Key Questions

The KQs for this update are the same questions that were addressed in the 2014 review with the exception of removing the prior KQ 6 on pharmacogenomics.

Key Question 1. Alcohol consumption outcomes

KQ 1a. Which medications are efficacious for improving consumption outcomes for adults with alcohol use disorder in outpatient settings?

KQ 1b. How do medications for adults with alcohol use disorder compare for improving consumption outcomes in outpatient settings?

Key Question 2. Health outcomes

KQ 2a. Which medications are efficacious for improving health outcomes (including functioning and quality of life outcomes) for adults with alcohol use disorder in outpatient settings?

KQ 2b. How do medications for adults with alcohol use disorder compare for improving health outcomes (including functioning and quality of life outcomes) in outpatient settings?

Key Question 3. Adverse effects

KQ 3a. What adverse effects are associated with medications for adults with alcohol use disorder in outpatient settings?

KQ 3b. How do medications for adults with alcohol use disorder compare for adverse effects in outpatient settings?

Key Question 4. Are medications for treating adults with alcohol use disorder effective in primary care settings?

Key Question 5. Are any of the medications more or less effective than other medications for older adults, young adults, persons who smoke, or those with co-occurring disorders?

Findings in Relation to What Is Known

Our main findings are consistent with existing guidelines and systematic reviews.^1-7 Some guidelines, including from the United Kingdom's National Institute for Clinical Evidence (2011)⁸ and the American Psychiatric Association (2018)⁹, recommend that naltrexone and/or acamprosate be considered as first-line treatment for patients with AUD in combination with addiction-focused counseling. The U.S. Department of Veterans Affairs guideline from 2021¹⁰ lists naltrexone and topiramate as recommended first options if choosing to add pharmacotherapy as part of treatment, and then suggests that acamprosate or disulfiram be considered if the first options are ineffective or cannot be tolerated.¹¹

Applicability

As in the prior report, most studies reported that all participants met criteria for alcohol dependence. The included literature used definitions from the Diagnostic and Statistical Manual version III (DSM-III) or DSM-IV. DSM-5 (2013) describes a single AUD category measured on a continuum from mild to severe and no longer has separate categories for alcohol abuse and dependence.201 Using DSM-5 terminology, most participants in the included studies likely had moderate to severe AUD. Thus, applicability of our findings to people with mild AUD is uncertain. The mean age of participants was generally in the 40s, with very few studies enrolling slightly younger or older populations. Thus, it is uncertain whether the medications have similar efficacy for older (e.g., those age 65 years or older) or younger (e.g., in the 20s) subgroups as they have for patients enrolled in the trials. Given generally higher numbers of comorbidities seen in older populations, this may be of concern. Most studies included low numbers of non-White participants or women, and none specified genders other than male or female.

Importantly, almost all studies included some sort of co-intervention, ranging from usual management to specific harm reduction or counseling approaches, so it is important to note that the benefits observed reflect a combination of medication and co-therapy relative to co-therapy alone.

Although the majority of included trials assessing the efficacy of acamprosate were conducted in Europe (16 of 23) and a minority were conducted in the United States (4 of 23), the opposite was true for naltrexone (32 of 49 in the United States and 8 of 49 in Europe). Further, the few studies of acamprosate conducted in the United States did not find that it demonstrated a benefit either for return to any drinking or return to heavy drinking. Trials conducted in the United States all recruited participants largely through advertisements, while trials in other countries tended to recruit from treatment settings and often from inpatient settings, where alcohol withdrawal may have abated and treatment may have been begun prior to discharge. Patients recruited to these trials in the United States may, therefore, represent a more general population and potentially one with a larger range of alcohol-related baseline data. Thus, the lack of efficacy in U.S.-based trials for acamprosate may be a reflection of differences in patient characteristics as well as differences in the healthcare systems.

Most studies required patients to abstain for at least a few days before initiating medication, and the medications are generally recommended for maintenance of abstinence. Acamprosate and injectable naltrexone are only approved for use in patients who have established abstinence, though the duration of required abstinence is not set. However, some studies enrolling patients who were not yet abstinent reported reduction in heavy drinking with naltrexone^12,13 or acamprosate.¹⁴

