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.
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.
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 We located unpublished trials through the National Institutes of Health (NIH) RePORTER service and the World Health Organization (WHO) International Clinical Trials Registry Platform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.
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 Chi2 and I2 heterogeneity statistics.
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.
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.
Plain language summary
Medication for treating anxiety disorders in people with alcohol use problems
Who may be interested in this review?
People with anxiety disorders and alcohol use problems, as well as their healthcare providers.
Why is this review important?
People with anxiety disorders often also abuse alcohol or have alcohol dependence. All anxiety disorders involve long-lasting and excessive fear, and can be classified according to the cause of the fear: generalized anxiety disorder (everyday situations), obsessive-compulsive disorder (repetitive thoughts and behaviours), panic disorder (panic attacks), post-traumatic stress disorder (previous traumatic events), social anxiety disorder (negative judgements by others) and specific phobia (specific objects or situations). When people with anxiety disorders abuse or are dependent on alcohol, they may be more disabled and difficult to treat than when they have either condition on its own. Psychotherapy is most often used in treating anxiety disorders in people with alcohol use problems. In psychotherapy people are encouraged to explore their feelings, moods, behaviours, thoughts and reactions to the cause of their anxiety. Psychotherapy does not always work though, so it is important to test whether medications are an effective treatment option.
What questions does this review aim to answer?
We wanted to find out whether medication is effective in treating people with both anxiety disorders and alcohol use problems. For this reason, we systematically searched for randomized controlled trials (RCTs) of medication in treating people with both disorders. RCTs provide a more accurate measure of the effectiveness of medication by making sure that people in the study have an equal chance of being treated with medication or placebo.
Which studies were included in the review?
This review found five RCTs in 290 adults (average age 37.4 years) with anxiety and alcohol use disorders. The evidence is current up to January 2014. Two trials looked at social anxiety disorder, two looked at post-traumatic stress disorder and one trial looked at generalized anxiety disorder. All of the included trials took place in the USA. Most of the study participants were male (70%), and were classified as having alcohol dependence (79%).
What does the evidence from the review tell us?
It was not possible to tell whether medication was effective in treating people with anxiety and alcohol use disorders. Although more than twice as many people (57.7%) with social anxiety disorder who were treated with paroxetine in two trials showed signs of clinical improvement compared with people receiving placebo (25.8%), the quality of the evidence was very low. One study reported that buspirone reduced anxiety disorder symptoms after 12 weeks of treatment. None of the other studies found reductions in symptoms. Treatment with medication appeared to be acceptable to participants, but again the quality of the evidence showing this was very low. Certain medication side effects, such as sexual problems, were commonly reported after treatment with paroxetine and sertraline. There was no evidence that treatment had an effect on alcohol use.
It was difficult to interpret the findings reported by the studies included in this review. Many participants (43.1% altogether) dropped out of the studies before treatment ended. In addition, outcomes that were reported were either not precise, or appeared to be based on the selective reporting of measures that showed an effect of medication. Funding of two of the studies by drug companies may also have led to reporting of results that favoured the medication.