16. Baclofen - clinical data

Editors: Spanagel, Rainer; Mann, Karl F.

Title: Drugs for Relapse Prevention of Alcoholism, 1st Edition

Copyright 2005 Springer

> Table of Contents > Baclofen: clinical data

Baclofen: clinical data

Giovanni Addolorato¹

Ludovico Abenavoli¹

Lorenzo Leggio¹

Giosu DeLorenzi¹

Anna Ferrulli¹

Fabio Caputo²

Roberta Agabio³

Gian Luigi Gessa^{3, 4}

Giancarlo Colombo⁴

Giovanni Gasbarrini¹

¹ Institute of Internal Medicine, Catholic University, Gemelli Hospital, L.go A. Gemelli 8, 00168 - Rome, Italy

² G. Fontana , Center for the Study and Treatment of Alcohol Addiction, University of Bologna, Bologna, Italy

³ Department of Neuroscience, University of Cagliari, Cagliari, Italy

⁴ C.N.R. Institute of Neuroscience, c/o Bernard B. Brodie Department of Neuroscience, University of Cagliari, Viale Diaz 182, I-09126 Cagliari, Italy

Introduction

Alcohol abuse and alcoholism represent a world wide problem, both from a medical and a social point of view. Alcohol dependence affects nearly 10% of the general population both in the United States [1] and in Europe [2], with the high prevalence rate of alcohol-related problems only highlighting the public health importance of this disorder.

The application of pharmacological means in the treatment of patients suffering from alcohol abuse and alcoholism represents an ever-growing field with which to enhance alcohol abstinence and prevent relapse, while also complementing psychosocial interventions which have been used for many years.

In recent years, several drugs useful in the treatment of alcohol addiction have been tested both in pre-clinical and clinical studies. Among them baclofen (beta-(4-chlorophenyl)- -aminobutyric acid) has shown promising results.

Baclofen is a lipophilic derivative of GABA and a stereoselective GABA_B receptor agonist [3]. At present, it is used clinically in order to control spasticity [4].

Recent pre-clinical studies (reviewed in another chapter included in this book [5]) and clinical data (reviewed in the present chapter) have shown that baclofen has been effective in the treatment of alcohol addiction, both in emergencies and in relapse prevention, as well as in the treatment of other substance abuse.

Baclofen in alcohol dependence: relapse prevention

Clinical management of the alcohol addiction disorder is aimed at attaining relief from withdrawal syndromes and ensuring a smooth transition into a

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treatment program so as to achieve alcohol abstinence. Thus, relapse prevention represents the main objective of the treatment. This program includes both pharmacological as well as psychosocial approaches [6, 7, 8 and 9].

As far as the pharmacological approach is concerned, clinical studies point to baclofen as a new useful drug in the treatment of patients with alcohol problems. Krupitsky and co-workers [10] showed that baclofen is effective in reducing affective disorders in alcoholic patients. Affective disorders alongside alcohol dependence can increase withdrawal severity and vulnerability to relapse. The sample included in their study had 3 to 4 weeks of alcohol abstinence, with all subjects suffering from secondary affective disorders, in particular anxiety, and depression, or both. Patients were randomly divided into 4 groups and treated for a period of 3 weeks with 37.5 mg/day baclofen, 15 mg/day diazepam, 75 mg/day of amitriptyline, or placebo. The Zung Scale, the Minnesota Multiphasic Personality Inventory, Spielberger's State-Trait Anxiety, blood platelet MAO-B activity, plasma levels of dopamine, serotonin and GABA, as well as an electroencephalogram (EEG), were evaluated at the start and at the end of the study. The results of the post-treatment rating scale scores showed a significant decrease in anxiety and depression in all drugtreated patients as compared to the placebo group. However, while subjects treated with diazepam and amitriptyline experienced sedation, no side-effects were found in the baclofen-treated patients. The results indicated that selective ligands of GABA_B receptors can be as effective in treating affective disorders in alcoholics as GABAA receptor ligands, and were associated with lower side-effects.

After promising data were obtained from an open pilot study, performed in a small sample of selected patients [11], the efficacy of baclofen was recently evaluated in patients affected by alcohol addiction in a controlled double-blind randomized study [12].

After 12-24 h of abstinence from alcohol, a total of 39 patients were randomly divided into two groups. The patients were treated with oral administration of baclofen or placebo for a total of 30 days, starting at a dose of 15 mg/day for the first three days and 30 mg/day for the subsequent 27 days. Each subject was checked as an outpatient every week and at each visit routine psychological support and counselling were provided, attended to by the same professional staff. Craving level was evaluated using the Italian version [13] of the Obsessive Compulsive Drinking Scale (OCDS) [14] at the start of the study (T0) and at each weekly outpatient visit. Abstinence from alcohol was measured on the basis of a patient's self-evaluation, a family member interview, as well as main biological markers of alcohol abuse. A self-reported alcohol intake was recorded as the average number of standard drinks consumed per day. Variation of state anxiety by the State and Trait Inventory test, Y1 axes, and of current depression by the Zung Self-Rating Depression Scale were recorded. The percentage of drop-outs was lower in the baclofen as compared to the placebo group. Furthermore, a significantly higher number of patients who achieved and maintained abstinence throughout the experimental

