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The article offers information on priority areas for improving medications development for alcohol use disorder and promoting. It mentions about the drug development process more efficient in terms of speed, cost, and predictability and also focuses on the U.S. Food and Drug Administration's (FDA's) approval of disulfiram.

Background Treatment for alcohol use disorders (AUDs) has traditionally been abstinence oriented, but new research and regulatory guidelines suggest that low-risk drinking may also be an acceptable treatment outcome. However, little is known about long-term outcomes for patients who become low-risk drinkers posttreatment. This study explores a posttreatment low-risk drinking outcome as a predictor of future drinking and psychosocial outcomes over 9 years. Methods Study participants were adults with AUDs at treatment entry who received follow-up interviews 6 months posttreatment intake ( N = 1,061) in 2 large randomized studies conducted at Kaiser Permanente Northern California, a large private, nonprofit, integrated health system. Six-month drinking status was defined as abstinent, low-risk (nonabstinent, no 5+ drinking days), or heavy drinking (1 or more days of 5+ drinks). Using logistic regression models, we explored the relationship between past 30-day drinking status at 6 months and odds of being abstinent or a low-risk drinker (compared to heavy drinking), and positive Addiction Severity Index psychosocial outcomes over 9 years (9-year follow-up rate of 73%). Results Abstainers and low-risk drinkers at 6 months had higher odds of recent abstinence/low-risk drinking over 9 years than heavy drinkers; abstainers had better drinking outcomes than low-risk drinkers. Additionally, among those with interview data, 95% of abstainers and 94% of low-risk drinkers at 6 months were abstinent/low-risk drinkers at 9 years; surprisingly, 89% of heavy drinkers at 6 months were also abstinent/low-risk drinkers although still significantly fewer than the other groups. Abstainers and low-risk drinkers at 6 months had better psychiatric outcomes, and abstainers had better family/social outcomes than heavy drinkers; medical outcomes did not differ. Low-risk drinkers and abstainers showed no reliable differences across psychosocial measures. Conclusions The findings suggest that a low-risk drinking outcome may be reasonable over the long-term for some alcohol-dependent individuals receiving addiction treatment. [ABSTRACT FROM AUTHOR]

The article presents insights on the development of the LY2940094 selective nociceptin/orphanin receptor antagonist for alcohol use disorder (AUD). Topics covered include the effectiveness of the drug in reducing the number of heavy drinking days, the most common side effects of the drug and the major advances that may help augment the effect size of alcohol treatment medications.

For more than 25 years, advances have been made in developing medications to treat alcohol use disorder (AUD), highlighted by the U.S. Food and Drug Administration's approval of naltrexone (oral and long-acting) and acamprosate. Despite this progress, more work remains to be done in this area because these medications, although effective for some people, do not work for everyone. A high priority for the National Institute on Alcohol Abuse and Alcohol is to put into place a solid infrastructure to aid in the development of medications that are more effective than those currently available and with few side effects. Medication development, especially for a disorder as complex as AUD, is challenging and involves multiple phases, including discovery of "druggable" targets, preclinical studies, human clinical trials, and the adoption and implementation of the new medication into mainstream medicine. A successful medications development program requires clearly established goals for each phase to ensure that a candidate compound is not trapped in one particular phase, a condition known as "the valley of death." In this article, the phases of medication development are described as they apply to AUD, and specific goals of each phase are identified for the next decade. In addition, several important crosscutting themes are outlined for each phase, all of which are essential for advancing medications development. These include identifying and validating screening models and druggable targets, making use of precision medicine, and establishing partnerships among key stakeholders. Our goal in writing this article is to provide a guide on medications development that will aid the alcohol research community in planning, testing, and developing medications for AUD. [ABSTRACT FROM AUTHOR]

The article discusses heterogeneity in disorders related to alcohol use and mentions mechanism for personalized treatment. Topics discussed include existence of several typologies of alcohol use disorder (AUD) due to reasons like drinking history, psychiatric co-existence and alcohol dependence, use of behavioral therapies based on specific patient characteristics and psychosocial and biological basis of mental disorders among patients.

The process of developing pharmacological treatments for alcohol use disorder is notoriously complex and challenging. The path to market is long, costly, and inefficient. One way of expediting and reducing the drug development process is through collaborations-building partnerships among government, academia, pharmaceutical and biotechnology companies, healthcare organizations and advocacy groups, and the patients (end consumers) themselves. By forging collaborations, particularly with pharmaceutical companies, the alcohol treatment field stands to reap benefits in generating new medications for use in mainstream treatment settings. At the same time, there are certain caveats that should be considered, particularly by academic researchers, before entering into such partnerships. This commentary examines the advantages and caveats of government and academia collaborations with pharmaceutical companies. [ABSTRACT FROM AUTHOR]

Objective: Several definitions of treatment response have been proposed for alcohol clinical trials (e.g., abstinence and no heavy drinking). However, each of these outcomes allows only one definition of successful response. In contrast, the cumulative proportion of responders analysis (CPRA) includes all of the possible drinking response cutoff points, providing a more complete picture of the therapeutic effects of a treatment. CPRA has been used to examine the efficacy of analgesics but not alcohol pharmacotherapy. To demonstrate its potential utility, we conducted CPRA in two large alcohol treatment trials: the COMBINE (Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence) trial (naltrexone) and a multisite topiramate trial. CPRA was used to demonstrate the efficacy of naltrexone and topiramate on continuous measures of in-treatment drinking--heavy drinking days and drinks per day and their reductions from pretreatment. Method: All possible cutoff points were portrayed for each measure. We provide graphs to illustrate the effects of the active medications compared with placebo and examined them statistically over a number of salient drinking outcomes to evaluate their efficacy. Results: Treatment group responder curves were not parallel across the entire range of cutoff points; rather, they separated only at lower levels of drinking. In general, effect sizes increased by 0.10-0.15 when going from the lowest drinking level cutoff (i.e., abstinence and no heavy drinking) to the cutoff associated with the maximal treatment effect. Conclusions: CPRA may be useful in designing subsequent trials and helping to illustrate for treatment providers the likelihood of treatment success given various definitions of a positive response. [ABSTRACT FROM AUTHOR]

