Abstract
Background
Alcohol use disorder (AUD) and alcohol‐related impairments belong to the most widespread psychiatric disorders leading to specific psychophysical, affective and cognitive symptoms and consequences for psychosocial well‐being and health. Alcohol consumption is increasingly becoming a problem in many developing regions and AUD prevalence is estimated at 4.1% worldwide, with highest prevalence in European countries (7.5%), and the North America (6.0%). Therapeutic approaches, including pharmacotherapy, play an important role in treating patients with AUD.
Objectives
To assess the efficacy and safety of baclofen for treating people with AUD, who are currently drinking, with the aim of achieving and maintaining abstinence or reducing alcohol consumption.
Search methods
We searched the Cochrane Drugs and Alcohol Specialised Register, CENTRAL, MEDLINE, Embase, two further databases and two clinical trials registries, conference proceedings, and the reference lists of retrieved articles. The date of the most recent search was 30 January 2018.
Selection criteria
Randomised controlled trials (RCTs) of at least four weeks' treatment duration and 12 weeks' overall study duration comparing baclofen for relapse prevention of AUD with placebo, no treatment or other treatments.
Data collection and analysis
We used standard methodological procedures expected by Cochrane.
Main results
We included 12 RCTs (1128 participants). All studies but three recruited fewer than 100 participants. Participants had a diagnosis of alcohol dependence according the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV or the International Classification of Diseases (ICD)‐10 criteria who were currently drinking. The mean age of participants was 48 years, and there were more men (69%), than women. All studies compared baclofen to placebo, except for one study that evaluated baclofen versus acamprosate. The included studies considered baclofen at different doses (range 10 mg a day to 150 mg a day). In all but one of the studies, participants in both the baclofen and placebo groups received psychosocial treatment or counselling of various intensity.
We judged most of the studies at low risk of selection, performance, detection (subjective outcome), attrition and reporting bias.
We did not find any difference between baclofen and placebo for the primary outcomes: relapse‐return to any drinking (RR 0.88, 95% CI 0.74 to 1.04; 5 studies, 781 participants, moderate certainty evidence); frequency of use by percentage of days abstinent (MD 0.39, 95% CI ‐11.51 to 12.29; 6 studies, 465 participants, low certainty evidence) and frequency of use by percentage of heavy drinking days at the end of treatment (MD 0.25, 95% CI ‐1.25 to 1.76; 3 studies, 186 participants, moderate certainty evidence); number of participants with at least one adverse event (RR 1.04, 95% CI 0.99 to 1.10; 4 studies, 430 participants, high certainty evidence); the dropout rate at the end of treatment (RR 0.98, 95% CI 0.77 to 1.26, 8 studies, 977 participants, high certainty evidence) and dropout due to adverse events (RR 1.11, 95% CI 0.59 to 2.07; 7 studies, 913 participants, high certainty evidence).
We found evidence that baclofen increases amount of use (drink per drinking days), (MD 1.55, 95% CI 1.32 to 1.77; 2 studies, 72 participants, low certainty evidence).
Among secondary outcomes, there was no difference on craving (MD 1.38, 95% CI ‐1.28 to 4.03, 5 studies, 469 participants), and anxiety (SMD 0.07, 95% CI ‐0.14 to 0.28; 5 trials, 509 participants). We found that baclofen increased depression (SMD 0.27, 95% CI 0.05 to 0.48; 3 studies, 387 participants).
Concerning the specific adverse events we found that baclofen increased: vertigo (RR 2.16, 95% CI 1.24 to 3.74; 7 studies, 858 participants), somnolence/sedation (RR 1.48, 95%CI 1.11 to 1.96; 8 studies, 946 participants), paraesthesia (RR 4.28, 95% CI 2.11 to 8.67; 4 studies, 593 participants), and muscle spasms/rigidity (RR 1.94, 95%CI 1.08 to 3.48; 3 studies, 551 participants). For all the other adverse events we did not find significant differences between baclofen and placebo.
For the comparison baclofen versus acamprosate, we were only able to extract data for one outcome, craving. For this outcome, we found that baclofen increased craving compared with acamprosate (MD 14.62, 95% CI 12.72 to 16.52; 1 study, 49 participants).
Authors' conclusions
None of the primary or secondary outcomes of the review showed evidence of a difference between baclofen and placebo. The high heterogeneity among primary studies results limits the interpretation of the summary estimate, the identification of moderators and mediators of baclofen's effects on alcohol use remains a challenge for further research. Even though some results from RCTs are promising, current evidence remains uncertain regarding the use of baclofen as a first‐line treatment for people with AUDs.
Plain language summary
Baclofen for alcohol use disorder
Review question
We reviewed the evidence about the effectiveness and safety of baclofen for treating people with alcohol use disorder (AUD), who are currently drinking, in order to achieve and maintain abstinence (stopping drinking), or to reduce alcohol consumption.
AUD and alcohol‐related impairments belong to the most widespread psychiatric disorders, leading to specific physical, mood, learning and memory problems and consequences for overall well‐being and health. The misuse of alcohol is one of the biggest risks to health worldwide, causing 20% to 30% of oesophageal cancer, liver disease, epilepsy, motor vehicle accidents, homicide and other intentional injuries.
For many years, the main treatments for AUD have been psychosocial strategies, but using only psychosocial treatments has limited success. A high proportion of people with AUD do not respond to the treatment at all, and those who do respond do not stay alcohol‐free in the long‐term. Drugs, such as baclofen, could play an important role in treating people with AUD.
Search date The evidence is current to January 2018.
Study characteristics
We found 12 randomised controlled trials (studies where people were allocated at random to one of two or more treatment or control groups), with 1128 participants. On average, the interventions lasted about five months, while investigators followed up participants from between 4 to 52 months. Five studies took place in the USA and one each in Australia, France, Germany, India, Israel, Italy, and the Netherlands.
The studies considered baclofen at different doses (ranging from 10 mg a day to 150 mg a day), and in some cases, the doses were increased during the treatment. None of the studies added other drugs or other treatments to the baclofen treatment. All the studies compared baclofen to placebo, except for one study that compared baclofen to acamprosate at a dose of 666.66 mg three times a day for three months.
Key results Compared with placebo, baclofen makes little or no difference to participants who dropped out from treatment, dropped out due to adverse events (side effects), or the number of participants with at least one adverse event. Baclofen probably makes little difference to the number of participants who start drinking again, nor to how much or how often they drink. Baclofen may make little or no difference in the percentage of days people remain alcohol‐free.
Baclofen may increase the amount of use measured by number of drinks per drinking days.
We found that baclofen increased adverse events like depression, vertigo, somnolence, numbness and muscle rigidity but we did not find significant differences between baclofen and placebo for other adverse events.
Ceratinty of evidence The certainty of evidence (how much we can be confident that the evidence is reliable) was high for results about the number of participants with at least one adverse event, and about people dropping out of the studies for any reason or dropping out due to adverse events. The certainty of the evidence was moderate for results about people returning to any drinking and how many heavy drinking days they had. It was low for results about drink per drinking days and percentage of days of abstinence.
Summary of findings
Summary of findings for the main comparison. Baclofen compared to placebo for alcohol use disorder.
| Baclofen compared to placebo for alcohol use disorder | |||||
|
Patient or population: adults (18 years and older) with alcohol use disorder
Setting: outpatient setting in USA (n = 5), Australia (n = 1), France (n = 1), Germany (n = 1), India (n = 1), Israel (n = 1), Italy (n = 1), the Netherlands (n = 1) Intervention: baclofen in any dose and route of administration Comparison: placebo or any other pharmacological relapse prevention treatment | |||||
| Outcomes | № of participants (studies) follow‐up | Certainty of the evidence (GRADE) | Relative effect (95% CI) | Anticipated absolute effects* (95% CI) | |
| Risk with placebo | Risk difference with baclofen | ||||
|
Relapse return to any drinking at the end of treatment |
781 (5 RCTs) | ⊕⊕⊕⊝ Moderate1 | RR 0.88 (0.74 to 1.04) | Study population | |
| 781 per 1000 | 94 fewer per 1000 (203 fewer to 31 more) | ||||
|
Frequency of use % days abstinence at the end of treatment |
465 (6 RCTs) | ⊕⊕⊝⊝ Low2 | The mean % days abstinence at end of treatment ranged from 36.7% to 70.9% |
MD 0.39 higher (11.51 lower to 12.29 higher) | |
|
Frequency of use % of heavy drinking days at the end of treatment |
186 (3 RCTs) | ⊕⊕⊕⊝ Moderate3 | ‐ | The mean frequency of use (% of heavy drinking days at end of treatment) ranged from 16.32% to 25.5% | MD 0.25 higher (1.25 lower to 1.76 higher) |
|
Amount of use drink per drinking days at the end of treatment |
72 (2 RCTs) | ⊕⊕⊝⊝ Low4 | ‐ | The mean amount of use (drink per drinking days at end of treatment) ranged from 2.14 drinks to 2.82 drinks | MD 1.55 higher (1.32 higher to 1.77 higher) |
|
Adverse events number of participants with at least one side effect at the end of treatment |
430 (4 RCTs) | ⊕⊕⊕⊕ High | RR 1.04 (0.99 to 1.10) | Study population | |
| 785 per 1000 | 31 more per 1000 (8 fewer to 78 more) | ||||
| Dropout at end of treatment | 977 (8 RCTs) | ⊕⊕⊕⊕ High | RR 0.98 (0.77 to 1.26) | Study population | |
| 301 per 1000 | 6 fewer per 1000 (69 fewer to 78 more) | ||||
| Dropout due to adverse events | 913 (7 RCTs) | ⊕⊕⊕⊕ High | RR 1.11 (0.59 to 2.07) | Study population | |
| 41 per 1000 | 8 more per 1000 (14 fewer to 47 more) | ||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RCT: randomised controlled trial; RR: risk ratio | |||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | |||||
1Downgraded one level for significant heterogeneity: I² = 77% 2Downgraded two levels for very high heterogeneity: I² = 96% 3Downgraded one level for imprecision: fewer than 400 participants included in the analysis 4Downgraded two levels for imprecision: fewer than 400 participants included in the analysis
Background
Description of the condition
Alcohol use disorder (AUD) is a behavioural disorder characterised by dysfunctional patterns of alcohol use, leading to specific psychophysical, affective and cognitive symptoms and consequences for psychosocial well‐being and health. AUD as a disease category has been introduced with the latest version of the Diagnostic and Statistical Manual of Mental Disorders (DSM), the DSM‐V (APA 2013). While the DSM‐IV version (APA 2000), and International Classification of Diseases (ICD)‐10 (WHO 2010), subdivide substance use disorders into dependence and a secondary category, called 'abuse' in DSM‐IV and 'harmful use' in ICD‐10 (Hasin 2006), the DSM‐V integrates both categories into a single substance use disorder concept that ranges along a continuum from mild to severe (Hasin 2013; Rehm 2013).
AUD and alcohol‐related impairments belong to the most widespread psychiatric disorders (Alonso 2004; Grant 2015). According to the WHO status report on alcohol and health (WHO 2014), the one‐year prevalence of AUDs is estimated at 4.1% worldwide, with highest prevalence in European countries (7.5%), and the North America (6.0%). Statistics vary between regions, with a higher prevalence of psychoactive substance use in high‐income countries compared to low‐ and middle‐income countries (WHO 2002a). There is evidence indicating an enormous increase in alcohol use, high‐risk drinking, and DSM‐IV AUD in the US population during the last decade (Grant 2017). Nevertheless, with the improved industrialisation and centralisation of alcohol production, alcohol consumption is increasingly becoming a problem in many low‐ and middle‐income countries (WHO 2002b). Irrespective of region, the prevalence of AUD is greater in men than in women (Rehm 2009), while there is evidence on converging drinking patterns between genders (White 2015).
The misuse of alcohol is one of the leading global health risk factors, causing 20% to 30% of oesophageal cancer, liver disease, epilepsy, motor vehicle accidents, homicide and other intentional injuries (WHO 2002a). Men with AUD have a threefold‐higher mortality risk compared to men without AUD; in women, the risk is even higher (Roerecke 2013). In 2004, 3.8% of all global deaths and 4.6% of global disability‐adjusted life‐years were attributable to alcohol (Rehm 2009). The costs attributable to alcohol consumption are estimated at more than 1% of the gross domestic products in high‐income and middle‐income countries (Rehm 2009). At the same time, alcohol consumption is one of the major, potentially avoidable risk factors, underscoring the need for effective strategies to reduce excessive drinking and to maintain abstinence in people who are dependent on alcohol.
The treatment of AUD was exclusively dominated by psychosocial strategies for many decades. Even though techniques from different theoretical and therapeutic backgrounds have been developed, treatment effects obtained by an exclusive application of psychosocial treatment are limited. A high proportion of patients do not respond to the interventions at all and of those who respond, few succeed in maintaining abstinence in the long term (Moos 2006). With the investigation of the neurobiological mechanism of AUD, several pharmacological agents have been examined for their potential to support people with AUD in achieving abstinence or in cutting down their alcohol consumption. Four agents are approved for pharmacological support of relapse prevention in AUDs: the opioid antagonists naltrexone and nalmefene; the glutamate antagonist acamprosate; and the aversive agent disulfiram (Mutschler 2016). While the primary mechanism of action of the two opioid antagonists is to block alcohol‐induced reward effects, acamprosate is assumed to work by restoring the balance between inhibitory and excitatory neurotransmitters (Rösner 2010a; Rösner 2010b). In contrast to naltrexone, nalmefene and acamprosate, which are assumed to modulate neurobiological mechanisms of addiction, disulfiram works by producing an aversive reaction when combined with alcohol (Mutschler 2016). Various Cochrane Reviews have investigated the effects of pharmacological interventions for the treatment of alcohol withdrawal (Amato 2010; Amato 2011; Gillman 2007; Leone 2010; Liu 2015; Minozzi 2010; Sarai 2013), and for relapse prevention in AUD (Pani 2014; Pedersen 2013; Rösner 2010a; Rösner 2010b; Vaz de Lima 2010).
Description of the intervention
Baclofen, also known as beta‐4‐chlorophenyl‐gamma‐aminobutyric acid (Steardo 1984), is an agonist of the γ‐aminobutyric acid type B (GABAB) receptor and sold under the brand names Kemstro and Lioresal. The substance was originally approved for use in spasticity associated with neurological conditions and has recently emerged as a treatment of major interest for AUD (Agabio 2014; Brennan 2013; Garbutt 2010; Ponizovsky 2015). Baclofen is available in oral formulations and intrathecal solutions, the latter reserved for treatment of spasticity unresponsive to oral administration of baclofen. The recommended oral daily dose for baclofen ranges from 15 mg to 80 mg, starting from 15 mg a day and gradually increasing by 5 mg every three days (Agabio 2014). Despite high individual variation in pharmacokinetics, baclofen is rapidly absorbed from the gastrointestinal tract following oral administration. Up to 80% of an oral dose is excreted in the urine, with only a limited hepatic metabolism, making it a useful agent in people with impaired hepatic function, while renal function should be carefully assessed prior to baclofen administration (Agabio 2013; Brennan 2013). In addition, baclofen has a short half‐life of three to four hours and is rapidly cleared from the blood. As a result, baclofen needs to be administered three or four times per day to maintain therapeutic effects (Schwarz Pharma 2003).
Preclinical studies have found that baclofen reduces the acquisition of alcohol‐drinking behaviour and its maintenance and reinstatement in alcohol‐experienced rats (Agabio 2014). Effects on reinstatement were assessed by the modification of the so‐called 'alcohol deprivation effect', a rodent model for studying relapse behaviour referring to the temporary increase in voluntary alcohol intake after a period of forced abstinence from alcohol in a free‐choice experiment (Martin‐Fardon 2013). Furthermore, baclofen has been shown to dose‐dependently reduce the number of lever‐responses for alcohol and the amount of self‐administered alcohol in rats under operant self‐administration conditions (e.g. Maccioni 2005; Maccioni 2012). In operant self‐administration experiments, a specific amount of 'work' is required to access alcohol, with predictive validity for human alcohol craving, and providing measures of alcohol consumption and the reinforcing properties of alcohol (Agabio 2014). Thereby baclofen was found to be more potent and effective in those rats seeking and taking larger amounts of alcohol (Maccioni 2012; Walker 2007).
