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Pregabalin, tiapride and lorazepam in alcohol
withdrawal syndrome: A multi-centre,
randomized, single-blind comparison...
Article in Addiction · February 2010
DOI: 10.1111/j.1360-0443.2009.02792.x · Source: PubMed
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RESEARCH REPORT
doi:10.1111/j.1360-0443.2009.02792.x
Pregabalin, tiapride and lorazepam in alcohol
withdrawal syndrome: a multi-centre, randomized,
single-blind comparison trial
add_2792
288..299
Giovanni Martinotti1,2, Marco di Nicola2, Alessandra Frustaci2, Roberto Romanelli3,
Daniela Tedeschi2, Riccardo Guglielmo2, Luigi Guerriero2, Angelo Bruschi2, Rocco De Filippis2,
Gino Pozzi2, Massimo Di Giannantonio4, Pietro Bria2 & Luigi Janiri2
Clinica ‘Villa Maria Pia’, Rome, Italy,1 Institute of Psychiatry, Catholic University Medical School, Rome, Italy,2 Casa di Cura ‘Villa Silvia’, Senigallia (An), Italy3 and
Department of Psychology, ‘G. D’Annunzio’ University, Chieti, Italy4
ABSTRACT
Introduction The aim of this trial was to compare lorazepam with non-benzodiazepine medications such as pregabalin and tiapride in the treatment of alcohol withdrawal syndrome (AWS). These drugs were chosen for their inhibitorial
effects on the hypersecretion of neurotransmitters usually observed in AWS. Craving reduction and improvement of
psychiatric symptoms were the secondary end-points. Methods One hundred and ninety subjects affected by current
alcohol dependence were considered consecutively: 111 were enrolled and divided into three groups of 37 subjects
each. Within a treatment duration of 14 days, medication was given up to the following maximum doses (pregabalin
450 mg/day; tiapride 800 mg/day; lorazepam 10 mg/day). Withdrawal (CIWA-Ar), craving [visual analogue scale
(VAS); Obsessive and Compulsive Drinking Scale (OCDS)], psychiatric symptoms [Symptom Check List 90 Revised
(SCL-90-R)] and quality of life (QL-index) rating scales were applied. Results On the CIWA-Ar score, all the groups
showed a significant reduction between times (P < 0.001) with a higher reduction for the pregabalin group (P < 0.01)
on items regarding headache and orientation. Retention in treatment was lower in the tiapride group (P < 0.05), while
the number of subjects remaining alcohol free was higher in the pregabalin group (P < 0.05). Significant reduction
between baseline and the end of the treatment was found in all the groups at the OCDS and the VAS for craving, at the
SCL-90-R and QL-index (P < 0.001). Discussion All the medications in the trial showed evidence of safety and
efficacy in the treatment of uncomplicated forms of AWS, with some particular differences. The efficacy of pregabalin
was superior to that of tiapride, used largely in research trials and, for some measures, to that of the ‘gold standard’,
lorazepam. Accordingly, pregabalin may be considered as a potentially useful new drug for treatment of AWS, deserving further investigation.
Keywords
Alcohol withdrawal, benzodiazepines, CIWA-Ar, craving, pregabalin, tiapride.
Correspondence to: Giovanni Martinotti, Clinica Villa Maria Pia, Via del Forte Trionfale 36, Rome 00135 Italy. E-mail: giovanni.martinotti@libero.it
Submitted 26 June 2009; initial review completed 10 August 2009; final version accepted 27 August 2009
INTRODUCTION
Alcohol withdrawal syndrome (AWS) can be a lifethreatening condition affecting alcohol-dependent
patients who discontinue or decrease their alcohol consumption too suddenly [1,2]. Discontinuation of alcohol
ingestion results in the nervous system hyperactivity and
dysfunction that characterizes alcohol withdrawal [3].
Chronic alcohol exposure induces brain neuroadaptative
changes in order to compensate for the alcohol-induced
destabilization to restore a neurochemical equilibrium
[4]. Long-term exposure to alcohol causes adaptive
changes in several neurotransmitter systems, including
gamma-aminobutyric acid (GABA) receptors, glutamate
receptors and central noradrenaline and dopamine activity [5]. Glutamate represents the most common excitatory neurotransmitter in the human brain, acting on
several types of receptors in the central nervous system
(CNS). The one most affected by alcohol is the N-methylD-aspartate (NMDA) receptor [6]. GABA is the major
inhibitory neurotransmitter, and binds to a fast-acting
receptor complex denoted as GABA-A, which hyperpolarizes the cell membrane and thereby inhibits neural activity [6]. GABA plays a key role in the neurochemical
© 2010 The Authors. Journal compilation © 2010 Society for the Study of Addiction
Addiction, 105, 288–299
Pregabalin, tiapride and lorazepam in AWS
mechanisms on the basis of intoxication, tolerance and
withdrawal [7]. In addition, alcohol withdrawal symptomatology has also been found to be correlated positively
with dopamine hyperactivity [8]. However, the neurobiology of AWS represents a complex system involving not
only glutamate and GABA but many other neurotransmitters and neuromodulators, such as dopamine, noradrenaline, serotonin (5-HT), corticotropin-releasing factor
(CRF) and adenosine acetylcholine (ACHe) [9].