Objective: Several definitions of treatment response have been proposed for alcohol clinical trials (e.g., abstinence and no heavy drinking). However, each of these outcomes allows only one definition of successful response. In contrast, the cumulative proportion of responders analysis (CPRA) includes all of the possible drinking response cutoff points, providing a more complete picture of the therapeutic effects of a treatment. CPRA has been used to examine the efficacy of analgesics but not alcohol pharmacotherapy. To demonstrate its potential utility, we conducted CPRA in two large alcohol treatment trials: the COMBINE (Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence) trial (naltrexone) and a multisite topiramate trial. CPRA was used to demonstrate the efficacy of naltrexone and topiramate on continuous measures of in-treatment drinking-heavy drinking days and drinks per day-and their reductions from pretreatment.Method: All possible cutoff points were portrayed for each measure. We provide graphs to illustrate the effects of the active medications compared with placebo and examined them statistically over a number of salient drinking outcomes to evaluate their efficacy.Results: Treatment group responder curves were not parallel across the entire range of cutoff points; rather, they separated only at lower levels of drinking. In general, effect sizes increased by 0.10-0.15 when going from the lowest drinking level cutoff (i.e., abstinence and no heavy drinking) to the cutoff associated with the maximal treatment effect.Conclusions: CPRA may be useful in designing subsequent trials and helping to illustrate for treatment providers the likelihood of treatment success given various definitions of a positive response. [ABSTRACT FROM AUTHOR]

During the past decade, significant advances have been made in the development of medications to treat alcohol dependence. Four medications have been approved by the U.S. Food and Drug Administration for treating alcohol dependence-naltrexone, injectable naltrexone, acamprosate, and disulfiram-and several others show promise. The fact remains, however, that because of the heterogeneity of alcohol dependence, these medications will not work for all people, in all circumstances. Moreover, clinicians are not routinely prescribing these medications for alcohol treatment. This commentary poses a number of issues that must be addressed in order to advance the alcohol research field and to make medications a mainstream treatment for problematic drinking. These issues are framed from the perspective of the various stakeholders involved, including clinicians, patients, regulatory agencies, the pharmaceutical industry, and third-party payers. Addressing these issues will not only help to improve treatment but, as further described, will also open up many new research opportunities for alcohol investigators in the coming decade. [ABSTRACT FROM AUTHOR]

Background The placebo effect often undermines efforts to determine treatment effectiveness in clinical trials. A significant placebo response occurs in alcohol trials, but it is not well understood. The purpose of this study was to characterize the placebo response across multiple naltrexone and acamprosate studies. Methods Fifty-one trials, 3 with a naltrexone and an acamprosate arm, 31 with at least 1 naltrexone arm, and 17 with at least 1 acamprosate arm, were identified from Cochrane reviews and Pub Med search. To be included in this study, patients had to be at least 18 years old, abstinent from alcohol before randomization, and meet a diagnosis of alcohol dependence. Pearson correlation coefficients ( rp) and simple linear regression were used to describe the strength of linear relationships between placebo response and treatment effect size. Spearman's rank correlation coefficients ( rs) were used to examine the strength of associations between study characteristics and placebo response. Results For the end point measures of percent days abstinent and total abstinence, a negative relationship was evident between placebo response and treatment effect size in the naltrexone trials ( rp = −0.55, p < 0.01 and rp = −0.20, p = 0.35, respectively) as well as in the acamprosate trials ( rp = −0.45, p = 0.09 and rp = −0.56, p = 0.01, respectively). The placebo response for percent days abstinent was negatively correlated with mean age of participants ( rs = −0.42, p = 0.05) across naltrexone trials and positively correlated with publication year ( rs = 0.57, p = 0.03) across acamprosate trials. However, these 2 study characteristics were not significantly correlated with treatment effect size. Conclusions The placebo response varied considerably across trials and was negatively correlated with the treatment effect size. Additional studies are required to fully understand the complex nature of the placebo response and to evaluate approaches to minimize its effects. [ABSTRACT FROM AUTHOR]

ABSTRACT More than 76 million people world-wide are estimated to have diagnosable alcohol use disorders (AUDs) (alcohol abuse or dependence), making these disorders a major global health problem. Pharmacotherapy offers promising means for treating AUDs, and significant progress has been made in the past 20 years. The US Food and Drug Administration approved three of the four medications for alcoholism in the last two decades. Unfortunately, these medications do not work for everyone, prompting the need for a personalized approach to optimize clinical benefit or more efficacious medications that can treat a wider range of patients, or both. To promote global health, the potential reorganization of the National Institutes of Health (NIH) must continue to support the National Institute on Alcohol Abuse and Alcoholism's (NIAAA's) vision of ensuring the development and delivery of new and more efficacious medications to treat AUDs in the coming decade. To achieve this objective, the NIAAA Medications Development Team has identified three fundamental long-range goals: (1) to make the drug development process more efficient; (2) to identify more efficacious medications, personalize treatment approaches, or both; and (3) to facilitate the implementation and adaptation of medications in real-world treatment settings. These goals will be carried out through seven key objectives. This paper describes those objectives in terms of rationale and strategy. Successful implementation of these objectives will result in the development of more efficacious and safe medications, provide a greater selection of therapy options and ultimately lessen the impact of this devastating disorder. [ABSTRACT FROM AUTHOR]

Background: Despite advances in developing medications to treat alcohol dependence, few such medications have been approved by the Food and Drug Administration. Identified molecular targets are encouraging and can lead to the development and testing of new compounds. Atypical antipsychotic medications have been explored with varying results. Prior research suggests that the antipsychotic quetiapine may be beneficial in an alcohol-dependent population of very heavy drinkers. Methods: In this double-blind, placebo-controlled trial, 224 alcohol-dependent patients who reported very heavy drinking were recruited across 5 clinical sites. Patients received either quetiapine or placebo and Medical Management behavioral intervention. Patients were stratified on gender, clinical site, and reduction in drinking prior to randomization. Results: No differences between the quetiapine and placebo groups were detected in the primary outcome, percentage heavy-drinking days, or other drinking outcomes. Quetiapine significantly reduced depressive symptoms and improved sleep but had no effect on other nondrinking outcomes. Results from a subgroup analysis suggest that patients who reduced their drinking prior to randomization had significantly better drinking outcomes during the maintenance phase ( p < 0.0001). No significant interactions, however, were observed between reducer status and treatment group. Finally, quetiapine was generally well tolerated. Statistically significant adverse events that were more common with quetiapine versus placebo include dizziness (14 vs. 4%), dry mouth (32 vs. 9%), dyspepsia (13 vs. 2%), increased appetite (11 vs. 1%), sedation (15 vs. 3%), and somnolence (34 vs. 9%). Conclusions: This multisite clinical trial showed no efficacy for quetiapine compared with placebo at reducing alcohol consumption in heavy-drinking alcohol-dependent patients. [ABSTRACT FROM AUTHOR]