A series of case reports found that the administration of baclofen markedly reduced alcohol intake in people affected by AUD (Agabio 2007; Ameisen 2005; Bucknam 2006; Flannery 2004; Pastor 2012). One of these reports (Ameisen 2005), described the personal history of a French physician, who conducted an original dose‐finding curve with baclofen with the aim of treating his own AUD (Agabio 2014). He tested oral baclofen, starting with the 'conventional' dose of 30 mg a day and increased the daily dose of baclofen up to 270 mg after five weeks, experiencing, “complete medication‐induced suppression of craving” for alcohol with alleviation of comorbid anxiety (Ameisen 2005).
While numerous case reports, case series, and open‐label trials have been published, indicating the effectiveness of baclofen in people with AUD (for an overview see Brennan 2013), randomised controlled trials (RCTs) conducted to date (e.g. Addolorato 2002; Addolorato 2007; Garbutt 2010; Ponizovsky 2015), have yielded conflicting results. The diversity of findings has stimulated the discussion on potential moderators of effectiveness. Among others, severity of alcohol dependence (Agabio 2014; Hauser 2017; Leggio 2010; Maccioni 2012; Walker 2007), baclofen dosing (Addolorato 2007; Agabio 2014; Beraha 2016; Muller 2015), and comorbid anxiety (Addolorato 2002; Addolorato 2007; Agabio 2014; Muller 2015), have been discussed to moderate the effects of baclofen on alcohol consumption.
Although data are mixed regarding baclofen’s efficacy in AUD, they are consistent in terms of safety if used as recommended (Brennan 2013). Extensive information on baclofen's safety is available from its widespread use for the treatment of spasticity for decades. Most adverse events are not severe, are dose‐related and are transient. Sedation, somnolence, weakness, vertigo and psychological disturbances are reported as the most common adverse events (Dario 2004). The administration of low doses of baclofen is considered to be safe in people affected by AUD, while an abrupt interruption and withdrawal from higher doses of baclofen may lead to serious adverse effects (Agabio 2014; Dario 2004). While such events are rare, the lack of noted adverse events may be a result of small sample sizes and low doses of baclofen utilised in available trials (Brennan 2013). In France, where baclofen is frequently prescribed for the treatment of AUDs, an alarming increase of self‐poisonings with baclofen, including suicide attempts and unintentional overdose, has been reported (e.g. Holla 2015; Pellisier 2017), leading to the advice that authorities should put forward a new policy for prescribing baclofen for this indication (Boels 2017).
How the intervention might work
The mesolimbic dopamine pathway, including dopamine cells in the ventral tegmental area projecting into the nucleus accumbens, has been shown to be crucial for drug reward and addiction (Volkow 2011; Wise 2009). Baclofen's primary mechanism of action for alcohol dependence is presumed to be the reduction of the reinforcing properties of alcohol by suppressing alcohol‐stimulated dopamine release in the mesolimbic dopamine system. Agonistic effects of baclofen at GABAB receptors located in several brain areas including the mesolimbic circuit (Pitman 2014), and the ventral tegmental area, inhibit alcohol‐induced firing of dopaminergic neurons and of the alcohol‐stimulated dopamine release in the nucleus accumbens, resulting in the reduction of reinforcing properties of alcohol and drugs (Agabio 2014; Maccioni 2009; Young 2014). As baclofen did not affect spontaneous motor activity in rats, baclofen's effects are shown not to be due to muscle‐relaxant or sedative properties of the drug, but can rather be considered as a result of its ability to reduce the appetitive strength of alcohol (Colombo 2003). In addition, substitutional effects of baclofen to replace alcohol have been discussed (Chick 2012; Rolland 2013).
In addition, GABAB receptors are highly expressed in limbic structures involved in the mediation of anxiety, while activation of GABAB receptors in these structures might reduce anxiety (Morley 2014). Evidence from various clinical studies (Addolorato 2002; Flannery 2004; Garbutt 2010; Krupitsky 1993; Morley 2014), shows that baclofen reduced anxiety in people with AUD. Post‐hoc analyses in one of the trials (Morley 2014), found that treatment with baclofen was most effective in people with comorbid anxiety. Following these lines of evidence, baclofen may also influence the subjective expression of craving and risk of relapse by suppressing anxiety associated with AUD (Morley 2014). Thus, besides dampening the reinforcing properties of alcohol through the suppression of alcohol‐stimulated dopamine release in the mesolimbic dopamine system, baclofen's effects on drinking might also be due, at least in part, to the relief of anxiety symptoms (Agabio 2014).
Why it is important to do this review
While a number of pharmacological treatments have been approved for the treatment of AUD (see Background), their clinical use is limited by a number of factors. The aversive agent disulfiram has been shown to support abstinence (Jorgensen 2011), but due to its safety profile it is only a therapeutic option for selected patient groups with a high self‐efficacy expectation to abstain from drinking after taking disulfiram (Mutschler 2016). Further substances like the opioid‐antagonists naltrexone and namlefene, and the glutamate antagonist, acamprosate appear to be safe and effective in people with AUD, but the strong variation in treatment response (Rösner 2010a; Rösner 2010b), indicates that patients might benefit from an extended range of treatment options that allow a further individualisation of pharmacological approaches. Baclofen as a treatment option for AUD has received much attention in recent years, initiated by pharmacological self‐experimentation of Olivier Ameisen (Ameisen 2005). Even though numerous case reports and case series confirmed the effectiveness of baclofen in people with AUD, data from RCTs yield conflicting results (Brennan 2013; Ponizovsky 2015). The planned review of baclofen to achieve abstinence or to reduce alcohol consumption in people with AUD who are currently drinking, will provide a systematic integration of the available evidence for health decision makers, therapists and patients, and aims to offer illustrative measures for estimating the therapeutic benefits and risks of baclofen, while indicating gaps in knowledge and methodological demands for future clinical research.
Objectives
To assess the efficacy and safety of baclofen for treating people with AUD, who are currently drinking, with the aim of achieving and maintaining abstinence or reducing alcohol consumption
Methods
Criteria for considering studies for this review
Types of studies
RCTs of at least four weeks' treatment duration and 12 weeks' overall study duration, comparing baclofen with placebo, no treatment or other pharmacological treatments for achieving alcohol abstinence and reducing consumption in people with AUD. We will include studies employing a cross‐over design, using data from the first active treatment stage only to remove the risk of carry‐over effects.
Types of participants
Adults (18 years and older), currently with AUD according to DSM‐III (APA 1980), DSM‐ III‐R (APA 1987), DSM‐IV‐TR (APA 2000), DSM‐5 (APA 2013), and ICD‐10 (WHO 1992; WHO 2010). There were no limitations on other participant characteristics such as concomitant substance use disorders or other comorbid psychiatric conditions. We also included trials with participants in methadone maintenance schemes. We excluded studies where baclofen was used to treat alcohol withdrawal.
We excluded people younger than 18 years of age and pregnant women because of the substantially different approach required for clinical management of these individuals.
Types of interventions
Experimental intervention
We included baclofen in any dose and route of administration. Studies could consider baclofen as monotherapy or in combination with further treatments provided that concomitant treatments were provided equally in both the experimental and control groups.
Control intervention
Placebo or any other pharmacological relapse prevention treatment, including acamprosate, naltrexone or nalmefene. We did not consider disulfiram as a control condition due to the psychological mediation of its effects.
Types of outcome measures
Primary outcomes
Relapse: return to any drinking, measured by number of people who had returned to any drinking at the end of the study and at follow‐up.
Frequency of use: measured as percentage abstinent days (ratio of the total sum of days with abstinence, related to the entire duration of the study, multiplied by the factor 100; or percentage of heavy drinking days.
Amount of use: number of drinks per drinking day or drinking occasion
Adverse events: measured by number of people with at least one adverse event, both subjectively or objectively assessed
Dropouts from treatment: number of participants who did not complete the study protocol
Dropout from treatment due to adverse events
Secondary outcomes
Cumulative abstinence duration (the total sum of days a participant remained abstinent in the course of the study, including continuous as well as interrupted abstinence intervals)
Craving, as measured by validated scales
Anxiety, as measured by validated scales
Depression, as measured by validated scales
Frequency of most relevant adverse events
We included drinking outcomes irrespective of the source of information, considering, for example, patient self‐reports, breathalyser tests, laboratory tests and collateral reports of others.
Search methods for identification of studies
The Cochrane Drugs and Alcohol Information Specialist conducted systematic searches for RCTs and controlled clinical studies. There were no language, publication year or publication status restrictions. The date of the search was 30 January 2018.
Electronic searches
We searched the following databases:
Cochrane Drugs and Alcohol Group (CDAG) Specialised Register (30 January 2018; Appendix 1);
Cochrane Central Register of Controlled Trials (CENTRAL; 2017, issue 12) via onlinelibrary.wiley.com (Appendix 2);
MEDLINE via PubMed (January 1966 to 30 January 2018), using the search strategy outlined in Appendix 3;
Embase (www.elsevier.com/solutions/embase‐biomedical‐research; January 1974 to 30 January 2018; Appendix 4);
PsycINFO (EBSCOhost; 1800 to 30 January 2018; Appendix 5);
Web of Science (Thomson Reuters; January 2006 to 30 January 2018; Appendix 6);
CINAHL (EBSCOhost; 1982 to 30 January 2018; Appendix 7).
We searched the databases using MeSH and free‐text terms relating to baclofen and alcohol dependence. We combined the PubMed search with the Cochrane Highly Sensitive Search Strategy for identifying RCTs in MEDLINE: sensitivity‐maximising version (Lefebvre 2011). We revised this strategy appropriately for each database to take account of differences in controlled vocabulary and syntax rules.
We searched the following trials registries on 30 January 2018:
ClinicalTrials.gov (www.clinicaltrials.gov);
World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/).
Searching other resources
We contacted key informants and experts to request any further, potentially relevant studies and seek information about unpublished or incomplete trials. We also handsearched the reference lists of included studies and current reviews. We included all eligible studies identified by the search, irrespective of language, publication type or status.
Data collection and analysis
Selection of studies
Two authors (SM, RS) independently screened the abstracts of all publications that were obtained by the search strategy. Two authors (SM, RS) independently assessed the full text of potentially‐relevant studies for inclusion. We used Covidence software (Covidence) for study selection. We resolved any disagreement by discussion; involving a third review author (SR) in case of persisting disagreements.
Data extraction and management
Two authors (RS, SM), independently extracted data. We resolved any doubts by discussion. We extracted the following information: number and characteristics of participants, setting, type of experimental and control intervention, length of follow‐up, types of outcomes, country of origin, funding and conflict of interest. We used Covidence software for data extraction (Covidence).
Assessment of risk of bias in included studies
Two authors (SM, RS) independently assessed the risk of bias of the included studies. We used the criteria recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). The recommended approach for assessing risk of bias in studies included in Cochrane Reviews is a two‐part tool, addressing the following specific domains: sequence generation and allocation concealment (selection bias), blinding of participants and providers (performance bias), blinding of outcome assessors (detection bias), incomplete outcome data (attrition bias), and selective outcome reporting (reporting bias). The first part of the tool involves describing what was reported to have happened in the study. The second part of the tool involves assigning a judgement relating to the risk of bias for that entry, in terms of low, high or unclear risk. To make these judgements we used the criteria indicated by the Cochrane Handbook for Systematic Reviews of Interventions, adapted to the addiction field. See Appendix 8 for details.
We addressed the domains of sequence generation and allocation concealment (avoidance of selection bias) by a single entry for each study.
We considered blinding of participants, personnel and outcome assessors (avoidance of performance bias and detection bias), separately for objective outcomes (e.g. dropout, duration of abstinence, relapse to use by urine or breath analysis), and subjective outcomes (e.g. patient self‐reported use of substance, adverse events, craving, psychiatric symptoms).
We considered incomplete outcome data (avoidance of attrition bias), for all outcomes except for dropout from the treatment, which is very often the primary outcome measure in trials on addiction.
Measures of treatment effect
We analysed dichotomous outcomes by calculating the risk ratio (RR) for each trial with the uncertainty in each result being expressed with a 95% confidence interval (CI). We analysed continuous outcomes by calculating the mean difference (MD) with 95% CI when the studies used the same instrument for assessing the outcome. We used the standardised mean difference (SMD) when the studies used different instruments.
Unit of analysis issues
If we included multi‐armed studies in the meta‐analyses and one arm was considered more than once in the same comparisons (e.g. two different dosages of baclofen compared with the same control group), we combined all the relevant experimental groups into a single group and we compared it with the control to avoid double counting of participants in the control groups. For cross‐over studies in meta‐analyses, we planned to use data from the first period only (i.e. before cross‐over), to address the risk of carry‐over effects. We did not include any cross‐over studies.
Dealing with missing data
For the analysis of binary outcome data (relapse), we included all randomised participants in the statistical analysis, with those who dropped out or who were lost to follow‐up assigned to the relapse category. For continuous outcomes, we used data reported in the studies without any imputation of missing data.
Assessment of heterogeneity
We analysed heterogeneity by means of the I² statistic (Higgins 2003), and the Chi² test. We regarded heterogeneity as substantial if the I² was greater than 50% or the P value lower than 0.10 for the Chi² test for heterogeneity (Deeks 2017). Following the guidance in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2017), we distinguished the following values to denote no important, moderate, substantial, and considerable heterogeneity, respectively: 0% to 40%, 30% to 60%, 50% to 90%, and 75% to 100%. If we found considerable levels of heterogeneity (i.e. 75% or above), we explored possible reasons by visually inspecting the forest plot to identify studies that might be contributing to heterogeneity.
Assessment of reporting biases
We planned to use visual inspection of funnel plots (plots of the effect estimate from each study against the sample size or effect standard error) to indicate possible publication bias if there were at least 10 studies included in the meta‐analysis. We did not inspect funnel plot because we included fewer than 10 studies in the meta‐analyses (Sterne 2017).
Data synthesis
We combined the outcomes from the individual trials through meta‐analysis where possible (comparability of intervention and outcomes between trials), using a random‐effects model, because we expected a certain degree of heterogeneity between trials. If the clinical or statistical heterogeneity between trials was too high (i.e. 75% to 100%), we considered not pooling the data.
Subgroup analysis and investigation of heterogeneity
We planned to investigate the sources of heterogeneity by performing subgroup analysis of studies for the following variables:
different dosages of baclofen;
participants with concomitant substance use disorders;
participants with other comorbid psychiatric conditions.
We did not perform subgroup analyses because there were too few studies included in the meta‐analyses. In particular, for the subgroup different dosages of baclofen, only one study (Beraha 2016), reported a high baclofen dose (150 mg a day), in a separate group from a low baclofen dose (30 mg a day), versus placebo, while Muller 2015 reported a single group with a dosage in a range from 30 mg a day to 270 mg a day versus placebo, not stratifying results from low or high dose.
Sensitivity analysis
To incorporate our assessment of risk of bias in the review process we first plotted the intervention effect estimates stratified by risk of bias for allocation concealment (selection bias). If differences in the results were present among studies at different risks of selection bias, we planned to perform sensitivity analysis by excluding studies at high risk of bias from the analysis. We also planned to perform sensitivity analysis to assess how sensitive the results were to changes in the assumptions about missing data for relapse, assuming dropout or loss to follow‐up as not relapsed. We did not perform any sensitivity analyses because there were no such cases.
