Les raisons de l’échec de l’étude hollandaise :
Another study of high-dose baclofen (multiple brands), widely used in France to treat alcohol dependence, found that the drug does not appear to bolster abstinence rates, suggesting its use should be reconsidered.
« The study was run in different clinics in the Netherlands, where patients received standard treatment, mostly 12-step, but also cognitive-behavioral therapy and motivational therapy, all widely available…and baclofen does not seem to add to the efficacy of these other psychosocial treatments, » study investigator Reinout Wiers, PhD, professor of developmental psychopathology, University of Amsterdam, the Netherlands, told Medscape Medical News.
« While there might be people for whom psychosocial treatment does not work who can be helped with baclofen, this should be carefully studied, » he added. The study was published in the December 2016 issue of European Neuropsychopharmacology.
No Difference in Abstinence
For the study, the investigators recruited alcohol-dependent patients from two inpatient and three outpatient treatment centers in the Netherlands. Prior to study enrollment, female participants consumed on average 14 or more units of alcohol per week, and male participants consumed 21 units or more per week.
A total of 151 patients were randomly allocated to receive either low-dose baclofen (30 mg/day), high-dose baclofen (up to 150 mg/day), or placebo. Patients in the high-dose and low-dose baclofen groups started with 30 mg/day baclofen in three pills of 10 mg each. From the second week on, the dose was increased with 10 mg baclofen (for the high-dose group) or placebo (for the low-dose and placebo groups) every other day, resulting in a dose increase of 30 mg/week and a maximum dose of 150 mg/day in week 6 in the high-dose group, the researchers report.
Patients from the inpatient detoxification programs had received either 4 or 6 weeks of psychosocial treatment based on cognitive-behavioral therapy. « Thereafter, these patients had weekly outpatient group sessions during the whole study period, » the authors note.
Patients recruited from the outpatient treatment centers had received either outpatient motivational interviewing or a program based on the Minnesota model. The Minnesota model is based on the approach taken by Alcoholics Anonymous. Its primary goal is lifetime abstinence from alcohol.
Patients from these centers received weekly outpatient group therapy or individual therapy during the entire study period as well. After 10 weeks of the high-dose phase of treatment as well as the complete medication period, which consisted of 16 weeks, there was no difference between the three groups in time to first relapse for either treatment arm.
Specifically, 27.5% of patients in the high-dose group relapsed in the high-dose phase compared with 20% in the low-dose group and 25% of placebo control patients. It should be noted that the low-dose group was discontinued owing to financial constraints, leaving just 100 patients in the study overall.
Results were comparable in the complete medication period; relapse rates in the high-dose, low-dose, and placebo groups were 50%, 48.4% and 46.8%, respectively. There were also no between-group differences in the proportion of patients who remained abstinent during either the high-dose phase or the complete medication phase.
Dr Wiers noted that relapse rates of approximately 30% after 4 months of treatment and slightly more than 50% after 1 year are « pretty normal » in this type of patient population. After 3 years, approximately 70% of patients relapse.
Moderate to Severe Side Effects
Adverse events (AEs) in all treatment groups were considered either moderate or severe. Dose-related AEs were highest in the high-dose baclofen group and consisted mainly of fatigue, sleepiness, and dry mouth.
In the BACLAD study, investigators at the Universitätsmedizin Berlin randomly assigned 56 alcohol-dependent patients to individually titrated baclofen or placebo. Doses of active therapy ranged from 30 mg/day to 270 mg/day. The mean dose of baclofen in this particular study was 180 mg/day.
More patients receiving baclofen maintained total abstinence during the 12-week high-dose phase of the study, at 68.2%, compared with 23.8% for patients who received placebo (P = .014).
The duration of cumulative abstinence was significantly higher in patients given baclofen, at a mean of 67.8 days compared with 51.8 days for patients receiving placebo (P = .047). No serious adverse events were recorded during the trial.
