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Background: Abstinence has historically been considered the preferred goal of alcohol use disorder (AUD) treatment. However, most individuals with AUD do not want to abstain and many are able to reduce their drinking successfully. Craving is often a target of pharmacological and behavioral interventions for AUD, and reductions in craving may signal recovery. Whether reductions in drinking during AUD treatment are associated with reductions in craving has not been well examined. Methods: We conducted secondary analyses of data from three AUD clinical trials (N's= 1327, 346, and 200). Drinking reductions from baseline to the end of treatment were measured as changes in World Health Organization (WHO) risk drinking levels; alcohol craving was measured using validated self‐report measures. Regression analyses tested whether drinking reductions were associated with end‐of‐treatment craving reductions; moderation analyses tested whether associations between drinking reduction and end‐of‐treatment craving differed across AUD severity. Results: Reductions of at least 1 or at least 2 WHO risk drinking levels were associated with lower craving (all p's < 0.05). Results were substantively similar after removing abstainers at the end‐of‐treatment. Associations between drinking reductions and craving were generally not moderated by AUD severity. Conclusions: Individuals with WHO risk drinking level reductions reported significantly lower craving, as compared to those who did not achieve meaningful reductions in drinking. The results demonstrate the utility of WHO risk drinking levels as AUD clinical trial endpoints and provide evidence that drinking reductions mitigate craving. [ABSTRACT FROM AUTHOR]

ObjectivesThis article presents an overview of the current literature on biological markers for alcoholism, including markers associated with the pharmacological effects of alcohol and markers related to the clinical course and treatment of alcohol-related problems. Many of these studies are well known, while other studies cited are new and still being evaluated.MethodsIn this paper we first describe known biomarkers of alcohol-related disorders, review their features and the problems involved in their use. We then consider future developments on biomarkers and their possible impact on the field.ResultsMore recent findings cited include the work on type 7 adenylcyclase (AC) polymorphism and its lower expression levels in female alcoholics. Neuroimaging studies involving biomarkers have also reported brain volume reductions of gray and white matter, including amygdala and subcortical regions in alcoholic patients, while a high association between the copy number variations (CNVs) in 6q14.1/5q13.2 and alcohol dependence has more recently been identified in genetic studies.ConclusionsIn addition to their possible importance for diagnosis, biomarkers may have utility for predicting prognosis, progression of the disorder, the development of new treatments, and monitoring treatment effects. Although such findings should be verified in independent studies, the search for new biomarkers is continuing. Several potential candidate biomarkers have been found recently in blood, imaging, and genetic studies with encouraging results.

Objective: Little is known about change over time in the prevalence of World Health Organization (WHO) risk drinking levels (very high, high, moderate, low) and their association with health conditions, overall and by gender. The authors used two sets of nationally representative U.S. survey data to determine whether changes over time varied by gender and to examine whether health conditions related to alcohol were associated with WHO risk drinking level within each survey, and whether these associations differed by gender.Methods: Data on current drinkers from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; N=26,655) and the 2012-2013 NESARC-III (N=25,659) were analyzed using logistic regression. Prevalence differences between surveys were estimated for each drinking level overall and by gender. Within each survey, prevalence differences by WHO risk drinking level were estimated for alcohol use disorder (AUD), drug use disorders, functional impairment, liver disease, and depressive and anxiety disorders.Results: In the 2012-2013 survey, the prevalences of moderate, high, and very high risk drinking were 5.9%, 3.2%, and 3.5%, respectively, representing significant increases from the prevalences in the 2001-2002 survey, which were 1.0%, 0.6%, and 0.9%, respectively. The increase for very high risk drinking among men (0.5%) was smaller than the increase among women (1.4%). Within both surveys, compared with low risk, health conditions were significantly associated with very high risk (range of prevalence differences, 2.2%-57.8%), high risk (2.6%-41.3%), and moderate risk (0.6%-29.8%) drinking. Associations were similar by gender, except that there were stronger effects for AUD in men and for functional impairment and depressive and anxiety disorders in women.Conclusions: The increase in potentially problematic drinking levels among U.S. adults emphasizes the need for better prevention and treatment strategies. The study results support the validity of the WHO risk drinking levels, which show clinical utility as nonabstinent drinking reduction treatment goals. Such goals could engage more people in treatment, improving public health by decreasing personal and societal consequences of risk drinking. [ABSTRACT FROM AUTHOR]

