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Alcohol & Alcoholism Vol. 37, No. 5, pp. 504–508, 2002 BACLOFEN EFFICACY IN REDUCING ALCOHOL CRAVING AND INTAKE: A PRELIMINARY DOUBLE-BLIND RANDOMIZED CONTROLLED STUDY GIOVANNI ADDOLORATO*, FABIO CAPUTO2, ESMERALDA CAPRISTO, MARCO DOMENICALI2, MAURO BERNARDI2, LUIGI JANIRI1, ROBERTA AGABIO3, GIANCARLO COLOMBO4, GIAN LUIGI GESSA3–5 and GIOVANNI GASBARRINI Institute of Internal Medicine and 1Institute of Psychiatry, Catholic University of Rome, Rome, 2‘G. Fontana’ Centre for the Study and Treatment of the Alcohol Addiction, University of Bologna, Bologna, 3‘Bernard B. Brodie’ Department of Neuroscience, University of Cagliari, 4C.N.R. Institute of Neurogenetics and Neuropharmacology, Cagliari and 5Neuroscienze S.c.a r.l., Cagliari, Italy (Received 15 March 2002; in revised form 19 April 2002; accepted 22 April 2002) Abstract Aims: The γ-aminobutyric acid (GABA ) receptor agonist, baclofen, has recently been shown to reduce alcohol intake
in alcohol-preferring rats and alcohol consumption and craving for alcohol in an open study in humans. The present study was aimed
at providing a first evaluation of the efficacy of baclofen in inducing and maintaining abstinence and reducing craving for alcohol in
alcohol-dependent patients in a double-blind placebo-controlled design. Methods: A total of 39 alcohol-dependent patients were
consecutively enrolled in the study. After 12–24 h of abstinence from alcohol, patients were randomly divided into two groups. Twenty
patients were treated with baclofen and 19 with placebo. Drug and placebo were orally administered for 30 consecutive days. Baclofen
was administered at the dose of 15 mg/day for the first 3 days and 30 mg/day for the subsequent 27 days, divided into three daily doses.
Patients were monitored as out-patients on a weekly basis. At each visit alcohol intake, abstinence from alcohol, alcohol craving and
changes in affective disorders were evaluated. Results: A higher percentage of subjects totally abstinent from alcohol and a higher number
of cumulative abstinence days throughout the study period were found in the baclofen, compared to the placebo, group. A decrease in
the obsessive and compulsive components of craving was found in the baclofen compared to the placebo group; likewise, alcohol intake
was reduced in the baclofen group. A decrease in state anxiety was found in the baclofen compared to the placebo group. No significant
difference was found between the two groups in terms of current depressive symptoms. Baclofen proved to be easily manageable and
no patient discontinued treatment due to the presence of side-effects. No patient was affected by craving for the drug and/or drug abuse.
Conclusions: Baclofen proved to be effective in inducing abstinence from alcohol and reducing alcohol craving and consumption in
alcoholics. With the limits posed by the small number of subjects involved, the results of this preliminary double-blind study suggest that
baclofen may represent a potentially useful drug in the treatment of alcohol-dependent patients and thus merits further investigations.
The present double-blind randomized placebo-controlled study was performed in order to determine the efficacy of In recent years, the use of pharmacotherapy together with short-term baclofen administration on craving for alcohol, psychosocial interventions (including Alcoholics Anonymous alcohol intake and abstinence from alcohol in patients affected and various counselling approaches) has enhanced the per- centage of success in maintaining alcoholic patients in remis-sion and assisting the development of a lifestyle compatiblewith long-term alcohol abstinence. However, to date, drugs with proven efficacy are very few (see Garbutt et al., 1999; Swift,1999; Kranzler, 2000) and the discovery of new medications A total of 39 alcohol-dependent patients (mean age ± SD: capable of positively affecting the components of alcohol 47.3 ± 10.5 years; mean daily drinks: 14.2 ± 7.9; mean years dependence syndrome, such as craving and loss of control on of addiction: 11.8 ± 4.2) were consecutively admitted to the drinking or protracted abstinence symptoms, would represent study. Inclusion criteria were: (1) age ranging from 18 to 70 an important step forward in the treatment of patients with years; (2) diagnosis of current alcohol dependence according alcohol problems (see Garbutt et al., 1999).
to DSM-IV criteria (American Psychiatric Association, 1994); Baclofen is a potent and stereoselective γ-aminobutyric acid (3) last alcohol intake reported to have taken place in the 24 h (GABA ) receptor agonist used clinically to control spasticity preceding observation; (4) presence of a referred family member.
