Topiramate Versus Naltrexone for Alcohol Use Disorder: A Genotype-Stratified Double-Blind Randomized Controlled Trial.

OBJECTIVE: There have been no well-controlled and well-powered comparative trials of topiramate with other pharmacotherapies for alcohol use disorder (AUD), such as naltrexone. Moreover, the literature is mixed on the effects of two polymorphisms-rs2832407 (in GRIK1) and rs1799971 (in OPRM1)-on response to topiramate and naltrexone, respectively. The authors sought to examine the comparative effectiveness of topiramate and naltrexone in improving outcomes in AUD and to examine the role of the rs2832407 and rs1799971 polymorphisms, respectively, on response to these medications. METHODS: In a 12-week, double-blind, placebo-controlled, randomized, multisite, genotype-stratified (rs2832407 and rs1799971) clinical trial comparing topiramate and naltrexone in treating AUD, 147 patients with AUD were randomly assigned to treatment with topiramate or naltrexone, stratified by genotype (rs2832407*CC and *AC/AA genotypes and rs1799971*AA and *AG/GG genotypes). The predefined primary outcome was number of heavy drinking days per week. Predefined secondary outcomes included standard drinks per drinking day per week, body mass index (BMI), craving, markers of liver injury, mood, and adverse events. RESULTS: For the number of heavy drinking days per week, there was a near-significant time-by-treatment interaction. For the number of standard drinks per drinking day per week, there was a significant time-by-treatment interaction, which favored topiramate. There were significant time-by-treatment effects, with greater reductions observed with topiramate than naltrexone for BMI, craving, and gamma-glutamyltransferase level. Withdrawal due to side effects occurred in 8% and 5% of the topiramate and naltrexone groups, respectively. Neither polymorphism showed an effect on treatment response. CONCLUSIONS: Topiramate is at least as effective and safe as the first-line medication, naltrexone, in reducing heavy alcohol consumption, and superior in reducing some clinical outcomes. Neither rs2832407 nor rs1799971 had effects on topiramate and naltrexone treatments, respectively.

Neuroimaging studies of cannabidiol and potential neurobiological mechanisms relevant for alcohol use disorders: a systematic review.

The underlying neurobiological mechanisms of cannabidiol's (CBD) management of alcohol use disorder (AUD) remains elusive.Aim We conducted a systematic review of neuroimaging literature investigating the effects of CBD on the brain in healthy participants. We then theorise the potential neurobiological mechanisms by which CBD may ameliorate various symptoms of AUD.Methods This review was conducted according to the PRISMA guidelines. Terms relating to CBD and neuroimaging were used to search original clinical research published in peer-reviewed journals.Results Of 767 studies identified by our search strategy, 16 studies satisfied our eligibility criteria. The results suggest that CBD modulates γ-Aminobutyric acid and glutamate signaling in the basal ganglia and dorso-medial prefrontal cortex. Furthermore, CBD regulates activity in regions associated with mesocorticolimbic reward pathways; salience, limbic and fronto-striatal networks which are implicated in reward anticipation; emotion regulation; salience processing; and executive functioning.Conclusion CBD appears to modulate neurotransmitter systems and functional connections in brain regions implicated in AUD, suggesting CBD may be used to manage AUD symptomatology.

Hypothalamic-pituitary-adrenocortical response in alcohol-dependent patients during baclofen treatment and association with clinical outcome: Preliminary results.

Baclofen has been shown to reduce alcohol consumption in some individuals with alcohol use disorder. This preliminary study aimed to evaluate i) the effect of baclofen versus placebo on hypothalamic-pituitary-adrenocortical activity (HPA axis), as measured by cortisol, and ii) the relationship between clinical outcomes such as alcohol consumption on a randomized controlled trial of baclofen (BAC) versus placebo (PL) (Kirsten C. Morley et al., 2018; K. C. Morley, Leung, Baillie, & Haber, 2013). We hypothesized that baclofen will reduce HPA-axis activity following a mild stressor in patients with alcohol dependence. Plasma cortisol levels were taken from N = 25 alcohol-dependent patients at two time points, approximately 60 (pre-MRI scan: PreCortisol) and 180 min (post MRI scan: PostCortisol) following administration of PL, BAC 10 mg, or BAC 25 mg. Participants were followed up for the remaining 10 weeks as part of the trial for clinical outcome (percentage days abstinent). Mixed models revealed a significant main effect of medication on cortisol levels (F = 3.88, p = 0.037), no significant effect of time (F = 0.04, p = 0.84), and a significant time × medication interaction (F = 3.54, p = 0.049). Linear regression (F = 6.98, p = 0.01, R2 = 0.66) revealed that abstinence at follow-up, weighted by gender, was predicted by blunted cortisol response (ß = -0.48 p = 0.023), in addition to medication (ß = 0.73 p = 0.003). In conclusion, our preliminary data suggest that baclofen moderates HPA-axis activity, as measured by blood cortisol, and that these alterations may play a role in long-term treatment response.

