What is baclofen?

Baclofen is a medication originally developed in 1962 by a German pharmaceutical company Ciba Geigy as a treatment for epilepsy in children.

When baclofen was tested on patients, it actually wasn’t very effective for epilepsy.

However the researchers noticed another effect of baclofen. Some of these epileptic patients had brain or spinal cord problems which caused their muscles to be tight or go into spasm – a problem called spasticity. Baclofen had the unexpected effect of relaxing these painful muscle spasms, making the patients much more comfortable. At the time, the only other medication for this problem was diazepam (Valium) which made patients very sleepy. However baclofen could relax muscles without nearly as much drowsiness so was a much better treatment than diazepam. So Ciba Geigy decided to market baclofen for this use instead.

Baclofen was released for sale in 1974 and since then has been used in millions of patients with spinal cord injuries, multiple sclerosis and strokes. The patients put on baclofen treatment would usually take it for the rest of their life so we have over 40 years of experience with baclofen and know a lot about it. We know it is a safe medication which can be taken for decades without harmful effects. We know that it needs to be started and stopped gradually or patients feel awful. We also know that baclofen’s effects only last around 3-4 hours so it’s normally taken three times a day.

Because baclofen has been in use for 40 years, it is no longer protected by a drug patent so can be manufactured and sold by any pharmaceutical company. This means that there are many cheap generic brands of baclofen and the price is low at around 20 cents per tablet.

How does baclofen work?

There are two aspects to this question covered by this section.

  • The first is the basic neurochemistry of baclofen – a GABA B receptor agonist.
  • The second looks at what we currently know about how baclofen acts on addiction.

Basic neurochemistry- the role of GABA

The best description of baclofen and GABA which I have found is Annexe 4 of the book “Verité et Mensonges sur le baclofène” by Dr Renaud de Beaurepaire. Here is my translation into english which is presented here with the generous permission of  Dr de Beaurepaire.

Baclofen acts on a receptor present in the brain, the receptor GABA-B. A receptor is a site of fixation for a molecule, whatever it is – a medication, a neurotransmitter or alcohol. Alcohol for example binds to certain receptors in the brain. GABA is a neurotransmitter present in large amounts in the brain and it binds to two specific receptors, GABA-A and GABA-B.

What is the link between the binding of baclofen to the GABA-B receptor and it’s therapeutic effect on alcoholism? The truth is that we don’t know. The link between GABA-B and alcoholism is a complete mystery. That baclofen works for alcoholism is not explained at all by the classic and current hypotheses about alcoholism and its treatment. Other hypotheses must therefore be considered.

For those who are interested, we will further discuss baclofen and its action in the brain in the following paragraphs.

  • Where did baclofen come from?
  • What is the GABA-B receptor?
  • What is the action of alcohol on the GABA-B receptor?
  • What action does alcohol have on other receptors?
  • What role does dopamine play in addictions?
  • How do addictions become established in the brain?
  • What are the hypotheses on how baclofen acts in the brain?
  • What we have learnt from treating alcoholic patients with baclofen?
  • How the GABA-B receptor is activated by baclofen?

Where did baclofen come from?

Baclofen is a molecule which was first synthesised in 1962. The intention of the researchers who synthesised it was to make a molecule which resembled GABA (gamma aminobutyric acid), but entered the brain more easily. GABA is a neurotransmitter present in very large amounts in the brain. Around 40% of the receptors in the brain are GABA receptors, which is enormous given that there are around 100 million neurons in the brain and each neuron has many thousands of receptors on its surface. GABA is critical in many physiological processes, in particular in the control of motor neurons in the spinal cord. People with spinal cord damage often have spastic movements, muscle spasms due to lesions of motor neurons. It has been established experimentally that increasing GABA concentrations around the motor neurons in the spinal cord decreases the muscle spasms. But GABA itself administered to patients as medication doesn’t get into the spinal cord. It’s for that reason that baclofen was synthesised; it is similar in structure to GABA but penetrates better into the spinal cord because it passes the blood:brain barrier. From 1967 it was known that baclofen was a good treatment for muscle spasms in patients with spinal cord lesions. Later it was realised that baclofen acts specifically on a subtype of GABA receptors, the GABA B receptor.

What is the GABA B receptor?

GABA, gamma aminobutyric acid, binds to two types of receptors, GABA-A and GABA-B (there is also a GABA-C receptor but it is less important). These two types of receptors are different in their structure and properties, but they are both inhibitory receptors, blocking the actions of the neurons they bind to.

