literature review on alcohol use disorder

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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

StatPearls [Internet].

Alcohol use disorder.

Sara M. Nehring ; Richard J. Chen ; Andrew M. Freeman .

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Last Update: March 16, 2024 .

• Continuing Education Activity

Alcohol, the most commonly used substance in the United States, has far-reaching health consequences that impact not only individual patients but the entire healthcare system. Alcohol use in and of itself is not problematic but exists along a spectrum from low-risk use to alcohol use disorder (AUD). The diagnosis, based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria, ranges from mild to severe, with withdrawal symptoms and tolerance as key indicators. Screening by primary care clinicians, supported by the United States Preventive Services Task Force, facilitates early detection. Treatment involves shared decision-making, combining pharmacotherapy and behavioral therapy with interdisciplinary collaboration essential for comprehensive care and improved outcomes.

This activity reviews the definition and diagnosis of AUD and the available evaluation and evidence-based treatments. Participating clinicians from primary care, emergency medicine, internal medicine, and relevant subspecialties are equipped with the current algorithm to intervene early, offer treatment options, and continue long-term follow-up for at-risk patients. Through this course, learners foster effective interprofessional team communication and collaboration to provide holistic care and improve patient outcomes.

• Screen patients for alcohol abuse potential using validated criteria across healthcare settings, including primary care, emergency departments, and inpatient facilities.
• Differentiate between alcohol use disorder and other substance use disorders to facilitate appropriate treatment planning.
• Select appropriate pharmacotherapy and/or behavioral health treatments for patients with alcohol use disorder.
• Implement interprofessional collaboration when assessing treatment efficacy, adherence, and compliance during treatment for alcohol use disorder.
• Introduction

Alcohol is the most commonly used substance in the United States, with 84% of people 18 and older reporting lifetime use, according to data from the 2022 National Survey on Drug Use and Health. Alcohol use exists along a spectrum from low risk to alcohol use disorder (AUD). The intervening category, known as risky drinking, includes heavy drinking as well as binge drinking. [1]  AUD is a chronic disease with significant medical, social, and psychological implications for the patient. AUD also significantly impacts the healthcare system, contributing to over 200,000 hospitalizations annually and 7.4% of emergency room visits. [2]  About 29.5 million people 12 and over have AUD in the United States; however, only 7.6% of this population receive treatment.[NIAAA.  AUD in the United States ] This large treatment gap allows clinicians to diagnose a prevalent medical condition with devastating health and societal consequences. 

Although the exact etiology of alcohol use disorder remains unknown, susceptibility to the disorder is likely multifactorial. According to twin and adoption studies, approximately 50% of the liability is genetic, with the remaining 50% attributed to environmental factors. [3]  Neurobiological and epigenetic adaptations likely play a role in the development of AUD, but further research is needed. [4]

• Epidemiology

Alcohol is the most commonly used substance in the United States, with 67.4% of those 18 and older reporting alcohol use in the past year, according to the 2022 National Survey on Drug Use and Health. In terms of risky drinking patterns, 23.5% of those 18 and older reported binge drinking in the past month, and 6.3% reported heavy alcohol use. The prevalence of AUD is estimated to be 29.5 million among those 12 and older as of 2022, and, as of 2019, AUD was the most commonly diagnosed substance use disorder, according to the Substance Abuse and Mental Health Administration.[SAMHA.  Age Groups and Demographic Characteristics ] 

• Pathophysiology

Alcohol use disorder involves a loss of control over the ability to drink moderately. This loss of control results in negative consequences that impact relationships, physical and mental health, and the ability to fulfill role obligations. Alcohol is used in increasing amounts to achieve the same effect, a phenomenon known as tolerance, and its absence results in withdrawal symptoms. Patients with AUD experience intense cravings for alcohol that drive ongoing consumption.

Alcohol causes the release of dopamine in the ventral tegmental area, which is a part of the reward pathway. Alcohol also affects other reward systems, such as the endogenous opioid system, γ-aminobutyric acid (GABAergic) system, glutamate, and serotonin. [5]  The reinforcing effects of alcohol include the ability to induce euphoria and anxiolysis. The fact that not every person who drinks alcohol will necessarily experience a loss of control and progression to addiction indicates that AUD is not solely driven by exposure to alcohol. As mentioned, genetic and environmental susceptibilities are not fully understood.

• History and Physical

The United States Preventive Services Task Force recommends screening adults for unhealthy alcohol use in the primary care setting. This grade B recommendation can be accomplished using either the 1-item Single Alcohol Screening Question (SASQ) or the 3-item Alcohol Use Disorders Identification Test-Consumption. [USPSTF.  Unhealthy Alcohol Use in Adolescents and Adults ] Those who screen positive should be evaluated for AUD using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DMS-V) criteria.

The diagnosis of AUD is established using the criteria in the DSM-V. Two or more criteria indicate mild AUD, 4 to 5 indicate moderate AUD and 6 or more criteria are consistent with severe AUD. These criteria, gleaned from the clinical history and collateral sources, generally assess the impact of alcohol on a patient’s relationships, health, activities (ie, employment), and the ability to moderate their drinking. The 2 criteria to make the diagnosis center around the patient experiencing withdrawal symptoms when not drinking alcohol and tolerance or requiring an increasing amount of alcohol to achieve the same effect.

While the diagnosis of AUD relies primarily on the history, labs may have utility in certain scenarios. The blood alcohol level can be used to evaluate for acute intoxication. To assess for alcohol use in the past 5 days, a serum ethyl glucuronide can be used. The carbohydrate deficient-transferrin can detect alcohol use from the past 2 weeks. The accuracy of the ethyl glucuronide and the CDT is limited by false positives. [1]  The PeTH (phosphatidylethanol) can also be used to detect alcohol use from 3 weeks prior. [6]

Clinicians in the general medical setting should evaluate for sequelae of chronic alcohol use, which are many, given alcohol’s widespread effects on various organ systems. Alcohol causes and worsens many medical conditions, as discussed below.

Gastrointestinal system : Alcohol is well known for its hepatotoxicity, which is reversible with cessation up until the point of cirrhosis. Hepatotoxicity secondary to alcohol use can be detected on liver enzyme testing that may show an elevation in alanine aminotransferase and aspartate aminotransferase as well as gamma-glutamyl transferase. Alcohol can cause alcohol-related hepatitis (formerly alcoholic hepatitis) and present with jaundice, fever, ascites, and leukocytosis. Patients with alcohol-related cirrhosis may exhibit some or all of the classic stigmata, such as spider angiomas, palmar erythema, and ascites, to name a few. Like all patients with cirrhosis, those with alcohol-related cirrhosis should be screened for hepatocellular carcinoma and, if appropriate, esophageal varices. They should also be vaccinated against hepatitis A and B if non-immune. [6]  In addition to liver disease, alcohol can cause both acute and chronic pancreatitis as well as exocrine insufficiency. Finally, alcohol contributes to the development of gastritis and acid reflux.

Hematologic system: Alcohol causes bone marrow suppression, which is reflected in the complete blood count as leukopenia, thrombocytopenia, and anemia. Thrombocythemia may also be driven by underlying liver disease. Macrocytosis with or without anemia may be seen due to deficiencies in B12 and folate.

Neuropsychiatric system:  Chronic alcohol use leading to thiamine deficiency can result in Korsakoff syndrome marked by antero- and retrograde amnesia. Alcohol can also cause peripheral neuropathy of small fibers in a “stocking-glove” distribution. Gait abnormalities may be seen in the presence of thiamine deficiency that affects large fibers. Alcohol can worsen various psychiatric diseases, such as depression, and increase the risk of stroke and dementia.

Cardiovascular system:  Acutely, alcohol can trigger atrial fibrillation. Chronic alcohol use can accelerate coronary artery disease and cause dilated cardiomyopathy. [1]  Alcohol use and withdrawal worsen hypertension.

Oncologic system:  The risk of certain cancers is increased by chronic alcohol use, including breast, esophageal, oral cavity, pharyngeal, liver, colorectal, gastric, and pancreatic. [7]

Endocrine system : Chronic alcohol use impairs bone health, leading to osteoporosis. Through a variety of mechanisms, alcohol can also lead to hypothyroidism.

Pulmonary system:  Alcohol worsens sleep apnea physiology in those with obstructive sleep apnea but also increases the risk of sleep apnea. [8]  The use is also associated with an increase in pulmonary infections such as pneumonia.

Immune system:  Alcohol impairs the function of B and T cells, thereby increasing the risk of both bacterial and viral infection. [9]

• Treatment / Management

The goal of AUD treatment is to reduce alcohol intake or have complete cessation; this includes pharmacotherapy with or without behavioral treatments. Three US Food and Drug Administration (FDA)-cleared medications for AUD are discussed below:

Naltrexone:  Naltrexone is a mu-opioid receptor antagonist that can be taken daily by mouth or as a monthly intramuscular injection administered in the clinic setting. The medication works by inhibiting the pleasurable and reinforcing effects of alcohol that patients experience, such as decreased drinking days and/or drinking amounts. Naltrexone also decreases craving for alcohol and rates of returning to drinking after cessation. [10]  Naltrexone is a first-line medication for AUD and should be considered, barring any contraindications such as concurrent use of opioid agonist medications for pain or opioid use disorder. Naltrexone should be used cautiously and in collaboration with the patient’s hepatologist if used in patients with decompensated cirrhosis.

Acamprosate : Acamprosate is another effective, first-line medication for alcohol use disorder. However, the 2 tablets 3 times a day dosing increases the pill burden and may be difficult for patients to take consistently. [11]  The medication cannot be used in renal failure and requires dose reduction in renal insufficiency. Acamprosate’s mechanism of action is unknown but likely modulates the GABAergic system. Ideally, the medication is started after a patient is abstinent from alcohol.  

Disulfiram:   The third FDA-approved medication for AUD, disulfiram, is an aversive therapy that causes an unpleasant reaction when alcohol is ingested. Mechanistically, the medication inhibits the enzyme acetaldehyde dehydrogenase, which causes an accumulation of acetaldehyde. Acetaldehyde causes the disulfiram reaction, including flushing, nausea, vomiting, tachycardia, palpitations, and diaphoresis. Because of the cardiac stress a disulfiram reaction induces, the medication should be avoided in those with significant cardiac disease. Treatment with disulfiram is best suited to those with a support person who can help administer or observe the patient taking the medication. After starting disulfiram, liver enzymes should be checked in the following weeks as it rarely can cause idiopathic hepatitis. [1]  For this reason, disulfiram should also be avoided in patients with hepatic impairment. 

Additional medications for alcohol use disorder:  Though not FDA-approved to treat AUD, medications such as gabapentin, topiramate, or baclofen may be used in the treatment of AUD. Generally, these medications have less robust evidence and outcomes supporting their efficacy in treating AUD. When using gabapentin to treat AUD, the optimal dosing for gabapentin is 600 mg 3 times daily. [12]  Due to the adverse event profile, topiramate use for AUD is limited. [13]

Behavioral treatment:  Multiple behavioral treatment options exist for patients with AUD; however, they should not be pursued at the exclusion of pharmacotherapy. Behavioral treatment may occur in various settings, from inpatient rehabilitation to outpatient individual therapy. Various types of group options exist, including intensive outpatient treatment or self-help groups such as Alcoholics Anonymous or SMART Recovery. 

