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Efficacy, tolerability and safety of low dose and high dose baclofen in the treatment of alcohol dependence: A systematic review and meta-analysis

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Abstract

A systematic review of the current literature on the efficacy of baclofen, particularly the effect of dosing, for the treatment of alcohol dependence (AD) is missing. We therefore conducted a systematic review and meta-analysis of currently available randomized placebo-controlled trials (RCTs). A systematic literature search for RCTs in AD patients comparing baclofen to placebo was performed in September 2017. The effect of baclofen treatment, and the moderating effects of baclofen dosing (low-dose (LDB) 30-60 mg versus high-dose (HDB) targeted as >60 mg/day), and the amount of alcohol consumption before inclusion were studied. Three treatment outcomes were assessed: time to lapse (TTL), percentage days abstinent (PDA), and percentage of patients abstinent at end point (PAE). 13 RCTs from 39 records were included. Baclofen was superior to placebo with significant increases in TTL (8 RCTs, 852 patients; SMD=0.42; 95% CI 0.19-0.64) and PAE (8 RCTs, 1244 patients; OR=1.93; 95% CI 1.17-3.17), and a non-significant increase in PDA (7 RCTs, 457 patients; SMD=0.21; 95% CI -0.24 to 0.66). Overall, studies with LDB showed better efficacy than studies with HDB. Furthermore, tolerability of HDB was low, but serious adverse events were rare. Meta-regression analysis showed that the effects of baclofen were stronger when daily alcohol consumption before inclusion was higher. Baclofen seems to be effective in the treatment of AD, especially among heavy drinkers. HDB is not necessarily more effective than LDB with low tolerability of HDB being an import limitation.

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... Baclofen is a GABA B receptor agonist approved by the FDA and used to reduce spasticity associated with neurologic disorders such as multiple sclerosis. Baclofen has been shown to significantly increase the time to first drinking lapse and the percentage of patients abstinent at the end point of the study while also resulting in a trend toward an increase in the percentage of abstinence days when compared to placebo [268]. Of note, the efficacy of a low dose of baclofen was higher than that of a high dose of this drug, which was accompanied by a decrease in tolerability, although the occurrence of serious adverse events was rare [268]. ...
... Baclofen has been shown to significantly increase the time to first drinking lapse and the percentage of patients abstinent at the end point of the study while also resulting in a trend toward an increase in the percentage of abstinence days when compared to placebo [268]. Of note, the efficacy of a low dose of baclofen was higher than that of a high dose of this drug, which was accompanied by a decrease in tolerability, although the occurrence of serious adverse events was rare [268]. In addition, it is worth noting that the effects of baclofen were more significant when the daily alcohol use at baseline was higher [268]. ...
... Of note, the efficacy of a low dose of baclofen was higher than that of a high dose of this drug, which was accompanied by a decrease in tolerability, although the occurrence of serious adverse events was rare [268]. In addition, it is worth noting that the effects of baclofen were more significant when the daily alcohol use at baseline was higher [268]. ...
Article
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Alcohol use disorder (AUD) encompasses the dysregulation of multiple brain circuits involved in executive function leading to excessive consumption of alcohol, despite negative health and social consequences and feelings of withdrawal when access to alcohol is prevented. Ethanol exerts its toxicity through changes to multiple neurotransmitter systems, including serotonin, dopamine, gamma-aminobutyric acid, glutamate, acetylcholine, and opioid systems. These neurotransmitter imbalances result in dysregulation of brain circuits responsible for reward, motivation, decision making, affect, and the stress response. Despite serious health and psychosocial consequences, this disorder still remains one of the leading causes of death globally. Treatment options include both psychological and pharmacological interventions, which are aimed at reducing alcohol consumption and/or promoting abstinence while also addressing dysfunctional behaviours and impaired functioning. However, stigma and social barriers to accessing care continue to impact many individuals. AUD treatment should focus not only on restoring the physiological and neurological impairment directly caused by alcohol toxicity but also on addressing psychosocial factors associated with AUD that often prevent access to treatment. This review summarizes the impact of alcohol toxicity on brain neurocircuitry in the context of AUD and discusses pharmacological and non-pharmacological therapies currently available to treat this addiction disorder.
... Baclofen, a selective g-aminobutyric acid type B (GABAB) receptor agonist, provides a potential treatment for alcohol dependence, with several clinical trials (19)(20)(21)(22), and metaanalyses (23,24) demonstrating efficacy. We have previously reported that baclofen delays time to lapse and relapse relative to placebo (25) in addition to attenuating alcohol cue-elicited brain activation (26), cardiovascular response (27), and emotional regulation during high threat stimuli (28). ...
... Nonetheless, it appears that not all patients respond favorably to baclofen (2,29), such that further understanding of the mechanisms of action of the pharmacotherapy is still required to facilitate a personalized approach (30). The response to baclofen has previously been found to be predicted by baseline anxiety levels (19) and the level of alcohol consumption (23,31). Interestingly, one recently completed trial by Garbutt et al. (22) supports a therapeutic effect of baclofen but also indicates the potential of an enhanced treatment effect for women at low doses and reduced tolerability at higher doses compared to men. ...
... These were the percentage of days abstinent, the number of heavy drinking days, and average drinks per drinking day at week 12. Although baseline differences in drinks per drinking day were not statistically significant, we conducted a follow-up sensitivity analysis including the covariate baseline "average drinks per drinking day" given previous reports that baseline drinking predict treatment response to baclofen (23,31). Finally, we examined the effect of baclofen vs. placebo for each of women and men. ...
Article
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Background and Aims Recent studies indicate that sex may moderate the response to baclofen in the treatment of alcohol use disorder (AUD). We conducted a secondary analysis of a double-blind randomized controlled trial, Baclofen in the treatment of Alcohol Liver Disease (BacALD), to examine the moderating role of sex on treatment response to baclofen in reducing alcohol consumption. Methods Alcohol-dependent patients ( n = 104 including 74 men and 30 women) were treated for 12 weeks with baclofen (30 mg/day or 75 mg) or placebo. Predefined primary outcomes included time to lapse (any drinking) and relapse (≥ 5 drinks per day in men and ≥ 4drinks per day in women). Other outcomes included drinks per drinking day, the number of heavy drinking days, and percentage of days abstinent. We also examined the frequency of adverse events with an exploratory dose–response analysis. Results There was a main effect of baclofen for days to first lapse for women (Log Rank: χ ² = 6.23, p = 0.01, d = 0.49) but not for men (Log Rank: χ ² = 2.48, p = 0.12, d = 0.22) and a marginal effect of baclofen for days to first relapse for women (Log Rank: χ ² = 3.15, p = 0.08, d = 0.27) but not for men (Log Rank: χ ² = 2.03, p = 0.16, d = 0.17). There were no significant effects of sex on the frequency of adverse events reported for the combined-dose or between-dose analysis (all p > 0.44). Conclusion Baclofen significantly delayed the time to lapse for women but not male participants. These findings provide some support for the hypothesis that sex may be a potential moderator of baclofen response in the treatment of AUD. Trial Registration https://clinicaltrials.gov/ct2/show/NCT01711125 , identifier: NCT01711125.
... Based on these preclinical findings, baclofen has been evaluated in multiple human studies. Although less consistent, these studies overall support for the efficacy of baclofen to attenuate alcohol withdrawal symptoms [3] and meta-analyses also support its ability to promote abstinence, in particular in patients with high baseline levels of alcohol consumption [4,5]. ...
... Results for longer-term clinical outcomes have been more mixed, but a meta-analysis found that baclofen significantly improved abstinence rates, with an odds ratio of 2.7 [4]. This conclusion was confirmed and extended by a subsequent meta-analysis, which found that baclofen was superior to placebo, with significant increases in time to lapse and proportion of patients abstinent at endpoint [5]. The latter report also identified a possible reason for apparent discrepancies in the clinical data; it found that baclofen's effects were stronger when daily alcohol consumption before inclusion was high. ...
... Conversely, the capacity of baclofen to restore cortical inhibition may contribute to its clinical efficacy. Targeting the GABA B R system has been suggested to alleviate alcohol withdrawal symptoms, relapse, craving for alcohol, and related AUD psychiatric disorders (e.g., anxiety, depression) [2,5,34]. LICI paradigms result in the inhibition of MEP, which is highly associated with the GABA B Rmediated inhibitory response. ...
Article
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The GABAB receptor (GABABR) agonist baclofen has been used to treat alcohol and several other substance use disorders (AUD/SUD), yet its underlying neural mechanism remains unclear. The present study aimed to investigate cortical GABABR dynamics following chronic alcohol exposure. Ex vivo brain slice recordings from mice chronically exposed to alcohol revealed a reduction in GABABR-mediated currents, as well as a decrease of GABAB1/2R and G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) activities in the motor cortex. Moreover, our data indicated that these alterations could be attributed to dephosphorylation at the site of serine 783 (ser-783) in GABAB2 subunit, which regulates the surface expression of GABABR. Furthermore, a human study using paired-pulse-transcranial magnetic stimulation (TMS) analysis further demonstrated a reduced cortical inhibition mediated by GABABR in patients with AUD. Our findings provide the first evidence that chronic alcohol exposure is associated with significantly impaired cortical GABABR function. The ability to promote GABABR signaling may account for the therapeutic efficacy of baclofen in AUD.
... Meta-analyses conclude that baclofen seems to be an effective treatment for AUD whereby high doses (>60 mg) were not more effective than low doses of baclofen (30-60 mg) although this may be explained by low tolerability (Pierce, Sutterland, Beraha, Morley, & van den Brink, 2018). ...
... Higher doses of baclofen (>60 mg/day) are not considered more efficacious in reducing alcohol consumption outcomes than lower doses, and patients generally demonstrate lower tolerability with higher doses (Pierce et al., 2018). However, further evaluation doseresponse relationships are an important direction for understanding the implications of higher doses of baclofen and potential subgroups that may derive most benefit (Agabio et al., 2018). ...
... Additionally, other dose-specific psychophysiological baclofen effects have been seen in our study exhibiting high-dose baclofen effects on attenuation of BOLD response during fMRI alcohol cue reactivity (Logge et al., 2019). Taken together, psychophysiological indices of baclofen treatment effects may reveal a subset of patients that are more tolerant or derive greater benefits from higher doses, such as heavier drinkers with more severe AUD (Pierce et al., 2018). ...
Article
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Objective: To assess whether baclofen-treated alcohol dependent participants show different subjective and psychophysiological responses to appetitive cues during an alcohol cue reactivity task compared to placebo, and whether these responses are associated with prospective drinking outcomes. Methods: Forty-two alcohol dependent participants (placebo: n = 12, low-dose baclofen [30 mg/day] n = 18, high-dose baclofen [75 mg/day]: n = 12) completed an alcohol cue reactivity task, whereby water and alcohol beverage cues were presented, with subsequent recovery periods, and subjective alcohol craving and psychophysiological indices (skin conductance; cardiovascular measures: heart rate, high-frequency heart rate variability) were recorded. Results: High-dose baclofen-treated participants showed both overall cue reactivity to water and alcohol cues and greater recovery effects during recovery periods, revealed by high-frequency heart rate variability, when compared to low-dose- and placebo-treated participants. There were no medication effects on subjective craving. In high-dose baclofen participants only, there was a predictive effect of lower baseline heart rate variability and fewer post-test percentage of heavy drinking days. Conclusion: There was a dose-specific rescuing effect of high-dose baclofen on the dynamic modulation of cardiovascular responses to eliciting cues. Investigation of treatment responses using psychophysiological techniques may elucidate baclofen's mechanisms of action, and identify subgroups amenable to treatment.
... On the other hand, an earlier meta-analysis (68), including only baclofen studies with 30 mg/day baclofen, reported that baclofen significantly increased the rate of abstinent patients, compared to controls, at the end of treatment. A significant effect of baclofen for the same outcome was confirmed by two other recent meta-analyses in which more RCTs were included (69,70). One of these meta-analyses also found that baclofen significantly increased the time to lapse, compared to placebo ...
... (69). However, a subgroup-analysis found a significant positive effect only across studies using 30-60 mg/day baclofen and not in the analysis of studies using higher doses of baclofen (69). 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 (67-70), alcohol craving (68,70), depression (70), or anxiety (70). ...
... Among the RCTs published to date (see Table 1), one study did not report the gender of patients (38) and the others recruited a total of 302 female patients (25.3% of the entire sample) and 893 male patients (74.7%) (33)(34)(35)(36)(37)(39)(40)(41)(42)(43)(44)(45). Unfortunately, the individual RCTs did not provide data analyzed by gender and none of the meta-analyses (to date) have evaluated this aspect (67)(68)(69)(70). The lack of gender analysis has been already described for the other medications approved for the treatment of AUD (84). ...
Article
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Alcohol use disorder (AUD) is a brain disorder associated with high rates of mortality and morbidity worldwide. Baclofen, a selective gamma-aminobutyric acid-B (GABA-B) receptor agonist, has emerged as a promising drug for AUD. The use of this drug remains controversial, in part due to uncertainty regarding dosing and efficacy, alongside concerns about safety. To date there have been 15 randomized controlled trials (RCTs) investigating the use of baclofen in AUD; three using doses over 100 mg/day. Two additional RCTs have been completed but have not yet been published. Most trials used fixed dosing of 30–80 mg/day. The other approach involved titration until the desired clinical effect was achieved, or unwanted effects emerged. The maintenance dose varies widely from 30 to more than 300 mg/day. Baclofen may be particularly advantageous in those with liver disease, due to its limited hepatic metabolism and safe profile in this population. Patients should be informed that the use of baclofen for AUD is as an “off-label” prescription, that no optimal fixed dose has been established, and that existing clinical evidence on efficacy is inconsistent. Baclofen therapy requires careful medical monitoring due to safety considerations, particularly at higher doses and in those with comorbid physical and/or psychiatric conditions. 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.
... Baclofen, a GABA B receptor agonist, is a relatively new medication for AUD that has demonstrated efficacy in some but not all clinical trials (for meta-analyses, see [7][8][9]), with some indications that higher doses of baclofen (>60 mg/day) are less tolerated and less effective than lower doses [7] even though open-label and case report studies have advocated for enhanced efficacy of baclofen with doses up to 300 mg/day, e.g., see de Beaurepaire [10]. Pierce et al. [7] found some evidence that higher levels of pretreatment alcohol consumption were associated with a stronger response to baclofen. ...
... Baclofen, a GABA B receptor agonist, is a relatively new medication for AUD that has demonstrated efficacy in some but not all clinical trials (for meta-analyses, see [7][8][9]), with some indications that higher doses of baclofen (>60 mg/day) are less tolerated and less effective than lower doses [7] even though open-label and case report studies have advocated for enhanced efficacy of baclofen with doses up to 300 mg/day, e.g., see de Beaurepaire [10]. Pierce et al. [7] found some evidence that higher levels of pretreatment alcohol consumption were associated with a stronger response to baclofen. ...