Impaired Decision-Making and Skin Conductance Responses Are Associated with Reward and Punishment Sensitivity in Individuals with Severe Alcohol Use Disorder.

INTRODUCTION: Individuals with alcohol use disorder (AUD) have difficulties regulating alcohol consumption, despite adverse drinking-related consequences. This may be due to incapacity incorporating previous negative feedback from drinking, resulting in impaired decision-making. METHODS: We assessed whether decision-making is impaired in participants with AUD related to severity of AUD, indexed by severe negative drinking consequences using the Drinkers Inventory of Consequences (DrInC) and reward and punishment sensitivity with the Behavioural Inhibition System Behavioural Activation System (BIS BAS) scales. 36 treatment-seeking alcohol-dependent participants completed the Iowa gambling task (IGT) with skin conductance responses (SCRs) measured continuously as an index of somatic autonomic arousal to evaluate impaired expectancy of negative outcomes. RESULTS: Two-thirds of the sample showed behavioural impairment during the IGT, with greater AUD severity related to worse performance. BIS moderated IGT performance according to severity of AUD, with increased anticipatory SCRs for those with fewer reported DrInC severe consequences. Participants with more DrInC severe consequences showed IGT deficits and reduced SCRs regardless of BIS scores. BAS-Reward was associated with increased anticipatory SCRs to disadvantageous deck choices among those with lower AUD severity, while SCRs did not differ related to AUD severity for reward outcomes. DISCUSSION: Effective decision-making in the IGT and adaptive somatic responses were moderated by punishment sensitivity contingent on severity of AUD in these drinkers, with impairments in expectancy to negative outcomes from risky choices, including reduced somatic responses, resulting in poor decision-making processes that may help explain impaired drinking and worse drinking-related consequences.

Assessing the validity of the Wechsler Adult Intelligence Scale (WAIS-IV) in predicting completion in a long-term residential rehabilitation for substance use problems.

BACKGROUND: We aimed to examine the predictive validity of the Weschler Adult Intelligence Scale (WAIS-IV) in predicting treatment completion, over and above educational status. METHODS: One hundred and ninety-six (N = 196) individuals from the Odyssey House Residential Rehabilitation Program, NSW, Australia between 2010 and 2016 were administered a structured interview including substance use disorders and the Verbal Comprehension (VCI), Perceptual Reasoning (PRI), Working Memory (WMI), and Processing Speed (PSI) domains of the WAIS-IV. RESULTS: There were significant differences between our clinical sample and the population norm with respect to the proportion below the mean for PSI (z = 12.27, p < .001), VCI (z = 2.33, p < .02) but not for WMI (z = 1.67, p < .10) or PRI (z = -1.76, p < .08). The WAIS-IV subscales did not significantly predict treatment completion (p's > .16) over and above educational status (p < .01). CONCLUSIONS: Our findings suggest that in clients in drug and alcohol rehabilitation settings a combination of skills may be impacted including Verbal Comprehension and Processing Speed. Moreover, our findings also suggest that WAIS-IV subscales do not predict treatment completion in a drug and alcohol residential setting, over and above a brief assessment of educational status.

Sex differences in the interrelations between stress, craving and alcohol consumption across individuals and time during baclofen treatment for alcohol dependence.

AIMS: Recent studies have suggested that females respond more favourably to baclofen treatment for alcohol use disorder. Females are generally more likely to drink to regulate stress reactivity and negative affect. This study thus aimed to evaluate the role of sex on the effect of baclofen on the relationship between daily alcohol consumption, stress and craving. METHODS: A network analysis of fluctuations using vectorized autoregressive modelling was used to explore the relationship between daily surveys of alcohol consumption, stress and craving from daily diary data over 84 days from a randomised controlled trial of baclofen (30 mg or 75 mg per day) versus placebo in 104 participants with alcohol dependence (1, 2). Symptom interrelations across patients and across time were examined including temporal networks (time lagged), contemporaneous and between-subjects networks, and were examined for placebo and baclofen stratified by sex. RESULTS: Overall, between persons, there was a significant relationship between stress and drinking in placebo treated individuals in females (r = -0.70, p < 0.001) but not males (r = 0.32, p = 0.054) that was not observed in baclofen treated individuals. No relationship was observed between stress and drinking in the baclofen group for either sex (p's < 0.45). DISCUSSION: There appears to be some sex-specific differences whereby baclofen abolishes an overall association between stress and drinking in females, but this is not observed in males. Network analyses may assist in elucidating the mechanism of action of alcohol pharmacotherapies such as baclofen and understanding which symptoms and mechanisms are key for effective interventions.

