Treatment of alcohol addiction with high-dose Baclofen. A randomised and placebo-controlled study (BACLAD) (European Neuropsychopharmacology, 2015)

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1 Treatment of alcohol addiction with high-dose Baclofen. A randomised and placebo-controlled study (BACLAD) (European Neuropsychopharmacology, 2015) Authors: Christian A. Müller, Olga Geisel, Patricia Pelz, Verena Higl, Josephine Krüger, Anna Stickel, Anne Beck, Klaus-Dieter Wernecke, Rainer Hellweg, Andreas Heinz The first randomised and placebo-controlled study with high-dose Baclofen (up to 270 mg/day). Summary: Previous randomised, placebo-controlled studies (RCTs), which deal with the efficacy of the selective gamma-aminobutyric acid (GABA)-B receptor agonist Baclofen in the treatment of alcohol addiction, reported varying results, which could be linked to the low to medium dosage of the active ingredient Baclofen (30 80 mg/day). Building on preclinical observations, which suggested dosage-dependent effects, and based on positive case studies of alcohol-dependent patients, it was the aim of this study to investigate the efficacy and safety of Baclofen treatment for alcohol addiction, with individually adjusted, high dosages. Out of 93 gradually selected alcohol-dependent patients, 56 were randomly allocated to a double-blind treatment with individually adjusted dosages of Baclofen or placebo ( mg/day). In this context, the main criteria were 1) total abstinence and 2) increasing abstinence duration within a 12-week high-dosage phase. During the highdosage phase, [significantly] more patients in the Baclofen group achieved total abstinence [criterion 1] than in the placebo group (15 out of 22 (68.2%) compared to 5 out of 21 (23.8%), p = 0.014). Baclofen patients also did significantly better with the increasing abstinence duration [criterion 2] compared to the placebo group (67.8 days (SD = 30) compared to 51.8 days (SD = 29.6), p = 0.047). During the study, no serious side effects were observed, which could be attributed to the medication. Individually adjusted, high-dose Baclofen effectively supports alcohol-dependent patients in maintaining alcohol abstinence, and even proved to be a compatible medication in the case of relapses. The results show further proof of the potential of Baclofen and therefore possibly extend current options in pharmacotherapy for alcohol addiction. Discussion In France, Baclofen recently obtained temporary authorisation for the treatment of alcohol dependency, with a dosage of up to 300 mg/day. This is remarkable, as until now there have only been individual case studies and observational series of tests with such a high dosage (de Beaurepaire, 2012; Pastor et al. 2012), however no results of controlled clinical studies. Now, as far as we know, with our work, the first randomised, placebo-controlled clinical study was carried out on the efficacy and tolerance of individual high doses of Baclofen in the treatment of alcohol-dependent patients. We have determined that patients treated with Baclofen both in the twelveweek phase of maximum dosage and in the whole medication phase (incl. introduction and reduction of the medication) come out better regarding abstinence than the placebo group. Our study is therefore further proof of the efficacy of Baclofen in the treatment

2 of alcohol dependency, which was also shown in previous controlled clinical studies (Addolorato et al., 2002; Addolorato et al., 2007). In comparison with these previous studies, the average dosage of 180 mg/day was relatively high in our study. This is possibly the basis for the superiority of Baclofen compared to the placebo, which could not be found in more extended investigations with a lower dosage (30 mg/day) (Garbutt et al., 2010). However, and contrary to the assumption of a dosage-dependent effect (Addolorato et al., 2011; Ameisen, 2005; Garbutt et al., 2010), the individual dose did not differ for the successfully and unsuccessfully treated patients. Further, and more extensive studies in terms of the number of patients, will need to further investigate the dosagedependent effects on abstinence. Around two thirds of Baclofen patients, compared with one third of the placebo group, did not reach the maximum dose of 270 mg/day. This was not really expected because in our other clinical practice, we did observe such high doses in individual cases. The test subjects in the Baclofen group of the current study could also have received comparably high doses, but as the subsequent evaluation showed they were not required. In contrast to previous studies (Addolorato et al., 2002; Addolorato et al., 2007), interestingly, we were not able to observe any effect of Baclofen on cravings and the characteristics of an anxiety disorder. Possibly, this is due to an effect mechanism, which does not necessarily require these symptoms (cravings and anxiety) in the case of alcohol addiction. Currently, primarily two psychopharmacological effect mechanisms of Baclofen are being discussed: On the one hand, a partial substitution (Rolland et al., 2013) and on the other hand, the alteration of the dopaminergic transmitters in the limbic reward system (Pastor et al. 2012). If you look at the hypothesis of partial substitution, then you would expect that the continued administration of high doses of Baclofen would lead to effects similar to those of alcohol, and that stopping the medication or dosage variations would lead to corresponding withdrawal symptoms. In line with the findings of earlier controlled clinical studies (Addolorato et al., 2002; Garbutt et al., 2010), none of the patients noticed effects similar to those of alcohol during our study. Furthermore, we also did not observe any craving for the medication or any withdrawal symptoms when stopping the medication. It is also currently unclear to what extent alcohol has a direct effect on the GABA-B receptors of the brain (Harris et al., 2008). Preclinical findings show that GABA-B receptor agonists, such as Baclofen, can directly modulate the dopaminergic transfer from the ventral tegmental area to the nucleus accumbens, a key component in the mesolimbic reward system (Westerink et al., 1996), by inhibiting the dopaminergic neurones. Therefore, an ethanol- or key stimulant- (alcohol-associated) induced increase of the dopaminergic transfer within the mesolimbic reward system (Di Chiara and Bassareo, 2007) could be inhibited by