... Baclofen, a GABA B receptor agonist, is a relatively new medication for AUD that has demonstrated efficacy in some but not all clinical trials (for meta-analyses, see [7][8][9]), with some indications that higher doses of baclofen (>60 mg/day) are less tolerated and less effective than lower doses [7] even though open-label and case report studies have advocated for enhanced efficacy of baclofen with doses up to 300 mg/day, e.g., see de Beaurepaire [10]. Pierce et al. [7] found some evidence that higher levels of pretreatment alcohol consumption were associated with a stronger response to baclofen. Baclofen has also attracted interest in the medical community as it is the only medication, to date, that has shown efficacy for reducing drinking safely in patients with clinically relevant alcohol-associated liver disease [11,12]. ...
Article
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Identification of new medications for alcohol use disorder (AUD) is important for improving treatment options. Baclofen, a GABA B agonist, has been identified as a potential pharmacotherapy for AUD. In a 16-week double-blind, randomized, placebo-controlled trial, we investigated 30 and 90 mg/day of baclofen compared to placebo and examined effects of dose, sex, and level of pretreatment drinking. One hundred and twenty participants with DSM-IV alcohol dependence (age 46.1 (sd = 10.1) years, 51.7% male) were randomized after exclusion for unstable medical/psychiatric illness and/or dependence on drugs other than nicotine. Seventy-three participants completed the trial. A main effect of baclofen was found [%HDD (F(2,112) = 4.16, p = 0.018, d = 0.51 95%CI (0.06–0.95), 13.6 fewer HDD) and %ABST (F(2,112) = 3.68, p = 0.028, d = 0.49 95%CI (0.04–0.93), 12.9 more abstinent days)] and was driven by the 90 mg/day dose. A sex × dose interaction effect was present for both %HDD (F(2,110) = 5.48, p = 0.005) and %ABST (F(2,110) = 3.19, p = 0.045). Men showed a marginally positive effect for 90 mg/day compared to PBO (%HDD t(110) = 1.88, p = 0.063, d = 0.36 95%CI (−0.09–0.80), 15.8 fewer HDD days; %ABST t(110) = 1.68 ( p = 0.096, d = 0.32 95%CI (−0.12–0.76), 15.7 more ABST)) with no effect for 30 mg/day. Women showed a positive effect for 30 mg/day (%HDD, t(110) = 3.19, p = 0.002, d = 0.61 95%CI (0.16–1.05), 26.3 fewer HDD days; %ABST t(110) = 2.73, p = 0.007, d = 0.52 95%CI (0.07–0.96), 25.4 more ABST days) with marginal effects for 90 mg/day on %ABST ( p = 0.06) with drop-outs/dose reduction from sedative side-effects of 59% in women at 90 mg/day compared to 5% for men. These findings support the hypothesis that baclofen has efficacy in AUD and suggest that dose and sex be further explored as potential moderators of baclofen response and tolerability.
... Baclofen has been extensively evaluated as a potential pharmacotherapy for relapse prevention in severe alcohol use disorder, with several case studies, open-label studies and RCTs. Additionally, there have been multiple meta-analyses evaluating the efficacy of baclofen (Bschor et al. 2018;Lesouef et al. 2014;Pierce et al. 2018;Rose and Jones 2018). Despite this body of work, the evidence is still equivocal regarding baclofen's superiority over placebo for relapse prevention, as presented in a recent consensus statement by leading researchers investigating baclofen (Agabio et al. 2018). ...
... Despite this body of work, the evidence is still equivocal regarding baclofen's superiority over placebo for relapse prevention, as presented in a recent consensus statement by leading researchers investigating baclofen (Agabio et al. 2018). Low-to-moderate baclofen doses are defined here as 60 mg/day, with high doses >60 mg/day (Pierce et al. 2018)the latter including very high doses of more than 300 mg/day (de Beaurepaire 2014). ...
... Factors that may account for the disparity in these studies' findings (Leggio et al. 2010) have included the relatively lower severity of AUD in the USA study, coupled with a high placebo response for both studies Ponizovsky et al. 2015), as compared to studies demonstrating significant baclofen treatment effects. Indeed, a recent meta-analysis showed that baclofen was more effective for high drinking levels (Pierce et al. 2018), and similar effect was found in the Australian baclofen trial (Rombouts et al. 2019), suggesting that baclofen may have a significant beneficial effect in severe AUD cases only. ...
Chapter
Harmful alcohol use and alcohol use disorders (AUD) result in major health and community burden worldwide, yet treatment options are limited. Novel pharmacotherapies are urgently required, and treatments involving GABAB receptors have been used in treating alcohol-related disorders. This chapter will review the clinical evidence of GABAB pharmacotherapies, such as baclofen and γ-hydroxybutyric acid. This includes the use of these treatments in individuals experiencing alcohol withdrawal symptoms and outlining the outcomes of studies of alcohol relapse prevention relapse including case studies, comparative studies and randomised controlled trials. Laboratory research investigating biobehavioural effects of baclofen will also be summarised and polymorphisms associated with baclofen treatment, and safety concerns of GABAB treatments will be addressed. In summary, pharmacological treatments targeting GABAB receptors such as baclofen may be modestly effective in the management of alcohol use disorder, but safety concerns limit the widespread applicability of the currently available agents.
... These trials were recently pooled in meta-analyses, 4 of which were published by different teams of authors during the same year, 2018. The different meta-analyses [11][12][13][14] examined different RCTs in specified analyses, studied different outcomes, were performed in different ways, and did not reach the same conclusions. These meta-analyses are therefore individually examined in the next sections. ...
... Four meta-analyses published in the same year looked at much the same research but in different ways, so it's not surprising that their findings differed. Baclofen was found superior to placebo for abstinence rates, 11 to be borderline superior to placebo for amount of drinking, 12 to outperform placebo with regard to both time to relapse and endpoint abstinence rates (but, clearly so, only in doses of 60 mg/d or lower), 13 and to be no better than placebo or even worse than placebo. 14 The only meta-analysis to find a clear advantage for baclofen was a meta-analysis that was also methodologically flawed. ...
... 14 The only meta-analysis to find a clear advantage for baclofen was a meta-analysis that was also methodologically flawed. 13 Only 1 meta-analysis stated a single primary outcome, and all meta-analyses tested multiple hypotheses without correcting for a type 1 statistical error (because such correction is not customary in metaanalysis). These findings discourage the consideration of baclofen for patients with AUD. ...
Article
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Alcohol use disorders (AUD) are common and impairing. Many pharmacologic interventions have been approved for AUD; baclofen is one among these. More than a dozen randomized controlled trials (RCTs) have examined the safety and efficacy of baclofen in AUD; these RCTs have been pooled in 4 recent meta-analyses, each with different study selection criteria, different objectives, different methods, and different results. The general impression from these meta-analyses is that the benefits with baclofen are unimpressive in patients with AUD. With the background that individualized, rather than fixed, high dosing with baclofen could be critical for success, a large (n = 320), industry-independent, 62-center French RCT (the Bacloville trial) examined whether individually uptitrated, high-dose baclofen could reduce alcohol consumption in heavy drinkers across a year of treatment. The study design, the high dropout rate, and the statistical methods of this trial threw up several complexities; in consequence, the main primary and secondary outcomes could not be satisfactorily interpreted. However, there were many other secondary outcomes that seemed to favor baclofen over placebo, though certain concerns remained. This RCT is explained and its findings are carefully dissected and interpreted. It is concluded that individualized treatment with high-dose baclofen (30-300 mg/d) may be a useful second-line approach in heavy drinkers who wish to reduce levels of alcohol intake; baclofen may be particularly useful in patients with liver disease, for whom certain other pharmacologic interventions are relatively contraindicated. However, the risk of serious adverse events with high-dose baclofen, and its pharmacodynamic interaction with alcohol, must both be kept in mind. Practical issues are discussed.
... There have been few studies investigating the predictive role of baseline clinical characteristics on treatment response to baclofen. Baclofen has been found to be more effective in patients that consumed a larger number of drinks at baseline (Pierce et al., 2018). In addition, baclofen has been found to be more effective in AUD patients with comorbid anxiety disorder relative to those without a comorbid anxiety disorder (Morley et al., 2014). ...
... patients consuming a greater number of drinks per drinking day before commencement of treatment. This is consistent with the findings of a recent meta-analysis which demonstrated that baclofen response is predicted by the number of drinks consumed at baseline whereby higher alcohol consumption at baseline resulted in beneficial treatment response (Pierce et al., 2018). It is of interest that in France, where baclofen as a treatment for alcohol dependence was widely publicised in recent years, patients who actively sought treatment with baclofen were indeed among the heavier drinkers (in one study averaging 980 g ethanol per week compared to those not specifically seeking baclofen who reported consuming 700 g/week- Simioni et al., 2016). ...
... The current medical debate focuses on the dose dependent effect of baclofen. A recent meta-analysis, which included the results of 13 baclofen trials amongst the results of the BacALD study, also concluded that high dose (>60 mg) was not more effective than low dose of baclofen (30-60 mg) in increasing time to lapse (Pierce et al., 2018). In the current analysis, we observed that the effectiveness of baclofen was greater in patients with higher baseline alcohol consumption, irrespective of the dose of baclofen such that we did not detect significant dose-dependent differences in predictors of baclofen effectiveness. ...
Article
Aim: To examine clinical predictors of treatment response to baclofen in patients with alcohol use disorder (AUD). Methods: Data from a randomised controlled trial (RCT) (N = 104), in which AUD patients received placebo or baclofen (30 mg/day or 75 mg/day) for 12 weeks, were analysed to determine predictive effects of the following four clinical characteristics: alcoholic liver disease (ALD), baseline alcohol consumption, craving and anxiety. Treatment outcomes included: (i) time to lapse and (ii) time to relapse. Results: For both outcome measures, baclofen, irrespective of dose, was more effective when alcohol consumption was higher at baseline. Relative to placebo, baclofen increased time to first lapse in patients with higher baseline alcohol consumption (HR = 0.459, 95% CI = 0.219-0.962, P < 0.05). Similarly, baclofen increased time to first relapse in patients with higher alcohol consumption at baseline (HR = 0.360, 95% CI = 0.168-0.772, P < 0.05). There were no predictive effects of other baseline characteristics on time to lapse nor time to relapse. Directly comparing high dose of baclofen (75 mg/day) with low dose of baclofen (30 mg/day) revealed no differences with regards to predictors of baclofen response. Conclusion: Baclofen, relative to placebo, was more effective when alcohol consumption was higher at baseline.
... This is reflected in recent meta-analyses evaluating baclofen's efficacy, with baclofen associated with higher abstinence rates in alcohol use disorder (AUD) samples versus placebo, but not with other drinking outcomes (Rose and Jones 2018), while the largest meta-analysis identified a modest positive effect superior to placebo when considering non-complicated AUD samples, but ambiguity surrounding baclofen's overall superior effect (Bschor et al. 2018). A meta-analysis examining alcohol-dependent samples indicates a dose-specific effect with efficacy in low doses (< 60 mg/day) for achieving abstinence (Pierce et al. 2018), and the recent Cagliari Consensus statement (Agabio et al. 2018) suggests baclofen's superiority over placebo is yet to be established, and further knowledge of dose-response relationships is required. ...
... However, patient tolerability is lower with higher doses of baclofen, and higher doses (i.e. > 60 mg) are not more effective than lower doses regarding clinical outcomes including time to lapse and overall days abstinent (Pierce et al. 2018). ...
Article
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Rationale Baclofen has been shown to effect fMRI alcohol cue reactivity in alcohol dependence, but potential varying effects related to baclofen dose levels have not been examined. Objective This study investigated whether baclofen attenuates craving and alcohol cue–elicited activation in alcohol-dependent treatment seekers, and the relationship between this response and clinical outcomes (Morley et al. 2018; Morley et al. 2013). Methods Participants included 30 alcohol-dependent individuals who had received daily baclofen 30 mg (n = 11), 75 mg (n = 8) or placebo (n = 11) for at least 2 weeks. Using functional magnetic resonance imaging (fMRI), we examined alcohol cue–elicited neural activation during a visual alcohol cue reactivity task 120 min following treatment administration, and alcohol cue reactivity and percentage of heavy drinking days (% HDD) associations were assessed. Results Both baclofen-treated groups reported fewer post-scan % HDD when compared to the placebo-treated group, but no subjective craving group differences were found. Increased alcohol cue–elicited activation was seen in placebo compared to the 75 mg/day baclofen participants in two clusters spanning prefrontal regions implicated in cue reactivity, chiefly frontal regions (i.e., frontal and precentral gyri, anterior cingulate cortex), but no observed alcohol cue reactivity differences between placebo and 30 mg/day baclofen groups. Post-scan % HDD was positively correlated with increased alcohol cue–elicited activation in a cluster encompassing the bilateral caudate nucleus and dorsal anterior cingulate cortex when comparing placebo versus 75 mg/day baclofen groups, and several clusters including prefrontal and mesolimbic regions when comparing placebo versus 30 mg/day baclofen groups. Conclusions Baclofen administration attenuates alcohol cue–elicited activation and reduced the association in baclofen-treated participants between increased activity in key drug cue reactivity regions and higher post-scan % HDD observed in placebo-treated participants, suggesting a dose-specific response effect that may lead to reduced heavy drinking in chronic alcohol-dependent individuals. Trial registration ClinicalTrials.gov, NCT01711125, https://clinicaltrials.gov/ct2/show/NCT01711125
... Review needed to achieve a therapeutically relevant concentration, but result in a number of side effects that complicate patient compliance and quality of life. 111,112 Upon oral administration, baclofen is rapidly absorbed from the gastrointestinal tract (evidenced by a T max that varies from 1 to 2.79 h in healthy patients), but only within the upper small intestine by saturable active transport mechanisms. 113−116 Oral administration of radiolabeled racemic baclofen achieves an absolute bioavailability of 70−85% with an observed half-life of 3−4 h. ...
... It is likely that baclofen's success in treating AUD is derived from its ability to reduce anxiety or negative mood states, risk factors for harmful drinking. 112,162 Regardless, baclofen has gained approval for the treatment of alcohol addiction/use disorder in France in 2018 and has been used off-label as such for over a decade. 112,163−165 Baclofen and arbaclofen have received increased media attention as a "wonder drug" for the treatment of drug and alcohol addiction, despite its mixed efficacy in appropriately controlled trials. ...
Article
Baclofen, -(4-chlorophenyl)--aminobutyric acid, holds a unique position in neuroscience, remaining the only FDA approved GABAB agonist. While intended to be a more brain penetrant version of GABA (-aminobutyric acid) for the potential treatment of epilepsy, baclofen’s highly efficacious muscle relaxant properties led to its approval, as a racemate, for the treatment of spasticity. Interestingly, baclofen received FDA approval before its receptor, GABAB, was discovered and its exact mechanism of action was known. In recent times, baclofen has a myriad of off-label uses, with the treatment for alcohol abuse and drug addiction garnering a great deal of attention. This article aims to capture the >60 year legacy of baclofen by walking through the history, pharmacology, synthesis, drug metabolism, routes of administration and societal impact of this Classic in chemical neuroscience
... Baclofen, a gamma-aminobutyric acid-B (GABA-B) agonist, increases the abstinence rate and prevents relapse in patients with AUD [189]. Notably, baclofen is the only AUD pharmacotherapy tested in patients with established cirrhosis, although several studies have reported inconsistent results [190][191][192][193]. Nevertheless, a recent international consensus statement recommended the consideration use of baclofen to treat AUD in patients with advanced ALD [194]. ...
