Clinical Trials of Baclofen in Alcoholism: Up to now and the 2016 results:
Introduction: There are relatively few clinical trials of baclofen for alcoholism although there have been calls for these to be carried out for more than a decade. As discussed in the section “If baclofen is so great, why isn’t everyone using it”, it’s hard to get the money for large clinical trials on medications without pharmaceutical company funding. This poses a particular problem for medications like baclofen which are out of patent protection but show promising results for new uses from small studies. They can end up stuck in relative obscurity because there is no money available for large clinical trials while new but less promising medications are extensively tested by pharmaceutical companies and the results widely publicised.
Baclofen’s acceptance by the wider medical community has undoubtedly been hampered by the lack of large trials but this looks set to end with the release of at least three large European studies at the World Congress for Alcohol and Alcoholism in Berlin on September 3rd 2016. They are discussed below.
But first, let’s review the clinical trials released so far.
References: please click on the links to see the original research articles:
- Addolorato G et al: Baclofen efficacy in reducing alcohol craving and intake: a preliminary double-blind randomized controlled study. Alcohol Alcohol. 2002 Sep-Oct; 37(5):504-8.
- Addolorato G et al: Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet. 2007 Dec 8; 370(9603):1915-22.
- James C Garbutt et al: Efficacy and Safety of Baclofen for Alcohol Dependence: A Randomized, Double-Blind, Placebo-Controlled Trial. Alcohol Clin Exp Res. 2010 Nov; 34(11): 1849–1857.
- Renaud de Beaurepaire et al: Suppression of Alcohol Dependence Using Baclofen: A 2-Year Observational Study of 100 Patients. Front Psychiatry. 2012; 3: 103.
- Müller CA et al: High-dose baclofen for the treatment of alcohol dependence (BACLAD study): a randomized, placebo-controlled trial. Eur Neuropsychopharmacol. 2015 Aug; 25(8):1167-77.
The clinical trials of baclofen for alcoholism go back at least 14 years.
The first of these is a 2002 study carried out by Italian researcher Giovanni Addolorato, a double blind randomised control trial of 39 consecutive treatment seeking alcohol dependent patients. They were randomised to baclofen or placebo given by a family member and went through outpatient detox and early post-detox for a total of 4 weeks. The dose of baclofen used was 15mg/day for 3 days then 30mg/day for the remainder of the 4 weeks. The baclofen and placebo groups were well matched on age and mean years of addiction but the baclofen group had a significantly higher baseline alcohol intake (mean of 18 drinks/day) vs that of the placebo group (mean of 10 drinks/day), potentially placing baclofen at a disadvantage. However the opposite occurred. The dropout rate of the baclofen group was 15% (3/20) compared to 42% (8/19) of the placebo group as patients rejected treatment and returned to drinking. This suggested that baclofen treatment was protective against this outcome. Moreover, of the 17 baclofen patients who completed the 4 week study period, 14 of them (82%) of them remained abstinent, representing an abstinence rate of 70% of the original baclofen treatment group (14/20). In contrast the placebo group not only lost 42% (8/19) of the patients before completion of the study but only 36% (4/11) of those remaining were abstinent at 4 weeks, only 21% (4/19) of the original placebo cohort.
The difference between the groups is striking despite the small, uniform dose of baclofen used. I think this is largely explained by the short study period of 4 weeks. Patients seeking treatment for their alcoholism are highly motivated at the start and often find it relatively easy to stay sober for a few weeks. However after this time it can be difficult to maintain this motivation if underlying cravings and anxiety are not well controlled and this is where the titrated baclofen is very useful. The study group was also relatively well connected socially because they had a family member who was prepared to supervise the medication for 4 weeks. This is not the case for many long term alcohol dependent people.
Addolorato recognised the limitations of small numbers and short observation times, calling for larger and longer studies, but these studies did not happen for a decade.
