Baklofen a zaburzenia związane z używaniem alkoholu: mechanizmy, skuteczność i zastosowanie

■ INTRODUCTION

Alcohol consumption has been deeply embedded in cultural, religious and social customs across the globe for centuries, which contributes to its widespread use [1]. Even low levels of alcohol consumption pose health risks while most alcohol-related harm stems from heavy binge drinking or chronic excessive use. In 2019, the World Health Organization (WHO) reported approximately 2.6 million deaths globally due to alcohol, with men accounting for 2 million of these events and the highest alcohol-related mortality rates observed in the European and African WHO regions. Notably, 13% of deaths from alcohol intoxication occurred in people aged 20-39 in 2019 [2]. The Center for Disease Control and Prevention (CDC) estimates that excessive alcohol consumption accounts for 27% of injury-related deaths and is present in 21% of suicide cases [3, 4]. As of 2024, WHO estimates that around 400 million people worldwide have alcohol use disorder (AUD) with 209 million affected by alcohol dependence [2].
AUD is a condition where individuals struggle to control alcohol intake despite its harmful consequences, leading to lasting changes in the brain and a higher risk of relapse. In 2023, about 10.9% of U.S. adults and 2.9% of adolescents were affected. Risk factors for AUD include high levels or early onset of drinking, family history of alcohol issues and co-occurring mental health conditions like depression and post-traumatic stress disorder (PTSD). Childhood trauma is also linked to a heightened susceptibility to AUD [5].
Effective treatment for AUD involves a comprehensive approach, including screening with tools such as the Alcohol Use Disorders Identification Test, pharmacological support for withdrawal, and medications including acamprosate, baclofen, naltrexone and disulfiram to aid recovery. Psychosocial interventions like cognitive behavioural therapy and motivational interviewing also provide crucial support. While most countries report some level of treatment availability, 10% have only limited initiatives and 7% offer no treatment services at all, highlighting gaps in global access to AUD care [6]. Swift et al. [7] reviewed various medications for AUD and showed that, while some treatments seem effective, their impact remains modest. Despite the availability of pharmacotherapies, overall success rates are limited, emphasising the importance of continued exploration to enhance efficacy and broadening of treatment possibilities [7].
To improve outcomes in AUD treatment, it is crucial to optimise and expand the availability of existing methods while also developing more effective, individualised therapies. A deeper understanding of the mechanisms underlying alcohol dependence will promote the design of better treatment and prevention strategies. Evaluating long-term treatment effects and identifying factors that contribute to its success will help to adjust and refine treatment approaches.

■ METHODS

A literature search was conducted in the PubMed and ScienceDirect databases using the keywords “baclofen”, “alcohol use disorder”, “alcohol dependence” and “alcohol”. The selection prioritised recent original studies and case reports to ensure the inclusion of the latest research. Additionally, key references cited in relevant studies were reviewed and integrated into the analysis.