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period, were found among the group of patients treated with baclofen. The study showed a significant effect of the drug in reducing alcohol intake. In the baclofen group, the average number of daily drinks was virtually completely suppressed within the first week of treatment (Fig. 1). The OCDS craving score in the baclofen group was constantly lower than that monitored in the placebo group (Fig. 2; top panel). A significant effect of drug treatment on both the compulsive (Fig. 2; central panel) and obsessive (Fig. 2; bottom panel) drinking sub-scale of OCDS was found, with scores in the baclofen group consistently lower than those of the placebo one throughout the study. While lower scores of state anxiety were found in the baclofen group relative to the placebo one, no significant difference was observed regarding the depression score. Tolerability was fair in all patients and no systemic or single-organ event leading to drug cessation was reported. No patient reported euphoria or any other pleasant effects caused by the drug. No subject showed craving for the drug either. Furthermore, at drug discontinuation, no withdrawal syndromes or side-effects due to drug suspension were observed.

In conclusion, the study showed that the administration of low doses of baclofen in alcohol-dependent patients has a significantly higher efficacy, when compared to placebo, in inducing alcohol abstinence, reducing alcohol intake and alcohol craving in both components (obsessive and compulsive) as well as reducing state anxiety. The higher efficacy of baclofen with respect to placebo could be related to its anti-reward and anti-craving action. In fact, the drug was effective in quickly decreasing both compulsive and obsessive components of craving. The anti-craving effect of baclofen could be due to the ability

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of the drug to interfere with the neuronal substrates mediating the reinforcing properties of ethanol [5].

Figure 1. Number of daily drinks in baclofen and placebo groups at T0 (baseline) and over the four weekly visits (T1-T4).

Figure 2. Obsessive-Compulsive Drinking Scale (OCDS) total (top panel), OCDS Compulsive Drinking subscale (centre panel) and OCDS Obsessive Drinking subscale (bottom panel) scores in baclofen and placebo groups at T0 (baseline) and over the four weekly visits (T1- T4).

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These data indicate that baclofen could have an important role in the treatment of patients affected by alcoholism, especially taking into account the safety of the drug. In particular, the ability of the drug in reducing the main components of craving, suppressing alcohol intake, and reducing anxiety as well as in suppressing alcohol withdrawal symptoms (see below) further emphasize its efficacy as a drug useful in relapse prevention.

Alcohol withdrawal syndrome

Recent preliminary data showed that baclofen could be effective in the treatment of alcohol-dependent patients affected by severe alcohol withdrawal syndrome (AWS) [15] also complicated by delirium tremens (DT) [16]. In particular, patients with a Clinical Institute of Withdrawal Assessment revised (CIWA-Ar) scale score higher than 20 points, showing the presence of severe AWS that required pharmacological treatment, were evaluated. Baclofen was orally administered at 10 mg, every 8 h. The CIWA-Ar was applied every hour for 4-8 h. A rapid decrease of the CIWA-Ar score and a marked improvement of AWS symptoms were observed in the first few hours after baclofen administration in all treated patients (Fig. 3). In particular, a rapid decrease of some withdrawal symptoms such as anxiety, agitation and depression was observed. Furthermore, these data could be of interest, as it has already been shown that a rapid decrease of these factors may facilitate the patient's transition into a long-term rehabilitation program [17].

A case of AWS complicated by DT, and successfully treated with baclofen (25 mg orally administered every 8 h for the first three days, then a tapering off of the dose to 10 mg every 8 h), has recently been reported [16]. In this case as well, a rapid decrease of the CIWA-Ar score and a marked improvement of AWS and DT symptoms were observed starting from the first hour on after baclofen administration, due to dissipation of nausea, vomiting, tactile disturbances and hallucinations, and a reduction in other symptoms. After drug discontinuation, AWS and DT symptoms did not recur. Furthermore, in AWS and DT treatment, baclofen was manageable, without resulting in any significant side-effects. In particular, no sedation or respiratory disorders were present in the treated patients.

Moreover, as it has been shown that baclofen is effective in reducing alcohol craving and intake and in inducing and maintaining abstinence from alcohol as well as in suppressing AWS (if the present data are confirmed), then the use of a single drug like baclofen could be more appropriate, as opposed to various drugs, for the management of AWS and DT, and then followed by a program to maintain alcoholic patients in long-term alcohol abstinence [16].

Future studies are needed to confirm the present data. At present, the use of baclofen for the treatment of AWS and DT in clinical practice is inappropriate, until its safety and effectiveness can be examined in controlled clinical trials.

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Figure 3. Scores on the revised Clinical Institute of Withdrawal Assessment for Alcohol scale of the patients included in the study during the 30-day observation period. Baclofen (10 mg, orally) was administered. CIWA-Ar was administered immediately after the observation at time 0; subsequently, baclofen (10 mg, orally) was administered every 8 h for 30 consecutive days. The withdrawal scale was administered every hour for the first 4-8 h, once a day from day 3 to 7 and once a week from week 2 to week 4.

