Preclinical and clinical findings clearly indicate a key role of the GABAB receptor in depression and anxiety disorders (21, 22). It has been suggested that the presence of a psychiatric comorbidity may be amongst the abovementioned factors playing a role in explaining different responses to baclofen treatment, in terms of alcohol drinking outcomes. Another frequent condition in clinical practice is the presence of comorbid mental disorders such as substance use disorder, mood disorder, and/or anxiety disorder, especially among patients with more severe AUD (14). The presence of a psychiatric comorbidity may be amongst the abovementioned factors playing a role in explaining different responses to baclofen treatment in terms of alcohol drinking outcomes. The GABA(B) receptor agonists baclofen and CGP prevent acquisition of alcohol drinking behaviour in alcohol-preferring rats.
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The severity of baclofen withdrawal depends on the rate at which it is discontinued. Adverse effects include drowsiness, dizziness, weakness, fatigue, headache, trouble sleeping, nausea and vomiting, poor concentration and recall (resembling dementia), urinary retention, or constipation. Baclofen is also used in the treatment of sleep-related painful erections.
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Gamma-hydroxybutyrate (GHB), a medication used in the treatment of AUD that activates GABA-B receptors, has been shown to markedly alter functional connectivity in healthy volunteers (109). The literature dealing with the effects of pharmacological treatments for AUD on brain connectivity is scarce. Therefore, inactivation of localized parts of the reward network may globally inhibit craving or compulsive drinking. Preclinical models have demonstrated that a direct inactivation of some of these structures can suppress craving or the reinstatement of drinking. The different components of the progressive set-up of the compulsive drinking behavior involve neural substrates that belong to the dopaminergic reward network. The concept of indifference is not a scientific concept, while those of craving and compulsive drinking are such concepts.
GABA(B) receptor baclofen addiction potential activation triggers BDNF release and promotes the maturation of GABAergic synapses. Distinctive roles for amygdalar CREB in reconsolidation and extinction of fear memory. Brain imaging biomarkers to predict relapse in alcohol addiction.
Retrospective Studies
Ovarian cysts have been found by palpation in about 4% of the multiple sclerosis patients that were treated with baclofen for up to one year. A dose-related increase in incidence of ovarian cysts and a less marked increase in enlarged and/or hemorrhagic adrenal glands was observed in female rats treated chronically with baclofen. In mice, no teratogenic effects were observed, although reductions in mean fetal weight with consequent delays in skeletal ossification were present when dams were given 17 and 34 times the human daily dose. Baclofen tablets, USP are not indicated in the treatment of skeletal muscle spasm resulting from rheumatic disorders.
Addiction Treatment Therapies
In the present paper, the biological effects of baclofen are reviewed in the light of its clinical effects, assuming that, in many instances, clinical effects can be reliable indicators of underlying biological processes. All these systems and functions are possibly involved in the anti-addictive effects of baclofen. In the present article, the biological effects of baclofen are reviewed in the light of its clinical effects in AUD, assuming that, in many instances, clinical effects can be reliable indicators of underlying biological processes. GABA-B receptors interact with many biological systems potentially involved in AUD, including transduction pathways and neurotransmitter systems. Baclofen, a GABA-B receptor agonist, is a promising treatment for alcohol use disorder (AUD). In patients with epilepsy, the clinical state and electroencephalogram should be monitored at regular intervals, since deterioration in seizure control and EEG have been reported occasionally in patients taking baclofen.
- Therefore, inactivation of localized parts of the reward network may globally inhibit craving or compulsive drinking.
- However, dopamine antagonists have never shown effectiveness in the treatment of AUD (42).
- Theses symptoms may be explained by an action of baclofen on GABA-B receptors in the brainstem and hypothalamus, which are among the structures most strongly activated by baclofen, and which control basic states of vigilance (in particular through the suprachiasmatic nucleus).
- In large quantities, baclofen can lead to pleasurable feelings similar to those created by drinking alcohol, which is why it can be addicting.
What may interact with this medication?