Grading of evidence and 'Summary of findings' tables
We assessed the overall quality of the evidence for the following primary outcomes using the GRADE system: relapse, frequency of use, amount of use, any adverse events and dropout from treatment. The GRADE Working Group developed a system for grading the quality of evidence (GRADE 2004; Guyatt 2008; Guyatt 2011; Schünemann 2006), which takes into account issues not only related to internal validity but also to external validity, such as directness of results.
We have presented the main findings of the review in a 'Summary of findings' table. This is a transparent and simple tabular format that provides key information concerning the quality of evidence, the magnitude of effect of the interventions examined and the sum of available data on the main outcomes.
The GRADE system uses the following criteria for assigning grades of evidence.
High: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
Grading is decreased for the following reasons:
serious (‐1) or very serious (‐2) study limitations for risk of bias;
serious (‐1) or very serious (‐2) inconsistency between study results;
some (‐1) or major (‐2) uncertainty about directness (the correspondence between the population, the intervention, or the outcomes measured in the studies actually found and those under consideration in our systematic review);
serious (‐1) or very serious (‐2) imprecision of the pooled estimate;
publication bias strongly suspected (‐1).
We used the GRADEpro GDT (GRADEpro GDT 2015), software to prepare 'Summary of findings' tables.
Results
Description of studies
Results of the search
The database searches (see Electronic searches) retrieved 858 records. Our searches of the trials registers identified 35 further records. Our screening of the reference lists of the included publications did not reveal additional RCTs. We therefore had a total of 893 records.
Once duplicates had been removed, we had a total of 469 records. We excluded 445 records based on titles and abstracts. We obtained and assessed the full texts of the remaining 24 records. We excluded four studies (see Characteristics of excluded studies), six records are awaiting classification (see Characteristics of studies awaiting classification), and we identified two ongoing studies (see Characteristics of ongoing studies).
We included 12 studies reported in 15 references.
For a further description of our screening process, see the PRISMA study flow diagram (Figure 1; Moher 2009).
1.
Study flow diagram
Included studies
We included 12 RCTs involving a total of 1128 participants (see Characteristics of included studies). The mean study size was 99 participants, ranging from 30 in Leggio 2015 to 320 in Reynaud 2017.
All studies but three (Beraha 2016; Hauser 2017; Reynaud 2017), recruited fewer than 100 participants. The mean age of participants was 48 years, and there were more men (69%) than women. All studies included participants with a diagnosis of alcohol dependence according the DSM IV or the ICD 10 criteria, who were currently drinking. Five studies took place in the USA and one each in Australia, France, Germany, India, Israel, Italy, and the Netherlands.
Most trials did not report comorbidity (Garbutt 2010a; Krupitskii 2017; Leggio 2015; Mishra 2010; Morley 2014 ; Muller 2015; Ponizovsky 2015); one study reported liver cirrhosis including Child‐Pugh, Hepatitis B virus‐positive, Hepatitis C virus‐positive (Addolorato 2007); three studies reported depression and anxiety comorbidity (Beraha 2016; Garbutt 2010a; Reynaud 2017). One study (Garbutt 2010b), excluded patients with significant medical or psychiatric problems, including other substance dependence.
The mean duration of the interventions was 19.2 weeks (range 12 to 26 weeks). The mean duration of studies was 22.8 weeks (range 12 to 52 weeks).
Types of interventions
The included studies considered baclofen at different doses (range 10 mg a day to 270 mg a day). In Muller 2015 the Baclofen dose varied from 30 mg a day to 270 mg a day. Morley 2014 randomised participants in treatment to receive baclofen at 30 mg a day in one group and baclofen at 60 mg a day in another group. Beraha 2016 grouped participants to receive baclofen at a low dose (30 mg a day) and at a high dose (150 mg a day).
In some cases, the dose was increased during the treatment, as in Mishra 2010 (15 mg a day for the first three days and 30 mg a day subsequently for a total duration of three consecutive months), in Addolorato 2007 (baclofen was given at a dose of 5 mg three times a day for the first three days; subsequently, the dose was increased to 10 mg three times per day), and in Reynaud 2017 (the initial dose was provided twice a day, 10 mg morning and evening for two days, then three times a day and the dose increased by 10 mg every four days; a 17‐week maintenance period at the dose reached at the end of the titration period).
In all but one study (Mishra 2010), participants in both the baclofen and placebo groups received psychosocial treatment or counselling of various intensity.
Types of comparison
All studies compared baclofen to placebo, except for one study (Mishra 2010), that evaluated baclofen versus acamprosate at a dose of 666.66 mg three times a day for three months. Garbutt 2010b divided participants into four groups: baclofen + placebo, baclofen + naltrexone, placebo + naltrexone, and placebo + placebo. For our analysis, we grouped participants into two groups: baclofen with or without naltrexone, placebo with or without naltrexone.
Excluded studies
We excluded four studies for various reasons: two studies because the objective of the study was not in our inclusion criteria (human laboratory study; Leggio 2011;Leggio 2013); one study because its study design was not in our inclusion criteria (“uncontrolled preliminary study on 14 participants”; Flannery 2004); and one because the duration of the study was less than 12 weeks (Addolorato 2002). For more details see Characteristics of excluded studies.
Studies awaiting classification
Six studies are awaiting classification. One published study reported only post hoc analyses (Addolorato 2011). We wrote to the study authors to request the results obtained from the primary analysis but they did not release them. Two are conference abstracts without enough useful data (Farokhnia 2014; Sharma 2012), and the other three are protocols published on clinicaltrials.gov, where it is reported that the studies have been completed but the results have not been posted (CTRI/2016/01/006525; Jaury 2014; Morley 2013). We wrote to the study authors to request the results obtained from the studies but they did not release them. See Characteristics of studies awaiting classification for more details.
Ongoing studies
Two studies are ongoing (CTRI/2011/11/002154; NCT01980706). See Characteristics of ongoing studies for more details.
Risk of bias in included studies
See Figure 2 and Figure 3. For a detailed description of the reasons supporting our judgment, see the 'Risk of bias' tables in the Characteristics of included studies.
2.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
3.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Allocation
Random sequence generation
We judged nine studies to be at low risk of bias; the study authors did not report any information about methods of sequence random generation for the other three studies, so we judged them to be at unclear risk of bias.
Allocation concealment
We judged seven studies to be at low risk of bias; the other five studies did not report methods of allocation concealment,so we judged them to be at unclear risk of bias.
Blinding
Performance bias
We judged 10 studies to be at low risk of bias for objective outcomes and one to be at high risk. One study did not provide information about blinding, so we judged it to be at unclear risk of bias.
We judged eight studies to be at low risk of bias for subjective outcomes and one to be at high risk.The other three studies did not report methods for blinding, so we judged them to be at unclear risk of bias.
Detection bias
For subjective outcomes, we considered four studies to be at low risk of bias and two studies to be at high risk of bias. The other six studies did not report enough information to make a judgement, so we judged them to be at unclear risk of bias.
For objective outcomes, we considered 10 studies to be at low risk of bias, one study to be at high risk of bias and one at unclear risk.
Incomplete outcome data
We deemed seven studies to be at low risk of bias and one study to be at high risk of bias. The other studies did not report numbers and reasons of dropouts or missing data for each group, so we judged them to be at unclear risk of bias.
Selective reporting
We judged 10 trials to be at low risk of bias and one study to be at high risk of bias. One study did not provide enough information, so we judged it to be at unclear risk of bias.
Effects of interventions
See: Table 1
We identified 12 randomised trials from which it was possible to extract numerical data. The only quantitative comparison was in relation to placebo (10 studies); just one study compared baclofen with acamprosate (Mishra 2010), and none of the included studies considered the effect of baclofen versus any other pharmacological treatment, including naltrexone or nalmefene.
Comparison 1: baclofen versus placebo
1.1 Relapse: return to any drinking at the end of treatment
For this outcome we found five relevant studies involving 781 participants. There was no difference between baclofen and placebo (RR 0.88, 95% CI 0.74, to 1.04; moderate certainty evidence). This outcome had important levels of heterogeneity (Chi² = 17.13; df = 4; P = 0.002; I² = 77%; Analysis 1.1).
1.1. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 1 Relapse: return to any drinking at end of treatment.
1.2 Frequency of use: percentage of days abstinent at the end of treatment
For this outcome we found six relevant studies involving 465 participants. We did not find any difference between the two treatments in this comparison (MD 0.39, 95% CI ‐11.51 to 12.29; low certainty evidence). Heterogeneity was very high (Chi² = 121.22; df = 5; P < 0.00001; I² = 96%; Analysis 1.2). One study with 40 participants (Garbutt 2010b), reported the main percentage of days abstinent for each group but didn't provide the SD; the mean percentage of days abstinent was 62.6% in the baclofen group and 46.1% in the placebo group.
1.2. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 2 Frequency of use: % days abstinence at end of treatment.
1.3 Frequency of use: percentage of heavy drinking days at the end of treatment
We identified three studies relevant to this outcome involving 186 participants. There was no difference between baclofen and placebo (MD 0.25, 95% CI ‐1.25 to 1.76; moderate certainty evidence; Analysis 1.3). One study with 40 participants (Garbutt 2010b), reported the main percentage of heavy drinking days for each group but didn't provide the SD; the mean percentage of days abstinent was 13.2 % in the baclofen group and 14.4 % in the placebo group.
1.3. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 3 Frequency of use: % of heavy drinking days at end of treatment.
1.4 Amount of use: drink per drinking days at the end of treatment
We identified two studies relevant to this outcome involving 72 participants. We found evidence for this outcome that baclofen increases drink per drinking days compared with placebo (MD 1.55, 95% CI 1.32 to 1.77; low certainty evidence; Analysis 1.4).
1.4. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 4 Amount of use: drink per drinking days at end of treatment.
1.5 Adverse events: number of participants with at least one side effect at the end of treatment
For this outcome we found four relevant studies involving 430 participants. We did not find evidence of a clear difference between the two treatments in this comparison (RR 1.04, 95% CI 0.99 to 1.10; high certainty evidence; Analysis 1.5).
1.5. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 5 Adverse events: number of participants with at least one adverse event at end of treatment.
1.6 Dropouts at the end of treatment
For this outcome we found eight relevant studies involving 977 participants. There was no difference between baclofen and placebo (RR 0.98, 95% CI 0.77 to 1.26; high certainty evidence; Analysis 1.6).
1.6. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 6 Dropout at end of treatment.
1.7 Dropout due to adverse events
For this outcome we found seven relevant studies involving 913 participants. There was no difference between baclofen and placebo (RR 1.11, 95% CI 0.59 to 2.07; high certainty evidence; Analysis 1.7).
1.7. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 7 Dropout due to adverse events.
1.8 Craving
For this outcome we found five relevant studies, with a total of 469 people. We did not find any difference between the two treatments in this comparison (MD 1.38, 95% CI ‐1.28 to 4.03). Heterogeneity was high (Chi² = 14.40; df = 4.0; P = 0.006; I² = 72%; Analysis 1.8).
1.8. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 8 Craving.
1.9 Anxiety
For this outcome we found five relevant studies involving 509 participants. We did not find any difference between baclofen and placebo (SMD 0.07, 95% CI ‐0.14 to 0.28; Analysis 1.9).
1.9. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 9 Anxiety.
1.10 Depression
We identified three studies relevant to this outcome involving 387 participants. We found evidence that baclofen reduces depression compared with placebo (SMD 0.27, 95% CI 0.05 to 0.48; Analysis 1.10).
1.10. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 10 Depression.
1.11 Adverse events: fatigue, tiredness
For this outcome we found six relevant studies involving 828 participants. There was no difference between baclofen and placebo (RR 1.24; 95% CI 0.98 to 1.56; Analysis 1.11).
1.11. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 11 Adverse events: fatigue, tiredness.
1.12 Adverse events: insomnia
We identified four studies relevant to this outcome involving 577 participants. There was no difference between baclofen and placebo (RR 0.59, 95% CI 0.23 to 1.51; Analysis 1.12).
1.12. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 12 Adverse events: insomnia.
1.13 Adverse events: pain (diverse)
We identified two studies relevant to this outcome involving 86 participants. We did not find evidence of any difference between the two treatments in this comparison (RR 0.95, 95% CI 0.28 to 3.27; Analysis 1.13).
1.13. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 13 Adverse events: pain (diverse).
1.14 Adverse events: vertigo, dizziness
For this outcome we found seven relevant studies involving 858 participants. We found evidence that baclofen increases the frequency of vertigo when compared with placebo (RR 2.16, 95% CI 1.24 to 3.74; Analysis 1.14).
1.14. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 14 Adverse events: vertigo, dizziness.
1.15 Adverse events: constipation
For this outcome we found four relevant studies involving 567 participants. There was no difference between baclofen and placebo (RR 0.93 95% CI 0.54 to 1.58; Analysis 1.15).
1.15. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 15 Adverse events: constipation.
1.16 Adverse events: somnolence, sleepiness, drowsiness or sedation
For this outcome we found nine relevant studies involving 986 participants. We found evidence that baclofen increased the frequency of somnolence when compared with placebo (RR 1.48, 95% CI 1.11 to 1.96; Analysis 1.16).
1.16. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 16 Adverse events: somnolence, sleepiness, drowsiness or sedation.
1.17 Adverse events: muscle pain
For this outcome we found four relevant studies involving 593 participants. There was no difference between baclofen and placebo (RR 0.94, 95% CI 0.39 to 2.26; Analysis 1.17).
1.17. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 17 Adverse events: muscle pain.
1.18 Adverse events: dry mouth
We identified three studies relevant to this outcome with 509 participants. For this outcome, we found that baclofen increased the frequency of dry mouth compared with placebo (RR 2.68, 95% CI 0.77 to 9.32; Analysis 1.18).
1.18. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 18 Adverse events: dry mouth.
1.19 Adverse events: nausea
For this outcome we found four relevant studies, with a total of 577 participants. There was no difference between baclofen and placebo (RR 1.19, 95% CI 0.61 to 2.30; Analysis 1.19).
1.19. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 19 Adverse events: nausea.
1.20 Adverse events: skin rash
We identified three studies relevant to this outcome with 251 participants. We did not find any difference between the two treatments in this comparison (RR 2.59 95% CI 0.78 to 8.55; Analysis 1.20).
1.20. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 20 Adverse events: skin rash.
1.21 Adverse events: headaches
We identified seven studies relevant to this outcome, with a total of 821 participants. We did not find a difference between the two treatments in this comparison (RR 1.23, 95% CI 0.84 to 1.81; Analysis 1.21).
1.21. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 21 Adverse events: headaches.
1.22 Adverse events: paraesthesia/numbness
We identified four studies relevant to this outcome, with a total of 593 participants. We found that baclofen increases the frequency of paraesthesia (RR 4.28, 95% CI 2.11 to 8.67; Analysis 1.22).
1.22. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 22 Adverse events: paresthesia/numbness.
1.23 Adverse events: diarrhoea
We identified two studies relevant to this outcome, with a total of 495 people. We did not find any difference between the two treatments in this comparison (RR 0.64, 95% CI 0.31 to 1.31; Analysis 1.23).
1.23. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 23 Adverse events: diarrhoea.
1.24 Adverse events: tinnitus
We identified two studies relevant to this outcome, with a total of 495 participants. We did not find any difference between the two treatments in this comparison (RR 1.78, 95% CI 0.16 to 20.05). Heterogeneity was high (Chi² = 8.36; df = 1.0; P = 0.004; I² = 88%; Analysis 1.24).
1.24. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 24 Adverse events: tinnitus.
1.25 Adverse events: muscle spasm/rigidity
We identified three studies relevant to this outcome, with a total of 551 participants. We found that baclofen increases the frequency of muscle spasm (RR 1.94, 95% CI 1.08 to 3.48; Analysis 1.25).
1.25. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 25 Adverse events: muscle spasm/rigidity.
1.26 Adverse events: hyperhidrosis
We identified two studies relevant to this outcome, with a total of 495 participants. We did not find any difference between the two treatments in this comparison (RR 2.00, 95% CI 0.86 to 4.63; Analysis 1.26
1.26. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 26 Adverse events: hyperhidrosis.
