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Research Report
Eur Addict Res 2011;17:2936
DOI: 10.1159/000320471
Topiramate for the Treatment of
Alcohol Dependence: Comparison
with Naltrexone
Gerardo Flrez
b
Pilar A. Saiz
a
Paz Garca-Portilla
a
Sandra lvarez
b

Luis Nogueiras
b
Julio Bobes
a


a
Department of Psychiatry, University of Oviedo, Centro de Investigacin Biomdica en Red de Salud Mental,
CIBERSAM, Oviedo , and
b
Addiction Treatment Unit, Galician Health System, Ourense , Spain
Introduction
Worldwide, more than 76 million people suffer from
alcohol dependence [1] . This condition includes follow-
ing features: tolerance to alcohol effects, withdrawal
symptoms upon stopping alcohol consumption, loss of
control, repeated unsuccessful attempts to quit or reduce
alcohol consumption, and/or continued use despite nega-
tive consequences [2] . In creating this condition, alco-
hol modifies the brains neurotransmission in different
ways. One of the most important changes that chronic
alcohol intake creates is stimulation of the brains inhibi-
tory pathway, the -aminobutyric acid (GABA) pathway
[3] , and inhibition of the brains excitatory pathway, the
glutamate pathway [4] . Repeated alcohol exposure in-
duces GABAergic down-regulation and glutamatergic
up-regulation [5] . When patients try to quit or reduce
their alcohol intake, their brains are left in a state of hy-
perexcitability and negative affect characterized by anx-
iety, dysphoria, and alcohol craving. Many patients re-
turn to heavy drinking in order to avoid these negative
expe riences [6] . The anti-convulsant topiramate, a sul -
fama te-substituted fructopyranose derivative, enhances
GABAergic transmission and inhibits glutamatergic
Key Words
Alcohol dependence Craving Naltrexone Topiramate
Treatment
Abstract
Background: A 6-month naturalistic, randomized and open-
label, trial of topiramate versus naltrexone was conducted,
with assessments at enrollment and after 3 and 6 months of
treatment. 182 alcohol-dependent patients who had been
drinking heavily during the past month were included.
Methods: Outcome was measured using tools that as-
sessed alcohol intake, cravings, disability, and quality of life;
changes in biomarkers of alcohol intake were also used. Re-
sults: At the 6-month evaluation, patients taking topiramate
had significantly lower scores on the OCDS (all subscales),
the EuropASI (medical, alcohol, family/social, and psychiat-
ric) and the WHO/DAS (employment/social). More patients
taking topiramate remained in the abstinence group and the
moderate drinking without problems group. Conclusions:
Topiramate at a mean dose of 200 mg/day was better than
naltrexone at a mean dose of 50 mg/day at reducing alcohol
intake and cravings throughout the study.
Copyright 2010 S. Karger AG, Basel
Published online: October 26, 2010
Addiction
c Re e s ar h
Gerardo Flrez
Unidad de Conductas Adictivas
Hospital Santa Mara Nai, CHOU
Ramn Puga 5256, ES32005 Ourense (Spain)
Fax +34 988 385 482, E-Mail gerardo.florez.menendez @ sergas.es
2010 S. Karger AG, Basel
10226877/11/01710029$38.00/0
Accessible online at:
www.karger.com/ear
Flrez /Saiz /Garca-Portilla /lvarez /
Nogueiras /Bobes
Eur Addict Res 2011;17:2936 30
transmission, antagonizing the consequences of chronic
alcohol exposure [7] . These mechanisms suggest that
topiramate may be effective for treating alcohol depen-
dence. Several studies, 2 of which were randomized trials,
have demonstrated the effectiveness of topiramate for the
treatment of alcohol dependence [811] .
In this trial, we have studied a larger group of patients
in order to have the statistical power to determine wheth-
er or not topiramate is superior to naltrexone in the treat-
ment of alcohol dependence.
Subjects and Methods
Design
This was a 6-month naturalistic, randomized, open-label trial
of topiramate versus naltrexone for the treatment of alcohol de-
pendence. Drinking parameters and consequences were assessed
at enrollment and during the 6 months of treatment. After 3 and
6 months of treatment, another assessment was done and a statis-
tical analysis was performed.