Although progress has been made in the treatment of alcohol use disorders, more effective treatments are needed. In the last 15 years, several medications have been approved for use in alcohol dependence but have only limited effectiveness and clinical acceptance. While academics have developed some 'standards' for the performance of clinical trials for alcohol dependence, they vary considerably, in the type of populations to be studied, the length of trials, salient outcome measures, and data analyses to be used (especially in the treatment of missing data). This variability impedes the commercial development of medications to treat alcohol dependence. Using a model similar to that used to develop an expert consensus for medications to improve cognitive aspects of schizophrenia (MATRICS) and in the treatment of pain (IMMPACT), a workgroup has been formed under the auspices of ACNP, known as the ACTIVE (Alcohol Clinical Trials Initiative) group, to evaluate data from completed clinical trials to develop a consensus on key issues in the conduct of clinical trials in alcohol dependence. ACTIVE consists of academic experts, industry representatives, and staff from the Food and Drug Administration, the National Institute on Alcohol Abuse and Alcoholism, and the National Institute on Drug Abuse. This paper describes the rationale behind the effort, its history and organization, and initial key questions that have been identified as the primary focus of the workgroup. Future papers will focus on knowledge gained from the re-analysis of completed trials and provide consensus opinions regarding the performance of clinical trials that might be undertaken in the future. [ABSTRACT FROM AUTHOR]

During the past decade, advances have been made in the identification, development, and application of alcohol biomarkers. This is important because of the unique functions that alcohol biomarkers can serve in various applied settings. To carry out these functions, biomarkers must display several features including validity, reliability, adequacy of temporal window of assessment, reasonable cost, and transportability. During the past two decades, several traditional alcohol biomarkers have been studied in multiple human studies. Meanwhile, several new, promising biomarkers, including various alcohol metabolites and alcohol biosensors, are being explored in human studies. In addition, researchers have explored using biomarkers in combination and using biomarkers in combination with self-reports, resulting in increased sensitivity with little sacrifice in specificity. Despite these advances, more research is needed to validate biomarkers, especially the new ones, in humans. Moreover, recent advances in high-throughput technologies for genomics, proteomics, and metabolomics offer unique opportunities to discover novel biomarkers, while additional research is needed to perfect newly developed alcohol sensors. Development of more accurate biomarkers will help practicing clinicians to more effectively screen and monitor individuals who suffer from alcohol use disorders. [ABSTRACT FROM AUTHOR]

Treatment of alcohol disorders through the use of combinations of pharmacological and behavioral modalities may more effectively address the multicomponent nature of the disorder than single-modality approaches. Interdisciplinary models of the biological, psychological and social components of alcohol disorders are emerging rapidly from basic research, and treatment researchers have begun to test various strategies to combine medications and behavioral treatments. In addition to behavioral and pharmacological combinations, effective treatment pairs can be composed of two medications whose mechanisms of action are believed to be compatible and potentially additive, or even synergistic. Combining Medications and Behavioral Interventions (COMBINE) is a large multisite clinical trial sponsored by the National Institute on Alcohol Abuse and Alcoholism. Its goal is to determine if improvements in treatment outcome for alcohol dependence can be achieved by combining pharmacotherapy and behavioral interventions. Under evaluation is the efficacy of two promising medications (naltrexone and acamprosate), both singly and together, when used in conjunction with two behavioral treatments of differing intensities. This supplement describes in detail the methods and rationale for the approach taken in COMBINE. This first article in the supplement has three objectives: (1) to review strategies for conducting combination treatment studies as illustrated with selected examples from the literature, (2) to summarize the main design features of COMBINE as background for the articles in this supplement and (3) to comment on future directions for combination treatment research as the field moves beyond COMBINE. [ABSTRACT FROM AUTHOR]

Background: Increasingly, biomarkers are being incorporated into the research design of clinical trials on medications to reduce drinking in alcoholics. To date, however, there has been little analysis of the unique roles that biomarkers can play in such investigations or of the practical and conceptual considerations that surround their best use in this context. Methods: Clinical trials of alcoholism medications published between 1985 and the present were abstracted to determine how biomarkers were used and how changes in them related to self-report measures of drinking. Results: Six uses of biomarkers were identified: determination of subjects to be included or excluded in the trial; description of baseline sample characteristics; primary and secondary outcome assessment; corroboration of self-reports of drinking status; specification of patients likely to respond to the medication; and evaluation of drug safety. Conclusion: Use of biomarkers in such studies appears warranted, particularly as an objective source of information on treatment efficacy that can be considered with patient self-report measures of drinking status. Biomarkers related to liver functioning also can assist in determination of drug safety for medications metabolized by the liver. [ABSTRACT FROM AUTHOR]

Although the primary use of biochemical markers of heavy drinking is to assist in screening for alcohol problems, laboratory tests may also aid in early identification of relapse. This report reviews research findings on a new marker, carbohydrate deficient transferrin (CDT), in alcoholics receiving treatment or in follow-up. It also offers recommendations on how CDT may be employed by clinicians monitoring drinking status. [ABSTRACT FROM AUTHOR]

Although the primary use of biochemical markers of heavy drinking is to assist in screening for alcohol problems, laboratory tests may also aid in early identification of relapse. This report reviews research findings on a new marker, carbohydrate deficient transferrin (CDT), in alcoholics receiving treatment or in follow-up. It also offers recommendations on how CDT may be employed by clinicians monitoring drinking status. [ABSTRACT FROM AUTHOR]