1.27 Adverse events: nasopharyngitis
We identified three studies relevant to this outcome, with a total of 551 participants. We did not find any difference between the two treatments in this comparison (RR 0.71, 95% CI 0.23 to 2.23). Heterogeneity was high (Chi² = 7.36; df = 2.0; P = 0.03; I² = 73%; Analysis 1.27).
1.27. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 27 Adverse events: nasopharyngitis.
1.28 Adverse events: decreased appetite/anorexia
We identified two studies relevant to this outcome, with a total of 495 participants. We did not find any difference between the two treatments in this comparison (RR 1.02, 95% CI 0.49 to 2.12; Analysis 1.28).
1.28. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 28 Adverse events: decrease appetite/anorexia.
1.29 Adverse events: dysgeusia/ageusia
We identified two studies relevant to this outcome, with a total of 495 participants. We did not find any difference between the two treatments in this comparison (RR 2.29, 95% CI 0.44 to 11.94. Heterogeneity was high (Chi² = 2.99; df = 1.0; P = 0.08; I² = 67%; Analysis 1.29).
1.29. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 29 Adverse events: dysgeusia/ageusia.
1.30 Adverse events: tremor
We identified two studies relevant to this outcome, with a total of 495 participants. We did not find difference between the two treatments in this comparison (RR 0.87, 95% CI 0.46 to 1.65; Analysis 1.30).
1.30. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 30 Adverse events: tremor.
1.31 Adverse events: weakness
We identified two studies relevant to this outcome, with a total of 495 participants. We did not find any difference between the two treatments in this comparison (RR 1.07, 95% CI 0.60 to 1.92; Analysis 1.31).
1.31. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 31 Adverse events: weakness.
1.32 Adverse events: vomiting
We identified two studies relevant to this outcome, with a total of 495 participants. We did not find any difference between the two treatments in this comparison (RR 0.97, 95% CI 0.50 to 1.88; Analysis 1.32).
1.33 Adverse events: urinary frequency
We identified three studies relevant to this outcome, with a total of 265 participants. We did not find any difference between the two treatments in this comparison (RR 1.64, 95% CI 0.35 to 7.63; Analysis 1.33).
1.33. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 33 Adverse events: urinary frequency.
Comparison 2: baclofen versus acamprosate
This comparison has only one outcome.
2.1 Craving
We identified one study relevant to this outcome, with a total of 49 participants. We found that baclofen increased craving compared with acamprosate (MD 14.62, 95% CI 12.72 to 16.52; Analysis 2.1).
2.1. Analysis.
Comparison 2 Baclofen vs acamprosate, Outcome 1 Craving.
Discussion
Summary of main results
We included a total of 12 RCTs with 1128 participants and a minimum duration of 12 weeks in the review. Eleven of the 12 RCTs compared baclofen with placebo, and the other RCT compared baclofen with acamprosate. Meta‐analyses did not find significant superiority of baclofen compared to placebo for any drinking outcome at the end of treatment (certainty of evidence low and moderate). In addition, we found no significant difference between baclofen and placebo for dropout, dropout due to adverse events (high‐certainty evidence), number of participants with at least one adverse event, craving and anxiety, while depression was even higher in the baclofen than in the placebo group.
In comparison to placebo, baclofen increased the frequency of vertigo, somnolence, dry mouth, paraesthesia and muscle spasms. For all the other adverse events we did not find significant differences between baclofen and placebo.
For the comparison between baclofen and acamprosate, only one outcome was available, showing higher craving scores under baclofen compared to acamprosate; however, this result was based on one study of 49 participants, so should be interpreted with caution.
In addition, various outcomes had a high level of heterogeneity, reflecting the dichotomous nature of primary evidence (with the majority of RCTs missing significance contrasted by a small subset of trials with proof of efficacy), and indicating the need to identify potential sources of heterogeneity (see also Quality of the evidence).
Overall completeness and applicability of evidence
The diversity of the outcomes used to assess effectiveness in the included studies, diversity that, in many cases, limited the possibility of pooling the results, reflects the fact that various outcomes are established in alcoholism research with no clear superiority for one outcome compared to another in terms of validity or clinical relevance.
There is high variability in the trials considered in the review, for baclofen dosing, titration schedules, compliance, and duration of treatment. Additionally, we defined inclusion criteria in a non‐restrictive way, so that samples would reflect a mix of different participant characteristics in terms of comorbidity and baseline alcohol use.
Nevertheless, heterogeneity of summary effects indicates that differences across effect sizes are likely due to sources other than sampling error, suggesting the impact of moderators and mediators that influence baclofen's effects on drinking outcomes. As subgroup analyses to investigate the impact of patient characteristics were not applicable due to the limited number of RCTs (see Methods), we qualitatively reviewed studies and 'Risk of bias' tables (see Characteristics of included studies), to identify differences between studies with and without proof of efficacy.
However, none of the considered variables could provide consistent explanations for the differences. While it has been suggested that baclofen may have more impact on higher severity of alcohol dependence by preclinical (Maccioni 2012; Walker 2007), and clinical evidence (Agabio 2014; Leggio 2010), Hauser 2017 did not find an effect of baclofen on drinking when accounting for baseline alcohol use. Among reasons that may contribute to the discrepancy of findings, differences in baclofen dosing are among the most discussed issues (Agabio 2014). Indeed, maximum baclofen dosing was lower in some studies with non‐significant results (e.g. Garbutt 2010a; Hauser 2017; Ponizovsky 2015), compared to those with significant findings (Addolorato 2007; Muller 2015), while therapeutic response was shown not to differ between the low‐ and high‐dose participants, as shown by subgroup analyses in one trial (Beraha 2016). In addition, the hypothesis that abstinence‐maintaining effects in alcohol‐dependent participants are mediated by the suppression of comorbid anxiety (Agabio 2014; Addolorato 2002; Addolorato 2007), a hypothesis consistent with the role of the GABAB receptor in the neural circuits of anxiety (Cryan 2005), was not confirmed by a recent trial (Muller 2015). Random error due to heterogeneity among the study sites may have lowered effect sizes for the opioid‐antagonist naltrexone in multicentre studies (Feinn 2005), but non‐significant effects have also been observed in single‐centre studies on baclofen as well (e.g. Garbutt 2010a; Krupitskii 2017; Ponizovsky 2015). In addition, further potential moderators of efficacy that could serve as a reason for contrasting results such as drinking status at baseline (abstinent versus actively drinking), or treatment setting (inpatient versus outpatient) do not systematically differ between RCTs with and without proof of efficacy.
The identification of moderators and mediators of efficacy by future research will not only be crucial for determining the therapeutic potential of baclofen, but also to assess the applicability of meta‐analytic results to different frame conditions of baclofen use in clinical practice.
Data on adverse events from RCTs are more consistent, but unlikely to cover all conditions in routine care. Evidence from RCTs shows adverse events of baclofen that are of mild and transient nature such as vertigo, somnolence and dry mouth. Nevertheless, the review does not allow conclusions on the safety of baclofen taken outside the recommended dose range or in specific patient subgroups, such as individuals with suicidal ideation (e.g. Holla 2015; Pellisier 2017).
Levels of the heterogeneity indicate that the summary effects shown in the meta‐analyses of the review are not generalisable over all studied conditions and are likely to be affected by variables like sample, setting, or design. Our qualitative review of selected sample characteristics, treatment and design features, did not yield systematic differences between studies with and without proof of efficacy. Accordingly, available evidence could not provide consistent explanations for the diversity of findings.
Quality of the evidence
Applying the criteria recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), we judged most of the RCTs to have a low risk of selection, performance, detection (subjective outcome), attrition and reporting bias.
While the systematic application of criteria for assessing bias risks allowed us to rate the quality of studies and outcomes, it did not identify sources of bias that could explain the contrasting findings on the primary level of evidence. One potential threat of bias that concerns all RCTs applying inert placebo is the unmasking of blinding ‐ a methodological limitation that has been shown to be associated with an overestimation of effects for antidepressant substances (Moncrieff 2004). Even though baclofen and placebo were of identical appearance in most RCTs, perceptible differences between treatment groups such as adverse events can reveal participants' affiliation to treatment conditions. Thus, from a theoretical perspective, we could not definitely exclude the possibility that proof of efficacy in some trials is attributable to an overestimation of effects caused by an unmasking of treatment allocation.
All in all, we rated the certainty of evidence as high for the outcomes dropouts, participants with at least one adverse event, and dropout due to adverse events; moderate for relapse to any drinking, percentage of heavy drinking days; and as low for number of drinks per drinking days and percent days abstinent. Reasons for downgrading were inconsistency among study results for the outcomes relapse and percentage of days abstinent, showed by high or very high heterogeneity among study results or imprecision because of few or very few participants included in the analysis for the outcome percentage of heavy drinking days at end of treatment, and drink per drinking days.
Potential biases in the review process
To lower the risk of bias in the review process, two review authors independently screened abstracts, assessed full texts, rated risk of bias for included studies and extracted data from primary studies. None of the review authors has any personal, scientific or financial conflicts of interest or expected advantages from significant results in terms of reviewer decisions or raising funds, lowering the risk for confirmation bias (Nickerson 1998), and significance bias (Kagereki 2016). We could not inspect funnel plots for risk of possible publication bias due to the small number of studies included in the meta‐analyses; however, we wrote to the authors of published studies and searched on ClincialTrials.gov and ICTRP to search for unpublished studies to minimise the risk of publication bias.
Agreements and disagreements with other studies or reviews
Overall, most conclusions of the review are in line with previous reviews, emphasising the inconsistency of results and the necessity for further research (e.g. Agabio 2014; Brennan 2013; Lesouef 2014). While the review corresponds with further meta‐analyses (Lesouef 2014; Rose 2018), by missing significance for frequency measures of alcohol use, it did not confirm the significance of effects for continuous abstinence ('return to any drinking'). While Lesouef 2014 identified a significant 2.8‐fold increase of the chance of maintaining abstinence under baclofen compared to placebo (RR 2.79 95% CI 1.79 to 4.34, 3 RCTs, 65 participants), and Rose 2018 a 2.7‐fold increase (OR 2.67 95% CI 1.03 to 6.93; 6 RCTs, 590 participants), effects on abstinence in the review at hand missed significance. At the same time, the discrepancy between findings is mainly attributable to differences in the dates of search and the criteria for including RCTs in the meta‐analytic integrations. The present review also considered newer RCTs with weaker effects (e.g. Beraha 2016; Hauser 2017; Krupitskii 2017; Reynaud 2017), but defined a duration of 12 weeks as a criteria of inclusion. We chose a minimum of 12 weeks' treatment to allow an adequate implementation of the intervention, but this led to the exclusion of a study with a comparatively large positive treatment effect (Addolorato 2002).
Authors' conclusions
Implications for practice.
None of the primary or secondary outcomes of the review showed evidence of a difference between baclofen and placebo. Baclofen was similar to placebo in both maintaining continuous abstinence and in reducing drinking frequency or drinking amount. Evidence from meta‐analytic integrations of primary evidence does not indicate positive effects of baclofen in the treatment of alcohol use disorder (AUD), and does not support the use of baclofen as a first‐line treatment for people with AUD. Even though some results from randomised controlled trials (RCTs) are promising, current evidence remains uncertain regarding the use of baclofen as a first‐line treatment for people with AUD. Nevertheless, the heterogeneity of summary effects and their susceptibility to marginal changes in the primary data illustrates the preliminary character of efficacy conclusions and the need for further research targeting moderators of efficacy and specific bias risks (see Implications for research).
Implications for research.
For exploring the inconsistency of effects shown in the review, factors like dosing schedules, treatment setting, severity of AUD and drinking status at the beginning of treatment might be potential mediators of efficacy. One factor requiring special attention in future studies is the titration of dose to obtain an optimal therapeutic response. Due to the high inter‐individual variation of effective doses (Thompson 2017), titration regimes might be advantageous compared to fixed dosing of baclofen in future studies. In addition, to ensure an adequate implementation of treatment and a sufficient 'fairness of testing', participants' compliance should be monitored to ensure that dosing schedules are implemented as foreseen in the study protocol.
One potential threat to bias that needs to be further addressed by research is the unmasking of blinding in the course of treatment. Even though quality of blinding is ensured by various measures of bias control, such as allocation concealment and blinding of participants and personnel, adverse events can potentially reveal a participant's affiliation to treatment conditions in the course of treatment. The use of active placebo mimicking adverse events of baclofen could prevent an overestimation of effects through response bias, placebo effects or differential attrition (Hróbjartsson 2014). If inert placebo is used, testing of blinding integrity by querying participants about their assumed group allocation would be a simple method that allows at least a retrospective assessment of blinding integrity (Wilsey 2016).
Thus, the further exploration of baclofen's profile of efficacy and safety and the identification of moderators and mediators of baclofen's effects on alcohol use remains a challenge for further research.
Acknowledgements
Parts of this review were generated using RevMan HAL v 4.0 (schizophrenia.cochrane.org/revman‐hal‐v4).
Appendices
Appendix 1. Cochrane Drug and Alcohol Group Specialised Register search strategy
CDAG Specialised Register (via CRSLive)
30 January 2018 (53 hits)
baclofen (all fields)
Appendix 2. CENTRAL search
Cochrane Central Register of Controlled Trials (CENTRAL) (via onlinelibrary.wiley.com)
2017, issue 12 (59 hits)
#1 MeSH descriptor: [Alcohol‐Related Disorders] explode all trees #2 MeSH descriptor: [Alcohol Drinking] explode all trees #3 (alcohol and (abuse* or addict* or dependen* or disorder* or drink* or consumption or treatment)):ti,ab,kw #4 #1 or #2 or #3 #5 MeSH descriptor: [Baclofen] explode all trees #6 "baclofen" (Word variations have been searched) #7 Lioresal:ti,ab,kw (Word variations have been searched) #8 #5 or #6 or #7 #9 #4 and #8 in Trials
Appendix 3. MEDLINE via PubMed search
30 January 2018 (125 hits)
alcohol‐related disorders[MeSH]
((alcohol[tiab]) AND (abuse*[tiab] OR addict*[tiab] OR dependen*[tiab] OR disorder*[tiab] OR drink*[tiab] OR consumption[tiab]))
Drinking behaviour[MeSH]
#1 OR #2 OR #3
Baclofen [MeSH]
Chlorophenyl GABA [tiab]
beta‐(p‐Chlorophenyl)‐gamma‐aminobutyric Acid [tiab]
"gamma‐amino butyric acid‐B receptor agonists
"Lioresal [tiab]
#5 OR #6 OR #7 OR #8 OR #9
randomized controlled trial [pt]
controlled clinical trial [pt]
random* [tiab]
placebo [tiab]
drug therapy [MeSH]
trial [tiab]
groups [tiab]
#11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17
animals [mh] NOT human [mh]
#18 NOT #19
#4 AND #10 AND #20
Appendix 4. Embase search strategy
Embase (OVID)
30 January 2018 (329 hits)
exp alcoholism/
exp drinking behavior/
alcohol.mp.
(abuse* or addict* or dependen* or disorder* or drink* or consumption or treatment).ti,ab.
3 and 4
1 or 2 or 5
exp baclofen/ or baclofen.mp.
6 and 7
exp randomized controlled trial/
exp randomization/
exp double blind procedure/
exp single blind procedure/
random$.tw.
9 or 10 or 11 or 12 or 13
(animal or animal experiment).sh.
human.sh.
15 and 16
15 not 17
14 not 18
exp clinical trial/
(clin$ adj3 trial$).tw.
exp crossover procedure/
exp double blind procedure/
exp controlled clinical trial/
(placebo or assign* or allocat* or volunteer* or random* or factorial* or crossover).ti,ab.