Ethanol withdrawal in humans and animals is characterized by CNS hyperexcitability that results in both
physical and ‘affective’ signs of dependence. GABA
agonists decrease CNS hyperexcitability during ethanol
withdrawal and decrease ethanol withdrawal-induced
convulsions [7].
Withdrawal symptoms usually develop within 6–24
hours after the last drink. In withdrawal syndromes
ranging from light to moderate forms, symptoms include
increase in blood pressure and pulse rate, tremors, hyperreflexia, irritability, anxiety and depression [1,2]. Mild
manifestations of AWS can contribute to the so-called
‘hangover’, although AWS and hangover represent two
different, even if partially overlapping, phenomena (for
review: [10]). The symptoms of severe AWS may progress
to more complicated forms characterized by delirium
tremens [11], seizures [12] and coma [13]. In these
forms, cardiac arrest and death may occur in 5–10% of
patients [14,15]. In alcohol-dependent patients, the possible development of AWS should also be considered after
an acute alcohol intoxication episode [16]. Repeated
withdrawal episodes may contribute to the development
of alcohol dependence and to negative consequences
associated with excessive alcohol consumption [17]. In
addition, a protracted withdrawal syndrome has been
described recently [18] as a combination of physical and
psychopathological symptoms that lasts for a long period
of time beyond the acute syndrome.
Assessment of AWS is critical to facilitate adequate
treatment measures. The Clinical Institute Withdrawal
Assessment for Alcohol (CIWA-A) has emerged as the
‘gold standard’ observer-rated measure of AWS severity
[19], particularly in the 10-item revised form (CIWA-Ar;
[20,21]).
The main objectives of the clinical management of
AWS are to decrease the severity of symptoms, prevent
more severe withdrawal clinical manifestations such as
seizures and delirium tremens and facilitate entry of the
patient into a treatment programme in order to attempt
to achieve and maintain long-term abstinence from
alcohol [22,23]. The ideal drug for AWS should have a
rapid onset and a long duration of action, few significant
side effects, a wide margin of safety, a metabolism not
dependent on liver function and absence of abuse potential [23,24].
289
At present, benzodiazepines (BZs) are the drugs of
choice in the treatment of AWS [25,26] as they have
proved their efficacy in ameliorating symptoms and
decreasing the risk of seizures and delirium tremens [27].
While BZs are widely accepted agents in the pharmacological management of AWS [28–30], side effects associated with these drugs are common. For example, the
use of BZs are associated with increased risk of excess
sedation, memory deficits and respiratory depression in
patients with liver impairment [26,31]. The sedative and
psychomotor deficits caused by BZs have an additive effect
with alcohol that is particularly problematic in the outpatient treatment of alcohol withdrawal [32]. Benzodiazepines have abuse and dependence liability [32–37]
which constitutes a limitation to their use in subjects
affected by substance use disorder [26,31].
In our study we compare lorazepam with nonbenzodiazepine medications such as pregabalin and
tiapride. These drugs were chosen for their inhibitorial
effects on the hypersecretion of neurotransmitters
usually observed in AWS.
Pregabalin acts as a presynaptic modulator of the
excessive release, in hyperexcited neurones, of excitatory
neurotransmitters, including glutamate [38] and
monoaminergic neurotransmitters [39,40]. Pregabalin
binds selectively to the a2–d subunit protein of voltagegated calcium channels, and rapidly reduces the influx of
calcium, subsequently reducing the exocytosis of synaptic vescicles in the synaptic cleft. Pregabalin has relatively
little effect on neuronal function under conditions of
normal activity [41] and its effect appears to be correlated
strongly with the degree of hyperexcitation of the presynaptic neurone. It is not protein-bound, has an eliminatory
half-life of 6 hours and is primarily (92%) excreted
renally. It exhibits few drug–drug interactions, does not
inhibit cytocrome P450 enzymes, nor do these enzymes
alter its pharmacokinetics. Evidence derived from different double-blind placebo-controlled studies suggests that
pregabalin may be efficacious in the treatment of general
anxiety disorder [42–46] and in the relapse prevention of
alcohol-dependent subjects [47,48]. The therapeutic
rationale of pregabalin is the putative effect on both
seizure risk and anxiety in alcohol withdrawal, without
significant risk for an abuse potential or risk of overdose.
Tiapride, a benzamide, has a D2 and a D3 receptor
antagonist activity with no affinity for D1 and D4 receptors in limbic brain areas [49], and is used frequently
for treatment of hyperkinetic disorders, agitation and
aggressiveness [50]. Tiapride does not cause dependence
or respiratory depression and does not reduce vigilance
during treatment. Recently, it has been suggested for
treatment of alcohol withdrawal syndrome [51] for its
effect in reducing dopamine hyperactivity. When evidenced in alcohol withdrawal, previous research suggests
© 2010 The Authors. Journal compilation © 2010 Society for the Study of Addiction
Addiction, 105, 288–299
290
G. Martinotti et al.
tiapride to be effective in psychovegetative symptoms,
such as hyperhidrosis and tremor, but not in seizures and
hallucinations [52–55]. Different studies have proposed
the association of tiapride and carbamazepine, with positive results [56–59]. The therapeutic rationale of tiapride
is the effect on psychovegetative symptoms in alcohol
withdrawal, without a significant risk for an abuse potential or risk of overdose. This may be of relevance for
patients with less severe forms of AWS, including outpatients.