Many prospective clinical studies have concluded that craving does not reliably predict relapse and that the concept is of little or no clinical utility. Contrary to earlier more simplistic clinical models of addiction, more recent models do not require that craving be present for relapse to occur. New approaches to study human craving may enhance its predictive validity and yield more knowledge of its nature, course, behavioural sequelae and regulatory function in alcohol/drug consumption. These approaches include empirical research that focuses on: (1) the elucidation of the domains of craving (i.e. subjective experience, physiological responses, behavioural sequelae and their inter-relationships); (2) the temporal dynamics of craving (i.e. its course over minutes or days, as well as its natural history over the course of a drinking career); (3) the factors that may mediate/moderate/determine the development and resolution of craving; (4) studies of the predictive validity of craving measures; and (5) the development of valid methods of measuring the different domains of craving. The conclusions are that future craving research should: (1) incorporate more sophisticated general theories of behaviour (conditioning, cognitive social learning, neurobiological, and genetic); (2) apply more sophisticated and standardized measurement methods and experimental paradigms, including studies in which alcohol is made available to human subjects; and (3) effective development of new pharmacological and behavioural therapies for relapse prevention depend on greater understanding of the nature and measurement of craving. [ABSTRACT FROM AUTHOR]

Background: Early identification of alcohol problems in women is important. Differences in patterns of drinking and in biological function between genders, however, may present unique difficulties in biochemical screening. Methods: Published alcohol-screening studies with female samples and use as biomarkers of carbohydrate-deficient transferrin (CDT), γ-glutamyltransferase (GGT), and macrocytic volume were reviewed. Results: A wide range of sensitivities and specificities of GGT and CDT have been reported, although, in general, the two markers seem approximately equal in accuracy. As in the case of males, use of them in combination substantially enhances sensitivity and little reduces specificity. Use of macrocytic volume improves the sensitivity of both GGT and CDT as alcohol-screening markers. Conclusions: GGT and CDT have moderate sensitivity in screening for alcohol problems in women. Use of them in concert offers further advantage. [ABSTRACT FROM AUTHOR]

Background: The γ‐aminobutyric acid‐B (GABAB) receptor is a promising target for the development of new medications to treat alcohol use disorder (AUD). The GABAB agonist baclofen has been reported to reduce alcohol consumption but is associated with some undesirable side effects, including sedation. ASP8062 is a novel compound that acts as a positive allosteric modulator at the GABAB receptor and may be more tolerable than baclofen. This proof‐of‐concept human laboratory clinical trial evaluated the safety profile of ASP8062 and tested its effects on cue‐elicited alcohol craving and alcohol use among treatment‐seeking individuals with AUD. Methods: This double‐blind, randomized, multisite trial tested the effect of ASP8062 (25 mg once daily), relative to placebo, on alcohol cue‐elicited craving in a laboratory setting and alcohol consumption, craving, mood, sleep, cigarette smoking, and alcohol‐related consequences in the natural environment over a 6‐week treatment period. Participants were 60 individuals (26 females and 34 males) with moderate or severe AUD. Results: ASP8062, relative to placebo, was well tolerated, and there were no adverse events (AEs) that significantly differed between treatment groups. Most AEs were mild/moderate, and there were no serious AEs among individuals treated with ASP8062. However, ASP8062 did not attenuate alcohol cue‐elicited craving compared with placebo. Moreover, exploratory analyses indicated that ASP8062, relative to placebo, did not significantly affect alcohol consumption, naturalistic alcohol craving, mood, sleep, cigarette smoking, or alcohol‐related negative consequences during the 6‐week treatment period. Conclusions: Although ASP8062 was well tolerated with no serious AEs, the novel compound did not significantly dampen alcohol cue‐elicited craving or improve other AUD‐related outcome measures. These data indicate positive allosteric modulation of the GABAB receptor at the dose evaluated here may not blunt alcohol cue‐elicited craving, and preliminary drinking outcome data suggest it may not be an efficacious treatment strategy for AUD. [ABSTRACT FROM AUTHOR]

Physiologic, behavioral, and social factors contribute to dependence on alcohol, nicotine, and other drugs. During the past decade substantial research has focused on identification/development of medications to assist in reducing urge to use these substances. This article describes these agents and reviews recent research findings on them. [ABSTRACT FROM AUTHOR]

Research on the core version of the Alcohol Use Disorders Identification Test (AUDIT) is reviewed. Sensitivities and specificities of the AUDIT for criteria of current hazardous use and, to a slightly lesser extent, lifetime alcohol dependence are high. In general, AUDIT scores are at least moderately related to other self-report alcohol screening tests. Several studies also show them as correlated with biochemical measures of drinking. Results of the AUDIT have also been associated with more distal indicators of problematic drinking. Indices of internal consistency, including Cronbach's α and item-total correlations, are generally in the 0.80's. Future directions for research on the AUDIT are suggested. [ABSTRACT FROM AUTHOR]

Research on medications to treat alcohol problems has flourished in the last 5 years. Whereas before this time most projects focused on withdrawal agents, at least equal interest has now extended to drugs that may directly reduce urge to drink. The most promising medications in this regard are the opiate antagonists and acamprosate. Considerable attention has also been devoted to serotonergic agents. As aids to detoxification, pharmacologic agents that affect the multiple neural systems disrupted by acute alcohol withdrawal remain under active investigation. Significant progress is also being made in identifying medications to assist alcoholics suffering collateral psychopathology, especially depression and anxiety based disorders. Unfortunately, fewer gains have been realized in the development of medications to assist patients simultaneously dependent on both alcohol and illicit drugs. Also, research to develop amethys-tic agents remains in its very early stages. [ABSTRACT FROM AUTHOR]

Both γ-glutamyltranspeptidase and carbohydrate-deficient transferrin have been extensively researched as biological markers of heavy alcohol consumption. The current study briefly describes each test, identifies subject variables that influence their relative sensitivities and specificities, and examines issues surrounding use of the two markers in combination. In addition, this study suggests five design features that should characterize projects evaluating the validity of biochemical markers. [ABSTRACT FROM AUTHOR]

A growing body of investigations demonstrate that elevated levels of carbohydrate-deficient transferrin (CDT) effectively distinguishes alcoholics recently consuming large amounts of alcohol from light social drinkers or teetotalers. Nevertheless, important questions still remain concerning the value of CDT as a more generalized marker of alcohol consumption. Most important, the nature of the drinking pattern, including quantity and frequency, necessary to raise levels of CDT significantly remains unclear. Neither has research convincingly demonstrated that CDT is as accurate a marker for women, young adults, or non-Caucasian ethnic groups as for White, middleaged men. Whereas CDT might serve as a useful outcome measure in trials of alcoholism treatment effectiveness, current research suggests that CDT is of limited value in identifying problematic drinking in general medical or community settings in which a broad continuum of drinkers is represented. Combining CDT with other biochemical or self-report screening measures may, however, improve sensitivity in these contexts. At present, the most accurate laboratory technique to detect CDT seems to be isoelectric focusing. Additional research, however, is needed to resolve the issue of whether CDT is best quantitated as a simple value or if its ratio to total transferrin or non-CDT results in higher predictive validity. [ABSTRACT FROM AUTHOR]

