Medications for Alcohol Use Disorder.

Excessive alcohol use is a leading cause of preventable death in the United States, with alcohol-related deaths increasing during the pandemic. The Substance Abuse and Mental Health Services Administration recommends that physicians offer pharmacotherapy with behavioral interventions for patients diagnosed with alcohol use disorder. Several medications are available to help patients reduce drinking and maintain abstinence; however, in 2019, only 7.3% of Americans with alcohol use disorder received any treatment, and only 1.6% were prescribed medications to treat the disorder. Strong evidence shows that naltrexone and gabapentin reduce heavy-drinking days and that acamprosate prevents return-to-use in patients who are currently abstinent; moderate evidence supports the use of topiramate in decreasing heavy-drinking days. Disulfiram has been commonly prescribed, but little evidence supports its effectiveness outside of supervised settings. Other medications, including varenicline and baclofen, may be beneficial in reducing heavy alcohol use. Antidepressants do not decrease alcohol use in patients who do not have mood disorders, but they may help patients who meet criteria for depression to decrease their alcohol intake. Systematic policies are needed to expand the use of medications when treating alcohol use disorder in inpatient and outpatient populations.

Patient Perspectives on Pharmacotherapy of Alcohol Dependence.

INTRODUCTION: Pharmacotherapy with drugs like naltrexone or acamprosate is a well-evaluated element in the treatment of alcohol dependence (AD). However, in many countries, these medications are rarely administered. The objective of the present study was to identify from patients' perspective factors that prevent the initiation and compliance with pharmacological treatment of AD. METHODS: Patients from inpatient alcohol withdrawal treatment underwent a standardized interview. Questions included socio-demographic data, history of AD, treatment history, knowledge and personal experience regarding pharmacotherapy of AD, and personal views about the causes of AD. RESULTS: Three hundred patients (mean age 47.3 years, 27.7% female, mean duration of AD 8.9 years, 67% with a history of previous inpatient withdrawal treatment) were included. The majority of patients (58.7%) already knew drugs for the pharmacotherapy of AD. Thirty percent had ever used such medications, most often acamprosate. Except for disulfiram, pharmacotherapy of AD had lasted only a few weeks, on average. Medication usually had been applied without additional psychotherapy. No severe side effects were reported. Patients had often stopped pharmacotherapy on their own, when assuming they had reached stable abstinence. Openness to start pharmacotherapy for AD was currently stated by 67% of the total sample. In multiple logistic regression, openness was predicted by having a concept of AD as a medical disease and by a shorter duration of AD. DISCUSSION: To improve the administration of pharmacotherapy for AD implementation strategies should be systematically developed and evaluated with a focus on the concept of AD as a medical disease.

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

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.

Repurposing disulfiram, an alcohol-abuse drug, in neuroblastoma causes KAT2A downregulation and in vivo activity with a water/oil emulsion.

Neuroblastoma, the most common type of pediatric extracranial solid tumor, causes 10% of childhood cancer deaths. Despite intensive multimodal treatment, the outcomes of high-risk neuroblastoma remain poor. We urgently need to develop new therapies with safe long-term toxicity profiles for rapid testing in clinical trials. Drug repurposing is a promising approach to meet these needs. Here, we investigated disulfiram, a safe and successful chronic alcoholism treatment with known anticancer and epigenetic effects. Disulfiram efficiently induced cell cycle arrest and decreased the viability of six human neuroblastoma cell lines at half-maximal inhibitory concentrations up to 20 times lower than its peak clinical plasma level in patients treated for chronic alcoholism. Disulfiram shifted neuroblastoma transcriptome, decreasing MYCN levels and activating neuronal differentiation. Consistently, disulfiram significantly reduced the protein level of lysine acetyltransferase 2A (KAT2A), drastically reducing acetylation of its target residues on histone H3. To investigate disulfiram's anticancer effects in an in vivo model of high-risk neuroblastoma, we developed a disulfiram-loaded emulsion to deliver the highly liposoluble drug. Treatment with the emulsion significantly delayed neuroblastoma progression in mice. These results identify KAT2A as a novel target of disulfiram, which directly impacts neuroblastoma epigenetics and is a promising candidate for repurposing to treat pediatric neuroblastoma.