Subjects
This study was conducted at an outpatient addiction treatment
clinic that receives alcohol-related referrals from the local public
health system. Inclusion criteria were: (1) meeting the Interna-
tional Classification of Diseases 10th Revision (ICD-10) [12] cri-
teria for alcohol dependence (diagnosed by an experienced psy-
chiatrist; ICD-10 criteria are mandatory in the Spanish national
health system); (2) having an ethanol intake, during the past
6months before detoxification, of at least 210 g/week for men and
140 g/week for women (the limit for low-risk ethanol consump-
tion set by the World Health Organization [13] ) assessed with the
European Addiction Severity Index (EuropASI) [14] and the Al-
cohol Timeline Followback [15] ; (3) expressing a desire to stop
drinking alcohol.
Exclusion criteria were: (1) being less than 18 or more than 65
years of age; (2) current diagnosis of dependence or abuse of oth-
er substances except nicotine, assessed with the European Addic-
tion Severity Index and a urine drug screen; (3) current psychiat-
ric diagnosis other than personality disorders, assessed with the
European Addiction Severity Index; (4) any clinically significant
medical condition that in the opinion of the researchers would
adversely affect safety or study participation, assessed with the
European Addiction Severity Index; (5) inability to give full in-
formed consent; (6) not speaking Spanish; (7) clinical history of
mental retardation, as it reduces the accuracy of the information
given; (8) pregnancy or breast-feeding; (9) not having a significant
other (i.e. a stable family or social situation) to provide accurate
daily alcohol-related information to the researchers.
All patients who came to the clinic seeking treatment for alco-
hol-related problems in an 18-month period, from January 2007
to June 2008, were screened. Of the 542 patients screened, 182 pa-
tients fulfilled the inclusion and exclusion criteria and were en-
rolled in the study as none of them refused to give written in-
formed consent. Patients were randomized to topiramate or nal-
trexone after detoxification.
The study was approved by the local ethics committee. Full
written informed consent was obtained from all subjects enrolled
in the study. The study was subject to and in compliance with
Spanish national legislation. It was conducted according to the
provisions of the World Medical Association Declaration of Hel-
sinki and received institutional approval.
Treatment Conditions
For detoxification, clorazepate was the only treatment used
[16] . All patients were detoxified before starting treatment with
naltrexone or topiramate. The mean duration of detoxification
was 12 days. Patients in the naltrexone group were prescribed a
50mg tablet once daily, the dosage used in the trials that support
the efficacy of naltrexone in the treatment of alcohol dependence
[17] . Patients in the topiramate group started their treatment with
a dosage of one 50 mg tablet once daily, which was increased by
50 mg every 7 days until a daily dose of 200 mg was reached. Treat-
ment was provided as usual in the Spanish public health system,
i.e. patients were given a public health prescription, which they
took to a chemist in order to receive the medication on a monthly
basis. Patients pay part of the cost of the medication (40%), with
no significant differences between the cost of naltrexone and topi-
ramate. This was the only cost to patients throughout the study.
If alcohol intake was not controlled (i.e. if patients did not
achieve abstinence or moderate drinking without problems with
naltrexone or topiramate), disulfiram was added to the treatment
at a daily dose of 250500 mg, if the patient agreed. Adding disul-
firam to the treatment was automatically considered a naltrexone
or topiramate failure and was analyzed that way. Patients saw the
psychiatrist at the outpatient addiction treatment clinic at least
once a month to review their alcohol treatment status.
All patients received weekly psychosocial therapy according to
an advice and treatment adherence enhancement model known
as BRENDA (Biopsychosocial evaluation, Report of findings to
patient, Empathetic understanding of patients situation, Needs to
be addressed, Direct advice to patient on how to meet those needs,
and Assessing reaction/behaviors of patient to advice and adjust-
ing treatment plan as necessary for best care) [18] . The use of
BRENDA is supported by empirical evidence. This treatment was
delivered by clinical psychologists trained in this model. During
these weekly visits and as part of the BRENDA approach, alcohol
intake was assessed.
Assessment
The following instruments, all validated and published for the
Spanish population, were used to assess patients at enrollment:
(1) EuropASI [14] , used to assess alcohol intake and its conse-
quences, and the inclusion and exclusion criteria; (2) Alcohol
Timeline Followback [15] , used to assess alcohol intake; (3) Obses-
sive Compulsive Drinking Scale (OCDS) [19] , used to assess alco-
hol craving; (4) Fagerstrm Test for Nicotine Dependence [20] ,
used to assess nicotine dependence; (5) International Personality
Disorder Examination (IPDE) [21] , used to assess if the patient has
a personality disorder; (6) Readiness to Change Questionnaire
(RCQ) [22] , used to assess how ready and motivated the patient
was to control his or her drinking; (7) WHO Psychiatric Disabil-
ity Assessment Schedule (WHO/DAS) [23] , used to assess alcohol
dependence-related disability; (8) European Quality of Life Ques-
tionnaire (EQ-5D) [24] , used to assess each patients quality of life.
