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Meta-Analysis
. 2015 Jan 20;1(1):CD007505.
doi: 10.1002/14651858.CD007505.pub2.

Pharmacotherapy for anxiety and comorbid alcohol use disorders

Jonathan C Ipser  1 , Don Wilson, Taiwo O Akindipe, Carli Sager, Dan J Stein
Affiliations
Meta-Analysis

Pharmacotherapy for anxiety and comorbid alcohol use disorders

Jonathan C Ipser et al. Cochrane Database Syst Rev. .

Abstract

Background: Anxiety disorders are a potentially disabling group of disorders that frequently co-occur with alcohol use disorders. Comorbid anxiety and alcohol use disorders are associated with poorer outcomes, and are difficult to treat with standard psychosocial interventions. In addition, improved understanding of the biological basis of the conditions has contributed to a growing interest in the use of medications for the treatment of people with both diagnoses.

Objectives: To assess the effects of pharmacotherapy for treating anxiety in people with comorbid alcohol use disorders, specifically: to provide an estimate of the overall effects of medication in improving treatment response and reducing symptom severity in the treatment of anxiety disorders in people with comorbid alcohol use disorders; to determine whether specific medications are more effective and tolerable than other medications in the treatment of particular anxiety disorders; and to identify which factors (clinical, methodological) predict response to pharmacotherapy for anxiety disorders.

Search methods: Review authors searched the specialized registers of The Cochrane Collaboration Depression, Anxiety and Neurosis Review Group (CCDANCTR, to January 2014) and the Cochrane Drugs and Alcohol Group (CDAG, to March 2013) for eligible trials. These registers contain reports of relevant randomized controlled trials (RCT) from: the Cochrane Central Register of Controlled Trials (CENTRAL, all years), MEDLINE (1950 to date), EMBASE (1974 to date) and PsycINFO (1967 to date). Review authors ran complementary searches on EMBASE, PubMed, PsycINFO and the Alcohol and Alcohol Problems Science Database (ETOH) (to August 2013). We located unpublished trials through the National Institutes of Health (NIH) RePORTER service and the World Health Organization (WHO) International Clinical Trials Registry Platform (to August 2013). We screened reference lists of retrieved articles for additional studies.

Selection criteria: All true RCTs of pharmacotherapy for treating anxiety disorders with comorbid alcohol use disorders. Trials assessing drugs administered for the treatment of drinking behaviour, such as naltrexone, disulfiram and acomprosate were not eligible for inclusion in this systematic review.

Data collection and analysis: A systematic review is a standardised evaluation of all research studies that address a particular clinical issue.Two review authors independently assessed RCTs for inclusion in the review, collated trial data and assessed trial quality. We contacted investigators to obtain missing data. We calculated categorical and continuous treatment effect estimates and their 95% confidence intervals (CI) for treatment using a random-effects model with effect-size variability expressed using Chi(2) and I(2) heterogeneity statistics.

Main results: We included five placebo-controlled pharmacotherapy RCTs (with 290 participants) in the review. Most of the trials provided little information on how randomization was performed or on whether both participants and study personnel were blinded to the intervention. Two of the three trials reporting superiority of medication compared with placebo on anxiety symptom outcomes were industry funded. We regarded one trial as being at high risk of bias due to selective reporting.Study participants had Diagnostic and Statistical Manual (DSM) III- and DSM IV-diagnosed alcohol use disorders and post-traumatic stress disorder (two studies), social anxiety disorder (SAD; two studies) or generalized anxiety disorder (GAD; one study). Four trials assessed the efficacy of the selective serotonin re-uptake inhibitors (SSRIs: sertraline, paroxetine); one RCT investigated the efficacy of buspirone, a 5-hydroxytryptamine (5-HT) partial agonist. Treatment duration lasted between eight and 24 weeks. Overall, 70% of participants included in the review were male.There was very low quality evidence for an effect of paroxetine on global clinical response to treatment, as assessed by the Clinical Global Impressions - Improvement scale (CGI-I). Global clinical response was observed in more than twice as many participants with paroxetine than with placebo (57.7% with paroxetine versus 25.8% with placebo; risk ratio (RR) 2.23, 95% CI 1.13 to 4.41; 2 trials, 57 participants). However, there was substantial uncertainty regarding the size of the effect of paroxetine due to the small number of studies providing data on clinically diverse patient samples. The second primary outcome measure was reduction of anxiety symptom severity. Although study investigators reported that buspirone (one trial) was superior to placebo in reducing the severity of anxiety symptoms over 12 weeks, no evidence of efficacy was observed for paroxetine (mean difference (MD) -14.70, 95% CI -33.00 to 3.60, 2 trials, 44 participants) and sertraline (one trial). Paroxetine appeared to be equally effective in reducing the severity of post-traumatic stress disorder (PTSD) symptoms as the tricyclic antidepressant desipramine in one RCT. The maximal reduction in anxiety disorder symptom severity was achieved after six weeks with paroxetine (two RCTs) and 12 weeks with buspirone (one RCT), with maintenance of medication efficacy extending to 16 with paroxetine and 24 weeks with buspirone. There was no evidence of an effect for any of the medications tested on abstinence from alcohol use or depression symptoms. There was very low quality evidence that paroxetine was well tolerated, based on drop-out due to treatment-emergent adverse effects. Nevertheless, levels of treatment discontinuation were high, with 43.1% of the participants in the studies withdrawing from medication treatment. Certain adverse effects, such as sexual problems, were commonly reported after treatment with paroxetine and sertraline.