The aim of our study was to compare lorazepam, a
benzodiazepine of choice in the treatment of AWS, with
non-benzodiazepines medications such as pregabalin and
tiapride. Primary outcome measures were the reduction
of withdrawal symptoms, the number of days remaining
in treatment and the maintenance of abstinence. Secondary outcomes measures were the reduction of alcohol
craving, psychiatric comorbid symptoms and safety
parameters.
METHODS
Patients and treatment
Between December 2006 and September 2008, 190 subjects affected by current alcohol dependence referring to
the alcohol treatment unit of the day hospital, department of psychiatry and drug dependence of the University General Hospital ‘A. Gemelli’ in Rome and to the
out-patient alcohol unit ‘Villa Silvia’ at Senigallia (AN)
were considered consecutively for the study. All the
patients were evaluated by attending psychiatrists using
the Structured Clinical Interviews for DSM-IV (SCID I,
SCID II) [60,61]. Inclusion criteria were: age between 18
and 75 years; a daily alcohol consumption of more than
80 g of alcohol during the previous 24 hours; and diagnosis of alcohol dependence according to DSM-IV-TR
[62] criteria. Exclusion criteria were the current presence
of: delirium tremens or hallucinosis; evidence of mental
disorders severely interfering with cognitive capacity; epilepsy; severe cardiac failure; diabetes mellitus; severe liver
impairment; liver encephalopathy; kidney failure; neoplastic diseases; lack of cooperating relatives; regular
intake of anticonvulsants, antidepressants or antipsychotics; pregnancy or lactation; or a history of severe
adverse reaction or well-known hypersensitivity to pregabalin, tiapride and benzodiazepines. Patients with
blood alcohol concentration lower than 0.1 g/l were
assessed using the Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-Ar) [20,21] scale, a
scoring system for quantitative evaluation of physical
symptoms of AWS. Only subjects with a CIWA-Ar score
equal to or higher than 10 (defined as moderate AWS
requiring pharmacological treatment) were enrolled
ultimately in the study. Consequently, severe AWS was
included in the study.
The diagram showing subject flow by treatment group
is described in Fig. 1.
Random assignment was achieved in a non-centrespecific manner and was stratified according to age and
sex to ensure a relative balance in the total number of
patients among groups.
Study procedures
Within a treatment duration of 14 days, medication was
given up to the following maximum doses (pregabalin
450 mg/day; tiapride 800 mg/day; lorazepam 10 mg/
day). Within this range, medication was score-guided to
achieve a minimum of withdrawal symptomatology as
measured with the CIWA-Ar. In a previous study the
administration of score-guided or symptom-triggered
medication as part of an individualized treatment
decreased both treatment duration and amount of medication used, and was as efficacious as standard fixedschedule therapy for alcohol withdrawal [25]. All
packaging of treatments was identical in appearance.
A placebo group was not included because we are
comparing novel treatments to well-established therapy
such as lorazepam, which was compared to placebo in
different trials [26].
The drug therapy was administered by the principal
investigator from 8 a.m. to 4 p.m. and by a referred family
member from 4 p.m. to 8 a.m.
CIWA-Ar [20,21] and the Visual Analogue Scale for
Craving (VASc) [63] were administered once a day
(immediately before the first daily administration of the
drug) on days 1, 2, 3, 4, 5, 6, 7 and 14. We decided to
assess craving and withdrawal at 8 a.m. because at that
time patients had to stay inside the out-patient unit, not
influenced by external stressors. The same time of assessment was reported in other studies concerning alcohol
detoxification [5,64]. The Italian version of the Obsessive
and Compulsive Drinking Scale (OCDS) [65] was administered on days 1 and 14. Psychiatric symptomatology,
assessed by the Symptom Check-List 90 Revised (SCL90-R) [66] and quality of life [67] were evaluated on days
1 and 14. Baseline values were those collected on day 1
before the first drug administration. The whole study was
performed on a single-blind design. However, investigators who performed CIWA-Ar and other scales at different
times of treatment were always the same, and they were
always unaware as to which drug being administered to
patients.
Abstinence from alcohol was evaluated on the basis of
the participant’s self-evaluation and a family member
interview. Abstinence was confirmed by determining
blood alcohol concentration randomly at each out-
© 2010 The Authors. Journal compilation © 2010 Society for the Study of Addiction
Addiction, 105, 288–299
Pregabalin, tiapride and lorazepam in AWS
291
Patients evaluated
(n=190)
Patients excluded
(n=79)
Patients included
(n=111)
Random assignment
Tiapride
Pregabalin
(n=37)
Lorazepan
(n=37)
Completed study
(n=23)
Completed study
(n=21)
Figure 1 Diagram of subject flow by
treatment group
patient control, and by measuring alcohol abuse hepatic
indices [aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase
(GGT) and mean cellular volume (MCV)]. Toxicological
urinalysis was performed at each out-patient control in
order to identify polydrug abuse.