((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
20 or 21 or 22 or 23 or 24 or 25
27 not 18
19 or 28
8 and 29
Appendix 5. PsycINFO
PsycINFO (OVID)
30 January 2018 (137 hits)
exp alcoholism/
((alcohol$ or drink$) adj5 (abstinen$ or abstain$ or abus$ or addict$ or crav$ or dependen$ or detox$ or disease$ or disorder$ or excessiv$ or heavy or intoxicat$ or misus$ or overdos$ or problem$ or rehab$ or relaps$ or treatment$ or withdraw$)).mp. [mp=title, abstract, heading word, table of contents, key concepts, original title, tests & measures]
1 or 2
exp BACLOFEN/
baclofen.mp.
4 or 5
3 and 6
(control* or random*).tw. or exp Treatment/
7 and 8
Appendix 6. Web of Science search strategy
30 January 2018 (126 hits)
TOPIC: (((alcohol$ or drink$) NEAR/5 (abstinen$ or abstain$ or abus$ or addict$ or crav$ or dependen$ or detox$ or disease$ or disorder$ or excessiv$ or heavy or intoxicat$ or misus$ or overdos$ or problem$ or rehab$ or relaps$ or treatment$ or withdraw$)))
TOPIC: (baclofen)
TOPIC: (randomi* OR randomly OR trial*)
#3 AND #2 AND #1
Appendix 7. CINAHL search strategy
CINAHL (EBSCOhost)
30 January 2018 (29 hits)
MH "Alcoholism"
TX (alcohol N3 (drink* or abus* or misus* or risk* or consum* or withdraw* or intoxicat* or detox* or treat* or therap* or excess* or reduc* or cessation or intervention))
TX(overdos* or intoxicat* or abstinen* or withdraw* or relaps*)
TX (drink* N3 (heavy or heavily or hazard* or binge or harmful))
MH "Clinical Trials+"
PT Clinical trial
TI clinic* N1 trial* or AB clinic* N1 trial*
TI ( singl* or doubl* or trebl* or tripl* ) and TI ( blind* or mask* )
AB ( singl* or doubl* or trebl* or tripl* ) and AB ( blind* or mask* )
TI randomi?ed control* trial* or AB randomi?ed control* trial*
MH "Random Assignment"
TI random* allocat* or AB random* allocat*
MH "Placebos"
TI placebo* or AB placebo*
MH "Quantitative Studies"
S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15
baclofen
S1 OR S2 OR S3
S16 AND S17 AND S18
Appendix 8. Criteria for 'Risk of bias' assessment
| Item | Judgment | Description |
| 1. Random sequence generation (selection bias) | Low risk | The investigators describe a random component in the sequence generation process such as: random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimisation. |
| High risk | The investigators describe a non‐random component in the sequence generation process such as: odd or even date of birth; date (or day) of admission; hospital or clinic record number; alternation; judgement of the clinician; results of a laboratory test or a series of tests; availability of the intervention. | |
| Unclear risk | Insufficient information about the sequence generation process to permit judgement of low or high risk. | |
| 2. Allocation concealment (selection bias) | Low risk | Investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web‐based, and pharmacy‐controlled, randomisation); sequentially‐numbered drug containers of identical appearance; sequentially‐numbered, opaque, sealed envelopes. |
| High risk | Investigators enrolling participants could possibly foresee assignments because one of the following methods was used: open random allocation schedule (e.g. a list of random numbers); assignment envelopes without appropriate safeguards (e.g. if envelopes were unsealed or nonopaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure. | |
| Unclear risk | Insufficient information to permit judgement of low or high risk This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement | |
| 3. Blinding of participants and providers (performance bias) Objective outcomes |
Low risk | No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding. Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken. |
| High risk | No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding. Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding. |
|
| Unclear risk | Insufficient information to permit judgement of low or high risk. | |
| 4. Blinding of participants and providers (performance bias) Subjective outcomes |
Low risk | Blinding of participants and providers ensured and unlikely that the blinding could have been broken. |
| High risk | No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding. Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding. |
|
| Unclear risk | Insufficient information to permit judgement of low or high risk. | |
| 5. Blinding of outcome assessor (detection bias) Objective outcomes |
Low risk | No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding. Blinding of outcome assessment ensured, and unlikely that the blinding could have been broken. |
| High risk | No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding. Blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding. |
|
| Unclear risk | Insufficient information to permit judgement of low or high risk. | |
| 6. Blinding of outcome assessor (detection bias) Subjective outcomes |
Low risk | Blinding of outcome assessment ensured, and unlikely that the blinding could have been broken. |
| High risk | No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding. Blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding. |
|
| Unclear risk | Insufficient information to permit judgement of low or high risk. | |
| 7. Incomplete outcome data (attrition bias) For all outcomes except retention in treatment or drop out |
Low risk | No missing outcome data. Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias). Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups. For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically‐relevant impact on the intervention effect estimate. For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically‐relevant impact on observed effect size. Missing data have been imputed using appropriate methods. All randomised patients are reported/analysed in the group they were allocated to by randomisation irrespective of non‐compliance and co‐interventions (intention to treat). |
| High risk | Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups. For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically‐relevant bias in intervention effect estimate. For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes enough to induce clinically‐relevant bias in observed effect size. ‘As‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation. |
|
| Unclear risk | Insufficient information to permit judgement of low or high risk (e.g. number randomised not stated, no reasons for missing data provided; number of dropouts not reported for each group). | |
| 8. Selective reporting (reporting bias) | Low risk | The study protocol is available and all of the study’s prespecified (primary and secondary) outcomes that are of interest in the review have been reported in the prespecified way. The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were prespecified (convincing text of this nature may be uncommon). |
| High risk | Not all of the study’s prespecified primary outcomes have been reported. One or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not prespecified. One or more reported primary outcomes were not prespecified (unless clear justification for their reporting is provided, such as an unexpected adverse effect). One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis. The study report fails to include results for a key outcome that would be expected to have been reported for such a study. |
|
| Unclear risk | Insufficient information to permit judgement of low or high risk. |
Appendix 9. Trials registers
ClinicalTrials.gov
30 January 2018
22 studies found for: baclofen | Interventional Studies | alcohol (www.clinicaltrials.gov)
World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP)
30 January 2018
34 records for 33 trials found for: baclofen AND alcohol (apps.who.int/trialsearch/)
Data and analyses
Comparison 1. Baclofen vs placebo.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Relapse: return to any drinking at end of treatment | 5 | 781 | Risk Ratio (IV, Random, 95% CI) | 0.88 [0.74, 1.04] |
| 2 Frequency of use: % days abstinence at end of treatment | 6 | 465 | Mean Difference (IV, Random, 95% CI) | 0.39 [‐11.51, 12.29] |
| 3 Frequency of use: % of heavy drinking days at end of treatment | 3 | 186 | Mean Difference (IV, Random, 95% CI) | 0.25 [‐1.25, 1.76] |
| 4 Amount of use: drink per drinking days at end of treatment | 2 | 72 | Mean Difference (IV, Random, 95% CI) | 1.55 [1.32, 1.77] |
| 5 Adverse events: number of participants with at least one adverse event at end of treatment | 4 | 430 | Risk Ratio (IV, Random, 95% CI) | 1.04 [0.99, 1.10] |
| 6 Dropout at end of treatment | 8 | 977 | Risk Ratio (IV, Random, 95% CI) | 0.98 [0.77, 1.26] |
| 7 Dropout due to adverse events | 7 | 913 | Risk Ratio (M‐H, Random, 95% CI) | 1.11 [0.59, 2.07] |
| 8 Craving | 5 | 469 | Mean Difference (IV, Random, 95% CI) | 1.38 [‐1.28, 4.03] |
| 9 Anxiety | 5 | 509 | Std. Mean Difference (IV, Random, 95% CI) | 0.07 [‐0.14, 0.28] |
| 10 Depression | 3 | 387 | Std. Mean Difference (IV, Random, 95% CI) | 0.27 [0.05, 0.48] |
| 11 Adverse events: fatigue, tiredness | 6 | 828 | Risk Ratio (M‐H, Random, 95% CI) | 1.24 [0.98, 1.56] |
| 12 Adverse events: insomnia | 4 | 577 | Risk Ratio (M‐H, Random, 95% CI) | 0.59 [0.23, 1.51] |
| 13 Adverse events: pain (diverse) | 2 | 86 | Risk Ratio (M‐H, Random, 95% CI) | 0.95 [0.28, 3.27] |
| 14 Adverse events: vertigo, dizziness | 7 | 858 | Risk Ratio (M‐H, Random, 95% CI) | 2.16 [1.24, 3.74] |
| 15 Adverse events: constipation | 4 | 567 | Risk Ratio (M‐H, Random, 95% CI) | 0.93 [0.54, 1.58] |
| 16 Adverse events: somnolence, sleepiness, drowsiness or sedation | 9 | 986 | Risk Ratio (M‐H, Random, 95% CI) | 1.48 [1.11, 1.96] |
| 17 Adverse events: muscle pain | 4 | 593 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.39, 2.26] |
| 18 Adverse events: dry mouth | 3 | 509 | Risk Ratio (M‐H, Random, 95% CI) | 2.68 [0.77, 9.32] |
| 19 Adverse events: nausea | 4 | 577 | Risk Ratio (M‐H, Random, 95% CI) | 1.19 [0.61, 2.30] |
| 20 Adverse events: skin rash | 3 | 251 | Risk Ratio (M‐H, Random, 95% CI) | 2.59 [0.78, 8.55] |
| 21 Adverse events: headaches | 7 | 821 | Risk Ratio (M‐H, Random, 95% CI) | 1.23 [0.84, 1.81] |
| 22 Adverse events: paresthesia/numbness | 4 | 593 | Risk Ratio (M‐H, Random, 95% CI) | 4.28 [2.11, 8.67] |
| 23 Adverse events: diarrhoea | 2 | 495 | Risk Ratio (M‐H, Random, 95% CI) | 0.64 [0.31, 1.31] |
| 24 Adverse events: tinnitus | 2 | 495 | Risk Ratio (M‐H, Random, 95% CI) | 1.78 [0.16, 20.05] |
| 25 Adverse events: muscle spasm/rigidity | 3 | 551 | Risk Ratio (M‐H, Random, 95% CI) | 1.94 [1.08, 3.48] |
| 26 Adverse events: hyperhidrosis | 2 | 495 | Risk Ratio (M‐H, Random, 95% CI) | 2.00 [0.86, 4.63] |
| 27 Adverse events: nasopharyngitis | 3 | 551 | Risk Ratio (M‐H, Random, 95% CI) | 0.71 [0.23, 2.23] |
| 28 Adverse events: decrease appetite/anorexia | 2 | 495 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.49, 2.12] |
| 29 Adverse events: dysgeusia/ageusia | 2 | 495 | Risk Ratio (M‐H, Random, 95% CI) | 2.29 [0.44, 11.94] |
| 30 Adverse events: tremor | 2 | 495 | Risk Ratio (M‐H, Random, 95% CI) | 0.87 [0.46, 1.65] |
| 31 Adverse events: weakness | 2 | 495 | Risk Ratio (M‐H, Random, 95% CI) | 1.07 [0.60, 1.92] |
| 32 Adverse events: vomiting | 2 | 495 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.50, 1.88] |
| 33 Adverse events: urinary frequency | 3 | 265 | Risk Ratio (M‐H, Random, 95% CI) | 1.64 [0.35, 7.63] |
1.32. Analysis.
Comparison 1 Baclofen vs placebo, Outcome 32 Adverse events: vomiting.
Comparison 2. Baclofen vs acamprosate.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Craving | 1 | 49 | Mean Difference (IV, Random, 95% CI) | 14.62 [12.72, 16.52] |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Addolorato 2007.
| Methods |
Study design: RCT Study grouping: parallel‐group |
|
| Participants |
Baseline characteristics Baclofen
Placebo
Inclusion criteria: age‐range 18–75 years; diagnosis of alcohol dependence according to DSM‐IV criteria; diagnosis of liver cirrhosis; an alcohol intake of ≥ 2 heavy drinking d/week on average (men ≥ 5 drinks/d; women ≥ 4 drinks/d) and an average overall consumption of ≥ 21 drinks/week for men and ≥ 14 drinks/week for women during the 4 weeks before enrolment (1 standard drink = 12 g absolute alcohol); and presence of a referred family member able to assist with drug administration and monitoring Exclusion criteria: severe heart or lung disease; abnormal renal function, hepatorenal syndrome, or both; malignant disease; metabolic diseases; hepatic encephalopathy; treatment with interferon or corticosteroids within the past 60 days; psychopathological illness treated with psychoactive drugs; epilepsy; and addiction to drugs other than nicotine |
|
| Interventions |
Intervention characteristics Baclofen (participants = 42) + counselling
Placebo (participants = 42) + counselling
|
|
| Outcomes |
Primary outcomes
Secondary outcomes
|
|
| Identification |
Sponsorship source: Italian Ministry for University, Scientific and Technological Research (MURST), and by the European Research Advisory Board (ERAB) Country: Italy Setting: Institute of Internal Medicine of the Catholic University in Rome, Italy (which has both a liver unit and an alcohol addiction unit) Author's name: Dr Giovanni Addolorato Institution: Institute of Internal Medicine, Catholic University of Rome Email: giovanni.addolorato@.unicatt.it Address: Largo A Gemelli 8, I‐00168 Rome, Italy |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "Randomisation was balanced with blocks." Quote: "eligible patients who provided informed consent were randomly allocated either oral baclofen or placebo." |
| Allocation concealment (selection bias) | Low risk | Quote: "were randomly allocated either oral baclofen or placebo. The randomisation sequence was generated by the pharmacist who prepared drug and placebo. Randomisation was balanced with blocks. The pharmacist did not have any further role in the study." |
| Blinding of participants and personnel (performance bias) objective outcomes | Low risk | Quote: "Participants and investigators were unaware of treatment assignment. To maintain masking, the randomisation code was concealed in a safe box in the pharmacy. For the duration of the study (including also the 4 weeks of follow‐up), the pharmacist or another employee of the same pharmacy could be contacted at any time to open the safe box in the case of a specific emergency." Quote: "Placebo tablets were identical in size, colour, shape, and taste to baclofen." |
| Blinding of participants and personnel (performance bias) subjective outcomes | Low risk | Quote: "Participants and investigators were unaware of treatment assignment. To maintain masking, the randomisation code was concealed in a safe box in the pharmacy. For the duration of the study (including also the 4 weeks of follow‐up), the pharmacist or another employee of the same pharmacy could be contacted at any time to open the safe box in the case of a specific emergency." Quote: "Placebo tablets were identical in size, colour, shape, and taste to baclofen." |
| Blinding of outcome assessment (detection bias) subjective outcomes | Low risk | Quote: "Participants and investigators were unaware of treatment assignment. To maintain masking, the randomisation code was concealed in a safe box in the pharmacy. For the duration of the study (including also the 4 weeks of follow‐up), the pharmacist or another employee of the same pharmacy could be contacted at any time to open the safe box in the case of a specific emergency." |
| Blinding of outcome assessment (detection bias) objective outcomes | Low risk | Quote: "Participants and investigators were unaware of treatment assignment. To maintain masking, the randomisation code was concealed in a safe box in the pharmacy. For the duration of the study (including also the 4 weeks of follow‐up), the pharmacist or another employee of the same pharmacy could be contacted at any time to open the safe box in the case of a specific emergency." |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Quote: "We assumed for this analysis that all patients who terminated treatment before the end of the study had relapsed." Quote: "Our analysis was done by intention to treat, insomuch that we assumed every patient took the drug allocated to them and counted them in that group." |
| Selective reporting (reporting bias) | Low risk | Study protocol available; results reported for all the primary and secondary outcomes described in the protocol |
Beraha 2016.
