reason for exclusion was
specified.
Thus 581 patients were randomized and included in the ITT sample.
Baseline data
At the point of randomization, the acamprosate (A) and placebo
(P) groups were well matched on the following variables: age (A
42.8, P 43.8 years), gender (A 87% male, P 80% male), marital
status (unmarried: A 43%, P 45%), and employment status (unemployed:
A 51%, P 46%); pattern of drinking (‘episodic’: one-third of
each group); mean SADQ score (A 34, P 33), CAGE [a score of 4 in
76% (A) and 74% (P)] and MAST [mean score 38(A), 37(P)], including
being matched for those items in MAST with an antisocial component
(involved in fights, been arrested, trouble with police, drunk
driving), blood MCV (A 98.3, P 98.2 fl), serum GGT (A 122 U/l, P
108 U/l, n.s.); mean craving at baseline (A 24 mm, P 22 mm, not
significant).
The groups were not matched on: prior weekly alcohol consumption (A 188 units/week, P 168 units/week, P = 0.022); place of detoxification (home not hospital: A 55%, P 45%, P = 0.020).
The mean interval between the beginning of detoxification and start of study medication was 24 days (A), 25 days (P). However, in 158 patients (27%) (A 74, P 84) this was between 29 and 42 days and in 34 patients (6%) (A 18, P 16) between 43 and 56 days. Patients for whom there was more than 5 weeks between the beginning of detoxification and randomization should not have been included according to the protocol; however, some were randomized and therefore are included in the analysis except when stated. Some patients (168) drank alcohol in the 7-day ‘wash-out’ period between the assessment intake interview and the start of study medication. This was controlled drinking in 13% (A) and 16% (P), and uncontrolled drinking in 15% (A), 14% (P), with no data available in 3% of patients in each group.
Attendance
There were no statistically significant differences in attendance
between the treatment groups at any time point in the study. At the
mid-point of the study (84 days) 51% of the acamprosate group and
54% of the placebo group attended; this fell to 35% (A) and 37% (P)
by the 24th week. Only 203 patients completed the study [A: 100
(35%), P: 103 (35%)]. The commonest reasons for early withdrawal
were: lost to follow-up (A 23%, P 25%), adverse events (A 14%, P
9%), condition worsened (A 7%, P 9%), refused medication (A 11%, P
8%), and ‘non-compliance’ (i.e. missing many appointments) (A 6%, P
9%). A major effort to contact all patients was made 1 month after
the end of the medication phase; 486 were interviewed. A summary of
patient retention in the study is shown Fig. 3.
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Efficacy
Continuous abstinence: survival analysis. The survival curve for
complete abstinence is shown in Fig. 4.
At randomization to study medication, 32% of patients had already
relapsed. No significant differences emerged at any visit in the
proportion of patients abstinent, nor in the proportion drinking in
a controlled way, between study groups. Continuous abstinence for
the 24 weeks was achieved by 12% (A) and 11% (P). A further 3% (A)
and 6% (P) drank some alcohol but without meeting criteria for our
definition of ‘uncontrolled’.
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Cumulative abstinence duration (CAD).
CAD is the totalled number of abstinent days recorded on all
diary cards for the period between first study medication and end
of medication. CAD did not differ between treatment groups: 77 days
(A) and 81 days (P) (P = 0.492).
‘Control’ and craving. Of the 203 patients still in contact at the end of the study, who answered the question ‘how effective they perceived their ‘control’ in abstaining from alcohol during the study’, 70% (A) and 73% (P) stated ‘good’ or ‘excellent’. In this group of compliant patients, investigators were also positive about the patient's response to treatment, rating 84% (A) and 82% (P) as ‘success’.
The mean decrease in craving was significantly greater in
the acamprosate group after 2 weeks of treatment (P < 0.001)
and after 4 weeks (P < 0.001) and there was a trend at 1
week (P = 0.079) and 12 weeks (P = 0.069). One month after
the end of the medication phase, the mean decrease in craving was
greater in the acamprosate-treated patients than in those receiving
placebo (P = 0.022, n = 486) (Fig. 5).
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The scores on the Alcohol-Related Problems Questionnaire
medication phase improved during the medication phase between
intake and 6 months by the same amount, a mean of 3.8 points, in
both groups.