A rescue protocol was available if the patient did not
respond to the treatment similarly to the randomization.
Specifically, if the CIWA-Ar remained higher than 10 or
increased during the first 2 hours, an oral dose of
0.75 mg/kg diazepam [22] and/or an intramuscular
dose of 10 mg haloperidol [68] would be administered.
Safety parameters were monitored through electrocardiogram (ECG), urinalysis, haematological and clinical chemical analyses of blood samples at the start and
end of the study (day 14).
The study protocol complied fully with the guidelines
of the Ethics Committee of the Catholic University of
Rome, and was approved by the Institutional Review
Boards in accordance with local requirements. It was
conducted in accordance with Good Clinical Practice
guidelines and the Declaration of Helsinki (1964) and
subsequent revisions. After receiving information about
the drug, any possible side effects and the dose rate, as
well as information about the possibility of dropping out
of the study at any time, all patients (or their legal representatives) provided their written informed consent prior
to randomization. Each patient was informed that an
(n=37)
Completed study
(n=14)
alcohol relapse, non-compliance or the onset of any side
effects would lead to their exclusion from the trial.
However, patients were free to leave the study at any time.
Data analysis
The three treatment groups were compared. Given a nonnormal distribution of the data, only non-parametric
tests were used. Baseline demographic and clinical features were compared across groups using a c2 test for
categorical variables and the Kruskal–Wallis test for continuous variables. Spearman’s correlation coefficient was
used to verify the correlations between OCDS and VASc.
Primary outcome measures were: time to dropout
(number of days remaining in treatment), reduction of
withdrawal symptoms as to CIWA-Ar and the maintenance of abstinence (a return to drinking any alcohol
marked the end of the abstinence). Secondary outcomes
measures were: reduction of alcohol craving (VASc;
OCDS), psychiatric symptoms (SCL-90-R) and safety
parameters.
Primary and secondary efficacy analyses were performed on the intent-to-treat population, which included
all randomly assigned patients who took at least one dose
of study medication.
Time to dropout was compared across groups using
Kaplan–Meier survival curves and the log-rank test.
Differences in psychiatric and withdrawal symptoms
and craving scores before and after the treatment were
© 2010 The Authors. Journal compilation © 2010 Society for the Study of Addiction
Addiction, 105, 288–299
292
G. Martinotti et al.
calculated for each group: comparisons within each
treatment group were carried out by Wilcoxon’s paired
test, while possible differences across treatment groups
were again investigated by Kruskal–Wallis test.
Next, we dichotomized the outcome of treatment considering patients remaining abstinent by the end of the
study or relapsed/dropped. We compared these two
groups according to baseline demographic and clinical
variables by means of c2 test for categorical variables and
the Mann–Whitney U-test for continuous variables.
Finally, to determine what factors, if any, were associated
with remaining abstinent, we entered variables that were
significant at P < 0.10 in the bivariate analyses into a
multivariable model using logistic regression. We examined all variables for multi-collinearity. We used the
Hosmer–Lemeshow goodness-of-fit statistic to check the
model fit. We defined P-values of 0.05 or below as statistically significant. We report the findings as odds ratios
(ORs) and P-values.
RESULTS
Patients and disposition
A total of 190 patients were screened, of whom 79 were
excluded from the study. There were no significant differences between the baseline characteristics of patients
who did not pass the screening compared with those who
were included in the study. The three groups of randomized patients did not vary in terms of socio-demographic
and clinical (SCID-I, SCID II) characteristics, craving
(OCDS, VASc), withdrawal (CIWA-Ar) scores and psychiatric symptomatology (SCL-90-R) at baseline (Table 1).
Patients affected by multiple substance abuse and with a
dual diagnosis were distributed equally in the three
samples. The additional Axis I diagnoses were in the areas
of mood disorders (pregabalin: 11; tiapride: 9; lorazepam:
10), anxiety disorders (pregabalin: 2; tiapride: 3;
lorazepam: 2), impulse control disorders (pregabalin: 3;
tiapride: 2; lorazepam: 1), and eating disorders (tiapride:
2; lorazepam: 1). The additional Axis II diagnosis were
borderline (pregabalin: 3; tiapride: 2; lorazepam: 1),
antisocial (pregabalin: 1), avoidant (pregabalin: 2;
lorazepam: 1), histrionic (pregabalin: 2; tiapride: 3;
lorazepam: 1), passive–aggressive (pregabalin: 2;
tiapride: 3; lorazepam: 3), non-otherwise specified (pregabalin: 2; tiapride: 1; lorazepam: 3) and schizoid (pregabali: 1; tiapride: 1) personality disorders.
Multiple substance abuse, other than alcohol abuse,
was represented by cannabis abuse (pregabalin: 8;
tiapride: 5; lorazepam: 6), cocaine abuse (pregabalin: 4;
tiapride: 3; lorazepam: 7), benzodiazepine abuse (pregabalin: 1; tiapride: 2) and tobacco smoking (pregabali:
20; tiapride: 18; lorazepam: 23).