The initial assessment also included blood tests to measure bio-
Topiramate for Alcohol Dependence Eur Addict Res 2011;17:2936 31
logical markers of alcohol consumption [25] : -glutamyltrans-
ferase, serum aspartate aminotransferase (AST), serum alanine
aminotransferase (ALT), mean corpuscular volume, and AST/
ALT ratio.
The 3- and 6-month assessments included the following
instruments: EuropASI, OCDS, Fagerstrm, WHO/DAS, and
EQ-5D. The 6-month assessment also included repeated blood
tests.
Each month, tolerability of the treatment was evaluated using
the UKU Side Effect Rating Scale [26] . Whenever a side effect
reached a score of 3, the treatment dosage was reduced by half.
None of the naltrexone patients and only 4 of the topiramate pa-
tients reached a score of 3.
Each month, medication compliance was evaluated using the
Morisky-Green test [27] . Patients were considered adherent to
treatment when they obtained the maximum score of 4 points,
and they were considered nonadherent when they obtained 3 or
fewer points. Both the patient and the significant other were in-
terviewed and the lower reported adherence level was used. As an
indirect method of measuring medication adherence, a pill count
(pills taken subtracted from pills dispensed) was done every
month on the returned blisters.
Alcohol intake was assessed at each treatment session. Both
the patient and the significant other were interviewed and the
higher reported intake level was used.
Drop-outs were defined as patients who stopped coming to
appointments for at least 1 month. To reduce the drop-out rate,
all patients and their significant other who did not come to an ap-
pointment were contacted by telephone.
Definition of Efficacy
Good outcome was defined not only as progress in the afore-
said instruments, but a composite outcome measure, used as the
primary outcome variable, was used following the recommenda-
tions of the MATCH and COMBINE study groups [2831] . This
measure defined the following groups: (1) Abstinence. No alcohol
intake reported during the previous 3 months. No problems re-
ported (problems were defined as a score of 4 or more on any of
the EuropASI scales). (2) Moderate drinking without problems.
Reported drinking was ! 40 g ethanol/day for men and ! 30 g for
women, with no more than 2 days of heavier reported drinking.
No problems reported. (3) Moderate drinking with problems.
Same as the previous, but problems were reported. (4) Heavy
drinking without problems. Reported drinking was greater than
moderate on 3 or more occasions per quarter. No problems re-
ported. (5) Heavy drinking with problems. Same as the previous,
but problems were reported. Patients taking disulfiram or drop-
outs were included in this group for outcome statistical analysis.
The following alcohol consumption-related variables, mea-
sured by timeline follow back using a diary card as a memory
guide, were also used [8, 28] : (a) number of heavy drinking days:
more than 60 g ethanol/day; (b) percentage of days abstinent dur-
ing the previous 3 months; (c) total drinking days during the pre-
vious 3 months; (d) days to first drink; (e) drinks per drinking day
(1 drink = 10 g ethanol) during the previous 3 months. Patients in
groups 3, 4, 5, and drop-outs were considered relapsed.
Statistical Methods
The data on all patients were analyzed on an intent-to-treat
basis. Drop-outs were assumed to have resumed heavy drinking
on the day after their last contact. Data quality, including double
data entry, was supervised by a database coordinator at Trabecu-
lae , Empresa de Base Tecnolgica (a private provider of health-
related technology). Individual patient plots were checked for un-
usual values and completeness.
Significant differences in the composite outcome measure and
on the assessment instruments between the 2 treatment condi-
tions were assessed at each point of the study, as were longitudinal
changes between the assessments.
The power analysis of the sample was based on the hypothesis
testing for 2 population percentages. The variable used to com-
pare the 2 drugs was the composite outcome measure, good out-
come (groups 1 and 2), used as the primary outcome variable.
Required information: (1) anticipated population percentage val-
ues: naltrexone 50% (p1 = 0.5), topiramate 75% (p2 = 0.75); (2) the
hypothesis is going to be unilateral: 1 of the parameters must be
greater than the other, thus indicating a direction of the differ-
ences; (3) security of the study (risk of error ), = 0.05 ] Z =
1.645; (4) statistical power (1 ) (risk of error ), 1 = 0.90 ]
Z = 1.282; (5) p is the mean of the 2 percentages (p = 0.625). The
equation used was:
( ) ( ) ( )
( )
2
2
2 1 1 1 1 2 1 2
62
1 2
Z p p Z p p p p
n
p p

l

l
l
=


where n is the number of patients in each group. In all studies it
is necessary to allow for drop-outs, so it is necessary to increase
the sample size. Sample adjusted to drop-outs = n (1 / 1 R), where
n = number of patients without drop-outs and R = expected per-
centage of drop-outs. In this study, we expected a 15% drop-out
rate, so the necessary sample size would be at least: 62 (1 / 1 0.15)
= 73 patients in each group.