Blood tests
Laboratory test results improved throughout the study in both
treatment groups; no significant differences were observed between
treatment groups in either mean values at any of the time points or
in the percentage change in values from baseline. The proportion of
patients attending at each visit with an elevated serum GGT (>50
U/l) did not differ between treatment groups. At visit 1, 50% of
patients had elevated serum GGT activities and at the end of the
medication phase 29% had raised activities. The proportions of
patients having an increased blood MCV (>97 fl) at baseline were
56% (A) and 49% (P). There was no difference between the groups at
any visit. At visit 10, increased blood MCV was detected in 35% (A)
and 36% (P). For patients completing the study in whom complete
data on blood tests were available, the mean GGT corroborated
self-reported drinking as recorded in the diary cards (Fig. 6).
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Secondary effects
Hamilton Anxiety and Depression scores. At baseline, the means
and SD for the Hamilton Anxiety scores were: mean 9.8 ± 8.1 (A) and
9.6 ± 7.9 (P). The mean decrease after 4 weeks was greater in the
acamprosate group (2.6 ± 7.7) than in the placebo group (1.0 ± 5.4)
(P = 0.017). A trend in the same direction was still visible
at 3 months (P = 0.076), but was no longer apparent at the end
of treatment. A significant difference was, however, again noted
at 1 month post treatment (P = 0.014). Improvements in the
Hamilton Depression ratings were noted overall, without differences
between the treatment groups.
Safety and tolerability
The most frequently reported adverse events were headache,
diarrhoea, nausea and vomiting. The protocol permitted a reduction
in the total daily dose from 6 to 4 tablets/day if gastrointestinal
symptoms were distressing and this was done in 11.4% of the
acamprosate group and 9.2% of the placebo group. Serious adverse
events were reported in 83 patients (29%) in the placebo group and
93 (28%) in the acamprosate group. Hospital admission occurred for
detoxification in 14 patients (2%): for an alcohol-related disorder
in six patients (1%) and a non-alcohol related disorder in nine
(1.5%). Two patients ingested large quantities of the active drug
in a deliberate overdose, the larger overdose being approximately
128 of the 333 mg tablets, but did not suffer harmful effects.
No changes which could be attributed to the drug occurred in body weight, electrocardiography, haematology or biochemistry test results.
Compliance
By the end of the first 2 weeks of receiving medication, 57% of
patients in each group were taking at least 90% of their tablets.
This gradually reduced until the end of the 6-month medication
phase, when 27% (A) and 28% (P) met this criterion. A separate
analysis of those patients attending and compliant with medication
was not conducted. It would have been a small subset and a separate
analysis could not be justified.
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SUB-GROUP ANALYSES |
Sub-groups according to certain baseline characteristics
The groups were not matched at baseline with respect to where
they were detoxified (Table 1).
However, this did not have an influence on outcome: of the 290
patients detoxified in hospital, 16.9% achieved 6 months of
abstinence or controlled drinking, compared to 14.8% of the 291
patients detoxified at home. There was no significant difference in
outcome in relation to gender: 21.8% of the 96 women attained 6
months of complete abstinence or controlled drinking, compared to
14.6% of the 485 men. Being abstinent in the ‘wash-out’ week before
starting study medication, not unexpectedly, predicted, indeed was
a necessary condition for, abstinence during the whole treatment
period. No patient who drank in the wash-out week attained complete
abstinence. However, three patients (one A, two P) who drank
in the wash-out week succeeded in not losing control of drinking
during the 6-month treatment period. There was a non-significant
trend for those who had had a longer abstinent period between
detoxification and starting the study to remain abstinent throughout
the study. This is to be expected: patients able to abstain
for a month tend to stay abstinent for longer. Baseline craving
predicted outcome, with only five of the 106 patients (4.7%) with
high craving (>50 cm on the visual analogue scale) achieving
controlled drinking or abstinence for 6 months.
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When outcome by treatment group was examined in subgroups
defined according to the predictor variables in Table 1
(namely: gender; place where detoxified; drinking pattern in
baseline week; severity of baseline craving; interval till start of
medication) no interaction with acamprosate emerged. Multiple
regression analyses including these five variables did not identify
an acamprosate effect. This was the finding when either continuous
abstinence, or continuous abstinence/controlled drinking, were used
as outcome criteria. Although baseline previous weekly consumption
had been higher in the acamprosate group, when added to this
multiple regression analysis, an acamprosate treatment effect did
not emerge. (The slightly higher baseline consumption in the
acamprosate group may have reflected the slightly greater
proportion of males.)
Compliant subgroup
A sub-group was defined excluding early non-compliance with
medication in the first two weeks and those patients randomized but
who had been ineligible on inclusion criteria. This group consisted
of 378 patients (A 194, P 184). In terms of their baseline
characteristics, these groups were slightly unbalanced in that the
patients receiving placebo were more likely to be female (P 22.3%,
A 13.4%, P = 0.024). They were, however, balanced for place
of detoxification as well as on all other baseline characteristics.
