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Alcohol use disorder AUD is a brain disorder associated with high rates of mortality and morbidity worldwide. The Frontiers - The Down Tools - .Should Be High of this drug remains controversial, in part due to uncertainty regarding dosing and efficacy, alongside concerns about safety.
Two additional RCTs have been completed but have not yet been published. The other approach involved titration until the desired clinical effect was achieved, or unwanted effects emerged. Baclofen may be particularly advantageous in those with liver disease, due to its limited hepatic metabolism and safe profile in this population.
Baclofen is mostly used in some European countries and Australia, and in particular, for patients who have not benefitted from the currently used and approved medications for AUD.
After promising preclinical evidence [for review see Colombo and Gessa 1 ], clinical studies started to investigate whether baclofen may be useful in the treatment of alcohol use disorder AUD. However, to date, clinical studies have yielded conflicting results. Despite the lack of consistent evidence, baclofen is often used off-label in clinical practice to treat AUD, especially in some European countries and Australia 2. AUD is a major public health problem associated with high rates of mortality and morbidity worldwide 3 — 7.
The previous editions of the Diagnostic and Statistical Manual of Mental Disorders DSM described two disorders related to a pattern of maladaptive alcohol consumption, alcohol abuse and alcohol dependence [e. The diagnosis of dependence required the No Place To Go - Peter Greens Fleetwood Mac* - Peter Greens Fleetwood Mac of three or more criteria out of a set of Spomen - Various - 101.
Brigada Za Hrvatsku, whereas the diagnosis of abuse required Frontiers - The Down Tools - .Should Be High least one out of four different criteria.
AUD is characterized by periods of excessive alcohol consumption and a chronic relapsing, remitting course 3. According to the different AUD phases, the goal of medical treatment may Frontiers - The Down Tools - .Should Be High to achieve and maintain abstinence, if patients are currently drinking—or just maintain abstinence.
Even if abstinence is the best goal for AUD medical treatment, some patients prefer to reduce their alcohol consumption to low-risk drinking, instead of total abstinence.
Accordingly, the recent guidelines of the American Psychiatric Association for the pharmacological treatment of AUD recommend the use of naltrexone, acamprosate, or disulfiram, based on the treatment objective reducing alcohol consumption or achieving and maintaining abstinencepatient preference, and presence of comorbidities that may contraindicate a specific drug In Europe, nalmefene has also been approved for the treatment of alcohol dependence Nevertheless, only a minority of people with AUD seek and receive medical treatment 41314 and current approved medications for AUD are of limited effectiveness Therefore, identification of other medications may contribute toward increasing Boogie On Down (Brass Version) - Sales Band - Boogie On Down number of AUD patients who benefit from pharmacological treatments with a different mechanism of action.
It has been marketed since the early s for the treatment of muscle spasticity, secondary to neurological conditions. The wide use of baclofen as a myorelaxant has provided detailed information on its safety and side effects in these patients From the s, research, largely in animal addiction models, suggested that baclofen may also be effective in the treatment of AUD 1. Animal studies showed that baclofen induced a dose-related reduction in a the behavioral effects caused by alcohol 18b acquisition and maintenance of alcohol consumption 19 — 21including binge-like drinking 22c relapse-like drinking 23d severity of alcohol withdrawal signs 20e cue-induced reinstatement of previously extinguished alcohol seeking behavior 24and f reinforcing and motivational properties I Wanna Talk About My Baby - The Riot Squad - I Wanna Talk About My Baby / Gonna Make You Mine alcohol 25 — 30 in different validated rodent models of AUD [for a recent review, see Colombo and Gessa 1 ].
Addolorato and colleagues were the first to investigate the efficacy of baclofen in reducing alcohol consumption in AUD patients Patients reported their last alcohol intake in the preceding 24 h. Seven patients achieved and maintained abstinence, and another two significantly reduced their alcohol consumption. Flannery and colleagues replicated these findings in 12 AUD patients, including three women, that were active drinkers three days abstinent before the beginning of the trialusing the same dose of baclofen for 12 weeks However, conclusions that Frontiers - The Down Tools - .Should Be High be drawn from these results are Frontiers - The Down Tools - .Should Be High by the open-label design and the absence of a placebo control group.
Participants were active drinkers last intake in the preceding 24 hdid not suffer from any other mental disorder, were treated as outpatients, and received psychological support every week. Their mean baseline alcohol consumption was Compared to placebo, baclofen increased the percentage of patients who achieved and maintained abstinence abstinent patientsas well as the number of abstinent days, and decreased the number of drinks per drinking day and anxiety levels However, a similar RCT found different results [ 34 ; see Table 1 ].
In this study, there was no difference between baclofen and placebo in the percentage of heavy drinking days, abstinent days, time to first drink time to lapseor time to heavy drinking day time to relapse. This RCT differed from the Addolorato et al. The third RCT found that baclofen treatment both dose group compositecompared to placebo, increased a time to first lapse, b time to first relapse, and c percentage of days abstinent.
The characteristics of these RCTs are described in detail below. InAddolorato et al. The rationale for selecting this specific sample was that, in these patients, certain AUD pharmacological agents e. Terrific - Crippled Old Farts / Unlogistic - Crippled Old Farts / Unlogistic each visit, patients received an individual session of counseling support lasting 30 min.
At the end of the weeks study, a higher rate of participants allocated baclofen achieved and maintained abstinence and had a longer cumulative abstinence duration compared with placebo. More recently, Hauser et al. These patients were active drinkers at least one heavy drinking day per week or more than 7 drinks per week, for each of the preceding 2 weeksdid not suffer from other mental disorders, and were seen every week for the first month, and then every 2 weeks.
