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Journal of Addiction MedicineWe aimed to determine medications' comparative efficacy and safety for adults with alcohol use disorders. (Meta-Analysis)
Meta-Analysis
BACKGROUND
We aimed to determine medications' comparative efficacy and safety for adults with alcohol use disorders.
METHODS
We searched eleven electronic data sources for randomized clinical trials with at least 4 weeks of treatment reporting on alcohol consumption (total abstinence and reduced heavy drinking), dropouts, and dropouts due to adverse events. We conducted network meta-analyses using random-effects, frequentist models, and calculated summary rate ratios (RRs) with 95% confidence intervals (CIs).
RESULTS
We included 156 trials (N = 27,334). Nefazodone (RR = 2.11; 95% CI, 1.42-3.13), aripiprazole (RR = 1.97; 95% CI, 1.36-2.88), carbamazepine (RR = 1.85; 95% CI, 1.03-3.32), and nalmefene (RR = 1.17; 95% CI, 1.01-1.35) were associated with the most dropouts. Baclofen (RR = 0.83; 95% CI, 0.70-0.97) and pregabalin (RR = 0.63; 95% CI, 0.43-0.94) caused fewer dropouts than placebo. Nalmefene (RR = 3.26; 95% CI, 2.34-4.55), fluvoxamine (RR = 3.08; 95% CI, 1.59-5.94), and topiramate (RR=2.18; 95% CI, 1.36-3.51) caused more dropouts from adverse events over placebo. Gamma-hydroxy-butyrate (RR = 1.90; 95% CI, 1.03-3.53), baclofen (RR = 1.80; 95% CI, 1.39-2.34), disulfiram (RR = 1.71; 95% CI, 1.39-2.10), gabapentin (RR = 1.66; 95% CI, 1.04-2.67), acamprosate (RR = 1.33; 95% CI, 1.15-1.54), and oral naltrexone (RR = 1.15; 95% CI, 1.01-1.32) improved total abstinence over placebo (Fig. 3C). For reduced heavy drinking, disulfiram (RR = 0.19; 95% CI, 0.10-0.35), baclofen (RR = 0.72; 95% CI, 0.57-0.91), acamprosate (RR = 0.78; 95% CI, 0.70-0.86), and oral naltrexone (RR = 0.81; 95% CI, 0.73-0.90) were efficacious against placebo.
CONCLUSIONS
The current meta-analyses provide evidence that several medications for AUDs are effective and safe and encourage the expanded use of these medications in the clinical setting. Our review found that acamprosate (2-3 g/d), disulfiram (250-500 mg/d), baclofen (30 mg/d), and oral naltrexone (50 mg/d) had the best evidence for improving abstinence and heavy drinking for patients with AUD.
PROSPERO
CRD42020208946.
Topics: Adult; Humans; Acamprosate; Alcoholism; Baclofen; Disulfiram; Naltrexone; Network Meta-Analysis; Randomized Controlled Trials as Topic
PubMed: 35653782
DOI: 10.1097/ADM.0000000000000992 -
Brain Sciences Mar 2022Although Alcohol Use Disorder (AUD) is highly prevalent worldwide, treating this condition remains challenging. Further, potential treatments for AUD do not fully... (Review)
Review
BACKGROUND
Although Alcohol Use Disorder (AUD) is highly prevalent worldwide, treating this condition remains challenging. Further, potential treatments for AUD do not fully address alcohol-induced neuroadaptive changes. Understanding the effects of pharmacotherapies for AUD on the human brain may lead to tailored, more effective treatments, and improved individual clinical outcomes.
OBJECTIVES
We systematically reviewed the literature for studies investigating pharmacotherapies for AUD that included neuroimaging-based treatment outcomes. We searched the PubMed, Scielo, and PsycINFO databases up to January 2021.
STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS
Eligible studies included those investigating pharmacotherapies for AUD and employing functional magnetic resonance imaging (fMRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and/or proton magnetic resonance spectroscopy (H-MRS).