The GABA-A receptor is very well known; its structure was elucidated in 1988 by cloning. It’s the receptor on which benzodiazepines and barbiturates act. It is also the site where alcohol acts, the GABA-A receptor being one of the most important targets of alcohol in the brain. But the GABA-B receptor is very different from the GABA-A receptor. It’s an extremely complex receptor, the structure of which was very difficult for researchers to identify. It was cloned only in 1997. It’s actually a double receptor, with long intertwined, entangled and spiral proteins. Even today we don’t understand how it functions.

The action of alcohol on the GABA-B receptor:

Alcohol does not appear to act on the GABA-B receptors. Or if it acts on them, it’s indirectly, perhaps via calcium channels or via interactions with other neurotransmitters. There is no known direct action of alcohol on GABA-B receptors. On the other hand we don’t yet have a good grasp of the GABA-B receptor’s function.

This is extremely important because if alcohol was shown to act directly or indirectly on the GABA-B receptor, one could postulate that baclofen is perhaps a treatment of substitution for alcohol. If not, it couldn’t be or we need to redefine “substitution”.

The action of alcohol on other receptors:

Alcohol has many targets in the brain, the first being, as we have seen, the GABA-A receptor. But alcohol also acts on the 5HT3 serotonergic receptors, glutamate receptors, calcium and potassium channels, endogenous cannabinoid receptors, opiate receptors, on G protein receptors, protein kinase receptors etc. Most importantly, alcohol acts indirectly (via many channels) on the dopaminergic neurons, those which synthesise the neurotransmitter dopamine.

The role of dopamine in addictions:

Dopamine is a neurotransmitter which acts on dopaminergic receptors. The dopaminergic system in the brain consists of a tiny group of neurons, only a couple of thousand in total. It is of immense functional importance – it controls the experiences of pleasure – the pleasure of existing, of learning, of experiences and repeating the experiences which bring pleasure. It therefore has a central role in psychological functioning. This system is found even in the most primitive of species, providing stimulus in life. Taking drugs is simply using an external stimulator of pleasure to provide sensations which would normally be elicited endogenously, by the pleasures of everyday life. All drugs, including alcohol, activate this system, which plays a central role in the biology of addiction.

What do we know about the creation of an addiction in the brain?

Addictions to drugs such as alcohol take hold progressively, in three stages. The first stage is the first experiences of the drug where its use is festive and feels liberating. The dopaminergic systems are critically important in this phase: the person is at liberty to stop at any time. The second phase is one of transition towards dependence. The need to take the drug becomes more insistent and the dose needed increases. The person is no longer as capable of stopping taking the drug if desired. Neurobiologically, the activity of the dopaminergic systems changes toward another way of acting and other systems in the brain become important. These are the systems involved in the memories of pleasurable experiences which form a link between the experience of pleasure itself and the pursuit to procure the drug. The systems which form these memories are found in another area of the brain called the limbic system.

In the third phase of addiction, the pursuit of the drug becomes a compulsion and the person loses any possibility of avoiding the need to procure the drug and is thereby rendered a slave to it. Neurobiologically, this corresponds to a set of marked changes in the brain in a region called the dorsal striatum which plays a central role in the compulsion to repeat behaviours. Now the dependence is a true biological illness. The addiction is no longer a pleasure but a source of suffering.

The hypothesis on the way baclofen acts in the brain:

Baclofen treatment produces a state of indifference towards alcohol. This is obtained by progressively increasing the dose until the indifference appears. There is therefore the concept of a threshold, meaning that above a certain level of activation of the GABA B receptors, the systems involved in addiction are inactivated. These systems may be the dopaminergic systems which we think are responsible for cravings but also the memory setting actions of the limbic system which we think are responsible for the link between an environmental stimulus, eg seeing a bottle of alcohol, and the desire to drink. There are also the systems involved in the compulsion to drink situated in the dorsal striatum. We don’t yet understand the links between GABA B receptors and the suppression of craving, indifference to alcohol and the suppression of compulsions.

What have we learned from the clinical use of baclofen in alcoholism?

We don’t generally ask patients treated with baclofen to stop drinking when they start the treatment. This means that amongst those patients who respond well to baclofen, the cessation of alcohol intake happens when they become indifferent to alcohol. But I’ve never seen these patients go into alcohol withdrawal ie they don’t have the symptoms normally seen with rapid cessation (anxiety, tremors, sweats, feeling unwell). This might mean that baclofen protects against the alcohol withdrawal syndrome. Under this hypothesis, baclofen would have some similar effects to alcohol in the brain which prevents the symptoms of withdrawal. There are also similarities between abrupt cessation of alcohol (delirium tremens) and some cases of abrupt cessation of high dose baclofen. In both cases, there may be seizures, confusion and hallucinations. This also supports the idea of a common mechanism of baclofen and alcohol and therefore the hypothesis that baclofen is a treatment of substitution.

