The new baclofen for alcoholism treatment studies were unveiled on Saturday 3rd September 2016 in Berlin at the World Congress for Alcohol and Alcoholism. It was a packed session as this was the most interesting news of the Congress.
At the Congress overall, there were a lot of rather obscure studies in animals and humans and studies observing patterns of alcohol use in various groups.
Here are some examples:
1. Investigating the role of one-carbon metabolism pathway in complicated alcohol withdrawal states.
2. SIAH1 mediates ethanol-induced apoptosis in neural crest cells by CBP/p300-mediated acetylation of P53.
It was as if the Congress participants were blind to a simple truth: the only useful way to treat alcohol related disease is to assist people to reduce or stop their excessive alcohol intake. The rest is just decoration. There was a lot of decoration at this Congress.
The baclofen session presented data from four studies:
1. BACLAD – this was published in 2015 and they had no new patient data to present. Their study was rigorously controlled (double blind, placebo controlled) and used individually titrated baclofen up to a maximum of 270mg/day with a three month study phase with success defined as complete abstinence for the whole three months. They had found 68.2% success in baclofen treated patients vs 23.8% in the placebo group, a whopping 44% improvement. The main problem with the BACLAD study was its small size, with only 43 patients in total.
At the Congress, they presented some MRI data done on the patient group but no data on any further patients.
2. Bacloville.-
Basically the results were: 56.8% of patients taking baclofen vs 36.5% of the placebo group achieved WHO criteria safe drinking levels measured in the last month of the 12 month study period.
Bacloville was the best of the studies by far: 60 general practices, 320 patients, all patients taken with no exclusions for psychiatric problems, psychotropic medications, or other types of substance abuse like opiates, THC or amphetamines. In fact they had their 320 patients after initial review of 323 patients proposed for the study: they excluded only three who were simply too close to death to go into a 12 month study.
This is very different from all the other studies. I found it hard to believe that the other studies could recruit ANY patients because they excluded anyone with really any problem (medical, psychiatric, other substance abuse) and this made their patient populations very atypical. But Bacloville steadfastly kept to a real life situation and accepted anyone with significant alcohol dependence.
As a result, Bacloville had a patient population with an elevated alcohol intake – it averaged 13 standard drinks per day (against WHO safe levels >2 for woman and >4 for men) so these are serious punters.
Bacloville was very different from the others in that it was done entirely in a General Practice setting with no detox or rehabilitation (inpatient or outpatient), no requirement to stop drinking or aim for abstinence and no prescribed psychosocial program. The baclofen was individually titrated to each patient’s needs with a maximum dose set at 300mg/day.
The primary outcome measured was simple: the % of patients who achieved WHO defined safe drinking levels (>2/day for woman and >4/day for men) in the last month of the 12 month study period. Result: 56.8% in patients taking baclofen vs 36.5% in the placebo group, an improvement of 20.3%
The Bacloville study only presented this primary outcome at the congress. The reason for this was the data was only unblinded (as to who got baclofen and who got placebo) 3 weeks ago so they did not have much time to pull out results. There are many other secondary outcomes that will be calculated for an upcoming research paper for publication. This will be very interesting as it will break down the data in more detail.
The 20.3% difference does not seem like a lot but you have to understand the details of the study to see why this is ok. The study used rigorous methodology that included strict “Intention to Treat”. What this means is that once a patient was entered into the Bacloville study, their outcome was counted, no exceptions. If the patient signed up for the study at a first visit and never came back, or stopped their study treatment after 3 weeks or died, they would be counted as a treatment failure even if it had nothing to do with baclofen treatment or the study.
This means that the baclofen failure group will include people who were not taking baclofen in the last month of the study when the outcome was measured and even people who had died months before. This is good methodology because it stops data being manipulated to improve results by excluding unfavourable patients but it does reduce the positive results, especially when the study period is long, in this case 12 months.
While initially I was disappointed that the difference was relatively small, on reflection I realized that it was what I should have expected. Of course what I really wanted to see was a big success rate in the baclofen group of 70-90% but this would be completely unrealistic given the “real life” conditions of the study. All baclofen prescribers know that if you take “all comers”, a reasonable proportion will simply drift away from baclofen treatment. It’s not that baclofen is not effective but the pain of being sober is not worthwhile for many patients whose lives have been decimated by alcohol.
There was a disarming simplicity and honesty about the Bacloville study.
Bacloville showed firstly that just having a GP 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 – this could be abstinence or low level drinking. That’s going to change their health and life expectancy a lot.
That’s pretty damn remarkable – alcohol dependence is considered to be largely untreatable. Not anymore.
And it’s not as if these GPs were specialised in this area although they are clearly motivated to use baclofen by agreeing to participate in the study. Each GP was only treating small numbers of patients – an average of 5.5 patients each. There are estimated to be around 10,000 baclofen treating GPs in France with most having only a couple of patients on baclofen.