Efficacy
The number of subjects remaining alcohol free for the
entire study period [pregabalin: 23 (62.2%); tiapride: 14
(37.8%); lorazepam: 21 (56.8%)] was significantly different in the three treatment groups, with a higher number
in the pregabalin group (c2 = 4.19, P = 0.04). The rescue
protocol was applied in just one patient of the tiapride
group for the presence of the typical symptoms of
delirium tremens.
The survival curve of time to dropout (retention in
treatment) is shown in Fig. 2. The survival function
showed that patients treated with pregabalin remained in
treatment for a longer time compared to both those
groups treated with tiapride and lorazepam, but differences are statistically significant only in comparison with
tiapride (log-rank test = 3.87, P = 0.04), while there were
no statistically significant differences between patients
treated with pregabalin and lorazepam (log-rank
test = 0.82, P = 0.36) or lorazepam and tiapride (logrank test = 0.88, P = 0.34). The survival curve of time to
relapse (first alcohol use), resemble closely the survival
curve of time to dropout (data not shown). However,
levels of significance were not reached, given the low
number of patients included in this analysis and the
resulting low statistical power.
At baseline, mean total CIWA-Ar score was not different between groups. When analysed separately, all the
groups showed a significant reduction between times
(Friedman test = 191.5, P < 0.001 for pregabalin, 136.7,
P < 0.001 for lorazepam, 167.65, P < 0.001 for tiapride).
The decrease in the CIWA-Ar score was significant
between all times except between days 6 and 7 in the
pregabalin group, days 5 and 6 in the lorazepam group
and days 6 and 7 in the tiapride group (Fig. 3).
Significant differences between groups of treatment
were found with regard to items 9 (headache, fullness in
head) and 10 (orientation and clouding of sensorium) of
CIWA with an higher reduction for pregabalin group
(Kruskal–Wallis test = 7.5, P = 0.02; 8.8, P = 0.01).
In relation to craving, a significant reduction between
baseline and the end of the treatment was found in all
groups at both the OCDS (Table 2) and the VASc (Fig. 4).
Significant differences were not evidenced between
groups. In the entire sample, VASc scores were correlated
significantly with those of obsessive symptoms of OCDS
at baseline (day 1) (Spearman’s rho = 0.31; P < 0.001)
and at the end of the study (day 14) (Spearman’s
rho = 0.32; P = 0.002).
All the treated patients showed a statistically significant improvement in scores on the quality of life scale
(Table 2). Between groups, differences were not found.
In relation to the comorbid psychiatric symptoms
(SCL-9-R), the global score (GSI: General Symptom Index)
© 2010 The Authors. Journal compilation © 2010 Society for the Study of Addiction
Addiction, 105, 288–299
293
Pregabalin, tiapride and lorazepam in AWS
Table 1 Socio-demographic characteristics, alcohol history and clinical data of the sample.
Parameter
Socio-demography
Age (mean, SD)
Males
Females
Marital status
Single
Married
Separated/divorced
Widowed
Level of education
Elementary school
Lower secondary school
High school education
Degree
Employment condition
Retired
Employed
Unemployed
Alcohol-related history
Duration of alcohol dependence (years: mean, SD)
Daily drinksa (mean, SD)
Values at the baseline
CIWA-Ar score (mean, SD)
VASc score (mean, SD)
Dual diagnosis (Axis I)
Affective disorders
Impulse-control disorder
Anxiety disorders
Eating disorders
Dual diagnosis (Axis II)
Cluster A
Cluster B
Cluster C
NOS
Lorazepam
n = 37
Tiapride
n = 37
Pregabalin
n = 37
n (%)
n (%)
n (%)
24 (65)
13 (35)
23 (62)
14 (38)
22 (59)
15 (41)
11 (29.7)
17 (45.9)
9 (24.4)
0
10
18
7
2
(27.1)
(48.6)
(18.9)
(5.4)
13
12
9
3
(35.1)
(32.4)
(24.4)
(8.1)
3
13
12
9
4
14
14
5
(10.8)
(37.8)
(37.8)
(13.6)
2
14
16
5
(5.4)
(37.8)
(43.2)
(13.6)
(8.1)
(35.1)
(32.4)
(24.4)
4 (10.8)
22 (59.5)
11 (29.7)
5 (13.6)
20 (54)
12 (32.4)
5 (13.6)
25 (67.5)
7 (18.9)
9.9, 4.5
8.9, 4.5
9.3, 5.2
7.9, 3.5
8.9, 4.8
8.2, 2.5
12.89, 9.06
3.28, 3.49
16.97, 8.81
5.26, 3.31
17.17, 8.32
3.45, 3.11
10
1
2
1
0
2
1
6
(27)
(2.7)
(5.4)
(1.7)
(5.4)
(2.7)
(16.2)
9
2
3
2
1
5
0
4
(24.4)
(5.4)
(8.1)
(5.4)
(2.7)
(13.6)
(10.8)
11
3
2
0
1
6
2
4
(29.7)
(8.1)
(5.4)
(2.7)
(16.2)
(5.4)
(10.8)
a
One drink = 12 g or 0.5 oz. CIWA-Ar: Clinical Institute Withdrawal Assessment for Alcohol-revised; VASc: Visual Analogue Scale for Craving; SD:
standard deviation; NOS: not otherwise stated.
reduced significantly in all the groups (Table 3). With
regard to the single items, the differences between baseline and the end of the treatment are also shown in
Table 3. Significant differences between the three groups
of treatment were found in single symptoms of interpersonal sensitivity (Kruskal–Wallis test = 10.7, P = 0.005),
depression (Kruskal–Wallis test = 8.5, P = 0.01), hostility
(Kruskal–Wallis test = 12.6, P = 0.002) and GSI
(Kruskal–Wallis test = 7.9, P = 0.02), with a higher
reduction in the pregabalin group.