• Differential Diagnosis

Various psychiatric conditions may present with unhealthy alcohol use; therefore, clinicians must screen for the following:

• Posttraumatic stress disorder
• Bipolar disorder
• Panic disorder
• Anxiety disorder
• Dysthymic disorder
• Major depression

AUD is a chronic condition where the prognosis is variable. In some, the course follows a relapsing-remitting course, while others are abstinent without participating in formal treatment. Factors that increase the risk of relapse include psychiatric comorbidities and other substance use disorders. [14]

• Complications

Alcohol use disorder can contribute to a host of complications as listed below:

• Accidental injuries (falls, car accidents, etc)
• Non-accidental injuries
• Malignancy (oropharyngeal, esophageal, gastric, breast, colorectal, hepatocellular, pancreatic)
• Periodontal disease
• Nutritional deficiencies
• Gastroesophageal reflux disorder
• Mallory-Weiss tears
• Delayed gastric emptying
• Acute and chronic pancreatitis
• Exocrine pancreatic insufficiency
• Upper gastrointestinal bleeds
• Coronary artery disease
• Atrial fibrillation
• Dilated cardiomyopathy
• Hypertension
• Immunosuppression
• Sleep apnea
• Bacterial pneumonia
• Malabsorption
• Sexually transmitted infections
• Wernicke-Korsakoff syndrome
• Hypothyroidism
• Osteoporosis
• Megaloblastic and sideroblastic anemia
• Thrombocytopenia
• Acute alcohol-related hepatitis [9]
• Deterrence and Patient Education

The key points of education for patients are as follows:

• Patients and their families must understand that AUD is a chronic medical condition where evidence-based treatments are available. 
• Patients and their clinicians should develop a treatment plan through shared decision-making, which may include pharmacotherapy and behavioral therapy.
• Goal setting may include abstinence or reduction in drinking.
• Education should be provided regarding the negative impact of alcohol on various organ systems.
• Pearls and Other Issues

The key points include the following:

• Evidence-based pharmacotherapy for patients with AUD should be offered and may be paired with behavioral therapies.
• Addressing the health consequences of alcohol use is important, such as for patients with liver disease, hypertension, or neuropathy.
• The Centers for Disease Control and Prevention recommend vaccinating people with AUD against pneumococcal disease.
• Enhancing Healthcare Team Outcomes

Treating patients with AUD requires the full complement of skills of the interdisciplinary team both in the inpatient and outpatient settings. In the inpatient setting, interdisciplinary collaboration improves care for patients with AUD and can potentially improve outcomes. [15]  A model for this type of collaboration exists in the United Kingdom where patients are treated by “Alcohol Care Teams” comprised of multiple specialties and healthcare professions. [16]  In the United States, addiction care is integrated into hepatology clinics utilizing social workers, psychiatrists, therapists, and hepatologists. [17]  Such collaborations improve various outcomes, including hepatic screening, vaccination rates for hepatitis, and treatment for AUD. [18]

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Disclosure: Sara Nehring declares no relevant financial relationships with ineligible companies.

Disclosure: Richard Chen declares no relevant financial relationships with ineligible companies.

Disclosure: Andrew Freeman declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Nehring SM, Chen RJ, Freeman AM. Alcohol Use Disorder. [Updated 2024 Mar 16]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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• Introduction
• Conclusions
• Article Information

Multiple comparisons within publications are presented separately.

“Overall” refers to pooled estimate for all forms of naltrexone (50 mg/d oral, 100 mg/d oral, and injection).

Heavy drinking is defined as ≥4 drinks/d for women and ≥5 drinks/d for men. Multiple comparisons within publications are presented separately.

“Overall” refers to pooled estimate for all forms of naltrexone (50 mg/d oral, 100 mg/d oral, and injection). Heavy drinking is defined as ≥4 drinks/d for women and ≥5 drinks/d for men.

IE indicates insufficient evidence; NA, not assessed. This figure includes all drugs with a rating of at least low strength of evidence for adverse events for at least 1 outcome. All doses of naltrexone were assessed together.

eTable 1. Definitions of Unhealthy Alcohol Use (Sometimes Previously Referred to as Alcohol Misuse)

eTable 2. Medications That Are FDA Approved for Treating Adults With Alcohol Dependence

eTable 3. Questions for the Full Technical Report and This Manuscript

eTable 4. Characteristics of Included Studies

eTable 5. Summary of Findings and Strength of Evidence for Efficacy of Medications Used Off-Label or Those Under Investigation

eAppendix. Reference List for Figures 2 Through 5

eReferences

Data Sharing Statement

• Pharmacotherapy for Alcohol Use Disorder—Reply JAMA Comment & Response March 5, 2024 Melissa McPheeters, PhD, MPH; Elizabeth A. O’Connor, PhD; Daniel E. Jonas, MD, MPH
• Pharmacotherapy for Alcohol Use Disorder JAMA Comment & Response March 5, 2024 Wenming Shi, MSc
• Does This Patient Have Alcohol Use Disorder? JAMA The Rational Clinical Examination April 9, 2024 This Rational Clinical Examination systematic review summarizes studies that examined the diagnostic accuracy of brief screening tools to identify individuals with alcohol use disorder. Evan Wood, MD, PhD; Jeffrey Pan, PharmD; Zishan Cui, PhD; Paxton Bach, MD; Brittany Dennis, MD, PhD; Seonaid Nolan, MD; M. Eugenia Socias, MD, MSc
• Error in Byline JAMA Correction October 22, 2024

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McPheeters M , O’Connor EA , Riley S, et al. Pharmacotherapy for Alcohol Use Disorder : A Systematic Review and Meta-Analysis . JAMA. 2023;330(17):1653–1665. doi:10.1001/jama.2023.19761

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Pharmacotherapy for Alcohol Use Disorder : A Systematic Review and Meta-Analysis

• 1 RTI International–University of North Carolina at Chapel Hill Evidence-Based Practice Center, Chapel Hill
• 2 RTI International, Research Triangle Park, North Carolina
• 3 Center for Health Research, Kaiser Permanente, Portland, Oregon
• 4 Department of Internal Medicine, The Ohio State University, Columbus
• 5 College of Pharmacy, The Ohio State University, Columbus
• Comment & Response Pharmacotherapy for Alcohol Use Disorder—Reply Melissa McPheeters, PhD, MPH; Elizabeth A. O’Connor, PhD; Daniel E. Jonas, MD, MPH JAMA
• Comment & Response Pharmacotherapy for Alcohol Use Disorder Wenming Shi, MSc JAMA
• The Rational Clinical Examination Does This Patient Have Alcohol Use Disorder? Evan Wood, MD, PhD; Jeffrey Pan, PharmD; Zishan Cui, PhD; Paxton Bach, MD; Brittany Dennis, MD, PhD; Seonaid Nolan, MD; M. Eugenia Socias, MD, MSc JAMA
• Correction Error in Byline JAMA

Question   Which pharmacotherapies are associated with improved outcomes for people with alcohol use disorder?

Findings   In this systematic review and meta-analysis that included 118 clinical trials and 20 976 participants, 50 mg/d of oral naltrexone and acamprosate were each associated with significantly improved alcohol consumption-related outcomes compared with placebo.

Meaning   These findings support oral naltrexone at 50 mg/d and acamprosate as first-line therapies for alcohol use disorder.

Importance   Alcohol use disorder affects more than 28.3 million people in the United States and is associated with increased rates of morbidity and mortality.

Objective   To compare efficacy and comparative efficacy of therapies for alcohol use disorder.

Data Sources   PubMed, the Cochrane Library, the Cochrane Central Trials Registry, PsycINFO, CINAHL, and EMBASE were searched from November 2012 to September 9, 2022 Literature was subsequently systematically monitored to identify relevant articles up to August 14, 2023, and the PubMed search was updated on August 14, 2023.

Study Selection   For efficacy outcomes, randomized clinical trials of at least 12 weeks’ duration were included. For adverse effects, randomized clinical trials and prospective cohort studies that compared drug therapies and reported health outcomes or harms were included.

Data Extraction and Synthesis   Two reviewers evaluated each study, assessed risk of bias, and graded strength of evidence. Meta-analyses used random-effects models. Numbers needed to treat were calculated for medications with at least moderate strength of evidence for benefit.

Main Outcomes and Measures   The primary outcome was alcohol consumption. Secondary outcomes were motor vehicle crashes, injuries, quality of life, function, mortality, and harms.

Results   Data from 118 clinical trials and 20 976 participants were included. The numbers needed to treat to prevent 1 person from returning to any drinking were 11 (95% CI, 1-32) for acamprosate and 18 (95% CI, 4-32) for oral naltrexone at a dose of 50 mg/d. Compared with placebo, oral naltrexone (50 mg/d) was associated with lower rates of return to heavy drinking, with a number needed to treat of 11 (95% CI, 5-41). Injectable naltrexone was associated with fewer drinking days over the 30-day treatment period (weighted mean difference, −4.99 days; 95% CI, −9.49 to −0.49 days) Adverse effects included higher gastrointestinal distress for acamprosate (diarrhea: risk ratio, 1.58; 95% CI, 1.27-1.97) and naltrexone (nausea: risk ratio, 1.73; 95% CI, 1.51-1.98; vomiting: risk ratio, 1.53; 95% CI, 1.23-1.91) compared with placebo.

Conclusions and Relevance   In conjunction with psychosocial interventions, these findings support the use of oral naltrexone at 50 mg/d and acamprosate as first-line pharmacotherapies for alcohol use disorder.

Unhealthy alcohol use is the third leading preventable cause of death in the United States, accounting for 145 000 deaths annually. 1 Data from the 2020 National Survey on Drug Use and Health suggested that more than 28.3 million people aged 12 years or older in the United States met Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) ( DSM-5 ) criteria for alcohol use disorder (eTable 1 in Supplement 1 ) in the past year. 2 , 3 The COVID-19 pandemic may have been associated with increased numbers of people with alcohol use disorder. 2 , 3 Among the 29.5 million people reporting a past-year alcohol use disorder in 2021, an estimated 0.9%, or 265 000 people, received pharmacotherapy for alcohol use disorder. 4

This systematic review and meta-analysis evaluated efficacy and comparative efficacy of 9 therapies for alcohol use disorder that are either approved by the US Food and Drug Administration (FDA) (eTable 2 in Supplement 1 ) or more commonly used in the United States for alcohol use disorder.

The protocol was registered with PROSPERO (CRD42022324376). A full technical report that addressed 5 questions (eTable 3 in Supplement 1 ) details methods, search strategies, and additional information.

PubMed, the Cochrane Library, the Cochrane Central Trials Registry, PsycINFO, CINAHL, and EMBASE were searched for English-language studies of adults aged 18 years or older from November 1, 2012, to September 9, 2022; eligible articles published before these searches were obtained from a previously published (2014) systematic review on this topic. 5 , 6 A librarian (C.V.) performed all searches. A second librarian peer-reviewed the searches using the validated Peer Review of Electronic Search Strategies (PRESS) checklist. 7 Reference lists of pertinent reviews and trials were manually searched for additional relevant citations. After September 9, 2022, an ongoing systematic monitoring of the literature was conducted through article alerts. An updated search of PubMed was conducted on August 14, 2023, to identify studies published since that may affect the conclusions or understanding of the evidence; those searches did not identify new studies for inclusion.

Studies that enrolled adults with alcohol use disorder and evaluated an FDA-approved medication (acamprosate, disulfiram, or naltrexone) or any of 6 off-label medications (baclofen, gabapentin, varenicline, topiramate, prazosin, and ondansetron) for at least 12 weeks of treatment in an outpatient setting were eligible for inclusion. Quiz Ref ID Twelve weeks of treatment were required because longitudinal studies reported that shorter treatment may yield misleading conclusions about efficacy due to fluctuations in drinking behavior. Eligible studies were required to assess 1 of the following outcomes: (1) alcohol consumption, consisting of return to any drinking, return to heavy drinking, percentage of drinking days, percentage of heavy drinking days (≥4 drinks per day for women; ≥5 drinks per day for men), or number of drinks per drinking day; (2) health outcomes—motor vehicle crashes, injuries, quality of life, function, or mortality; or (3) adverse events.

For efficacy outcomes, double-blind randomized clinical trials (RCTs) that compared 1 of the FDA-approved or off-label medications listed above with placebo or with another medication were eligible for inclusion. For adverse effects, in addition to the double-blind RCTs included for efficacy, studies with the following designs were eligible if they compared 2 drugs of interest: nonrandomized or open-label trials, subgroup analyses from trials, prospective cohort studies, and case-control studies. Nonrandomized and observational studies were included to address harms because RCTs had insufficient sample sizes and duration to identify rare harms.

Two investigators independently reviewed each title and abstract. Studies marked for possible inclusion by either reviewer underwent independent full-text review by 2 reviewers. If the reviewers disagreed, they resolved conflicts by discussion and consensus or by consulting a third, senior member of the team.

Structured data extraction forms were used to gather relevant data from each article. At least 2 investigators reviewed all data extractions for completeness and accuracy.