Pharmacodynamic benefits of disulfiram in the treatment of alcoholism have yet to be clearly demonstrated. Nevertheless, research does suggest that disulfiram may well have positive effects on drinking if medicational compliance procedures are employed. This paper reviews research on four strategies for enhancing disulfiram compliance: implants, incentives, contracts, end patient information. Generalizations about the strategies are drawn and needs for future research are briefly addressed. [ABSTRACT FROM AUTHOR]

The past 10 years have witnessed important advances in research on pharmacotherapy for alcoholism. Promising drugs are discussed under six headings: agents to treat alcohol withdrawal; anticraving agents; agents that make drinking an aversive experience; agents to alleviate concomitant psychiatric problems; agents to treat concurrent drug abuse; and amethystic ('sobering-up') agents. Research on the drug classes is summarized and clinical issues surrounding specific agents and alcoholism pharmacotherapy in general are discussed. Finally, long-range therapeutic implications of recent findings on the actions of alcohol on basic mechanisms of the brain are offered. [ABSTRACT FROM AUTHOR]

A review of the article "Clinical validation of reduced alcohol consumption after treatment for alcohol dependence using the World Health Organization risk drinking levels" by Witkiewitz K, et al, which appeared in the periodical "Alcoholism: Clinical & Experimental Research" in 2017, is presented.

Background: Reductions in the World Health Organization (WHO) risk drinking levels have been proposed as an alternative primary outcome for alcohol clinical trials. Yet, little is known about whether reductions in WHO risk drinking levels can be maintained over time. The current study examined whether reductions in WHO risk drinking levels were maintained for up to 1 year following treatment, and whether reductions over time were associated with improvements in functioning. Methods: Secondary data analysis of individuals with alcohol dependence (n = 1,226) enrolled in the COMBINE study, a multisite, randomized, placebo‐controlled clinical trial. Logistic regression was used to examine the maintenance of end‐of‐treatment WHO risk level reductions and WHO risk level reductions at the 1‐year follow‐up. Repeated‐measures mixed models were used to examine the association between WHO risk level reductions and functional outcomes over time. Results: Achieving at least a 1‐ or 2‐level reduction in risk by the end of treatment was significantly associated with WHO risk level reductions at the 1‐year follow‐up assessment (p < 0.001). Among individuals who achieved at least a 1‐level reduction by the end of treatment, 85.5% reported at least a 1‐level reduction at the 1‐year follow‐up. Among individuals who achieved at least a 2‐level reduction by the end of treatment, 77.8% reported at least a 2‐level reduction at the 1‐year follow‐up. WHO risk level reductions were associated with significantly lower alcohol consumption, better physical health (p < 0.01), and fewer alcohol‐related consequences (p < 0.001) up to 1 year following treatment. Conclusions: One‐ and 2‐level reductions in WHO risk levels during alcohol treatment were maintained after treatment and associated with better functioning over time. These findings support the use of the WHO risk level reductions as an outcome measure that reflects clinically significant improvement in how individuals seeking treatment for alcohol use disorder feel and function. [ABSTRACT FROM AUTHOR]

Introduces several articles that focus on self-report measures and biochemical markers of alcohol consumption and abuse. Conditions that will maximize the validity of self-reports; Measurement of drinking patterns using alcohol interlock records; Reliability and accuracy of collateral informants; Gamma glutamyltransferase; Aspartate aminotransferase; Alanine aminotransferase; Red blood cell volume or mean corpuscular volume.

This article proposes a heuristic framework for the Addictions Neuroclinical Assessment that incorporates key functional domains derived from the neurocircuitry of addiction. We review how addictive disorders (ADs) are presently diagnosed and the need for new neuroclinical measures to differentiate patients who meet clinical criteria for addiction to the same agent while differing in etiology, prognosis, and treatment response. The need for a better understanding of the mechanisms provoking and maintaining addiction, as evidenced by the limitations of current treatments and within-diagnosis clinical heterogeneity, is articulated. In addition, recent changes in the nosology of ADs, challenges to current classification systems, and prior attempts to subtype individuals with ADs are described. Complementary initiatives, including the Research Domain Criteria project, that have established frameworks for the neuroscience of psychiatric disorders are discussed. Three domains—executive function, incentive salience, and negative emotionality—tied to different phases in the cycle of addiction form the core functional elements of ADs. Measurement of these domains in epidemiologic, genetic, clinical, and treatment studies will provide the underpinnings for an understanding of cross-population and temporal variation in addictions, shared mechanisms in addictive disorders, impact of changing environmental influences, and gene identification. Finally, we show that it is practical to implement such a deep neuroclinical assessment using a combination of neuroimaging and performance measures. Neuroclinical assessment is key to reconceptualizing the nosology of ADs on the basis of process and etiology, an advance that can lead to improved prevention and treatment. [ABSTRACT FROM AUTHOR]

Background Treatment for alcohol disorders has traditionally been abstinence-oriented, but evaluating the merits of a low-risk drinking outcome as part of a primary treatment endpoint is a timely issue given new pertinent regulatory guidelines. This study explores a posttreatment low-risk drinking outcome as a predictor of future drinking and problem severity outcomes among individuals with alcohol use disorders in a large private, not for profit, integrated care health plan. Methods Study participants include adults with alcohol use disorders at 6 months ( N = 995) from 2 large randomized studies. Logistic regression models were used to explore the relationship between past 30-day drinker status at 6 months posttreatment (abstinent [66%], low-risk drinking [14%] defined as nonabstinence and no days of 5+ drinking, and heavy drinking [20%] defined as 1 or more days of 5+ drinking) and 12-month outcomes, including drinking status and Addiction Severity Index measures of medical, psychiatric, family/social, and employment severity, controlling for baseline covariates. Results Compared to heavy drinkers, abstinent individuals and low-risk drinkers at 6 months were more likely to be abstinent or low-risk drinkers at 12 months (adj. ORs = 16.7 and 3.4, respectively; p < 0.0001); though, the benefit of abstinence was much greater than that of low-risk drinking. Compared to heavy drinkers, abstinent and low-risk drinkers were similarly associated with lower 12-month psychiatric severity (adj. ORs = 1.8 and 2.2, respectively, p < 0.01) and family/social problem severity (adj. OR = 2.2; p < 0.01). While abstinent individuals had lower 12-month employment severity than heavy drinkers (adj. OR = 1.9; p < 0.01), low-risk drinkers did not differ from heavy drinkers. The drinking groups did not differ on 12-month medical problem severity. Conclusions Compared to heavy drinkers, low-risk drinkers did as well as abstinent individuals for many of the outcomes important to health and addiction policy. Thus, an endpoint that allows low-risk drinking may be tenable for individuals undergoing alcohol specialty treatment. [ABSTRACT FROM AUTHOR]