... Notably, baclofen is the only AUD pharmacotherapy tested in patients with established cirrhosis, although several studies have reported inconsistent results [190][191][192][193]. Nevertheless, a recent international consensus statement recommended the consideration use of baclofen to treat AUD in patients with advanced ALD [194]. Baclofen [191][192][193][194]199,200] Corticosteroids are the most widely studied interventions in severe AH; they can change the cytokine balance, reduce pro-inflammatory cytokines, and increase anti-inflammatory cytokines [211]. The Maddrey discriminant function is the mostly widely used scoring system for AH, and a cut-off value of 32 identifies patients for initiating corticosteroid therapy [12,212]. ...
Article
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Alcohol-related liver disease (ALD) refers to the liver damage occurring due to excessive alcohol consumption and involves a broad spectrum of diseases that includes liver steatosis, steatohepatitis, hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The progression of ALD is mainly associated with the amount and duration of alcohol usage; however, it is also influenced by genetic, epigenetic, and environmental factors. The definite diagnosis of ALD is based on a liver biopsy, although several non-invasive diagnostic tools and serum biomarkers have emerging roles in the early detection of ALD. While alcohol abstinence and nutritional support remain the cornerstone of ALD treatment, growing evidence has revealed that the therapeutic agents that target oxidative stress or gut-liver axis, inflammatory response inhibition, and liver regeneration enhancement also play a role in ALD management. Furthermore, microRNAs modulation and mesenchymal stem cell-based therapy have emerging potential as ALD therapeutic options. This review summarizes the updated understanding of the pathophysiology, diagnosis, and novel therapeutic approaches for ALD.
... The results of the second trial (NCT01604330) were published as positive despite major limitations, including major changes to the initial protocol and a 2-fold increase in mortality with baclofen. 3 Mortality was not statistically significant, the series being short, but a large-scale French pharmacoepidemiologic study of patients with alcohol use disorder (n¼165,334) retrieved a dose-dependent increase in mortality with baclofen vs acamprosate and naltrexone (see reference 8 in the article by Wallach et al 4 ). Accordingly, the Special Scientific Committee for the assessment of baclofen in alcohol use disorder concluded that the benefit to harm ratio was negative. ...
... Regarding the level of evidence of these studies, the sources we cited were a metaanalysis consisting of 5 randomized controlled trials for namefene 2 and a meta-analysis consisting of 13 randomized controlled trials for baclofen. 3 In the spirit of evidence-based medicine, it would be irresponsible to neglect these data. This sentiment is not a deviation of care as these medications have been discussed in other prominent medical journals regarding pharmacotherapy for alcohol use disorder, including the New England Journal of Medicine 4 and the Journal of American Medical Association. ...
... Based on the present case, the GABA-B agonist baclofen might be considered as a substitute for phenibut, helping to reduce craving and relapse risk. Baclofen has shown similar potential as an anticraving drug in alcohol use disorders 17 and GHB use disorder. 18,19 It can be speculated that baclofen acts as a more long-acting substitute for other short-acting GABA-ergic substances of abuse, including phenibut, GHB, or alcohol. ...
... 18,19 It can be speculated that baclofen acts as a more long-acting substitute for other short-acting GABA-ergic substances of abuse, including phenibut, GHB, or alcohol. [17][18][19] It is unclear whether there is cross-tolerance between baclofen, mainly acting at GABA-B, and substances of abuse mainly acting at GABA-A, such as benzodiazepines. Similarly, it remains to be investigated whether other GABA-analogs, such as gabapentin or pregabalin, might also prove useful for the treatment of phenibut dependence. ...
... While results of randomized controlled trials (RTCs) have been mixed (e.g. Addolorato et al., 2007;Morley et al., 2014;Morley et al., 2018) a recent meta-analysis reported evidence of efficacy at low doses (30-60 mg) for achieving abstinence especially amongst heavy drinkers (Pierce et al., 2018). There has been a growing rate of off-label baclofen prescriptions in Europe, particularly in France (Rolland et al., 2012;Chaignot et al., 2015). ...
... High dose baclofen prescribing is supported by a German RCT (Müller et al., 2015), and has been both widely promoted and conditionally approved for the treatment of AUD in France (Rolland et al., 2016). Most clinical trials report a high tolerability of baclofen (Pierce et al., 2018). Despite this, a number of serious adverse events have been reported in patients treated with baclofen using doses less than 270 mg (Leung et al., 2006;Auffret et al., 2017). ...
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Aim: to describe trends in baclofen reports to Australia's largest Poisons Information Centre (PIC) and present a case series detailing severity of overdoses. Short summary: PBS data demonstrates baclofen use is increasing in Australia, while calls to NSWPIC illustrate an increase in number of exposures associated with toxicity. Baclofen toxicity may require prolonged intensive care admission. To minimize harms associated, especially with off-label baclofen prescribing for AUD, prescribers should pay careful attention to psychiatric comorbidities, and closely monitor treatment and dispensing. Methods: this is a retrospective observational study of baclofen overdoses reported to New South Wales PIC (NSWPIC) from January 1 2004 to 31 December 2016. In addition, referrals to a metropolitan toxicology service relating to baclofen toxicity from 2014 to 2017 were analysed. The number of Pharmaceutical Benefit Scheme (PBS) claims for baclofen were also reviewed. Results: during the 13-year study period, 403 cases of baclofen toxicity were reported to NSWPIC. There was a 230% increase in annual exposures over this period, 71% of patients were symptomatic, with 77% requiring hospitalization. Coingestants were reported in 53%, with 57% being psychoactive medications (including alcohol). An increase in number of baclofen dispensing episodes was also noted. From the five cases of deliberate self-harm reported to the metropolitan toxicology service, three obtained baclofen for management of alcohol use disorder (AUD) and required prolonged treatment in the intensive care unit (ICU). Conclusions: NSWPIC data shows an increase in number of calls regarding intentional baclofen exposures in parallel with increase the number of baclofen PBS claims. These closely parallel the increase in dispensing of baclofen since 2008. Case studies presented reinforce the severity of baclofen toxicity. Together, they demonstrate the potential risk of harm of baclofen prescribing, and the greater need for caution. Baclofen should be considered carefully in patients high risk of overdose or be used only in specialist services with close monitoring.
... A recent meta-analysis of 12 RCTs (N = 703) showed that baclofen in comparison to placebo was associated with higher abstinence rates [81][82][83]; however, it did not increase abstinent days or decrease craving, heavy drinking, depression, or anxiety [84]. Another meta-analysis of 13 RCTs (N = 1492) indicated that baclofen (again vs placebo) was associated with longer time to relapse and a larger percentage of abstinent patients [85]. Furthermore, greater alcohol use at baseline was correlated with a greater treatment effect [85]. ...
... Another meta-analysis of 13 RCTs (N = 1492) indicated that baclofen (again vs placebo) was associated with longer time to relapse and a larger percentage of abstinent patients [85]. Furthermore, greater alcohol use at baseline was correlated with a greater treatment effect [85]. In contrast, however, another recent meta-analysis of 12 RCTs with 1128 total participants found no significant differences between baclofen and placebo in primary (i.e., percent abstinent days, percent heavy-drinking days, return to any drinking, and study dropout) or secondary outcomes of interest (i.e., anxiety and craving); however, baclofen did increase depression and adverse effects including sedation and vertigo [86]. ...
Article
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Alcohol use disorder (AUD) is a highly prevalent but severely under-treated disorder, with only three widely-approved pharmacotherapies. Given that AUD is a very heterogeneous disorder, it is unlikely that one single medication will be effective for all individuals with an AUD. As such, there is a need to develop new, more effective, and diverse pharmacological treatment options for AUD with the hopes of increasing utilization and improving care. In this qualitative literature review, we discuss the efficacy, mechanism of action, and tolerability of approved, repurposed, and novel pharmacotherapies for the treatment of AUD with a clinical perspective. Pharmacotherapies discussed include: disulfiram, acamprosate, naltrexone, nalmefene, topiramate, gabapentin, varenicline, baclofen, sodium oxybate, aripiprazole, ondansetron, mifepristone, ibudilast, suvorexant, prazosin, doxazosin, N-acetylcysteine, GET73, ASP8062, ABT-436, PF-5190457, and cannabidiol. Overall, many repurposed and novel agents discussed in this review demonstrate clinical effectiveness and promise for the future of AUD treatment. Importantly, these medications also offer potential improvements towards the advancement of precision medicine and personalized treatment for the heterogeneous AUD population. However, there remains a great need to improve access to treatment, increase the menu of approved pharmacological treatments, and de-stigmatize and increase treatment-seeking for AUD.
... 23 Previously for AUD, a meta-analysis of 13 RCTs showed that baclofen was associated with greater time to first lapse of drinking and greater likelihood of abstinence versus placebo. 83 A more recent Cochrane review did not replicate these positive results or any other positive alcohol-related outcome. 84 Baclofen is dosed 30 to 80 mg by mouth daily. ...
Article
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Pathologic alcohol use affects more than 2 billion people and accounts for nearly 6% of all deaths worldwide. There are three medications approved for the treatment of alcohol use disorder by the US Food and Drug Administration (FDA): disulfiram, naltrexone (oral and long-acting injectable), and acamprosate. Of growing interest is the use of anticonvulsants for the treatment of alcohol use disorder, although currently none are FDA approved for this indication. Baclofen, a γ-aminobutyric acid B receptor agonist used for spasticity and pain, received temporary approval for alcohol use disorder in France. Despite effective pharmacotherapies, less than 9% of patients who undergo any form of alcohol use disorder treatment receive pharmacotherapies. Current evidence does not support the use of pharmacogenetic testing for treatment individualization. The objective of this review is to provide knowledge on practice parameters for evidenced-based pharmacologic treatment approaches in patients with alcohol use disorder.
... 2,3 Previous reviews on the subject 4,5 demonstrated that the advances in the field of pharmacogenetics in AUD are slow due to many difficulties and it is important to advance the precision medicine approaches for the treatment of AUD. According to available data of meta-analyses and systematic reviews, the following medications showed their efficacy in comparison with placebo: disulfiram, 6 naltrexone, 7 extended-release injectable naltrexone, 7 acamprosate, 7 nalmefene, 8 baclofen, 9 gabapentin, 10 and topiramate. 11 We may now consider the available scientific evidence bearing on the effects of single nucleotide polymorphisms (SNPs) on pharmacokinetics, pharmacodynamics, as well as on clinical efficacy and safety of the alcohol addiction treatment. ...
Article
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Genetics of alcohol addiction is currently a contradictive and complex field, where data in the most studies reflect methods' limitations rather than meaningful and complementary results. In our review, we focus on the genetics of alcohol addiction, leaving genetics of acute alcohol intoxication out of the scope. A review of the literature on pharmacogenetic biomarkers development for the pharmacotherapy personalization reveals that today the evidence base concerning these biomarkers is still insufficient. In particular, now the researches with the design of randomized controlled trials and meta-analysis investigating the effect of the SNPs as biomarkers on the therapy efficacy are available for naltrexone only. For other medications, there are only a few studies in small samples. It decreases the possibilities to implement the pharmacogenetic algorithms for the pharmacotherapy personalization in patients with alcohol use disorders (AUD). In view of the importance of the precision approaches development not in addiction medicine only, but in other fields of medicine also to increase the efficacy and safety of the therapy, studies on pharmacogenetic biomarkers development for the medications used in patients with AUD (eg, naltrexone, disulfiram, nalmefene, acamprosate, etc.) remain relevant to this day.
... There are additional approved medications that have some support for their efficacy in alcohol addiction, suggesting that they could be considered for repurposing. These include the nicotinic partial agonist varenicline 33,34 that has marketing approval for smoking cessation, and the GABA-B agonist baclofen [35][36][37][38][39][40][41][42] , which has long been used for spasticity. ...
Article
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Excessive alcohol use is the cause of an ongoing public health crisis, and accounts for ~5% of global disease burden. A minority of people with recreational alcohol use develop alcohol addiction (hereafter equated with “alcohol dependence” or simply “alcoholism”), a condition characterized by a systematically biased choice preference for alcohol at the expense of healthy rewards, and continued use despite adverse consequences (“compulsivity”). Alcoholism is arguably the most pressing area of unmet medical needs in psychiatry, with only a small fraction of patients receiving effective, evidence-based treatments. Medications currently approved for the treatment of alcoholism have small effect sizes, and their clinical uptake is negligible. No mechanistically new medications have been approved since 2004, and promising preclinical results have failed to translate into novel treatments. This has contributed to a reemerging debate whether and to what extent alcohol addiction represents a medical condition, or reflects maladaptive choices without an underlying brain pathology. Here, we review this landscape, and discuss the challenges, lessons learned, and opportunities to retool drug development in this important therapeutic area.
... In humans, Baclofen has been found to be more effective in patients that consumed a larger number of drinks at baseline (Pierce et al., 2018). We previously showed in the post-dependent state model of AUD that the blood Baclofen levels were correlated to the efficacy to decrease alcohol drinking in male rats, at the two tested doses of RS(±)-Baclofen (1 or 2mg/kg) (Echeverry-Alzate et al., 2020). ...
... The role of the GABA B receptor as a pharmacological target in the treatment of alcohol use disorder (AUD) has received increased attention in recent decades, with some clinical trials indicating that baclofen may reduce alcohol craving and drinking and promote abstinence [for review see de Beaurepaire et al., 2019]. However, human data are inconsistent (see meta-analytic studies: Bschor et al., 2018;Minozzi et al., 2018;Pierce et al., 2018;Rose and Jones, 2018), which may be due, at least in part, to the heterogeneity of the enrolled samples, and differences in study designs and dosage regimes. Baclofen has been approved for AUD treatment in France, in patients who have not responded to other approved treatments (de Beaurepaire et al., 2019). ...
Article
Given the high coexistence of anxiety symptoms in people with alcohol use disorder (AUD), we aimed to determine the influence of anxiety symptoms on outcomes in patients with AUD treated with GABAB receptor agonist baclofen. A meta-analysis of 13 comparisons (published 2010-2020) including baseline and outcome data on alcohol consumption and anxiety after 12 weeks was undertaken. There were significantly higher rates of abstinent days in patients treated with baclofen compared to placebo (p = 0.004; high certainty evidence); specifically in those with higher baseline anxiety levels (p < 0.00001; high certainty evidence) compared to those with lower baseline anxiety levels (p = 0.20; moderate certainty evidence). The change in anxiety ratings over 12 weeks did not differ between those treated with baclofen or placebo (p = 0.84; moderate certainty evidence). This may be due to different anxiety constructs being measured by scales not validated in this patient group, or that anxiety is not a biobehavioral mechanism by which baclofen may reduce alcohol drinking. Given the prevalence of anxiety symptoms in AUD all these factors warrant further research.