To assess the risk of bias of studies, the investigators used predefined criteria based on established guidance. 8 - 10 The studies were rated as having low, medium, high, or unclear risk of bias. 8 , 9 Questions were included about adequacy of randomization, allocation concealment, similarity of groups at baseline, masking, attrition, validity and reliability of measures, approaches to analyses, and methods of handling missing data. Two independent reviewers assessed risk of bias for each study. Disagreements were resolved by consensus.

The strength of evidence was graded as high, moderate, low, or insufficient based on established guidance. 11 The approach incorporated 4 key domains: risk of bias, consistency, directness, and precision. Two reviewers assessed each domain for each outcome and determined an overall grade. Differences were resolved by consensus.

In these analyses, results are presented for medications for which there was at least low strength of evidence for benefit for some outcomes.

The primary outcome was alcohol consumption, defined as any alcohol use, return to heavy drinking, and number of drinks per week. Meta-analyses of RCTs were performed using random-effects models. 12 We used the DerSimonian and Laird estimator for our primary analyses, with sensitivity analyses using a restricted maximum likelihood model when the pooled effects were statistically significant. For continuous outcomes, weighted mean differences (WMDs) and 95% CIs were calculated. For binary outcomes, risk ratios (RRs) between groups and 95% CIs were calculated. The I 2 statistic was calculated to assess statistical heterogeneity. 13 , 14 Potential sources of heterogeneity were examined by analyzing subgroups defined by patient population (eg, US vs non-US studies). Analyses were conducted using Stata version BE-17 (StataCorp). Statistical significance was assumed when 95% CIs of pooled results did not cross 0. All testing was 2-sided. Numbers needed to treat were calculated when pooled RRs for binary outcomes found a statistically significant result and there was at least moderate strength of evidence for benefit. When quantitative synthesis was not appropriate (eg, <2 similar studies), the data were synthesized qualitatively.

The database search identified 2860 citations, and 2543 citations were excluded during title and abstract review. Of 317 full-text articles included after title and abstract review, 267 were excluded, leaving 156 articles that described results of 118 RCTs ( Figure 1 ). Of these, 81 RCTs (106 articles) were included in the 2014 systematic review on this topic, 5 and 37 RCTs (50 articles) were new. No observational studies providing data on adverse effects were identified, and therefore all data on adverse events were obtained from RCTs.

Characteristics of the 37 RCTs that were new since 2104 are shown in eTable 4 in Supplement 1 . Sample sizes ranged from 12 to 921. Treatment duration ranged from 12 to 52 weeks. All participants met criteria for alcohol dependence in 103 of 118 of the clinical trials. Recruitment methods varied and included treatment programs, advertisements, referrals, or a combination. Eighty-seven (73.7%) of 118 studies included psychosocial co-interventions. For these studies, effect sizes reflect the benefits of medications added to psychosocial interventions compared with placebo added to psychosocial interventions. Of 23 studies that assessed efficacy of acamprosate, 16 were conducted in Europe and 4 were conducted in the United States. Of 49 studies of naltrexone, 32 were conducted in the United States and 8 were conducted in Europe. Of the 118 included studies, 100 included a co-intervention such as medical management, specific harm reduction, or counseling approaches.

Three medications (ondansetron, varenicline, and prazosin) had either low strength of evidence suggesting benefit or insufficient evidence and are not further discussed (eTable 5 in Supplement 1 ).

Quiz Ref ID Among the medications with an FDA indication for alcohol use disorder, acamprosate and naltrexone were associated with statistically significant improvement in alcohol consumption outcomes ( Table , Figure 2 , Figure 3 , Figure 4 , Figure 5 , and Figure 6 ; eAppendix in Supplement 1 ). 15 - 66 Compared with placebo, numbers needed to treat to prevent 1 person from returning to any drinking were 11 (95% CI, 1-32; 20 trials; n = 6380) for acamprosate and 18 (95% CI, 4-32; 16 trials; n = 2347) for oral naltrexone (50 mg/d), respectively. There was no significant difference in return to heavy drinking between acamprosate and placebo (RR, 0.99; 95% CI, 0.94-1.05; P  = .69; range, 41.9%-81.5% with acamprosate, 45.8%-82.9% with placebo). Compared with placebo, oral naltrexone (50 mg/d) was associated with a statistically significant improvement in return to heavy drinking (RR, 0.81; 95% CI, 0.72-0.90; P  < .001; range, 14.3%-94.6% with naltrexone, 29.7%-93.5% with placebo) with a number needed to treat of 11 (95% CI, 5-41; 19 trials; n = 2875). Compared with placebo, injectable naltrexone was not associated with lower rates of return to any drinking (RR, 0.96; 95% CI, 0.90-1.03; P  = .14; 2 trials; n = 939; range, 82.3%-93.5% with naltrexone, 89.8%-94.7% with placebo) or return to heavy drinking (RR, 1.00; 95% CI, 0.82-1.21; P  = .09; 2 trials; n = 615; range, 59.2%-77.2% with naltrexone, 52.7%-84.1% with placebo). Compared with placebo, injectable naltrexone was associated with greater reduction in percentage of drinking days (WMD, −4.99; 95% CI, −9.49 to −0.49; P  = .23; 2 trials; n = 467) and percentage of heavy drinking days (WMD, −4.7; 95% CI, −8.6 to −0.73; P  = .80; 3 trials; n = 956). Data from 3 RCTs that included 622 participants did not show an association of disulfiram compared with placebo for preventing return to any drinking (RR, 1.03; 95% CI, 0.90-1.17; P  = .28; range, 22.7%-81.2% with disulfiram, 34.4%-88.1% with placebo) ( Table ).

Among medications without an FDA indication for alcohol use disorder treatment, compared with placebo, topiramate was associated with statistically significant improvement in the weighted mean of absolute percentage of drinking days (WMD, −7.2; 95% CI, −14.3 to −0.1; P  = .14; range, 5.5%-62.4% with topiramate, 6.4%-70.9%), percentage of heavy drinking days (WMD, −6.2; 95% CI, −10.9 to −1.4; P  = .32; range, 2.3%-43.8% with topiramate, 5.3%-51.8% with placebo), and number of drinks per drinking day (WMD, −2.0; 95% CI, −3.1 to −1.0; P  = .19; range, 1.2-6.5 with topiramate, 4.0-8.8 with placebo). These findings were associated with moderate strength of evidence. Of 13 double-blind placebo-controlled RCTs that included 1607 participants, compared with placebo, baclofen was associated with significantly lower rates of return to any drinking (RR, 0.83; 95% CI, 0.70-0.98; P  < .001; range, 28.6%-92.4% with baclofen, 53.2%-89.9% with placebo). Because of imprecision of the effect estimate and inconsistency of results, baclofen data were graded as having low strength of evidence. Compared with placebo, gabapentin was not significantly associated with lower rates of return to any drinking (RR, 0.92; 95% CI, 0.83-1.02: P  = .08; range, 79.5-86.1 with gabapentin, 88.2-95.9 with placebo) or with significant reduction in return to heavy drinking (RR, 0.90; 95% CI, 0.82-0.98; P  = .75; range, 63.4-75.9 with gabapentin, 77.6-87.0 with placebo), but both results had low strength of evidence and only 3 clinical trials reported these outcomes.

A meta-analysis of 4 RCTs including 1141 participants that directly compared acamprosate with naltrexone 19 , 37 , 45 , 48 found no statistically significant difference between the 2 medications for improvement in alcohol use outcomes consisting of return to any drinking (RR, 1.03; 95% CI, 0.96-1.10; P  = .57; range, 75.0-80.5 with acamprosate, 65.0-83.0 with naltrexone; 3 trials; n = 800) or return to heavy drinking (RR, 1.02; 95% CI, 0.93-1.11; P  = .65; range, 50.0-72.7 with acamprosate, 50.9-73.6 with naltrexone; 4 trials; n = 1141).

Quiz Ref ID There was insufficient evidence from RCTs to assess whether treatment with most medications was associated with improved health outcomes. Outcomes such as motor vehicle crashes, injuries, quality of life, function, and mortality were infrequently reported in the included studies ( Table ).

Adverse event data were often not collected using standardized measures, and methods for systematically capturing adverse events were often not reported ( Figure 7 ).

Among medications with at least some (low) strength of evidence for benefit in any outcome, compared with placebo, dizziness was the most common mild adverse effect across medications and was reported with naltrexone (RR, 1.99; 95% CI, 1.47-2.69; P  = .37; range, 2.9%-34.8% with naltrexone, 0.0%-20.6% with placebo), baclofen (RR, 1.89; 95% CI, 1.40-2.55; P  = .40; range, 4.8%-30.2% with baclofen, 0.0%-22.8% with placebo), topiramate (RR, 2.29; 95% CI, 1.39-3.78; P  = .65; range, 0.0%-28.0% with topiramate, 1.9%-10.7% with placebo), and gabapentin (RR, 1.70; 95% CI, 1.24-2.32; P  = .83; range, 6.5%-7.8% with gabapentin, 3.8%-6.0% with placebo). Compared with placebo, any gastrointestinal distress was more common for acamprosate (diarrhea: RR, 1.58; 95% CI, 1.27-1.97; P  = .03; range, 3.0%-63.7% with acamprosate, 1.6%-64.9% with placebo) and naltrexone (nausea: RR, 1.73; 95% CI, 1.51-1.98; P  = .19; range, 2.5%-57.6% with naltrexone, 0.0%-47.1% with placebo; vomiting: RR, 1.53; 95% CI, 1.23-1.91; P  = .79; range, 0.0%-25.6% with naltrexone, 0.0%-23.4% with placebo). Compared with placebo, baclofen was associated with higher rates of drowsiness (RR, 1.46; 95% CI, 1.15-1.86; P  = .28; range, 6.3%-50.0% with baclofen, 9.4%-32.6% with placebo), numbness (RR, 7.78; 95% CI, 1.42-42.56; P  = .48; range, 7.1%-12.6% with baclofen, 0.0%-1.1% with placebo), and sleepiness (RR, 1.81; 95% CI, 1.11-2.97; P  = .77; range, 2.4%-36.2% with baclofen, 0.0%-17.7% with placebo). Compared with placebo, topiramate was associated with higher risks of many adverse events, including paresthesias (RR, 3.08; 95% CI, 2.11-4.49; P  = .06; range, 0.0%-57.3% with topiramate, 1.9%-29.4% with placebo), taste abnormalities (RR, 3.01; 95% CI, 1.70-5.34; P  = .04; range, 15.1%-53.3% with topiramate, 4.8%-31.3% with placebo), and cognitive dysfunction (RR, 2.37; 95% CI, 1.58-3.55; P  = .48; range, 12.6%-23.9% with topiramate, 5.4%-11.3% with placebo). Compared with placebo, gabapentin was associated with cognitive dysfunction (RR, 2.76; 95% CI, 1.51-5.06; P  = .37; range, 5.9%-25.5% with gabapentin, 5.7%-17% with placebo) and dizziness (RR, 1.70; 95% CI, 1.24-2.32; P  = .83; range, 21.2%-56.8% with gabapentin, 13.7%-32.6% with placebo). In direct comparisons of acamprosate and oral naltrexone in RCTs, patients treated with acamprosate had lower rates of nausea (RR, 0.56; 95% CI, 0.35-0.88; P  = .11; range, 3.8%-23.8% with acamprosate, 2.5%-55.6% with naltrexone) and vomiting (RR, 0.60; 95% CI, 0.39-0.93; P  = .88; range, 8.9%-11.1% with acamprosate, 14.6%-22.2% with naltrexone) compared with those treated with naltrexone.

In this systematic review and meta-analysis that included 118 clinical trials, the highest strength of evidence for treatment of alcohol use disorder was available for acamprosate and oral naltrexone (50 mg/d). Randomized clinical trials that directly compared naltrexone, 50 mg/d, with acamprosate did not consistently established superiority of either medication. Studies of naltrexone had moderate strength of evidence for reducing return to any drinking, return to heavy drinking, percentage of drinking days, and percentage of heavy drinking days at the 50-mg/d oral dose compared with placebo. Fewer data were available for the 100-mg/d oral and injectable doses. Studies of acamprosate showed moderate strength of evidence for significant reduction in return to any drinking and reduction in drinking days compared with placebo. Acamprosate was not associated with benefit for return to heavy drinking (moderate strength of evidence).