The Bacloville study was a slap in the face for the many Addiction specialists present because it showed GPs treating a severe group of alcoholics and doing better than the other two new studies (shown below) which were done in specialized Addiction Services, one with less severely dependent patients.
I’m hoping that the secondary analysis of the Bacloville data includes looking at the patients who continued to see their GP took the medication for the whole treatment period of 12 months. I would expect more difference between these baclofen and placebo groups but, of course, only the data can tell us the truth!
So after some reflection, I think that the results of Bacloville are spot on. Not extraordinary because there is so much complexity in these patients and the cohort studied was severely affected by alcohol – multiple patients died from alcohol related illness in both the baclofen and placebo groups during the study. Someone from the audience questioned this as a dangerous effect of baclofen, even though it happened in the placebo group in equal numbers. The presenter, Prof Philippe Jaury, just shrugged his shoulders in a very french way and said “these were very ill people”. That’s right. Alcoholism causes a lot of premature death.
You can hear Prof Jaury’s actual Berlin talk on an MP3 recording (link) and see the slides (link).
The other two baclofen studies were negative in that there was no difference baclofen vs placebo. But the study designs were of such complexity with so many restrictions and such restrictive outcomes that they were always going to have problems.
The contrast between them and the simplicity of Bacloville was striking.
3. The Aldapir study was funded by the French pharmaceutical company Ethypharm which hopes to market higher dose baclofen tablets in France and thinks they can make a profit by charging a premium price for the convenience. At present only 10mg tablets are available in France and this means handfuls of pills are needed for patients taking high doses of baclofen.
Aldapir was done in a couple of French specialist alcohol treatment clinics as outpatients with a total study group of 316 patients. Despite this specialist setting, they had mild alcoholics overall, averaging 9.5 standard drinks/day (vs average 13/day for Bacloville). In the baclofen group, 13.5% had WHO safe levels of drinking as were 15.5% of the placebo group which is complete nonsense! Why would they be in a treatment trial? The presenter had trouble explaining why this was. In addition, 18.1% of the baclofen group and 14.2% of the placebo group were drinking at moderate risk levels. Only 70% of their patients were drinking at high or very high risk levels.
The reason they ended up with this skewed group is that their list of exclusions was monumental including any psychiatric illness or needing any “heavy” psychological or psychiatric support, any psychiatric medications apart from stable antidepressants.
At the Congress overall, there were a lot of rather obscure studies in animals and humans and studies observing patterns of alcohol use in various groups.
Here are some examples:
1. Investigating the role of one-carbon metabolism pathway in complicated alcohol withdrawal states.
2. SIAH1 mediates ethanol-induced apoptosis in neural crest cells by CBP/p300-mediated acetylation of P53.
It was as if the Congress participants were blind to a simple truth: the only useful way to treat alcohol related disease is to assist people to reduce or stop their excessive alcohol intake. The rest is just decoration. There was a lot of decoration at this Congress.
The baclofen session presented data from four studies:
1. BACLAD – this was published in 2015 and they had no new patient data to present. Their study was rigorously controlled (double blind, placebo controlled) and used individually titrated baclofen up to a maximum of 270mg/day with a three month study phase with success defined as complete abstinence for the whole three months. They had found 68.2% success in baclofen treated patients vs 23.8% in the placebo group, a whopping 44% improvement. The main problem with the BACLAD study was its small size, with only 43 patients in total.
At the Congress, they presented some MRI data done on the patient group but no data on any further patients.
2. Bacloville.-
Basically the results were: 56.8% of patients taking baclofen vs 36.5% of the placebo group achieved WHO criteria safe drinking levels measured in the last month of the 12 month study period.
Bacloville was the best of the studies by far: 60 general practices, 320 patients, all patients taken with no exclusions for psychiatric problems, psychotropic medications, or other types of substance abuse like opiates, THC or amphetamines. In fact they had their 320 patients after initial review of 323 patients proposed for the study: they excluded only three who were simply too close to death to go into a 12 month study.
This is very different from all the other studies. I found it hard to believe that the other studies could recruit ANY patients because they excluded anyone with really any problem (medical, psychiatric, other substance abuse) and this made their patient populations very atypical. But Bacloville steadfastly kept to a real life situation and accepted anyone with significant alcohol dependence.
As a result, Bacloville had a patient population with an elevated alcohol intake – it averaged 13 standard drinks per day (against WHO safe levels >2 for woman and >4 for men) so these are serious punters.
Bacloville was very different from the others in that it was done entirely in a General Practice setting with no detox or rehabilitation (inpatient or outpatient), no requirement to stop drinking or aim for abstinence and no prescribed psychosocial program. The baclofen was individually titrated to each patient’s needs with a maximum dose set at 300mg/day.