... Although the subgroups of low-, medium-and high-alcohol-drinking rats did not differ in their response to these compounds, we did observe substantial variation in the responsivity to baclofen and naltrexone across the subpopulations. The variation between individuals in their response to baclofen and to naltrexone parallels human reports of variation in efficacy of these compounds in the treatment of AUD (Kiefer et al., 2008;Pierce et al., 2018). Taken together, these findings suggest that individual differences in alcohol consumption and in responsivity to baclofen and naltrexone treatment are orthogonal processes, which likely involve differential biological mechanisms. ...
Article
In humans, there is profound individual variation in the risk of alcohol use disorder (AUD). Because GABA, opioid and glutamate neurotransmission have been implicated in AUD, functional differences in these neural systems may underlie the individual vulnerability to AUD. We therefore determined the effects of drugs affecting GABA, opioid and glutamatergic neurotransmission on alcohol consumption in rats that differed in baseline alcohol intake. Subgroups of low-, medium- and high-alcohol-drinking rats were selected on the basis of alcohol consumption using an intermittent alcohol access procedure. The subgroups were treated with the GABAB receptor agonist baclofen, the opioid receptor antagonist naltrexone and the cysteine precursor N-acetylcysteine, and the effects on alcohol intake and preference were determined. Both baclofen and naltrexone reduced alcohol consumption, but N-acetylcysteine did not. These effects were comparable for low-, medium- and high-alcohol-drinking rats. However, there was a substantial degree of individual variation in the responsivity to baclofen and naltrexone, across the subgroups. Taken together, these results suggest that variation in alcohol consumption does not predict the responsivity to baclofen and naltrexone. This implies that individual variability in alcohol consumption on the one hand and sensitivity to treatment with these drugs on the other hand represent separate processes that likely involve distinct biological mechanisms.
... These analyses report results from 7 to 14 studies totaling anywhere from 590 to 1522 subjects in multiple trials utilizing different dosages across different countries in diverse populations with multiple outcomes. Not surprisingly given this heterogeneity, the evidence for efficacy is mixed though only a few outcomes (total abstinence, time to lapse) in two meta-analyses (Rose and Jones, 2018;Pierce et al., 2018) were reported as showing superiority for baclofen. Furthermore, Pierce et al. (2018) noted low tolerability to higher doses of baclofen (>60 mg/day). ...
... Tais pačiais metais metaanalizė (Pierce, M et al., 2018), kuri apžvelgė 13 atsitiktinių imčių placebu kontroliuotų tyrimų su 1 492 pacientais, demonstravo baklofeno efektyvumą, lyginant su placebu. Metaanalizė parodė, kad baklofenu gydyti pacientai žymiai vėliau nuo tyrimo pradžios pavartodavo alkoholio ir tikimybė, kad visiškai susilaikys nuo alkoholio vartojimo gydymo pabaigoje, buvo žymiai didesnė, lyginant su placebu. ...
Book
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Guidelines include description about usefulness of screening questionnaires (AUDIT, AUDIT C) and biological markers in diagnostics and management of alcohol use disorders. Diagnostic criteria for alcohol dependence, harmful alcohol use and alcohol withdrawal according ICD-10 are presented. Guidelines for medical treatment of alcohol withdrawal and alcohol dependence are presented (disulfiram, acamprosate, naltrexone, nalmefene, baclofen). Guidelines for the care of co-morbid conditions are also presented.
... Baclofen (BAC), [4-amino-3-(β-chlorophenyl) butyric acid], is an analog of γ-aminobutyric acid (GABA), which is an inhibitory neurotransmitter. It is one of the stereoselective agonists for the GABAB receptor (Bowery, 1989) and is mostly used as a muscle relaxant in treatment of spasticity occurring secondary to multiple sclerosis, tardive dystonia, cerebral and spinal cord injury, tetanus, cerebral palsy (Hayek et al., 2003) and in long-term treatment of alcohol dependence and disorder at both normal and high doses (Bschor et al., 2018;Pierce et al., 2018). ...
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An efficient, economic and high yielding method is described for the synthesis of baclofen (BAC) pharmacopoeial impurities (impurities A and B) which can be used for gram scale synthesis. Furthermore, a novel ecofriendly TLC‐densitometric method was established and validated for the determination of BAC and its synthesized impurities. The developed TLC‐densitometric method is based on the chromatographic separation using thin layer chromatographic (TLC) plates (60 F254) using a green mobile phase of ethyl acetate: methanol: ammonia solution "33%" (8:2:0.1, by volume) with UV scanning at 220 nm. The proposed method was validated with respect to ICH guidelines. The validated method was successfully applied for determination of BAC in pure form and in its commercial dosage form. Additionally, greenness profile of the developed method was evaluated and compared to those of the reported chromatographic methods. The developed method was found to be superior over the published methods being environmentally benign.
... Clinically, baclofen has shown promising, although conflicting, results for the treatment of alcohol addiction (Addolorato et al. 2007;Pierce et al. 2018;; see also For instance, we have recently found that the selective GABA B PAM, ADX71441 (3, 10 mg/kg), potently suppressed both cue-and stress (footshock)-induced reinstatement of alcohol seeking in Wistar rats (Augier et al. 2017a). Moreover, ADX71441 attenuated stress-induced neuronal activity, indexed by cFos activity, in an interconnected network of brain structures that included NAc shell, mPFC and the dorsal raphe nucleus. ...
Article
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Alcohol addiction is a chronic relapsing brain disease characterized by an impaired ability to stop or control alcohol use despite adverse consequences. A main challenge of addiction treatment is to prevent relapse, which occurs in more than >50% of newly‐abstinent patients with alcohol disorder within 3 months. In people suffering from alcohol addiction, stressful events, drug‐associated cues and contexts, or re‐exposure to a small amount of alcohol trigger a chain of behaviors that frequently culminates in relapse. In this review, we first present the preclinical models that were developed for the study of alcohol seeking behavior, namely the reinstatement model of alcohol relapse and compulsive alcohol seeking under a chained schedule of reinforcement. We then provide an overview of the neurobiological findings obtained using these animal models, focusing on the role of opioids systems, corticotropin‐release hormone and neurokinins, followed by dopaminergic, glutamatergic, and GABAergic neurotransmissions in alcohol seeking behavior.
... This receptor provides a negative feedback loop for the GABA-ergic system thereby downregulating GABA-A activity and mimicking some of the effects of alcohol induced action on the GABA-A receptor [for more in depth discussion of the baclofen mechanism see (9)]. Baclofen was initially and is commonly used as a muscle relaxant but has been found to have a positive effect on alcohol craving and relapse prevention [for a review see (10)]. In the light of this, animal studies were conducted and baclofen was shown to prevent withdrawal in rats made dependent on alcohol (11,12). ...
Article
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The Alcohol Withdrawal Syndrome (AWS), which may occur with or without delirium, is a frequent consequence of sudden alcohol cessation in patients with moderate to severe Alcohol Dependence Syndrome (ADS). Withdrawal as a result of habituation to alcohol is part of the definition of the Alcohol Dependence Syndrome (ICD10). Since the recognition of Delirium Tremens, in the early nineteenth century, the management of the syndrome, an acute medical emergency, has proven controversial. The barbiturates, chlormethiazole, and recently the safer benzodiazepines transformed the management of these conditions. The benzodiazepines, particularly diazepam and chlordiazepoxide, are now the most used first line agents in the treatment of AWS. In addition, a number of other agents, including baclofen, a GABA-B receptor agonist, have the potential to suppress the alcohol withdrawal syndrome. In this review we review the potential use of baclofen in its role to treat AWS. We summarize initial case reports as well as more recent randomized trials of AWS treatment with baclofen. We conclude that currently there is not enough evidence to support the use of baclofen as a first line treatment for AWS. More research will be needed to determine where baclofen might have a role in second-line management of the Alcohol Withdrawal Syndrome on its own or in combination with benzodiazepines or other agents.
... The authors did not find any difference between baclofen and placebo and concluded that the evidence regarding the use of baclofen as a first-line treatment for AUD is uncertain. Conversely, a meta-analysis by Pierce et al. 21 evaluated 13 randomized controlled trials and concluded that baclofen seems to be effective in the treatment of alcohol dependence, especially among heavy drinkers. ...
Article
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Baclofen is an effective therapeutic for the treatment of spasticity related to multiple sclerosis, spinal cord injuries, and other spinal cord pathologies. It has been increasingly used off-label for the management of several disorders, including musculoskeletal pain, gastroesophageal reflux disease, and alcohol use disorder. Baclofen therapy is associated with potential complications, including life-threatening toxicity and withdrawal syndrome. These disorders require prompt recognition and a high index of suspicion. While these complications can develop following administration of either oral or intrathecal baclofen, the risk is greater with the intrathecal route. The management of baclofen toxicity is largely supportive while baclofen withdrawal syndrome is most effectively treated with re-initiation or supplementation of baclofen dosing. Administration of other pharmacologic adjuncts may be required to effectively treat associated withdrawal symptoms. This narrative review provides an overview of the historical and emerging uses of baclofen, offers practical dosing recommendations for both oral and intrathecal routes of administration, and reviews the diagnosis and management of both baclofen toxicity and withdrawal.
... The current FDA-approved pharmacotherapuetic options (naltrexone, disulfiram, acamprosate) for AUD are lacking in that no single agent has proven to be a safe and effective outpatient treatment for alleviating withdrawal symptoms, reducing harmful drinking, and promoting abstinence. Evidence-based non-FDA approved AUD pharmacotherapy (Kranzler & Soyka, 2018), including gabapentin (Kranzler et al., 2019;Leung et al., 2015), topiramate (Blodgett et al., 2014), and baclofen (Pierce et al., 2018), is available, but not frequently prescribed in the community. ...
Article
Background Despite advances in development of pharmacotherapy for alcohol use disorder (AUD), the need for medication treatment that can be administered to actively drinking outpatients that promotes reduction in harmful alcohol consumption remains. The primary aim of this pilot study was to determine whether high-dose gabapentin (3600 mg/daily) is more effective than placebo in reducing harmful alcohol consumption in outpatients with alcohol use disorder. Methods Women and men (n = 40) who met DSM-IV-TR criteria for alcohol dependence and reporting at least 4 heavy drinking days (HDD) per week were recruited at a single site. Participants were actively-drinking at study entry and received double-blind gabapentin (3600 mg/day) or placebo for 8-weeks. Study medication was titrated over 5 days and administered in three divided doses (1200 mg three times per day). The proportion of HDD (primary outcome) and percent days abstinent (PDA) (secondary outcome) were analyzed using generalized longitudinal mixed models with predictors study arm, week, study arm by week interaction, and baseline outcome. Results A significant interaction between study arm and week was found (F7,215=3.33, p=.002) for proportion of HDD per week. A significant interaction between study arm and week was found (F7,215=3.11, p=0.004) for PDA per week. The overall retention rate was 67.5% with no significant difference in time-to-dropout between treatment groups. There were no serious adverse events. No participants were removed from the trial for the development of moderate-to-severe alcohol withdrawal (CIWA ≥ 13). Conclusions Gabapentin treatment rapidly titrated to a dose of 3600 mg per day is associated with a reduction in the proportion of HDD per week and an increase in PDA per week in actively drinking outpatients with AUD. High-dose gabapentin is potentially a feasible approach to treating AUD and deserving of further study.
... According to randomised clinical trials, baclofen may reduce craving for alcohol and significantly reduce alcohol consumption ( Addolorato et al. 2011, Muller et al. 2015, Ponizovsky et al. 2015, Reynaud et al. 2017. Meta-analyses confirm that the drug significantly increases the chances of maintaining abstinence and extends the time to relapse (Thomson et al. 2017, Pierce et al. 2018). This drug is more effective in patients with severe addiction, who drink alcohol intensively in large quantities ( Beraha et al. 2016, Agabio et al. 2018). ...
Article
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The article presents update of the 2013 Guidelines of the Pharmacotherapy Section of the Polish Society for Research on Addictions (PTBU) and the Psychopharmacology Section of the Polish Psychiatric Association (PTP) on long-term pharmacotherapy aimed at maintaining abstinence or reducing alcohol intake in adult alcohol-dependent patients. Apart from practical guidelines for long-term pharmacotherapy of alcohol dependence, the authors present the areas of uncertainty, which still require further studies and scientific debate.
Article
Outcome assessment in the pharmacological treatment of alcohol use disorders (AUDs) faces specific challenges resulting from low adherence to treatment, high rates of dropout, and the susceptibility of patient self-reports to bias. This review discusses methodological issues in planning, conducting, and interpreting clinical trials on AUD treatment against the background of the principle of ‘strictness and fairness’ of testing. Threats to fairness include factors that limit the implementation of an intervention, such as low compliance and early treatment termination. In turn, fairness of testing is increased by factors that support the degree to which an intervention is implemented, such as the use of adequate pretreatments and the matching of psychosocial and pharmacological treatment strategies. Furthermore, selecting outcomes on the basis of an intervention’s mechanism of action and including continuous outcomes as sensitive measures of drinking change further increases fairness by increasing the likelihood that the data will adequately reflect the effects of the intervention. On the other hand, strictness of testing is increased by all measures that limit the influence of confounders that could potentially lead to an overestimation of effects. The use of a side effect-mimicking placebo to prevent an unmasking of blinding and the repeated assessment of alcohol biomarkers to validate drinking self-reports might be valid strategies to further increase the strictness of testing by limiting risks of bias in trials of AUD treatment.
Article
Introduction: Depression and alcohol dependence are frequently co-morbid and among the most prevalent mental disorders. They are a serious global health problem with social, interpersonal, and legal interpolations. Among pharmacological alternatives, anti-craving compounds as well as antidepressants, antipsychotics, anticonvulsants, benzodiazepines, and beta-blockers have shown efficacy for depression as well as alcohol consumption. The pharmacological treatment of both complex interwoven mental diseases is still challenging given the inconsistent results of open and double-blind randomized placebo-controlled studies with approved and open label medications. Areas covered: The authors provide a systematic review of the literature with PubMed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to obtain an overview of the pharmacotherapeutic options for co-morbid depression and alcohol dependence. Expert opinion: The effect of treating only depressive or alcohol-related symptoms appears limited. Therapies directly targeting the addiction are warranted among such dually diagnosed patients. Despite limited data, the reviewed pharmacotherapeutic treatments demonstrated efficacy in most but not in all relevant parameters of alcohol dependence and depression.