This overview of the Addiction supplement on 'Research Perspectives on Alcohol Craving' has three objectives. The first is to familiarize readers with the variety of theoretical models relevant to craving and the definitions of craving generated by them that are discussed in the supplement. These include phenomenological models, classical and operant conditioning models, the incentive-sensitization theory, a tonic-phasic model of dopamine system regulation, cognitive social learning theory and the cognitive processing theory of craving. The second objective is to provide a brief summary of the methodological articles which focus as a whole more on what can be done than on what has been done in alcohol craving research. The final objective is to emphasize the potential importance of transdisciplinary research-research that integrates components of different theoretical models-for delineating the role of alcohol and drug craving in the complex biobehavioral process known as addiction. It is the hope of the guest editors (the authors of this overview) that the Addiction supplement and this introduction to it will contribute to development of a framework for future transdisciplinary research on alcohol craving. [ABSTRACT FROM AUTHOR]

Aims: To examine whether World Health Organization (WHO) risk‐level reductions in drinking were achievable, associated with improved functioning and maintained over time among patients at varying initial alcohol dependence severity levels. Design and setting Secondary data analysis of multi‐site randomized clinical trials: the US Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study and the UK Alcohol Treatment Trial (UKATT). Participants: Individuals with alcohol dependence enrolled in COMBINE (n = 1383; 68.8% male) and seeking treatment for alcohol problems in UKATT (n = 742; 74.1% male). Interventions Naltrexone, acamprosate or placebo, and combined behavioral intervention or medication management in COMBINE. Social behavior network therapy or motivational enhancement therapy in UKATT. Measurements WHO risk‐level reductions were assessed via the calendar method. Alcohol dependence was measured by the Alcohol Dependence Scale, the Leeds Dependence Questionnaire and the Diagnostic and Statistical Manual of Mental Disorders. Measures of functioning included alcohol‐related consequences (Drinker Inventory of Consequences and Alcohol Problems Questionnaire), mental health (Short Form Health Survey) and liver enzyme tests. Findings One‐ and two‐level reductions in WHO risk levels in the last month of treatment were maintained at the 1‐year follow‐up [adjusted odds ratio (OR), 95% confidence interval (CI) = one‐level reduction in COMBINE: 3.51 (2.73, 4.29) and UKATT: 2.65 (2.32, 2.98)] and associated with fewer alcohol‐related consequences [e.g. B, 95% CI = one‐level reduction COMBINE: –26.22 (–30.62, –21.82)], better mental health [e.g. B, 95% CI = one‐level reduction UKATT: 9.53 (7.36, 11.73)] and improvements in γ‐glutamyltransferase [e.g. B, 95% CI = one‐level reduction UKATT: –89.77 (–122.50, –57.04)] at the end of treatment, even among patients with severe alcohol dependence. Results were similar when abstainers were excluded. Conclusions Reductions in World Health Organization risk levels for alcohol consumption appear to be achievable, associated with better functioning and maintained over time in both the United States and the United Kingdom. [ABSTRACT FROM AUTHOR]

Background: The alcohol cue reactivity paradigm is increasingly used to screen medications for the treatment of alcohol use disorder (AUD) and other substance use disorders. Yet, its prospective association with craving and naturalistic drinking outcomes in clinical trials remains unknown. This study embedded repeated human laboratory assessments of alcohol cue reactivity within the context of a randomized controlled trial to examine the effects of varenicline tartrate (Chantix®), a partial agonist of α4β2 nicotinic acetylcholine receptors, on alcohol craving among treatment‐seeking heavy drinkers with AUD. Our main objectives were to test whether varenicline, as compared to placebo, blunts alcohol cue–elicited craving and test whether alcohol cue reactivity observed in the human laboratory predicts subsequent alcohol craving and use during the remainder of the trial. Design and Methods: This double‐blind, randomized, 2‐site study compared the effects of varenicline (up to 2 mg/d) and placebo on responses to in vivo alcohol cue and affective picture cue exposure in the human laboratory. Forty‐seven volunteers (18 females, 29 males), ages 23 to 67 years (M = 43.7, SD = 11.5), were recruited from the community via advertisements to participate in a clinical trial designed to study the effects of varenicline on alcohol use. Participants were randomized to either varenicline or placebo for 6 weeks. Results: Varenicline did not attenuate cue‐induced alcohol craving relative to placebo, but craving captured during the cue reactivity paradigm significantly predicted subsequent alcohol use in real‐world settings during the clinical trial. Higher craving predicted heavier alcohol use. Conclusions: Our results are among the first to show alcohol cue–induced craving captured during a human laboratory paradigm predicts drinking outcomes in the context of a clinical trial. [ABSTRACT FROM AUTHOR]