Oral naltrexone is more convenient than acamprosate, requiring a single daily dose, whereas acamprosate is typically prescribed as 2 tablets administered 3 times daily. Acamprosate is contraindicated for people with severe kidney impairment and requires dose adjustments for moderate kidney impairment. Oral naltrexone is contraindicated for patients with acute hepatitis or liver failure and for those using opioids or who have anticipated need for opioids. Naltrexone can precipitate severe withdrawal for patients dependent on opioid medications.

Disulfiram has been FDA approved for alcohol use disorder since the 1950s. However, relatively limited evidence exists to support the efficacy of disulfiram compared with placebo for preventing return to any drinking or other alcohol consumption outcomes. Four RCTs of disulfiram have been published that were not eligible for this review because of their trial designs and comparisons. 67 - 70 These small trials (with 15 or fewer disulfiram-treated patients in each) had limitations that included a small sample size and inability to distinguish between benefits from disulfiram and benefits of counseling or benefits from therapeutic relationships with the investigative team. 71 , 72

Among medications without FDA approval for alcohol use disorder, studies of topiramate compared with placebo had moderate strength of evidence for significant reductions in percentage of drinking days, percentage of heavy drinking days, and drinks per drinking days. However, topiramate was associated with adverse effects that included cognitive dysfunction, dizziness, numbness and/or tingling, and taste abnormalities. Studies of baclofen and gabapentin had low strength of evidence for benefit in at least 1 outcome. Evidence was largely insufficient or low for benefit on health outcomes, including quality of life, motor vehicle crashes, and mortality.

Alcohol use disorder is associated with numerous health problems, including but not limited to hypertension, heart disease, stroke, cognitive impairment, sleep problems, depression, anxiety, peripheral neuropathy, gastritis and gastric ulcers, liver disease including cirrhosis, pancreatitis, osteoporosis, anemia, fetal alcohol spectrum disorders, and several types of cancer. 73 , 74 Excessive alcohol consumption is also associated with higher rates of homicide, suicide, motor vehicle crashes and deaths, sexual violence, domestic violence, and drownings. 75

Using DSM-5 criteria, most participants in the included studies likely had moderate to severe alcohol use disorder. Thus, applicability of the findings to people with mild alcohol use disorder is uncertain. The mean age of participants was typically between 40 and 49 years, with only 21 studies enrolling younger or older populations. Thus, it is uncertain whether the medications have similar efficacy for older (eg, aged ≥65 years) or younger (eg, aged in their 20s) people. Of the 70 studies that provided data on race and sex, most (n = 63) included a majority of White male participants, and none specified sex other than male or female. Because 100 of 118 clinical trials studied drug therapy combined with a nonmedication treatment (such as counseling), results reflect benefits from a combination of medication and cotherapy compared with placebo and cotherapy.

Of the 5 studies of acamprosate that were conducted in the United States, most reported no significant benefit either for return to any drinking or return to heavy drinking. Clinical trials conducted in the United States recruited patients largely through advertisements, while 15 of 22 clinical trials in other countries recruited participants from inpatient settings, where patients may have undergone alcohol withdrawal and medications may have been initiated before discharge. Patients recruited in the clinical trials conducted in the United States may have represented a more general population with a larger range of alcohol use at baseline. Thus, the lack of efficacy in US-based trials for acamprosate may reflect differences in patient characteristics and differences in the health care systems compared with clinical trials from other countries.

Most studies required patients to abstain for at least a few days before initiating medication, and the medications were generally recommended for maintenance of abstinence. Acamprosate and injectable naltrexone are FDA approved only for use in patients who have established abstinence, although the duration of required abstinence is not established. Three studies enrolling patients who were not yet abstinent reported reduction in heavy drinking with naltrexone compared with placebo 30 , 76 or acamprosate compared with placebo. 33

This review has several limitations. First, clinical trials with less than 12 weeks of follow-up from the time of medication initiation were excluded. Second, the meta-analysis combined studies of participants with diagnoses of both alcohol dependence and depression and studies of participants without both alcohol dependence and depression. Third, studies may have selectively reported outcomes. Fourth, long-term information about adverse effects was not available. Fifth, for adverse event outcomes, due to small sample sizes and relatively small numbers of events, evidence was often insufficient to determine whether adverse event outcomes were increased. Sixth, in some included studies, less than 100% of participants had alcohol use disorder. Specifically, 3 studies reported that less than 90% of participants had alcohol use disorder. 24 , 77 , 78

In conjunction with psychosocial interventions, these findings support the use of oral naltrexone, 50 mg/d, and acamprosate as first-line pharmacotherapies for alcohol use disorder.

Corresponding Author: Melissa McPheeters, PhD, MPH, RTI International, 3040 E Cornwallis Rd, Research Triangle Park, NC 27709 ( [email protected] ).

Accepted for Publication: September 12, 2023.

Author Contributions: Dr McPheeters had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: McPheeters, O’Connor, Edlund, Bobashev, Jonas.

Acquisition, analysis, or interpretation of data: McPheeters, O’Connor, Riley, Kennedy, Voisin, Kuznacic, Coffey, Bobashev, Jonas.

Drafting of the manuscript: McPheeters, O’Connor, Riley, Kennedy, Kuznacic, Coffey, Jonas.

Critical review of the manuscript for important intellectual content: McPheeters, O’Connor, Voisin, Edlund, Bobashev, Jonas.

Statistical analysis: McPheeters, O’Connor, Riley, Jonas.

Obtained funding: McPheeters, Jonas.

Administrative, technical, or material support: Kennedy, Voisin, Bobashev, Jonas.

Supervision: McPheeters, Jonas.

Conflict of Interest Disclosures: None reported.

Funding/Support: This project was funded under contract 75Q80120D00007, task order 75Q80122F32004 from the Agency for Healthcare Research and Quality (AHRQ) of the US Department of Health and Human Services.

Role of the Funder/Sponsor: This topic was nominated by the AHRQ program official for EvidenceNow: Managing Unhealthy Alcohol Use Initiative and selected by AHRQ for systematic review by an evidence-based practice center. A representative from AHRQ served as a contracting officer’s representative and provide technical assistance during the conduct of the full evidence report and provided comments on draft versions of the full evidence report. AHRQ did not directly participate in the literature search, determination of study eligibility criteria, data analysis or interpretation, or preparation, review, or approval of the manuscript for publication.

Disclaimer: The authors of this article are responsible for its content. Statements in the article do not necessarily represent the official views of or imply endorsement by AHRQ or the US Department of Health and Human Services. AHRQ retains a license to display, reproduce, and distribute the data and the report from which this manuscript was derived under the terms of the agency’s contract with the author.

Data Sharing Statement: See Supplement 2 .

Additional Contributions: We gratefully acknowledge the following individuals for their contributions to this project, none of whom received compensation: from AHRQ: Meghan Wagner, PharmD, AHRQ Task Order Officer Elisabeth Kato, MD, MRP, and Cleo Alford, MPS, MSc; from the American Psychiatric Association: Laura Fochtmann, MD, and Jennifer Medicus; from the American Society of Addiction Medicine: Anna Pagano, PhD, and Ray Denny, PhD; from RTI International–University of North Carolina at Chapel Hill Evidence-Based Practice Center (for administrative support, review, and/or editing): Roberta Wines, MPH, Carol Woodell, BSPH, Nila Sathe, MA, MLIS, Sharon Barrell, MA, Mary Gendron, and Teyonna Downing.

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• Published: 13 November 2019

Evidence-based models of care for the treatment of alcohol use disorder in primary health care settings: protocol for systematic review

• Susan A. Rombouts 1 ,
• James Conigrave 2 ,
• Eva Louie 1 ,
• Paul Haber 1 , 3 &
• Kirsten C. Morley   ORCID: orcid.org/0000-0002-0868-9928 1  

Systematic Reviews volume  8 , Article number:  275 ( 2019 ) Cite this article

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Metrics details

Alcohol use disorder (AUD) is highly prevalent and accounts globally for 1.6% of disability-adjusted life years (DALYs) among females and 6.0% of DALYs among males. Effective treatments for AUDs are available but are not commonly practiced in primary health care. Furthermore, referral to specialized care is often not successful and patients that do seek treatment are likely to have developed more severe dependence. A more cost-efficient health care model is to treat less severe AUD in a primary care setting before the onset of greater dependence severity. Few models of care for the management of AUD in primary health care have been developed and with limited implementation. This proposed systematic review will synthesize and evaluate differential models of care for the management of AUD in primary health care settings.

We will conduct a systematic review to synthesize studies that evaluate the effectiveness of models of care in the treatment of AUD in primary health care. A comprehensive search approach will be conducted using the following databases; MEDLINE (1946 to present), PsycINFO (1806 to present), Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL) (1991 to present), and Embase (1947 to present).

Reference searches of relevant reviews and articles will be conducted. Similarly, a gray literature search will be done with the help of Google and the gray matter tool which is a checklist of health-related sites organized by topic. Two researchers will independently review all titles and abstracts followed by full-text review for inclusion. The planned method of extracting data from articles and the critical appraisal will also be done in duplicate. For the critical appraisal, the Cochrane risk of bias tool 2.0 will be used.

This systematic review and meta-analysis aims to guide improvement of design and implementation of evidence-based models of care for the treatment of alcohol use disorder in primary health care settings. The evidence will define which models are most promising and will guide further research.

Protocol registration number

PROSPERO CRD42019120293.

Peer Review reports

It is well recognized that alcohol use disorders (AUD) have a damaging impact on the health of the population. According to the World Health Organization (WHO), 5.3% of all global deaths were attributable to alcohol consumption in 2016 [ 1 ]. The 2016 Global Burden of Disease Study reported that alcohol use led to 1.6% (95% uncertainty interval [UI] 1.4–2.0) of total DALYs globally among females and 6.0% (5.4–6.7) among males, resulting in alcohol use being the seventh leading risk factor for both premature death and disability-adjusted life years (DALYs) [ 2 ]. Among people aged 15–49 years, alcohol use was the leading risk factor for mortality and disability with 8.9% (95% UI 7.8–9.9) of all attributable DALYs for men and 2.3% (2.0–2.6) for women [ 2 ]. AUD has been linked to many physical and mental health complications, such as coronary heart disease, liver cirrhosis, a variety of cancers, depression, anxiety, and dementia [ 2 , 3 ]. Despite the high morbidity and mortality rate associated with hazardous alcohol use, the global prevalence of alcohol use disorders among persons aged above 15 years in 2016 was stated to be 5.1% (2.5% considered as harmful use and 2.6% as severe AUD), with the highest prevalence in the European and American region (8.8% and 8.2%, respectively) [ 1 ].

Effective and safe treatment for AUD is available through psychosocial and/or pharmacological interventions yet is not often received and is not commonly practiced in primary health care. While a recent European study reported 8.7% prevalence of alcohol dependence in primary health care populations [ 4 ], the vast majority of patients do not receive the professional treatment needed, with only 1 in 5 patients with alcohol dependence receiving any formal treatment [ 4 ]. In Australia, it is estimated that only 3% of individuals with AUD receive approved pharmacotherapy for the disorder [ 5 , 6 ]. Recognition of AUD in general practice uncommonly leads to treatment before severe medical and social disintegration [ 7 ]. Referral to specialized care is often not successful, and those patients that do seek treatment are likely to have more severe dependence with higher levels of alcohol use and concurrent mental and physical comorbidity [ 4 ].

Identifying and treating early stage AUDs in primary care settings can prevent condition worsening. This may reduce the need for more complex and more expensive specialized care. The high prevalence of AUD in primary health care and the chronic relapsing character of AUD make primary care a suitable and important location for implementing evidence-based interventions. Successful implementation of treatment models requires overcoming multiple barriers. Qualitative studies have identified several of those barriers such as limited time, limited organizational capacity, fear of losing patients, and physicians feeling incompetent in treating AUD [ 8 , 9 , 10 ]. Additionally, a recent systematic review revealed that diagnostic sensitivity of primary care physicians in the identification of AUD was 41.7% and that only in 27.3% alcohol problems were recorded correctly in primary care records [ 11 ].