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Heavy drinking and alcohol use disorder are major public health problems. Practitioners not specialising in alcohol treatment are often unaware of the guidelines for preventing, identifying, and treating heavy drinking and alcohol use disorder. However, a consensus exists that clinically useful and valuable tools are available to address these issues. Here, we review existing information and developments from the past 5 years in these areas. We also include information on heavy drinking and alcohol use disorder among individuals with co-occurring psychiatric disorders, including drug use disorders. Areas covered include prevention; screening, brief intervention, and referral for treatment; evidence-based behavioural interventions; medication-assisted treatment; technology-based interventions (eHealth and mHealth); and population-level interventions. We also discuss the key topics for future research.
Chapter
Neuromuscular blocking agents and skeletal muscle relaxants are commonly used medications in the critically ill patient population. Like all medications, these come with adverse effects that must be evaluated and taken into consideration when choosing a particular medication. Adverse effects are directly related to their mechanism of action on the central nervous system and skeletal muscle, but can also extend to multiple other organ systems such as respiratory system, cardiovascular system, gastrointestinal system, and renal system. The following literature is an update from previous volumes of Side Effects of Drug Annual that describes adverse effects with neuromuscular blockers and skeletal muscle relaxants.
Article
Alcohol Use Disorder (AUD) is a common mental disorder with severe medical, psychological and social consequences [1]. AUD leads up to 3- and 4-fold increases in the risk of mortality in men and women, respectively [2]. Nevertheless, less than 10% of people with AUD seek and receive treatment for their disorder and less than 4% receive any pharmacological intervention [3]. The identification of new medications is crucial to increase the number of people with AUD who receive effective treatment. Baclofen, a GABAB receptor agonist approved for clinical use as a muscle relaxant, has emerged as a promising drug for AUD [4]. Preclinical studies have provided consistent evidence that baclofen administration dose-dependently reduces alcohol consumption in validated animal models of AUD [5]. On the other hand, clinical studies have yielded less consistent results [6]. Some randomized controlled trials (RCTs) found that AUD patients treated with baclofen significantly reduced alcohol consumption compared to patients treated with placebo, whereas other RCTs found no differences between AUD patients treated with baclofen or placebo [6]. In addition, recent meta-analyses report there is insufficient evidence of effectiveness to support the use of baclofen to treat AUD [7], [8], [9], [10]. Several methodological differences among these RCTs may have contributed to these contrasting results, including (i) the daily dose of baclofen (ranging from 30 to 300 mg), (ii) prescribing regimes (fixed doses or titration until the desired clinical effect was achieved), and (iii) presence/absence of comorbid medical (e.g. liver disease) or psychiatric diseases (e.g. anxiety disorders) [6], [11]. Nevertheless, baclofen is used off-label to treat AUD in several countries, and in France baclofen was officially approved for AUD treatment in October 2018 [6]. In May 2018, during the GABAB Receptor Conference, held in Cagliari, Italy, a group of international experts in the clinical use of baclofen for AUD met and combined their expertise to provide concise and well-balanced information regarding this controversial topic. This group included 26 researchers and physicians who had contributed to the majority of RCTs (both positive and negative) on baclofen and AUD as well as studies focused on the side effects of baclofen in patients with AUD. A modified Delphi method was used. Each statement was discussed, modified, and rated until consensus was reached by the entire group. The final draft included 18 statements and was recently published as “the Cagliari Statement” in Lancet Psychiatry [12]. This Consensus paper is intended as a helpful tool for clinicians deciding whether or not prescribe baclofen off-label to their patients with AUD and to researchers planning investigations with baclofen. The Cagliari Statement may be particularly useful clinicians in France, where baclofen has been officially approved for AUD treatment [6].
Article
Alcohol Use Disorder (AUD) is a complex and devastating disorder, resulting in a myriad of medical, psychological, social, and economic problems. Harmful alcohol drinking costs the U.S. society more than $249 billion annually and is the 5th leading risk factor for premature death and disability. Each year, more than 15 million Americans are diagnosed with AUD and 88,000 die from alcohol‐related causes.
Article
Continuous‐flow synthesis of baclofen precursor (2) was achieved using achiral and chiral heterogeneous catalysts in high yield with high enantioselectivity. The key steps are chiral calcium‐catalyzed asymmetric 1,4‐addition of a malonate to a nitroalkene and chemoselective reduction of a nitro compound to the corresponding amino compound by using molecular hydrogen. A dimethylpolysilane (DMPS)‐modified platinum catalyst supported on activated carbon (AC) and calcium phosphate (CP) has been developed that has remarkable activity for the selective hydrogenation of nitro compounds.
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Alcoholic hepatitis is the severest clinical presentation of alcoholic liver disease. Lacking an effective pharmacologic treatment, alcoholic hepatitis is associated with a poor prognosis and its recovery relies mostly on abstinence. With alcohol use disorder being universally on the rise, the impact of alcoholic hepatitis on society and health-care costs is expected to increase significantly. Prognostic factors and liver biopsy can help with timely diagnosis, to determine eligibility and response to corticosteroids, and for prognostication and transplant referral. Although recent discoveries in the pathophysiology of alcoholic hepatitis are encouraging and could pave the way for novel treatment modalities, a multidisciplinary approach considering timely identification and treatment of liver-related complications, infectious and metabolic disease, malnutrition, and addiction counseling should be emphasized. Apart from proper selection of candidates, transplant programs should provide adequate post-transplant addiction support in order to make of early liver transplantation for alcoholic hepatitis the ultimate sobering experience in the next decade.
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Additions define neurobehavioral disorders in which the brain circuits responsible for pleasure, motivation, stress and decision-making are structurally and functionally disturbed. In this section we will talk about how people become addicted and how the activation of the reward system of the brain by alcohol and drugs not only generates rewarding sensations associated with these substances, but also triggers changes in the way a person responds to associated stimuli.
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Introduction In the last decades, many medications have been tested for the treatment of Alcohol Use Disorder (AUD). Among them, disulfiram, acamprosate, naltrexone, nalmefene, sodium oxybate and baclofen have been approved in different countries, with different specific indications. Topiramate is not approved for the treatment of AUD, however, it is suggested as a therapeutic option by the American Psychiatric Association for patients who do not tolerate or respond to approved therapies. Areas covered In this narrative review we have analyzed the main studies available in literature, investigating the efficacy and safety of these medications, distinguishing whether they were oriented towards abstinence or not. Randomized controlled studies, analyzing larger populations for longer periods were the main focus of our analysis. Conclusions The medications currently available for the treatment of AUD are quite effective, yet further progress can still be achieved through the personalized strategies. Also, these medications are still markedly underutilized in clinical practice and many patients do not have access to specialized treatment.
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Die Antwort der Gesellschaft auf die alte Frage – was einen Suchtkranken dazu verleitet Alkohol, Tabak oder Drogen (erneu) zu konsumieren – auch nachdem ihr Leben bereits signifikant von diesen geschädigt wurde – führt oft zu einer allzu simplen Antwort: Schwacher Wille!
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Background Alcohol use disorder (AUD) affects nearly 5% of the world’s adult population. Despite treatment, AUD often manifests with relapse to binge drinking, which has been associated with corticostriatal hypersynchrony involving the nucleus accumbens (NAc). Methods A modified “Drinking in the Dark” protocol was used to provoke binge-like alcohol drinking. We implemented Coordinated Reset Stimulation (CRS), a computationally designed, spatio-temporal stimulation algorithm, to desynchronize abnormal neuronal activity via a deep brain stimulation (DBS) electrode in the NAc of mice exhibiting binge-like alcohol drinking. Integral CRS charge injected would be 2.5% of that of conventional high-frequency DBS. Results NAc CRS delivery during only the initial phase of exposure to alcohol and prior to the exposure (but not during) significantly reduced binge-like drinking without interfering with social behavior or locomotor activity. Conclusions NAc CRS ameliorates binge-like alcohol drinking and preliminarily exhibits sustained aftereffects that are suggestive of an unlearning of hypersynchrony.
Article
Introduction: Compared to other medical disorders, including other brain diseases, the number of medications approved for AUD is small and they generally have limited efficacy, which is due to several factors including the wide heterogeneity of patients with AUD. Areas covered: In this review, the authors aim to synthesise literature for new approved and emerging pharmacotherapies for AUD. Recently approved medications include nalmefene, which was approved in Europe and Australia for the purposes of controlled drinking. Baclofen has also been approved in France but not in other countries. Off label medications including topiramate and gabapentin have received significant attention with multiple RCTs and meta-analyses and have widespread use in several countries including the USA. Several novel medications have emerged over the last decade but further work is required to determine their efficacy and safety for the widespread management of AUD. Expert opinion: Despite significant advances in our understanding of the neurobiological basis of factors that contribute to the development and maintenance of AUD, there have been few new AUD medications approved for almost 20 years. There are many challenges to the development and intoduction of new pharmacotherapies for AUD. Strategies for improving the translational pipeline include drug repurposing and utilisation of human acute laboratory models.
Article
The GABA B agonist, baclofen, has been shown to reduce alcohol consumption in patients with alcohol use disorder and also those with comorbid anxiety. This study aimed to evaluate the effect of baclofen versus placebo on the BOLD response during an anticipatory anxiety fMRI task in treatment seeking alcohol patients. Participants included 28 alcohol dependant individuals who had received daily baclofen 30 mg (n = 10), 75 mg (n = 8) or placebo (n = 10) for at least 2 week on a randomized controlled trial (Morley, Leung et al. 2013, Morley, Baillie et al. 2018). Using functional magnetic resonance imaging (fMRI), we examined threat cue-elicited neural activation during a threat reactivity task 120 min following administration of BAC (30 mg or 75 mg) or placebo. Whole-brain analyses revealed no significant differences between the combined BAC doses versus PL. However, there were significant decreases in anticipatory threat cue-elicited activation observed in BAC 75 mg/day compared to PL participants in the insula. In response to threat cues, high dose (75 mg/day) baclofen administration attenuates activation in the insula and inferior frontal gyrus, relative to placebo. These preliminary findings suggests that modulating emotional regulation and attentional allocation during high threat stimuli may be mediated by GABA B receptors and may be a potential mechanism of action for baclofen's beneficial treatment effects for alcohol use disorder.
Article
Background: With 14.4 million U.S. adults diagnosed with alcohol use disorder (AUD) annually, effective treatments for combatting this condition are essential. Clinicians are often guided by systematic reviews and meta-analyses – considered the gold standard of research. Spin, a biased way of reporting results, may lead to misinterpretation of research findings, resulting in suboptimal patient care. Objective: Our primary objective was to investigate the presence of spin in the abstracts of systematic reviews of AUD treatments. Methods: After systematically searching MEDLINE and Embase for systematic reviews of AUD treatments, abstracts were evaluated for the nine most severe types of spin. Additional article characteristics were concurrently extracted and study quality was evaluated. Descriptive statistics of spin were calculated and associations between spin and study characteristics were determined through Fisher’s exact and logistic regression. Results: Among 79 included systematic reviews, 44 instances of spin were identified spanning 43% of our sample (34/79). Of the nine forms of spin, eight were found with a majority of instances being “selective reporting of or overemphasis on efficacy outcomes” (13/44, 29.5% of cases). The majority of articles were rated as critically low quality (51/79, 64.6%). No association was found between the presence of spin and extracted study characteristics. Conclusions: Spin was found in more than 40% of systematic review abstracts that evaluated pharmacotherapies in the treatment of AUD. Coupled with the finding that the majority of systematic reviews on the subject were of low quality, increased awareness of spin among physicians may be warranted.