STUDY APPRAISAL AND SYNTHESIS METHODS
Two independent reviewers screened studies' titles and abstracts for inclusion. Data extraction forms were shared among all the authors to standardize data collection. We gathered information on the following variables: sample size; mean age; sociodemographic and clinical characteristics; alcohol use status; study design and methodology; main neuroimaging findings and brain-regions of interest (i.e., brain areas activated by alcohol use and possible pharmacological interactions); and limitations of each study.
RESULTS
Out of 177 studies selected, 20 studies provided relevant data for the research topic. Findings indicate that: (1) Acamprosate and gabapentin may selectively modulate limbic regions and the anterior cingulate cortex; (2) Naltrexone and disulfiram effects may involve prefrontal, premotor, and cerebellar regions; (3) Pharmacotherapies acting on glutamate and GABA neurotransmission involve primarily areas underpinning reward and negative affective states, and; (4) Pharmacotherapies acting on opioid and dopamine systems may affect areas responsible for the cognitive and motor factors of AUD.
LIMITATIONS
Most of the studies were focused on naltrexone. A small number of studies investigated the action of disulfiram and gabapentin, and no neuroimaging studies investigated topiramate. In addition, the time between medication and neuroimaging scans varied widely across studies.
CONCLUSIONS
We identified key-brain regions modulated by treatments available for AUD. Some of the regions modulated by naltrexone are not specific to the brain reward system, such as the parahippocampal gyrus (temporal lobe), parietal and occipital lobes. Other treatments also modulate not specific regions of the reward system, but play a role in the addictive behaviors, including the insula and dorsolateral prefrontal cortex. The role of these brain regions in mediating the AUD pharmacotherapy response warrants investigation in future research studies.
PubMed: 35326342
DOI: 10.3390/brainsci12030386 -
PloS One 2022The current research aims to systematically review the rates of adherence reported in randomised controlled clinical trials of acamprosate. It also sought to determine...
AIM
The current research aims to systematically review the rates of adherence reported in randomised controlled clinical trials of acamprosate. It also sought to determine the reliability of the adherence monitoring and measurement methods used in these trials.
METHODS
The protocol for this review was pre-registered (PROSPERO: CRD42021230011). A search of the literature was conducted using OVID MEDLINE, Embase and PsycINFO from database inception to January 2021. Randomised controlled trials with a minimum sample size of 10 per treatment arm that compared the efficacy of acamprosate with placebo or other active medication in adults with a diagnosis of alcohol dependence were included. Data on rates of adherence, methods of measurement and monitoring of adherence was extracted from eligible studies independently in duplicate by two reviewers. A weighted mean adherence rate was calculated. The reliability of adherence monitoring methods was determined by calculating an adherence-assurance score based on the adherence monitoring method used. Risk of bias was assessed using the Cochrane Risk of Bias Tool.
RESULTS
Fifteen studies met the eligibility criteria involving 4,450 participants (2,480 participants in the placebo arms). A mean adherence rate of 88% (54.2-95.0%) was reported across studies that reported the percentage of medication taken. A mean adherence rate of 84.9% (56.4-91.3%) was reported for trials that reported the percentage of participants taking more than 80% of medication prescribed. There is low confidence in the methods used to monitor adherence with all clinical trials having a low adherence-assurance rating. Risk of bias was judged to be high for all included studies.
CONCLUSIONS
Adherence to acamprosate in clinical trials can be poor with low confidence in the methods used to measure it. Adherence rates therefore might not be accurate, which has implications for determining the efficacy of acamprosate.
Topics: Acamprosate; Adult; Alcohol Deterrents; Alcoholism; Clinical Decision-Making; Humans; Medication Adherence; Middle Aged; Randomized Controlled Trials as Topic; Reproducibility of Results
PubMed: 35113930
DOI: 10.1371/journal.pone.0263350 -
Alcohol and Alcoholism (Oxford,... Aug 2021There are potential clinical, ethical and legal concerns with overdosing benzodiazepines (or barbiturates) for the treatment of moderate to severe alcohol withdrawal...