Within this subgroup, there were no differences between those
receiving acamprosate and those receiving placebo on any of the
outcome criteria, except for craving at weeks 2 and 4 which was
lower in the acamprosate group (P = 0.045 and 0.050
respectively).
There were no significant interactions between treatment group and any of the baseline factors singled out as likely predictors of outcome (gender, previous weekly consumption, place where detoxified, interval to starting medication, drinking between enrolment and commencing medication, and baseline craving). In the 78 patients who started study medication within 14 days of the start of detoxification, four (5%) sustained abstinence, and all were in the acamprosate group (P = 0.052).
Post-medication assessment
At a minimum of 1 month after stopping medication, 385 patients
were assessed. Of these, 203 had completed the study (A 100; P 103)
and they tended to be seen at or near to the 1-month point
post-treatment; others had withdrawn early for various reasons and
hence tended to be seen at a relatively later point than the
completers. The proportion of patients abstinent 1 month after
medication ended was slightly higher than at the last visit on
medication. This was because some patients who had relapsed and
terminated before the end of the study were now abstinent. There
was no evidence of sudden relapse in drinking when the medication
was discontinued.
Centre differences and psychosocial treatments
offered
Analysis of outcomes by centre did not suggest that acamprosate
was more effective in some centres than others, but the numbers
analysed were small, and the data by centre are not presented here.
Data were available on the psychosocial treatments offered at the 16 centres which contributed most patients to the study. Nine were specialized alcohol problem clinics, five were addiction centres, one was a general psychiatric setting and one a general medical setting which contributed 72 patients. Day-patient facilities were available in 11 centres. All but two centres reported that a typical in-patient stay, if indicated, would be less than 4 weeks, with two centres specifying less than 2 weeks. Cognitive–behavioural group therapy was offered at 13 centres, and out-patient support groups at nine centres. Eight offered ‘educational groups’. Only five offered marital therapy, and five social skills training. Only two centres had on-site meetings of Alcoholics Anonymous (AA), but 14 centres used AA as a resource. The amount of other treatment taken up by patients in the study period was not documented at the time. However, later estimates revealed that, at seven centres, less than 20% of the patients attended appointments outside the research visits, whereas at five centres more than 75% did so. When asked to compare their clinical impression of patients they had recruited to the study, nine centres said that patients recruited had been ‘typical’, but six said they had been ‘less severe’ than typical patients.
Typology
An attempt was made to trace all 149 patients randomized into the
study at the two main centres. Two patients were too cognitively
disabled to give an interview, 10 refused, 29 were untraceable and
32 had died. An interview was obtained and a classification made in
76. The two Lesch types tending to be responsive to acamprosate in
the Austrian study of Lesch and Walter (1996), Types I and II,
accounted for 25% and 18% of the sample interviewed respectively.
Types III and IV, which in the Austrian study tended to be
non-responsive to acamprosate, accounted for 15% and 42%. ‘Types'
were equally distributed between the two treatment groups; 17 Type
I and II patients received the placebo while 16 received
acamprosate. There was no trend suggesting that these Type I and II
patients had a better outcome in one treatment group rather than
another.
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DISCUSSION |
In terms of abstinence for the duration of study, the success of this patient population was low, at ~11%. Analysing data on the whole population, no evidence of an effect of acamprosate on drinking in the 6 months following detoxification was found. This is not explained by effects of those baseline characteristics which were imbalanced between the groups, namely gender, place of detoxification and mean previous weekly alcohol consumption.
The craving rating at weeks 2, 4 and at the month after medication ceased was lower in patients treated with the active drug.
The findings of this study differ from those of previously
published randomized controlled trials (Table 2),
all of which have shown that acamprosate improves self-reported
abstinence rates in recently abstinent alcoholics, over periods
varying from 3 to 12 months of medication, with two exceptions:
Roussaux et al. (1996), and Lhuintre et al. (1990)
who did not report consumption data. Not all studies reported
corroborative advantages in objective markers of alcohol
consumption, such as serum GGT activity. There are a number of
possible explanations for these contrasting findings.
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Patient characteristics
Severity of condition or resistance to treatment may have been
greater in the UK patient population, than in some other samples.
Thus, in the study of Paille et al. (1995), half of the patients
treated were receiving treatment for their alcohol problem for
the first time. While previous treatment experience was not
recorded in the UKMAS sample, it is believed that more than 50% had
a history of treatment failure. Where details have been published,
it appears that patients' social supports in the positive studies
were greater than in UKMAS. Thus, in the study of Sass et al.