Background: Abstinence and no heavy drinking days are currently the only Food and Drug Administration–approved end points in clinical trials for alcohol use disorder (AUD). Many individuals who fail to meet these criteria may substantially reduce their drinking during treatment, and most individuals with AUD prefer drinking reduction goals. One‐ and two‐level reductions in World Health Organization (WHO) drinking risk levels have been proposed as alternative end points that reflect reduced drinking and are associated with reductions in drinking consequences, improvements in mental health, and reduced risk of developing alcohol dependence. The current study examined the association between WHO drinking risk level reductions and improvements in physical health and quality of life in a sample of individuals with alcohol dependence. Methods: Secondary data analysis of individuals with alcohol dependence (n = 1,142) enrolled in the longitudinal, prospective COMBINE study, a multi site randomized placebo‐controlled clinical trial, examining the association between reductions in WHO drinking risk levels and change in blood pressure, liver enzyme levels, and self‐reported quality of life following treatment for alcohol dependence. Results: One‐ and two‐level reductions in WHO drinking risk level during treatment were associated with significant reductions in systolic blood pressure (p < 0.001), improvements in liver enzyme levels (all p < 0.01), and significantly better quality of life (p < 0.001). Conclusions: One‐ and two‐level reductions in WHO drinking risk levels predicted significant improvements in markers of physical health and quality of life, suggesting that the WHO drinking risk level reduction could be a meaningful surrogate marker of improvements in how a person "feels and functions" following treatment for alcohol dependence. The WHO drinking risk levels could be useful in medical practice for identifying drinking reduction targets that correspond with clinically significant improvements in health and quality of life. At least 1‐ and 2‐level reductions in the World Health Organization (WHO) drinking risk levels by the end of treatment were associated with significant improvements at the end of treatment for physical health and quality of life outcomes. The WHO drinking risk level reductions capture considerable improvement in how patients feel and function in alcohol clinical trials. [ABSTRACT FROM AUTHOR]

Incentive salience, negative emotionality, and executive function are functional domains that are etiologic in the initiation and progression of addictive disorders, having been implicated in humans with addictive disorders and in animal models of addictions. Measures of these three neuroscience-based functional domains can capture much of the effects of inheritance and early exposures that lead to trait vulnerability shared across different addictive disorders. For specific addictive disorders, these measures can be supplemented by agent specific measures such as those that access pharmacodynamic and pharmacokinetic variation attributable to agent-specific gatekeeper molecules including receptors and drug-metabolizing enzymes. Herein, we focus on the translation and reverse translation of knowledge derived from animal models of addiction to the human condition via measures of neurobiological processes that are orthologous in animals and humans, and that are shared in addictions to different agents. Based on preclinical data and human studies, measures of these domains in a general framework of an Addictions Neuroclinical Assessment (ANA) can transform the assessment and nosology of addictive disorders, and can be informative for staging disease progression. We consider next steps and challenges for implementation of ANA in clinical care and research. This article is part of the Special Issue entitled “Alcoholism”. [ABSTRACT FROM AUTHOR]

Background Recently, the Food and Drug Administration ( FDA) proposed to expand the options for primary end points in the development of medications for alcohol use disorder to include either abstinence from alcohol or a nonabstinent outcome: no heavy drinking days (with a heavy drinking day defined as more than 3 drinks per day for women and more than 4 drinks per day for men [>3/>4 cutoff]). The FDA also suggested that 6 months would be the most appropriate length for a clinical trial to demonstrate the stability of this nonabstinent drinking outcome. However, few alcohol clinical trials have examined the stability of nonheavy drinking during and after treatment. Methods In a secondary analysis of the COMBINE study data ( n = 1,383), we examined transitions in heavy drinking days during the course of treatment (months 1 through 4), during the transition out of treatment (months 4 through 7), and up to 12 months afterward (months 13 through 16) using latent variable mixture models. Results Heavy drinking and nonheavy drinking were relatively stable in consecutive months (minimum agreement [kappa] = 0.64 for months 1 to 2). Most individuals were stable low-risk drinkers/abstainers or heavy drinkers by the end of treatment, as characterized by a 10% probability (or less) of transitioning out of either a no heavy drinking state or a heavy drinking state. More than two-thirds of the heavy drinkers who exceeded the heavy drinking threshold during treatment reported, on average, a 64% reduction in drinking frequency and a 38% reduction in drinking intensity from pretreatment drinking levels. Conclusions The results show stability of no heavy drinking as an outcome within the first 4 months of treatment and that the >3/>4 drink cutoff may mask substantial reductions in alcohol consumption among some patients. Future studies should explore the clinical utility of reduction end points. [ABSTRACT FROM AUTHOR]

Background Alcohol use disorder (AUD) is a highly prevalent public health problem associated with considerable individual and societal costs. Abstinence from alcohol is the most widely accepted target of treatment for AUD, but it severely limits treatment options and could deter individuals who prefer to reduce their drinking from seeking treatment. Clinical validation of reduced alcohol consumption as the primary outcome of alcohol clinical trials is critical for expanding treatment options. One potentially useful measure of alcohol treatment outcome is a reduction in the World Health Organization (WHO, International Guide for Monitoring Alcohol Consumption and Related Harm. Geneva, Switzerland, 2000) risk levels of alcohol use (very high risk, high risk, moderate risk, and low risk). For example, a 2-shift reduction in WHO risk levels (e.g., high risk to low risk) has been used by the European Medicines Agency (2010, Guideline on the Development of Medicinal Products for the Treatment of Alcohol Dependence. UK) to evaluate nalmefene as a treatment for alcohol dependence (AD; Mann et al. 2013, Biol Psychiatry 73, 706-13). Methods The current study was a secondary data analysis of the COMBINE study ( n = 1,383; Anton et al., ) to examine the association between reductions in WHO risk levels and reductions in alcohol-related consequences and mental health symptoms during and following treatment in patients with AD. Results Any reduction in WHO risk drinking level during treatment was associated with significantly fewer alcohol-related consequences and improved mental health at the end of treatment and for up to 1 year posttreatment. A greater reduction in WHO risk drinking level predicted a greater reduction in consequences and greater improvements in mental health. Conclusions Changes in WHO risk levels appear to be a valid end point for alcohol clinical trials. Based on the current findings, reductions in WHO risk drinking levels during treatment reflect meaningful reductions in alcohol-related consequences and improved functioning. [ABSTRACT FROM AUTHOR]

Placebo-controlled pharmacotherapy trials for alcohol use disorder (AUD) require an active behavioral platform to avoid putting participants at risk for untreated AUD and to better assess the effectiveness of the medication. Therapist-delivered platforms (TDP) can be costly and present a risk to study design because of the variability in therapist fidelity. Take Control is a novel computer-delivered behavioral platform developed for use in pharmacotherapy trials sponsored by the National Institute on Alcohol Abuse and Alcoholism Clinical Investigations Group (NCIG). This behavioral platform was developed with the goal of reducing trial implementation costs and limiting potential bias introduced by therapists providing TDP. This exploratory study is the first to compare Take Control with TDP on measures related to placebo response rate, medication adherence, and participant retention. Data were drawn from the placebo arms of four multisite, double-blind, randomized controlled trials (RCT) for AUD conducted by NCIG from 2007 to 2015. Data were compared from subjects receiving TDP (n = 156) in two RCTs and Take Control (n = 155) in another two RCTs. Placebo response rate, as represented by weekly percentage of heavy drinking days, was similar between groups. Subjects who received Take Control had a higher rate of medication adherence than those who received TDP. Subject retention was not significantly different between groups. The findings suggest that Take Control is comparable to TDP on measures of retention, medication adherence, and placebo response. Additional research is needed to evaluate Take Control directly against TDPs in a randomized trial. [ABSTRACT FROM AUTHOR]