Article
Background: There is a need for alcohol use disorder (AUD) pharmacotherapy that can be administered to actively drinking outpatients. Pregabalin, a gabapentoid anticonvulsant, has preliminary evidence supporting effects on alcohol withdrawal and AUD. Objectives: To evaluate the safety, tolerability, and optimal dosing of pregabalin for treating AUD. Methods: In an open-label, 8-week, outpatient trial of eighteen adults (nine women) with AUD, participants were titrated to 600 mg/day (or the maximum tolerated dose) over 3 weeks and then maintained for 5 weeks. Results: The majority (11/14, 78.6%) of participants with at least one-week of medication exposure achieved a maximum dose of 600 mg/day. Mean retention was 6.8 weeks (SD = 2.6). Eighty percent (12/15) of participants with post-enrollment data reported any adverse effects during the trial; and for those reporting adverse effects the most common were drowsiness (33.3%, 4/12), and fogginess (25%, 3/12), dizziness (25%, 3/12), and insomnia (25%, 3/12). Two participants discontinued study medication due to adverse effects and one had a dose reduction. Mean Heavy Drinking Days (HDD)/week decreased significantly by 3.43 days (SD = 2.47; median (IQR) = 4.00 (1.00 to 5.50)); Wilcoxon signed rank test statistic ((S) = 49.5, p = .0006). Mean proportion of HDD significantly decreased on average by 48.7% (SD = 35.1%; median (IQR) = 57.1% (14.3% to 78.6%)). The proportion of abstinent days increased significantly on average by 36.1% (SD = 35.0%; median (IQR) = 17.9% (14.3% to 75.0%); S = 49.5, p = .0005). Conclusions: Pregabalin treatment of AUD appears to be safe and well tolerated in doses up to 600 mg per day. Trial Registration: clinicaltrials.gov identifier: NCT03256253
Article
Summary of recommendations and levels of evidence Chapter 2: Screening and assessment for unhealthy alcohol use Screening • Screening for unhealthy alcohol use and appropriate interventions should be implemented in general practice (Level A), hospitals (Level B), emergency departments and community health and welfare settings (Level C). • Quantity–frequency measures can detect consumption that exceeds levels in the current Australian guidelines (Level B). • The Alcohol Use Disorders Identification Test (AUDIT) is the most effective screening tool and is recommended for use in primary care and hospital settings. For screening in the general community, the AUDIT-C is a suitable alternative (Level A). • Indirect biological markers should be used as an adjunct to screening (Level A), and direct measures of alcohol in breath and/or blood can be useful markers of recent use (Level B). Assessment • Assessment should include evaluation of alcohol use and its effects, physical examination, clinical investigations and collateral history taking (Level C). • Assessment for alcohol-related physical problems, mental health problems and social support should be undertaken routinely (GPP). • Where there are concerns regarding the safety of the patient or others, specialist consultation is recommended (Level C). • Assessment should lead to a clear, mutually acceptable treatment plan which specifies interventions to meet the patient’s needs (Level D). • Sustained abstinence is the optimal outcome for most patients with alcohol dependence (Level C). Chapter 3: Caring for and managing patients with alcohol problems: interventions, treatments, relapse prevention, aftercare, and long term follow-up Brief interventions • Brief motivational interviewing interventions are more effective than no treatment for people who consume alcohol at risky levels (Level A). • Their effectiveness compared with standard care or alternative psychosocial interventions varies by treatment setting. They are most effective in primary care settings (Level A). Psychosocial interventions • Cognitive behaviour therapy should be a first-line psychosocial intervention for alcohol dependence. Its clinical benefit is enhanced when it is combined with pharmacotherapy for alcohol dependence or an additional psychosocial intervention (eg, motivational interviewing) (Level A). • Motivational interviewing is effective in the short term and in patients with less severe alcohol dependence (Level A). • Residential rehabilitation may be of benefit to patients who have moderate-to-severe alcohol dependence and require a structured residential treatment setting (Level D). Alcohol withdrawal management • Most cases of withdrawal can be managed in an ambulatory setting with appropriate support (Level B). • Tapering diazepam regimens (Level A) with daily staged supply from a pharmacy or clinic are recommended (GPP). Pharmacotherapies for alcohol dependence • Acamprosate is recommended to help maintain abstinence from alcohol (Level A). • Naltrexone is recommended for prevention of relapse to heavy drinking (Level A). • Disulfiram is only recommended in close supervision settings where patients are motivated for abstinence (Level A). • Some evidence for off-label therapies baclofen and topiramate exists, but their side effect profiles are complex and neither should be a first-line medication (Level B). Peer support programs • Peer-led support programs such as Alcoholics Anonymous and SMART Recovery are effective at maintaining abstinence or reductions in drinking (Level A). Relapse prevention, aftercare and long-term follow-up • Return to problematic drinking is common and aftercare should focus on addressing factors that contribute to relapse (GPP). • A harm-minimisation approach should be considered for patients who are unable to reduce their drinking (GPP). Chapter 4: Providing appropriate treatment and care to people with alcohol problems: a summary for key specific populations Gender-specific issues • Screen women and men for domestic abuse (Level C). • Consider child protection assessments for caregivers with alcohol use disorder (GPP). • Explore contraceptive options with women of reproductive age who regularly consume alcohol (Level B). Pregnant and breastfeeding women • Advise pregnant and breastfeeding women that there is no safe level of alcohol consumption (Level B). • Pregnant women who are alcohol dependent should be admitted to hospital for treatment in an appropriate maternity unit that has an addiction specialist (GPP). Young people • Perform a comprehensive HEEADSSS assessment for young people with alcohol problems (Level B). • Treatment should focus on tangible benefits of reducing drinking through psychotherapy and engagement of family and peer networks (Level B). Aboriginal and Torres Strait Islander peoples • Collaborate with Aboriginal or Torres Strait Islander health workers, organisations and communities, and seek guidance on patient engagement approaches (GPP). • Use validated screening tools and consider integrated mainstream and Aboriginal or Torres Strait Islander-specific approaches to care (Level B). Culturally and linguistically diverse groups • Use an appropriate method, such as the “teach-back” technique, to assess the need for language and health literacy support (Level C). • Engage with culture-specific agencies as this can improve treatment access and success (Level C). Sexually diverse and gender diverse populations • Be mindful that sexually diverse and gender diverse populations experience lower levels of satisfaction, connection and treatment completion (Level C). • Seek to incorporate LGBTQ-specific treatment and agencies (Level C). Older people • All new patients aged over 50 years should be screened for harmful alcohol use (Level D). • Consider alcohol as a possible cause for older patients presenting with unexplained physical or psychological symptoms (Level D). • Consider shorter acting benzodiazepines for withdrawal management (Level D). Cognitive impairment • Cognitive impairment may impair engagement with treatment (Level A). • Perform cognitive screening for patients who have alcohol problems and refer them for neuropsychological assessment if significant impairment is suspected (Level A). Summary of key recommendations and levels of evidence Chapter 5: Understanding and managing comorbidities for people with alcohol problems: polydrug use and dependence, co-occurring mental disorders, and physical comorbidities Polydrug use and dependence • Active alcohol use disorder, including dependence, significantly increases the risk of overdose associated with the administration of opioid drugs. Specialist advice is recommended before treatment of people dependent on both alcohol and opioid drugs (GPP). • Older patients requiring management of alcohol withdrawal should have their use of pharmaceutical medications reviewed, given the prevalence of polypharmacy in this age group (GPP). • Smoking cessation can be undertaken in patients with alcohol dependence and/or polydrug use problems; some evidence suggests varenicline may help support reduction of both tobacco and alcohol consumption (Level C). Co-occurring mental disorders • More intensive interventions are needed for people with comorbid conditions, as this population tends to have more severe problems and carries a worse prognosis than those with single pathology (GPP). • The Kessler Psychological Distress Scale (K10 or K6) is recommended for screening for comorbid mental disorders in people presenting for alcohol use disorders (Level A). • People with alcohol use disorder and comorbid mental disorders should be offered treatment for both disorders; care should be taken to coordinate intervention (Level C). Physical comorbidities • Patients should be advised that alcohol use has no beneficial health effects. There is no clear risk-free threshold for alcohol intake. The safe dose for alcohol intake is dependent on many factors such as underlying liver disease, comorbidities, age and sex (Level A). • In patients with alcohol use disorder, early recognition of the risk for liver cirrhosis is critical. Patients with cirrhosis should abstain from alcohol and should be offered referral to a hepatologist for liver disease management and to an addiction physician for management of alcohol use disorder (Level A). • Alcohol abstinence reduces the risk of cancer and improves outcomes after a diagnosis of cancer (Level A).
Article
Background ASP8062 is a novel orally active GABA B receptor positive allosteric modulator in clinical development for the treatment of alcohol use disorder (AUD) and opioid use disorder (OUD). Aims This study assessed the potential pharmacokinetic/pharmacodynamic interaction between ASP8062 and alcohol under single-dose conditions in healthy adults. Methods A double-blind, placebo-controlled, crossover phase 1 study was conducted in which 20 subjects were randomly assigned to four treatment sequences (ASP8062 + alcohol; ASP8062 + placebo alcohol; placebo + alcohol; placebo + placebo alcohol) each consisting of four treatment periods, separated by washout periods of at least 14 days. An analysis of variance was used to assess pharmacokinetic interaction and a mixed-effects analysis of covariance was used to assess pharmacodynamic interaction. Results/outcomes After administration of alcohol, a mild to minimal increase in plasma exposure (AUC inf and C max ) of ASP8062 was observed, but t max and t ½ for ASP8062 remained unchanged after administration of alcohol. In contrast, ASP8062 did not affect the AUC last and C max of ethanol. No clinically relevant differences in cognition measurements were observed with ASP8062 compared with placebo, but there were expected impairments in psychomotor and executive function with alcohol alone. ASP8062 in combination with alcohol resulted in worse scores in cognition measurements than alcohol alone, but this potentiation was not consistent. ASP8062 administered alone was safe and well-tolerated and safety findings in subjects administered alcohol alone were not augmented when ASP8062 was administered in combination with alcohol. Conclusion/interpretation The data support further clinical studies investigating ASP8062 in patients with AUD.
Article
Background and aims Baclofen, a selective γ‐aminobutyric acid (GABA)B receptor agonist, has emerged as a potential treatment for alcohol use disorder with much unexplained variation in response to treatment efficacy and dose regimen. Several positive studies include patients with alcoholic liver disease (ALD) and/or history of heavy drinking. The aim of this paper was to examine the association of cortical GABA+ concentration with severity of liver disease (including markers of liver injury) and other clinical characteristics in alcohol patients. Methods Proton magnetic resonance spectroscopy (¹H‐MRS), from the parietal lobe, was analyzed to yield absolute concentration of GABA in 24 alcohol‐dependent individuals. Diagnosis of ALD, markers of liver injury, severity of liver disease (Model for End‐Stage Liver Disease [MELD]), and alcohol history were assessed. Covariates included concurrent medication, age, and recent alcohol consumption. Results Multiple linear regression revealed that GABA+ concentration was significantly predicted by MELD scores (F = 5.02, R² = 0.59, P = 0.01; MELD: B = −0.63, P = 0.02), when controlling for covariates concurrent medication, age, and recent alcohol consumption. Conclusion Severity of ALD is associated with lower cortical concentrations of GABA+. These results may explain variations in response to the GABAB agonist, baclofen, in the alcohol‐dependent population.
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Systematic reviews should build on a protocol that describes the rationale, hypothesis, and planned methods of the review; few reviews report whether a protocol exists. Detailed, well-described protocols can facilitate the understanding and appraisal of the review methods, as well as the detection of modifications to methods and selective reporting in completed reviews. We describe the development of a reporting guideline, the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 (PRISMA-P 2015). PRISMA-P consists of a 17-item checklist intended to facilitate the preparation and reporting of a robust protocol for the systematic review. Funders and those commissioning reviews might consider mandating the use of the checklist to facilitate the submission of relevant protocol information in funding applications. Similarly, peer reviewers and editors can use the guidance to gauge the completeness and transparency of a systematic review protocol submitted for publication in a journal or other medium.
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Alcohol dependence (AD) presents with substantial clinical heterogeneity, including concurrent use of non-alcohol drugs. Here, we examine specific patterns of concurrent non-alcohol substance use during the previous year among a nationally representative sample of adults with DSM-IV AD, and estimate their population prevalence in the U.S. We then evaluate alcohol use behavior and comorbid psychopathology among respondents with AD according to their patterns of concurrent non-alcohol substance use. These analyses utilized data from Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions. Latent class analyses classified respondents with AD into four clinically meaningful patterns of concurrent substance use: (1) use of alcohol only; (2) use of alcohol and tobacco only; (3) use of alcohol, tobacco and cannabis; and (4) use of alcohol, tobacco, cannabis, cocaine, and other illicit drug(s). Among AD respondents, the most prevalent pattern was the use of alcohol and tobacco only (weighted percentage, 32.4%), followed by the use of alcohol only (weighted percentage, 27.5%). AD respondents who used alcohol, tobacco, cannabis, cocaine, and other illicit drug(s) (weighted percentage, 25.3%) manifested the most severe pattern of alcohol consumption, and had significant overrepresentations of major depression, panic, and other anxiety disorders as well as paranoid, schizotypal, borderline, antisocial, and histrionic personality disorders compared with those who used alcohol alone. Specific patterns of concurrent substance use convey important information regarding the clinical presentation and prognosis for AD. In particular, concurrent use of illicit drugs over the past year by AD individuals was associated with greater severity and comorbid psychopathology. These data suggest the need for pragmatic trials of AD interventions that take into account patterns of substance use behavior in addition to an AD diagnosis. Published by Elsevier Ltd.
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Background: Limited clinical trials and case-reports yielded conflicting results regarding the efficacy of baclofen (a GABAB agonist) in the treatment of alcohol dependence. The aim of this study was to test the efficacy and tolerability of baclofen in alcohol dependent patients in Israel. Methods: The study was a double-blind, placebo-controlled, randomized trial comparing 50mg/day of baclofen to placebo over 12 weeks, in addition to a standard psychosocial intervention program, with 26-week and 52-week follow-up observations. The percentages of heavy drinking days and abstinent days were the primary outcome measures, and craving, distress and depression levels; self-efficacy; social support from different sources; and health-related quality of life (HRQL) were secondary outcomes. Tolerability was also examined. Results: Sixty-four patientswere randomized; 62% completed the 12-week trial and 37% completed the 52-week follow-up. No between group differenceswere found in the percentages of heavy drinking and abstinent days. A significant reduction in levels of distress, depression and craving and improved HRQL occurred for both arms, whereas self-efficacy and social support remained unchanged in both groups. No adverse events were observed. Conclusions: Unlike previous positive trials in Italy, and similarly to a negative trial in the USA, we found no evidence of superiority of baclofen over placebo in the treatment of alcohol dependence. However, the high placebo response undermines the validity of this conclusion. Therefore, more placebo-controlled trials are needed to either verify or discard a possible clinical efficacy of baclofen for alcohol dependence.
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Aim: To conduct a double-blind, placebo-controlled randomized clinical trial of baclofen in the treatment of alcohol dependence. Methods: Out of 69 participants consecutively screened, 42 alcohol-dependent patients were randomized to receive placebo, baclofen 30 mg/day or baclofen 60 mg/day for 12 weeks. All subjects were offered BRENDA, a structured psychosocial therapy for alcohol dependence that seeks to improve motivation for change, enhance strategies to prevent relapse and encourage compliance with treatment. Results: Intention-to-treat analyses revealed that alcohol consumption (heavy drinking days, drinks per drinking day) significantly reduced across all three groups during the treatment period. There were no statistically significant advantages to treatment on time to first heavy drinking day (relapse) (P = 0.08), nor time to first drink (lapse) (P = 0.18). A post hoc analysis stratifying according to whether there had been a comorbid anxiety disorder, revealed a beneficial effect of baclofen 30 mg/day versus placebo on time to lapse and relapse (P < 0.05). There was also a beneficial effect for baclofen 60 mg/day relative to placebo on time to relapse in this comorbid group (P < 0.05). Both doses of baclofen were well tolerated. There were no serious adverse events. Conclusions: In spite of the small sample for a 3-arm clinical trial, this study suggests a specific role of baclofen in alcohol-dependent individuals with comorbid anxiety. Replication in larger, fully-powered studies is required.
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Objective To evaluate, among alcohol specialists belonging to the Société Française d’Alcoologie (SFA), i.e., the French Alcohol Society, the proportion of physicians who prescribed off-label baclofen for alcohol use disorders (AUDs). The secondary objective was to depict the features of individual prescribing and monitoring practices. Methods On-line survey among 484 French alcohol specialists. Physicians were asked whether they prescribed baclofen for AUDs. If they did not, the reasons for this choice were investigated. If they did, the features of the physician’s prescribing practice were explored, including the number of patients treated, the mean and maximum doses, the monitoring precautions and the pharmacovigilance reporting. Participants were also asked about their empirical findings on HDB’s efficacy and safety. Results In total, 302 physicians (response rate of 62.4%) participated in the survey. Data from 296 participants were analysed, representing 59.4% of all active prescribing physicians belonging to the SFA. HDB use was declared by 74.6% of participants (mean dose 109.5±43.6 mg/d; maximum dose 188±93.3 mg/d). However, 79.2% of prescribers had treated less than 30 patients, and 67.8% used HDB as a second-line medication. Although HDB was perceived as more efficacious than approved drugs by 54.3% of prescribers, it was also declared less safe by 62.8%. Nonetheless, 79.7% of prescribers had never filed any pharmacovigilance report. Non-prescribers (25.6%) were primarily deterred by the current lack of scientific data and official regulation. Conclusion A majority of French alcohol specialists reported using HDB, although often on a limited number of their patients. HDB was considered efficacious but also potentially hazardous. Despite this, physicians reported minimal safety data to the health security system. While French health authorities are planning to draft a specific regulatory measure for framing off-label HDB prescribing practices, the sustained education of prescribers on spontaneous pharmacovigilance reporting should be enhanced.