■ RESULTS

The effects of alcohol on the body

Alcohol negatively impacts multiple organs, contributing to cardiovascular issues like cardiomyopathy and hypertension, liver diseases including cirrhosis and hepatitis and an increased risk of cancer. Additionally, it weakens the immune system, heightening vulnerability to infections like pneumonia and tuberculosis. In 2019, alcohol was the leading risk factor for disease among people aged 25-49 and the second highest for those aged 10-24 [8, 9]. One of the key mechanisms behind these negative effects is how the body metabolises alcohol. It is primarily processed in the liver, where it is converted into acetaldehyde, a toxic, carcinogenic substance, before breaking down further into acetate, carbon dioxide and water. Although acetaldehyde is short-lived, it can cause immediate damage to the liver, brain and digestive tissues, contributing to behavioural and psychological effects including impaired coordination, memory deficits and drowsiness [10].
Dependence follows a three-stage binge/intoxication, withdrawal/negative affect and preoccupation/anticipation cycle with each intensifying with continued substance use. This cycle is fuelled by changes to the brain, particularly in the basal ganglia, extended amygdala and prefrontal cortex, which are responsible for rewarding effects of substance use, the distressing emotions experienced during withdrawal and the executive functions tied to self-control, making them central to the development of substance use disorder [11]. Chronic excessive alcohol use triggers neuroadaptive changes in the brain’s reward and stress systems, promoting dependence. Initially, alcohol stimulates the reward system with effects such as euphoria and anxiety relief but stopping its use disrupts this balance, causing withdrawal symptoms. At the same time, chronic alcohol exposure alters hypothalamic–pituitary–adrenal (HPA) axis function, raising corticosteroid levels while weakening the body’s stress response [12]. The HPA axis regulates the stress response by triggering glucocorticoid release. Stressors activate corticotropin-releasing factor (CRF) neurons in the hypothalamus, prompting adrenocorticotropic hormone secretion from the pituitary, which then stimulates cortisol release from the adrenal cortex. Cortisol mobilises energy, modulates immune and cognitive functions and negative feedback prevents overactivation [13]. Alcohol also directly affects CRF, further heightening stress and craving, which fuels a cycle of increased consumption and dependence. These neuroadaptive changes are thought to shift alcohol use from controlled to compulsive drinking [12].
In a study conducted by Myrick et al. [14], alcohol-dependent individuals who were not seeking treatment reported significantly higher “real-time” alcohol craving levels and exhibited unique activation patterns in limbic and cortical brain regions compared to control subjects. Specifically, after consuming a small quantity of alcohol, these individuals displayed activation in the bilateral nucleus accumbens, ventral tegmental area, bilateral insula and anterior cingulate cortex while viewing alcohol-related cues as opposed to non-alcoholic beverage cues. Furthermore, real-time craving ratings correlated with activation in the left nucleus accumbens, anterior cingulate cortex and left orbitofrontal cortex [14].

Baclofen: mechanism of action

Baclofen (β-[4-chlorophenyl]-γ-aminobutyric acid) is a selective agonist of the γ-aminobutyric acid GABA-B receptor, exerting effects on mono- and polysynaptic pathways in the spinal cord and brain. It reduces spasticity by inhibiting excitatory neurotransmitter release in presynaptic neurons and enhancing inhibitory signalling in postsynaptic neurons. Additionally, baclofen interacts with voltage-gated calcium channels. Following oral administration, it is rapidly absorbed through the gastrointestinal tract with a bioavailability of 70-85%, achieving peak plasma levels within 2-3 hours. Its absorption is dose dependent. The drug has a volume of distribution of 0.7 l/kg and shows limited crossing of the blood–brain barrier due to its high-water solubility, leading to significantly lower cerebrospinal fluid (CSF) concentrations compared to plasma. About 30% of baclofen binds to plasma proteins. Metabolism occurs primarily for the S-enantiomer, producing the metabolite S-M1, while the R-enantiomer undergoes minimal transformation and is more effective in reducing alcohol cravings. Baclofen’s elimination is predominantly renal (70% unchanged) with a short plasma half-life of 2-6 hours, necessitating frequent dosing. Intrathecal administration shows a CSF elimination half-life of approximately 1.5 hours, with a lumbar-cisternal gradient indicating higher lumbar concentrations. Baclofen’s limited hepatic metabolism makes it suitable for patients with liver impairment or those at risk for cytochrome P450 interactions [15, 16].