AIM
There are potential clinical, ethical and legal concerns with overdosing benzodiazepines (or barbiturates) for the treatment of moderate to severe alcohol withdrawal symptoms (AWS) through telemedicine or ambulatory outpatients. A rapid systematic review to (a) qualitatively summarize the non-benzodiazepine treatment alternatives, (b) evaluate the quality of evidence for the same to effectively manage moderate to severe AWS.
METHODS
We conducted searches on PubMed (January 1990 to 31 March 2020), Cochrane Central Register of Controlled Trials, and Google Scholar. We selected the English language randomized controlled trials (RCTs) assessing the efficacy and adverse effects of non-benzodiazepine and non-barbiturate medications among adults with a diagnosis of AWS. Data extraction was done in a predefined format. Risk of bias (RoB) assessment and qualitative synthesis of evidence was done with the RoB2 tool and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) proGDT.
RESULTS
Thirty-four RCTs were included. Gabapentin (n = 6), carbamazepine (n = 5), baclofen (n = 5), valproate (n = 3), clonidine/lofexidine (n = 3) and acamprosate (n = 2) had more than one trial with a particular comparison group. Four studies were found to have a low ROB. The GRADE evidence summary showed gabapentin had a 'moderate' level of evidence against standard benzodiazepine treatments for reducing the severity of AWS. The level of certainty was 'low' for carbamazepine, baclofen and valproate and 'very low' for acamprosate and clonidine/lofexidine. Reported adverse events between these alternative medications and benzodiazepines or placebo were generally unremarkable.
CONCLUSIONS
Although benzodiazepines remain the treatment of choice for AWS, during particular circumstances, gabapentin could be an alternative although like benzodiazepines is not without risk when used in the community. Future RCTs must aim to improve upon the quality of evidence.
Topics: Alcohol Deterrents; Anti-Anxiety Agents; Anticonvulsants; Barbiturates; Benzodiazepines; Evidence-Based Medicine; Humans; Randomized Controlled Trials as Topic; Substance Withdrawal Syndrome; Sympatholytics
PubMed: 33264386
DOI: 10.1093/alcalc/agaa125 -
BMJ (Clinical Research Ed.) Nov 2020To determine the most effective interventions in recently detoxified, alcohol dependent patients for implementation in primary care. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To determine the most effective interventions in recently detoxified, alcohol dependent patients for implementation in primary care.
DESIGN
Systematic review and network meta-analysis.
DATA SOURCES
Medline, Embase, PsycINFO, Cochrane CENTRAL, ClinicalTrials.gov, and the World Health Organization's International Clinical Trials Registry Platform.
STUDY SELECTION
Randomised controlled trials comparing two or more interventions that could be used in primary care. The population was patients with alcohol dependency diagnosed by standardised clinical tools and who became detoxified within four weeks.
DATA EXTRACTION
Outcomes of interest were continuous abstinence from alcohol (effectiveness) and all cause dropouts (as a proxy for acceptability) at least 12 weeks after start of intervention.
RESULTS
64 trials (43 interventions) were included. The median probability of abstinence across placebo arms was 25%. Compared with placebo, the only intervention associated with increased probability of abstinence and moderate certainty evidence was acamprosate (odds ratio 1.86, 95% confidence interval 1.49 to 2.33, corresponding to an absolute probability of 38%). Of the 62 included trials that reported all cause dropouts, interventions associated with a reduced number of dropouts compared with placebo (probability 50%) and moderate certainty of evidence were acamprosate (0.73, 0.62 to 0.86; 42%), naltrexone (0.70, 0.50 to 0.98; 41%), and acamprosate-naltrexone (0.30, 0.13 to 0.67; 17%). Acamprosate was the only intervention associated with moderate confidence in the evidence of effectiveness and acceptability up to 12 months. It is uncertain whether other interventions can help maintain abstinence and reduce dropouts because of low confidence in the evidence.