The role of impulsivity in the relationship between affect and alcohol consumption in young adults.

BACKGROUND: Theoretical models of alcohol use posit that individuals consume alcohol to ameliorate negative affect or to heighten positive affect. It is important, however, to consider the influence of factors that may determine an individual's tendency to consume excessive amounts of alcohol under positive and negative circumstances. Thus, the current study examined a large sample of young adults to clarify whether positive and negative affect predict total alcohol consumption on drinking days and whether facets of impulsivity moderate these relationships. METHODS: Six-hundred ninety-three young adults (Mage = 19.71 years, SD = 2.04; female = 62.9%) completed the Behavioral Inhibition System/Behavioral Activation System (BIS/BAS) scales at baseline followed by daily measures of positive and negative affect and self-reported alcohol use for 13 days. Generalized linear mixed models were specified to assess the role of pre-consumption affect on total drinks consumed across drinking days and to determine the moderating effect of each BIS/BAS subscale. RESULTS: Participants were significantly more likely to drink in greater quantities on occasions preceded by higher positive affect but not negative affect. While fun-seeking positively predicted total drinks consumed, there were no significant interaction effects between the BIS/BAS subscales and affect on total drinks consumed. CONCLUSIONS: These findings challenge existing affect regulation models and have implications for ecological momentary interventions aimed at addressing hazardous drinking behaviors.

Daily experiences of hangover severity and food consumption in young adults.

OBJECTIVES: Our aim was to determine whether alcohol hangover is associated with eating unhealthy foods (hot chips, soft drink) or healthy foods (fruit, vegetables). DESIGN: Daily diary study across 13 days (micro-longitudinal design). METHODS: We examined a sample of 605 young adults (71% women; ages 17-25; mean age 19.91 [SD 1.86] years) who completed daily diaries in the university community and reported drinking alcohol at least twice during the 13-day study period. Each day, participants reported on their hangover severity, their consumption of fruit, vegetables, hot chips (French fries), and soft drink, and their alcohol consumption from the previous day. Linear mixed models were used to examine within-person associations between hangover severity and food consumption, by gender. Exploratory models also controlled for previous day alcohol consumption to acknowledge potential variability in hangover susceptibility. RESULTS: On days when participants reported higher severity of hangovers, they reported consuming more hot chips (ß = .09, p = .001), more soft drink (ß = .08, p = .001) and less fruit (ß = -.06, p = .05). In our exploratory model controlling for previous day alcohol consumption, the predictive effect of hangover severity on hot chips remained (ß = .08, p = .009) and significant interaction effects were observed between gender and previous day alcohol consumption on fruit (ß = -.03, p = .003) and vegetable (ß = -.03, p = .03) servings. CONCLUSIONS: Higher hangover severity may lead to greater intake of some unhealthy foods such as hot chips, an effect that may not be reduceable to those associated with alcohol consumption per se. Interventions that target excessive drinking primarily, but also emphasize the importance of a healthy diet, should be considered for this population.

GABAB Receptors and Alcohol Use Disorders: Clinical Studies.

Harmful alcohol use and alcohol use disorders (AUD) result in major health and community burden worldwide, yet treatment options are limited. Novel pharmacotherapies are urgently required, and treatments involving GABAB receptors have been used in treating alcohol-related disorders. This chapter will review the clinical evidence of GABAB pharmacotherapies, such as baclofen and γ-hydroxybutyric acid. This includes the use of these treatments in individuals experiencing alcohol withdrawal symptoms and outlining the outcomes of studies of alcohol relapse prevention relapse including case studies, comparative studies and randomised controlled trials. Laboratory research investigating biobehavioural effects of baclofen will also be summarised and polymorphisms associated with baclofen treatment, and safety concerns of GABAB treatments will be addressed. In summary, pharmacological treatments targeting GABAB receptors such as baclofen may be modestly effective in the management of alcohol use disorder, but safety concerns limit the widespread applicability of the currently available agents.