Importance: The US Food and Drug Administration recognizes total abstinence and no heavy drinking days as outcomes for pivotal pharmacotherapy trials for alcohol use disorder (AUD). Many patients have difficulty achieving these outcomes, which can discourage seeking treatment and has slowed the development of medications that affect alcohol use.Objective: To compare 2 drinking-reduction outcomes with total abstinence and no heavy drinking outcomes.Design, Setting, and Participants: Data were obtained from 3 multisite, randomized, placebo-controlled clinical trials of medications for treating alcohol dependence (naltrexone, varenicline, and topiramate) in adults with DSM-IV-categorized alcohol dependence.Main Outcomes and Measures: Within each trial, the percentage of participants in active and placebo conditions who met responder definitions of abstinence, no heavy drinking days, a WHO 1-level reduction, and a WHO 2-level reduction was computed by month with corresponding effect sizes (Cohen h).Results: Across the 3 trials (N = 1169; mean [SD] age, 45 [10] years; 824 [70.5%] men), the percentage of participants classified as responders during the last 4 weeks of treatment was lowest for abstinence (naltrexone, 34.7% [100 of 288]; varenicline, 7.3% [7 of 96]; topiramate, 11.7% [21 of 179]) followed by no heavy drinking days (naltrexone, 51.0% [147 of 288]; varenicline, 24.0% [23 of 96]; topiramate, 20.7% [37 of 179]), WHO 2-level reduction (naltrexone, 75.0% [216 of 288]; varenicline, 55.2% [53 of 96]; topiramate, 44.7% [80 of 179]), and WHO 1-level reduction (naltrexone, 83.3% [240 of 288]; varenicline, 69.8 [67 of 96]; topiramate, 54.7% [98 of 179]) outcomes. Standardized treatment effects observed for the WHO 2-level reduction outcomes (naltrexone, Cohen h = 0.214 [95% CI, 0.053 -0.375]; varenicline, 0.273 [95% CI, -0.006 to 0.553]; topiramate, 0.230 [95% CI, 0.024-0.435]) and WHO 1-level reduction (naltrexone, Cohen h = 0.116 [95% CI, -0.046 to 0.277]; varenicline, 0.338 [95% CI, 0.058-0.617]; topiramate, 0.014 [95% CI, -0.192 to 0.219]) were comparable with those obtained using abstinence (naltrexone, Cohen h = 0.142 [95% CI, -0.020 to 0.303]; varenicline, 0.146 [95% CI, -0.133 to 0.426]; topiramate, 0.369 [95% CI, 0.163-0.574]) and no heavy drinking days (naltrexone, Cohen h = 0.140 [95% CI, -0.021 to 0.302]; varenicline, 0.232 [95% CI, -0.048 to 0.511]; topiramate, 0.207 [95% CI, 0.002-0.413]).Conclusions and Relevance: WHO drinking risk level reductions appear to be worthwhile indicators of treatment outcome in AUD pharmacotherapy trials. These outcomes may align with drinking reduction goals of many patients and capture clinically meaningful improvements experienced by more patients than either abstinence or no heavy drinking days.Trial Registration: ClinicalTrials.gov identifiers: NCT00006206; NCT01146613; NCT00210925. [ABSTRACT FROM AUTHOR]

Nalmefene, a mu- and delta-opioid receptor (MOR, DOR) antagonist and a partial kappa-opioid receptor (KOR) agonist, is approved in the European Union and other countries for the reduction of alcohol consumption in alcohol dependent patients with a high drinking risk level according to WHO (“target population”). This review presents an overview of nalmefene׳s pharmacology, its mechanisms of action and a meta-analysis on its efficacy in reducing alcohol consumption. The review was based on a systematic search of the literature. Random effects meta-analyses were performed on published and unpublished trials directed at drinking reduction using the changes in heavy drinking days (HDDs) and daily total alcohol consumption (TAC) from baseline to the primary endpoint. For each included study and each dose, Hedges’ g was used as an unbiased estimator of the standardised mean differences between nalmefene and placebo. Preclinical data suggests that nalmefene counters alcohol-induced dysregulations of the MOR/endorphine and the KOR/dynorphin system. Evidence further suggests that reduced alcohol consumption is an effective treatment strategy that appeals to patients not ready for abstinence. Finally, meta-analyses confirmed the efficacy of 20 mg nalmefene for reducing HDDs in the ITT population (Hedge׳s g=−0.20; 95% CI −0.30 to −0.09) and the target population (Hedge׳s g=−0.33; 95% CI −0.48 to −0.18). Similar results were seen for TAC. Several meta-analyses, including this new meta-analysis, support nalmefene׳s efficacy in reducing alcohol consumption. In conclusion, because it does not require abstinence, this treatment has the potential to motivate more patients for treatment and thus helps to address a major public health concern. [ABSTRACT FROM AUTHOR]