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Effective treatments for alcohol use disorders in those with significant liver disease are critically lacking. The primary aim of the current study is to explore the effectiveness and biobehavioural basis of low and high dose baclofen in improving treatment outcomes for alcohol dependence in people with alcoholic liver disease (The BacALD study). This double-blind, placebo-controlled study will randomize 180 participants to a 12-week regime of either baclofen (30 mg/day baclofen, 75 mg/day baclofen) or placebo. Participants must meet the ICD-10 criteria for alcohol dependence in addition to alcoholic liver disease (ALD) defined as the presence of symptoms and/or signs referable to liver disease or its complications with or without cirrhosis. Primary outcome measures will include total abstinence duration, time to lapse and relapse. Furthermore, 60 of the ALD patients enrolled in the trial will also participate in a pharmacokinetic and cue-reactivity component along with an additional 30 healthy volunteers matched for age and gender randomised to either 1 week regime of 30 mg/day baclofen or 75 mg/day baclofen. At week 1, plasma levels of baclofen and β-p-chlorophenol-γ-hydroxybutric acid will be measured at 0, 1 and 4 hours following baclofen administration and psychophysiological responses to alcohol-associated stimuli will be assessed in a cue reactivity paradigm. Recruitment commenced in late March 2013. This trial will demonstrate the efficacy and safety of two doses of baclofen in patients with alcoholic liver disease and will explore the biobehavioural mechanisms of the treatment effect.
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Baclofen, an agonist at the B subunit of gaba-aminobutyric acid receptor, possesses pharmacologic properties that may confer utility for the treatment of alcohol dependence. Research suggests that not only can it be useful in promoting maintenance of alcohol abstinence but also it may play a key role in decreasing alcohol cravings and anxiety often associated with alcohol dependence. To assess the benefit of baclofen for alcohol dependence, a review of the literature was conducted to identify published data investigating this off-label treatment. Four randomized controlled trials to date have been published and were included in this review. Although primary outcomes differ between studies, patients randomized to baclofen experience higher rates of abstinence from alcohol than those taking placebo in two of the trials. Secondary analyses indicate that baclofen is safe in patients with alcohol dependence, including those with moderate to severe liver cirrhosis, and may provide beneficial anxiolytic effects. Despite some positive data, the largest available randomized controlled trial failed to find any differences between baclofen and placebo. In all studies, individuals with severe medical comorbidities, seizure disorders, and psychiatric disorders were excluded from trials, which may limit external validity. In summary, there may be beneficial effects from using baclofen for the treatment of alcohol dependence; however, limited conclusions can be drawn from the small number of studies currently available for review. Larger well-designed trials are needed to further define baclofen's role for the treatment of alcohol dependence.
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Alcohol consumption is a major risk factor for the burden of disease, and Alcohol Dependence (AD) is the most important disorder attributable to this behavior. The objective of this study was to quantify mortality associated with AD and the potential impact of treatment. For the EU countries, for the age group 15-64 years, mortality attributable to alcohol consumption in general, to heavy drinking, and to AD were estimated based on the latest data on exposure and mortality. Potential effects of AD treatment were modeled based on Cochrane and other systematic reviews of the effectiveness of the best known and most effective interventions. In the EU 88.9% of men and 82.1% of women aged 15-64 years were current drinkers; and 15.3% of men and 3.4% of women in this age group were heavy drinkers. AD affected 5.4% of men and 1.5% of women. The net burden caused by alcohol consumption was 1 in 7 deaths in men and 1 in 13 deaths in women. The majority of this burden was due to heavy drinking (77%), and 71% of this burden was due to AD. Increasing treatment coverage for the most effective treatments to 40% of all people with AD was estimated to reduce alcohol-attributable mortality by 13% for men and 9% for women (annually 10,000 male and 1700 female deaths avoided). Increasing treatment rates for AD was identified as an important issue for future public health strategies to reduce alcohol-attributable harm and to complement the current focus of alcohol policy.
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To explore the effect of baclofen in a dose of 20 mg three times per day, compared with the already studied dose of 10 mg three times per day, in the treatment of alcohol dependence. We present a secondary analysis of a 12-week double-blind, placebo-controlled, randomized clinical trial with two doses of baclofen, specifically 10 mg t.i.d. and 20 mg t.i.d. Out of 94 subjects consecutively screened, 42 were randomized into the study. Fourteen of the 42 patients were randomly allocated to placebo, 14 to the group treated with baclofen 10 mg t.i.d. (B10 mg) and 14 to the group treated with baclofen 20 mg t.i.d. (B20 mg). Compared with patients allocated to placebo, patients allocated to the B10 mg group had a 53% reduction in the number of drinks per day (P < 0.0001) and patients allocated to the B20 mg group had a 68% reduction in the number of drinks per day (P < 0.0001), with respect to the number of drinks per day during the 28 days before randomization. The effect of baclofen 20 mg t.i.d. was greater than that of baclofen 10 mg t.i.d. (P = 0.0214, Wald test) showing a dose-effect relationship. Both doses of baclofen were well tolerated. This is provisional evidence of a dose-response effect for baclofen in the treatment of alcohol dependence.
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Cochrane Reviews have recently started including the quantity I 2 to help readers assess the consistency of the results of studies in meta-analyses. What does this new quantity mean, and why is assessment of heterogeneity so important to clinical practice? Systematic reviews and meta-analyses can provide convincing and reliable evidence relevant to many aspects of medicine and health care.1 Their value is especially clear when the results of the studies they include show clinically important effects of similar magnitude. However, the conclusions are less clear when the included studies have differing results. In an attempt to establish whether studies are consistent, reports of meta-analyses commonly present a statistical test of heterogeneity. The test seeks to determine whether there are genuine differences underlying the results of the studies (heterogeneity), or whether the variation in findings is compatible with chance alone (homogeneity). However, the test is susceptible to the number of trials included in the meta-analysis. We have developed a new quantity, I 2, which we believe gives a better measure of the consistency between trials in a meta-analysis. Assessment of the consistency of effects across studies is an essential part of meta-analysis. Unless we know how consistent the results of studies are, we cannot determine the generalisability of the findings of the meta-analysis. Indeed, several hierarchical systems for grading evidence state that the results of studies must be consistent or homogeneous to obtain the highest grading.2–4 Tests for heterogeneity are commonly used to decide on methods for combining studies and for concluding consistency or inconsistency of findings.5 6 But what does the test achieve in practice, and how should the resulting P values be interpreted? A test for heterogeneity examines the null hypothesis that all studies are evaluating the same effect. The usual test statistic …
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Aims: Alcohol dependence is a major public health issue with a need for new pharmacological treatments. The ALPADIR study assessed the efficacy and safety of baclofen at the target dose of 180 mg/day for the maintenance of abstinence and the reduction in alcohol consumption in alcohol-dependent patients. Methods: Three hundred and twenty adult patients (158 baclofen and 162 placebo) were randomized after alcohol detoxification. After a 7-week titration, the maintenance dose was provided for 17 weeks, then progressively decreased over 2 weeks before stopping. Results: The percentage of abstinent patients during 20 consecutive weeks (primary endpoint) was low (baclofen: 11.9%; placebo: 10.5%) and not significantly different between groups (OR 1.20; 95%CI: 0.58 to 2.50; P = 0.618). A reduction in alcohol consumption was observed from month 1 in both groups, but the difference of 10.9 g/day at month 6 between groups, in favour of baclofen, was not statistically significant (P = 0.095). In a subgroup of patients with high drinking risk level at baseline, the reduction was greater with a difference at month 6 of 15.6 g/day between groups in favour of baclofen (P = 0.089). The craving assessed with Obsessive-Compulsive Drinking Scale significantly decreased in the baclofen group (P = 0.017). No major safety concern was observed. Conclusions: This study did not demonstrate the superiority of baclofen in the maintenance of abstinence at the target dose of 180 mg/day. A tendency towards a reduction in alcohol consumption and a significantly decreased craving were observed in favour of baclofen. Short summary: Baclofen was assessed versus placebo for maintenance of abstinence and reduction in alcohol consumption in alcohol-dependent patients. This study did not demonstrate the superiority of baclofen in the maintenance of abstinence. A tendency towards a reduction in alcohol consumption and a significantly decreased craving were observed in favour of baclofen.
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Baclofen is often prescribed in high doses to fight cravings experienced by alcohol-dependent patients. Such an increase in the availability of baclofen is concerning. This study aimed to determine the change in number and profile of self-poisoning with baclofen over time, since baclofen has become increasingly popular, in order to describe the severity of self-poisoning with baclofen and to focus on co-existing alcohol use disorders and psychiatric illnesses determine predictors of severity. This was a retrospective study of self-poisoning with baclofen as reported by the western France Poison Control Center (PCC), which represents a population of more than 12 million people from January 2008 to March 2014. 111 cases of self-poisoning with baclofen were reported to the western France PCC (62 males and 49 females; average age 39±12). Poisoning severities were: “null” (9 cases), “minor” (37 cases), “moderate” (19 cases) and “high” (46 cases, including 4 deaths). The most frequently reported symptoms were neurological (45%) and cardiovascular (27%). The severity was significantly associated with psychiatric disorders (OR=2.9; p=0.03). Baclofen, prescribed in high doses, may lead to severe poisoning, particularly in patients with psychiatric illnesses. Authorities should put forward a new policy for prescribing the drug as a treatment for alcohol dependence. This article is protected by copyright. All rights reserved.
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Background and aims: Alcohol use disorders (AUDs) are common among people with chronic hepatitis C (HCV) and accelerate the development of fibrosis and cirrhosis caused by HCV. Baclofen, a gamma-aminobutyric acid (GABA) beta-receptor agonist, differs from medications for AUDs currently approved by the United States Food and Drug Administration (FDA), as it is metabolized primarily through the kidneys. The primary outcome of this study was to compare baclofen with a placebo in the percentage of days abstinent from alcohol. Design: A double-blind, placebo-controlled randomized trial. Setting: Hepatology clinics in four separate US Veteran Affairs Medical Centers in the United States. Participants: One hundred and eighty Veteran men and women older than 18 years with chronic HCV, a comorbid AUD and current alcohol use. Intervention and comparator: Oral baclofen was given at dosages of 0 (placebo) or 30 mg/day over 12 weeks with concomitant manual-guided counseling. Measurements: The primary measurement was percentage of days abstinent during the 12-week study period between the baclofen and placebo groups [measured by time-line follow-back (TLFB)]. Secondary measurements were the percentage of Veterans who achieved complete abstinence, the percentage of Veterans who achieved no heavy drinking between weeks 4 and 12 of the study, alcohol craving, anxiety, depression and post-traumatic stress disorder (PTSD). Findings: Primary outcome: compared with placebo, baclofen did not improve the percentage of days abstinent. For all subjects there were significant reductions from baseline to 12 weeks in percentage of days abstinent from 37.0% [standard error (SE) = 2.7] to 68.6% (SE = 2.8, F(1151.1) = 66.1, P < 0.001). However, there was no statistically significant difference between groups for change in percentage of days abstinent over the 12-week study period [absolute difference 1.3% (-9.1 to 1.7%), F(1152.6) = 0.005, P = 0.95]. Secondary outcomes: Of subjects who completed the first 4 weeks of the study, 8.9% (15 of 168) achieved complete abstinence; 10.1% (nine of 89) in the placebo group and 7.6% (six of 79) in the baclofen group [χ2(1) = 0.33, odds ratio (OR) = 0.73 (0.24-2.15)]. The percentage of no heavy drinking for all subjects between weeks 4 and 12 was 20.2% (34 of 168), but no statistically significant differences were found between placebo 15.7% (14 of 89) and baclofen 25.3% (20 of 79) [χ2(1) = 2.38, OR = 1.82 (0.85-3.90)]. There were significant reductions for all subjects in all other secondary variables over the course of the study, but no differences between groups. Measures of various biomarkers of alcohol use did not change significantly throughout the course of the study for either the baclofen or placebo groups. Conclusions: Baclofen administered at 30 mg/day does not appear to be superior to placebo in increasing abstinence or in reducing alcohol use, cravings for alcohol or anxiety among people with alcohol use disorder.
Article
Previous randomised placebo-controlled trials with low-to-medium doses of baclofen (30–60 mg) showed inconsistent results, but case studies suggested a dose-response effect and positive outcomes in patients on high doses of baclofen (up to 270 mg). Its prescription was temporary permitted for the treatment of alcohol dependence (AD) in France, and baclofen is now widely prescribed. Recently, a small RCT found a strong effect of a mean dose of 180 mg baclofen. In the present study the efficacy and safety of high doses of baclofen was examined in a multicentre, double-blind, placebo-controlled trial. 151 patients were randomly assigned to either six weeks titration and ten weeks high-dose baclofen (N=58; up to 150 mg), low-dose baclofen (N=31; 30 mg), or placebo (N=62). The primary outcome measure was time to first relapse. Nine of the 58 patients (15.5%) in the high-dose group reached 150 mg and the mean baclofen dose in this group was 93.6 mg (SD=40.3). No differences between the survival distributions for the three groups were found in the time to first relapse during the ten-weeks high-dose phase (χ²=0.41; p=0.813) or the 16-weeks complete medication period (χ²=0.04; p=0.982). There were frequent dose-related adverse events in terms of fatigue, sleepiness, and dry mouth. One medication related serious adverse event occurred in the high-dose baclofen group. Neither low nor high doses of baclofen were effective in the treatment of AD. Adverse events were frequent, although generally mild and transient. Therefore, large-scale prescription of baclofen for the treatment of AD seems premature and should be reconsidered.
Article
Background: Missing data are common in alcohol clinical trials for both continuous and binary end points. Approaches to handle missing data have been explored for continuous outcomes, yet no studies have compared missing data approaches for binary outcomes (e.g., abstinence, no heavy drinking days). This study compares approaches to modeling binary outcomes with missing data in the COMBINE study. Methods: We included participants in the COMBINE study who had complete drinking data during treatment and who were assigned to active medication or placebo conditions (N = 1,146). Using simulation methods, missing data were introduced under common scenarios with varying sample sizes and amounts of missing data. Logistic regression was used to estimate the effect of naltrexone (vs. placebo) in predicting any drinking and any heavy drinking outcomes at the end of treatment using 4 analytic approaches: complete case analysis (CCA), last observation carried forward (LOCF), the worst case scenario (WCS) of missing equals any drinking or heavy drinking, and multiple imputation (MI). In separate analyses, these approaches were compared when drinking data were manually deleted for those participants who discontinued treatment but continued to provide drinking data. Results: WCS produced the greatest amount of bias in treatment effect estimates. MI usually yielded less biased estimates than WCS and CCA in the simulated data and performed considerably better than LOCF when estimating treatment effects among individuals who discontinued treatment. Conclusions: Missing data can introduce bias in treatment effect estimates in alcohol clinical trials. Researchers should utilize modern missing data methods, including MI, and avoid WCS and CCA when analyzing binary alcohol clinical trial outcomes.