New Australian guidelines for the treatment of alcohol problems: an overview of recommendations.

OF RECOMMENDATIONS AND LEVELS OF EVIDENCE: Chapter 2: Screening and assessment for unhealthy alcohol use Screening Screening for unhealthy alcohol use and appropriate interventions should be implemented in general practice (Level A), hospitals (Level B), emergency departments and community health and welfare settings (Level C). Quantity-frequency measures can detect consumption that exceeds levels in the current Australian guidelines (Level B). The Alcohol Use Disorders Identification Test (AUDIT) is the most effective screening tool and is recommended for use in primary care and hospital settings. For screening in the general community, the AUDIT-C is a suitable alternative (Level A). Indirect biological markers should be used as an adjunct to screening (Level A), and direct measures of alcohol in breath and/or blood can be useful markers of recent use (Level B). Assessment Assessment should include evaluation of alcohol use and its effects, physical examination, clinical investigations and collateral history taking (Level C). Assessment for alcohol-related physical problems, mental health problems and social support should be undertaken routinely (GPP). Where there are concerns regarding the safety of the patient or others, specialist consultation is recommended (Level C). Assessment should lead to a clear, mutually acceptable treatment plan which specifies interventions to meet the patient's needs (Level D). Sustained abstinence is the optimal outcome for most patients with alcohol dependence (Level C). Chapter 3: Caring for and managing patients with alcohol problems: interventions, treatments, relapse prevention, aftercare, and long term follow-up Brief interventions Brief motivational interviewing interventions are more effective than no treatment for people who consume alcohol at risky levels (Level A). Their effectiveness compared with standard care or alternative psychosocial interventions varies by treatment setting. They are most effective in primary care settings (Level A). Psychosocial interventions Cognitive behaviour therapy should be a first-line psychosocial intervention for alcohol dependence. Its clinical benefit is enhanced when it is combined with pharmacotherapy for alcohol dependence or an additional psychosocial intervention (eg, motivational interviewing) (Level A). Motivational interviewing is effective in the short term and in patients with less severe alcohol dependence (Level A). Residential rehabilitation may be of benefit to patients who have moderate-to-severe alcohol dependence and require a structured residential treatment setting (Level D). Alcohol withdrawal management Most cases of withdrawal can be managed in an ambulatory setting with appropriate support (Level B). Tapering diazepam regimens (Level A) with daily staged supply from a pharmacy or clinic are recommended (GPP). Pharmacotherapies for alcohol dependence Acamprosate is recommended to help maintain abstinence from alcohol (Level A). Naltrexone is recommended for prevention of relapse to heavy drinking (Level A). Disulfiram is only recommended in close supervision settings where patients are motivated for abstinence (Level A). Some evidence for off-label therapies baclofen and topiramate exists, but their side effect profiles are complex and neither should be a first-line medication (Level B). Peer support programs Peer-led support programs such as Alcoholics Anonymous and SMART Recovery are effective at maintaining abstinence or reductions in drinking (Level A). Relapse prevention, aftercare and long-term follow-up Return to problematic drinking is common and aftercare should focus on addressing factors that contribute to relapse (GPP). A harm-minimisation approach should be considered for patients who are unable to reduce their drinking (GPP). Chapter 4: Providing appropriate treatment and care to people with alcohol problems: a summary for key specific populations Gender-specific issues Screen women and men for domestic abuse (Level C). Consider child protection assessments for caregivers with alcohol use disorder (GPP). Explore contraceptive options with women of reproductive age who regularly consume alcohol (Level B). Pregnant and breastfeeding women Advise pregnant and breastfeeding women that there is no safe level of alcohol consumption (Level B). Pregnant women who are alcohol dependent should be admitted to hospital for treatment in an appropriate maternity unit that has an addiction specialist (GPP). Young people Perform a comprehensive HEEADSSS assessment for young people with alcohol problems (Level B). Treatment should focus on tangible benefits of reducing drinking through psychotherapy and engagement of family and peer networks (Level B). Aboriginal and Torres Strait Islander peoples Collaborate with Aboriginal or Torres Strait Islander health workers, organisations and communities, and seek guidance on patient engagement approaches (GPP). Use validated screening tools and consider integrated mainstream and Aboriginal or Torres Strait Islander-specific approaches to care (Level B). Culturally and linguistically diverse groups Use an appropriate method, such as the "teach-back" technique, to assess the need for language and health literacy support (Level C). Engage with culture-specific agencies as this can improve treatment access and success (Level C). Sexually diverse and gender diverse populations Be mindful that sexually diverse and gender diverse populations experience lower levels of satisfaction, connection and treatment completion (Level C). Seek to incorporate LGBTQ-specific treatment and agencies (Level C). Older people All new patients aged over 50 years should be screened for harmful alcohol use (Level D). Consider alcohol as a possible cause for older patients presenting with unexplained physical or psychological symptoms (Level D). Consider shorter acting benzodiazepines for withdrawal management (Level D). Cognitive impairment Cognitive impairment may impair engagement with treatment (Level A). Perform cognitive screening for patients who have alcohol problems and refer them for neuropsychological assessment if significant impairment is suspected (Level A). SUMMARY OF KEY RECOMMENDATIONS AND LEVELS OF EVIDENCE: Chapter 5: Understanding and managing comorbidities for people with alcohol problems: polydrug use and dependence, co-occurring mental disorders, and physical comorbidities Polydrug use and dependence Active alcohol use disorder, including dependence, significantly increases the risk of overdose associated with the administration of opioid drugs. Specialist advice is recommended before treatment of people dependent on both alcohol and opioid drugs (GPP). Older patients requiring management of alcohol withdrawal should have their use of pharmaceutical medications reviewed, given the prevalence of polypharmacy in this age group (GPP). Smoking cessation can be undertaken in patients with alcohol dependence and/or polydrug use problems; some evidence suggests varenicline may help support reduction of both tobacco and alcohol consumption (Level C). Co-occurring mental disorders More intensive interventions are needed for people with comorbid conditions, as this population tends to have more severe problems and carries a worse prognosis than those with single pathology (GPP). The Kessler Psychological Distress Scale (K10 or K6) is recommended for screening for comorbid mental disorders in people presenting for alcohol use disorders (Level A). People with alcohol use disorder and comorbid mental disorders should be offered treatment for both disorders; care should be taken to coordinate intervention (Level C). Physical comorbidities Patients should be advised that alcohol use has no beneficial health effects. There is no clear risk-free threshold for alcohol intake. The safe dose for alcohol intake is dependent on many factors such as underlying liver disease, comorbidities, age and sex (Level A). In patients with alcohol use disorder, early recognition of the risk for liver cirrhosis is critical. Patients with cirrhosis should abstain from alcohol and should be offered referral to a hepatologist for liver disease management and to an addiction physician for management of alcohol use disorder (Level A). Alcohol abstinence reduces the risk of cancer and improves outcomes after a diagnosis of cancer (Level A).