Several models for primary care have been created to increase identification and treatment of patients with AUD. Of those, the model, screening, brief interventions, and referral to specialized treatment for people with severe AUD (SBIRT [ 12 ]) is most well-known. Multiple systematic reviews exist, confirming its effectiveness [ 13 , 14 , 15 ], although implementation in primary care has been inadequate. Moreover, most studies have looked primarily at SBIRT for the treatment of less severe AUD [ 16 ]. In the treatment of severe AUD, efficacy of SBIRT is limited [ 16 ]. Additionally, many patient referred to specialized care often do not attend as they encounter numerous difficulties in health care systems including stigmatization, costs, lack of information about existing treatments, and lack of non-abstinence-treatment goals [ 7 ]. An effective model of care for improved management of AUD that can be efficiently implemented in primary care settings is required.

Review objective

This proposed systematic review will synthesize and evaluate differential models of care for the management of AUD in primary health care settings. We aim to evaluate the effectiveness of the models of care in increasing engagement and reducing alcohol consumption.

By providing this overview, we aim to guide improvement of design and implementation of evidence-based models of care for the treatment of alcohol use disorder in primary health care settings.

The systematic review is registered in PROSPERO international prospective register of systematic reviews (CRD42019120293) and the current protocol has been written according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) recommended for systematic reviews [ 17 ]. A PRISMA-P checklist is included as Additional file  1 .

Eligibility criteria

Criteria for considering studies for this review are classified by the following:

Study design

Both individualized and cluster randomized trials will be included. Masking of patients and/or physicians is not an inclusion criterion as it is often hard to accomplish in these types of studies.

Patients in primary health care who are identified (using screening tools or by primary health care physician) as suffering from AUD (from mild to severe) or hazardous alcohol drinking habits (e.g., comorbidity, concurrent medication use). Eligible patients need to have had formal assessment of AUD with diagnostic tools such as Diagnostic and Statistical Manual of Mental Disorders (DSM-IV/V) or the International Statistical Classification of Diseases and Related Health Problems (ICD-10) and/or formal assessment of hazardous alcohol use assessed by the Comorbidity Alcohol Risk Evaluation Tool (CARET) or the Alcohol Use Disorders Identification test (AUDIT) and/or alcohol use exceeding guideline recommendations to reduce health risks (e.g., US dietary guideline (2015–2020) specifies excessive drinking for women as ≥ 4 standard drinks (SD) on any day and/or ≥ 8 SD per week and for men ≥ 5 SD on any day and/or ≥ 15 SD per week).

Studies evaluating models of care for additional diseases (e.g., other dependencies/mental health) other than AUD are included when they have conducted data analysis on the alcohol use disorder patient data separately or when 80% or more of the included patients have AUD.

Intervention

The intervention should consist of a model of care; therefore, it should include multiple components and cover different stages of the care pathway (e.g., identification of patients, training of staff, modifying access to resources, and treatment). An example is the Chronic Care Model (CCM) which is a primary health care model designed for chronic (relapsing) conditions and involves six elements: linkage to community resources, redesign of health care organization, self-management support, delivery system redesign (e.g., use of non-physician personnel), decision support, and the use of clinical information systems [ 18 , 19 ].

As numerous articles have already assessed the treatment model SBIRT, this model of care will be excluded from our review unless the particular model adds a specific new aspect. Also, the article has to assess the effectiveness of the model rather than assessing the effectiveness of the particular treatment used. Because identification of patients is vital to including them in the trial, a care model that only evaluates either patient identification or treatment without including both will be excluded from this review.

Model effectiveness may be in comparison with the usual care or a different treatment model.

Included studies need to include at least one of the following outcome measures: alcohol consumption, treatment engagement, uptake of pharmacological agents, and/or quality of life.

Solely quantitative research will be included in this systematic review (e.g., randomized controlled trials (RCTs) and cluster RCTs). We will only include peer-reviewed articles.

Restrictions (language/time period)

Studies published in English after 1 January 1998 will be included in this systematic review.

Studies have to be conducted in primary health care settings as such treatment facilities need to be physically in or attached to the primary care clinic. Examples are co-located clinics, veteran health primary care clinic, hospital-based primary care clinic, and community primary health clinics. Specialized primary health care clinics such as human immunodeficiency virus (HIV) clinics are excluded from this systematic review. All studies were included, irrespective of country of origin.

Search strategy and information sources

A comprehensive search will be conducted. The following databases will be consulted: MEDLINE (1946 to present), PsycINFO (1806 to present), Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL) (1991 to present), and Embase (1947 to present). Initially, the search terms will be kept broad including alcohol use disorder (+synonyms), primary health care, and treatment to minimize the risk of missing any potentially relevant articles. Depending on the number of references attained by this preliminary search, we will add search terms referring to models such as models of care, integrated models, and stepped-care models, to limit the number of articles. Additionally, we will conduct reference searches of relevant reviews and articles. Similarly, a gray literature search will be done with the help of Google and the Gray Matters tool which is a checklist of health-related sites organized by topic. The tool is produced by the Canadian Agency for Drugs and Technologies in Health (CADTH) [ 20 ].

See Additional file  2 for a draft of our search strategy in MEDLINE.

Data collection

The selection of relevant articles is based on several consecutive steps. All references will be managed using EndNote (EndNote version X9 Clarivate Analytics). Initially, duplicates will be removed from the database after which all the titles will be screened with the purpose of discarding clearly irrelevant articles. The remaining records will be included in an abstract and full-text screen. All steps will be done independently by two researchers. Disagreement will lead to consultation of a third researcher.

Data extraction and synthesis

Two researchers will extract data from included records. At the conclusion of data extraction, these two researchers will meet with the lead author to resolve any discrepancies.

In order to follow a structured approach, an extraction form will be used. Key elements of the extraction form are information about design of the study (randomized, blinded, control), type of participants (alcohol use, screening tool used, socio-economic status, severity of alcohol use, age, sex, number of participants), study setting (primary health care setting, VA centers, co-located), type of intervention/model of care (separate elements of the models), type of health care worker (primary, secondary (co-located)), duration of follow-up, outcome measures used in the study, and funding sources. We do not anticipate having sufficient studies for a meta-analysis. As such, we plan to perform a narrative synthesis. We will synthesize the findings from the included articles by cohort characteristics, differential aspects of the intervention, controls, and type of outcome measures.

Sensitivity analyses will be conducted when issues suitable for sensitivity analysis are identified during the review process (e.g., major differences in quality of the included articles).

Potential meta-analysis

In the event that sufficient numbers of effect sizes can be extracted, a meta-analytic synthesis will be performed. We will extract effect sizes from each study accordingly. Two effect sizes will be extracted (and transformed where appropriate). Categorical outcomes will be given in log odds ratios and continuous measures will be converted into standardized mean differences. Variation in effect sizes attributable to real differences (heterogeneity) will be estimated using the inconsistency index ( I 2 ) [ 21 , 22 ]. We anticipate high degrees of variation among effect sizes, as a result moderation and subgroup-analyses will be employed as appropriate. In particular, moderation analysis will focus on the degree of heterogeneity attributable to differences in cohort population (pre-intervention drinking severity, age, etc.), type of model/intervention, and study quality. We anticipate that each model of care will require a sub-group analysis, in which case a separate meta-analysis will be performed for each type of model. Small study effect will be assessed with funnel plots and Egger’s symmetry tests [ 23 ]. When we cannot obtain enough effect sizes for synthesis or when the included studies are too diverse, we will aim to illustrate patterns in the data by graphical display (e.g., bubble plot) [ 24 ].

Critical appraisal of studies

All studies will be critically assessed by two researchers independently using the Revised Cochrane risk-of-bias tool (RoB 2) [ 25 ]. This tool facilitates systematic assessment of the quality of the article per outcome according to the five domains: bias due to (1) the randomization process, (2) deviations from intended interventions, (3) missing outcome data, (4) measurement of the outcome, and (5) selection of the reported results. An additional domain 1b must be used when assessing the randomization process for cluster-randomized studies.

Meta-biases such as outcome reporting bias will be evaluated by determining whether the protocol was published before recruitment of patients. Additionally, trial registries will be checked to determine whether the reported outcome measures and statistical methods are similar to the ones described in the registry. The gray literature search will be of assistance when checking for publication bias; however, completely eliminating the presence of publication bias is impossible.

Similar to article selection, any disagreement between the researchers will lead to discussion and consultation of a third researcher. The strength of the evidence will be graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach [ 26 ].

The primary outcome measure of this proposed systematic review is the consumption of alcohol at follow-up. Consumption of alcohol is often quantified in drinking quantity (e.g., number of drinks per week), drinking frequency (e.g., percentage of days abstinent), binge frequency (e.g., number of heavy drinking days), and drinking intensity (e.g., number of drinks per drinking day). Additionally, outcomes such as percentage/proportion included patients that are abstinent or considered heavy/risky drinkers at follow-up. We aim to report all these outcomes. The consumption of alcohol is often self-reported by patients. When studies report outcomes at multiple time points, we will consider the longest follow-up of individual studies as a primary outcome measure.

Depending on the included studies, we will also consider secondary outcome measures such as treatment engagement (e.g., number of visits or pharmacotherapy uptake), economic outcome measures, health care utilization, quality of life assessment (physical/mental), alcohol-related problems/harm, and mental health score for depression or anxiety.

This proposed systematic review will synthesize and evaluate differential models of care for the management of AUD in primary health care settings.

Given the complexities of researching models of care in primary care and the paucity of a focus on AUD treatment, there are likely to be only a few studies that sufficiently address the research question. Therefore, we will do a preliminary search without the search terms for model of care. Additionally, the search for online non-academic studies presents a challenge. However, the Gray Matters tool will be of guidance and will limit the possibility of missing useful studies. Further, due to diversity of treatment models, outcome measures, and limitations in research design, it is possible that a meta-analysis for comparative effectiveness may not be appropriate. Moreover, in the absence of large, cluster randomized controlled trials, it will be difficult to distinguish between the effectiveness of the treatment given and that of the model of care and/or implementation procedure. Nonetheless, we will synthesize the literature and provide a critical evaluation of the quality of the evidence.

This review will assist the design and implementation of models of care for the management of AUD in primary care settings. This review will thus improve the management of AUD in primary health care and potentially increase the uptake of evidence-based interventions for AUD.

Availability of data and materials

Not applicable.

Abbreviations

Alcohol use disorder

Alcohol Use Disorders Identification test

Canadian Agency for Drugs and Technologies in Health

The Comorbidity Alcohol Risk Evaluation

Cochrane Central Register of Controlled Trials

Diagnostic and Statistical Manual of Mental Disorders

Human immunodeficiency virus

10 - International Statistical Classification of Diseases and Related Health Problems

Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols

Screening, brief intervention, referral to specialized treatment

Standard drinks

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Susan A. Rombouts, Eva Louie, Paul Haber & Kirsten C. Morley

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James Conigrave

Drug Health Services, Royal Prince Alfred Hospital, Camperdown, NSW, Australia

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KM and PH conceived the presented idea of a systematic review and meta-analysis and helped with the scope of the literature. KM is the senior researcher providing overall guidance and the guarantor of this review. SR developed the background, search strategy, and data extraction form. SR and EL will both be working on the data extraction and risk of bias assessment. SR and JC will conduct the data analysis and synthesize the results. All authors read and approved the final manuscript.

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PRISMA-P 2015 Checklist.

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Draft search strategy MEDLINE. Search strategy.

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Rombouts, S.A., Conigrave, J., Louie, E. et al. Evidence-based models of care for the treatment of alcohol use disorder in primary health care settings: protocol for systematic review. Syst Rev 8 , 275 (2019). https://doi.org/10.1186/s13643-019-1157-7

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• Model of care
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• Systematic review

Systematic Reviews

ISSN: 2046-4053

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Pharmacotherapy for Alcohol Use Disorder: A Systematic Review and Meta-Analysis

Affiliations.

• 1 RTI International-University of North Carolina at Chapel Hill Evidence-Based Practice Center, Chapel Hill.
• 2 RTI International, Research Triangle Park, North Carolina.
• 3 Center for Health Research, Kaiser Permanente, Portland, Oregon.
• 4 Department of Internal Medicine, The Ohio State University, Columbus.
• 5 College of Pharmacy, The Ohio State University, Columbus.
• PMID: 37934220
• PMCID: PMC10630900
• DOI: 10.1001/jama.2023.19761

Importance: Alcohol use disorder affects more than 28.3 million people in the United States and is associated with increased rates of morbidity and mortality.