Background: The latest French good practice recommendations (GPRs) for the screening, prevention, and treatment of alcohol misuse were recently published in partnership with the European Federation of Addiction Societies (EUFAS). This article aims to synthesize the GPRs focused on the pharmacotherapy of alcohol dependence. Methods: A four-member European steering committee defined the questions that were addressed to an 18-member multiprofessional working group (WG). The WG developed the GPRs based on a systematic, hierarchical, and structured literature search and submitted the document to two review processes involving 37 French members from multiple disciplines and 5 non-French EUFAS members. The final GPRs were graded A, B, or C, or expert consensus (EC) using a reference recommendation grading system. Results: The treatment of alcohol dependence consists of either alcohol detoxification or abstinence maintenance programs or drinking reduction programs. The therapeutic objective is the result of a decision made jointly by the physician and the patient.For alcohol detoxification, benzodiazepines (BZDs) are recommended in first-line (grade A). BZD dosing should be guided by regular clinical monitoring (grade B). Residential detoxification is more appropriate for patients with a history of seizures, delirium tremens, unstable psychiatric comorbidity, or another associated substance use disorder (grade B). BZDs are only justified beyond a 1-week period in the case of persistent withdrawal symptoms, withdrawal events or associated BZD dependence (grade B). BZDs should not be continued for more than 4 weeks (grade C). The dosing and duration of thiamine (vitamin B1) during detoxification should be adapted to nutritional status (EC).For relapse prevention, acamprosate and naltrexone are recommended as first-line medications (grade A). Disulfiram can be proposed as second-line option in patients with sufficient information and supervision (EC). For reducing alcohol consumption, nalmefene is indicated in first line (grade A). The second-line prescription of baclofen, up to 300 mg/day, to prevent relapse or reduce drinking should be carried out according to the “temporary recommendation for use” measure issued by the French Health Agency (EC).During pregnancy, abstinence is recommended (EC). If alcohol detoxification is conducted during pregnancy, BZD use is recommended (grade B). No medication other than those for alcohol detoxification should be initiated in pregnant or breastfeeding women (EC). In a stabilized pregnant patient taking medication to support abstinence, the continuation of the drug should be considered on a case-by-case basis, weighing the benefit/risk ratio. Only disulfiram should be always stopped, given the unknown risks of the antabuse effect on the fetus (EC).First-line treatments to help maintain abstinence or reduce drinking are off-label for people under 18 years of age and should thus be considered on a case-by-case basis after the repeated failure of psychosocial measures alone (EC). Short half-life BZDs should be preferred for the detoxification of elderly patients (grade B). The initial doses of BZDs should be reduced by 30 to 50% in elderly patients (EC). In patients with chronic alcohol-related physical disorders, abstinence is recommended (EC). Any antidepressant or anxiolytic medication should be introduced after a psychiatric reassessment after 2–4 weeks of alcohol abstinence or low-risk use (grade B). A smoking cessation program should be offered to any smokers involved in an alcohol treatment program (grade B). [ABSTRACT FROM AUTHOR]

Individuals with alcohol-dependent parents show an elevated risk of developing alcohol-related problems themselves. Modulations of the mesolimbic reward circuit have been postulated as a pre-existing marker of alcoholism. We tested whether a positive family history of alcoholism is correlated with ventral striatum functionality during a reward task. All participants performed a modified version of the monetary incentive delay task while their brain responses were measured with functional magnetic resonance imaging. We compared 206 healthy adolescents (aged 13-15) who had any first- or second-degree relative with alcoholism to 206 matched controls with no biological relative with alcoholism. Reward anticipation as well as feedback of win recruited the ventral striatum in all participants, but adolescents with a positive family history of alcoholism did not differ from their matched peers. Also we did not find any correlation between family history density and reward anticipation or feedback of win. This finding of no differences did not change when we analyzed a subsample of 77 adolescents with at least one parent with alcohol use disorder and their matched controls. Because this result is in line with another study reporting no differences between children with alcohol-dependent parents and controls at young age, but contrasts with studies of older individuals, one might conclude that at younger age the effect of family history has not yet exerted its influence on the still developing mesolimbic reward circuit. [ABSTRACT FROM AUTHOR]