For the statistical analysis, untransformed data were tested for
normality with the Kolmogorov-Smirnov test. If the data were
normally distributed, a 2-tailed t test was performed to determine
inter- or intragroup differences. Levenes test was used to test the
homogeneity of variance for each dependent variable across all
level combinations of the between-patient factors. If the data were
not normally distributed, a nonparametric Kruskal-Wallis test
was performed. Pairwise
2
and z tests were used, as appropriate,
to analyze differences between the 2 treatment conditions or lon-
gitudinal differences in each treatment group.
The composite outcome measure was evaluated in 2 different
ways: firstly, abstinence versus the rest (including patients taking
disulfiram and drop-outs), and secondly, good outcome (absti-
nence and moderate drinking without problems) versus the rest
(including patients taking disulfiram and drop-outs).
All statistical analyses were carried out by Trabeculae , Em-
presa de Base Tecnolgica S.L. (Spain), using the Statistical Pack-
age for Social Sciences (SPSS Inc., Chicago, Ill., USA), v. 17.0 for
Windows. p ! 0.05 was considered statistically significant.
Results
At baseline, the 2 treatment groups were homogeneous
with respect to sociodemographic, clinical, and alcohol-
related variables ( tables 13 ).
Flrez /Saiz /Garca-Portilla /lvarez /
Nogueiras /Bobes
Eur Addict Res 2011;17:2936 32
As shown in tables 2 and 3 , at the 3-month evaluation,
the following significant differences were found. Patients
taking topiramate had lower scores on the following in-
struments indicating better progress: OCDS obsessive
(2.04 vs. 0.81, t = 2.932, d.f. = 135.62, p = 0.004), OCDS
compulsive (3.34 vs. 1.95, t = 2.357, d.f. = 139.11, p = 0.020),
OCDS total (5.37 vs. 2.77, t = 2.728, d.f. = 134.03, p =
0.007), and EuropASI psychiatric (2.54 vs. 1.73, t = 2.055,
d.f. = 155.73, p = 0.042).
As shown in tables 2 and 3 , at the 6-month evaluation,
the following significant differences were found. Patients
taking topiramate had lower scores on the following in-
struments indicating better progress: OCDS obsessive
(1.91 vs. 0.74, t = 2.952, d.f. = 125.88, p = 0.004), OCDS
compulsive (3.95 vs. 2.13, t = 2.774, d.f. = 133.85, p =
0.006), OCDS total (5.86 vs. 2.87, t = 2.939, d.f. = 126.93,
p = 0.004), EuropASI medical (1.55 vs. 0.7, t = 2.750,
d.f. = 149, p = 0.006), EuropASI alcohol (2.33 vs. 1.28,
t = 2.779, d.f. = 148.79, p = 0.006), EuropASI family/so-
cial (1.83 vs. 0.94, t = 2.421, d.f. = 146.95, p = 0.016),
EuropASI psychiatric (2.35 vs. 1.01, t = 3.400, d.f. = 142.5,
p ! 0.001), WHO/DAS family (1.05 vs. 0.58, t = 2.198,
d.f.= 154.84, p = 0.029), and WHO/DAS social (0.83 vs.
0.46, t = 1.978, d.f. = 158.33, p = 0.049).
Tables 2 and 3 show significant changes in each treat-
ment group for all instruments in the longitudinal intra-
group comparison between the baseline and 3-month
assessments including the biological markers compar-
ison between the baseline and 6-month assessments
except for the Fagerstrm test in the naltrexone group.
No significant changes were detected in the naltrexone
group for all instruments in the longitudinal intragroup
comparison between the 3- and 6-month assessments.
The following significant changes were found in the to-
piramate group in the longitudinal intragroup compar-
ison between the 3- and 6-month assessments: Fager-
strm test (2.90 vs. 2.71, t = 2.656, d.f. = 83, p = 0.009),
EuropASI medical (1.19 vs. 0.7, t = 2.734, d.f. = 84, p =
0.008), EuropASI alcohol (1.69 vs. 1.28, t = 2.316, d.f. = 84,
p = 0.023), EuropASI family/social (1.31 vs. 0.94, t = 2.211,
d.f. = 84, p = 0.030), and EuropASI psychiatric (1.73 vs.