These medicines can include prescription pain medicines, sleep medicines, and anxiety medicines. It is best to limit the amount of alcohol that you drink. There are no known interactions between baclofen and foods or drinks. Your healthcare provider will advise you if you should use baclofen while breastfeeding.
What side effects may I notice from receiving this medication?
Similarly to phenibut (β-phenyl-GABA), as well as pregabalin (β-isobutyl-GABA), which are close analogues of baclofen, baclofen (β-(4-chlorophenyl)-GABA) has been found to block α2δ subunit-containing voltage-gated calcium channels (VGCCs). Baclofen produces its effects by selectively activating the GABAB receptor. It is believed to work by activating (or agonizing) GABA receptors, specifically the GABAB receptors. Overdose may require intubation and length of mechanical ventilation required may correlate with serum baclofen levels shortly after ingestion. These effects are likely mediated not by activation of the GABAB receptor, but rather by activation of the GHB receptor. Thus to minimise withdrawal symptoms, the dose should be tapered down slowly when discontinuing baclofen therapy.
These side effects may vary depending on the condition that is being treated. Other baclofen liquids should be stored in a refrigerator between 36 F to 46 F (2 C to 8 C). Various forms of baclofen are available. Talk with your healthcare provider if you have trouble taking baclofen or if you feel the medicine is not working very well.
Clinical experience also shows that when the effective dose is reached—the threshold dose producing a state of indifference—the treatment has to be continued for several months at the same dose before it can be reduced. This could be in accordance with studies that show that higher doses of baclofen are correlated with a higher severity of addiction (8, 132). The dose of baclofen needed to achieve this effect could be very variable from one subject to another in relation to each individual’s variable strength of the Pavlovian association between the cue and the reward. Interestingly, endogenous substances like dopamine and corticotropin-releasing factor and exogenous acute and chronic ethanol act in brain regions that regulate stress and anxiety-related behaviors (119), the most important region being the amygdala. It is well established that craving and the subsequent sequence of compulsive drinking are triggered by feelings of stress that can themselves be triggered by the exposition to alcohol cues (118). If the sight of alcohol has no more effect than looking at nappies or washing powder, the effective dose of baclofen has been reached.” Patients indifferent to alcohol are no longer concerned or stressed by the sight of alcohol.
Localization of GABAB receptors in midbrain monoamine containing neurons in the rat. Cortical and amygdalar neuronal ensembles in alcohol seeking, drinking and withdrawal. Agabio R, Leite-Morris KA, Addolorato G, Colombo G. Targeting the GABAB receptor for the treatment of alcohol use disorder. Furthermore, GHB itself is used as a treatment of AUD, and it is possible that the effectiveness of GHB is related to its ethanol-mimicking action, making it behave as a substitute for alcohol in the brain (142). He highlighted the similar behavioral effects of alcohol, baclofen and GHB. Similarly, GABA-B stimulation may substitute the GABA transporter GAT-3 deficiency in the brains of alcoholics, leading to a normalized GABA function in the amygdala (30).
It has been highlighted that, in patients indifferent to alcohol, those who remain completely free of alcohol for many months are those who will be able to stop taking baclofen, while those who continue to drink, even at moderate levels and without any real desire for alcohol but who do so out of habit or on certain social occasions, will have greater difficulty in stopping baclofen (79). We have previously mentioned that chronic baclofen produces plastic changes in regions of the reward system, including desensitization in G-protein-dependent systems and alterations in signaling of several kinase cascades (FAK, GSK3ß, DARPP-32) that are resistant to desensitization (37). But the important point in the context of the present article is to highlight that there are dysfunctional networks in the brains of AUD patients, and to try to understand how effective pharmacological treatments used in AUD can normalize these dysfunctional networks. Central GABA-B receptors are involved in the regulation of a large number of systems and functions, including several neurotransmitter systems (dopamine, serotonin, norepinephrine, glutamate), transduction pathways, memory, and other cognitive functions, as well as inflammation. In large quantities, baclofen can lead to pleasurable feelings similar to those created by drinking alcohol, which is why it can be addicting.
