Pharmacotherapy for adults with alcohol use disorders in outpatient settings

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Patriek Mistiaen, Sabine Stordeur, Dominique Roberfroid, Dominique Paulus

Pharmacotherapy is one of many options to treat people with an alcohol use disorder. The American AHRQ did a review on the effectiveness of medications.

Researchers found that both acamprosate and oral naltrexone were associated with improvement in consumption outcomes, e.g. number of drinking days and return to drinking. Moreover, oral naltrexone prevents return to heavy drinking, but has more adverse events. It is unclear what effects are on long term health outcomes.
For most of the medications used off-label (among which Baclofen), evidence was either insufficient to determine whether they are associated with reduced consumption or evidence suggested that they are not.

1. Alcohol use disorders

Alcohol use disorders (AUDs) are worldwide a highly prevalent problem. The Flemish Society for Alcohol and Drug problems (VAD)¹ estimates that approximately 5-7% of the adult Belgian population presents a problematic drinking pattern (i.e. the regular consumption of ≥ 40g of alcohol per day for women or ≥ 60g of alcohol for men, as defined by WHO), and Rehm et al.² state that 5.4% of Belgian men and 1.9% of Belgian women aged 18–64 are affected with alcohol dependence.

Alcohol use significantly impacts the health and is a significant cause of morbidity and mortality. According to a recent WHO-report³ the harmful use of alcohol is a contributing factor in more than 200 types of injury conditions and diseases, including liver cirrhosis and cancers. Mortality attributed to alcohol use is estimated at 1 in 7 deaths for men and 1 in 13 deaths for women.⁴

Treatment can reduce alcohol-related problems and alcohol-related mortality. However, treatment uptake of the population with alcohol dependency is estimated around 10% only.^{2, 5}

KCE is currently conducting a study involving patients and health care professionals on the reasons for this low treatment initiation and on possible measures to increase it (Study 2014-02 (HSR) Persons with an alcohol problem: how to improve their treatment uptake ?).

2. Effects of pharmacotherapy on alcohol use disorders

Common treatments for alcohol use disorders (AUDs) include cognitive behavioral therapy, motivational enhancement therapy and pharmacotherapy. Pharmacotherapy for AUDs was initiated in the 1950s and consisted only of disulfiram (Antabuse®).

Nowadays there are many more medications used for AUD. Four drugs are registered in Belgium for that indication: disulfiram (Antabuse®), acamprosate (Campral®), naltrexone (Nalorex®) and nalmefene (Selincro®) (In the USA, nalmefene is currently not FDA-approved for AUD; therefore the review summarized below considered nalmefene as “off label”). Many other medications are used as well, off label: antidepressants, mood stabilizers, anticonvulsants, alpha-adrenergic blockers, antipsychotics and anxiolytics. In particular there is a recent trend for prescribing Baclofen (muscle relaxant) in that indication.

In May 2014 the US Agency for Healthcare Research and Quality (AHRQ) published a guideline6 on the benefits and harms of the pharmacological treatment options for adult outpatients with AUDs, covering over 25 different drugs. Along with this 447 pages report, a short 12 pages account of the systematic review was published as an article in the JAMA⁷.

The paragraphs below summarize the main results of this JAMA publication, based on 123 studies (out of the 135 studies from the initial AHRQ guideline). Most patients met criteria for alcohol dependence; mean age was in the 40s. Studies typically included psychosocial co-interventions. Evidence from primary care settings was scarce.
A quality appraisal by KCE researchers, found that this publication was of very high quality (AMSTAR score of 11/11).

This summary focuses on the four drugs registered in Belgium for the indication of AUD.

Effect of medications on health outcomes
Insufficient direct evidence was found to conclude whether medications for alcohol-use disorders are effective for improving health outcomes.

Effect of medications on consumption outcomes
There is some evidence that medications for alcohol use disorder influence consumption outcomes and prevents return to drinking.