Objective: To compare efficacy and comparative efficacy of therapies for alcohol use disorder.

Data sources: PubMed, the Cochrane Library, the Cochrane Central Trials Registry, PsycINFO, CINAHL, and EMBASE were searched from November 2012 to September 9, 2022 Literature was subsequently systematically monitored to identify relevant articles up to August 14, 2023, and the PubMed search was updated on August 14, 2023.

Study selection: For efficacy outcomes, randomized clinical trials of at least 12 weeks' duration were included. For adverse effects, randomized clinical trials and prospective cohort studies that compared drug therapies and reported health outcomes or harms were included.

Data extraction and synthesis: Two reviewers evaluated each study, assessed risk of bias, and graded strength of evidence. Meta-analyses used random-effects models. Numbers needed to treat were calculated for medications with at least moderate strength of evidence for benefit.

Main outcomes and measures: The primary outcome was alcohol consumption. Secondary outcomes were motor vehicle crashes, injuries, quality of life, function, mortality, and harms.

Results: Data from 118 clinical trials and 20 976 participants were included. The numbers needed to treat to prevent 1 person from returning to any drinking were 11 (95% CI, 1-32) for acamprosate and 18 (95% CI, 4-32) for oral naltrexone at a dose of 50 mg/d. Compared with placebo, oral naltrexone (50 mg/d) was associated with lower rates of return to heavy drinking, with a number needed to treat of 11 (95% CI, 5-41). Injectable naltrexone was associated with fewer drinking days over the 30-day treatment period (weighted mean difference, -4.99 days; 95% CI, -9.49 to -0.49 days) Adverse effects included higher gastrointestinal distress for acamprosate (diarrhea: risk ratio, 1.58; 95% CI, 1.27-1.97) and naltrexone (nausea: risk ratio, 1.73; 95% CI, 1.51-1.98; vomiting: risk ratio, 1.53; 95% CI, 1.23-1.91) compared with placebo.

Conclusions and relevance: In conjunction with psychosocial interventions, these findings support the use of oral naltrexone at 50 mg/d and acamprosate as first-line pharmacotherapies for alcohol use disorder.

Publication types

• Comparative Study
• Meta-Analysis
• Research Support, U.S. Gov't, P.H.S.
• Systematic Review
• Acamprosate* / adverse effects
• Acamprosate* / therapeutic use
• Alcohol Deterrents* / adverse effects
• Alcohol Deterrents* / therapeutic use
• Alcohol Drinking
• Alcoholism* / drug therapy
• Alcoholism* / epidemiology
• Alcoholism* / psychology
• Alcoholism* / therapy
• Drug-Related Side Effects and Adverse Reactions / epidemiology
• Drug-Related Side Effects and Adverse Reactions / etiology
• Naltrexone* / adverse effects
• Naltrexone* / therapeutic use
• Prospective Studies
• Psychosocial Intervention
• Quality of Life
• United States / epidemiology
• Acamprosate
• Alcohol Deterrents

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Alcohol use disorder: pathophysiology, effects, and pharmacologic options for treatment

Robin c wackernah, matthew j minnick, peter clapp.

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Correspondence: Peter Clapp, Regis University, Rueckert-Hartman College for Health Professions, School of Pharmacy, 3333 Regis Blvd, H-28, Denver, CO 80221-1099, USA, Tel +1 303 625 1312, Fax +1 303 625 1305, Email [email protected]

Collection date 2014.

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Alcohol use disorders (AUD) continue to be a concerning health issue worldwide. Harmful alcohol use leads to 2.5 million deaths annually worldwide. Multiple options exist for the management of dependence on alcohol, not all of which are approved by drug-regulating agencies. Current practice in treating AUD does not reflect the diversity of pharmacologic options that have potential to provide benefit, and guidance for clinicians is limited. Few medications are approved for treatment of AUD, and these have exhibited small and/or inconsistent effects in broad patient populations with diverse drinking patterns. The need for continued research into the treatment of this disease is evident in order to provide patients with more specific and effective options. This review describes the neurobiological mechanisms of AUD that are amenable to treatment and drug therapies that target pathophysiological conditions of AUD to reduce drinking. In addition, current literature on pharmacologic (both approved and non-approved) treatment options for AUD offered in the United States and elsewhere are reviewed. The aim is to inform clinicians regarding the options for alcohol abuse treatment, keeping in mind that not all treatments are completely successful in reducing craving or heavy drinking or increasing abstinence.

Keywords: abuse, alcohol, alcoholism, craving, dependence, relapse

Introduction

Alcoholic beverages are consumed around the world as an acceptable part of many recreational and ceremonial activities. Low-to-moderate use of alcohol may facilitate socialization, as it reduces anxiety and has a disinhibiting effect on social behaviors. Compared to other drugs of abuse, relatively large amounts of alcohol are required to produce physiological effects. Consider that the average drink contains 14 grams of ethanol, 1 whereas a tobacco cigarette or a tablet of oxycodone hydrochloride contains only milligram quantities of the active substance. The US National Institute on Alcohol Abuse and Alcoholism defines “heavy drinking” as consuming more than four drinks a day or 14 drinks a week for males, and consuming more than three drinks a day or seven drinks a week for females. It is estimated that one in four heavy drinkers have alcohol-related problems, such as dependence. 1

Addiction treatment trials often use the Diagnostic and Statistical Manual of Mental Disorders (Text Revision), 4th edition (DSM-IV-TR) definition of alcohol use disorders ([AUD] abuse or dependence) to define study participants. The DSM-IV definition of alcohol dependence requires significantly harmful impact caused by at least three out of seven target conditions within a single year. These dependence symptoms include tolerance; withdrawal; increased amounts of alcohol consumed over time; ineffective efforts to reduce use; interference with personal or professional life; significant amount of time spent obtaining, using, and recovering from alcohol; or continued use of alcohol despite harmful sequelae. 2 Alcohol abuse is defined broadly and requires the presence of at least one of the four abuse criteria for diagnosis.

The DSM-5, which was released in May 2013, has combined criteria for alcohol dependence and abuse into a single term (AUD). Craving was added as a diagnostic criteria and at least two target conditions are now required for diagnosis of AUD. 3 New International Statistical Classification of Diseases and Related Health Problems (ICD) 10 codes that correspond to DSM-5 will be used beginning in October 2014. The majority of clinical trials in this review include subjects with DSM-IV alcohol dependence diagnosis.

Although approved pharmacologic treatment options for patients with AUD are limited in number, recent trials describe a host of alternative approaches to reducing alcohol consumption. These include the use of antipsychotics, antidepressants, anticonvulsants, and others, under the rationale that these drugs target the neurotransmitter systems that have been shown to undergo changes with chronic exposure to alcohol. This review describes current evidence for the clinical use of a broader range of pharmacotherapies in AUD, along with available information on patient characteristics (eg, genetic, demographic, behavioral) that may predict positive outcomes of treatment.

Clinical trials associated with alcohol abuse or dependence were identified using PubMed, Ovid, Cochrane Library, and MEDLINE. Search terms included “alcohol abuse,” “alcoholism,” “antipsychotics,” “antidepressants,” “anticonvulsants,” and “treatments for alcohol use disorders” through October 2013. Articles that focus on alcohol detoxification and managing alcohol withdrawal syndrome were excluded, as this topic is outside the scope of this review. Medications within and outside the United States are included in this review. Only articles available in English are included. Studies using dual diagnosis, articles older than 10 years, uncontrolled trials, and review articles were excluded, except where noted.

Neurobiology and pathophysiology of AUD

The acute and chronic effects of alcohol on brain physiology have been well studied and help to rationalize the investigation of psychotropic drugs in the treatment of AUD. In particular, neurotransmitter pathways involved in learning and reward have proven to be effective targets, based on the mechanisms of action of two currently approved AUD drugs, acamprosate and naltrexone. Other compounds under current investigation similarly produce effects by targeting monoamine (eg, serotonin [5-HT], norepinephrine, dopamine) or amino acid (eg, glutamate, γ-aminobutyric acid [GABA]) neurotransmitters.

Alcohol neuroadaptation and reward

Alcohol, like other addictive drugs, stimulates release of the neurotransmitter dopamine from cells originating in a region of the brain called the ventral tegmental area (VTA). 4 The VTA is a component of a neuronal circuit called the mesolimbic dopamine system that has been associated with behavioral motivation and reward. Following exposure to alcohol, dopamine released into the nucleus accumbens (NAc) and prefrontal cortex has been postulated to reinforce drinking behaviors or make the experience of drinking more salient. Recent reviews of the neurobiological literature have described evidence that neuronal plasticity and metaplasticity in the mesolimbic system can promote reward-based learning and the development of addiction. 5 Whereas alcohol does not appear to selectively bind dopamine receptors, its effects on dopamine release are likely mediated through interactions with other neurotransmitter systems, such as glutamate, GABA, corticotropin-releasing factor, and 5-HT, as well as through interactions with the endogenous opioid system (eg, endorphins, enkephalins). 6

Electrochemical activation of neurons is controlled by a balance between excitatory and inhibitory neurotransmitters. Acutely, alcohol inhibits the flow of ions through N-methyl-D-aspartate (NMDA)-type glutamate receptors and enhances the activity of GABA receptor channels, producing an overall inhibitory effect on neurons. 7 Chronic exposure to alcohol promotes neuroadaptive responses that increase the potential excitability of neurons through upregulation or trafficking of NMDA receptors. 8 Changes in glutamate signaling pathways associated with chronic exposure to alcohol may enhance the response to cues associated with drinking. Plasticity at glutamatergic synapses on dopamine neurons exists in many forms and may regulate how efficiently drug-related events and actions affect vulnerability to developing addiction. 5 Furthermore, changing the balance between glutamate and GABA signaling establishes a state of hyperexcitability that is manifest upon cessation of drinking and that may contribute to the negative symptoms of alcohol withdrawal. 9 Changes in the GABA system contribute to the anxiogenic and aversive effects of alcohol withdrawal and can persist over long periods of abstinence from alcohol. The desire to relieve anxiety and negative sensations of withdrawal can contribute to relapse to drinking and lead to the repetitive and compulsive behaviors that characterize alcohol dependence. 9

Pharmacologic strategies to reduce drinking in patients with AUD may attempt to correct the imbalance between excitatory and inhibitory pathways, and relieve the intense craving for alcohol brought about by neuroadaptation. Alternatively, compounds that target reward pathways may compensate for the plasticity in dopamine signaling that enhances the drinking experience of patients with AUD.

In spite of increasing knowledge of the neurobiological disturbances caused by habitual drinking, a common etiological cause for AUD has not been established. Furthermore, the complex interplay of genetic and environmental factors predisposing an individual to the development of AUD exacerbates the search for pharmacologic treatment options that are generally effective across patient populations. 10

Pathophysiological consequences of alcohol use

Even in otherwise healthy individuals, alcohol is toxic to most organ systems at doses above one to two drinks per day. 11 Long-term exposure to alcohol generally increases the risk of damage to the gastrointestinal, cardiovascular, immune, nervous, and other systems. Cellular toxicity can be initiated by the metabolism of ethanol and subsequent accumulation of acetaldehyde, a metabolite that can damage intracellular proteins and induce cell death through apoptosis. 11 Additionally, changes in the oxidation–reduction state of a cell following substantial ethanol metabolism can have an impact on cellular respiration and the metabolism of fats in both animals and humans. 12

Alcohol can promote gastrointestinal bleeding through inflammation of the esophagus and stomach, or through vomiting that can damage the gastrointestinal mucosa. Acute pancreatitis is more prevalent in alcoholics than in the general population and can progress to chronic disease or pancreatic cancer with prolonged exposure. 13 Accumulation of fat in the liver as a result of decreased oxidation of fatty acids and other metabolic changes can progress to fatty liver disease, alcohol-induced hepatitis, and cirrhosis. 14

Low-to-moderate alcohol consumption (one to two drinks per day) causes peripheral vasodilation and decreases contractility of the heart, resulting in a mild decrease in blood pressure. 15 Changes in clotting mechanisms or increases in high-density lipoprotein in alcohol users who typically have one drink per day may even confer a cardioprotective effect. 16 However, consuming three or more drinks per day is a factor in mild-to-moderate hypertension and heavy drinkers are at increased risk for coronary artery disease and cardiomyopathy. The effects of heavy drinking can range from left ventricular impairment and arrhythmia to heart failure as a result of limited contractility of heart muscle. Binge drinking (eg, a single exposure to 90 mL of 80-proof whiskey) can produce atrial or ventricular arrhythmias, even in individuals who have no other evidence of heart disease, a syndrome known as “holiday heart.” 17

Alcohol-dependent individuals may experience peripheral neuropathy characterized by tingling or numbness, especially in the hands and feet. A progressive neurologic syndrome that affects gait and stance, often accompanied by nystagmus, can result from atrophy of the cerebellum due to alcohol toxicity. 18 Less common are neurologic syndromes that result from thiamine deficiency secondary to heavy drinking: Wernicke’s syndrome consists of encephalopathy, uncoordinated muscle movement, and eye muscle weakness; and Korsakoff’s syndrome is characterized by amnesia.