CONCLUSIONS
Evidence is lacking for benefit from interventions that could be implemented in primary care settings for alcohol abstinence, other than for acamprosate. More evidence from high quality randomised controlled trials is needed, as are strategies using combined interventions (combinations of drug interventions or drug and psychosocial interventions) to improve treatment of alcohol dependency in primary care.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42016049779.
Topics: Adult; Alcohol Abstinence; Alcoholism; Behavior Therapy; Female; Humans; Male; Middle Aged; Network Meta-Analysis; Primary Health Care; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 33239318
DOI: 10.1136/bmj.m3934 -
Current Pharmaceutical Design 2021Alcohol use disorders (AUD) are among the most prevalent mental disorders around the world, yet still remain the most undertreated. Many studies report the low rate of...
BACKGROUND AND AIMS
Alcohol use disorders (AUD) are among the most prevalent mental disorders around the world, yet still remain the most undertreated. Many studies report the low rate of treatment uptake, less than 20%, among people with AUD. Among those accessing care, a large majority only approach their GP for help. Therefore, primary care is a strategic setting for the identification and the management of AUD. International recommendations stress AUD pharmacotherapy for withdrawal and craving management, but very few studies have shown interest in the management of AUDs in primary care. The main objective of this study was to analyse pharmacotherapy in AUD management in primary care by means of a systematic literature review.
METHODS
A systematic literature review (PRISMA) was carried out. 5 databases were screened: PUBMED via MEDLINE, LiSSa, the SUDOC catalogue, PASCAL and EMBASE. Search algorithms were used integrating the concepts of pharmacotherapy management, alcohol use disorders and primary care, only in the English language.
RESULTS
296 studies were selected and 10 were included. One was a follow-up study on the national prescription database, while four were cross-sectional studies with an auto-questionnaire survey. Of the 10 studies included, two were conducted in Europe, five in North America, two in Australia and one in South Africa. These pharmacotherapy studies were concerned with the anti-craving treatment, and 3 types of medications were used: Disulfiram, Acamprosate and Naltrexone. Factors identified as limiting or facilitating prescriptions concerned cost, indications, efficacy, training and adjuncts to pharmacotherapy.
CONCLUSION
Knowledge and prescription of pharmacotherapy for AUD, more specifically, anti-craving treatment, is insufficient in primary care. There is a lack of data and studies on the efficacy of anti-craving treatment in primary care. Guidelines for AUD management, including psychological and medical management and pharmacotherapy, do exist but have not been adapted to primary care practice. Barriers and facilitators of pharmacotherapy prescription in AUD in primary care were identified in this study.
Topics: Alcoholism; Cross-Sectional Studies; Disulfiram; Family Practice; Follow-Up Studies; Humans
PubMed: 33059563
DOI: 10.2174/1381612826666201015154051 -
Alcoholism, Clinical and Experimental... Oct 2020Alcohol use disorder (AUD) presents a significant public health concern given the high prevalence estimates and numerous deleterious-associated consequences. The FDA...
A Call to Action: A Systematic Review Examining the Failure to Include Females and Members of Minoritized Racial/Ethnic Groups in Clinical Trials of Pharmacological Treatments for Alcohol Use Disorder.
Alcohol use disorder (AUD) presents a significant public health concern given the high prevalence estimates and numerous deleterious-associated consequences. The FDA currently has approved 3 pharmacological treatments for alcohol use disorder: acamprosate, naltrexone, and disulfiram. Previous research suggests that there may exist differences in the prevalence of and outcomes related to AUD across sex and racial/ethnic groups. Other work indicates that there may be differences in the efficacy of existing pharmacological treatments for AUD across demographic groups. The purpose of the present study was to examine the inclusion of women and members of minoritized racial/ethnic groups in published randomized clinical trials of pharmacological treatments for alcohol use disorder since 1994, in accordance with the NIH Revitalization Act of 1993. PubMed was systematically searched using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The initial search located 842 articles. After exclusion of ineligible articles, 102 remained for analysis. Of those included in the review, only 11.8% reported full sex and racial/ethnic characteristics of their study participants. Of the total sample, 6 articles were specifically examining 1 racial/ethnic group, and 11 were specifically examining 1 sex. Two articles (2.2%) did not report information regarding the sex breakdown of their participants, while 47 (49.0%) did not report any information regarding the racial/ethnic breakdown of their sample. Despite guidelines set forth by NIH, only 5.9% of articles conducted subgroup analyses to examine differences in treatment outcomes by sex or race/ethnicity, and only 16.7% of articles included considerations related to cultural inclusion when discussing study limitations. These results varied by medication type. Results suggest that considerably greater efforts must be put forth by the larger scientific community regarding the inclusion, analysis, and reporting of data focused on women and non-White racial and ethnic groups.