| Methods |
Study design: RCT Study grouping: parallel‐group |
|
| Participants |
Baseline characteristics Baclofen: HD baclofen (participants = 58); LD baclofen (participants = 31)
Placebo: (participants = 62)
Inclusion criteria: aged 18‐70 years; DSM‐IV AD‐diagnosis; breath alcohol concentration < 0.5% at the screening visit (informed consent); an average alcohol consumption of ≥ 14 units for women and ≥ 21 units for men/week over a consecutive 30‐day period in the 90‐day period before the start of the study and ≥ 2 heavy drinking days (women ≥ 5 units; men ≥ 6 units) in the past 90 days; a minimum of 96 h and a maximum of 21 d of abstinence prior to the start of the study medication; sufficient Dutch language skills; provision of a contact person in the event of loss of contact. Exclusion criteria: current severe axis I disorder (other than depression, anxiety, and bipolar disorder); any primary diagnosis of substance dependence other than alcohol dependence (nicotine dependence was allowed); severe physical illnesses (e.g. Parkinson's disease, gastric ulcer, duodenal ulcer, cerebrovascular disease, respiratory insufficiency, hepatic or renal insufficiency, epilepsy); antihypertensive medication; risk of suicide; cognitive impairment interfering with the understanding of the study; current or recent (3 months before start of the study), pharmacological treatment for AD (i.e. acamprosate, naltrexone, disulfiram, ortopiramate); pregnancy or breast feeding; > 7 d inpatient treatment for SUD in the 30 days before the start of the study; and use of baclofen in the past 30 days. |
|
| Interventions |
Intervention characteristics Baclofen HD baclofen (participants = 58); LD baclofen (participants = 31) + CBT
Placebo (participants = 62) + CBT
|
|
| Outcomes |
Primary outcomes
Secondary outcomes
|
|
| Identification |
Sponsorship source: funding for this study was provided by a private donation through the University of Amsterdam Fund (AUF7344) Country: The Netherlands Setting: SolutionS Center, Voorthuizen, The Netherlands; U‐Center, Epen, The Netherlands; The Home Clinic, Weesp, The Netherlands; Roder Sana Addiction Treatment, Oirschot, The Netherlands Author's name: Dr Esther M. Beraha Institution: Addiction Development and Psychopathology (ADAPT) Laboratory, Department of Psychology, University of Amsterdam, Amsterdam, The Netherlands Email: R.W.H.J.Wiers@uva.nl (R.W.Wiers) Address: Addiction Development and Psychopathology Lab, Department of Psychology, University of Amsterdam, Nieuwe Achtergracht 129 B, 1018 WS Amsterdam, The Netherlands |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Randomization (blocks of 6; pre‐stratification by gender and centre) was conducted by the Clinical Research Unit of the AMC and patients were assigned to one of the three groups via an electronic database after baseline assessment" |
| Allocation concealment (selection bias) | Low risk | Quote: "Only the study pharmacist had access to the randomization list and had no further role in the trial" |
| Blinding of participants and personnel (performance bias) objective outcomes | Low risk | Stated as double‐blind; quote: "The study medication was manufactured, packaged, and labelled by Tiofarma and stored and provided by the pharmacy of the AMC. Baclofen and placebo were provided in identical 10 mg tablets and supplied in containers with 24, 42, 63, 147, or 168 tablets." |
| Blinding of participants and personnel (performance bias) subjective outcomes | Low risk | Stated as double‐blind; quote: "The study medication was manufactured, packaged, and labelled by Tiofarma and stored and provided by the pharmacy of the AMC. Baclofen and placebo were provided in identical 10 mg tablets and supplied in containers with 24, 42, 63, 147, or 168 tablets." |
| Blinding of outcome assessment (detection bias) subjective outcomes | Low risk | Quote: "The investigators and responsible physicians remained blind with regard to the study medication during the whole study period." |
| Blinding of outcome assessment (detection bias) objective outcomes | Low risk | Quote: "The investigators and responsible physicians remained blind with regard to the study medication during the whole study period." |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Quote: "Analyses were done by intention to treat, counting pills every visit and assuming that patients took the drugs they were given". Comment: only 3 participants were lost at follow‐up in the baclofen group (3%) |
| Selective reporting (reporting bias) | Low risk | Study protocol available; results reported for all the primary and secondary outcomes reported in the protocol |
Garbutt 2010a.
| Methods |
Study design: RCT Study grouping: parallel‐group |
|
| Participants |
Baseline characteristics Baclofen
Placebo
Inclusion criteria: meeting DSM‐IV criteria for current alcohol dependence; ≥ 2 heavy drinking d/week (heavy drinking defined for men as ≥ 5 standard drinks/d and for women as ≥ 4 standard drinks/d) on average during the 4 weeks prior to screening; ability to understand and sign written informed consent; ability to refrain from alcohol for 3 days prior to the randomisation visit Exclusion criteria: clinically significant medical disease that might interfere with the evaluation of the study medication or presence of a safety concern (e.g. cirrhosis, kidney impairment, unstable hypertension, diabetes mellitus, seizure disorder); clinically significant psychiatric illness including any psychotic disorder, bipolar disorder, or severe depression; suicidal ideation; concurrent use of any psychotropic medication including antidepressants mood stabilisers, antipsychotics, anxiolytics, stimulants, or hypnotics with the exception that stable doses of antidepressants for 2 months prior to screening was permitted (6 men and 17 women were on antidepressants); concurrent use of anticonvulsants, insulin, or oral hypoglycemics; aspartate aminotransferase (AST), alanine transaminase (ALT), or gamma‐glutamyl transferase (GGT) level > 3 times the ULN, bilirubin > ULN, or serum creatinine > ULN. Additional exclusionary criteria included: positive urine toxicology screen with the exception of cannabis. Individuals with positive cannabis screens were excluded only if they had a history of cannabis dependence. Pregnant women and women of childbearing potential who did not practice a medically acceptable form of birth control (oral or depot contraceptive, or barrier methods such as diaphragm or condom with spermicidal) were excluded, as were individuals requiring inpatient treatment or more intense outpatient treatment for their alcohol dependency |
|
| Interventions |
Intervention characteristics Baclofen (participants = 40)
Placebo (participants = 40)
|
|
| Outcomes |
Primary outcomes
Secondary outcomes
|
|
| Identification |
Sponsorship source: National Institute of Alcohol Abuse and Alcoholism Grant R21 AA015392 and by GCRC Grant RR00046 and CTSA grant UL1RR025747 from the National Institutes of Health Country: North Carolina (USA) Setting: Department of Psychiatry and the Bowles Center forAlcohol Studies (JCG, ABKP, LKJ, BAF), University of North Carolina (outpatients) Author's name: James C. Garbutt Institution: Department of Psychiatry and the Bowles Center for Alcohol Studies Email: jc_garbutt@med.unc.edu Address: Chapel Hill, CB#7160, ChapelHill, NC 27599‐7160 |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Randomization was implemented stratifying on gender, based on a computerized random number generator where assignment to baclofen or placebo was randomly ordered within gender." |
| Allocation concealment (selection bias) | Unclear risk | Information not reported |
| Blinding of participants and personnel (performance bias) objective outcomes | Low risk | Only stated that study was double‐blind. Outcome unlikely to be biased by lack of, or inadequate blinding. |
| Blinding of participants and personnel (performance bias) subjective outcomes | Unclear risk | Only stated that study was double‐blind: no further description provided |
| Blinding of outcome assessment (detection bias) subjective outcomes | High risk | Quote: "Medical monitoring was conducted by study physicians and consisted of taking vital signs, recording use of con‐comitant medication(s), and in‐depth side effect monitoring using an Adverse Events Form that included common baclofen side effects (e.g., drowsiness, sedation, fatigue)" Comment: not stated whether the outcome assessor was blinded; common side effects of baclofen easy recognisable |
| Blinding of outcome assessment (detection bias) objective outcomes | Low risk | Quote: "Medical monitoring was conducted by study physicians and consisted of taking vital signs, recording use of con‐ comitant medication(s), and in‐depth side effect monitoring using an Adverse Events Form that included common baclofen side effects (e.g., drowsiness, sedation, fatigue)" Comment: not stated whether the outcome assessor was blinded, but objective outcomes unlikely to be biased by lack or incomplete blinding |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 20% and 27.5% of participants lost at follow‐up from placebo and baclofen groups. But reasons balanced between groups and most unlikely to be related to the intervention or the outcome |
| Selective reporting (reporting bias) | Low risk | Study protocol not available; results reported for all the declared outcomes in the methods section |
Garbutt 2010b.
| Methods |
Study design: randomised phase 1 study Study grouping: parallel‐group Masking: quadruple (participant, care provider, investigator, outcomes assessor) |
|
| Participants |
Baseline characteristics 40 men and women aged 25‐60 years meeting DSM‐IV criteria for current alcohol dependence. Inclusion criteria: admitted to University of North Carolina Hospitals for a medical detoxification from alcohol; receiving benzodiazepines for detoxification or recruited from the general population; average ≥ 2 HDDs per/week (≥ 5 drinks/d for men or ≥ 4 drinks/d for women); average overall consumption of ≥ 21 drinks/week (men) and ≥ 14 drinks/week (women) during the 4 weeks prior to admission or screening; ≤ 3 months of abstinence in the previous year; able to understand and sign written informed consent; willingness to engage in treatment and motivation to achieve abstinence or to greatly reduce alcohol consumption; stable residence and able to identify an individual who could locate them if needed; must have the logistical ability to come to each weekly study visit for 12 weeks in Chapel Hill, NC, USA |
|
| Interventions |
Intervention characteristics Baclofen + placebo naltrexone + behavior therapy (participants = 10)
Baclofen + naltrexone + behavior therapy (participants = 10)
Placebo baclofen + naltrexone + behavioral therapy (participants = 10)
Placebo characteristics Placebo baclofen + placebo naltrexone + behavior therapy (participants = 10)
|
|
| Outcomes |
Primary outcomes
Secondary outcomes
|
|
| Identification | ||
| Notes | The pilot study is a protocol published on ClinicalTrials.gov, where it is reported that the study has been completed without results being posted. Preliminary results have been reported in a conference proceeding. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | No information provided |
| Allocation concealment (selection bias) | Unclear risk | No information provided |
| Blinding of participants and personnel (performance bias) objective outcomes | Unclear risk | Stated as double‐blind, double‐dummy without further details |
| Blinding of participants and personnel (performance bias) subjective outcomes | Unclear risk | Stated as double‐blind, double‐dummy without further details |
| Blinding of outcome assessment (detection bias) subjective outcomes | Unclear risk | Stated as double‐blind, double‐dummy without further details |
| Blinding of outcome assessment (detection bias) objective outcomes | Unclear risk | Stated as double‐blind, double‐dummy without further details |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | No withdrawals from the study |
| Selective reporting (reporting bias) | Unclear risk | Study protocol not available; data available only from conference proceedings |
Hauser 2017.
| Methods |
Study design: RCT Study grouping: parallel‐group |
|
| Participants |
Baseline characteristics Baclofen
Placebo
Inclusion criteria: men or women, veterans ages ≥ 18 years; chronic HCV diagnosis with confirmed viraemia bypolymerase chain reaction (PCR); an AUD (abuse or dependence) according to the DSM‐IV or DSM‐IV‐TR , using the nStructured Clinical Interview for the DSM‐IV‐TR, or SCID; and ongoing alcohol use as defined by > 7 standard drinks /week for each of the preceding 2 weeks or 1 HDD/week for each of the preceding 2 weeks (HDD: > 4 drinks in 1 day for men and > 3 drinks in 1 day for women). There were no requirements for any period of abstinence before entry into the study. Exclusion criteria: presence of DSM‐IV‐TR (SCID) cocaine, methamphetamine or opioid dependence within the past 6 months; concurrent use of ondansetron, disulfiram, topiramate, naltrexone, acamprosate, buprenorphine or methadone; any metabolic kidney condition affecting renal function, including haemodialysis, renal replacement or peritoneal dialysis; and any known pre‐existing medical conditions that could interfere with participation in the protocol, such as known cognitive impairment, dementia, encephalopathy from liver disease, acute psychiatric instability (significant psychosis, mania, or elevated risk for suicide). |
|
| Interventions |
Intervention characteristics Baclofen (participants = 88) + BBCET
Placebo (participants = 92) + BBCET
Concurrent with dispensing study medication, study personnel provided BBCET, which is a standardised 15‐min psychosocial treatment intervention that emphasises medication adherence as a crucial element to change alcohol use behavior |
|
| Outcomes |
Primary outcomes
Secondary outcomes
|
|
| Identification |
Sponsorship source: the work was supported by the U.S. Department
of Veteran Affairs (VA) Clinical Sciences Research and Development Service‐ VA Merit Country: USA Setting: outpatients setting in four VA medical centres with established hepatology clinics (VA Long Beach, VA Minneapolis, VA Portland and VA San Diego) Author's name: Peter Hauser Institution: Division of Mental Health, Long Beach VA Medical Center, Long Beach, CA, USA Email: peter.hauser2@va.gov Address: Long Beach VA Medical Center, 300 Oceangate, Suite 700, Long Beach, CA 90802, USA |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Consented patients were randomized to oral baclofen 30 mg (10 mg three times per day) or placebo at each site 1 : 1 using random assignment software administered by the central site" |
| Allocation concealment (selection bias) | Low risk | Quote: "The blocked randomization sequence code was concealed from research staff. The research pharmacy at each site kept the randomization code in sequential sealed envelopes and provided study medication to research staff who then distributed study medication to participants." |
| Blinding of participants and personnel (performance bias) objective outcomes | Low risk | Stated as double‐blind; quote: "Study medication and placebo were placed in identical capsules" |
| Blinding of participants and personnel (performance bias) subjective outcomes | Low risk | Stated as double‐blind; quote: "Study medication and placebo were placed in identical capsules" |
| Blinding of outcome assessment (detection bias) subjective outcomes | Unclear risk | Information not reported |
| Blinding of outcome assessment (detection bias) objective outcomes | Low risk | Information not reported but objective outcomes unlikely to be biased by lack of blinding |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | All participants included in the analysis |
| Selective reporting (reporting bias) | Low risk | Study protocol not available; results reported for all the declared outcomes in the methods section |
Krupitskii 2017.
| Methods |
Study design: RCT Study grouping: parallel‐group |
|
| Participants |
Baseline characteristics Baclofen
Placebo
Inclusion criteria: patients of different genders aged 18–65 years with negative tests for alcohol in exhaled air, ICD‐10 diagnoses of alcohol dependence, and abstention from alcohol consumption for at least 7 days (recovered alcohol withdrawal syndrome). An additional inclusion criterion for women was the absence of ongoing pregnancy and agreement to use adequate contraception during study participation. All participants included in the study had to provide a telephone number for qualitative follow‐up assessment (compliance with weekly clinic visits). Exclusion criteria: marked organic brain disease, marked somatic pathology (liver, kidney, cardiovascular, nervous system pathology), psychotic states, or history of severe mental illness (schizophrenia, epilepsy, manic‐depressive psychosis, etc.), any additional chemical dependency other than on alcohol and tobacco, and use of any other medication or psychotherapy for alcohol dependence (including so‐called placebo therapy ('chemical protection'), 'coding', etc |
|
| Interventions |
Intervention characteristics Baclofen (participants = 16) + CBT
placebo (participants = 16) + CBT
|
|
| Outcomes |
Primary outcomes
Secondary outcomes
|
|
| Identification |
Sponsorship source: Pharmaceutical Company Akrikhin Country:Russia Setting: Department of Narcology, Bekhterev St. Petersburg Science Research Psychoneurological Institute Author's name: E.M. Krupitskii Institution: Bekhterev St. Petersburg Research Psychoneurological Institute Email: kruenator@gmail.com. Address: Bekhterev St. Petersburg Research Psychoneurological Institute, St. Petersburg, Russia |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Patients were randomized using a random number generator running in Excel." |
| Allocation concealment (selection bias) | Low risk | Quote: "Agents (baclofen, placebo) were placed in numbered containers and issued to patients in double‐blind conditions at each weekly visit for three months such that they always had a three‐week supply of agent (in case of missing 1–2 visits). Randomization codes were kept at the institute and could be opened at any moment in case of emergency." |
| Blinding of participants and personnel (performance bias) objective outcomes | Low risk | Stated as double‐blind, quote: "The institute pharmacists, working with the pharmaceuticals company Bios (St. Petersburg), ground baclofen tablets and prepared baclofen capsules (25 mg) and externally identical placebo capsules (starch). Both baclofen capsules and placebo were supplemented with 50 mg of riboflavin as fluorescent marker of drug ingestion" |
| Blinding of participants and personnel (performance bias) subjective outcomes | Low risk | Stated as double‐blind, quote: "The institute pharmacists, working with the pharmaceuticals company Bios (St. Petersburg), ground baclofen tablets and prepared baclofen capsules (25 mg) and externally identical placebo capsules (starch). Both baclofen capsules and placebo were supplemented with 50 mg of riboflavin as fluorescent marker of drug ingestion" |
| Blinding of outcome assessment (detection bias) subjective outcomes | Low risk | Quote: "Investigators, physicians, and other staff taking part in the study, like the patients, were unaware of which treatment group they were in" |
| Blinding of outcome assessment (detection bias) objective outcomes | Low risk | Quote: "Investigators, physicians, and other staff taking part in the study, like the patients, were unaware of which treatment group they were in" |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No clear data reported about dropout from the study |
| Selective reporting (reporting bias) | Low risk | Study protocol not available; results reported for all the declared outcomes in the methods section |
Leggio 2015.