1.01, t = 3.809, d.f. = 84, p ! 0.001).
Tables 2 and 3 show no significant changes for all in-
struments in the longitudinal intergroup comparison
with the following exceptions, which indicate better
progress for patients taking topiramate: at 3 months, the
EuropASI psychiatric (4.78 vs. 5.67, t = 2.085, d.f. = 156.95,
p = 0.039), WHO/DAS employment (1.64 vs. 2.2, t = 1.999,
d.f. = 161.57, p = 0.047), EQ-5D VAS (12.9 vs. 18.47, t =
2.484, d.f. = 167, p = 0.014), and at 6 months, the WHO/
DAS family (0.06 vs. 0.13, t = 2.126, d.f. = 63, p = 0.035)
( tables 4 , 5 ).
As indicated in the Statistical Methods section, the
following analyses were performed to compare naltrex-
one and topiramate: (1) Group 1 (abstinence) versus the
rest at 3 months: 42.9 vs. 48.4%,
2
= 0.355, d.f. = 1, p =
0.551. Group 1 versus the rest at 6 months: 41.8 vs. 47.3%,

2
= 0.206, d.f. = 1, p = 0.650. (2) Groups 1 and 2 (mod-
erate drinking without problems) versus the rest at 3
months: 63.8 vs. 78%,
2
= 3.153, d.f. = 1, p = 0.076. Groups
1 and 2 versus the rest at 6 months: 51.7 vs. 74.8%,
2
=
8.974, d.f. = 1, p = 0.003. (3) Percentage of days abstinent
at 3 months: 66.84 vs. 65.98%, t = 0.195, d.f. = 166, p =
0.893. Percentage of days abstinent at 6 months: 62.31 vs.
66.40%, t = 0.575, d.f. = 163, p = 0.566. (4) Total drink-
ing days at 3 months: 28.54 vs. 25.91, t = 0.468, d.f. = 167,
p = 0.641. Total drinking days at 6 months: 33.94 vs. 30.35,
t = 0.556, d.f. = 163, p = 0.579. (5) Drinks per drinking day
at 3 months: 2.19 vs. 1.39, t = 1.093, d.f. = 167, p = 0.276.
Drinks per drinking day at 6 months: 2.3 vs. 1.41, t =
2.538, d.f. = 163, p = 0.013. (6) Number of heavy drinking
days at 3 months: 5.55 vs. 4.63, t = 0.508, d.f. = 167, p =
0.623. Number of heavy drinking days at 6 months: 8.65
vs. 3.35, t = 2.342, d.f. = 163, p = 0.021. (7) Days to first
drink during the whole study: 92.264 vs. 98.977,
2
=
0.455, d.f. = 1, p = 0.5 ( fig.1 ).
The 2 treatments did not differ with respect to treat-
ment adherence, which was high in both groups. At 6
months, excluding the drop-outs, 76 (83.5%) patients in
the naltrexone group reported 100% adherence and, in
the topiramate group, 84 (92.3%) also reported 100% ad-
Table 1. D emographic, clinical, and alcohol-related characteris-
tics of the sample at baseline
Naltrexone
n (%)
Topiramate
n (%)
p
Age, mean8SD 47.4688.96 48.0589.54 0.672
Men 80 (87.91) 75 (82.41) 0.297
Married 59 (64.83) 54 (59.34) 0.445
Employed 46 (50.54) 39 (42.85) 0.298
Elementary school only 77 (84.61) 83 (91.20) 0.373
Living with family 71 (78.02) 75 (82.41) 0.758
Family history of alcoholism 68 (74.72) 63 (69.23) 0.171
Alcohol intake: reporting
>700 g ethanol/week 69 (75.82) 66 (72.52) 0.614
Personality disorders 19 (20.87) 23 (25.27) 0.559
n = 91 in both treatment groups.
Topiramate for Alcohol Dependence Eur Addict Res 2011;17:2936 33
Table 2. E volution through the study of the Fagerstrm, OCDS and EuropASI instruments
Instrument Baseline (n = 182) 3 months (n = 169) 6 months (n = 165) L ongitudinal intragroup comparisons
Nal.
(n = 91)
Top.
(n = 91)
Nal.
(n = 83)
Top.
(n = 86)
Intergroup,
baseline
3 mo.
Nal.
(n = 80)
Top.
(n = 85)
Intergroup,
36 mo.
Nal.,
baseline
3 mo.
Nal.,
36 mo.
Top.,
baseline
3 mo.
Top.,
36 mo.