Topics: Alcoholism; Female; Humans; Male; Minority Groups; Patient Selection; Racial Groups; Randomized Controlled Trials as Topic; Sex Factors; Women
PubMed: 32997374
DOI: 10.1111/acer.14440 -
JAMA Network Open Jun 2020Substance use disorders (SUDs) represent a pressing public health concern. Combined behavioral and pharmacological interventions are considered best practices for... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Substance use disorders (SUDs) represent a pressing public health concern. Combined behavioral and pharmacological interventions are considered best practices for addiction. Cognitive behavioral therapy (CBT) is a first-line intervention, yet the superiority of CBT compared with other behavioral treatments when combined with pharmacotherapy remains unclear. An understanding of the effects of combined CBT and pharmacotherapy will inform best-practice guidelines for treatment of SUD.
OBJECTIVE
To conduct a meta-analysis of the published literature on combined CBT and pharmacotherapy for adult alcohol use disorder (AUD) or other SUDs.
DATA SOURCES
PubMed, Cochrane Register, MEDLINE, PsychINFO, and Embase databases from January 1, 1990, through July 31, 2019, were searched. Keywords were specified in 3 categories: treatment type, outcome type, and study design. Collected data were analyzed through September 30, 2019.
STUDY SELECTION
Two independent raters reviewed abstracts and full-text articles. English language articles describing randomized clinical trials examining CBT in combination with pharmacotherapy for AUD and SUD were included.
DATA EXTRACTION AND SYNTHESIS
Inverse-variance weighted, random-effects estimates of effect size were pooled into 3 clinically informative subgroups: (1) CBT plus pharmacotherapy compared with usual care plus pharmacotherapy, (2) CBT plus pharmacotherapy compared with another specific therapy plus pharmacotherapy, and (3) CBT added to usual care and pharmacotherapy compared with usual care and pharmacotherapy alone. Sensitivity analyses included assessment of study quality, pooled effect size heterogeneity, publication bias, and primary substance moderator effects.
MAIN OUTCOMES AND MEASURES
Substance use frequency and quantity outcomes after treatment and during follow-up were examined.
RESULTS
The sample included 62 effect sizes from 30 unique randomized clinical trials that examined CBT in combination with some form of pharmacotherapy for AUD and SUD. The primary substances targeted in the clinical trial sample were alcohol (15 [50%]), followed by cocaine (7 [23%]) and opioids (6 [20%]). The mean (SD) age of the patient sample was 39 (6) years, with a mean (SD) of 28% (12%) female participants per study. The following pharmacotherapies were used: naltrexone hydrochloride and/or acamprosate calcium (26 of 62 effect sizes [42%]), methadone hydrochloride or combined buprenorphine hydrochloride and naltrexone (11 of 62 [18%]), disulfiram (5 of 62 [8%]), and another pharmacotherapy or mixture of pharmacotherapies (20 of 62 [32%]). Random-effects pooled estimates showed a benefit associated with combined CBT and pharmacotherapy over usual care (g range, 0.18-0.28; k = 9). However, CBT did not perform better than another specific therapy, and evidence for the addition of CBT as an add-on to combined usual care and pharmacotherapy was mixed. Moderator analysis showed variability in effect direction and magnitude by primary drug target.