However, unlike the RCT by Addolorato et al. Some case reports 47 — 49 suggested the potential utility of increasing Frontiers - The Down Tools - .Should Be High doses of baclofen to treat patients with AUD.
Similar observational studies started being published from 50 — The effectiveness of baclofen was also reported in AUD patients affected by liver disease 5564 Subsequently, a series of RCTs investigated the efficacy of higher doses of baclofen in the treatment of AUD compared to those administered in early studies Table 1as detailed below. In both studies, participants did not suffer from other severe mental disorders, were seen every week, as outpatients, for 12 weeks, and received an individual psychosocial intervention.
This study did not find differences in the percentages of heavy drinking and abstinent days between the baclofen and the placebo group. However, a high placebo effect was observed e. The study found no differences between baclofen and placebo in alcohol consumption and time to relapse.
Each participant was seen as an outpatient, every week for the first month, and then every 2 weeks. In contrast, the second RCT found no difference between baclofen 60 mg, baclofen 30 mg, and placebo on time to relapse, nor time to lapse A post-hoc analysis showed a beneficial effect of baclofen, compared to placebo, only among AUD patients with comorbid anxiety disorders.
Namely, AUD patients with anxiety disorder treated with baclofen had the first lapse and relapse after a significantly longer period of time, compared to AUD patients with anxiety treated with placebo. In this study, participants were seen as outpatients every 2 weeks, and, at each visit, received adherence therapy lasting 20—60 min. The aims of treatment included both abstinence and reduction of alcohol consumption.
The study found that baclofen treatment both dose groups combinedcompared to placebo, increased: a time to first lapse, b time to first relapse, and c percentage of days abstinent. When the results were analyzed according to the presence of liver disease, baclofen both dose group composite was shown to be effective in increasing the time to lapse and relapse among participants affected by liver disease, but not among those without liver disease.
Participants were looking for treatment for both AUD and smoking, but with different treatment goals i. The results of the study showed that the rate of abstinent days from co-use of alcohol and tobacco was higher among participants treated with baclofen compared to those treated with placebo The trial did not find any difference between the three groups in any outcome evaluated time to first relapse, total alcohol consumption, and proportion of abstinent patients.
However, the results showed a very high placebo effect e. The RCT comprised two phases. In the second phase lasting 10 weeksparticipants received the maximum dose achieved during the previous phase. In this multicenter trial, the setting varied between the centers. In all centers, participants received weekly group or individual psychotherapy sessions. Overall, these patients received a mean of This RCT found no difference between baclofen and placebo in the percentage of abstinent patients and in the reduction of alcohol consumption.
Compared to the study of Beraha et al. However, the two RCTs differed in the duration, mean actual baclofen dose, presence of comorbid mental disorders, setting, and frequency of psychosocial treatment. The duration of the Reynaud et al. In this RCT, a higher percentage of participants reached the maximum dose of baclofen 66 vs. Both RCTs excluded Spring Song (DJ Emjay Mix) - Huun-Huur-Tu - Spirits From Tuva with current severe mental disorders.
However, participants with bipolar disorder were excluded in Reynaud et al. In the Reynaud Various - 12x12 al. Participants also received psychotherapy sessions less frequently every 2 weeks vs. Unlike the other two similar RCTs presented above 4344this study found that baclofen substantially increased the percentage of abstinent patients and cumulative abstinence duration compared to placebo [ 45 ; see Table 1 ].
This RCT was conducted at a single outpatient unit and recruited 56 AUD participants with high baseline levels of alcohol consumption The 3 RCTs did not differ in other characteristics. To date, there have been four meta-analyses of baclofen for the treatment of AUD, based on the studies described above [ 67 — 70 ; see Table 2 ].
These meta-analyses vary in the number of RCTs evaluated between five 68 and 14 67as well as in the outcomes Frontiers - The Down Tools - .Should Be High . The most inclusive study 67 evaluated the efficacy of baclofen pooling the outcomes chosen by each single study as the primary outcome, and in two subgroups of outcomes, one related to abstinence and one to alcohol consumption.
According to the results of this meta-analysis, baclofen did not differ significantly from placebo in any of the outcomes investigated. A significant effect of baclofen for the same outcome was confirmed by two other recent meta-analyses in which more RCTs were included 69 One of these meta-analyses also found that baclofen significantly increased the time to lapse, compared to placebo Moreover, these meta-analyses did not find significant differences between baclofen and placebo on other important outcomes, such as the rate or number of abstinent days 67 — 70alcohol craving 6870 Tonights The Night - Rod Stewart - A Night On The Town, depression 70or anxiety In one of the meta-analyses, the role of potential influencing factors was also explored 69 and found greater baclofen vs.
Human laboratory studies have investigated the effects of baclofen in experimental settings 73 — In this study, participants received three different doses of baclofen 0, 40, and 80 mg and 0. The study found that both baclofen and alcohol impaired performance, but that few performance indicators were impaired to a greater extent when baclofen was combined with alcohol.
Furthermore, baclofen affected the biphasic effects of alcohol during the experimental alcohol administration session They found that baclofen did not reduce the amount of alcohol consumed, but altered the subjective effects of alcohol, including an increase in the ratings of feeling high and intoxicated Furthermore, in the same clinical study, they also found that baclofen may work by dissociating the link between an initial drink priming and subsequent alcohol consumption self-administration Based on these results, the authors proposed that baclofen may act as a partial substitution AUD medication.
A recent pharmaco-fMRI study found that baclofen specifically decreased alcohol cue-reactivity in brain areas involved in the processing of salient appetitive and aversive stimuli However, the exact underlying biobehavioral mechanisms of baclofen in AUD individuals are still not completely understood 78 — The reasons for inter-study discrepancies are not fully understood.
In general, it is well-established that clinical trials in AUD exhibit large variability because of a myriad of factors that affect outcome in AUD patients
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