High-dose baclofen attenuates insula activation during anticipatory anxiety in treatment-seeking alcohol dependant individuals: Preliminary findings from a pharmaco-fMRI study.

The GABA B agonist, baclofen, has been shown to reduce alcohol consumption in patients with alcohol use disorder and also those with comorbid anxiety. This study aimed to evaluate the effect of baclofen versus placebo on the BOLD response during an anticipatory anxiety fMRI task in treatment seeking alcohol patients. Participants included 28 alcohol dependant individuals who had received daily baclofen 30 mg (n = 10), 75 mg (n = 8) or placebo (n = 10) for at least 2 week on a randomized controlled trial (Morley, Leung et al. 2013, Morley, Baillie et al. 2018). Using functional magnetic resonance imaging (fMRI), we examined threat cue-elicited neural activation during a threat reactivity task 120 min following administration of BAC (30 mg or 75 mg) or placebo. Whole-brain analyses revealed no significant differences between the combined BAC doses versus PL. However, there were significant decreases in anticipatory threat cue-elicited activation observed in BAC 75 mg/day compared to PL participants in the insula. In response to threat cues, high dose (75 mg/day) baclofen administration attenuates activation in the insula and inferior frontal gyrus, relative to placebo. These preliminary findings suggests that modulating emotional regulation and attentional allocation during high threat stimuli may be mediated by GABA B receptors and may be a potential mechanism of action for baclofen's beneficial treatment effects for alcohol use disorder.

Baclofen attenuates fMRI alcohol cue reactivity in treatment-seeking alcohol dependent individuals.