Demographics of alcohol use

Consumption of alcoholic beverages in the US is common, with two-thirds of adults over 18 years of age having consumed alcoholic beverages within the past year, according to the 2011 National Health Interview survey. 19 The highest prevalence of heavy use (13.7%) is observed in the age group from 18 to 25 years. 20 Estimates in the general population are similar or higher in Europe, according to the World Health Organization. 21

Severe repetitive problems with alcohol are reported to have a lifetime risk in men of almost 20% and in women of 10%–15%. 22 Annual costs associated with health and productivity problems caused by heavy drinking have been estimated to be $185 billion in the US in recent years, and this substance contributes to hundreds of thousands of deaths annually in the US (ie, 2.1 deaths per 100,000) and across Europe. 20 , 21 Because of alcohol’s adverse effects on several physiological systems and interactions with many therapeutic medications, medical management and patient care is greatly impacted by modern, heavy levels of alcohol consumption. 23

Pharmacotherapy: approved medications for AUD

Pharmacologic strategies for treating alcohol dependence include generating an aversive physiological reaction to alcohol to mask positive subjective effects and administering medications that block alcohol reinforcement. Medications that target the reward pathways in the brain have been suggested to normalize adaptations to chronic alcohol exposure and reduce craving for alcohol. 7 Other strategies aim to reduce negative symptoms of alcohol withdrawal that may promote relapse drinking by restoring the balance between inhibitory and excitatory neurotransmitter pathways. 7 Three medications are currently approved by the US Food and Drug Administration for the treatment of alcohol dependence in adults: disulfiram, acamprosate, and naltrexone. Nalmefene is approved for alcohol dependence in Europe.

The primary pharmacologic action of disulfiram involves the disruption of normal alcohol metabolism. After ethyl alcohol is absorbed by the body, it becomes converted to acetaldehyde, which is oxidized in the liver by the mitochondrial enzyme aldehyde dehydrogenase (ALDH). 24 Disulfiram produces an irreversible inhibition of ALDH activity. When alcohol is ingested after taking disulfiram, acetaldehyde can accumulate to concentrations that are five to ten times higher than those found after consuming alcohol alone. The accumulation of acetaldehyde leads to unpleasant physiologic reactions including nausea, vomiting, flushing, rapid heartbeat, and falling blood pressure that deter continued drinking. The degree of response to the disulfiram–alcohol reaction increases with the dose of disulfiram and blood alcohol concentration, but even small amounts of alcohol consumed with disulfiram can produce mild reactions. 24

Due to the adverse effects of the ethanol–disulfiram reaction, disulfiram has the greatest potential for benefit in alcohol-dependent patients who are highly motivated to quit drinking. 25 Patients must set a goal of abstinence when initiating disulfiram therapy, and providers should encourage patients to establish the resources and self-motivation to maintain abstinence once the drug is discontinued. Noncompliance is one of the biggest challenges in the use of disulfiram, illustrated by the 20% compliance measure in the largest controlled trial to date, administered among male US veterans. 26 A very recent, single-blind trial in Japanese males with AUD demonstrated improved rates of abstinence only among subjects with an inactive ALDH2 allele. 27 Disulfiram should be used with caution in patients with liver disease due to rare but fatal cases of hepatitis, and it is contraindicated for those with cardiac disease due to hypotension during the disulfiram reaction. 28

The clinical efficacy of disulfiram to reduce craving and prevent relapse to drinking may be related to changes in neurotransmission. Metabolites of disulfiram can alter neurotransmitter levels in the NAc that are implicated in the response to alcohol, and other studies suggest the acetaldehyde reaction may not be necessary to achieve favorable treatment outcomes. 29 , 30

Acamprosate

Acamprosate has been approved for use in alcohol-dependent individuals since 2004. Acamprosate is structurally similar to the endogenous amino acids (eg, glutamate, GABA, glycine) that act as neurotransmitters or neuromodulators in several different brain regions. 31 The primary beneficial mechanism of action remains unclear; however, acamprosate is believed to normalize the balance between excitatory and inhibitory pathways that become adapted to chronic alcohol use and alleviate psychological and physiological discomfort that follows withdrawal. These effects may be due to some combination of antagonizing NMDA glutamate receptors, modulating type 5 metabotropic glutamate receptors, or reducing glutamate accumulation during repeated episodes of alcohol withdrawal. 31

Initial findings from US multisite studies, including the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) trial, 32 differed significantly from earlier European trials, showing no benefit for acamprosate when compared to placebo in reducing alcohol use in treatment-seeking alcoholics. 33 The recent PREDICT trial found no effect of acamprosate in extending time to first heavy drinking day among a predominantly male German patient population that had undergone inpatient treatment prior to enrollment, including an average 18 days of lead-in abstinence. 34 It is possible that the high percentage of abstinent days across all groups in the COMBINE and PREDICT trials masked any benefit of acamprosate to promote abstinence above the combined behavioral intervention and/or medical management provided to all subjects. Large placebo effects are common in AUD trials, making the demonstration of significant effect sizes difficult. 35 Primary care patients in the US also failed to benefit from acamprosate treatment, but exhibited a higher percentage of days abstinent during the study if they expressed a goal of abstinence at baseline. 36 Meta-analysis of the European trial database, consisting primarily of middle-aged males with 7 years or more of dependence on alcohol, confirmed significant improvements in abstinence rates, percent days abstinent, and time to first drink with acamprosate treatment. 33 Acamprosate also has a favorable safety and tolerability profile. 37

Naltrexone is available for oral or intramuscular administration to reduce the craving for alcohol. The clinical efficacy of naltrexone is believed to be mediated through interactions between dopamine and the endogenous opioid neuropeptide systems. 8 The endogenous opioids are involved in the expression of alcohol’s reinforcing effects and may promote drug-seeking behaviors. Naltrexone functions as a competitive antagonist at opioid receptors. In animal models, alcohol administration was shown to promote β-endorphin release in regions of the brain that are involved in reward. 38 Relief of the tonic inhibiting effects of GABA neurons by β-endorphins in the VTA promotes dopaminergic signaling from this area of the brain to the NAc.

Naltrexone is relatively well tolerated and the primary side effect is gastrointestinal discomfort. High doses have been suggested to increase the risk of hepatotoxicity and because naltrexone is an antagonist that can precipitate opioid withdrawal syndrome, it is contraindicated in patients who currently use opioid drugs. 39

In the COMBINE trial, naltrexone demonstrated improvements in maintaining abstinence and reducing heavy drinking, especially in patients who received no behavioral intervention. 32 Further analyses demonstrated high clinical efficacy in the use of naltrexone with psychotherapy for short treatment periods. 40 PREDICT failed to show an effect of oral naltrexone on heavy drinking in a patient population with a greater duration of continuous abstinence prior to randomization. 34 A recent multisite investigation of the efficacy of intramuscular naltrexone in a randomized placebo-controlled trial found 25% reduction in the event rate of heavy drinking days, especially in males who had achieved 7 days of lead-in abstinence. 41 A secondary analysis revealed naltrexone effects on any drinking and complete abstinence in patients with a more clinically relevant period of 4 days lead-in abstinence. 42 Direct comparison between oral and intramuscular administration has not been reported.

Nalmefene is an opioid receptor modulator that is approved by the Committee for Medicinal Products for Human Use of the European Medicines Agency for use in the European Union. 43 Nalmefene was approved for marketing in February 2013 and is approved for “the reduction of alcohol consumption in adult patients with alcohol dependence who have a high drinking risk level.” 43 It works in a similar fashion to naltrexone, as an opioid antagonist at μ and δ receptors, and as an agonist at κ receptors. 43 It is hypothesized that the blockade of opioid receptors interferes with the reinforcing effects of alcohol, in turn reducing alcohol cravings. 38

Nalmefene has been recorded to reduce the number of drinks per drinking day in alcohol-dependent subjects; 44 however, when measuring days abstinent, 44 , 45 number of heavy drinking days, 45 – 47 time to relapse, 44 – 46 and subjective cravings 44 , 47 the data are controversial. While nalmefene may be superior to naltrexone in its ability to reduce alcohol cravings, 48 and does not carry the same hepatotoxicity risk, its role in treating alcohol-dependent patients remains unclear.

Pharmacotherapy: non-approved medications for AUD

A variety of non-approved medications have been studied in the treatment of AUD. Medications like disulfiram and naltrexone have been associated with hepatic toxicity. This can be an issue with chronic drinking, as alcohol is associated with hepatotoxicity and 55% of deaths associated with alcohol are the result of liver disease. 49 Acamprosate should be avoided in patients with severe renal impairment. 50 Additionally, these medications are not effective in all patients for an indeterminate period of time, 51 leading clinicians to seek additional options for the treatment of AUD.

Common measurements to determine the efficacy of medications for AUD include: percentage of drinking days; total amount of drinking; relapse; abstinence; cravings; and brain activation in the reward pathways of the brain.

Many published studies of non-approved medications included patients on psychotropic agents (eg, antipsychotics, antidepressants, anticonvulsants), suggesting the presence of a comorbid psychiatric illness and dual diagnosis of AUD with a mood or thought disorder. Dual diagnosis is an important and challenging issue, which can, however, introduce a number of variables that can lead to relapse. Clinical trials in patients with uncontrolled comorbid psychiatric diagnoses are not included in this review but can be found in other publications. 52 , 53

Antipsychotics

Antipsychotics are used for the treatment of schizophrenia and bipolar disorder and as adjunctive treatment for depression and autism. They block various dopamine receptors, and the second-generation antipsychotics are unique in that they also block 5-HT 2 receptors. Due to dopamine’s implication in the reward pathways associated with AUD, these medications are targets for current research.

Aripiprazole

Aripiprazole at higher doses (23.3 mg daily) may be helpful in reducing number of drinks per day 54 and reducing urges after follow-up drinks (15 mg daily); 55 however, when measuring number of heavy drinking days, days abstinent, 54 and subjective craving, 56 aripiprazole performed poorly against placebo. Despite objective evidence that ventral striatum activation is blunted with aripiprazole, 56 and that aripiprazole may be as efficacious as naltrexone in reducing craving and increasing time to relapse in patients with a goal of abstinence, 57 its precise usefulness in alcohol-dependent patients is not clear.

Olanzapine reduced alcohol cravings in young adult subjects (23 years average age) 58 and reduced the number of drinks per day in AUD patients with higher baseline drinking habits, 59 , 60 but only in individuals with the long version of the D4 dopamine receptor gene ( DRD4 ). When studied in patients with no DRD4 allele stratification, 5–15 mg daily for 12 weeks was not different from placebo in reducing drinking measures. 61 Given the minimal use of genetic information in AUD patient assessment, olanzapine may be considered on a trial-and-error basis in AUD.

Quetiapine 400 mg daily for 6 weeks has shown positive results in drink reduction and impulsivity 62 and, over 12 weeks, demonstrated reduced drinking in type B alcoholics (early onset, more severe) compared to type A alcoholics (late onset, less severe). 63 Quetiapine may not be useful in very heavy drinkers 64 or as an adjunct to naltrexone, 65 but may be an option to reduce drinking in less heavy drinkers or type B alcoholics.