| Methods |
Study design: RCT Study grouping: parallel‐group |
|
| Participants |
Baseline Characteristics Baclofen
Placebo
Inclusion criteria: participants were alcohol‐dependent heavy‐drinking and heavy‐smoking individuals: aged 18‐75 years; DSM‐IV diagnoses of both alcohol and nicotine codependency, with heavy use of alcohol (men ≥ 5 SDUs, women ≥ 4 SDUs, a day on average) and cigarettes (≥ 10 cigarettes per day on average) during the last 90 d before screening; interested in receiving treatment for both drinking and smoking (either reducing or stopping both substances; or reducing one substance and stopping the other). Exclusion criteria: current (i.e. past year) DSM‐IV diagnosis of dependence on any psychoactive substance other than alcohol and nicotine; lifetime DSM‐IV diagnosis of schizophrenia, bipolar disorder, or other psychosis; past year diagnosis of major depression, anxiety disorders, and eating disorders; risk of suicide (e.g. active plan or recent attempt in last year); positive urine drug screen at baseline for any illegal substance other than marijuana; significant alcohol withdrawal symptoms, as assessed by a Clinical Institute Withdrawal Assessment for Alcohol revised (CIWA‐Ar) score > 10; history of hospitalisation for alcohol intoxication delirium, alcohol withdrawal delirium or seizure; participation in any research study for alcoholism and/or smoking treatment within 3 months prior to signing the consent document; pharmacological treatment with naltrexone, acamprosate, topiramate, disulfiram, nicotine replacement, bupropion, and varenicline within 1 month prior to randomisation; current use of psychotropic medications or medications that interfere with the metabolism of Baclofen, history of allergy to Baclofen or medical contraindications to take Baclofen; severe medical diseases, such as cancer, cirrhosis, chronic kidney failure, and chronic neurological disorders; and women who were of child bearing potential and not practicing effective birth control |
|
| Interventions |
Intervention characteristics Baclofen (participants = 15) + Medical Management (personalised education regarding alcohol and smoking, helped participants to develop and implement a plan to reduce/stop alcohol and smoking, motivated participants for medication adherence
Placebo (participants = 15) + Medical Management (personalised education regarding alcohol and smoking, helped participants to develop and implement a plan to reduce/stop alcohol and smoking, motivated participants for medication adherence
|
|
| Outcomes |
Primary outcomes/secondary outcomes (no distinction)
|
|
| Identification |
Sponsorship source: supported by a grant from the ABMRF/The Foundation for Alcohol Research (PI: Leggio). The human laboratory cue‐reactivity substudy was supported by an NIH grant jointly funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA) (R03AA020169; PI: Leggio). Both grants were awarded to Dr. Leggio, while he was at Brown University. Dr. Leggio’s current work is supported by the NIAAA Division of Intramural Clinical and Biological Research and the NIDA Intramural Research Program Country: USA Setting: Brown University Center for Alcohol and Addiction Studies (CAAS) and Roger Williams Medical Center (RWMC), Providence, RI Author's name: Lorenzo Leggio Institution: Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health Email: lorenzo.leggio@nih.gov Address: 10 Center Drive (10CRC/15330) MSC1108; Room 1‐5429, Bethesda, MD 20892‐1108, USA |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "At week 01 visit, eligible participants were randomized to BACL or PLA using a 3‐urn variable procedure , |
| Allocation concealment (selection bias) | Unclear risk | Information not reported |
| Blinding of participants and personnel (performance bias) objective outcomes | Low risk | Quote: "BACL at 80 mg/day (20 mg, q.i.d.), or PLA was placed into blister packs as opaque capsules containing drug and 25 mg riboflavine" Comment: outcome unlikely to be biased by lack or inadequate blinding |
| Blinding of participants and personnel (performance bias) subjective outcomes | Unclear risk | Quote: "BACL at 80 mg/day (20 mg, q.i.d.), or PLA was placed into blister packs as opaque capsules containing drug and 25 mg riboflavine" Comment: study described as double‐blind. No further information provided about blindness a part opaque capsules |
| Blinding of outcome assessment (detection bias) subjective outcomes | Unclear risk | Quote: "BACL at 80 mg/day (20 mg, q.i.d.), or PLA was placed into blister packs as opaque capsules containing drug and 25 mg riboflavine" Comment: study described as double‐blind; no further information provided about blinding a part the use of opaque capsules |
| Blinding of outcome assessment (detection bias) objective outcomes | Low risk | Quote: "BACL at 80 mg/d (20 mg, q.i.d.), or PLA was placed into blister packs as opaque capsules containing drug and 25 mg riboflavine " Comment: study described as double‐blind. Outcome unlikely to be biased by lack or inadequate blinding |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Quote: "while 30 individuals were eligible and randomized; 24 completed the study (Supplemental Fig. 1)." Comment: 20% dropout. Number of participants who dropped out from each group not reported. The figure (Figure 1), reporting participants lost to follow‐up and those who completed the study is unreadable in the supplementary file so that it's impossible to give a judgments on this. |
| Selective reporting (reporting bias) | Low risk | Study protocol available. Results reported for all the primary and secondary outcomes declared in the protocol |
Mishra 2010.
| Methods |
Study design: RCT Study grouping: parallel‐group |
|
| Participants |
Baseline characteristics Baclofen
Acamprosate
Inclusion criteria: aged 18‐70 years; diagnosis of current AD according to the (ICD‐10) criteria; last alcohol intake reported to have taken place in the 24 h preceding observation; presence of a key relative Exclusion criteria: presence of severe liver, kidney, heart or lung diseases requiring urgent medical attention; currently under treatment for any mental disorder with psychotic drugs; any dependence to drug other than nicotine; age > 70 years |
|
| Interventions |
Intervention characteristics Baclofen (participants = 25)
Acamprosate (participants = 24)
|
|
| Outcomes |
Primary outcome/secondary outcome (no distinction)
|
|
| Identification |
Sponsorship source: NR Country: India Setting: outpatients Author's name: Suvendu N Mishra Institution: IMS & SUM Hospital, Bhubaneswar. Mental Health Institute, Dept of Psychiatry SCB Medical college, Cuttack Email: dr.sar07@gmail.com Address: Mental Health Institute, SCB Medical college, Cuttack |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Information not provided |
| Allocation concealment (selection bias) | Unclear risk | Information not provided |
| Blinding of participants and personnel (performance bias) objective outcomes | High risk | Participants given written informed consent, subsequently randomised into 2 groups to receive either open–label baclofen or acamprosate |
| Blinding of participants and personnel (performance bias) subjective outcomes | High risk | Participants given written informed consent, subsequently randomised into 2 groups to receive either open–label baclofen or acamprosate |
| Blinding of outcome assessment (detection bias) subjective outcomes | High risk | Participants given written informed consent, subsequently randomised into 2 groups to receive either open–label baclofen or acamprosate |
| Blinding of outcome assessment (detection bias) objective outcomes | High risk | Participants given written informed consent, subsequently randomised into 2 groups to receive either open–label baclofen or acamprosate |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Information not reported |
| Selective reporting (reporting bias) | High risk | Study protocol not available. Primary and secondary outcomes not reported in the method section. Some results on specific outcomes were partially reported (e.g. for abstinence: "A significantly higher number of patients who achieved and maintained abstinence throughout the experiment were found in the group of patients treated with baclofen compared with acamprosate." |
Morley 2014.
| Methods |
Study design: RCT Study grouping: parallel‐group |
|
| Participants |
Baseline characteristics Baclofen
Placebo
Inclusion criteria: men and women aged 18‐60; DSM‐IV criteria for current alcohol dependence; ability to understand and provide written informed consent; abstinence from alcohol for at least 3 days prior to randomisation and resolution of any withdrawal symptoms; desire to achieve abstinence or to reduce alcohol consumption; evidence of a stable residence; proof of an individual who could locate participant if needed Exclusion criteria: clinically significant medical diseases that might interfere with the evaluation of the study medication or present a safety concern (e.g. kidney impairment, unstable hypertension, hypotension, diabetes mellitus, seizure disorder); clinically significant psychiatric illness (e.g. psychotic disorder, bipolar disorder, severe depression); suicidal ideation or concurrent SUD other than nicotine or cannabis, concurrent use of any psychotropic medication (participants who had been on a stable dose of selective serotonin reuptake inhibitors (SSRIs) for 2 months were still considered eligible); concurrent use of anticonvulsants, insulin or oral hypoglycaemic; women who were pregnant or breastfeeding; participation in any clinical trial within the last 60 days; use of alcohol pharmacotherapy within the last 60 d; court‐mandated participation in alcohol treatment or pending incarceration |
|
| Interventions |
Intervention characteristics Baclofen (participants = 28) + up to 9 sessions of BRENDA, a low‐intensity psychosocial intervention
Placebo (participants = 14) + up to 9 sessions of BRENDA, a low‐intensity psychosocial intervention
|
|
| Outcomes |
Primary outcomes
Secondary outcomes
|
|
| Identification |
Sponsorship source: trial was funded by a New South Wales Health Drug and Alcohol grant (PH, AB, KM). Conflict of interest statement. None declared Country: Australia Setting: outpatients Author's name: Morley K.C. Institution: NHMRC Centre of Research Excellence in Mental Health and Substance Use, Discipline of Addiction Medicine, University of Sydney, Sydney, NSW, Australia Email: kirsten.morley@sydney.edu.au Address: University of Sydney, Sydney, NSW 2006, Australia |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Participants were allocated 1:1:1 as per a computer‐generated randomization sequence conducted by the hospital clinical trials pharmacist." |
| Allocation concealment (selection bias) | Low risk | Quote: "Participants were allocated 1:1:1 as per a computer‐generated randomization sequence conducted by the hospital clinical trials pharmacist." |
| Blinding of participants and personnel (performance bias) objective outcomes | Low risk | Quote: "participants in the (a) baclofen 30 mg/day group took a dose of 5 mg, three times a day, for the first 3 days, a dose of 10 mg, three times a day, on Days 4–81, and finally a dose of 5 mg, three times a day, for the last 3 days; (b) baclofen 60 mg/day group took a dose of 5 mg, three times a day, for the first 3 days, a dose of 10 mg, three times a day on Days 4–7, a dose of 20 mg, three times a day, on Days 8–77, a dose of 10 mg three times a day on Days 78–81, and finally a dose of 5 mg, three times a day, for the last 3 days. The placebo pills, which were identical in appearance, were also titrated upward and downward to maintain the double blind." |
| Blinding of participants and personnel (performance bias) subjective outcomes | Low risk | Quote: "participants in the (a) baclofen 30 mg/day group took a dose of 5 mg, three times a day, for the first 3 days, a dose of 10 mg, three times a day, on Days 4–81, and finally a dose of 5 mg, three times a day, for the last 3 days; (b) baclofen 60 mg/day group took a dose of 5 mg, three times a day, for the first 3 days, a dose of 10 mg, three times a day on Days 4–7, a dose of 20 mg, three times a day, on Days 8–77, a dose of 10 mg three times a day on Days 78–81, and finally a dose of 5 mg, three times a day, for the last 3 days. The placebo pills, which were identical in appearance, were also titrated upward and downward to maintain the double blind." |
| Blinding of outcome assessment (detection bias) subjective outcomes | Unclear risk | Information not reported |
| Blinding of outcome assessment (detection bias) objective outcomes | Low risk | Information not reported; objective outcomes unlikely to be biased by lack or incomplete blinding of outcome assessor |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Quote: "Twenty‐eight (67%) patients out of the enrolled 42 completed the follow‐up interviews (up to Week 12–16)." Quote: "There were no significant differences between groups on study retention (χ 2 = 1.5, P = 0.47) or medication compliance rates (χ 2 = 0.77, P = 0.68), the number of BRENDA sessions attended (F = 1.93, P = 0.826) or days on medication (F = 1.04, P = 0.36). Time‐survival analysis revealed that the treatment retention rates did not significantly differ between randomized groups over the follow‐up assessments (χ 2 = 1.21, P = 0.55)." |
| Selective reporting (reporting bias) | Low risk | Study protocol available. 2 primary outcomes not listed in the protocol were reported in the full publication (time to relapse, time to lapse); however authors found no significant difference for any of these outcomes. Comment: selective reporting bias judged unlikely |
Muller 2015.
| Methods |
Study design: RCT Study grouping: parallel‐group |
|
| Participants |
Baseline characteristics Baclofen
Placebo
Inclusion criteria: aged ≥ 18 and < 65 years; diagnosis of AD according to ICD‐10 and DSM‐IV‐TR; alcohol consumption of ≥ 2 HDDs/week on average (men ≥ 5 drinks/d; women < 4 drinks/day; 1 standard drink = 12 g absolute alcohol) and an average overall alcohol intake of ≥ 21 drinks/week (men) and ≥ 14 drinks/week (women) during the 4 weeks before detoxification; completed in‐or outpatient detoxification before randomisation; last alcohol consumption within 7–21 d before randomisation; sufficient German language skills Exclusion criteria: neurological conditions; current treatment with psychotropic drugs that could affect study outcome (i.e. sedatives, alcohol relapse prevention such as acamprosate, disulfiram, naltrexone, antidepressants, antipsychotics, anticonvulsants); epilepsy or epileptiform convulsions; pregnancy and/or currently breastfeeding; intolerance to baclofen; terminal renal failure; alanine amino‐transferase (ALAT) or aspartate aminotransferase (ASAT) values 5 times the ULN, bilirubin 41.9 mg/dL, International Normalized Ratio 41.6; gastrointestinal ulcers; and treatment mandated by a legal authority |
|
| Interventions |
Intervention characteristics baclofen (participants = 28) + up to 9 Medical Management sessions that focus on psychoeducation and enhancement of motivation and adherence
Placebo (participants = 28) + up to 9 Medical Management sessions that focus on psychoeducation and enhancement of motivation and adherence
|
|
| Outcomes |
Primary outcomes
Secondary outcomes
|
|
| Identification |
Sponsorship source: the work was supported by the German Research Foundation (DFG; Cluster of Excellence EXC 257) Country: Germany Setting: outpatients Author's name: Christian A. Müllera Institution: Department of Psychiatry, Campus Charité Mitte, Charité, Universitätsmedizin Berlin Email: ch.mueller@charite.de Address: Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "patients were randomly assigned at the baseline visit to double‐blind treatment with baclofen or placebo in a 1:1 ratio according to a computer‐generated randomization list (in blocks of 4; stratification with regard to sex)." |
| Allocation concealment (selection bias) | Low risk | Quote: "The randomization list was kept by the biometrician and the study pharmacist who prepared the study medication packages. The study pharmacist did not have any further role in the trial. Sealed envelopes containing study medication details were kept at the outpatient unit to be opened by a staff member in case of a study drug‐related emergency. During the whole study, no unblinding was necessary." |
| Blinding of participants and personnel (performance bias) objective outcomes | Low risk | Stated as double‐blind. Participants received baclofen or placebo in identical capsules in a dose of 5 mg 3 times/d |
| Blinding of participants and personnel (performance bias) subjective outcomes | Low risk | Stated as double‐blind treatment. Participants received baclofen or placebo in identical capsules in a dose of 5 mg 3 times/d |
| Blinding of outcome assessment (detection bias) subjective outcomes | Unclear risk | Information not reported |
| Blinding of outcome assessment (detection bias) objective outcomes | Low risk | Information not reported but objective outcomes unlikely to be biased by lack of blinding |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Few lost at follow‐up (7%), balanced between groups |
| Selective reporting (reporting bias) | Low risk | Study protocol not available; results reported for all the outcomes declared in the methods section |
Ponizovsky 2015.