(Davidoff, 1985). Recent preclinical experiments have demon- Exclusion criteria were the presence of: (1) severe liver, kidney, strated the efficacy of baclofen in suppressing both alcohol heart or lung diseases; (2) psychopathological illness undergoing withdrawal signs in rats made physically dependent on alcohol treatment with psychoactive drugs, epilepsy or epileptiform and voluntary alcohol intake in alcohol-preferring rats (Colombo convulsion; (3) addiction to drugs other than nicotine. Each et al., 2000, 2002). Moreover, preliminary clinical open studies patient was required to provide his/her informed consent after have confirmed the ability of baclofen to reduce alcohol craving having received information on the characteristics, dosing rate and intake (Addolorato et al., 2000b) and alcohol withdrawal and possible side-effects of the drug, as well as on the possibility symptoms (Addolorato et al., 2002) in alcohol-dependent of dropping out of the study at any time. The study protocol fully complied with the guidelines of the Ethics Committeesof the Università Cattolica in Rome and of the University ofBologna, where the study was performed.
Patients were randomized in two groups; 20 patients were *Author to whom correspondence should be addressed at: Institute of Internal treated with baclofen (mean age: 45.8 ± 10.6 years; mean Medicine, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, I-00168Rome, Italy.
daily drinks: 17.6 ± 7.5; mean years of addiction: 12.6 ± 4.8) and 19 patients with placebo (mean age: 48.8 ± 10.4 years; of patients maintaining abstinence in the two groups were mean daily drinks: 10.7 ± 6.7; mean years of addiction: compared using the Fisher exact test for a 2 × 2 table 11.0 ± 3.4). Patients were recruited among those contacting [treatment (baclofen; placebo) × drop-out (presence; absence) our Alcohol Treatment Units. Randomization was performed or treatment (baclofen; placebo) × abstinence (presence; as follows: the 39 consecutive patients received either absence)]. The numbers of patients maintaining abstinence baclofen or placebo in a double-blind fashion. Baclofen and and CAD were analysed with the intention-to-treat principles placebo were entrusted to a referred family member. Placebo (see Lehert, 1993), i.e. entering into the analysis any random- tablets were identical in size, colour, shape and taste to baclofen ized patient, including drop-outs. In this analysis, it was tablets. Baclofen or placebo was orally administered for assumed that all patients who terminated treatment before 4 consecutive weeks. For the first 3 days, baclofen was admin- the end of the study were abstinence failures and CAD was istered at a dose of 15 mg/day refracted in three times/day; calculated on the data available at the time of the last weekly subsequently, the daily dose of baclofen was increased to visit. Analysis of the effect of baclofen on daily drinks, OCDS 30 mg/day refracted in three times/day. The dose prescribed scales, scales of state anxiety and depression, and main bio- was chosen on the basis of the results obtained in a previous logical markers of alcohol misuse was performed by the two- open clinical study (Addolorato et al., 2000b), and represents way (treatment × time) analysis of covariance (ANCOVA) the minimum therapeutic dosage recommended by the drug with repeated measures on the time factor, and baseline data as manufacturer in order to avoid side-effects.
In cases where symptoms of alcohol withdrawal could not have been controlled effectively by baclofen or placebo, a‘rescue’ protocol would have been adopted, based on admin- istration of diazepam (0.5–0.75 mg/kg body weight). However,no patients required this treatment intervention.
No statistically significant difference in mean age and All patients were strongly advised against the use of drugs mean years of addiction was found between the two groups capable of potentially affecting craving for alcohol. Specific- (P > 0.05, Mann–Whitney test).
ally, the use of benzodiazepines, antidepressants, metadoxine, A schematic diagram on recruitment, group allocation, naltrexone, acamprosate, γ-hydroxybutyric acid (GHB), as well treatment retention and success in achieving and maintaining as alcohol-sensitizing drugs (e.g. disulfiram) was not allowed complete abstinence is presented in Figure 1. Although stat- during the study period and subsequent follow-up.
istical significance was not reached (P = 0.06, Fisher’s exact Each subject was checked as an out-patient every week for test), the number of drop-outs was lower in the baclofen than the duration of the study; at each visit, routine psychological in the placebo group; indeed, three subjects in the baclofen support counselling as previously described (Addolorato et al., group (corresponding to 15.0%) and eight subjects in the 1993) was provided by the same professional staff. Craving placebo group (42.1%) dropped out and were excluded from level was evaluated by administration of the Obsessive– Compulsive Drinking Scale (OCDS) at the start of the study A significantly higher number of patients who achieved (T0) and at each weekly out-patient visit (T1–T4). The OCDS and maintained abstinence throughout the experimental period is a validated scale consisting of two subscales which evaluate was found in the group of patients treated with baclofen the obsessive and compulsive components of craving (Anton (14 out of 20, corresponding to 70.0%) compared to subjects et al., 1995). Abstinence from alcohol was evaluated, at each treated with placebo (four out of 19, or 21.1%) (P < 0.005; out-patient visit, on the basis of: (1) patient’s self-evaluation Fisher’s exact test). CAD was ~3-fold higher in baclofen- than [reporting alcohol intake as the mean number of standarddrinks consumed per day (one standard drink equal to 12 g ofabsolute alcohol) (Secretary of Health and Human Services,1997)]; (2) family member interview; (3) determination ofalcohol concentration in blood and saliva by QED (EnzymaticsInc., Horsham, UK). Cumulative abstinent duration (CAD),defined as the total number of days of abstinence, was also calculated in both the baclofen and placebo groups.