Baclofen in other substance dependence

Heroin

The first studies examining the use of baclofen in opioid-dependent patients were carried out by Krystal and co-workers [18]. In an open label pilot study, five opiate-dependent patients underwent a baclofen-assisted opiate detoxification after an abrupt discontinuation of methadone. Baclofen was administered in 80 mg/day doses, and all patients reported some reduction in discomfort. However, 3 out of the 5 patients did not manage to complete the detoxification process with baclofen, primarily because of an insufficient suppression of vomiting, myalgias and headache. These patients completed their detoxification with clonidine. Therefore, the findings suggest a limited use of baclofen as a primary treatment choice for opiate dependence.

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Akhondzadeh and coworkers [19] compared the efficacy of baclofen with clonidine regarding acute detoxification of opioid-dependent subjects. The authors found that baclofen proved as effective as clonidine in the management of physical symptoms of opiate withdrawal syndromes. Further, baclofen showed a significantly higher efficacy with respect to clonidine in the management of mental symptoms. In a subsequent randomised, double-blind controlled study, the same authors showed that there was no significant difference between the baclofen and clonidine treatment in terms of dropout and overall side-effects among the opioid-dependent subjects treated [20]. However, the low incidence of hypotension in patients treated with baclofen could suggest that this drug may be suitable for outpatient ambulatory treatment of opiate withdrawal syndrome [20].

Recently, Assadi and co-workers evaluated the efficacy of baclofen in maintenance treatment of opioid-addicted patients [21]. In this study, 40 opioid-dependent patients were detoxified and randomly assigned to receive baclofen (60 mg/day) or placebo. Treatment retention was significantly higher in the baclofen group. Baclofen showed a significantly higher efficacy with respect to placebo in terms of opiate withdrawal syndrome and depressive symptoms. A generally favorable response was also found in the baclofen group as regards some outcome parameters, including opioid craving and self-reported opioid and alcohol use. However, no difference was found in the rates of opioid-positive urine tests.

Cocaine

Preclinical studies have shown that baclofen a) prevents the development of cocaine-induced behavioral sensitization, b) abolishes the motor stimulant actions of cocaine, and c) suppresses the intravenous self-administration of cocaine [22, 23]. Shoptaw and co-workers carried out a randomized placebo-controlled trial of baclofen with respect to cocaine dependence [24]. This screening trial evaluated whether baclofen demonstrated sufficient clinical efficacy so as to recommend an adequately powered trial of the medication as a pharmacotherapy for cocaine dependence. Project findings showed an initial clinical efficacy of baclofen over placebo in reducing cocaine use, when administered concurrently with thrice-weekly drug abuse counselling sessions. The effects of baclofen were particularly apparent for those participants with chronic levels of cocaine use at baseline and provide support for a full-scale efficacy trial for baclofen, especially among this subgroup of patients.

Very interesting data have been reported in recent imaging studies performed in cocaine-dependent patients [23]. These subjects were given baclofen (10-20 mg twice daily) for 7-10 days prior to a Positron Emission Tomography (PET) session, with results showing a substantial blunting of cue-induced craving and no limbic anterior cingulate and amygdalar activation to cocaine (versus non-drugs) videos [23]. These data indicate that craving is

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reduced and limbic activation eliminated in cocaine-dependent patients treated with baclofen, suggesting that baclofen may help protect against cue-induced craving and that its benefits can potentially be sustained for years.

Finally, Lile and co-workers [25] showed that pre-treatment with baclofen does not influence acute behavioral effects (e.g., the reinforcing, subject-rated or cardiovascular effects) of intranasal cocaine administration in humans.

Nicotine

The mesolimbic dopamine system has been implicated in the reinforcing effects of nicotine, a drug which appears to act, at least in part, through the ventral tegmental area (VTA). Nicotine activates a circuitry in which -opioid receptors are situated, especially GABAergic elements [26]. In 2001, Cousins and coworkers [27] studied the acute effect of a single dose of baclofen on cigarette smoking, craving for nicotine, cigarette taste, and smoking satisfaction. Baclofen did not change the number of cigarettes smoked by the subjects, nor did it change ratings of nicotine craving. However, baclofen did alter the sensory properties of smoked cigarettes. It also produced mild sedative-like subjective effects, such as increases in feeling relaxed . Thus, although baclofen did not reduce cigarette craving or smoking, it did produce some mood-altering effects and changes in sensory aspects of smoking that may facilitate smoking cessation.

Conclusions

A growing number of both pre-clinical and clinical studies support the idea that GABA_B compounds may attenuate the craving and the reinforcing effects of alcohol, cocaine, heroin and nicotine [28]. The findings reviewed in the present chapter suggest that the GABA_B agonist baclofen may offer a powerful method for controlling drug abuse in humans.

Acknowledgement

Supported by grants from Associazione Ricerca in Medicina , Bologna-Roma, Italy.

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