Importantly, in the current Dutch study, only about 15% of patients in the high-dose, 150-mg group reached this dose; the mean dose in the high-dose group was 94 mg.
« Compared to the study of Mueller et al, where patients were titrated up to 270 mg within 4 weeks, our titration schema could be considered as more cautious, or, perhaps in retrospect, overly cautious, » said Dr Wiers.
The investigators note that « it is possible that many patients in our study were suboptimally titrated and stopped at a relatively low dose. »
This seems to be borne out in a post hoc analysis conducted on patients in the high-dose group. For the complete medication period, there was a suggestion that for those who achieved higher doses of baclofen, the time to first relapse was longer.
« This was also confirmed by the fact that the individual doses in the high-dose baclofen group were significantly lower in patients that relapsed (mean = 84.8 mg/day) compared to patients that remained abstinent (mean = 102.4 mg/day; p = 0.029), » the researchers report.
However, they note that it was not possible to reach higher baclofen doses because of side effects, which limited the clinical feasibility of using high-dose baclofen effectively for the treatment of alcohol dependence.
Dr Wiers said that his team is currently working on a follow-up study in severely alcohol-dependent patients who do not respond to regular psychosocial treatment.
However, he concluded that « widespread subscription of baclofen as a primary treatment option seems, at best, premature. »
Failure Tied to Low Dose?
Commenting on the findings for Medscape Medical News, Philippe Jaury, MD, PhD, Paris Descartes University, in Paris, France, who is a leading proponent of the use of baclofen to treat alcohol dependence, felt that in the current study, the failure of high-dose baclofen to enhance abstinence rates in comparison with placebo was entirely attributable to the relatively low dose of baclofen, at a mean of 94 mg/day, that the « high-dose » group received.
In the more recent study, a total of 320 patients randomly assigned to receive either placebo or baclofen could receive up to 300 mg/day, and in fact, one quarter of the group that received active therapy reached doses approaching 250 mg/day by the end of the titration interval.
This year at the World Congress for Alcohol and Alcoholism in Berlin, Dr Jaury reported that in the Bacloville study, 56.8% of patients taking baclofen met the World Health Organization (WHO) criteria of safe drinking levels in the last month of the 12-month study period compared to 36.5% of control patients who received placebo (P = .004).
Low-risk alcohol consumption or abstinence 12 months after initiation of treatment was defined as a WHO mean daily consumption of between 1 and 20 g of alcohol for women (approximately 2 drinks a day) and between 1 and 40 g of alcohol for men (approximately 4 drinks a day).
At study outset, both groups reported a mean alcohol intake of 12.9 units per day.
The Bacloville study included all patient types; no patients were excluded on the basis of psychiatric illness, use of psychotropic medications, or other types of substance abuse, including use of opiates, amphetamines, and cannabis.
No prescribed psychosocial program was included in the Bacloville study. In addition, the study was carried out entirely in a general practice setting, and there was no detoxification or rehabilitation program, as there was in the Dutch study.
Commenting on the Bacloville study, Amanda Stafford, MD, an emergency department physician at the Royal Perth Hospital, in Australia, noted in her summary of the World Congress for Alcohol and Alcoholism in Berlin that the findings showed that « just having a general practitioner supporting treatment for alcoholism was already a powerful therapeutic tool with a 36.5% success rate in the placebo group and that’s a very important message.
« And if you add baclofen to the treatment, nearly 60% of these previously really heavy drinkers are now drinking at safe levels, and that’s pretty remarkable. Alcohol dependence was considered to be largely untreatable. Not anymore, » she added.
Funding for the study was provided by a private donation through the University of Amsterdam Fund. Dr Wiers has received a speaker fee from Lundbeck and was a coapplicant in two awarded grants from ERAB, an independent foundation funded by the alcohol industry that awards alcohol-related research after the research is peer reviewed. Dr Jaury has received funding from Bouchara-Recordatai, Ethypharm, Novartis, Polypharma and Sanofi.