Fagerstrm 3.6983.64 3.4883.76 3.5483.70 2.9083.45 t = 0.995
p = 0.341
3.3783.95 2.7183.22 t = 0.782
p = 0.435
t = 1.566
p = 0.121
t = 0.093
p = 0.926
t = 3.043
p = 0.003
t = 2.656
p = 0.009
OCDS
Obsessive 6.9084.77 6.1784.47 2.0483.24 0.8182.00 t = 0.398
p = 0.691
1.9183.08 0.7481.80 t = 0.413
p = 0.680
t = 8.605
p < 0.001
t = 0.236
p = 0.814
t = 11.672
p < 0.001
t = 0.428
p = 0.670
Impulsive 11.8083.74 11.2784.28 3.3484.53 1.9582.91 t = 0.853
p = 0.396
3.9584.97 2.1383.21 t = 1.218
p = 0.225
t = 14.058
p < 0.001
t = 1.741
p = 0.086
t = 17.652
p < 0.001
t = 0.479
p = 0.633
Total 18.7687.59 17.487.57 5.3787.48 2.7784.52 t = 0.654
p = 0.514
5.8687.89 2.8784.68 t = 0.930
p = 0.354
t = 12.404
p < 0.001
t = 1.144
p = 0.256
t = 17.123
p < 0.001
t = 0.147
p = 0.884
EuropASI
Medical 6.1082.31 6.2182.23 1.7282.27 1.1981.85 t = 1.365
p = 0.174
1.5582.19 0.7081.70 t = 1.546
p = 0.124
t = 13.681
p < 0.001
t = 0.049
p = 0.961
t = 17.776
p < 0.001
t = 2.734
p = 0.008
Employment/
resources
3.2183.46 3.4983.54 0.6681.69 0.4381.34 t = 0.989
p = 0.324
0.5681.58 0.3881.32 t = 0.106
p = 0.916
t = 7.394
p < 0.001
t = 0.151
p = 0.881
t = 8.441
p < 0.001
t = 0.369
p = 0.713
Alcohol 7.7480.50 7.8280.48 2.3682.72 1.6982.15 t = 1.890
p = 0.061
2.3382.71 1.2882.10 t = 1.510
p = 0.133
t = 17.885
p < 0.001
t = 0.302
p = 0.763
t = 25.396
p < 0.001
t = 2.316
p = 0.023
Legal 1.0282.48 1.2782.52 0.2581.15 0.1380.80 t = 0.981
p = 0.328
0.0780.67 0.1881.21 t = 1.414
p = 0.159
t = 3.054
p < 0.001
t = 1.557
p = 0.124
t = 4.554
p = 0.005
t = 0.583
p = 0.562
Family/social 6.9381.73 7.0081.76 1.8482.77 1.3182.16 t = 1.237
p = 0.218
1.8382.66 0.9482.04 t = 1.498
p = 0.136
t = 14.462
p < 0.001
t = 0.417
p = 0.678
t = 20.353
p < 0.001
t = 2.211
p = 0.030
Psychiatric 7.3281.10 7.4080.94 2.5482.83 1.7382.23 t = 2.085
p = 0.039
2.3582.83 1.0182.03 t = 1.702
p = 0.091
t = 14.732
p < 0.001
t = 0.352
p = 0.726
t = 22.177
p < 0.001
t = 3.809
p < 0.001
Dat a are means 8 SD. Statistically significant intergroup differences are in bold.
EuropASI = European Addiction Severity Index; mo. = months; Nal. = naltrexone; OCDS = Obsessive Compulsive Drinking Scale; Top. = topiramate.
Table 3. E volution through the study of WHO/DAS, EQ-5D (visual analogical scale only), and blood tests
Instru-
ment
Baseline (n = 182) 3 months (n = 169) 6 months (n = 165) L ongitudinal intragroup comparisons
1
Nal.
(n = 91)
Top.
(n = 91)
Nal.
(n = 83)
Top.
(n = 86)
Intergroup,
baseline
3 mo.
Nal.
(n = 80)
Top.
(n = 85)
Intergroup,
36 mo.
Na l.,
baseline
3 mo.
Nal.,
36 mo.
Top.,
baseline
3 mo.
Top.,
36 mo.