Background Effect sizes of pharmacotherapy in alcoholism are modest. They might improve if subjects could be divided into more homogeneous subgroups and would then be treated targeted to their neurobiological profile. In such an effort, we tested neural cue reactivity as a potential predictor of treatment response to naltrexone. Alcohol-associated cues cause brain activations in mesocorticolimbic networks due to the positive reinforcing properties of alcohol. These activations were reported to be associated with relapse behavior. Naltrexone, an antagonist at the mu-opioid receptor, improves drinking behavior in some but not all patients probably by blocking the positive reinforcement of alcohol. Conversely, acamprosate is proposed to modulate negative reinforcement (withdrawal and cue-induced withdrawal). Identifying subjects with elevated cue reactivity and testing their response to medical treatment could thus improve our understanding of some of the mechanisms underlying pharmacotherapy response. Methods A picture-perception task featuring alcohol-related and neutral stimuli was presented to 64 recently detoxified alcohol-dependent patients. Patients came from 1 center of a larger double-blind randomized multicenter clinical trial (the 'PREDICT Study'). They were scanned prior to being randomized to either naltrexone or acamprosate. We examined the interaction between medication and functional magnetic resonance imaging ( fMRI) cue reactivity, as measured by the percentage of voxels activated, using the time to the first severe relapse as the outcome criterion. Our a priori formulated hypothesis was that naltrexone but not acamprosate should be efficacious in subjects with high cue reactivity. Results We observed an interaction effect between pretreatment brain activation induced by alcohol images and medication (acamprosate/naltrexone) on relapse behavior. In line with our hypothesis, this interaction was driven by treatment response to naltrexone in patients with elevated pretreatment cue reactivity in the ventral striatum. Conclusions fMRI has the potential for predicting treatment response to naltrexone in a subgroup of alcohol-dependent patients. However, this approach will be limited to researching the mechanisms and principles of treatment response. [ABSTRACT FROM AUTHOR]

Abstract: Recent publications calculated an annual prevalence of 38% of the population within the European Union having a “disorder of the brain” including substance use disorders (SUD) (Wittchen et al., 2011). The overall economic burden was estimated at 789 billion € (Gustavsson et al., 2011). While these calculations included alcohol dependence, harmful use of alcohol, a common ICD-10 diagnosis, was not considered appropriately. Tobacco related figures were completely left out. We hence estimated burden and costs of these diagnoses for the European Union by extrapolating basic figures from Germany, which have average proportions of alcohol and tobacco related consumption and prevalence rates. Several German Data sets were used to estimate prevalence, disability adjusted life years (DALYs) and Cost-of-Illness for alcohol and tobacco use disorders in Germany. Results were obtained by focussing on the burden of SUD including well-known comorbidities. Results were then extrapolated to the European level. Compared with the earlier estimations DALYs increased from 2.8 million to over 6.6 million for SUDs. Costs augmented from 65.68 billion € PPP to about 350 billion € PPP. We discuss the robustness and validity of our findings under different assumptions and with regard to methodology. We further took into account that in the new DSM 5 alcohol abuse and alcohol dependence – and similar tobacco – will be collapsed into one category of “alcohol related disorder”. If added to the burden and cost calculations the substance use disorders rank on top of all disorders of the brain in Europe. Regardless of the calculation procedure our figures represent lower estimates and have to be regarded as conservative approaches. [Copyright &y& Elsevier]

A literature review of existing research on the prevalence of alcohol use disorders (AUDs) and availability of alcohol interventions in Europe was conducted. The review also explored what is known about the gap between need and provision of alcohol interventions in Europe. The review search strategy included: (i) descriptive studies of alcohol intervention systems in Europe; (ii) studies of alcohol service provision in Europe; and (iii) studies of prevalence of AUD and alcohol needs assessment in Europe. Europe has a relatively high level of alcohol consumption and the resulting disabilities are the highest in the world. Most research on implementation of alcohol interventions in Europe has been restricted to screening and brief interventions. Alcohol needs assessment methodology has been developed but has not been applied in comparative studies across countries in Europe. This review points to key gaps in knowledge related to alcohol interventions in Europe. There is a lack of comparative data on variations in alcohol treatment systems across European countries and there is also a lack of comparative data on the prevalence of alcohol use disorders across European countries and the relative gap between need and access to treatment. The forthcoming Alcohol Measures for Public Health Research Alliance (AMPHORA) research project work package on 'Early identification and treatment' aims to address these gaps. [ABSTRACT FROM AUTHOR]