Addolorato’s next paper, published in 2007, was important because it specifically studied the patient group who have the most urgent need of sustained abstinence from alcohol, those with liver cirrhosis. The study looked at 84 individuals who were randomised into two groups of 42, receiving either placebo or baclofen in the same regime described in the 2002 study above, 30mg/day. The study drug was only started after inpatient withdrawal treatment with diazepam had ceased. Patients were given the study medication (placebo or baclofen) for 12 weeks. This patient cohort had significant liver disease with only 12% being in the mildest category, Child-Pugh class A cirrhosis. The other 88% had more severe cirrhosis: 48% Child-Pugh B and 40% Child-Pugh C.
The cohort included patients with chronic Hepatitis B or C; 52% in the placebo group and 36% in the baclofen group. These patients were only included in the study if they ALSO had alcohol dependence and the large alcohol intake required by inclusion criteria.
The results were striking with 71% (30/42) of the baclofen group achieving total abstinence compared to 29% (12/42) of the placebo group. The careful clinical and biochemical surveillance demonstrated that there was no deterioration in the baclofen group, confirming its safety in this group. This is of particular importance because the other treatments for alcohol dependence, acamprosate, naltrexone and disulfiram all have some level of restriction of use in patients with liver disease and this severely limits the treatment options for patients with cirrhosis.
The 2010 study by American researcher James Garbutt appeared to contradict the results of the Addolorato studies, showing no difference in effect of baclofen on drinking patterns and this has contributed to the perception that baclofen is not effective, especially in the USA.
However Garbutt studied a very different cohort of subjects compared to the European studies and this explains why the results are so different. The participants were recruited via TV and radio advertisements rather than presentation to medical facilities for treatment. Over half of Garbutt’s subjects had never previously tried any treatment for their alcohol issues. Importantly, only 19/80 (24%) had abstinence as a goal with the other 76% seeking to continue drinking at some level. They had alcohol problems at the low end of the range of severity: subjects’ average daily alcohol intake was around half of the 2002 Addolorato study and their alcohol dependence was relatively mild on Alcohol Dependency Scale (ADS). There was a also a high drop out rate from the study medication: only 54% (43/80) of subjects finished the 3 month medication regime as prescribed. The targets set were modest with abstinence being measured in one day “units” rather than a continuous state. There was also a relatively intense psychosocial support program of 8 x 30 minute sessions of BRENDA with a trained therapist. The primary outcome measure was only a reduction in heavy drinking days.
The act of volunteering to participate in the study and the program itself was quite effective, irrespective of medication. Heavy drinking days dropped from an average of 70% of days to 25% of days and abstinent days rose from average of 12% of days to 50% of days. The confidence intervals for all these averages was large, all of the order of +/- 25% which suggests that there was wide individual difference within the groups.
What is not presented is any idea of how many participants reached their goal (abstinence, occasional drinking or reduced drinking), how many participants reached safe levels of drinking or whether these gains were sustained after the interventions of the program ceased eg 3-6 months later. It’s not clear if the program produced any lasting changes in drinking behaviour because that’s what is required to change health outcomes.
Importantly the results of Garbutt’s study cannot be extrapolated to suggest that baclofen has no benefit in alcoholism, especially for the more severely alcohol dependent patients who have failed detox/rehab programs, often repeatedly. These patients need pharmacological therapy to achieve control but the other options like acamprosate only improve abstinence rates by 10% over placebo.
The 2012 study by Renaud de Beaurepaire was the first to use the Ameisen regime of titrated baclofen rather than a fixed dose regime. It was also the first to allow patients to drink as usual from the start of treatment with no requirement for detox, reduction or cessation of alcohol. It tested the ability of baclofen to change the drinking pattern. Patients had no treatment other than baclofen – no rehabilitation program (in- or outpatient) and no concomitant psychosocial therapy program.
De Beaurepaire’s study also had an unusually long follow up period of 2 years, which allowed the long term stability of baclofen treated patients to be studied.