WHO/DAS
Personal 1.4781.49 1.4381.62 0.3580.80 0.1580.58 t = 0.718
p = 0.474
0.2680.71 0.1880.75 t = 0.863
p = 0.389
t = 6.837
p < 0.001
t = 0.948
p = 0.346
t = 7.548
p < 0.001
t = 0.287
p = 0.775
Employ-
ment
2.1682.03 2.5181.91 0.5281.01 0.3180.88 t = 1.999
p = 0.047
0.3580.93 0.2780.89 t = 0.391
p = 0.696
t = 6.857
p < 0.001
t = 1.016
p = 0.313
t = 11.196
p < 0.001
t = 0.506
p = 0.614
Family 3.7181.03 3.6381.65 0.8981.36 0.7381.23 t = 0.303
p = 0.762
1.0581.49 0.5881.26 t = 2.126
p = 0.035
t = 15.303
p < 0.001
t = 1.501
p = 0.137
t = 17.626
p < 0.001
t = 1.521
p = 0.132
Social 3.3880.90 3.4180.96 0.8981.35 0.5981.12 t = 1.447
p = 0.150
0.8381.25 0.4681.12 t = 0.883
p = 0.154
t = 14.519
p < 0.001
t = 0.090
p = 0.928
t = 20822
p < 0.001
t = 1.315
p = 0.192
EQ-5D
VAS
81.26819.18 77.63819.05 94.16811.57 96.1088.75 t = 2.484
p = 0.014
96.6388.85 96.47816.16 t = 0.698
p = 0.486
t = 5.967
p < 0.001
t = 1.550
p = 0.125
t = 10.304
p < 0.001
t = 0.214
p = 0.831
AST/ALT 1.4280.75 1.3280.64 1.1980.48 1.1480.32 t = 0.416
p = 0.678
t = 2.060
p = 0.043
t = 2.615
p = 0.011
MCV (fl) 99.4386.46 98.2985.39 93.7085.28 92.3284.61 t = 0.005
p = 0.996
t = 9.189
p < 0.001
t = 12.537
p < 0.001
GGT (U/l) 194.28234.18 217.68266.38 49.95855.47 42.03836.11 t = 0.962
p = 0.338
t = 6.020
p < 0.001
t = 6.232
p < 0.001
AST (U/l) 75.32879.37 75.46856.25 32.83820 31.82829.41 t = 0.169
p = 0.866
t = 4.590
p < 0.001
t = 7.290
p < 0.001
ALT (U/l) 52.53839.16 60.06842.17 28.51815.68 27.96820.23 t = 1.311
p = 0.191
t = 5.244
p < 0.001
t = 6.856
p < 0.001
Dat a are means 8 SD. Statistically significant differences are in bold.
WHO/DAS = World Health Organization Psychiatric Disability Assessment Schedule; EQ-5D = European Quality of Life Questionnaire; VAS = Visual Analog Scale;
MCV = mean corpuscular volume; GGT = -glutamyltransferase; AST = serum aspartate aminotransferase; ALT = serum alanine aminotransferase; mo = months.
1
Blood test longitudinal studies compare baseline to 6 months.
Flrez /Saiz /Garca-Portilla /lvarez /
Nogueiras /Bobes
Eur Addict Res 2011;17:2936 34
herence. Pill counts confirmed this high treatment ad-
herence, although, as these methods are indirect and li-
able to manipulation, we cannot conclude that patients
took each and every pill.
Statistically significant differences were found in the
percentage of adverse effects reported by each group. At
3 months, a greater percentage of patients taking topira-
mate reported adverse effects (19.78 vs. 5.49%, t = 2.928,
d.f. = 135.72, p = 0.004). These differences disappeared at
the 6-month evaluation (4.3 vs. 1.5%, t = 1.056, d.f. = 84,
p = 0.088).
No significant differences were found when compar-
ing the following variables: drop-outs and use of disulfi-
ram.
Discussion
In this study, topiramate, at a mean dose of 200 mg/
day, was superior to naltrexone, at a mean dose of 50 mg/
day, in the treatment of alcohol dependence assessed with
the following instruments and variables: OCDS (all sub-
scales), EuropASI (medical, alcohol, family/social, psy-
chiatric), WHO/DAS (employment, family/social), EQ-
Table 4. E volution of the composite outcome measure at 3 months
1 2 3 4 5 Drop-outs Disulfiram
Naltrexone 39 19 1 1 17 8 6
42.9% 20.9% 1.1% 1.1% 18.7% 8.8% 6.6%
Topiramate 44 26 2 0 7 5 7
48.4% 28.6% 2.2% 7.7% 5.5% 7.7%
1 = Abstinence; 2 = moderate drinking without problems; 3 = moderate drinking with problems; 4 = heavy
drinking without problems; 5 = heavy drinking with problems.