| Methods |
Study design: RCT Study grouping: parallel‐group |
|
| Participants |
Baseline characteristics Baclofen:
Placebo
Inclusion criteria: aged 18‐60 years; 2) had an ICD‐ 10 diagnosis of AD; had sought treatment to stop alcohol consumption; had an alcohol intake of ≥ 2 HDDs/week (men ≥ 5 drinks/d; women ≥ 4 drinks/d) and average overall consumption of ≥ 21 drinks/week (men) and ≥ 14 drinks/week (women) during the month preceding recruitment (1 standard drink = 12 g absolute alcohol); < 6 total abstinent days (ABS) per month on average; and had a reliable family member able to help with drug administration and monitoring. The study population could be defined as mild alcohol use disorder according to DSM 5 criteria Exclusion criteria: a detoxification treatment for acute alcohol withdrawal syndrome (requiring hospitalisation) during the month before randomisation, chronic use of psychotropic medication before randomisation, dependence on psychoactive substances other than nicotine, liver cirrhosis, acute alcohol psychosis, severe depression, organic brain syndromes, pregnancy and lactation |
|
| Interventions |
Intervention characteristics Baclofen (participants = 32) + standard psychosocial intervention (motivational interviewing, education and therapy)
Placebo (participants = 32) + standard psychosocial intervention (motivational interviewing, education and therapy)
|
|
| Outcomes |
Primary outcomes
Secondary outcomes
|
|
| Identification |
Sponsorship source: study was supported by Israeli Anti‐Drug Authority Grant #535‐28. A.M. Ponizovsky was supported in part by the Ministry of Immigrant Absorption Country: Israel Setting: outpatients Author's name: Ponizovsky A.M. Institution: Research Unit, Mental Health Services, Ministry of Health, Jerusalem, Israel Email: alexpon8@gmail.com Address: Ministry of Health 39 Yirmiyahu St. POBox 1176 Jerusalem 9446724 Israel |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Randomization was performed by the pharmacist who prepared drug and placebo by using a random number generator, with the only restriction that the groups should be of equal size. |
| Allocation concealment (selection bias) | Unclear risk | Information not reported |
| Blinding of participants and personnel (performance bias) objective outcomes | Low risk | Stated as double‐blind, quote: "Placebo tablets were identical in all organoleptic characteristics to baclofen" |
| Blinding of participants and personnel (performance bias) subjective outcomes | Low risk | Stated as double‐blind, quote: "Placebo tablets were identical in all organoleptic characteristics to baclofen" |
| Blinding of outcome assessment (detection bias) subjective outcomes | Unclear risk | Not reported whether the outcome assessor was blinded |
| Blinding of outcome assessment (detection bias) objective outcomes | Low risk | Not reported whether the outcome assessor was blinded, but objective outcomes unlikely to be biased by lack of blinding |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Quote: "All outcome variables for patients who discontinued treatment before the end of the medication period were computed with the registers of the visit preceding discontinuation (last observation carried forward), which were compared between the treatment groups by Fisher's exact test. Based on the assumption that every patient took the allocated drug, intention to treat analysis was made All randomized patients were analyzed (intent‐to‐treat)" |
| Selective reporting (reporting bias) | Low risk | Study protocol not available; results reported for all the outcomes declared in the method section |
Reynaud 2017.
| Methods |
Study design: RCT Study grouping: parallel‐group |
|
| Participants |
Baseline Characteristics Baclofen:
Placebo
Inclusion criteria: adult men or non‐pregnant, non‐breastfeeding women, with a diagnosis of AD according to DSM‐IV, who had experienced at least 1 previous abstinence attempt, and had been fully abstinent for 3–14 days before randomisation; this range of 3–14 days was established in order to allow patients needing in‐patient detoxification to participate in the study. Comorbid psychiatric diseases were assessed according to the investigator’s judgment. Exclusion criteria: need for a prolonged residential treatment after detoxification; need for an intensive psychosocial intervention during follow‐up; history of baclofen intake by prescription or by self‐medication; epilepsy or history of epilepsy; concomitant treatment with 1 or several drugs for the maintenance of abstinence; concomitant treatment with psychotropic medications, except antidepressants at stable dose for ≥ 2 months, diazepam and oxazepam; severe renal, cardiac or pulmonary disorders; severe psychiatric conditions (schizophrenia and bipolar disorder); clinically significant cognitive disorders; hepatic encephalopathy; suicidal risk or history of suicide; other current dependence except nicotine |
|
| Interventions |
Intervention characteristics Baclofen (participants = 158 + BRENDA sessions were provided during each visit to support participants in changing their behaviour and to enhance adherence to treatment.
Placebo (participants = 162) + BRENDA sessions were provided during each visit to support participants in changing their behaviour and to enhance adherence to treatment.
|
|
| Outcomes |
Primary outcomes
Secondary outcomes
|
|
| Identification |
Sponsorship source: study was supported by Ethypharm SAS Country: France Setting: outpatients Author's name: Reynaud M Institution: Actions Addictions‐Saint Joseph Hospital, 185 Rue Raymond Losserand, 75014 Paris, France Email: michel.reynaud@actions‐addictions.org Address: Saint Joseph Hospital, 185 rue Raymond Losserand, 75014 Paris, France |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Patients were randomly assigned to baclofen or placebo in a 1:1 ratio, according to a computer generated randomization list (blocks size of 4)" |
| Allocation concealment (selection bias) | Low risk | Quote: "The allocation sequence was centralized via an Interactive Web Response System" |
| Blinding of participants and personnel (performance bias) objective outcomes | Low risk | Quote: "The identical aspect of verum (20 mg coated scored baclofen tablet) and placebo tablets allowed a double‐blind design. Sealed code envelopes were sent to the investigator centres with the corresponding study treatments. Access to the randomization codes and unblinding could only be performed in case of emergency" |
| Blinding of participants and personnel (performance bias) subjective outcomes | Low risk | Quote:"The identical aspect of verum (20 mg coated scored baclofen tablet) and placebo tablets allowed a double‐blind design. Sealed code envelopes were sent to the investigator centres with the corresponding study treatments. Access to the randomization codes and unblinding could only be performed in case of emergency" |
| Blinding of outcome assessment (detection bias) subjective outcomes | Low risk | Quote: "The identical aspect of verum (20 mg coated scored baclofen tablet) and placebo tablets allowed a double‐blind design. Sealed code envelopes were sent to the investigator centres with the corresponding study treatments. Access to the randomization codes and unblinding could only be performed in case of emergency" |
| Blinding of outcome assessment (detection bias) objective outcomes | Low risk | Quote: "The identical aspect of verum (20 mg coated scored baclofen tablet) and placebo tablets allowed a double‐blind design. Sealed code envelopes were sent to the investigator centres with the corresponding study treatments. Access to the randomization codes and unblinding could only be performed in case of emergency" |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Quote: "The safety population, defined as patients having received at least one dose of study treatment, and considered for safety purpose; The full analysis set population, defined as randomized patients, having received at least one dose of study treatment and having reported at least one data regarding alcohol consumption in their diary, which is the main population for efficacy assessments" "Three methods of imputation were used for the management of missing data related to alcohol consumption: Multiple imputation with a placebo pattern mixture model (assuming that the alcohol consumption of dropped out patients was the same as those in the placebo group) was the main imputation method; it is one of the recommended method for handling missing data in alcohol clinical trials. Most plausible outcome (for abstinence endpoint only): for patients who did not report any alcohol consumption during the 20 consecutive weeks and had at least one missing data during the period, their profiles were reviewed by 2 blinded medical experts who filled in the missing data; Worst case: missing data were imputed to alcohol intake" |
| Selective reporting (reporting bias) | Low risk | Study protocol not available; results reported for all the outcomes declared in the method section |
AD: alcohol dependence; ADS: alcohol dependence scale; BBCET: brief behavioral compliance enhancement treatment; BDI: Beck's Depression Inventory;BSI: Brief Symptom Inventory; CBT: cognitive behavioural therapy; DSM‐IV (TR):Diagnostic and Statistical Manual of Mental Disorders, 4th revision (text revision); HCV: hepatitis C virus; HD: high‐dose; HDD: heavy drinking day; ICD: International Classification of Diseases; LD: low‐dose; N/A: not applicable;NR: not reported; OCDS: obsessive compulsive drinking scale; RCT: randomised controlled trial; SD: standard deviation; SDU: standard drink unit; STAI: State‐Trait Anxiety Inventory; SUD: substance use disorder; TAC: total alcohol consumption; ULN: upper limit of normal
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Addolorato 2002 | Duration of the study < 12 weeks |
| Flannery 2004 | Study design not in the inclusion criteria: uncontrolled preliminary study on 14 participants |
| Leggio 2011 | Study objective not in the inclusion criteria: human laboratory study to investigate putative behavioral mechanisms by which baclofen reduces drinking |
| Leggio 2013 | Study objective not in the inclusion criteria: human laboratory study to investigate putative behavioral mechanisms by which baclofen reduces drinking |
Characteristics of studies awaiting assessment [ordered by study ID]
Addolorato 2011.
| Methods | Study design: 12‐week, 3‐armed, parallel, double‐blind, randomised clinical trial (post hoc analysis) |
| Participants | 42 participants with a diagnosis of AD according to DSM IV‐TR; median age of 44 years (range 23–60 years). 76% were men |
| Interventions |
|
| Outcomes |
|
| Notes | The published study is a post hoc analysis. We wrote to the study authors to receive the results obtained from the primary analysis but we have not yet received the data. |
CTRI/2016/01/006525.
| Methods | Prospective, randomised, open‐label study |
| Participants | 60 men aged 18‐65 years, meeting diagnostic criteria for AD as per ICD‐10 classification |
| Interventions | Baclofen (20‐40 mg/d in 3 divided doses, orally for 12 weeks) vs topiramate (50‐300 mg/day in 2 divided doses, orally for 12 weeks) |
| Outcomes |
Primary outcomes
Secondary outcomes
|
| Notes |
Farokhnia 2014.
| Methods | Double‐blind, placebo‐controlled RCT |
| Participants | 30 treatment‐seeking alcoholic smokers meeting the inclusion criteria of DSM‐IV diagnoses of both alcohol and nicotine dependence in addition to heavy use of both alcohol (> 4 and > 5 standard drink units/d on average for women and men, respectively) and nicotine (> 10 cigarettes per day on average) during the last 90 d before screening |
| Interventions | Baclofen (80 mg/day) vs placebo for 12 weeks |
| Outcomes |
|
| Notes | Conference abstract without enough usable data |
Jaury 2014.
| Methods | Multicentric, pragmatic, therapeutic, randomised, double‐blind, phase 2 and phase 3 trial in primary care assessing the efficacy and safety of high‐dose baclofen versus placebo during 1 year |
| Participants |
|
| Interventions |
|
| Outcomes |
Primary outcome Proportion of abstainer participants and participants with a low‐risk consumption (time frame: 12 months after the initiation of treatment) Secondary outcome
|
| Notes | The pilot study is a protocol published on ClinicalTrials.gov, where it is reported that the study has been completed without results posted. Preliminary results where presented at the ISBRA/ESBRA Conference, Berlin 2016. We received information from the study authors that the study is under publication. |
Morley 2013.
| Methods | This is a double‐blind, randomised, placebo‐controlled, phase 3 study investigating the efficacy of baclofen for the treatment of alcohol dependence in people with alcoholic liver disease. Medications will be given for 12 weeks, with a further 6 months' follow‐up. Both male and female participants will be recruited to this study. Trial participants will be randomised to one of three treatment groups:
This study will also include a second, parallel group of participants with AD (non alcoholic‐liver disease patients), who will undergo the trial protocol as described above. These participants will be randomised according to a separate list into one of three treatment groups:
Masking: 1uadruple (participant, care provider, investigator, outcomes assessor) Primary purpose: treatment |
| Participants |
|
| Interventions |
|
| Outcomes |
Primary outcomes
Secondary outcomes
|
| Notes | The pilot study is a protocol published on ClinicalTrials.gov, where it is reported that the study has been completed without results being posted. We received information form the study authors that the study is under publication. |
Sharma 2012.
| Methods | Randomised, double‐blind, controlled trial |
| Participants | 54 participants |
| Interventions | Baclofen 10 mg/d vs 12 mg for 12 weeks (n: 18) vs placebo (n:18) |
| Outcomes | Daily number of drinks |
| Notes | Conference abstract without enough usable data |
AD: alcohol dependence; DSM‐IV (TR):Diagnostic and Statistical Manual of Mental Disorders, 4th revision (text revision); HDD: heavy drinking days; ICD: International Classification of Diseases; OCDS: obsessive compulsive drinking scale; RCT: randomised controlled trial; WHO: World Health Organization
Characteristics of ongoing studies [ordered by study ID]
CTRI/2011/11/002154.
| Trial name or title | CTRI/2011/11/002154 |
| Methods | Randomised, phase III, parallel‐group, placebo‐controlled trial |
| Participants | 180 male or female participants aged 21‐75 years, meeting DSM‐IV‐TR criteria for current AD |
| Interventions | Baclofen vs placebo |
| Outcomes |
Safety variables
|
| Starting date | 24 December 2011 |
| Contact information | shravanti.bhowmik@sparcmail.com |
| Notes |
NCT01980706.
| Trial name or title | NCT01980706 |
| Methods | Phase II, randomised, placebo‐controlled trial |
| Participants | Men and women aged 18‐65 meeting DSM‐IV criteria for current AD |
| Interventions | Baclofen vs placebo Baclofen will be titrated to 10 mg 3 times/d over 3 days and to 30 mg 3 times/d over 12 days and maintained at that level for 12 weeks and then down‐titrated for a total study time of 16 weeks |
| Outcomes |
Primary outcome
Secondary outcomes
|
| Starting date | 28 October 2013 |
| Contact information | Principal investigator: James C Garbutt, MD |
| Notes |
AD: alcohol dependence; DSM‐IV (TR):Diagnostic and Statistical Manual of Mental Disorders, 4th revision (text revision); HDD: heavy drinking days
Differences between protocol and review
We added the primary outcome, 'dropout due to adverse events' and the secondary outcome, 'frequency of most relevant adverse events' because of their relevance.
Contributions of authors
SM conceived and co‐ordinated the protocol. SR wrote the background section, the discussion and the conclusion section. SM and RS wrote the Methods section. SM and RS conducted screenings, extracted data and completed the 'Risk of bias' assessment. SM and RS undertook data analysis. SR contributed to screening in case of doubt or disagreement and wrote the discussion. All review authors contributed to writing and revising the final report.
Sources of support
Internal sources
Department of Epidemiology, Lazio Regional Health Service, Rome, Italy.
External sources
No sources of support supplied
Declarations of interest
Silvia Minozzi: no conflict of interest known
Rosella Saulle: no conflict of interest known
Susanne Rösner: no conflict of interest known
New
References
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