CONCLUSIONS AND RELEVANCE
The present study supports the efficacy of combined CBT and pharmacotherapy compared with usual care and pharmacotherapy. Cognitive behavioral therapy did not perform better than another evidence-based modality (eg, motivational enhancement therapy, contingency management) in this context or as an add-on to combined usual care and pharmacotherapy. These findings suggest that best practices in addiction treatment should include pharmacotherapy plus CBT or another evidence-based therapy, rather than usual clinical management or nonspecific counseling services.
Topics: Adult; Cognitive Behavioral Therapy; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Substance-Related Disorders; Treatment Outcome
PubMed: 32558914
DOI: 10.1001/jamanetworkopen.2020.8279 -
Current Neuropharmacology 2020Pharmacological treatment for alcohol dependence has only three approved drugs: disulfiram, naltrexone and acamprosate. The effects of these drugs are, however, limited,...
BACKGROUND
Pharmacological treatment for alcohol dependence has only three approved drugs: disulfiram, naltrexone and acamprosate. The effects of these drugs are, however, limited, presenting several side effects and a modestly higher efficacy compared to placebo. The administration of omega-3 might bring new perspectives to relapse prevention.
METHODS
This systematic review aimed to analyze the available literature, compiling the studies that used omega-3 to prevent relapse in alcohol dependents.
RESULTS
The databases used were PubMed and Web of Science. We identified 2,231 studies and only five articles addressed the administration of omega-3 and alcoholism. Preclinical studies evaluating the effects of PUFAs related to chronic alcohol administration showed improvements in behavioral, cellular and molecular levels. The clinical trial yielded inconclusive results.
CONCLUSION
Despite the reduced number of studies, omega-3 interventions seem to be promising for controlling issues related to alcohol dependence.
Topics: Alcoholism; Animals; Behavior, Animal; Clinical Trials as Topic; Fatty Acids, Omega-3; Humans; Secondary Prevention; Treatment Outcome
PubMed: 31989899
DOI: 10.2174/1570159X18666200128120729 -
Frontiers in Pharmacology 2019Sleep disorders are commonly associated with acute and chronic use of alcohol and with abstinence. To date, there are four approved drugs to treat alcohol use disorder...
Sleep disorders are commonly associated with acute and chronic use of alcohol and with abstinence. To date, there are four approved drugs to treat alcohol use disorder (AUD): disulfiram, acamprosate, naltrexone, and nalmefene. These AUD therapies reduce the craving and risk of relapse into heavy drinking, but little is known about their effect on sleep. As recent evidences indicate a crucial role of sleep disorders in AUD, claiming that sleep problems may trigger alcohol abuse and relapses, it is fundamental to clarify the impact of those drugs on the sleep quality of AUD patients. This systematic review aims to answer the question: how does the pharmacotherapy for AUD affect sleep? We searched PubMed, Embase, CINAHL Plus, Cochrane, and Scopus using sleep- and AUD pharmacotherapy-related keywords. The articles included were appraised using the CASP checklists, and the risk of bias was assessed following the Cochrane risk-of-bias assessment tool. Finally, we pooled sleep outcomes in a meta-analysis to measure the overall effect. We included 26 studies: only three studies focused on sleep as a main outcome, two with polysomnography (objective measurement), and one with subjective self-reported sleep, while all the other studies reported sleep problems among the adverse effects (subjective report). The only study available on disulfiram showed reduced REM sleep. Acamprosate showed no/little effect on self-reported sleep but improved sleep continuity and architecture measured by polysomnography. The two opioidergic drugs naltrexone and nalmefene had mainly detrimental effect on sleep, giving increased insomnia and/or somnolence compared with placebo, although not always significant. The meta-analysis confirmed significantly increased somnolence and insomnia in the naltrexone group, compared with the placebo. Overall, the currently available evidences show more sleep problems with the opioidergic drugs (especially naltrexone), while acamprosate seems to be well tolerated or even beneficial. Acamprosate might be a more suitable choice when patients with AUD report sleep problems. Due to the paucity of information available, and with the majority of results being subjective, more research on this topic is needed to further inform the clinical practice, ideally with more objective measurements such as polysomnography.
PubMed: 31680952
DOI: 10.3389/fphar.2019.01164