Reported Risky Alcohol Use Among US Adults Prescribed 3 Classes of Chronic Alcohol-Interactive Medications.

This study uses data from the 2013­March 2020 National Health and Nutrition Examination Survey to assess contemporary patterns of risky alcohol use among adults taking high-risk alcohol-interactive medications (benzodiazepine receptor agonists, opioids, and antiepileptics).

Overview of Alcohol Use Disorder.

Alcohol is regularly consumed throughout most of the world, including by nearly half the U.S. population age 12 or older. Heavy drinking, which is also common, contributes to multiple adverse medical, psychiatric, and social outcomes and more than 140,000 deaths annually in the United States. It is the major risk factor for alcohol use disorder (AUD), whose current U.S. prevalence is 11%. However, AUD is undertreated, with less than 15% of individuals with a lifetime diagnosis receiving any treatment. Risk of AUD is nearly equally genetic and environmental. AUD is responsive to psychosocial treatments, including cognitive-behavioral therapy and motivational enhancement therapy. Alcohol affects multiple neurotransmitter systems, and thus pharmacotherapy for AUD is also effective. The three medications approved in the United States to treat AUD-disulfiram, naltrexone (oral and long-acting injectable formulations), and acamprosate-are underprescribed, despite being considered first-line treatments in clinical practice guidelines. Two medications not approved for treating AUD, topiramate and gabapentin, have shown efficacy in treating the disorder and are used off-label. Recent studies of novel drug candidates, including psychedelics and phosphodiesterase-4 inhibitors, are promising additions for the treatment of AUD, although they require further evaluation before being used clinically. Despite the growing availability of efficacious psychosocial and pharmacological treatments for AUD, it remains a highly stigmatized condition. Research aimed at enhancing the identification and treatment of AUD, including precision therapeutics, could broaden the acceptability of AUD treatment, benefiting affected individuals and their families and reducing the stigma associated with the disorder.

Medications for the Treatment of Alcohol Dependence-Current State of Knowledge and Future Perspectives from a Public Health Perspective.

No single effective therapy for alcohol abuse has been found, despite it being a serious sociological and economic problem for hundreds of years. It seems difficult to find a single drug as a panacea for the alcohol problem due to the complexity of the pathophysiology of alcohol dependence. The purpose of this narrative review is to review existing and potentially future pharmaceuticals for the treatment of alcohol dependence in the most affordable way possible. Psychotherapy is the mainstay of treatment for alcoholism, while few drugs approved by legislators are available in the augmentation of this treatment, such as acamprosate, disulfiram, and naltrexone, approved by the FDA, and nalmefene by the EMA. There are recent reports in the literature on the possibility of using baclofen, topiramate, varenicline, and gabapentin in the treatment of alcohol dependence. Moreover, the results of recent clinical trials using psychoactive substances such as psilocybin and MDMA appear to be a breakthrough in the modern treatment of alcohol abuse. Despite this initial optimism, a lot of scientific effort is still needed before new pharmacological methods supporting the treatment of alcohol dependence syndrome will be widely available.

Impact of policy changes and drug shortages on acamprosate and naltrexone use in Ontario, Canada.

BACKGROUND: Acamprosate and naltrexone, evidence-based pharmacotherapies for alcohol use disorder (AUD), are publicly covered by the Ontario Drug Benefit (ODB) programs; however, their availability has changed over time, with expanded formulary access in July 2018, followed by an acamprosate shortage in February 2019 and ending in July 2020. We evaluated the impact of these events on the use of these medications in Ontario, Canada. METHODS: We conducted a time-series analysis among individuals with AUD dispensed acamprosate or naltrexone through the ODB from July 2016 to December 2020. Outcomes included monthly rates of those with AUD on therapy (primary), and rate of initiation (secondary) overall and by treatment type. We used autoregressive moving average models to evaluate the impact of expanded coverage and the acamprosate shortage on rates of use, and reported characteristics at first dispensation. RESULTS: Over the study period, 10,637 individuals (61.0% male) initiated acamprosate or naltrexone. Expanded coverage increased monthly utilization rates of acamprosate (p = 0.0004), naltrexone (p < 0.0001), and either AUD pharmacotherapy (p < 0.0001). The acamprosate shortage led to a 98.1% reduction in acamprosate use (p = 0.0003) but did not impact naltrexone (p = 0.51). Our secondary analysis yielded consistent results with respect to the shortage; however, the expanded formulary listing did not impact the rate of new acamprosate patients (p = 0.3). By December 2020, 5.3% of ODB recipients with AUD were accessing pharmacotherapy. CONCLUSIONS: Although coverage expansion increased access to medications that treat AUD, the shortage of acamprosate led to large reductions in its use, with no responsive increase in naltrexone prescribing.