(1996), 26% were unemployed, and in the study of Paille et al.
(1995), 21% were unemployed, compared to 48% in UKMAS. [In the
other negative study (Roussaux et al., 1996)
60% were unemployed and only 20% married, resembling the low
social support of the UKMAS sample.]
Response to the MAST questionnaire is sometimes used as an index of severity of alcoholism. However, great caution must be used when comparing MAST scores between cultures, and between samples with differing proportions of men and women, because some items depend on the interaction between the drinker and society. For example, 5 MAST points can be scored for attending AA, but the availability of AA varies between countries; similarly, several points can be scored for legal infringements, but the rate of police activity towards drinkers also varies between societies and in relation to gender. However, the UKMAS sample scored a mean of 37, similar to the Ladewig et al. (1993) sample (mean 38), but higher than those of Whitworth et al. (1996) (mean 32) and Poldrugo (1997) (mean 27). The other studies did not use MAST.
Within our population, therefore, we proceeded to examine whether groups of different severity, defined on baseline MAST or consumption, had a greater or lesser response to acamprosate. However, no such interaction was found. The UKMAS sample may have contained a higher proportion of patients with personality disorder than the other studies. No specific measure was used in any study, but there are certain MAST items relating to social disorder, police trouble and violence, which, to illustrate this point, we have calculated as a separate index. The mean score on these ‘sociopathic’ items in the UKMAS patients was 6.5 (SD 2.7, max. score 11), but these data are not available for other studies.
As regards typology, the Austrian study (Whitworth et al.,
1996)
contained 39% of non-responding patient types, Types III and IV
(Lesch and Walter 1996).
If the two UKMAS centres are representative of patients from other
centres, then the UKMAS sample contained a higher proportion (57%)
of Type III and IV than at least one of the studies from
continental Europe. However, there was no trend in the limited data
obtained to suggest that Type I and II patients had relapsed less
if receiving acamprosate than if receiving placebo.
Pattern of drinking
One-third of our patients drank episodically rather than continuously.
Few data on patterns of drinking are given in the other trials
of acamprosate. However, in the study of Whitworth et al. (1996),
18% were episodic drinkers and Poldrugo (1997) reported that,
in his Italian study, 86% of patients drank on 7 days per week. At
this juncture, there are insufficient data to state whether an
acamprosate response is more likely in continuous than episodic
drinkers.
Diary card
Using such a card, which the patient had to return in person,
may introduce stricter criteria for monitoring alcohol consumption
than employed in some of the previously reported studies. Perversely,
it could encourage less accurate overall recording of consumption
if the assessors did not also use careful questioning and their
clinical sense. We have no way of assessing either of these
possibilities, though we can state that the objective marker, serum
GGT activity, correlated well with our diary card measures and did
not reveal any advantage to the acamprosate group.
Timing of the medication
The mean interval between the last drink and the start of medication
was 25 days and, in some patients who were randomized and given
medication, was over the 5 weeks specified in the protocol.
The range of intervals in the other studies was shorter (Table 2).
The effect of acamprosate in the German and Austrian studies was
most prominent in the first 30 days. In the UKMAS study, only 78
(13%) of the patients began study medication within 14 days of the
start of detoxification, and of the four patients who achieved
complete abstinence all were in the acamprosate group, a difference
which, however, failed to reach significance (P = 0.052).
Altogether, 35% of patients had relapsed before starting
medication. In some of the published studies (e.g. Besson et al.,
1998), patients were withdrawn from the study before medication was
started if they were drinking on the day of commencement.
If the calcium channel abnormalities or NMDA receptor changes in the recovering alcohol-dependent patient are most marked in the immediate weeks after the last drink, then it may be that, if acamprosate is to be effective, it should be started as soon after detoxification as possible, or even during detoxification.
There was a very early relapse in our UKMAS sample: 155 (27%) drank in the first 7 days after detoxification, that is, the week between evaluation and randomization during which they were on no medication, and no data are available for a further 33 patients, suggesting that these individuals had already been lost to follow-up and were probably drinking. If acamprosate could prevent this early relapse in, say, half of these patients, then the difference in overall total abstinence rates could have been 16%. In retrospect, if patients had been given a placebo preparation during that period they might have been less likely to drink.
Location of withdrawal treatment
Approximately 50% of patients entering the UKMAS study were
detoxified as outpatients. This contrasts with other studies, in
which home detoxification was uncommon. Even in the study of Paille
et al. (1995), only 20% had not been hospitalized for
detoxification. It is difficult to see why this should influence
the efficacy of acamprosate; it may however indicate that UKMAS
patients had slightly lower motivation/were not willing to come
into hospital; or it may reflect the relatively low intensity of
the UKMAS clinic approaches compared to approaches in the centres
taking part in some of the other studies; or that, compared to
those in the other studies, UKMAS patients tended to be less
severely dependent, which was also mentioned by six UKMAS centres.