Further, main biological markers of alcohol abuse [aspartateaminotransferase (AST), alanine aminotranferase (ALT), γ-glutamyltranspeptidase (GGT) and mean cell volume(MCV)] were determined at the start (T0) and at the end (T4)of the study. Finally, possible changes in state anxiety andcurrent depression were assessed by means of the State andTrait Inventory test, Y1 axes (Spielberg et al., 1983), and ZungSelf-Rating Depression Scale (Zung et al., 1965), respectively.
At drug discontinuation, the presence of possible side-effects due to drug suspension was recorded on a weekly basis for thefirst 4 weeks.
Statistical evaluation of patients’ age, years of addiction and CAD in the baclofen and placebo groups was performed Fig. 1. Diagram on recruitment, group allocation, treatment retention by the Mann–Whitney test. The number of drop-outs and and success in achieving and maintaining complete abstinence.
placebo-treated patients [19.6 ± 2.6 and 6.3 ± 2.4 (mean ± SEM),respectively; P < 0.005, Mann–Whitney test].
Figure 2 shows daily alcohol intake in the two groups of patients at the different observation times of the study.
ANCOVA revealed a significant effect of treatment on alcoholintake [F (1,78) = 10.71, P < 0.005; F P > 0.05]. In the baclofen group, the mean number of dailydrinks was virtually completely suppressed within the firstweek of the treatment, being reduced from ~18 (value at T0)to <0.5 (values at T1–T4); in the placebo group, the dailydrinks were reduced from approximately a mean number of 10 (T0) to 3.5–4.5 (T1–T4).
Figure 3 (top panel) shows the craving score in the two groups of patients at the different observation times.
ANCOVA showed a significant effect of both treatment andtime on total OCDS score [F (3,78) = 10.30, P < 0.00005]. From T1 to T4, the score in the baclofen group was constantly lower than that monitoredin the placebo group. ANCOVA also revealed significant effectsof treatment and time on both compulsive [F (3,78) = 6.40, P < 0.0005] (Fig. 3, centre panel) (1,78) = 5.06, P < 0.05; F P < 0.00005] (Fig. 3, bottom panel) drinking subscales ofOCDS, with scores in the baclofen groups constantly lowerthan those of the placebo group throughout T1–T4.
ANCOVA revealed significant effects of both treatment and (3,78) = 3.05, P < 0.05] (Fig. 4, top panel), with lower scores in the baclofen than placebo group at T1–T4. Incontrast, no significant difference was observed in depressionscore [F (1,78) = 0.70, P > 0.05; F P > 0.05] (Fig. 4, bottom panel).
Table 1 reports values obtained in laboratory investigations before and after baclofen or placebo administration.
No serious systemic or single-organ event leading to drug Fig. 3. Obsessive–Compulsive Drinking Scale (OCDS) total (top panel), cessation was reported and no patient discontinued the drug.
OCDS Compulsive Drinking subscale (centre panel) and OCDS Tolerability was fair in all patients; as previously reported Obsessive Drinking subscale (bottom panel) scores in baclofen and (Addolorato et al., 2000b), the most common side-effects placebo groups at T0 (baseline) and over the four weekly visits (T1–T4).
were sleepiness (two patients), tiredness (one patient), vertigo Each value is the mean ± SEM of 17 patients in the baclofen group and (one patient) in the baclofen group and abdominal pain (one patient) in the placebo group, which resolved within 1–2weeks of drug treatment and did not recur. No patient reportedeuphoria or other pleasant effects caused by the drug. Nosubject showed craving for baclofen. At drug discontinuation,neither drug withdrawal syndrome nor side-effect due to drugsuspension was observed.
Recent preclinical (Colombo et al., 2000, 2002) and preliminary clinical data (Addolorato et al., 2000b, 2002)suggest that the GABA receptor agonist, baclofen, may be effective in the treatment of patients with alcohol problems.
However, to date, no double-blind, randomized placebo- Fig. 2. Number of daily drinks in baclofen and placebo groups at T0 controlled study has been conducted. In spite of the limitation (baseline) and over the four weekly visits (T1–T4).