Baclofen’s effects on alcohol craving, stress response and withdrawal
Despite its original purpose of reducing spasticity, baclofen has recently been used to treat AUD off-label [14]. Alcohol consumption and its reinforcing effects are primarily regulated by mesolimbic dopamine pathways, which contain a high density of GABA-B receptors. Activating these receptors can inhibit nearby dopaminergic pathways, reducing dopamine release in response to alcohol intake, potentially diminishing cravings [17, 18].
Baclofen has been shown to influence subjective sensations associated with alcohol. Farokhnia et al. [19] found that baclofen may enhance subjective sensations associated with alcohol like feelings of intoxication and euphoria, suggesting a potential role as a substitution therapy. By mimicking some of the effects of alcohol, baclofen may help reduce alcohol craving while offering a safer alternative [19]. By activating the GABA-B receptor, baclofen enhances the inhibitory action of GABA in the brain [20-24], leading to a reduction in excitability and a diminished response to alcohol-related stimuli, which could weaken the brain’s reward response to alcohol [19, 25-27].
Additionally, Farokhnia et al. [19] also examined the effects of baclofen on individuals with AUD and high anxiety levels. The primary findings indicate that baclofen influences subjective responses to alcohol intake. Participants receiving baclofen reported heightened feelings of “high” and intoxication after consuming alcohol. Importantly, no effect was observed on blood alcohol concentrations during the alcohol administration procedure, ruling out changes in alcohol pharmacokinetics as a source of these subjective effects. Although baclofen did not reduce the quantity of alcohol consumed, it weakened the positive correlation between blood alcohol levels during the initial drink and subsequent alcohol consumption. The authors suggest that baclofen may reduce the urge for further consumption by enhancing subjective effects after the first drink as the desired effects are achieved earlier [19]. Moreover, this study also has shown that baclofen can disrupt the connection between the initial exposure to alcohol and subsequent drinking, reducing the likelihood that one drink will lead to further, uncontrolled alcohol consumption [19, 28]. Additionally, baclofen appears to diminish the impact of alcohol cravings triggered by priming, preventing an increase in consumption despite strong cravings, suggesting that baclofen may help individuals regain control over their drinking behaviours [28].
Baclofen may also modulate the stress response in individuals with AUD. A study by Logge et al. [29] demonstrated that it may reduce cortisol levels following mild stress exposure, highlighting its potential role in normalising the HPA axis [29]. This effect is thought to stem from GABA-B receptor activation and may contribute to reduced alcohol-seeking behaviours and long-term relapse prevention [30]. A suppressed cortisol response, observed both independently and in interaction with baclofen treatment, was found to predict improved treatment outcomes, including increased abstinence from alcohol over a 10-week follow-up period [29]. Similarly, Pelz et al. [31] found that patients with AUD may benefit from high-dose baclofen (individually adjusted between 30 and 270 mg/day) as it decreases activation of the right anterior insula, which is partially responsible for anxiety during abstinence [31, 32]. The study also showed that patients with baclofen intake had higher abstinent rates than patients taking placebo. Additionally, an inverse correlation was observed between serum baclofen levels and insular activity, supporting the hypothesis that baclofen may alter brain reward processes, possibly through effects on dopaminergic neurotransmission [31, 33].
Neuroimaging studies further support baclofen’s role in reducing alcohol cue reactivity. Logge et al. [34] suggests that baclofen, particularly at a higher dose of 75 mg/day, reduces brain activation in response to alcohol-related cues in regions associated with cue reactivity like the medial prefrontal cortex (mPFC), dorsal anterior cingulate cortex (dACC) and dorsal striatum. Participants exhibited reduced activation in the mPFC and the dACC when presented with alcohol-related images compared to the placebo group [34]. These brain regions are strongly associated with attention, memory and the encoding of motivational value of stimuli, and their increased activity is often observed in alcohol-dependent individuals. The decreased activation in these areas suggests that baclofen may “suppress” responses to alcohol-related cues, reducing their salience and the likelihood of relapse [35-39]. They also highlight the significant role of the dorsal striatum in alcohol cue reactivity. In individuals with AUD, there is a shift in activation from the ventral to the dorsal striatum as compulsive drinking increases [40, 41]. Baclofen reduces activation in the dorsal striatum, which may suggest a decrease in compulsive alcohol cravings. Furthermore, the study found a positive correlation between increas¬ed dorsal striatum, dACC activity and a higher number of heavy drinking days in patients receiving placebo compared to those receiving 75 mg/day of baclofen [34].
Baclofen may also aid in managing alcohol withdrawal syndrome (AWS). According to a trial conducted by Crunelle et al. [42], baclofen (30 mg/day and 60 mg/day) may effectively reduce AWS, including delirium tremens in its most severe manifestation, hallucinations and seizures in individuals with AUD. Compared to placebo, baclofen significantly decreased the need for diazepam, with only 32% of patients on 60 mg/day requiring additional medication. This suggests that baclofen could serve as an effective alternative or complement to benzodiazepines, particularly for patients with liver impairment where benzodiazepines are less suitable [43-45].