Acamprosate (Campral®) and naltrexone (Nalorex®)
The two drugs being assessed the most frequently were acamprosate (Campral®) (27 studies, n = 7 519) and naltrexone (Nalorex®) (53 studies, n = 9 140), or a combination of both.
For both drugs, compared to placebo, there was moderate level of evidence they improved some consumption outcomes (measured after at least 12 weeks after medication initiation):

• the Number Needed to Treat (NNT) to prevent 1 person from ‘returning to any drinking’ was 12 (95%CI, 8 to 26) for acamprosate and was 20 (95%CI, 11 to 500) for oral naltrexone (50 mg/day);
• the Number Needed to Treat (NNT) for ‘return to heavy drinking’ was 12 (95% CI, 8 to 26) for oral naltrexone (50mg/day) whilst acamprosate was not associated with any improvement.

Meta-analyses of trials comparing acamprosate to naltrexone found no statistically significant difference between the two drugs for return to any drinking or heavy drinking.

Disulfiram (Antabuse®)
Evidence from well-controlled trials does not support efficacy of disulfiram (Antabuse®) for any consumption outcome, except possibly for patients with excellent adherence.

Medications used off-label in the USA
There is moderate level of evidence that nalmefene (Selincro®), accepted in Belgium for the treatment of AUD, improves some consumption outcomes (in comparison with placebo): there was a reduction in number of days of heavy drinking days per month (WMD= −2.0 days; 95%CI, −3.0 to −1.0).
For most of the other medications used off-label (USA), evidence was either insufficient to determine whether they are associated with reduced consumption or available evidence suggested that they do not reduce the consumption.
For Baclofen in particular the authors conclude that the level of evidence for all outcomes is insufficient (2 small scale trials only met the inclusion criteria).

Adverse effects of medications
The review highlights potential adverse effects of the drugs used in Belgium (in comparison with placebo):

• Patients treated with acamprosate reported higher risk of anxiety, diarrhea and vomiting.
• Patients treated with naltrexone had a higher risk of dizziness, nausea and vomiting. The number needed to harm, defined as withdrawal from trials due to adverse events, was 48 (95%CI, 30 to 112).
• Patients treated with nalmefene had a higher risk of dizziness, headache, insomnia, nausea, and vomiting. For nalmefene, the number needed to harm was 12 (95%CI, 7 to 50).

3. Conclusions of the review and implications for the practice in Belgium

Acamprosate, naltrexone and nalmefene can improve alcohol consumption outcomes (after 12 weeks) for patients with alcohol-use disorders. They are usually combined with some type of psychotherapy in the studies. No trials have consistently established the superiority of one medication on the other. Thus, other factors may guide medication choices, such as frequency of administration, potential type of benefits, potential adverse events, coexisting symptoms, concomitant drugs consumption (e.g. opioids), contraindications (e.g. renal impairment, acute hepatitis, liver failure) and the treatment costs.

4. References

1. Mobius D. Dossier Alcohol. Brussel: VAD, Vereniging voor Alcohol- en andere Drugproblemen; 2009.

2. Rehm J, Shield KD, Rehm MX, Gmel G, Frick U. Alcohol Consumption, Alcohol Dependence, and Attributable Burden of Disease in Europe: Potential Gains from Effective Interventions for Alcohol Dependence. Toronto: Centre for Addiction and Mental Health; 2012.

3. World Health Organization. Global status report on alcohol and health – 2014. Geneva: 2014. 

4. Rehm J, Shield KD, Gmel G, Rehm MX, Frick U. Modeling the impact of alcohol dependence on mortality burden and the effect of available treatment interventions in the European Union. Eur Neuropsychopharmacol. 2013;23(2):89-97.

5. Alonso J, Angermeyer MC, Bernert S, Bruffaerts R, Brugha TS, Bryson H, et al. Use of mental health services in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatr Scand Suppl. 2004(420):47-54.

6. Jonas DE, Amick HR, Feltner C, Bobashev G, Thomas K, Wines R, et al. Pharmacotherapy for Adults With Alcohol-Use Disorders in Outpatient Settings. Comparative Effectiveness Review No. 134. . Rockville (MD): Agency for Healthcare Research and Quality (US); 2014.

7. Jonas DE, Amick HR, Feltner C, Bobashev G, Thomas K, Wines R, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA. 2014;311(18):1889-900.

Definitions of the grades of overall strength of evidence
Grade	Definition
High	High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect.
Moderate	Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of the effect and may change the estimate.
Low	Low confidence that the evidence reflects the true effect. Further research is likely to change our confidence in the estimate of the effect and is likely to change the estimate.
Insufficient	Evidence either is unavailable or does not permit estimation of an effect.