3 Baclofen. The fact that Baclofen can only pass the blood-brain barrier to a limited extent (Taira, 2009) could explain why some patients need a higher dose to achieve the described effects on the central nervous system. Imaging procedures could provide information about this in further research. With regards to the safety and tolerance of the medication Baclofen, our study confirmed the previous advantageous findings (Addolorato et al., 2007; Garbutt et al., 2010). In the Baclofen group, only two patients stopped the treatment due to unwanted side effects of the medication (particularly tiredness). Apart from that, no relevant events could be attributed to the medication. In line with the results of another experiment (Evans and Bisaga, 2009), even in the case of (alcohol) consumption relapses and taking Baclofen at the same time, there were no other serious incidents, which could have been attributed to the medication Baclofen. In contrast, in the past there were some incidents of attempted self-intoxication with alcohol-dependent patients taking Baclofen, as Franchitto et al., 2014 reported. Therefore, it is critical that the prescription of Baclofen for patients with psychiatric comorbidities and/or prior suicide attempts is carried out with the utmost care. The following limiting remarks on our study are required: First of all, the tested patient group is too small to show the conclusive role of Baclofen in the treatment of alcohol dependency for the future (81% total abstinence, but just 48% permanent abstinence duration). More extended studies will have to confirm our results. Secondly, our study was only carried out in one clinical location. Therefore, some factors, e.g. patient base, and our procedure could have influenced the result. On the other hand, just such varied location influences were avoided due to this setting. And thirdly, however, as long as objective criteria remains limited, we could not rule out the fact that individual relapses remained undiscovered in both groups (Baclofen and placebo). Fourthly, we only tested Baclofen regarding the maintenance of abstinence. It remains unclear whether Baclofen can also be effective in the reduction of alcohol consumption, particularly in patients who are not striving for absolute abstinence. To summarise, we determined that individual high doses of Baclofen effectively supported the patients in maintaining abstinence and all in all was also well tolerated, even in the case of individual alcohol relapses. The results also show that there is no generally binding effective dose and that this would probably have to be found for each individual patient. As there are currently no more extensive studies regarding safe usage, this individual dosage adjustment must be carried out with care and close accompaniment of the patients. Our data showed that Baclofen did not primarily work by reducing craving or the effects of an anxiety disorder. The underlying psychopharmacological mechanisms of Baclofen have yet to be investigated in future experiments. However, our experiment strengthened the findings that administering Baclofen can support some patients in maintaining abstinence, and that in this way the possibilities of medicinal treatment of alcohol dependency could probably be extended.

4 Further evaluations of inclusion and exclusion criteria Inclusion criteria Age 18 < 65 years Diagnosis of alcohol addiction in accordance with ICD 10 (WHO, 1994) and DSM IV (APA, 2000) Alcohol consumption of on average at least 2 heavy drinking days per week (men 5 standard drinks per day, women 4 standard drinks per day (one standard drink corresponds to12 g of pure alcohol) and an average total alcohol consumption of 21 standard drinks per week or more for men and 14 standard drinks per week or more for women during the four weeks before the start of the detoxification phase. Complete in-patient or out patient detoxification before randomisation ("random allocation to groups") Last alcohol consumption 7 to 21 days before randomisation and sufficient knowledge of German. Exclusion criteria Further "I-axis disorders" apart from alcohol or nicotine addiction or neurological disorders Current treatment with psychotropic drugs, which could influence the results of the study (e.g. sedatives, medication for relapse prophylaxis / prevention, e.g. Acamprosat, Disulfiram, Naltrexon, antidepressants, antipsychotics, anticonvulsives) Epilepsy or epileptic seizures Current pregnancy or breastfeeding Intolerance to Baclofen, terminal kidney failure, Alaninaminotransferase (ALAT) or Aspartat-Aminotransferase (ASAT) with values five times over the normal limit, Bilirubin > 1.9 mg/dl, International Normalized Ratio (INR) > 1.6 Stomach / intestinal ulcers. The results in detail During the high-dosage phase, [significantly] more patients in the Baclofen group achieved total abstinence [criterion 1] than in the placebo group (15 out of 22 (68.2%) compared to 5 out of 21 (23.8%), p = 0.014). Baclofen patients also did significantly better with the increasing abstinence duration [criterion 2] compared to the placebo group (67.8 days (SD = 30) compared to 51.8 days (SD = 29.6), p = 0.047). These results are far better than those known from practice and comparable studies with other medications (Acamposat, Nalmefen (Selincro), Disulfiram (Antabus), Naltrexon, etc.).

5 A total of 93 potential trial participants were considered (screened). 17 of them did not fulfil the required criteria, 20 refused to participate. So, 56 people were left. These were randomised equally into a placebo group (28 people) and a Baclofen group (28 peole). Then the dosage was slowly increased. Before the "high-dosage phase" was reached, another 13 people dropped out. They relapsed during the medication phase. Concretely, these were 7 participants from the placebo group and 6 participants from the Baclofen group. Then there were 43 left (21 in the placebo group and 22 in the Baclofen group). Out of the 21 remaining participants in the placebo group, 11 people relapsed under high dosage, 3 stopped treatment for reasons of their own and one of each infringed the protocol or "went astray". 5 participants (23.8%) remained abstinent with a highdose placebo. Out of the 22 remaining participants in the Baclofen group, 4 people relapsed with the high dosage, none stopped treatment for their own reasons or infringed the protocol, 2 ended participation due to unwanted events ( adverse event, was not necessarily caused by the study) and another person "went astray". 15 participants (68.2%) remained abstinent with a high dosage of Baclofen.