Aims During the development of drug addiction, initial hedonic effects decrease when substance use becomes habitual and ultimately compulsive. Animal research suggests that these changes are represented by a transition from prefrontal cortical control to subcortical striatal control and within the striatum from ventral to dorsal domains of the striatum, but only limited evidence exists in humans. In this study we address this hypothesis in the context of alcohol dependence. Design, setting and participants Non-abstinent heavy social drinkers ( n = 21, 5.0 ± 1.5 drinks/day, 13 of them were alcohol-dependent according to DSM-IV) and light social drinkers ( n = 10, 0.4 ± 0.4 drinks/day) were examined. Measurements We used a cue-reactivity functional magnetic resonance imaging (fMRI) design during which pictures of alcoholic beverages and neutral control stimuli were presented. Findings In the dorsal striatum heavy drinkers showed significant higher activations compared to light drinkers, whereas light social drinkers showed higher cue-induced fMRI activations in the ventral striatum and in prefrontal areas compared to heavy social drinkers [region of interest analyses, P < 0.05 false discovery rate (FDR)-corrected]. Correspondingly, ventral striatal activation in heavy drinkers correlated negatively with obsessive-compulsive craving, and furthermore we found a positive association between cue-induced activation in the dorsal striatum and obsessive-compulsive craving in all participants. Conclusions In line with our hypothesis we found higher cue-induced activation of the ventral striatum in social compared to heavy drinkers, and higher dorsal striatal activation in heavy drinkers. Increased prefrontal activation may indicate that social drinkers activate cortical control when viewing alcohol cues, which may prevent the development of heavy drinking or alcohol dependence. Our results suggest differentiating treatment research depending on whether alcohol use is hedonic or compulsive. [ABSTRACT FROM AUTHOR]

Background: Activation of the anterior cingulate cortex (ACC) in a spatial working memory task has been associated with risk factors for alcohol use disorders such as low alcohol effects and positive alcohol expectations in adolescents. To transfer these results into adults, we used the same task in adults. Methods: During functional magnetic resonance imaging, 12 light social, 7 heavy social, and 11 non-abstinent-dependent alcohol drinkers performed a spatial working memory task and completed measures of automatic alcohol-related thoughts and behavior (Obsessive–Compulsive Drinking Scale—OCDS), alcohol use of the last 90 days, and general intelligence. Results: Behavioral performance in the spatial working memory task was not significantly different in all 3 groups. Controlling for differences in general intelligence alcohol-dependent participants showed a higher task-related activation of the dorsal ACC (dACC) in comparison with light and heavy social drinkers. Measures of the OCDS were positively correlated with the activation in the left hippocampus and right thalamus in all participants. Conclusions: Our results support the findings of increased dACC activation during a spatial working memory task as a risk factor for alcohol dependence. Increased task-related activation in the dACC was only observed in alcohol-dependent participants and not in heavy social drinkers with comparable alcohol consumption. Furthermore, the absence of behavioral performance differences between groups as well as an association between dACC activation and working memory performance indicates subtle working memory deficits. Low capacity of working memory has been linked to more automatic and less self-regulated behavior in studies on natural reward processing. Therefore, additional neural activation during performance of the non-alcohol-related working memory task in participants with higher OCDS values in the left hippocampus and the right thalamus may be a consequence of decreased neural capacity because of distracting alcohol-related thoughts. [ABSTRACT FROM AUTHOR]

Background: Human alcohol self-administration studies employing oral intake are subject to high variability of the resulting blood alcohol concentrations because of idiosyncrasies of gastrointestinal absorption kinetics among subjects. We sought to improve the subjects’ opportunity to control their brain alcohol exposure by computer-assisted i.v. self-administration. Methods: Instead of drinking, subjects could request increments of their arterial blood alcohol concentration (aBAC) of precisely 7.5 mg% at any time they wanted by pressing a button, provided their aBAC would not exceed 100 mg%. The latency between pushing the button and reaching the new aBAC peak was preset to be 2.5 minutes on the first day and was randomly changed to 1.5 or 3.5 minutes on days 2 and 3 in a crossover design. The necessary rate and amount of alcohol infusion was calculated by the software about once every second. Nine healthy social drinkers (4 females/5 males; mean age 25.0 ± 4.0 year) participated in 3 sessions each. Outcome measures were mean and maximum observed aBAC, and the number of alcohol requests. Results: Maximum aBAC was 76.5 ± 26.3 mg% on average over all experiments. When grouping days 2 and 3 according to latency (1.5 vs. 3.5 minutes), maximum aBAC and the number of requests in the session were significantly higher with the faster rise and all 3 outcome measures were significantly correlated between days. No such correlations were found between the first and either of the following days. Conclusions: These data suggest that CASE is practical and safe, and results in considerable alcohol exposure that can be manipulated with parameters chosen for the incremental exposure. Following 1 practice day, test–retest stability was good, suggesting a potential for use in scientific studies. [ABSTRACT FROM AUTHOR]