The study was observational rather than placebo controlled. The “control” was the previous history of the patient –all were long term, heavy, daily drinkers who had failed other treatments. The ability to use a placebo controlled group was limited because these individuals sought Dr de Beaurepaire’s care specifically for baclofen treatment, not to participate in a clinical trial in which half the cohort would receive a placebo. But an observational study meant that patients could be followed for much longer than the usual 3-6 month duration of most clinical trials. This study therefore looked at whether baclofen treatment could produce the “holy grail”, a durable change in alcohol intake measured in years rather than months.
The results of de Beaurepaire’s study were remarkable, with 50% of patients achieving and maintaining a low risk pattern of drinking – sobriety or drinking within safe limits- for 2 years. It is especially notable given this treatment resistant cohort was managed with no detox, no restrictions on drinking as desired, no other treatment modality and had an unusually long period of follow up.
It was observed that 92% of patients had a noticeable decrease in cravings but only 50% achieved the desired effortless control over their alcohol use. This reflects my experience with baclofen treatment. Almost all will feel a decrease in cravings if they stick with treatment long enough to titrate up to an effective dose. Some patients drift out of treatment quickly and others continue to drink despite a marked effect on their cravings. This is further discussed in the section “Why does baclofen fail in some patients?”
The BACLAD study (link) was published in 2015 and answered the criticism that there were no randomised, placebo controlled trials of baclofen titrated to individualised doses as per Ameisen’s regime. BACLAD was a small study of only 43 subjects but had rigorous methodology and allowed baclofen doses up to 270mg/day via a titration phase of up to 4 weeks, a 12 week period on the patients’ individualised dose (the “high dose” phase) and a tapering phase of up to 4 weeks to take the patient off the baclofen completely. The patients were asked to be alcohol free for 7-21 days prior to entering the study (although this was not always enforced) and had a standardised supportive therapy program. The average mean dose of baclofen was 180mg/day in the baclofen treated group.
The percentage of patients maintaining total abstinence during the 12 week high dose phase in the two groups was starkly different. It was achieved in 68.2% of baclofen treated patients but only 23.8% of placebo treated patients.
The large clinical trials of baclofen for alcoholism have been a long time coming. There have been calls to undertaken large scale clinical trials of baclofen in alcoholism for nearly 15 years now.
Clinical research on medications is very expensive and usually financed by pharmaceutical companies for their patented medications. The aim is to gather the data needed for approval and marketing purposes, so the medication can be sold. Because baclofen is no longer under patent, the time taken to acquire the money for large studies took many years. The long wait for large clinical trials is almost over and their results are eagerly awaited.
On September 3rd 2016, the results of three large European studies of baclofen in alcoholism will be announced at the World Congress on Alcohol and Alcoholism in Berlin World Congress for Alcohol and Alcoholism in Berlin on September 3rd 2016.
Here’s a brief description of these clinical trials:
Bacloville is a French multi-centre double blind RCT, placebo vs baclofen of 323 participants receiving individually titrated doses of medication up to 300mg/day in the general practice setting for a one year period. The treatment is entirely ambulatory with no preceding detox or abstinence. This study is rigorously practical being the closest to normal clinical practice and the classic Ameisen regime.
Alpadir is also a French multi-centre double bind, placebo controlled RCT of approximately 316 patient which has been undertaken by the pharmaceutical company Ethypharm, which hopes to market a high dose (60mg) baclofen tablet. The study has taken place in hospital outpatient settings with a pre-requisite of abstinence for 3-14 days prior to starting treatment. The baclofen is titrated to a target dose of 180mg/day (60mg tds) over 7 weeks with maintenance at this dose for 17 weeks followed by tapering off to cessation over 2 weeks.
A Dutch study will also be presented: Efficacy and safety of low dose and high-dose baclofen for the treatment of alcohol dependence in the Dutch multi-centre, randomised, double-blind controlled trial.
Information from the European clinical trials website suggests that it is likely to be a double bind, placebo controlled RCT of 250 patients treated with baclofen at 30-150mg/day for 18 weeks after a 4-21 day period of abstinence from alcohol.
The results presented in Berlin will be posted on the News section of the website once released.