Looking Back, Looking Forward: Current Medications and Innovative Potential Medications to Treat Alcohol Use Disorder.

This article is part of a Festschrift commemorating the 50th anniversary of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Established in 1970, first as part of the National Institute of Mental Health and later as an independent institute of the National Institutes of Health, NIAAA today is the world's largest funding agency for alcohol research. In addition to its own intramural research program, NIAAA supports the entire spectrum of innovative basic, translational, and clinical research to advance the diagnosis, prevention, and treatment of alcohol use disorder and alcohol-related problems. To celebrate the anniversary, NIAAA hosted a 2-day symposium, "Alcohol Across the Lifespan: 50 Years of Evidence-Based Diagnosis, Prevention, and Treatment Research," devoted to key topics within the field of alcohol research. This article is based on Dr. Mason's presentation at the event. NIAAA Director George F. Koob, Ph.D., serves as editor of the Festschrift.

Disulfiram's journey from rubber vulcanization to T-cell activation.

Disulfiram, a drug prescribed for the treatment of alcohol use disorders for more than 60 years, has recently been repurposed for cancer treatment. New work in The EMBO Journal now describes a disulfiram role in immunotherapy of cancer, involving direct binding to Lck to mediate activation of tumor-infiltrating T cells.

Identifying chronic alcoholism drug disulfiram as a potent DJ-1 inhibitor for cancer therapeutics.

As a key regulator involved in tumor development and progression, DJ-1 has been proposed as a potential therapeutic target against cancer. Also, the development of DJ-1 inhibitors holds great interests in cancer treatment. In the current study, by utilizing a small molecule covalent compounds library screening, we found that disulfiram (DSF), an FDA-approved chronic alcoholism drug, is a potent DJ-1 inhibitor. Glyoxalase assay and microscale thermophoresis analysis suggested that DSF exhibits strong inhibitory activity and high affinity to DJ-1 protein. Additionally, DSF similarly inhibited the methylglyoxal detoxification function of DJ-1 protein at the intracellular level. Notably, we discovered that DSF could significantly enhance N-(4-hydroxyphenyl) retinamide-based proliferation inhibition and apoptosis induction in different types of cancer cell lines, but not in normal tissue lines. Thus, our data suggest DSF functions as a potential inhibitor targeting DJ-1, which may provide a potential synergistic treatment option for cancer therapy.

The rates and measurement of adherence to acamprosate in randomised controlled clinical trials: A systematic review.

AIM: The current research aims to systematically review the rates of adherence reported in randomised controlled clinical trials of acamprosate. It also sought to determine the reliability of the adherence monitoring and measurement methods used in these trials. METHODS: The protocol for this review was pre-registered (PROSPERO: CRD42021230011). A search of the literature was conducted using OVID MEDLINE, Embase and PsycINFO from database inception to January 2021. Randomised controlled trials with a minimum sample size of 10 per treatment arm that compared the efficacy of acamprosate with placebo or other active medication in adults with a diagnosis of alcohol dependence were included. Data on rates of adherence, methods of measurement and monitoring of adherence was extracted from eligible studies independently in duplicate by two reviewers. A weighted mean adherence rate was calculated. The reliability of adherence monitoring methods was determined by calculating an adherence-assurance score based on the adherence monitoring method used. Risk of bias was assessed using the Cochrane Risk of Bias Tool. RESULTS: Fifteen studies met the eligibility criteria involving 4,450 participants (2,480 participants in the placebo arms). A mean adherence rate of 88% (54.2-95.0%) was reported across studies that reported the percentage of medication taken. A mean adherence rate of 84.9% (56.4-91.3%) was reported for trials that reported the percentage of participants taking more than 80% of medication prescribed. There is low confidence in the methods used to monitor adherence with all clinical trials having a low adherence-assurance rating. Risk of bias was judged to be high for all included studies. CONCLUSIONS: Adherence to acamprosate in clinical trials can be poor with low confidence in the methods used to measure it. Adherence rates therefore might not be accurate, which has implications for determining the efficacy of acamprosate.

Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder.

Alcohol use disorder (AUD) is a highly prevalent but severely under-treated disorder, with only three widely-approved pharmacotherapies. Given that AUD is a very heterogeneous disorder, it is unlikely that one single medication will be effective for all individuals with an AUD. As such, there is a need to develop new, more effective, and diverse pharmacological treatment options for AUD with the hopes of increasing utilization and improving care. In this qualitative literature review, we discuss the efficacy, mechanism of action, and tolerability of approved, repurposed, and novel pharmacotherapies for the treatment of AUD with a clinical perspective. Pharmacotherapies discussed include: disulfiram, acamprosate, naltrexone, nalmefene, topiramate, gabapentin, varenicline, baclofen, sodium oxybate, aripiprazole, ondansetron, mifepristone, ibudilast, suvorexant, prazosin, doxazosin, N-acetylcysteine, GET73, ASP8062, ABT-436, PF-5190457, and cannabidiol. Overall, many repurposed and novel agents discussed in this review demonstrate clinical effectiveness and promise for the future of AUD treatment. Importantly, these medications also offer potential improvements towards the advancement of precision medicine and personalized treatment for the heterogeneous AUD population. However, there remains a great need to improve access to treatment, increase the menu of approved pharmacological treatments, and de-stigmatize and increase treatment-seeking for AUD.

Treatment of alcohol use disorder in patients with liver disease.

Alcohol contributes to more than 5% of global mortality, and causes more than half of all liver-related deaths. The Alcohol Use Disorders Identification Test (AUDIT) can be used to detect those patients with hazardous drinking and alcohol dependence who will benefit from psychosocial and pharmacological alcohol treatment. Psychosocial treatments range from brief interventions and cognitive behavioral therapy, to experimental neuropsychological treatments. Psychosocial intervention can be combined with acamprosate or naltrexone as first line pharmacological treatments. For patients with liver disease, abstinence increases survival and is therefore an important treatment goal. Acamprosate is a good choice, as it prevents relapse to drinking with a number needed to treat of 12. There are no reports indicating high risks of liver toxicity for acamprosate or naltrexone, but evidence is scarce. We recommend vigorous screening for alcohol use disorder in liver disease patients, followed by psychosocial intervention and complemented by pharmaceutical therapy.

Genetic variants associated with acamprosate treatment response in alcohol use disorder patients: A multiple omics study.

BACKGROUND AND PURPOSE: Acamprosate is an anti-craving drug used for the pharmacotherapy of alcohol use disorder (AUD). However, only some patients achieve optimal therapeutic outcomes. This study was designed to explore differences in metabolomic profiles between patients who maintained sobriety and those who relapsed, to determine whether those differences provide insight into variation in acamprosate treatment response phenotypes. EXPERIMENTAL APPROACH: We previously conducted an acamprosate trial involving 442 AUD patients, and 267 of these subjects presented themselves for a 3-month follow-up. The primary outcome was abstinence. Clinical information, genomic data and metabolomics data were collected. Baseline plasma samples were assayed using targeted metabolomics. KEY RESULTS: Baseline plasma arginine, threonine, α-aminoadipic acid and ethanolamine concentrations were associated with acamprosate treatment outcomes and baseline craving intensity, a measure that has been associated with acamprosate treatment response. We next applied a pharmacometabolomics-informed genome-wide association study (GWAS) strategy to identify genetic variants that might contribute to variations in plasma metabolomic profiles that were associated with craving and/or acamprosate treatment outcome. Gene expression data for induced pluripotent stem cell-derived forebrain astrocytes showed that a series of genes identified during the metabolomics-informed GWAS were ethanol responsive. Furthermore, a large number of those genes could be regulated by acamprosate. Finally, we identified a series of single nucleotide polymorphisms that were associated with acamprosate treatment outcomes. CONCLUSION AND IMPLICATIONS: These results serve as an important step towards advancing our understanding of disease pathophysiology and drug action responsible for variation in acamprosate response and alcohol craving in AUD patients.