Background: Missing data are common in alcohol clinical trials for both continuous and binary end points. Approaches to handle missing data have been explored for continuous outcomes, yet no studies have compared missing data approaches for binary outcomes (e.g., abstinence, no heavy drinking days). This study compares approaches to modeling binary outcomes with missing data in the COMBINE study. Methods: We included participants in the COMBINE study who had complete drinking data during treatment and who were assigned to active medication or placebo conditions (N = 1,146). Using simulation methods, missing data were introduced under common scenarios with varying sample sizes and amounts of missing data. Logistic regression was used to estimate the effect of naltrexone (vs. placebo) in predicting any drinking and any heavy drinking outcomes at the end of treatment using 4 analytic approaches: complete case analysis (CCA), last observation carried forward (LOCF), the worst case scenario (WCS) of missing equals any drinking or heavy drinking, and multiple imputation (MI). In separate analyses, these approaches were compared when drinking data were manually deleted for those participants who discontinued treatment but continued to provide drinking data. Results: WCS produced the greatest amount of bias in treatment effect estimates. MI usually yielded less biased estimates than WCS and CCA in the simulated data and performed considerably better than LOCF when estimating treatment effects among individuals who discontinued treatment. Conclusions: Missing data can introduce bias in treatment effect estimates in alcohol clinical trials. Researchers should utilize modern missing data methods, including MI, and avoid WCS and CCA when analyzing binary alcohol clinical trial outcomes. [ABSTRACT FROM AUTHOR]

Background: The development and approval of an efficacious pharmacotherapy for stimulant use disorders has been limited by the lack of a meaningful indicator of treatment success, other than sustained abstinence.Methods: In March, 2015, a meeting sponsored by Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) was convened to discuss the current state of the evidence regarding meaningful outcome measures in clinical trials for stimulant use disorders. Attendees included members of academia, funding and regulatory agencies, pharmaceutical companies, and healthcare organizations. The goal was to establish a research agenda for the development of a meaningful outcome measure that may be used as an endpoint in clinical trials for stimulant use disorders.Results and Conclusions: Based on guidelines for the selection of clinical trial endpoints, the lessons learned from prior addiction clinical trials, and the process that led to identification of a meaningful indicator of treatment success for alcohol use disorders, several recommendations for future research were generated. These include a focus on the validation of patient reported outcome measures of functioning, the exploration of patterns of stimulant abstinence that may be associated with physical and/or psychosocial benefits, the role of urine testing for validating self-reported measures of stimulant abstinence, and the operational definitions for reduction-based measures in terms of frequency rather than quantity of stimulant use. These recommendations may be useful for secondary analyses of clinical trial data, and in the design of future clinical trials that may help establish a meaningful indicator of treatment success. [ABSTRACT FROM AUTHOR]

Background Attrition is common in alcohol clinical trials and the resultant loss of data represents an important methodological problem. In the absence of a simulation study, the drinking outcomes among those who are lost to follow-up are not known. Individuals who drop out of treatment and continue to provide drinking data, however, may be a reasonable proxy group for making inferences about the drinking outcomes of those lost to follow-up. Methods We used data from the COMBINE study, a multisite, randomized clinical trial, to examine drinking during the 4 months of treatment among individuals who dropped out of treatment but continued to provide drinking data (i.e., 'treatment dropouts;' n = 185). First, we estimated the observed treatment effect size for naltrexone versus placebo in a sample that included both treatment completers ( n = 961) and treatment dropouts ( n = 185; total N = 1,146), as well as the observed treatment effect size among just those who dropped out of treatment ( n = 185). In both the total sample ( N = 1,146) and the dropout sample ( n = 185), we then deleted the drinking data after treatment dropout from those 185 individuals to simulate missing data. Using the deleted data sets, we then estimated the effect of naltrexone on the continuous outcome percent heavy drinking days using 6 methods to handle missing data (last observation carried forward, baseline observation carried forward, placebo mean imputation, missing = heavy drinking days, multiple imputation ( MI), and full information maximum likelihood [ FIML]). Results MI and FIML produced effect size estimates that were most similar to the true effects observed in the full data set in all analyses, while missing = heavy drinking days performed the worst. Conclusions Although missing drinking data should be avoided whenever possible, MI and FIML yield the best estimates of the treatment effect for a continuous outcome measure of heavy drinking when there is dropout in an alcohol clinical trial. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to examine the relations between drinking (mean quantity and heavy drinking patterns) and alcohol use disorders (AUDs) in the U.S. general population. Method: Data from three telephone National Alcohol Surveys (in 2000, 2005, and 2010) were pooled, with separate analyses for men and women restricted to current drinkers (ns = 5,922 men, 6,270 women). Predictors were 12-month volume (mean drinks per day), rates of heavy drinking (5+/4+ drinks in a day for men/women), and very heavy drinking (8+, 12+, and 24+ drinks in a day). Outcomes were negative alcohol-related consequences constituting abuse (1+ of 4 DSM-IV-based domains assessed by 13 items) and alcohol dependence (symptoms in 3+ of 7 DSMIV based domains), together taken to indicate an AUD. Segmentation analyses were used to model risks of problem outcomes from drinking patterns separately by gender. Results: In the general population, men and women who consumed <1 drink/day on average with no heavy drinking days did not incur substantial risks of an AUD (<10%). Men who drank from 1 to 2 drinks/day on average but never 5+ incurred a 16% risk of reporting an AUD (3.5% alcohol dependence). At higher volumes, men and women who indicated higher rates of drinking larger amounts per day and/or involving 8+ and 12+ drinks/day (and even 24+ drinks/ day for men) showed much higher risks of experiencing AUDs. Conclusions: The findings provide quantitative guidance for primary care practitioners who wish to make population-based recommendations to patients who might benefit by reducing both overall intake and amounts per occasion in an effort to lower their risks of developing AUDs. [ABSTRACT FROM AUTHOR]