Each value is the mean ± SEM of 17 patients in the baclofen group and due to the low number of patients evaluated, the results of the present study indicate that administration of relatively In agreement with our previous observation (Addolorato et al., 2000b), abstinence from alcohol or reduction in alcoholintake was achieved within the first week of baclofen treatmentand was maintained throughout the treatment period. Theincreased efficacy of baclofen over placebo may be related toits suppressant effect on craving; indeed, the drug produced arapid decrease in the ‘compulsive’ and ‘obsessive’ componentsof craving, as indicated by the immediate reduction in meanscore of both OCDS subscales. It is noteworthy that an anti-craving effect of baclofen has already been observed withother substances of abuse, particularly cocaine in cocaine users(Ling et al., 1998). The anti-craving effect of baclofen maydepend on its ability to interfere with the neuronal substratesmediating the reinforcing properties of ethanol. GABAB receptors located in the ventral tegmental area (VTA) havebeen reported to control the activity of mesolimbic dopamineneurons, a major neural pathway in the regulation of the rein-forcing properties of addictive drugs, including alcohol (seeDi Chiara, 1995; Koob et al., 1998; Spanagel and Weiss, 1999).
Accordingly, pharmacological stimulation of VTA GABAB receptors has been found to inhibit the firing activity of theseneurons (Kalivas, 1993) as well as basal (Yoshida et al., 1994)and alcohol-stimulated (Carta et al., 2001) dopamine releasefrom their terminals in the nucleus accumbens.
Moreover, it is conceivable that the suppressing effect of baclofen on alcohol withdrawal symptomatology (Addoloratoet al., 2002) may have helped the patients to achieve and main-tain alcohol abstinence.
In contrast to the observation by Krupitsky et al. (1993) that Fig. 4. State anxiety score, evaluated by the State Anxiety Inventory Test baclofen ameliorates affective disorders in alcoholics, in the (STAI-Y1), and current depression score, evaluated by the Zung Self- present study baclofen was found to be effective in reducing rating Depression scale, in baclofen and placebo groups at T0 (baseline) state anxiety, but not current depression. It may be hypo- and over the four weekly visits (T1–T4).
thesized that the decrease in state anxiety found in the present Each value is the mean ± SEM of 17 patients in the baclofen group and study and the decrease in depression observed by Krupitsky et al. (1993) in alcoholics after a 3-week treatment withbaclofen were secondary to the ability of baclofen to achieveboth a rapid detoxification (Addolorato et al., 2002) and a Table 1. Main biological markers of alcohol misuse in patients treated with baclofen or placebo at the start (T0) and at the end (T4) decrease in craving, resulting in a rapid reduction of physical and psychological symptoms. Finally, it should be emphasizedthat the absence of a significant decrease in Zung depression scale score in the present study could be influenced by therelatively low score recorded in some patients at the start of In agreement with both previous observations (Krupitsky GGT (81–99 U/l) 103.6 ± 24.8 150.9 ± 41.8 50.5 ± 11.2 56.9 ± 16.7 et al., 1993; Ling et al., 1998; Addolorato et al., 2000a), baclofen proved to be devoid of serious side-effects in alcoholics. Moreover, side-effects were present only duringthe first week of the treatment.
MCV, mean cell volume; GGT, γ-glutamyltranspeptidase; AST, aspartate aminotransferase; ALT, alanine aminotransferase. Each value is the Preclinical data suggest that baclofen might be liable to mean ± SEM of 17 patients in the baclofen group (with the exception misuse since the drug shares several pharmacological effects of the GGT data for 16 patients) and 11 patients in the placebo group.
with the alcohol-mimicking agent, γ-hydroxybutyrate (GHB),and craving for and abuse of GHB have been observed indifferent alcoholic patients (see Addolorato et al., 2000a). How- low doses of baclofen to alcohol-dependent patients is more ever, baclofen failed to show euphorigenic effects and no effective than placebo in inducing and maintaining abstinence patient consumed the drug above the prescribed dose. The lack from alcohol (both in terms of number of patients reaching of misuse liability of baclofen is an important factor in pharma- complete abstinence and CAD), reducing alcohol intake, cological treatments of alcohol and other substance addictions.
suppressing alcohol craving in both its ‘obsessive’ and In conclusion, with the limits of the low number of patients ‘compulsive’ features, and reducing state anxiety. Baclofen, recruited and the short time of observation, the results of the however, did not differ from placebo in terms of reduction of present preliminary double-blind study confirm that baclofen, because of its anti-craving and anti-reward action on the one hand, and safety on the other, may have an important role in Colombo, G., Serra, S., Brunetti, G., Atzori, G., Pani, M., Vacca, G., the treatment of patients with alcohol problems. Future studies Addolorato, G., Froestl, W., Carai M. A. M. and Gessa, G. L. (2002) with larger patient samples and longer periods of observation receptor agonists baclofen and CGP 44532 prevent acquisition of alcohol drinking behavior in alcohol-preferring rats.
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