Considering the entire sample of patients, logistic
regression analysis showed that a higher OCDS subscore
for compulsive craving at baseline was associated with a
higher risk (OR = 1.17, P = 0.03) of relapse in alcohol
consumption before the end of the treatment.
Safety and tolerability
Common adverse events (whether or not considered
treatment-related) occurred in one (2.7%) patient in the
pregabalin group (confusion) and in one (2.7%) patient
in the lorazepam group (sedation). In the tiapride group
no adverse event was observed during the entire study
period. The overall rate of study discontinuation due to
adverse event was 2.7 % (n = 1) in the pregabalin group,
due to confusion.
No clinically relevant differences between groups were
seen in the mean change from baseline for any vital signs,
ECGs, haematology or clinical chemistry parameters.
Comparing hepatic alcohol abuse indices before and
after treatment administration, we found a significant
© 2010 The Authors. Journal compilation © 2010 Society for the Study of Addiction
Addiction, 105, 288–299
294
G. Martinotti et al.
1.1
Pregabalin
Cumulative Survival
1.0
Tiapride
Lorazepam
.9
.8
.7
PRE*
.6
LOR
.5
TIA*
.4
2
4
6
8
10
12
14
16
Figure 2 Survival remaining in treatment.
*P < 0.05 between pregabalin and tiapride
Days of treatment
Table 2 Mean change from baseline (pre) at last assessment (post) for the Obsessive and Compulsive Drinking Scale (OCDS) total,
obsessive and compulsive components and quality of life (QL index) in the three groups. Differences within and between groups are
reported.
Differences between
groups
Differences within groups
Pre (T1)
Post (T2)
Medication
n
Mean ⫾ SD
Mean ⫾ SD
Za(p)
X2b(P)
Lorazepam
Tiapride
Pregabalin
37
37
37
20.03 ⫾ 8.71
18.1 ⫾ 7.44
19.25 ⫾ 7.09
10.94 ⫾ 9.4
11.16 ⫾ 9.34
8.47 ⫾ 7.71
-3.982 (<0.001)
-2.814 (0.005)
-4.991 (<0.001)
4.129 (0.127 NS)
Obsessive
Lorazepam
Tiapride
Pregabalin
37
37
37
8.53 ⫾ 5.25
9.06 ⫾ 4.61
8.2 ⫾ 4.29
4.97 ⫾ 4.51
5.72 ⫾ 4.67
4.16 ⫾ 3.84
-3.331 (<0.001)
-2.619 (0.009)
-4.095 (<0.001)
0.672 (0.715 NS)
Compulsive
Lorazepam
Tiapride
Pregabalin
37
37
37
12.32 ⫾ 4.35
15.03 ⫾ 12.42
12.4 ⫾ 3.69
5.97 ⫾ 5.29
6.32 ⫾ 5.33
5.16 ⫾ 4.66
-4.208 (<0.001)
-3.918 (<0.001)
-5.19 (<0.001)
0.925 (0.630 NS)
QL index
Lorazepam
Tiapride
Pregabalin
37
37
37
5.78 ⫾ 1.06
6.35 ⫾ 1.46
6 ⫾ 0.816
7.19 ⫾ 1.22
7.15 ⫾ 1.22
7.47 ⫾ 0.87
-3.25 (<0.001)
-3.307 (<0.001)
-3.482 (<0.001)
3.570 (0.168 NS)
Parameter
OCDS
Total
a
Wilcoxon signed-ranks test; bKruskall–Wallis test. NS: not significant; SD: standard deviation.
decrease in the values of GGT (P < 0.01), AST (P < 0.01)
and ALT (P < 0.01) in all the treatment groups with no
significant difference between groups. Apart from a significant decrease in cholesterol levels (P < 0.05), biochemical analysis of glucose, low-density lipoprotein,
high-density lipoprotein, non-esterified fatty acids and
triglycerides, there were no significant differences in biochemical markers between baseline and the end of treatment. Mean change in weight from baseline to the end of
treatment was +0.3 kg in the pregabalin group, -0.3 in
the lorazepam group and +0.4 in the tiapride group.
At drug discontinuation, we observed no side effects
due to drug suspension in either group.
DISCUSSION
At present, benzodiazepines represent the ‘gold standard’
in the management of patients with AWS [26,29].
However, the use of benzodiazepines is associated with
several side effects, such as risk of excess sedation,
memory deficits and respiratory depression in patients
with liver impairment, as is often the case in alcoholics.