The primary outcome measured was simple: the % of patients who achieved WHO defined safe drinking levels (>2/day for woman and >4/day for men) in the last month of the 12 month study period. Result: 56.8% in patients taking baclofen vs 36.5% in the placebo group, an improvement of 20.3%
The Bacloville study only presented this primary outcome at the congress. The reason for this was the data was only unblinded (as to who got baclofen and who got placebo) 3 weeks ago so they did not have much time to pull out results. There are many other secondary outcomes that will be calculated for an upcoming research paper for publication. This will be very interesting as it will break down the data in more detail.
The 20.3% difference does not seem like a lot but you have to understand the details of the study to see why this is ok. The study used rigorous methodology that included strict “Intention to Treat”. What this means is that once a patient was entered into the Bacloville study, their outcome was counted, no exceptions. If the patient signed up for the study at a first visit and never came back, or stopped their study treatment after 3 weeks or died, they would be counted as a treatment failure even if it had nothing to do with baclofen treatment or the study.
This means that the baclofen failure group will include people who were not taking baclofen in the last month of the study when the outcome was measured and even people who had died months before. This is good methodology because it stops data being manipulated to improve results by excluding unfavourable patients but it does reduce the positive results, especially when the study period is long, in this case 12 months.
While initially I was disappointed that the difference was relatively small, on reflection I realized that it was what I should have expected. Of course what I really wanted to see was a big success rate in the baclofen group of 70-90% but this would be completely unrealistic given the “real life” conditions of the study. All baclofen prescribers know that if you take “all comers”, a reasonable proportion will simply drift away from baclofen treatment. It’s not that baclofen is not effective but the pain of being sober is not worthwhile for many patients whose lives have been decimated by alcohol.
There was a disarming simplicity and honesty about the Bacloville study.
Bacloville showed firstly that just having a GP 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 – this could be abstinence or low level drinking. That’s going to change their health and life expectancy a lot.
That’s pretty damn remarkable – alcohol dependence is considered to be largely untreatable. Not anymore.
And it’s not as if these GPs were specialised in this area although they are clearly motivated to use baclofen by agreeing to participate in the study. Each GP was only treating small numbers of patients – an average of 5.5 patients each. There are estimated to be around 10,000 baclofen treating GPs in France with most having only a couple of patients on baclofen.
The Bacloville study was a slap in the face for the many Addiction specialists present because it showed GPs treating a severe group of alcoholics and doing better than the other two new studies (shown below) which were done in specialized Addiction Services, one with less severely dependent patients.
I’m hoping that the secondary analysis of the Bacloville data includes looking at the patients who continued to see their GP took the medication for the whole treatment period of 12 months. I would expect more difference between these baclofen and placebo groups but, of course, only the data can tell us the truth!
So after some reflection, I think that the results of Bacloville are spot on. Not extraordinary because there is so much complexity in these patients and the cohort studied was severely affected by alcohol – multiple patients died from alcohol related illness in both the baclofen and placebo groups during the study. Someone from the audience questioned this as a dangerous effect of baclofen, even though it happened in the placebo group in equal numbers. The presenter, Prof Philippe Jaury, just shrugged his shoulders in a very french way and said “these were very ill people”. That’s right. Alcoholism causes a lot of premature death.
You can hear Prof Jaury’s actual Berlin talk on an MP3 recording (link) and see the slides (link).
The other two baclofen studies were negative in that there was no difference baclofen vs placebo. But the study designs were of such complexity with so many restrictions and such restrictive outcomes that they were always going to have problems.
The contrast between them and the simplicity of Bacloville was striking.
3. The Aldapir study was funded by the French pharmaceutical company Ethypharm which hopes to market higher dose baclofen tablets in France and thinks they can make a profit by charging a premium price for the convenience. At present only 10mg tablets are available in France and this means handfuls of pills are needed for patients taking high doses of baclofen.
Aldapir was done in a couple of French specialist alcohol treatment clinics as outpatients with a total study group of 316 patients. Despite this specialist setting, they had mild alcoholics overall, averaging 9.5 standard drinks/day (vs average 13/day for Bacloville). In the baclofen group, 13.5% had WHO safe levels of drinking as were 15.5% of the placebo group which is complete nonsense! Why would they be in a treatment trial? The presenter had trouble explaining why this was. In addition, 18.1% of the baclofen group and 14.2% of the placebo group were drinking at moderate risk levels. Only 70% of their patients were drinking at high or very high risk levels.
The reason they ended up with this skewed group is that their list of exclusions was monumental including any psychiatric illness or needing any “heavy” psychological or psychiatric support, any psychiatric medications apart from stable antidepressants.
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