Abstinence, consumption and relapse prevention
The BACLAD study by Müller et al. [46] investigated the impact of baclofen on achieving and maintaining abstinence in individuals with AUD. Over a 12-week high-dose phase, patients receiving baclofen were more likely to maintain total abstinence with a higher cumulative duration of abstinence compared to the placebo group. Survival analysis indicated a notably greater likelihood of sustained abstinence for patients receiving baclofen compared to those on placebo both during the high-dose phase and across the entire treatment period. Notably, no correlation was observed between the individually titrated dose of baclofen and the maintenance of abstinence, suggesting that dose level did not predict abstinence outcomes. Additionally, baclofen also showed no impact on alcohol craving or anxiety, pointing to a mechanism of action unrelated to these symptoms [46]. This finding contrasts with the studies previously discussed, which reported a reduction in alcohol craving associated with baclofen treatment [19, 28, 29, 31]. There were no euphoria or stimulant effects associated with baclofen and no patients reported drug cravings after its discontinuation. Notably, the study focused solely on baclofen’s effects in maintaining abstinence rather than on reducing alcohol consumption in individuals not aiming for abstinence [46].
In a trial by Garbutt et al. [47], baclofen demonstrated a superior effect over placebo in increasing abstinent days and reducing heavy drinking days, with outcomes varying by dose and sex. Women showed more significant effects at a lower dose (30 mg/day), while higher doses (90 mg/day) resulted in only marginal improvements, with a higher incidence of side effects like sedation and drowsiness. In contrast, men showed no response at 30 mg/day, but experienced moderate benefits at 90 mg/day, with a notable reduction in heavy drinking days and a slight increase in abstinent days. Overall, baclofen at 90 mg/day reduced heavy drinking days by 13.6 and increased abstinent days by 12.9 over a 16-week period compared to placebo [47].
The ALPADIR study [48] did not demonstrate a clear advantage of baclofen over placebo in maintaining abstinence. However, it showed a trend toward reduced alcohol consumption among patients receiving baclofen, with reductions appearing as early as the first month of treatment. Among patients with high-risk drinking at baseline, alcohol consumption decreased more in the baclofen group. Importantly, the study also reported a statistically significant reduction in alcohol craving among patients treated with baclofen [48].
Similarly, the study by Rigal et al. [49] suggests that baclofen could be a viable treatment option for individuals with AUD who aim to lower their alcohol consumption to low-risk levels without undergoing prior detoxification. Findings indicate that baclofen was more effective than placebo in achieving this outcome as patients receiving baclofen had a higher success rate (defined as either abstinence or low-risk drinking), a reduction in average daily alcohol intake and an increase in the number of abstinent days. The authors propose that a harm-reduction strategy focusing on lowering alcohol consumption rather than enforcing complete abstinence may be a practical alternative, particularly in primary care settings, potentially encouraging more individuals with AUD to seek treatment [49].
De Beaurepaire et al. [50] suggest that baclofen administration can significantly reduce alcohol consumption and alleviate alcohol cravings. Data from the French “Temporary Recommendation for Use” (TRU) programme conducted between 2014 and 2017 indicate a substantial decrease in average daily alcohol intake, accompanied by a reduction in the alcohol craving scale score. Moreover, the proportion of individuals with zero or low-risk alcohol consumption, as per WHO criteria, increased following baclofen treatment. Similar effects were observed in patients receiving higher doses. These findings suggest that individually tailored baclofen dosing may be effective in managing AUD [50].
The BacALD study [45] provides the evidence supporting baclofen’s potential efficacy in treating AUD, particularly in patients with alcohol-related liver disease (ALD). This study evaluated the effects of different doses of baclofen (30 mg/day and 75 mg/day) on AUD patients with and without ALD. Baclofen, at both dose levels, significantly extended the time to relapse defined as drinking five or more drinks per day for men and four or more for women. Patients on baclofen remained abstinent longer than those on placebo, with baclofen also delaying the time to first lapse (first drink) and increasing the overall percentage of abstinent days compared to placebo [45]. When comparing doses, no statistically significant differences in efficacy were observed between the 30 mg and 75 mg baclofen groups. Notably, in the ALD subgroup, baclofen treatment was associated with a significant delay in both lapse and relapse times compared to placebo, whereas no significant differences were observed in the non-ALD group. The study, however, did not find a statistically significant interaction between ALD status and baclofen treatment on alcohol consumption outcomes [45, 51].
Analysis by Rombouts et al. [51] found that the presence of ALD did not predict a positive response to baclofen like prolonged time to lapse or relapse when baseline alcohol consumption was controlled. This suggests that pre-treatment drinking levels are a more direct predictor of baclofen efficacy than ALD. While ALD may affect brain GABA-B levels through neuroadaptation, in this study, patients with ALD still showed a tendency to delay lapse and relapse, possibly due to increased motivation driven by severe health risks associated with ALD regardless of treatment group [51, 52].