Chronic alcohol consumption is associated with neural damage that manifests in deficits in information processing. Previous studies evaluated higher cognitive functions such as working memory, but basic sensory information processing circuits have never been investigated before. Therefore, we applied a simple visual and acoustic stimulation paradigm in this functional magnetic resonance imaging (fMRI) pilot study. Nine recently detoxified male alcohol-dependent patients and nine healthy volunteers were presented a well-established 6-Hz checkerboard and auditory stimuli in the form of drumbeats in a block-design fMRI paradigm. During visual and acoustic stimulation, alcoholics and controls activated widespread occipital and temporal brain areas, as well as parts of the dorsolateral prefrontal cortex and thalamus. In a comparison of the stimulation-induced activation of alcoholics and controls, the alcoholics showed a significantly lower blood oxygen level dependent (BOLD) signal in an extended bilateral occipital area ( P < 0.001) as compared with healthy controls. In no region was the BOLD signal significantly higher in the alcohol-dependent subjects compared with controls. The reason for the new finding of a highly significant lower activation of the occipital cortex is unclear. It is in line with studies of neuropsychological tests in recently detoxified alcohol-dependent patients that also reported deficits in visual abilities. Attention deficits or a persisting neuronal alteration in the first weeks of alcohol abstinence may have contributed to this result. [ABSTRACT FROM AUTHOR]

Objectives: This pilot study has been designed to collect preliminary data on the use of a new antiepileptic drug in the management of alcoholic patients. Oxcarbazepine (OXC) blocks voltage-sensitive sodium channels. Its metabolite reduces high-voltage–activated calcium currents in striatal and cortical neurons, thus reducing glutamatergic transmission at corticostriatal synapses. This reduction is of interest in the treatment of alcohol dependence, as acamprosate (ACP) modulates NMDA receptors, resulting in an inhibition of glutamatergic transmission. Furthermore, OXC has revealed a mood-stabilizing effect in bipolar affective disorders. We have compared OXC with ACP in relapse prevention in recently withdrawn alcohol-dependent patients. Methods: We investigated the efficacy and safety of OXC (vs ACP) by conducting a 24-week randomized, parallel-group, open-label, clinical trial on 30 acutely detoxified alcoholic patients. Survival analyses (Kaplan–Meier) were performed to look for evidence of a longer “survival” of patients receiving OXC. We assessed time to first severe relapse and additional secondary endpoints. Results: After withdrawal, time to severe relapse and time to first consumption of any ethanol by OXC patients were not longer than for ACP patients. Abstinent patients in both study groups showed a significantly lower obsessive compulsive drinking scale—German version (OCDS-G) than relapsed patients. No undesired effects occurred when OXC patients consumed alcohol. Conclusion: Our findings indicate that it could be worthwhile to test relapse prevention using OXC in an adequate sample. While the current sample size clearly limits further conclusions from this pilot study, it is noteworthy that OXC is well tolerated, even when alcohol is on board. Thus, in medication-based relapse prevention, OXC could be a promising alternative for alcoholic patients unable to benefit from ACP or naltrexone or those who have affective liability. OXC certainly merits a larger placebo-controlled trial. [ABSTRACT FROM AUTHOR]

Abstract: The treatment of alcohol dependence mainly consists of psychological, social, and pharmacotherapeutic interventions aiming to reduce physical withdrawal, craving, and alcohol relapse. During the last years, it has become increasingly clear that adjuvant pharmacotherapy is efficacious especially in rehabilitation programs for alcohol dependent patients. The development of alcohol dependence seems to involve adaptive changes in amino acid neurotransmitter systems, stimulation of dopamine and opioid peptide systems, and changes in serotonergic activity. Disulfiram, naltrexone and acamprosate are approved treatments for the management of abstinence maintenance treatment. New compounds are under investigation. This review discusses the neurobiological basis of alcohol addiction, pharmacological targets for relapse prevention treatment and pre-clinical and clinical results with the most promising drugs. [Copyright &y& Elsevier]

Objective: Alcohol and other drugs of abuse stimulate dopamine release in the ventral striatum, which includes the nucleus accumbens, a core region of the brain reward system, and reinforce substance intake. Chronic alcohol intake is associated with down-regulation of central dopamine D2 receptors, and delayed recovery of 2 receptor sensitivity after detoxification is positively correlated with high risk for relapse. Prolonged 2 receptor dysfunction in the ventral striatum may interfere with a dopamine-dependent error detection signal and bias the brain reward system toward excessive attribution of incentive salience to alcohol-associated stimuli. Method: Multimodal imaging, with the radioligand [18F] desmethoxyfallypride and positron emission tomography as well as functional magnetic resonance imaging (fMRI), was used to compare 11 detoxified male alcoholics with 13 healthy men. The authors measured the in the ventral striatum with alcohol craving and central processing of alcohol cues. Results: Activation of the medial prefrontal cortex and striatum by alcohol-associated stimuli, relative to activation by neutral visual stimuli, was greater in the detoxified alcoholics than in the healthy men. The alcoholics displayed less availability of 2-like receptors in the ventral striatum, which was associated with alcohol craving severity and with greater cueinduced activation of the medial prefrontal cortex and anterior cingulate as assessed with fMRI. Discussion: In alcoholics, dopaminergic dysfunction in the ventral striatum may attribute incentive salience to alcohol-associated stimuli, so that alcohol cues elicit craving and excessive activation of neural networks associated with attention and behavior control. [ABSTRACT FROM AUTHOR]