Authors' conclusions: The evidence-base for the effectiveness of medication in treating anxiety disorders and comorbid alcohol use disorders is currently inconclusive. There was a small amount of evidence for the efficacy of medication, but this was limited and of very low quality. The majority of the data for the efficacy and tolerability of medication were for SSRIs; there were insufficient data to establish differences in treatment efficacy between medication classes or patient subgroups. There was a small amount of very low quality evidence that medication was well tolerated. There was no evidence that alcohol use was responsive to medication.Large, rigorously conducted RCTs would help supplement the small evidence-base for the efficacy and tolerability of pharmacotherapy for anxiety and comorbid alcohol use disorders. Further research on patient subgroups who may benefit from pharmacological treatment, as well as novel pharmacological interventions, is warranted.

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Conflict of interest statement

Potential conflicts of interest for individual review authors:

Jonathan Ipser has no known conflicts of interest.

Don Wilson is employed by the University of Cape Town and the Western Cape Provincial government. As part of his duties, he occasionally conducts clinical trials, some of which are funded by pharmaceutical companies (including GlaxoSmithKline and Organon). He has presented on behalf of Sanofi‐Synthélabo and Eli Lilly in the past. He has previously participated in industry‐sponsored trials in mood disorders. From 2011‐2014, Dr. Wilson received no research grants or consultancy honoraria. Dr. Wilson was involved in a Servier‐sponsored trial of agomelatine for depression, which ended in 2014, for which his department/faculty received reimbursement. He also gave lectures at meetings sponsored by Sanofi‐Synthélabo and Eli Lilly.

Taiwo Akindipe has no known conflicts of interest.

Carli Sager is currently contracted to Parexel International and sub contracted to MSD and Eli Lilly. Carli Sager had no known conflicts of interest while retrieving studies for inclusion in this review.

Dan Stein received research grants or consultancy honoraria (or both) from AMBRF, Biocodex, Cipla, Lundbeck, National Responsible Gambling Foundation, Novartis, Servier and Sun from 2011‐2014.

Clarification statement added from the Co‐ordinating Editor on 12 November 2020: This review was found by the Cochrane Funding Arbiters, post‐publication, to be noncompliant with theCochrane conflict of interest policy, which includes the relevant parts of theCochrane Commercial Sponsorship Policy. It will be updated within 12 months. The update will have a majority of authors and lead author free of conflicts.

Figures

1
1
PRISMA flowchart
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: Medication versus placebo, Outcome 1: Treatment response
1.2
1.2. Analysis
Comparison 1: Medication versus placebo, Outcome 2: Symptom severity reduction
1.3
1.3. Analysis
Comparison 1: Medication versus placebo, Outcome 3: Treatment acceptability
1.4
1.4. Analysis
Comparison 1: Medication versus placebo, Outcome 4: Proportion of days abstinent
1.5
1.5. Analysis
Comparison 1: Medication versus placebo, Outcome 5: Drinks per drinking day
2.1
2.1. Analysis
Comparison 2: Medication versus other medications, Outcome 1: Symptom severity reduction
2.2
2.2. Analysis
Comparison 2: Medication versus other medications, Outcome 2: Treatment acceptability
2.3
2.3. Analysis
Comparison 2: Medication versus other medications, Outcome 3: Mean number of drinking days
2.4
2.4. Analysis
Comparison 2: Medication versus other medications, Outcome 4: Drinks per drinking day
2.5
2.5. Analysis
Comparison 2: Medication versus other medications, Outcome 5: Proportion heavy drinking days
2.6
2.6. Analysis
Comparison 2: Medication versus other medications, Outcome 6: Reduction in depression symptoms
See this image and copyright information in PMC

Comment in

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