© 2010 The Authors. Journal compilation © 2010 Society for the Study of Addiction
Addiction, 105, 288–299
295
Pregabalin, tiapride and lorazepam in AWS
CIWA-Ar score
20
18
Pregabalin
16
Tiapride
14
Lorazepam
12
10
8
6
Figure 3 Clinical Institute Withdrawal
Assessment for Alcohol-revised (CIWAAr) has emerged as the ‘gold standard’
observer-rated measure of alcohol withdrawal syndrome (AWS) severity-revised
[19], (CIWA-Ar) scores over days of
detoxification
4
2
0
0
1
2
3
4
5
6
7
15
Days of treatment
6
Pregabalin
5
Tiapride
VASc score
Lorazepam
4
3
2
1
0
Figure 4 Visual Analogue Scale for
Craving (VASc) scores over days of
detoxification
1
Moreover, benzodiazepines could have addictive properties, which constitutes a limitation to their use in subjects
affected by substance use disorders [31,33]. Consequently, the discover of new potentially useful drugs for
the treatment of AWS is of considerable practical importance, as confirmed by the growing research interest in
non-benzodiazepines medications in the treatment of
AWS [69].
To our knowledge, this multi-centre, randomized,
single-blind clinical trial is the first parallel group study to
compare the efficacy of lorazepam, tiapride and pregabalin for alcohol dependence. Additionally, our sample was
composed of heavy drinking alcoholics, with moderate to
severe AWS, an average intake of eight drinks per day and
a history of abuse/dependence for more than 3 years.
All the medications in the study showed evidence of
safety and efficacy, with some particular differences.
Overall, our results indicate that pregabalin and
2
3
5
7
15
Days of treatment
lorazepam are comparable for the treatment of AWS and
craving for alcohol. However, pregabalin at flexible
dosages (mean: 275.8 ⫾ 95.6 mg/day), lower than those
prescribed for treatment of partial seizures [70], was
shown to be more effective than lorazepam and tiapride in
the management of some symptoms of the AWS (headache and clouding of sensorium), at least in its uncomplicated form. Moreover, pregabalin showed a better
outcome in terms of relapse rate and the number of
patients retained in treatment.
The observed suppressant effect of pregabalin on
AWS, as in the present study, together with its efficacy in
reducing alcohol craving and intake [47,48], feature pregabalin as a promising, and perhaps unique, pharmacotherapy for alcohol dependence. This drug is of particular
interest in view of its efficacy in two major aspects of the
disorder, namely AWS and maintaining abstinence from
alcohol intake. This specific ability of pregabalin should,
© 2010 The Authors. Journal compilation © 2010 Society for the Study of Addiction
Addiction, 105, 288–299
296
G. Martinotti et al.
Table 3 Mean change from baseline (pre) at last assessment (post) for the Symptom Check List 90 Revised (SCL-90-R) scores in the
three groups. Differences within and between groups are reported.
Differences within groups
Pre (T1)
Post (T2)
Differences between groups
Parameter
Medication
n
Mean ⫾ SD
Mean ⫾ SD
Za(p)
X2b(P)
Somatization
Lorazepam
Tiapride
Pregabalin
37
37
37
0.90 ⫾ 0.51
1.21 ⫾ 0.65
0.93 ⫾ .60
0.47 ⫾ 0.39
0.75 ⫾ 0.64
0.41 ⫾ 0.36
-4.160 (<0.001)
-3.213 (<0.001)
-4.586 (<0.001)
1.171 (0.557 NS)
Obsessive–compulsive
Lorazepam
Tiapride
Pregabalin
37
37
37
1.17 ⫾ 0.72
1.09 ⫾ .73
1.3 ⫾ .82
0.67 ⫾ 0.65
0.60 ⫾ 0.45
0.67 ⫾ 0.61
-4.380 (<0.001)
-3.276 (<0.001)
-4.317 (<0.001)
4.703 (0.095 NS)
Interpersonal sensitivity
Lorazepam
Tiapride
Pregabalin
37
37
37
0.90 ⫾ 0.65
0.69 ⫾ 0.49
1.01 ⫾ 0.77
0.53 ⫾ 0.54
0.47 ⫾ 0.51
0.47 ⫾ 0.50
-3.573 (<0.001)
-2.566 (0.01)
-4.641 (<0.001)
10.75 (0.005)
Depression
Lorazepam
Tiapride
Pregabalin
37
37
37
1.11 ⫾ 0.74
1.27 ⫾ 0.76
1.48 ⫾ 0.87
0.66 ⫾ 0.62
0.77 ⫾ 0.69
0.76 ⫾ 0.60
-3.937 (<0.001)
-2.724 (0.006)
-4.736 (<0.001)
8.514 (0.014)
Anxiety
Lorazepam
Tiapride
Pregabalin
37
37
37
1.07 ⫾ 0.73
1.1 ⫾ 0.69
1.21 ⫾ 0.79
0.59 ⫾ 0.64
0.63 ⫾ 0.65
0.53 ⫾ 0.43
-3.862 (<0.001)
-3.466 (<0.001)
-4.796 (<0.001)
Anger–hostility
Lorazepam
Tiapride
Pregabalin
37
37
37
0.61 ⫾ 0.45
0.72 ⫾ 0.53
0.89 ⫾ 0.81
0.47 ⫾ 0.47
0.49 ⫾ 0.66
0.39 ⫾ 0.48
-2.465 (0.014)
-2.685 (0.007)
-4.668 (<0.001)
Phobic anxiety
Lorazepam
Tiapride
Pregabalin
37
37
37
0.49 ⫾ 0.47
0.75 ⫾ 0.79
0.66 ⫾ 0.71
0.25 ⫾ 0.33
0.45 ⫾ 0.62
0.31 ⫾ 0.40
-3.627 (<0.001)
-2.555 (0.011)
-4.122 (<0.001)
2.126 (0.345 NS)
Paranoid ideation
Lorazepam
Tiapride
Pregabalin
37
37
37
0.99 ⫾ 0.67
0.84 ⫾ 0.64
1.05 ⫾ 0.72
