Spatial distribution of GABA(B)R1 receptor mRNA and binding sites in the rat brain. GABA-B receptors structure and function. This review on the mode of action of baclofen from a clinical standpoint and with a biological perspective highlighted three potential modes of action of baclofen; namely on dopamine, functional connectivity, and as a substitution drug. However, there are no solid theoretical bases supporting the hypothesis that baclofen is a substitution treatment in AUD. According to Ameisen, a deficit in brain GHB could cause dysphoria, itself promoting alcohol misuse.

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Despite this discrepancy, baclofen is often used to treat AUD, especially in European countries and Australia, as a consequence of the wide off-label prescription of the drug by general practitioners (20). For all these reasons, the identification of new, safe, and effective medications is a critical priority in the field of AUD treatment (16–18). AUD medications are also contraindicated in patients with some medical comorbidities (4, 5, 12, 13). Globally, the magnitude of the therapeutic effects of AUD medications is relatively modest (4), and patient response may differ to a specific drug (10, 11). Unfortunately, only a very small number of AUD patients receive these medications.

• It is sometimes used transdermally (applied topically to the skin) in combination with gabapentin and clonidine prepared at a compounding pharmacy.
• The action of baclofen on neurons of the substantia nigra and of the ventral tegmental area.
• It is therefore hypothesized that chronic baclofen treatment produces a state of indifference through a normalization of brain network connectivity.
• From a clinical standpoint, this hypothesis is not entirely satisfying because the clinical effects of baclofen in AUD patients are not really those of an antidopaminergic effect.
• It reduced alcohol consumption in some studies (23, 49, 50, 54, 55, 57), but not in others (24, 51–53, 55, 58, 59).
• A study by Morley et al. showed no anticraving effect in AUD patients, but a secondary analysis showed that baclofen was effective in the group of anxious patients included in the study (33).

Baclofen may be used off-label as a treatment for alcohol use disorder to reduce the risk of relapse, and to increase the number of days that a person can go without drinking alcohol (abstinence days). Intrathecal baclofen is used for severe spasticity of spinal cord origin, that is refractive to maximum doses of oral antispasmodic agents, or who experience intolerable side effects. It seems, in a simplified way, that in AUD patients connectivity is increased in regions that are involved in appetitive drive and reduced in regions that mediate executive control, while in long-term abstinent patients activity is decreased in reward circuitry and increased in executive control regions (98–102). For instance, it has been shown that inactivation of the prelimbic cortex inhibits ethanol self-administration (80); that the inactivation of the baso-lateral amygdala attenuates context-induced alcohol-seeking (81); or that the inactivation of the ventral subiculum decreases context-induced relapse to alcohol seeking (82). References, only the first author is cited; Two references on the substitution line, the first refers to alcohol, the second to baclofen or other GABA-B agonists. One of the biggest risks of baclofen is that it’s easy to overdose on it.

Most often, residential treatment is suggested as a transitional option after an inpatient program. Generally, enrolling in a residential treatment facility requires a commitment of 21 days or more. Instead, a residential recovery center might have a large team of therapists and specialists who can create a customized treatment program based on your needs. The difference is that a residential recovery center cannot provide the same medical treatment that a hospital can. Residential treatment programs offer 24/7 assistance just like an inpatient program. Intensive inpatient treatment means you’ll be admitted to a hospital where you will get 24/7 medical supervision and care.

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Baclofen is a selective GABA-B agonist, and alcohol has no direct action on GABA-B receptors. Buprenorphine and other substitution substances used in the treatment of opiate addiction indeed act directly as baclofen addiction potential full agonists, or as agonist/antagonists, on opiate receptors. Abrupt withdrawal from alcohol and high-dose baclofen may also produce similar symptoms, including confusion, hallucinations, delirium, and seizures (16, 91) (Table 1). Alcohol and baclofen produce many similar symptoms or behavioral effects in patients.

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• However, because they are recovering from addictions, these people are at a higher risk of misusing baclofen, which is why it needs to be closely monitored.
• Baclofen-induced reduction of alcohol reinforcement in alcohol-preferring rats.
• All these studies reported that baclofen reduced alcohol consumption.
• Most often, residential treatment is suggested as a transitional option after an inpatient program.
• In both studies, baclofen amplified the subjective effects of alcohol, which was suggested as a potential biobehavioral mechanism of how baclofen may affect alcohol drinking (26, 48).

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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GABA(B) receptor 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.

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.

Zhu X, Du X, Kerich M, Lohoff FW, Momenan R. Random forest based classification of alcohol dependence patients and healthy controls using resting state MRI. Disrupted control network connectivity in abstinent patients with alcohol dependence. Ethanol modulates GABA(B) receptor expression in cortex and hippocampus of the adult rat brain. Maccioni P, Lorrai I, Contini A, Leite-Morris K, Colombo G. Microinjection of baclofen and CGP7930 into the ventral tegmental area suppresses alcohol self-administration in alcohol-preferring rats.

However, dopamine antagonists have never shown effectiveness in the treatment of AUD (42). In summary, chronic baclofen produces G-protein desensitization in a certain number of structures, and alterations in signaling via kinase cascades, with resistance to desensitization, in a set of structures that are closely related to the dopamine network. Such decreases demonstrate a general desensitization of G-protein-dependent systems. It is characterized by an effortless suppression of craving, but goes beyond it. While it is clearly established that the myorelaxant properties of baclofen are related to a dampening of the spinal motor reflex (13), its potential mechanism of action in AUD remains elusive.