1. Jonas DE, Amick HR, Feltner C, et al. Pharmacotherapy for adults with alcohol-use disorders in outpatient settings. Comparative Effectiveness Review No. 134. (Prepared by the RTI International-University of North Carolina Evidence-based Practice Center under Contract No. 290-2012-00008-I.). AHRQ Publication No. 14-EHC029-EF. Rockville, MD: Agency for Healthcare Research and Quality; May 2014. https://effectivehealthcare.ahrq.gov/products/alcohol-misuse-drug-therapy/research
2. Rosner S, Hackl-Herrwerth A, Leucht S, et al. Acamprosate for alcohol dependence. Cochrane Database Syst Rev. 2010(9):CD004332. doi: 10.1002/14651858.CD004332.pub2. PMID: 20824837.
3. Rosner S, Hackl-Herrwerth A, Leucht S, et al. Opioid antagonists for alcohol dependence. In Cochrane Database of Systematic Reviews
4. National Collaborating Centre for Mental Health, National Institute for Health & Clinical Excellence. Alcohol-use disorders: the NICE guidelines on diagnosis, assessment and management of harmful drinking and alcohol dependence. The British Psychological Society and The Royal College of Psychiatrists; 2011. www.nice.org.uk/nicemedia/live/13337/53190/53190.pdf. Accessed on 22 April 2014.
5. U.S. Department of Veterans Affairs, U.S. Department of Defense. VA/DoD Clinical Practice Guideline for Management of Substance Use Disorders (SUD). 2009.
6. Pettinati HM, Weiss RD, Miller WR, et al. Medical management treatment manual: a clinical research guide for medically trained clinicians providing pharmacotherapy as part of the treatment for alcohol dependence. COMBINE Monograph Series, COMBINE Monograph Series, Volume 2. DHHS Publication No. (NIH) 04–5289. Bethesda, MD: National Institute on Alcohol Abuse and Alcoholism; 2004.
7. Center for Substance Abuse and Treatment. Incorporating Alcohol Pharmacotherapies Into Medical Practice. Treatment Improvement Protocol (TIP) No. 49. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2009.
8. National Collaborating Centre for Mental Health, National Institute for Health & Clinical Excellence. Alcohol-use disorders: the NICE guidelines on diagnosis, assessment and management of harmful drinking and alcohol dependence. The British Psychological Society and The Royal College of Psychiatrists. 2011. http://www.nice.org.uk/nicemedia/live/13337/53190/53190.pdf
9. Reus VI, Fochtmann LJ, Bukstein O, et al. The American Psychiatric Association practice guideline for the pharmacological treatment of patients with alcohol use disorder. American Journal of Psychiatry. 2018;175(1):86-90. doi: 10.1176/appi.ajp.2017.1750101.
10. Department of Veterans Affairs and Department of Defense. VA/DoD Clinical Practice Guideline for the Management of Substance Use Disorders, version 4.0. 2021. https://www.healthquality.va.gov/guidelines/MH/sud/VADoDSUDCPG.pdf
11. US Army Medical Department, Psychological Health Center of Excellence. Medications for the Treatment of Alcohol Use Disorder. 2022. https://www.qmo.amedd.army.mil/substance%20abuse/22-001_05_AUD_medications_SUD_CST_508.pdf. Accessed on 15 September 2022.
12. Garbutt JC, Kranzler HR, O'Malley SS, et al. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. JAMA. 2005 Apr 6;293(13):1617-25. doi: 10.1001/jama.293.13.1617. PMID: 15811981.
13. Kranzler HR, Armeli S, Tennen H, et al. Targeted naltrexone for early problem drinkers. J Clin Psychopharmacol. 2003 Jun;23(3):294-304. doi: 10.1097/01.jcp.0000084030.22282.6d. PMID: 12826991.
14. Gual A, Lehert P. Acamprosate during and after acute alcohol withdrawal: a double-blind placebo-controlled study in Spain. In Alcohol and alcoholism (Oxford, Oxfordshire)

Implications for Clinical and Policy Decision Making

Three medications (naltrexone, acamprosate and topiramate) had moderate SOE for some consumption outcomes, but they differ in terms of ease of use and side effect profiles. Oral naltrexone (50 mg) had moderate strength of evidence for benefit across multiple outcomes and relative ease of use as a once-daily oral medication. Acamprosate and topiramate also have evidence of benefit, but topiramate has a less desirable side effect profile and acamprosate may be less convenient to take. Injectable naltrexone has low SOE for reduction in drinking days and heavy drinking days. Baclofen had low SOE for benefit for return to any drinking. Gabapentin had low SOE for benefit for return to any drinking and return to heavy drinking. Decisions will be affected by ease of use, including the need to take multiple pills (acamprosate three times daily and topiramate twice daily) over the course of a day and the side-effect profile, which is greater with topiramate. Also, acamprosate and naltrexone can be initiated at therapeutic doses, while topiramate requires an upward titration. To some degree, decisions may also be driven by desired outcomes. For example, acamprosate has evidence for effectiveness in abstinence outcomes, while topiramate only does for harm reduction outcomes.

Regardless, decisions about treatment should be made collaboratively between the patient and the clinical provider with considerations for desired outcomes, tolerance of side effects, contraindications, and the potential to adhere to the medication regimen.

For example, acamprosate is typically dosed as two 333 mg tablets given 3 times daily, whereas oral naltrexone is one tablet given once daily, and injectable naltrexone is given once monthly. Acamprosate is contraindicated for people with severe renal impairment and requires dose adjustments for moderate renal impairment. Oral naltrexone is contraindicated for patients with acute hepatitis or liver failure and for those currently using opioids or with anticipated need for opioids, and it can precipitate severe withdrawal for patients dependent on opioids (see Harms section above for injectable naltrexone contraindications). Trials of topiramate have reported a significantly increased risk of many adverse events, including difficulty with concentration/attention, paresthesias, taste abnormalities, anorexia, nervousness, dizziness, pruritis, psychomotor slowing, and weight loss.