Few medications for treating alcohol dependence exist. Greater partnership is needed between academia and the pharmaceutical industry to develop, licence and market efficacious medications for treating alcohol dependence. Methodologies that span the divide between preclinical and large-scale clinical studies need to be developed in order to provide sufficient information on safety, toleration, drug-interaction profile and efficacy, with which to guide development decisions. Due to the heterogeneous nature of alcohol dependence, the effort of developing an efficacious medication is likely to be enhanced by clearer choices about the characteristics of the population. Careful consideration of potential mechanism of action of the putative therapeutic medication should enable the appropriate choice of drinking endpoint. The pharmaceutical industry in collaboration with academia might need to develop new approaches to determining appropriate treatment endpoints with regulatory bodies. The investment risk to industry should be appraised not only in terms of the rather poor results of previous marketing efforts but with a view to the opportunity to penetrate a potentially enormous and largely untapped market. [ABSTRACT FROM AUTHOR]

Thyroid dysfunction is a prominent finding in alcoholism. Subclinical and clinical hypothyroidism have been associated with clinical depression and cognitive impairment and may increase the relapse risk among alcoholics. In spite of these important clinical associations, there is no consensus on thyroid dysfunction in alcoholism in the literature. In this paper, we present a review of the literature and develop a hypothesis that may explain dysfunction of the hypothalamic-pituitary-thyroid axis in alcoholism. Based on a Medline research of the years 1980-2001 we found 33 empirical studies that assessed thyroid function in alcoholism. The most consistent findings were a reduction in total thyroxine and total and free triiodothyronine concentrations during early abstinence. About one-third of all alcoholics also displayed a blunted thyroid stimulation hormone (TSH) response in the thyrotrophin-releasing hormone test (TRH-test). Blunting was observed frequently during detoxification, but was also present in some alcoholics after several weeks of abstinence. We suggest that a reduction in peripheral thyroid hormones may be caused by a direct toxic effect of alcohol on the thyroid gland, which induces a central compensatory activation of the hypothalamic-pituitary axis with an increased TRH release. The TRH release induces a downregulation of pituitary TRH receptors, which manifest as a blunted TSH response to the TRH test. We discuss further additional effects of alcohol on thyroid-hormone metabolizing deiodinases and on monoaminergic systems, which may interact directly with mood states among abstinent alcoholics. [ABSTRACT FROM AUTHOR]

During the first weeks of abstinence, alcohol craving in patients may increase or "incubate." We hypothesize that Naltrexone (NTX) blocks this incubation effect. Here, we compared NTX effects on neural alcohol cue reactivity (CR) over the first weeks of abstinence and on long-term clinical outcomes to standard treatment. Male alcohol-dependent patients (n = 55) and healthy controls (n = 35) were enrolled. Participants underwent baseline psychometric testing and functional magnetic resonance imaging (fMRI) assessment of mesolimbic alcohol CR. Patients participated in a standard treatment program with the option of adjuvant NTX. They received another scan after 2 weeks of treatment. We found higher CR in several brain regions in patients versus healthy controls. CR significantly increased over 2 weeks in the standard treatment group (n = 13) but not in the NTX group (n = 22). NTX significantly attenuated CR in the left putamen and reduced relapse risk to heavy drinking within 3 months of treatment. Additionally, increased CR in the left putamen and its course over time predicted both NTX response and relapse risk. Carrier status for the functional OPRM1 variant rs1799971:A > G was considered but had no effect on NTX efficacy. In conclusion, NTX was most effective in patients with high CR in the left putamen. While the results from our naturalistic study await further confirmation from prospective randomized trials, they support a potential role of neural CR as a biomarker in the development of precision medicine approaches with NTX. [ABSTRACT FROM AUTHOR]