Examining a brief measure and observed cutoff scores to identify reward and relief drinking profiles: Psychometric properties and pharmacotherapy response.

BACKGROUND: Precision medicine approaches attempt to reduce variability in alcohol use disorder (AUD) outcomes by identifying patient characteristics that predict response to a particular treatment. Recent work has examined the extent to which individuals with AUD may seek alcohol to enhance positive experiences (reward drinking) or relieve negative states (relief drinking) and shown that a high reward/low relief phenotype predicts naltrexone treatment response. Yet, limitations of reward/relief drinking measures may hamper efforts to translate findings to clinical practice. We sought to refine a brief measure of reward/relief drinking and develop cutoff scores to identify reward/relief subgroups that predict pharmacotherapy response. METHODS: The Inventory of Drinking Situations (IDS), used in previous studies to measure reward/relief drinking, was administered to 426 participants (77% male; average age = 45.3) in a clinical trial examining naltrexone and acamprosate. RESULTS: Item response theory and tests of differential item functioning across sex, age, and alcohol dependence severity were used to create a 10-item measure, titled the Reward and Relief IDS (RR-IDS). Cutoff scores on the RR-IDS for the reward/relief drinking subgroups were identified using latent profile and area under the curve analyses. The cutoff scores demonstrated good construct validity. Individuals in the high reward/low relief subgroup who received naltrexone or acamprosate had a decreased likelihood of heavy drinking (large effect sizes) versus those who received placebo. CONCLUSIONS: The RR-IDS is a practical measure for identifying reward/relief subgroups and predicting pharmacotherapy response. Pending replication of these findings, the RR-IDS could be a critical precision medicine tool for prescribing AUD medications.

Naltrexone moderates the association of alcohol use and affect among adolescent drinkers in daily life.

BACKGROUND: Naltrexone is an efficacious medication for the treatment of alcohol use disorder in adults. As an opioid receptor antagonist, naltrexone blocks activation of the endogenous opioid system, which is involved in the affectively reinforcing properties of substance use. Few studies, however, have examined the moderating effect of naltrexone on the association between affect and alcohol use. Additionally, most existing research on naltrexone has been with adults in the human laboratory. METHOD: We conducted a secondary analysis of ecological momentary assessment data from a randomized, double-blinded, placebo-controlled cross-over study that compared naltrexone (50 mg/daily) and placebo in 26 adolescents (15 to 19 years old) who exhibited problematic drinking patterns. Multilevel models tested whether naltrexone moderated associations of alcohol use with both positive and negative affect (PA, NA). RESULTS: Results indicated that, during naltrexone treatment, greater estimated blood alcohol concentration (eBAC) levels were associated with greater NA further into drinking episodes. In turn, greater NA after the first drink of an episode was associated with reduced subsequent eBAC values during naltrexone treatment. Low PA was also associated with lower subsequent eBAC levels in the naltrexone condition after the first drink. CONCLUSIONS: These findings support the idea that naltrexone can disrupt the association between affect and alcohol use, effects that emerge later in drinking episodes. Greater attention to the effects of naltrexone on affect and reinforcement may help to tailor psychotherapy to maximize the benefits of naltrexone. However, in the present study, as most drink reports were in the first 2 h of the drinking episode and participants reported affect only at the first three end-drink reports of a drinking episode (limiting the number of drinks reported), we had reduced power to detect effects in the continuation phase. Thus, replication of the findings is needed using a design that assesses the impact of naltrexone across the entire episode.