0.69 ⫾ 0.62
0.62 ⫾ 0.70
0.70 ⫾ 0.67
-2.367 (0.018)
-1.766 (0.077)
-3.657 (<0.001)
3.519 (0.172 NS)
Psychoticism
Lorazepam
Tiapride
Pregabalin
37
37
37
0.61 ⫾ 0.55
0.65 ⫾ 0.55
0.57 ⫾ 0.53
0.35 ⫾ 0.41
0.42 ⫾ 0.55
0.32 ⫾ 0.38
-3.175 (<0.001)
-2.492 (0.013)
-4.562 (<0.001)
1.864 (0.394 NS)
Global severity index
Lorazepam
Tiapride
Pregabalin
37
37
37
0.94 ⫾ 0.52
1 ⫾ 0.53
1.08 ⫾ 0.62
0.56 ⫾ 0.48
0.62 ⫾ 0.53
0.54 ⫾ 0.41
-4.639 (0.000)
-3.771 (0.000)
-4.923 (0.000)
7.932 (0.019)
3.67 (0.160 NS)
12.601 (0.02)
a
Wilcoxon Signed Ranks Test; bKruskall Wallis Test. NS: not significant; SD: standard deviation.
theoretically, results in a vastly simplified pharmacotherapy and higher compliance of treatment.
Other points in favour of the employment of pregabalin were represented by the reduction of specific symptoms in the areas of anxiety, hostility and psychoticism.
The results presented are in agreement with those
observed in our previous studies on alcohol relapse prevention, where pregabalin was comparable to naltrexone
to reduce craving and alcohol consumption, but with a
significantly higher reduction of withdrawal scores
[47,48].
Despite the use of pregabalin in the treatment of
anxiety symptoms, no rebound anxiety was noted during
drug discontinuation. This profile is in contrast to the
occurrence of discontinuation symptoms and rebound
anxiety when therapeutic doses of benzodiazepines are
discontinued abruptly after some weeks of therapy
[71,72].
With regard to tiapride, it is interesting to note its
favourable effect on the compulsive aspect of alcohol
craving during the first days of withdrawal. This may be
determined by the reduction of the hypersecretion of
dopamine induced by alcohol withdrawal. Apart from
these aspects, the results of the present study show that
the administration of low doses of tiapride are as effective
as lorazepam in the treatment of AWS. The application of
the rescue protocol for a patient of the tiapride group for
delirium tremens suggests that the use of tiapride should
© 2010 The Authors. Journal compilation © 2010 Society for the Study of Addiction
Addiction, 105, 288–299
Pregabalin, tiapride and lorazepam in AWS
be limited to non-severe and non-complicated types of
alcohol withdrawal.
Finally, liver function tests in all the treated subjects
showed significantly improved results, with no difference
between groups. This is due clearly to the suspension of
alcohol intake, as indicated by the decrease in GGT, but
the parallel reduction in indices of hepatocellular damage
point to the safety of the drug. These data, together with
haematological and ECG responses, corroborate what has
been described previously with lorazepam, tiapride and
pregabalin in other psychopathological and neurological
conditions [73–85], confirming their favourable safety
profile in alcoholics.
The results of this study need to be interpreted with
caution due to its limitations. First, the absence of a
placebo group is a weakness that tempers the interpretation of the results. Secondly, the single-blind design possibly caused a bias in evaluating efficacy, although
investigators who gave the scales were always unaware as
to which drug being administered to patients. Thirdly, the
findings for AWS must be treated with caution due to the
high number of statistical comparisons, and also because
there was a tendency (non-significant) for CIWA-Ar baseline scores to be higher in the lorazepam and pregabalin
groups compared with the tiapride group.
In conclusion, the results of the present study indicate
that the efficacy of pregabalin in the treatment of
uncomplicated forms of AWS is superior to that of
tiapride, used largely in research trials and clinical practice and, for some measures, to that of the ‘gold standard’,
lorazepam. Accordingly, pregabalin may be considered as
a new potentially useful drug for treatment of AWS,
deserving further investigation. Despite this, we wish to
emphasize that at present benzodiazepines still represent
the drug of choice in treating AWS, also considering their
proven efficacy in preventing complicated forms such as
delirium tremens and epileptic seizures.
Acknowledgements
We wish to thank Dr S. Geri for clinical assistance in the
recruitment and evaluation of patients.
Declaration of interest
No pharmaceutical and industry support was employed
in this study.
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