Baclofen’s adverse effects
Although generally well-tolerated, baclofen may cause dose-dependent adverse effects particularly in women [47, 53]. Rigal et al. [53] reported that 78% of participants experienced at least one adverse event with an average of 2.8 per patient. The ALPADIR study [48] found that over 90% of patients experienced mostly mild to moderate adverse effects. French “Temporary Recommendation for Use” reported that 14.98% of patients receiving ≤ 80 mg baclofen per day and 23.26% receiving > 80 mg/day experienced adverse effects. Serious events were more common in the high-dose group (3.75% vs. 1.87%) with baclofen- related deaths occurring more frequently (0.09% vs. 0.04%) [50].
The most frequently reported side effects include sleep-wake cycle disturbances (drowsiness, sudden sleep attacks, fatigue and insomnia) affecting 63% of patients. Other reported adverse effects included dizziness, headaches, sedation, nausea, itching or rash, dry mouth, paresthesia and muscle and joint pain, shortness of breath and libido changes [45, 47, 48, 53, 54]. These effects often arise early or after rapid dose escalation. The risk of sedation increases with concurrent use of alcohol or central nervous system (CNS) depressants, potentially leading to deep sedation, coma or respiratory depression [54, 55]. Rolland et al. [55] found high-dose baclofen heightened sedation particularly in patients consuming over 35 drinks per week.
Baclofen may also cause neuropsychiatric effects. Rigal et al. [49] found higher rates of severe adverse effects and mortality in baclofen users compared to placebo. Cases of overdose and hospital admissions due to suicidal ideation and alcohol intoxication were also documented [45, 48, 56].
Rigal et al. [53] observed that patients with psychosis or on neuroleptic treatment reported fewer adverse effects. However, caution is needed in patients with bipolar disorder due to hypomanic episode risk. The study also highlighted the importance of informing patients about the risk of sudden sleep attacks particularly for vehicle drivers [53].
Baclofen has been linked to sleep-disordered breathing (SDB). Olivier et al. [57] reported severe central sleep apnea (CSA) in four patients undergoing baclofen therapy for alcohol withdrawal despite no preexisting CSA risk factors. Symptoms included snoring, nocturnal choking and daytime sleepiness. CSA resolved in one patient after discontinuing baclofen, while others improved with adaptive servo-ventilation (ASV) therapy. Given baclofen’s potential impact on sleep breathing, monitoring for CSA is recommended with ASV as a potential intervention without necessarily discontinuing baclofen, particularly when it supports alcohol abstinence [57]. A study involving healthy volunteers found no adverse effects associated with baclofen up to 60 mg/day; however, the authors cautioned against its use in individuals with intermittent breathing disorders (or an increased risk of such conditions, particularly those with heart failure and impaired renal function) due to its potential to destabilise sleep breathing during hypoxia [58].
Baclofen overdose can cause severe neurological and psychiatric complications, including encephalopathy, seizures, respiratory depression, delirium, coma (particularly with doses > 200 mg), muscular hypotonia and hyporeflexia. Psychiatric effects include acute psychosis with catatonia, hallucinations and mania. A 300 mg overdose case described unconsciousness, followed by psychotic symptoms and catatonia, resolving with lorazepam and olanzapine [59]. Toxicity can develop at doses as low as 150 mg and progress rapidly with severe cases requiring prolonged mechanical ventilation. In overdoses exceeding 200 mg, continuous monitoring for at least two hours is recommended, with management focusing on respiratory support and cardiovascular and neurological stabilisation while accounting for potential drug interactions [60].
Patients with renal impairment have a higher risk of prolonged toxicity due to reduced clearance, presenting with encephalopathy, seizures, hypotonia, cardiac abnormalities and coma. Co-administration with CNS depressants like gabapentin exacerbates severity. Given baclofen’s slow diffusion across the blood–brain barrier, hemodialysis and ICU monitoring may be necessary in cases of severe toxicity [54, 60-62].
Abrupt discontinuation of baclofen can cause severe withdrawal symptoms, including delirium, hallucinations, agitation, confusion, cognitive impairment, tremors, spasticity, rigidity, limb weakness and autonomic instability (tachycardia, tachypnea, hypertension, hyperpyrexia) [63, 64]. Though more common with intrathecal use, oral withdrawal can occur, particularly in patients with renal impairment, where reduced drug clearance increases the risk of psychosis, seizures and severe withdrawal effects [65]. Symptoms typically emerge within 1-3 days and may mimic conditions such as sepsis, neuroleptic malignant syndrome or alcohol withdrawal, potentially leading to life-threatening complications, including respiratory failure and rhabdomyolysis [64]. Case reports describe progressive neurological and autonomic deterioration, requiring intensive medical intervention, with symptom resolution following baclofen reintroduction and gradual tapering. Gradual dose reduction is crucial, especially in high-risk groups such as chronic kidney disease patients [54, 62, 64, 65].
Baclofen is not officially approved for AUD treatment and is used off-label. Its administration requires individualised dosing to balance efficacy and safety, beginning at a low dose with gradual titration to minimise adverse effects. Patients with renal impairment warrant special consideration, as baclofen is primarily excreted by the kidneys, and its accumulation can increase the risk of toxicity. In particular, patients with a glomerular filtration rate (GFR) below 30 ml/min/1.73 m² should avoid baclofen use [54, 61]. Comorbid conditions, including epilepsy (due to potential seizure threshold reduction), mood disorders (with a risk of manic or hypomanic episodes) and suicidal tendencies (as baclofen overdose could be used for intentional self-harm) must also be considered. There is no evidence supporting the efficacy of baclofen as a substitute for benzodiazepines in the management of alcohol withdrawal syndrome, nor does it prevent life-threatening complications like seizures or delirium tremens. Baclofen should be considered a second-line treatment for patients who have not responded to approved pharmacological therapies. However, in cases where contraindications to standard treatments exist (e.g., advanced liver disease precluding the use of disulfiram or naltrexone), baclofen may be considered a first-line option. Additionally, there is a lack of evidence supporting the combined use of baclofen with other medications for alcohol use disorder like disulfiram, naltrexone, acamprosate or nalmefene [54].

