The American Psychiatric Association Practice Guideline for the Pharmacological Treatment of Patients With Alcohol Use Disorder

The goal of this guideline¹ is to improve the quality of care and treatment outcomes for patients with alcohol use disorder (AUD), as defined by DSM-5 (American Psychiatric Association, 2013). The guideline focuses specifically on evidence-based pharmacological treatments for AUD but also includes statements related to assessment and treatment planning that are an integral part of using pharmacotherapy to treat AUD. AUD pharmacotherapy is a topic of increasing interest given the availability of several medications approved by the U.S. Food and Drug Administration (FDA) for this disorder and the burden of AUD in the population.

Worldwide, the estimated 12-month adult prevalence of AUD is 8.5%, with an estimated lifetime prevalence of 20% (Slade et al., 2016). In the United States (U.S.), AUD has estimated values for 12-month and lifetime prevalence of 13.9% and 29.1%, respectively, with approximately half of individuals with lifetime AUD having a severe disorder (Grant et al., 2015). AUD places a significant strain on both the personal and public health of the U.S. population. According to a 2006 Centers for Disease Control and Prevention-sponsored study (Bouchery et al., 2011), AUD and its sequelae cost the U.S. $223.5 billion annually and account for significant excess mortality (Kendler et al., 2016). Despite its high prevalence and numerous negative consequences, AUD remains undertreated. Effective and evidence-based interventions are available, and treatment is associated with reductions in the risk of relapse (Dawson et al, 2006) and AUD-associated mortality (Timko et al., 2006). Nevertheless, fewer than 1 in 10 individuals in the U.S. with a 12-month diagnosis of AUD receive any treatment (Substance Abuse and Mental Health Services Administration, 2014; Grant et al., 2015). Receipt of evidence-based care is even less common. For example, one study found that of the 11 million people in the U.S. with AUD, only 674,000 received psychopharmacological treatment (Mark et al., 2009). Accordingly, this practice guideline provides evidence-based statements aimed at increasing knowledge and the appropriate use of medications for AUD. The overall goal of this guideline is to enhance the treatment of AUD for millions of affected individuals, thereby reducing the significant psychosocial and public health consequences of this important psychiatric condition.

The Agency for Healthcare Research and Quality (AHRQ) undertook a systematic review of AUD pharmacotherapy in outpatients (Jonas et al., 2014), which serves as the foundation of the systematic review for this practice guideline. The specific medications that are discussed in the guideline include: acamprosate, naltrexone, disulfiram, gabapentin, and topiramate. The guideline does not apply to the use of these same medications for indications other than AUD. It also does not address the management of individuals who are intoxicated with alcohol, who require pharmacotherapy for the acute treatment of alcohol withdrawal, or who are experiencing other acute medical problems related to alcohol use. Evidence-based psychotherapeutic treatments for AUD, including cognitive-behavioral therapy, twelve-step facilitation, and motivational enhancement therapy (Anton et al., 2006; Martin and Rehm, 2012, Project MATCH Research Group, 1998), also play a major role in the treatment of AUD, but specific recommendations related to these modalities are outside the scope of this guideline.

Naltrexone and acamprosate have the best available research evidence as pharmacotherapy for patients with AUD. The potential benefit of each medication was viewed as far outweighing the harms of treatment or the harms of continued alcohol use, particularly when nonpharmacological approaches have not produced an effect or when patients prefer to use one of these medications as an initial treatment option. Accordingly, APA recommends (Statement 9) that that these medications be offered to patients with moderate to severe alcohol use disorder in specific clinical circumstances. Both naltrexone and acamprosate have positive effects overall although not all studies or outcomes show a statistically significant benefit from these medications. Acamprosate is associated with a small benefit on the outcomes of returning to any drinking and number of drinking days (moderate strength of research evidence). Naltrexone is associated with a small benefit on the outcomes of returning to any drinking, returning to heavy drinking, frequency of drinking days, and frequency of heavy drinking days (moderate strength of research evidence). In the AHRQ meta-analysis of head-to-head comparisons, neither acamprosate nor naltrexone showed superiority to the other medication in terms of return to heavy drinking (moderate strength of research evidence), return to any drinking (moderate strength of research evidence), or percentage of drinking days (low strength of research evidence). However, in the U.S. COMBINE study (but not the German PREDICT study), naltrexone was associated with better outcomes than acamprosate.

For both acamprosate and naltrexone, the harms of treatment are considered minimal, particularly compared with the harms of continued alcohol use, as long as there is no contraindication to the use of the medication (e.g. pregnancy, renal impairment for acamprosate, acute hepatitis/hepatic failure for naltrexone). Harms of acamprosate are small in magnitude, with slight overall increases in diarrhea and vomiting as compared with placebo (moderate strength of research evidence). Harms of naltrexone are also small in magnitude, with slight overall increases in dizziness, nausea, and vomiting relative to placebo (moderate strength of research evidence). Alterations in hepatic function are also possible with naltrexone. For many other potential harms, including mortality, evidence was not available or was rated by the AHRQ review as insufficient. However, withdrawals from the studies due to adverse events did not differ from placebo for acamprosate (low strength of research evidence) and were only slightly greater than placebo for naltrexone although statistically significant (moderate strength of research evidence).

APA suggests (Statement 10) that disulfiram be offered to patients with moderate to severe alcohol use disorder in specific clinical circumstances. Although the bulk of the research evidence for benefits and harms of disulfiram was from randomized open-label studies, the potential benefits of disulfiram were viewed as likely to outweigh the harms for most patients given the medium to large effect size for the benefit of disulfiram and particularly compared with the harms of continued alcohol use. With carefully selected patients in clinical trials, adverse events (e.g. drowsiness, increased levels of hepatic enzymes, drug-drug reactions) were somewhat greater with disulfiram. However, serious adverse events were few and comparable in numbers to serious adverse events in comparison groups consistent with the long history of safe use of disulfiram in clinical practice.

Topiramate and gabapentin are also suggested as medications to be offered to patients with moderate to severe alcohol use disorder in specific clinical circumstances (Statement 11). It was noted that even small effect sizes for these medications may be clinically meaningful because of the significant morbidity associated with AUD. A moderate strength of research evidence from multiple randomized controlled trials showed moderate benefit of topiramate on drinks per drinking day, percentage of heavy drinking days, and percentage of drinking days. Despite the benefits, adverse events such as an increased likelihood of cognitive dysfunction, dizziness, taste abnormalities, and decreased appetite or weight loss were also reported more often with topiramate in placebo-controlled trials in AUD.

Gabapentin was associated with moderate benefit on rates of abstinence from drinking and abstinence from heavy drinking (low strength of research evidence). Gabapentin was not associated with an increased likelihood of adverse events relative to placebo (low strength of research evidence); however, in studies that examined side effects of the medication in other conditions, side effects are typically mild and have included dizziness and somnolence. Although gabapentin had a small positive effect, the harm of treatment was seen as being minimal, particularly compared with the harms of continued alcohol use, as long as there was no contraindication to the use of the medication (e.g. pregnancy).

The full text of the practice guideline includes a detailed description of research evidence related to effects of medication in individuals with AUD. It also describes aspects of guideline implementation that are relevant to individual patients’ circumstances and preferences.