Other antipsychotics (flupenthixol, amisulpride, and tiapride)

Flupenthixol intramuscular injection, 66 , 67 amisulpride, 68 and tiapride 69 all performed poorly in placebo-controlled studies on measures of alcohol intake, craving, and abstinence.

Antidepressants

The majority of antidepressants studied in alcohol dependence use selective 5-HT reuptake inhibitors (SSRIs). These work by blocking the reuptake of 5-HT, allowing increased agonism of 5-HT receptors. 5-HT agonists have shown reduction in alcohol consumption in animal studies, 70 and, due to these findings, may be a future option for AUD treatment.

Citalopram 40 mg has been found to reduce alcohol consumption in moderate drinkers, 71 particularly in men; 72 however, this effect did not carry over to very heavy drinkers. 73 Potential lack of efficacy in very heavy drinking was further illustrated when subjects with lower baseline average daily drinking had 50% or more reduction in baseline drinking with citalopram 40 mg compared to subjects with higher daily drinking averages. 74

Sertraline 200 mg daily has been found to reduce drinking behaviors in type A alcoholic men; 75 these results were not seen in type B alcoholic men or women. 76 Sertraline’s efficacy in less severe alcohol dependence was again replicated in late-onset/low-vulnerability alcoholics who were homozygous for the long allele of the 5-HT transporter. 77

Its effectiveness as an adjunct to naltrexone is not clear. Trials that evaluated sertraline as adjunctive therapy to naltrexone used 100 mg, 78 , 79 compared to other trials where 200 mg was used when sertraline was tested as monotherapy in AUD. 75 – 77

Fluoxetine lacks consistent evidence for its usefulness in alcohol dependence. In undiagnosed alcohol-dependent patients, 60 mg daily of fluoxetine reduced total and daily drinks 80 and significantly reduced craving compared to baseline, but not to placebo; 81 however, 60 mg did not affect abstinence 80 or relapse rates in very heavy drinkers (average 18.6 drinks/day), 82 nor reduce daily baseline or drinks per drinking day when compared to placebo. 81 When dosed at 40 mg, fluoxetine did not reduce intake levels. 80 At higher doses of 80 mg, daily fluoxetine reduced alcohol intake the initial week of a 4-week study. 83

Anticonvulsants

Anticonvulsants are used for seizure disorders and several have indications for chronic pain conditions and mood stabilization. They have a variety of mechanisms, including blockage of sodium channels, enhancing GABA, antagonizing glutamate receptors, and blocking calcium channels.

Gabapentin titrated to 1,200 mg daily reduced craving after an alcohol cue, 84 increased days abstinent in subjects with more severe alcohol withdrawal, reduced relapse to heavy drinking in patients with insomnia, 85 and improved other drinking measures. 86 Gabapentin 600 mg daily found positive benefits in very heavy drinkers. 86 As an adjunct to naltrexone, gabapentin reduced total drinking and urges. 87 Reduction in craving was not found in a real-world design amount of drinking. 88

In placebo-controlled, blinded studies using target doses of topiramate of 300 mg daily, topiramate outperformed placebo in multiple drinking measures 89 – 91 and craving. 91 Topiramate was equivalent to naltrexone in a blinded design measuring relapse and abstinence. 92 Craving 93 and intake 94 were superior in naturalistic open designs.

Topiramate 150 mg daily was compared to disulfiram in a non-blinded randomized study. The study found disulfiram to be superior in abstinence and daily drinks, while topiramate significantly reduced craving compared to disulfiram; 95 the lack of blinding and the low dose of topiramate, however, suggests that a more robust design with adequate topiramate dosing is warranted before drawing strong conclusions regarding the superiority of either medication. Topiramate can also be considered an effective adjunctive therapy in lower doses (75 mg daily) when combined with psychotherapy for alcohol dependence. 96

Levetiracetam

An open-label trial with levetiracetam on alcohol dependence found positive results; 97 however, double-blind, placebo-controlled trials failed to find a benefit of levetiracetam for alcohol dependence. 98 , 99 One study found that moderate-to-heavy drinkers taking levetiracetam increased their drinking during the study period. 100

Oxcarbazepine

Oxcarbazepine has been shown to be equivalent in efficacy to acamprosate 101 and naltrexone 102 in open-label studies comparing time to first relapse. At higher doses, 1,500–1,800 mg daily, oxcarbazepine was superior to naltrexone in a number of patients who remained alcohol-free. 102 There are currently no placebo-controlled blinded studies testing oxcarbazepine’s place in alcohol dependence.

Divalproex sodium (VPA)

VPA significantly decreased relapse to heavy drinking in a blinded study against placebo and also decreased amount of drinking and craving compared to baseline. 103 A small non-blinded study found VPA treatment increased abstinence at 6 weeks post-detoxification, though this was not statistically significant. 104

Other anticonvulsants (carbamazepine zonisamide, tiagabine, pregabalin)

Carbamazepine and zonisamide have placebo-controlled trials supporting their potential use in alcohol dependence. 105 , 106 Zonisamide was significantly better than placebo in reducing number of heavy drinking days, reduction in number of drinks per week, and urge to drink. Days abstinent were similar to placebo. 105 Similarly, carbamazepine outperformed placebo in longer time to relapse to heavy drinking. 106

Tiagabine 107 and pregabalin 108 both have open-label trials supporting their potential usefulness in alcohol dependence; however, placebo-controlled and head-to-head trials are needed to ascertain their particular place in therapy.

Other off-label medications

Ritanserin is a 5-HT 2 receptor antagonist with documented use to improve sleep, mood, and vigilance. 109 The feedback inhibition of dopaminergic activity related to blocking 5-HT receptors may act as a substitute for alcohol effects. 110

Multiple large clinical trials revealed poor results with ritanserin when compared to placebo when measuring daily drinks, craving in heavy drinkers, 110 , 111 and relapse rates. 112

Baclofen is a skeletal muscle relaxant that is approved for use in muscle spasticity. It is a GABA-B agonist and, through this mechanism, the dopaminergic response to alcohol may be inhibited. 113

In addition to a 12-week open-label study, 114 baclofen 30 mg daily has shown positive benefit compared to placebo in abstinence, 115 – 117 craving, and daily alcohol intake. 115 Higher doses (60 mg/day) produced a more robust response in reduction of number of drinks per day compared to 30 mg daily. 118 Studies that failed to replicate the benefits of baclofen used patients with a lower daily drink intake and no comorbid liver problems who were recruited via advertisements, 119 as opposed to subjects seeking treatment.

Ondansetron

Ondansetron is an antiemetic medication that blocks 5-HT 3 receptors. Due to alcohol’s activity on 5-HT 3 , it is thought that ondansetron can be a useful medication in alcohol dependence. 120

Ondansetron has been studied in four blinded placebo-controlled trials comparing low doses for alcohol dependence. Ondansetron significantly reduced daily drinking in light drinkers. No benefit was seen in heavy drinkers (>10 drinks/day). 121 Additional studies using weight-based dosing found benefits in craving, 122 abstinence, and total drinks. 123 One study showed increase in craving but reduced drinks per day. When used with naltrexone ondansetron, 0.5 mg reduced cue-induced craving and activation of the ventral striatum. 124

Prazosin is an alpha 1-receptor adrenergic blocker that is used for the treatment of hypertension. 125 At a titrated target dose of 16 mg daily, prazosin has been shown to reduce stress-induced craving, 126 drinks per weeks, and drinking days. 125 Simpson et al did not see a reduction in craving, though craving was not stress elicited. 125

Varenicline

Varenicline is a nicotine agonist used for smoking cessation. 127 Varenicline reduced number of drinks consumed, abstinence, and craving after a priming drink in a 2-hour session in smokers with AUD. 127 It also reduced number of drinks per week and craving in a 16-week trial, but did not have an effect on total days abstinent. 128

Kudzu extract

The kudzu root has been historically studied for its use in alcoholism; of particular interest are the extracts of the plant. The mechanism is not fully understood, but it is proposed that the extracts of the kudzu root may alter alcohol dehydrogenase or monoamine oxidase–acetaldehyde pathways, 129 , 130 leading to reduced alcohol consumption.

Kudzu root extract was studied in non-treatment-seeking male drinkers over the course of a 4-week period. When compared to placebo, the kudzu extract reduced weekly alcohol consumption and increased the amount of consistent abstinent days. 130 Additionally, puerarin (one of the three main isoflavones of the kudzu root) was found to reduce the amount of beer consumed when compared to placebo in non-diagnosed heavy drinkers. 129 Both studies, however, indicate that the kudzu extract did not reduce subjective alcohol cravings, 129 , 130 which may limit clinical use. The kudzu root extract appears to be beneficial in lowering alcohol consumption in heavy drinkers.

Disulfiram, naltrexone, acamprosate, and nalmefene all have benefits in the treatment of AUD. Considering the potential for treatment failure with approved pharmacological options or the inability to use a medication due to comorbid health conditions, a number of medications have been studied in AUD. For example, in the presence of a failed response to naltrexone or a contraindication (current opioid withdrawal) to its use, aripiprazole 57 and topiramate 92 both appear to be equal to naltrexone in efficacy for AUD. Perhaps the continued exploration of non-approved medications will result in the identification of a drug or combination of drugs that demonstrates generalized effectiveness in all AUD patient types.

Alternatively, heterogeneity of AUD patients and the complex etiology of the disease may preclude the discovery of such a drug. Varying patterns of consumption and differences in onset of drinking have defined AUD patient subtypes that respond differently to pharmacotherapy. Reported outcomes in subpopulations of study cohorts have followed a range of demographics, including sex and genetic background. Recognizing trends in current reports and strengthening associations between AUD subtypes and treatment outcomes with new studies may provide clinical guidance to prescribers in the near future. For example, an individual’s drinking goal (eg, controlled drinking, conditional abstinence, complete abstinence) established prior to treatment has been shown to be highly associated with clinical outcome, validating the importance of patient motivation for behavioral change. 131 Clinical outcomes and drinking behavior just prior to treatment have also been shown to associate with medication effect. Acamprosate is slightly more efficacious in promoting abstinence than naltrexone, and it has a larger effect size in patients who have undergone detoxification. 132 Naltrexone is slightly more efficacious in reducing heavy drinking than acamprosate, and it is associated with a larger medication effect in patients who enter treatment after a period of lead-in abstinence. 132 Therefore, a patient’s drinking goals and current drinking status, as well as the intended clinical outcome, should be determined prior to treatment.

With regard to sex, although women with AUD enter treatment earlier in the course of the disease than men, 133 clinical studies of pharmacologic AUD treatment tend to be comprised of mostly male patient populations. Treatment responses have been suggested in some cases to be better in men than women (eg, naltrexone, 41 citalopram, 72 and sertraline 75 ), but a recent meta-analysis of over 50 naltrexone and acamprosate trials found no effect of sex on response to treatment. 35 Although flupenthixol decanoate increased relapse rates among AUD patients, the risk was significantly lower in women than in men. 67 Further AUD treatment studies that separate male and female populations are warranted.

Other examples of patient-specific criteria that might guide clinical decisions include the use of gabapentin in patients with comorbid insomnia, 85 prazosin in patients who drink secondary to a stress response, 126 and varenicline in patients who smoke, 127 , 128 and data suggest olanzapine’s usefulness in patients with genetic predispositions related to the dopamine receptor gene. 58

The influence of genetic background on patient response has been exemplified by the interaction between naltrexone response and polymorphisms in the μ opioid receptor gene OPRM1 . In a review of the studies that included genetic information, Chamorro et al report that AUD patients who carry the A118G allele demonstrate lower rates of relapse to heavy drinking, with no change in abstinence. 134 Evidence for a genetic influence on treatment response has also been reported for disulfiram, 27 olanzapine, 58 and ondansetron. 135 As genetic testing becomes more cost-effective, it may represent a feasible strategy to tailor AUD treatments to an individual patient’s disease. The use of genetic information has become standard practice in other areas of medicine, including anticoagulation and oncology.

Research with well-designed studies will continue to be a necessity in the area of pharmacologic treatment for AUD. Based on the current state of AUD treatment research, it appears unlikely that a single agent or combination regimen will prove to be effective in all patients with AUD. Instead, clinicians may be obligated to match medication strategies to individuals or AUD subtypes, and this approach demands stronger evidence of treatment efficacy in particular patient groups.

The authors report no conflicts of interest in this work.

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