The activation of the GABA B receptor by baclofen.

Baclofen is a selective agonist of the GABA B receptor ie it activates this receptor but is not known to have any action on any other type of receptor. The GABA B receptor is very complex and is involved in many physiological processes. Baclofen appears to have an effect in alcohol addiction (and other addictions) but also many effects other than causing indifference to alcohol. Baclofen has also been shown to have anti-anxiety effects, analgesic effects (facial neuralgias, diabetic neuropathy, some types of migraine), appetite suppressant effects and some anticancer effects. It has been successfully used in the treatment of gastro-oesophageal reflux. Baclofen also has many side effects, as we have seen. Knowing that baclofen acts specifically via the GABA B receptors, this means that these receptors are involved in all these effects. The GABA B receptor is very complex and made up of numerous proteins. One could reasonably hope to find molecules which act specifically on certain binding sites on the GABA B receptor and which would have more selective effects. The search for such molecules is underway and one could hope, for example, that they will have a selective effect on alcohol intake without side effects.

This is the end of Annexe 4 of the book “Verité et Mensonges sur le baclofène” by Dr Renaud de Beaurepaire.

Baclofen and addiction pathways:

Some fascinating clues as to how baclofen acts to help addicted patients can be found in a 2014 paper entitled:
Nipping Cue Reactivity in the Bud: Baclofen Prevents Limbic Activation Elicited by Subliminal Drug Cues. Young, KA et al: The Journal of Neuroscience, April 2, 2014 • 34(14):5038 –5043.

Now “Nipping Cue Reactivity in the Bud: Baclofen Prevents Limbic Activation Elicited by Subliminal Drug Cues” doesn’t sound very exciting from the title alone but stay with me here.

Baclofen is known to reduce cravings for alcohol but also for cocaine. That’s an interesting mix of addictive substances because they are not similar at all, either chemically or in the effect sought from taking them.

The USA has a big cocaine problem, especially from cheap “crack” cocaine and this study from the US looked at cocaine addicts. They took 23 active cocaine addicts and put them into a closed facility where they could not use any drugs. They started half the subjects on baclofen and half on placebo and titrated the medications up over 7 days until the baclofen subjects were on a daily dose of 60mg. The subjects then each had a functional MRI of their brain.

Functional MRI allows the researcher to deliver some type of stimulus to the subject and then see on the MRI scan which parts of the brain are activated in response.

In this study, the stimulus was visual, a specially concocted sequence of images which the patient watched during the MRI scan. The researchers were interested in seeing which parts of the brain reacted to “drug cues”. These are images around cocaine use which might stimulate the desire to use cocaine – images of crack cocaine crystals, crack pipes or people dealing or using cocaine.

But there were a couple of tricks in there: the cocaine images were slotted into a sequence of other images over an 8 minute period. Some were neutral like pleasant scenery and some stimulating such as erotic images or horrific images like mutilated bodies which the brain would respond strongly to. The researchers were looking to see which brain responses were specific to the cocaine images, the “drug cues”.

The other trick was that all the stimulating images were shown very briefly, for only half a second each. With this brief exposure, the brain can perceive the image but doesn’t have time to process it or bring it into conscious thought – it’s a subliminal image. This means that the “raw”, unfiltered response of the brain can be seen on the MRI image.

The study participants who were given the placebo medication showed us how the brains of cocaine addicts normally respond to cocaine stimuli such as a picture of crack cocaine crystals. On the MRI scans, their brains showed strong activation of an area crucial in producing drug cravings, the mesolimbic dopaminergic pathway. So just a half second exposure to a cocaine image was enough to flood the brain with cravings. The brain has literally been hijacked so fast that the addict has not even consciously registered what they’ve seen nor had time to think about it. When addicted people say they find themselves using the substance “before I can even think about it”, they are absolutely correct. This explains why cognitive techniques go out the window in the presence of drug cues.

However in the baclofen treated group the MRI scans were very different – these participants showed a dramatically reduced response to cocaine images. The baclofen subdued the craving centre, the mesolimbic dopaminergic pathway. The cravings don’t scream at them anymore; it’s more like a suggestion. The thinking part of the brain has the opportunity to step in and put logic, forward thinking and planning into place and make a decision to not use cocaine. The battle to resist the drug of addiction is much easier to fight.

And that is what my alcoholic patients describe happening when they are on baclofen. They describe a “distance” between feeling cravings and acting on them, that they could think and reason with themselves instead of caving into the cravings. They also found that the baclofen allowed them to successfully use techniques like deep breathing and mindfulness to push past cravings. They had been taught them in the past but couldn’t get them to work when cravings were severe. Now these techniques did work and helped them. The battle was now “winnable”.

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