Studies in AUD patients have shown the same kind of results. These structures are the nucleus accumbens/ventral striatum; the anterior, posterior and dorsal cingulate cortex; the orbitofrontal cortex; the dorso-medial prefrontal cortex; the amygdala, the hippocampus and para-hippocampus; and the cerebellum (93–95). Patients indifferent to alcohol are no longer interested in alcohol, but they experience normal enjoyment for the other aspects of their life. The large majority of patients never experience these symptoms. This state is possibly related to a hypo-dopaminergic state.
- Baclofen and GHB share several common neurobiological effects, including GABA-B activation; among alcohol, baclofen and GHB, only GHB occurs naturally in the brain and has brain specific receptors.
- We have previously mentioned that chronic baclofen produces plastic changes in regions of the reward system, including desensitization in G-protein-dependent systems and alterations in signaling of several kinase cascades (FAK, GSK3ß, DARPP-32) that are resistant to desensitization (37).
- This is why seeking addiction treatment is critical to protecting your well-being and ensuring a safe recovery.
- All these systems and functions are possibly involved in the anti-addictive effects of baclofen.
- These regions are not primarily dopaminergic, but nevertheless receive dopaminergic projections, and, for many of them, they are part of the reward network (38).
The main difference between alcohol and baclofen is that alcohol progressively produces a state of dependence, while this is not the case with baclofen (although a few cases have been reported 133—likely because these are exceptional). In other words, the dose of baclofen would be that which is necessary to overcome the strength of a long-lasting associative learning “carved” in the limbic memory. Baclofen also has important neuromodulatory effects in the amygdala, through its inhibitory action on neurotransmitters and complex effects on second-messenger signaling (37). Amygdala CREB is known to be involved in the modulation of fear memory (124); and baclofen suppresses stimulant-induced increases in pCREB levels in the amygdala (125). The passage from a state of extreme vulnerability to compulsive drinking to a state of indifference is however not always as abrupt as in the case of Olivier Ameisen.
Regarding the mechanism of action of baclofen in these models, it is generally hypothesized that baclofen reduces alcohol consumption through an anti-dopaminergic effect. Such dopamine antagonist properties do not a priori posit baclofen as a good candidate for the treatment of subjects who have a dopamine-impoverished brain. Furthermore, preclinical studies have shown that baclofen inhibits dopamine transmission (43–48).
What should I do if I forget a dose?
Preclinical studies have highlighted such plastic effects of baclofen or other GABA-B agonists on brain systems after chronic treatment. This could imply that complete indifference to alcohol does not result from an immediate or short-term effect of baclofen on GABA-B receptors, but is rather the result of long-term plastic remodeling of certain brain systems. Adverse effects generally occur before anticraving effects during baclofen treatment of AUD, especially when baclofen is used in order to make patients reach a state of complete indifference, for which high or very high doses are most often necessary. One study found that baclofen reduced alcohol self-administration but not cue-elicited craving; furthermore, baseline anxiety levels did not modulate alcohol drinking (48).
Clinical Pharmacology for Baclofen
Use an accurate measuring device to measure your baclofen oral liquid dose. People who are aged 65 years and older can be at greater risk for some side effects from baclofen. While less common, the most serious side effects of baclofen are described below, along with what to do if they happen. There may be other side effects of baclofen that are not listed here. The most common side effects of baclofen are listed below.
The withdrawal period is when your brain and body adjust to not having baclofen in your system. However, this drug affects everyone differently, and the side effects may be more severe when combining baclofen with other medications, such as antidepressants. Some off-label uses for baclofen include supporting the recovery of people who previously misused tobacco, alcohol, and certain drugs. A person prescribed baclofen may begin misusing it over time to strengthen its effects. Altman E, Gilmore C, Peterson J, Andriukaitis S. Psychiatric rating scales in diagnostic assessment and clinical treatment. Antidepressants for the treatment of people with co-occurring depression and alcohol dependence.