Background: Non-abstinent drinking reductions that predict improvement in how individuals feel or function, such as the World Health Organization (WHO) drinking risk levels, may be useful outcomes in clinical trials for alcohol use disorders (AUD).Methods: Current drinkers in a U.S. national survey (n = 22,005) were interviewed in 2001-02 (Wave 1) and re-interviewed 3 years later (Wave 2). WHO drinking risk levels, a 4- level categorization system (very-high-risk, high-risk, moderate-risk, and low-risk drinkers) defined using estimated mean ethanol consumption (grams) per day in the prior 12 months, and DSM-IV depressive and anxiety disorders were assessed at both waves. Logistic regression was used to produce adjusted odds ratios (aOR) testing the associations of changes between Wave 1 and Wave 2 WHO risk levels to the presence or persistence of depression and/or anxiety disorder by each initial Wave 1 risk level.Results: Among Wave 1 very-high-risk drinkers, lower odds of depression and/or anxiety disorders at Wave 2 were predicted by reductions in WHO risk levels of one-, two- or three-levels (aOR = 0.42, 0.37, 0.67, p-values 0.04-<.0001), as was the persistence of depression and/or anxiety disorders among those with such disorders at Wave 1 (aOR = 0.37, 0.29, 0.51, p-values .03-<.0001). Results were less consistent for participants initially drinking at lower risk levels.Conclusions: Among very-high-risk drinkers, reductions in the WHO drinking risk categories were associated with lower risk of depression and/or anxiety disorders. These results add to findings indicating reductions in WHO risk levels are a meaningful indicator of how individuals feel and function. [ABSTRACT FROM AUTHOR]

Abstract: Since the application of the Obsessive Compulsive Drinking Scale (OCDS) has been reported to be problematic when used to measure alcohol craving in longitudinal studies, we examined the following questions: (1) Is it possible to skip problematic quantity items? (2) Is the score calculation rule using the higher value of item pairs necessary? (3) Can the shortened version of the OCDS be applied alternatively? We examined two samples including a total of 355 alcohol-dependent patients: a multi center study sample (n =149) and a validation control sample (n =206). Neither an advantage of the score calculation rule nor the necessity of including items regarding alcohol consumption could be demonstrated. The exclusion of consumption items lead to a clear, stable 2-factor structure with a maximum stability (.81–.91). Retest-reliability ranged from r tt =.73 to r tt =.76 at an average time interval of 5 weeks. Concerning stability (.68–.81) and reliability (r tt =.76), the short version turned out to be equivalent. The short version of the OCDS seems to be sufficient. If different effects on cognitive and behavioral levels are expected, the 12-item version without the quantity items should be applied. [Copyright &y& Elsevier]

Abstract: A variety of environmental and genetic factors modulating the risk for alcoholism have been described, which predominantly act by interacting with each other. For example, the family, peers and society determine the level of exposure to stress and alcohol, while genes modulate how sensitive an individual responds to both. The resulting behaviors feed back to the social environment, modulating and in the worst case increasing further stress exposure. We here review neurobiological evidence how such a process of mutual interaction can involve and affect drinking. In at-risk adolescents it may have been in force for many years before they have their first alcoholic drink, increasing their risk for addiction by generating allostatic load. As an example, psychiatric disorders involving attention deficit, hyperactivity, or disruptive behaviors first evolve during childhood and are influenced by all the above factors. They are also strongly associated with harmful adolescent drinking and later alcohol use disorders. One important implication of this concept is that issues such as family adversity, adolescent psychiatric disorders, or adolescent drinking might not only be associated with, but causally related to, the risk for later addiction. They are targets for preventive interventions, which should start as early as possible in subjects at-risk. [Copyright &y& Elsevier]

Background: This study focused on metabolic brain alterations in recently detoxified alcohol-dependent patients (S1) and their possible reversibility after 3 (S2) and 6 months (S3) of abstinence. Methods: Thirty-three alcohol-dependent patients and 30 healthy control subjects were studied with multislice proton magnetic resonance spectroscopic imaging (echo time = 135 msec at 1.5 T at three time points). Results: In the patient group, we found that choline-containing compounds (Ch) in three frontal and cerebellar subregions at S1 were significantly below normal, whereas N-acetyl aspartate (NAA) differences did not reach significance but showed a trend toward below-normal values in frontal white matter. Abstinent patients showed a significant increase of Ch in all subregions at S2. At S3, no further significant metabolite changes in abstinent patients compared with S2 could be detected. No significant increase of NAA could be detected at follow-up. Conclusions: The increase of the Ch signal in the follow-up measurement after 3 months in abstinent alcohol-dependent patients supports the hypotheses of an alcohol- or alcohol detoxification–induced altered cerebral metabolism of lipids in membranes or myelin, which seems to be reversible with duration of alcohol abstinence. [Copyright &y& Elsevier]