Article
Aim: To study efficacy and safety of baclofen for treatment of alcohol dependence. Material and methods: 32 patients with alcohol dependence had been randomized into one of two treatment groups (16 patients in each): patients of the 1st group were treated with baclofen (50 mg/day) for 3 months while patients of the 2nd one received identically looking placebo. All the study subjects were scheduled to come to the clinic on the weekly basis to control alcohol use and compliance with the study medications (by riboflavin marker in urine) and also - for psychiatric evaluations (severity of craving for alcohol, anxiety and depression). Alcohol use evaluated with the Time Line Follow Back technique and gamma-glutamiltranspeptidase activity in blood. To assess anxiety Spielberger state-trait inventory and Hamilton scale were used. Depression was assessed with Montgomery-Ashberg scale. To evaluate carving for alcohol used Obsessive-Compulsive Drinking scale, Penn Alcohol Craving scale, and Visual Analog Scale of Craving. Overall treatment effect assessed with the Clinical Global Impression scale. The study design was double blind. Results and conclusion: Baclofen did no differ significantly from placebo on either of primary or secondary outcome variables. However, primary outcome variables of retention in treatment and drinking were slightly better in the baclofen group compared to placebo, and those differences were close to the level of statistical significance. There were no differences between the groups in either rate of adverse events or liver enzymes activity which is an evidence of safety and good tolerability of baclofen in alcohol dependent patients. Further studies of baclofen for alcohol dependence in the larger sample size are needed.
Article
Résumé Objectif Quantifier et décrire pour la période 2007-2013 la population débutant en France un traitement de baclofène pour alcoolodépendance. Méthodes Utilisation du système national d’information inter-régimes de l’Assurance maladie (SNIIRAM) et du programme de médicalisation des systèmes d’information (PMSI) pour identifier la population débutant un traitement de baclofène, déterminer par algorithme le motif de prescription, définir les caractéristiques des patients et de leur traitement. Résultats Environ 200 000 personnes ont débuté un traitement de baclofène entre 2007 et 2013, dont 52,0 % pour alcoolodépendance. En 2013, ces personnes étaient majoritairement des hommes (62,3 %), avaient en moyenne 50,1 ans, 58,9 % avaient eu un primoprescripteur généraliste, 48,8 % étaient encore sous traitement 6 mois après leur instauration et parmi eux la moitié consommaient quotidiennement au moins 57,0 mg de baclofène. Conclusion L’utilisation du baclofène pour une alcoolodépendance a fortement augmenté depuis 2008, avec en 2013 plus de 34 000 nouveaux utilisateurs et plus de 9 000 primoprescripteurs généralistes.
Article
AIMS: Alcohol dependence is associated with high rates of co-occurring disorders which impact health-related quality of life (HRQoL) and add to the cost-of-illness. This study investigated the burden of alcohol dependence and associated co-occurring conditions on health and productivity. METHODS: A cross-sectional survey was conducted in eight European countries. Physicians (Psychiatrists and General Practitioners) completed patient record forms, which included assessment of co-occurring conditions, and patients completed matching self-completion forms. Drinking risk level (DRL) was calculated and the relationship between DRL, co-occurring conditions, work productivity, hospitalisations and rehabilitation stays was explored. RESULTS: Data were collected for 2979 alcohol-dependent patients (mean age 48.8 ± 13.6 years; 70% male). In total, 77% of patients suffered from moderate-to-severe co-occurring psychiatric and/or somatic conditions. High DRL was significantly associated with depression, greater work productivity losses, increased hospitalisations and rehabilitation stays. Co-occurring conditions were significantly associated with poorer HRQoL and decreased work productivity, with a statistical trend towards an increased frequency of rehabilitation stays. CONCLUSIONS: Alcohol-dependent patients manifest high rates of co-occurring psychiatric and somatic conditions, which are associated with impaired work productivity and HRQoL. The continued burden of illness observed in these already-diagnosed patients suggests an unmet need in both primary and secondary care.
Article
Previous randomized, placebo-controlled trials (RCTs) assessing the efficacy of the selective γ-aminobutyric acid (GABA)-B receptor agonist baclofen in the treatment of alcohol dependence have reported divergent results, possibly related to the low to medium dosages of baclofen used in these studies (30-80mg/d). Based on preclinical observations of a dose-dependent effect and positive case reports in alcohol-dependent patients, the present RCT aimed to assess the efficacy and safety of individually titrated high-dose baclofen for the treatment of alcohol dependence. Out of 93 alcohol-dependent patients initially screened, 56 were randomly assigned to a double-blind treatment with individually titrated baclofen or placebo using dosages of 30-270mg/d. The multiple primary outcome measures were (1) total abstinence and (2) cumulative abstinence duration during a 12-week high-dose phase. More patients of the baclofen group maintained total abstinence during the high-dose phase than those receiving placebo (15/22, 68.2% vs. 5/21, 23.8%, p=0.014). Cumulative abstinence duration was significantly higher in patients given baclofen compared to patients of the placebo group (mean 67.8 (SD 30) vs. 51.8 (SD 29.6) days, p=0.047). No drug-related serious adverse events were observed during the trial. Individually titrated high-dose baclofen effectively supported alcohol-dependent patients in maintaining alcohol abstinence and showed a high tolerability, even in the event of relapse. These results provide further evidence for the potential of baclofen, thereby possibly extending the current pharmacological treatment options in alcohol dependence. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
Article
Background Attrition is common in alcohol clinical trials and the resultant loss of data represents an important methodological problem. In the absence of a simulation study, the drinking outcomes among those who are lost to follow-up are not known. Individuals who drop out of treatment and continue to provide drinking data, however, may be a reasonable proxy group for making inferences about the drinking outcomes of those lost to follow-up.Methods We used data from the COMBINE study, a multisite, randomized clinical trial, to examine drinking during the 4 months of treatment among individuals who dropped out of treatment but continued to provide drinking data (i.e., “treatment dropouts;” n = 185). First, we estimated the observed treatment effect size for naltrexone versus placebo in a sample that included both treatment completers (n = 961) and treatment dropouts (n = 185; total N = 1,146), as well as the observed treatment effect size among just those who dropped out of treatment (n = 185). In both the total sample (N = 1,146) and the dropout sample (n = 185), we then deleted the drinking data after treatment dropout from those 185 individuals to simulate missing data. Using the deleted data sets, we then estimated the effect of naltrexone on the continuous outcome percent heavy drinking days using 6 methods to handle missing data (last observation carried forward, baseline observation carried forward, placebo mean imputation, missing = heavy drinking days, multiple imputation (MI), and full information maximum likelihood [FIML]).ResultsMI and FIML produced effect size estimates that were most similar to the true effects observed in the full data set in all analyses, while missing = heavy drinking days performed the worst.Conclusions Although missing drinking data should be avoided whenever possible, MI and FIML yield the best estimates of the treatment effect for a continuous outcome measure of heavy drinking when there is dropout in an alcohol clinical trial.
Article
Purpose: We conducted a meta-analysis in order to estimate the efficacy of baclofen on the maintenance of abstinence and the decrease of craving in alcohol-dependent patients. Methods: All randomized controlled clinical trials assessing baclofen for at least four weeks' treatment duration versus placebo or other comparators were included. The primary outcome measure was the percentage of patients who had not consumed alcohol at the end of the treatment. Measures of cumulative abstinence and indexes of craving were also assessed. Results: Compared to placebo, baclofen was associated with a significant increase of 179% in the percentage of abstinent patients at the end of the trial, without heterogeneity. For secondary outcome measures, based on a random-effect model, no significant effect of baclofen was observed compared to placebo. Conclusions: Our meta-analysis brings weak support towards an efficacy of low dosages of baclofen on the maintenance of abstinence in alcohol-dependent patients.
Article
Rationale There is presently no approved single treatment for dual alcohol and nicotine dependencies. Objective This pilot study investigated baclofen effects in alcoholic smokers. Methods This was a preliminary double-blind placebo-controlled randomized clinical study with 30 alcoholic smokers randomized to baclofen at 80 mg/day or placebo. A subgroup (n = 18) participated in an alcohol cue-reactivity experiment. Results Baclofen, compared with placebo, significantly decreased the percent days of abstinence from alcohol-tobacco co-use (p = 0.004). Alcohol dependence severity moderated baclofen effects, with the higher severity group having the greater baclofen response (p < 0.001). Although the percent days of alcohol-tobacco co-use declined in both groups, this decline was greater after placebo than baclofen (p < 0.001). Secondary analyses on alcohol or tobacco use alone suggested that the increase in percent days of co-abstinence was driven by the medication differences on heavy drinking days and on percent days smoking. In the cue-reactivity substudy, baclofen slightly decreased alcohol urge (p = 0.058) and significantly reduced salivation (p = 0.001), but these effects were not related to cue type. Conclusions This study provides preliminary evidence suggesting a possible role of baclofen in the treatment of alcoholic smokers. However, the mixed results and the small sample require larger confirmatory studies.
Article
Background: Recent clinical trials and case-reports indicate that baclofen, a GABA(B) agonist, may have efficacy for alcohol dependence. Baclofen has been shown to enhance abstinence, to reduce drinking quantity, to reduce craving, and to reduce anxiety in alcohol-dependent individuals in 2 placebo-controlled trials in Italy. However, the clinical trial data with baclofen is limited. The purpose of the present study was to test the efficacy and tolerability of baclofen in alcohol dependence in the United States. Methods: The study was a double-blind, placebo-controlled, randomized study comparing 30 mg/d of baclofen to placebo over 12 weeks of treatment and utilizing 8 sessions of BRENDA, a low-intensity psychosocial intervention. One hundred and twenty-one subjects were screened to yield 80 randomized subjects (44 men) with randomization balanced for gender. Percent heavy drinking days was the primary outcome measure with other drinking outcomes, anxiety levels, and craving as secondary outcomes. Tolerability was examined. Results: Seventy-six percent of subjects completed the study. No difference by drug condition was seen in percentage of heavy drinking days where on-average rates were 25.5% (±23.6%) for placebo and 25.9% (±23.2%) for baclofen during treatment (t(73)=0.59, p=0.56). Similarly, no differences were seen by drug condition in percentage of days abstinent, time to first drink, or time to relapse to heavy drinking. Baclofen was associated with a significant reduction in state anxiety (F(1,73)= 5.39, p=0.02). Baclofen was well tolerated with only 2 individuals stopping baclofen because of adverse events. There were no serious adverse events. Conclusions: Baclofen, a GABA(B) agonist, represents a possible new pharmacotherapeutic approach to alcohol dependence. Despite encouraging preclinical data and prior positive clinical trials with baclofen in Italy, the current trial did not find evidence that baclofen is superior to placebo in the treatment of alcohol dependence. Additional clinical trial work is necessary to establish whether baclofen does or does not have therapeutic efficacy in alcohol dependence and, if it does, what factors are predictive of response.
Article
Drug addiction is a chronically relapsing disorder that has been characterized by (1) compulsion to seek and take the drug, (2) loss of control in limiting intake, and (3) emergence of a negative emotional state (eg, dysphoria, anxiety, irritability) reflecting a motivational withdrawal syndrome when access to the drug is prevented. Drug addiction has been conceptualized as a disorder that involves elements of both impulsivity and compulsivity that yield a composite addiction cycle composed of three stages: 'binge/intoxication', 'withdrawal/negative affect', and 'preoccupation/anticipation' (craving). Animal and human imaging studies have revealed discrete circuits that mediate the three stages of the addiction cycle with key elements of the ventral tegmental area and ventral striatum as a focal point for the binge/intoxication stage, a key role for the extended amygdala in the withdrawal/negative affect stage, and a key role in the preoccupation/anticipation stage for a widely distributed network involving the orbitofrontal cortex–dorsal striatum, prefrontal cortex, basolateral amygdala, hippocampus, and insula involved in craving and the cingulate gyrus, dorsolateral prefrontal, and inferior frontal cortices in disrupted inhibitory control. The transition to addiction involves neuroplasticity in all of these structures that may begin with changes in the mesolimbic dopamine system and a cascade of neuroadaptations from the ventral striatum to dorsal striatum and orbitofrontal cortex and eventually dysregulation of the prefrontal cortex, cingulate gyrus, and extended amygdala. The delineation of the neurocircuitry of the evolving stages of the addiction syndrome forms a heuristic basis for the search for the molecular, genetic, and neuropharmacological neuroadaptations that are key to vulnerability for developing and maintaining addiction.
Article
The gamma-aminobutyric acid (GABA(B)) receptor agonist, baclofen, has recently been shown to reduce alcohol intake in alcohol-preferring rats and alcohol consumption and craving for alcohol in an open study in humans. The present study was aimed at providing a first evaluation of the efficacy of baclofen in inducing and maintaining abstinence and reducing craving for alcohol in alcohol-dependent patients in a double-blind placebo-controlled design. A total of 39 alcohol-dependent patients were consecutively enrolled in the study. After 12-24 h of abstinence from alcohol, patients were randomly divided into two groups. Twenty patients were treated with baclofen and 19 with placebo. Drug and placebo were orally administered for 30 consecutive days. Baclofen was administered at the dose of 15 mg/day for the first 3 days and 30 mg/day for the subsequent 27 days, divided into three daily doses. Patients were monitored as out-patients on a weekly basis. At each visit alcohol intake, abstinence from alcohol, alcohol craving and changes in affective disorders were evaluated. A higher percentage of subjects totally abstinent from alcohol and a higher number of cumulative abstinence days throughout the study period were found in the baclofen, compared to the placebo, group. A decrease in the obsessive and compulsive components of craving was found in the baclofen compared to the placebo group; likewise, alcohol intake was reduced in the baclofen group. A decrease in state anxiety was found in the baclofen compared to the placebo group. No significant difference was found between the two groups in terms of current depressive symptoms. Baclofen proved to be easily manageable and no patient discontinued treatment due to the presence of side-effects. No patient was affected by craving for the drug and/or drug abuse. Baclofen proved to be effective in inducing abstinence from alcohol and reducing alcohol craving and consumption in alcoholics. With the limits posed by the small number of subjects involved, the results of this preliminary double-blind study suggest that baclofen may represent a potentially useful drug in the treatment of alcohol-dependent patients and thus merits further investigations.
Article
Evidence recently provided has suggested a specific involvement of the GABAergic system in modulating positive reinforcing properties of several drugs of abuse through an action on mesolimbic dopaminergic neurons. The GABA(B) receptor agonist baclofen has been proposed as a potential therapeutic agent for the clinical treatment of several forms of drug addiction. In the present study, using the in vivo microdialysis technique, we investigated the effect of baclofen on nicotine, cocaine, and morphine-induced increase in extracellular dopamine (DA) levels in the shell of the nucleus accumbens, a brain area supposedly involved in the modulation of the central effects of several drugs of abuse, of freely moving rats. As expected, nicotine (0.6 mg/kg s.c.), morphine (5 mg/kg s.c.), and cocaine (7.5 mg/kg i.p.) administration in rats induced a marked increase in extracellular DA concentrations in the nucleus accumbens, reaching a maximum value of +205 +/- 8.4%, +300 +/- 22.2%, and +370 +/- 30.7%, respectively. Pretreatment with baclofen (1.25 and 2.5 mg/kg i.p.) dose-dependently reduced the nicotine-, morphine-, and cocaine-evoked DA release in the shell of the nucleus accumbens. Furthermore, baclofen alone did not elicit changes in basal DA extracellular levels up to 180 min. Taken together, our data are in line with previous reports demonstrating the ability of baclofen to modulate the mesolimbic DAergic transmission and indicate baclofen as a putative candidate in the pharmacotherapy of polydrug abuse.