■ CONCLUSIONS

Baclofen, a GABA-B receptor agonist, has shown potential as an off-label treatment for AUD that acts on the mesolimbic dopamine system and the HPA axis by reducing cortisol levels in response to stress, reducing alcohol-seeking behaviours and promoting abstinence. Several studies suggested that baclofen can increase abstinent days and reduce heavy drinking, with notable effects in individuals with ALD. Additionally, baclofen has been shown to alleviate alcohol withdrawal symptoms, potentially reducing the need for additional medications like benzodiazepines, and helps to diminish alcohol cravings by altering brain reward systems.
However, the existing research has several limitations. Many studies have small sample sizes, varied dosing regimens and inconsistent treatment durations, making it difficult to draw definitive conclusions. Baclofen’s side effects like sedation, dizziness and drowsiness, are commonly reported, especially at higher doses, and there have been isolated reports of more severe adverse effects, including suicidal ideation and overdose. Further studies are needed to fully understand baclofen’s mechanism of action, optimal dosing and long-term treatment outcomes. Despite these gaps, baclofen presents a promising option for supporting sustained recovery, particularly for individuals struggling with alcohol dependence.

Conflict of interest/Konflikt interesów

None declared./Nie występuje.

Financial support/Finansowanie

None declared./Nie zadeklarowano.

Ethics/Etyka

The work described in this article has been carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) on medical research involving human subjects, Uniform Requirements for manuscripts submitted to biomedical journals and the ethical principles defined in the Farmington Consensus of 1997.
Treści przedstawione w pracy są zgodne z zasadami Deklaracji Helsińskiej odnoszącymi się do badań z udziałem ludzi, ujednoliconymi wymaganiami dla czasopism biomedycznych oraz z zasadami etycznymi określonymi w Porozumieniu z Farmington w 1997 roku.

References/Piśmiennictwo