Table 5. E volution of the composite outcome measure at 6 months
1 2 3 4 5 Drop-outs Disulfiram
Naltrexone 38 9 3 0 17 11 13
41.8% 9.9% 3.3% 18.7% 12.1% 14.3%
Topiramate 43 25 3 0 6 6 8
47.3% 27.5% 3.3% 6.6% 6.6% 8.8%
1 = Abstinence; 2 = moderate drinking without problems; 3 = moderate drinking with problems; 4 = heavy
drinking without problems; 5 = heavy drinking with problems.
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
P
r
o
p
o
r
t
i
o
n
t
o
f
i
r
s
t
d
r
i
n
k
0 25 50 75 100 125 150 175 200
Days to first drink
Topiramate
Naltrexone
Fig. 1. Time to first drink during the whole study.
Topiramate for Alcohol Dependence Eur Addict Res 2011;17:2936 35
5D VAS, the composite measure (abstinence plus moder-
ate drinking), drinks per drinking day at 6 months and
number of heavy drinking days at 6 months. These out-
comes for topiramate are similar to those found in prior
trials [811] .
The efficacy of naltrexone at 6 months (41.8% were
abstinent and 51.7% had not relapsed) was within the
range of other naltrexone studies [17] , including another
study where naltrexone was compared with another an-
tiepileptic drug such as oxcarbazepine (40.70% of patients
remained alcohol free in the naltrexone group) [32] .
Based on the 3-pathway psychobiological model of for
alcohol craving developed by Verheul et al. [33] , we sug-
gest that topiramates greater efficacy comes from its ca-
pacity to reduce all types of alcohol craving: (1) Reward
craving by reducing dopamine release in the nucleus
accumbens through facilitation of -aminobutyric acid
activity and antagonism of glutamate activity [7] . (2) The
-aminobutyric acid facilitated neuronal activity and
glutamate antagonism reduce relief craving in a direct
way. (3) Obsessive craving, which, although related to se-
rotoninergic dysregulation, was decreased in our study
and in previous topiramate clinical trials [8] proving its
efficacy for reducing this type of craving, as with other
-aminobutyric acid agonists, such as baclofen [34] .
Meanwhile, naltrexone can only improve reward craving
by blocking -endorphin uptake and subsequent down-
stream dopamine release [17] . Other authors suggest that
topiramate may exert its therapeutic effects by altering
the subjective experiences of alcohol consumption rather
than reducing craving. This effect may explain why topi-
ramate is able to retain more patients than naltrexone in
the moderate drinking without problems group and to
reduce the drinks per drinking day and the episodes of
heavy drinking [35] .
From our point of view, topiramate is not superior to
naltrexone for abstinence for the same reason that topi-
ramate and naltrexone were not superior to placebo [8
11, 17] or to psychotherapy [28] for abstinence in previous
trials. Not having any drinks at all seems to be related
more to internal motivational variables than to craving
reduction.
In this study topiramate was titrated to a maximum of
200 mg/day. These data indicate that a dose lower than
the 300 mg/day used in the topiramate blind trials [8, 10]
is also clinically effective. The topiramate dose escalation
schedule was the same as in the blind trials [8, 10] , but
topiramate was started at a higher dose of 50 mg/day, with
patients reporting a similar adherence rate (92.3 vs. the
91.46% of the 2007 topiramate blind trial [10] ). Starting
the dose escalation schedule at 50 mg per day allows a
7-day reduction in order to achieve an effective dose. In
alcohol-dependent patients, the state of hyperexcitability
in which their brains are left when they stop drinking re-
duces the risk of neurocognitive side effects compared
with epileptic patients, and permits more rapid titration
[36] .
As in previous trials [37] , we saw a reduction in nico-
tine intake assessed with the Fagerstrm test in patients
taking topiramate, indicating the efficacy of this com-
pound for the treatment of patients with alcohol plus nic-
otine dependence.
This study has some limitations. The trial was not
blinded and there was no placebo group. Although there
is a risk of bias with this design, it also creates a study
condition that more closely resembles daily clinical prac-
tice, making it possible to assess the effectiveness of both
treatments. The exclusion criteria used in the study con-
figured a group of alcohol-dependent patients with good
prognosis no physical or mental illness, not living alone,
not taking other drugs. This should be borne in mind
when comparing this study with others. Compliance was
assessed by questionnaires corroborated by information
from significant others, but a urinary marker, such as ri-
boflavin, would have been more accurate. The 6-month
duration allowed the study to investigate the efficacy of
both treatments during the dishabituation period, but
not during the relapse prevention phase.
In conclusion, topiramate, at a mean dose of 200 mg/
day, was more effective than naltrexone, at a mean dose
of 50 mg/day, in the treatment of alcohol dependence
during the first 6 months of treatment.
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