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From a clinical standpoint, this hypothesis is not entirely satisfying because the clinical effects of baclofen in AUD patients are not really those of an antidopaminergic effect. However, some studies have shown that baclofen could have dose-dependent effects on dopamine systems, with low doses increasing dopamine transmission and high doses inhibiting it. Given that craving for alcohol is closely related to states of stress (34, 35), the stress-relieving effects of baclofen may contribute to reduce craving in AUD patients.

Baclofen in the Treatment of Patients With Alcohol Use Disorder and Other Mental Health Disorders

GABA-B receptors are heterodimeric metabotropic receptors consisting of one GABA-B receptor-1 subunit (GABBR1) and one GABA-B receptor-2 subunit (GABBR2). As mentioned above, baclofen is a selective GABA-B receptor agonist. In negative reinforcement, craving is induced by the motivational value of the negative states of alcohol withdrawal.

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It is therefore hypothesized that chronic baclofen treatment produces a state of indifference through a normalization of brain network connectivity. The challenge is to explain how a chronic treatment with a GABA-B agonist is able to overcome these numerous and complex brain adaptations, and to lead to a state of indifference toward alcohol. Another reason why the therapeutic effect of baclofen in AUD is likely not to be related to a global anti-dopaminergic effect is that it is not compatible with the phenomenology of the state of indifference toward alcohol. However, the experience of baclofen treatment in patients with AUD shows that most often the stimulant effect is not dose-dependent; it appears at any dose, and sometimes at high doses.

If benefits are not evident after a reasonable trial period, patients should be slowly withdrawn from the drug (See WARNINGS, Abrupt Drug Withdrawal). The lowest dose compatible with an optimal response is recommended. Thereafter additional increases may be necessary but the total daily dose should not exceed a maximum of 80 mg daily (20 mg q.i.d.). The efficacy of baclofen in stroke, cerebral palsy, and Parkinson’s disease has not been established and, therefore, it is not recommended for these conditions.

The idea of a strict hypo-dopaminergic state in the brain of AUD patients remains controversial (41). And it is widely accepted that, in patients with chronic AUD, reward thresholds are increased and dopamine function is decreased, leading to a general “dopamine-impoverished” brain (40). All addictive substances alter dopaminergic signaling in the mesocorticolimbic system, and models of addiction posit positive and negative reinforcement as closely linked to dopaminergic reward systems (39). Frequently occurring adverse sensory effects (tinnitus, paresthaesias, blurred vision, etc.) may be explained by the high density of receptors in the thalamus, and memory problems by the high density of receptors in the hippocampus. Studies have shown that GABA-B receptors are highly expressed all throughout the brain, some regions having a very high density of receptors, other regions a low or a very low density, and some regions insignificant densities. A challenge in alcohol research is to explain how specific cues or contexts are paired with states of craving, while explaining which mechanisms of brain encoding are involved in these associations.

In his 2008 book, Le Dernier Verre (translated literally as The Last Glass or The End of My Addiction), French-American cardiologist Olivier Ameisen described how he treated his alcoholism with baclofen. In 2014, the French drug agency ANSM issued a three-year temporary recommendation allowing the use of baclofen in alcoholism. Intrathecal pumps offer much lower doses of baclofen because they are designed to deliver the medication directly to the spinal fluid rather than going through the digestive and blood system first. As such, the actions of baclofen on α2δ subunit-containing VGCCs are likely not clinically relevant. Moreover, baclofen is in the range of 100-fold more potent by weight as an agonist of the GABAB receptor in comparison to phenibut, and in accordance, is used at far lower relative dosages.

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In conclusion, it is proposed that baclofen may suppress the Pavlovian association between cues and rewards through an action in a critical part of the dopaminergic network (the amygdala), thereby normalizing the functional connectivity in the reward network. Although baclofen is an analog of the putative inhibitory neurotransmitter gamma-aminobutyric acid (GABA), there is no conclusive evidence that actions on GABA systems are involved in the production of its clinical effects. Agonism of GABAB receptors is thought to be responsible for baclofen’s range of therapeutic properties, as GABAB knockout mice are unresponsive to the neurobiological effects of baclofen. Indeed, in terms of connectivity and synaptic strength, it is likely that the continuation of regular drinking reactivates the Pavlovian association between the cue and the reward every time, making it impossible to suppress, and paving the way for relapse if baclofen is stopped.

On the other hand, AUD patients frequently develop temporary alcohol-induced depressive and/or anxiety symptoms during intoxication and/or withdrawal (63). The pharmacological treatment of AUD patients affected by comorbid mental disorders represents a significant challenge (61, 62). Baclofen reduced alcohol consumption in studies in which participants had high (23, 50, 56) or low (57) baseline anxiety levels. Among the studies in which the anxiety and depression levels of participants were evaluated, baclofen administration reduced anxiety but not depression levels (45–47). All these studies reported that baclofen reduced alcohol consumption. In all studies, participants received daily doses of baclofen ranging from 30 to 145 mg and were monitored from 4 to 52 weeks.