Although we did not evaluate the effectiveness or comparative effectiveness of psychosocial interventions for AUD (e.g., cognitive behavioral therapy, 12-step programs, combined behavioral intervention), such interventions were often included in the pharmacotherapy studies. In order to fully understand how to design effective programs, decisionmakers should consult other sources to better understand the efficacy of psychosocial interventions.

Finally, given that effective medications for AUD have been underused, it is unlikely that these medications will deliver their full potential impact unless policies and programs are put into place to increase education and uptake.

This review does not provide cost information.

Limitations of the Comparative Effectiveness Review Process

Our review focused specifically on efficacy and comparative effectiveness of medications. We included only medications currently in use in the United States, whether they have a specific FDA indication for AUD or not. Reporting of previous and ongoing psychosocial interventions was variable across the included studies, and we were unable to determine whether participants actually received some co-interventions (e.g., Alcoholics Anonymous was recommended, but no information was reported about how many participants adhered to the recommendation).

We excluded trials that had less than 12 weeks of follow up from the time of medication initiation. But since longitudinal studies have found that shorter treatment periods may yield misleading conclusions about treatment efficacy we do not consider this a significant limitation. We combined studies that described including populations with a dual diagnosis (e.g., alcohol dependence and depression) and those that did not have a dual diagnosis in our meta-analyses.

For KQ 5 (on subgroups), we did not review subgroup analyses from placebo-controlled trials. The question we aimed to answer was a comparative question. We were looking for direct evidence for whether any of the medications are more or less effective than other medications for certain subgroups. To be eligible, studies had to compare at least two medications. Multiple studies were placebo controlled and were in specific populations (e.g., HIV positive, PTSD, persons who smoke only) that were not eligible for this KQ.

Finally, publication bias and selective reporting are potential limitations. Although we searched for unpublished studies and unpublished outcomes and did not find direct evidence of either of these biases, many of the included trials were published before the availability of trial registries (e.g., clinicaltrials.gov) that would allow for greater certainty in determining the potential for either type of bias.

Limitations of the Evidence Base

The biggest limitations of the evidence base were a lack of direct evidence on health outcomes, limited and varying reporting on harms, a lack of trials conducted in primary care settings, and scant head-to-head evidence on differences for population subgroups.

We found insufficient direct evidence to determine whether medications are efficacious for improving health outcomes. Although evidence from epidemiologic literature consistently relates high average and heavy per-occasion alcohol use to an increased risk of health problems as noted in our introduction, it is challenging to estimate the magnitude of reduction in the risk of health problems that is derived from a reduction in consumption. For example, it is unclear how much benefit (for health outcomes) is derived from 10 percent fewer patients returning to any drinking, or from 8 percent fewer patients returning to heavy drinking. That said, with increasing numbers of individuals in the United States diagnosed with AUD, the potential effect is large.

Many of the included trials had methodological limitations introducing some risk of bias. The most common issue was high proportions of participants lost to followup. High attrition rates are not uncommon in studies of psychiatric conditions. Methods of handling missing data varied, and some trials did nothing to address missing data (i.e., only analyzing completers). However, many trials conducted true intention-to-treat analyses and used appropriate methods of handling missing data, such as imputing return to heavy drinking for participants lost to followup or multiple imputation. Where possible, we used data from intention-to-treat analyses.

Reporting of previous treatments and ongoing treatments (i.e., co-interventions) was variable across the included studies. We were often unable to determine whether participants had received any previous treatments for AUD.

Research Gaps

Although evidence continues to grow that some medications are effective for improving consumption outcomes, the preponderance of the data for benefit derives from research on two medications, acamprosate and naltrexone. There is a need for continued research on those medications for which there is promising data but few studies, including baclofen and gabapentin. New areas of research that were not a part of this review are emerging and appear promising, such as one recent study on psilocybin. We expect the field to continue to grow.

Current data are largely insufficient for understanding health outcomes and long-term outcomes. Conducting longer studies or followup studies will be helpful for better understanding the implications of pharmacotherapy in AUD at both the individual and population levels. Engaging patients to ensure that outcomes are patient centered and meet a range of patient needs also will benefit the field.

To make a decision about what medication to pursue for given patients, clinicians and patients need to understand what medications are likely to be most beneficial for which patients. However, understanding the potential role of specific medications for important subpopulations is largely lacking. Many studies have very strict exclusion criteria that may exclude participants at greatest risk of some known harms or that reflect a broader patient population, thus providing a challenge for assessing applicability to typical AUD clinical care. There are particular gaps in studies of non-White participants, older adults, and women. No studies included recognition of gender identities other than male and female. With different risks for AUD, potentially differential risks of poor outcomes, and varying comorbidities, it is important that studies include the variety of patient populations that experience AUD. For example, given that risks of having an AUD and of specific associated health outcomes may differ between men and women, it is important that future studies ensure that women are included.

Finally, only one study was carried out in primary care. Given the increasing numbers of patients with an AUD, it is likely that many will seek care with primary care providers. Understanding best approaches to using pharmacotherapy for treatment in primary care is an area worthy of specific study.