Type of psychosocial treatments offered
Descriptions of the psychosocial treatments offered in the
other studies are sparse. However, it should be noted that, in UK
centres, relatively few were offering those psychosocial therapies
which are perhaps of most proven value, such as 12-step
facilitation leading to regular attendance at AA meetings, marital
therapy, social skills training (Miller et al., 1995;
Project Match, 1997). Attendance at AA was more common in the
German study, in that, during the first month, 25% of patients went
to at least one meeting and by the end of the 12 months, 14%
were still attending. The figures for the present UK study are not
exact, but it is believed that there was much less AA attendance.
Drop-outs
In all the other studies, even those of 12-month duration,
completion rates were better than in UKMAS. This may reflect higher
rates of patients with personality disorder or lack of social
resources, or reflect that with some exceptions the UK centres
tended to offer a less intensive approach.
Loss to follow-up is a major problem when interpreting results of treatment outcome in alcohol-dependent samples when studies extend over many months. All the studies described here, including UKMAS, reported results analysed using ‘the intention to treat’ principle, which classifies patients who drop out as treatment failures, and does not risk sub-group analyses where original matching between the groups may be lost. It takes no account of whether or not those patients remaining in the study actually complied with treatment. Many consider the ‘intention to treat’ analysis to be the only correct approach in analysing treatment outcome. Nevertheless, one other analysis was carried out here, of the sample defined as those who had not violated the protocol in any way and who complied for the first 2 weeks, taking at least 50% of their medication according to tablet count. However, no evidence of a trend towards an effect of acamprosate on outcome was revealed.
Was the sample too small to show a treatment
difference?
The effect size in the other studies has been at least the 15%
allowed for when the power calculations for the UKMAS study were
made: at first sight, the UK result seems unlikely to be due to a
lack of statistical power. However, the power calculation had
assumed that all patients would be abstinent at the start of the
treatment period. The fact that 155 patients were no longer
abstinent at the start of treatment would have reduced the
statistical power of the study.
By chance, a negative study has occurred
As the number of controlled studies of apparently successful
treatments increases, the proportion of studies which fail to show
an effect may also increase. This may be due to variations in the
application of the treatment, characteristics of the sample or
treatment setting, or perhaps chance. For example, Morris and Beck
(1974) reviewed all the randomized controlled studies of tricyclic
antidepressant drugs which had been published up to 1 January 1973.
Out of 93 studies, tricyclic antidepressants were more effective
than placebo in 61 studies, no difference was found in 32 studies,
and there were no studies where placebo was more effective than
tricyclic drug. Despite the many negative studies, tricyclic
antidepressants became accepted as a valuable therapy for
depression. It remains to be seen what will be the eventual
proportion of positive to negative studies for acamprosate.
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GENERAL CONCLUSIONS AND COMMENTS |
The weight of results of the other studies reported to date
lead to the conclusion that acamprosate is a helpful adjunct
to conventional outpatient treatment after detoxification, approximately
doubling the number of patients achieving continuous abstinence,
and increasing by some 30–40% the cumulative total of days
abstinent. This UK study does not support these findings.
Contributing to an explanation of this negative result may be loss
of statistical power due to a higher drop-out rate and relapse into
drinking before starting the drug, but also a background of less
intensive treatment in general, although the amount and type of
preceding and collateral psychosocial and/or pharmacological
treatment which best facilitates response to acamprosate has yet to
be specified.
From the other studies it is, of course, clear that not all
patients respond. The characteristics of responders have yet
to be defined. Perhaps the delta (continuous) rather than the gamma
(episodic) alcoholic might respond better (Jellinek, 1960),
and our UK sample probably had a much higher proportion (33%)
of episodic drinkers than other centres, particularly the wine-drinking
centres of Italy, Austria, France and Southern Germany. Lesch
and Walter (1996) showed that a more classical, primary type of
alcoholic, rather than the alcoholic with other psychiatric or
organic disorder or many social problems, is more likely to benefit
from acamprosate. Specification of the optimal patient
characteristics and optimal accompanying psychosocial treatments is
required so that acamprosate can be used to its best advantage.
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| Alexander DeLuca, M.D. |
Originally posted: 8/29/2004 |
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All website Email to: adeluca@doctordeluca.com |
Most recently revised:
8/29/2004 |
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