RATIONALE: Baclofen has been shown to effect fMRI alcohol cue reactivity in alcohol dependence, but potential varying effects related to baclofen dose levels have not been examined. OBJECTIVE: This study investigated whether baclofen attenuates craving and alcohol cue-elicited activation in alcohol-dependent treatment seekers, and the relationship between this response and clinical outcomes (Morley et al. 2018; Morley et al. 2013). METHODS: Participants included 30 alcohol-dependent individuals who had received daily baclofen 30 mg (n = 11), 75 mg (n = 8) or placebo (n = 11) for at least 2 weeks. Using functional magnetic resonance imaging (fMRI), we examined alcohol cue-elicited neural activation during a visual alcohol cue reactivity task 120 min following treatment administration, and alcohol cue reactivity and percentage of heavy drinking days (% HDD) associations were assessed. RESULTS: Both baclofen-treated groups reported fewer post-scan % HDD when compared to the placebo-treated group, but no subjective craving group differences were found. Increased alcohol cue-elicited activation was seen in placebo compared to the 75 mg/day baclofen participants in two clusters spanning prefrontal regions implicated in cue reactivity, chiefly frontal regions (i.e., frontal and precentral gyri, anterior cingulate cortex), but no observed alcohol cue reactivity differences between placebo and 30 mg/day baclofen groups. Post-scan % HDD was positively correlated with increased alcohol cue-elicited activation in a cluster encompassing the bilateral caudate nucleus and dorsal anterior cingulate cortex when comparing placebo versus 75 mg/day baclofen groups, and several clusters including prefrontal and mesolimbic regions when comparing placebo versus 30 mg/day baclofen groups. CONCLUSIONS: Baclofen administration attenuates alcohol cue-elicited activation and reduced the association in baclofen-treated participants between increased activity in key drug cue reactivity regions and higher post-scan % HDD observed in placebo-treated participants, suggesting a dose-specific response effect that may lead to reduced heavy drinking in chronic alcohol-dependent individuals. TRIAL REGISTRATION: ClinicalTrials.gov , NCT01711125, https://clinicaltrials.gov/ct2/show /NCT01711125.

Genetic Polymorphisms on OPRM1, DRD2, DRD4, and COMT in Young Adults: Lack of Association With Alcohol Consumption.

Background: Risk behaviors for young adults such as alcohol use are associated with increased risk of morbidity and mortality. Patterns of risk behavior may be genetically determined and vary between genders. Previous studies in both young adults and heavy drinking adult samples have demonstrated that some genotypes, such as OPRM1 A118G, COMT Val158Met and DRD2 Taq1A and DRD4 C52IT, may predict addictive behaviors including alcohol consumption and impulsivity, although results have been mixed. Methods: This study aimed to investigate the predictive relationship of these four single nucleotide polymorphisms (SNPs) prospectively on student patterns of drinking using a micro-longitudinal daily diary design in a sample of 628 young adults ages 18-25 of predominantly of European ethnicity. Linear mixed models were used to examine the effect of SNPs on the number of drinks per drinking session with gender as a moderating variable. Results: There were no main effects for genotype on alcohol consumption, nor for gender × genotype for any of the SNPs. There was a trend for an effect of the DRD2 Taq1A on the number of drinks per drinking day and for the interaction of gender and DRD2 Taq1A on the number of drinks per drinking day. Conclusion: These findings suggest that the DRD2 Taq1A, OPRM1 A118G, DRD4 C521T, or COMT Val158Met polymorphisms, are not associated with alcohol consumption in young adults, although there may be a relationship between DRD2 Taq1A and alcohol consumption in young adult males.

Baclofen modulates cardiovascular responses to appetitive cues in treatment-seeking alcohol use disorder individuals.

OBJECTIVE: To assess whether baclofen-treated alcohol dependent participants show different subjective and psychophysiological responses to appetitive cues during an alcohol cue reactivity task compared to placebo, and whether these responses are associated with prospective drinking outcomes. METHODS: Forty-two alcohol dependent participants (placebo: n = 12, low-dose baclofen [30 mg/day] n = 18, high-dose baclofen [75 mg/day]: n = 12) completed an alcohol cue reactivity task, whereby water and alcohol beverage cues were presented, with subsequent recovery periods, and subjective alcohol craving and psychophysiological indices (skin conductance; cardiovascular measures: heart rate, high-frequency heart rate variability) were recorded. RESULTS: High-dose baclofen-treated participants showed both overall cue reactivity to water and alcohol cues and greater recovery effects during recovery periods, revealed by high-frequency heart rate variability, when compared to low-dose- and placebo-treated participants. There were no medication effects on subjective craving. In high-dose baclofen participants only, there was a predictive effect of lower baseline heart rate variability and fewer post-test percentage of heavy drinking days. CONCLUSION: There was a dose-specific rescuing effect of high-dose baclofen on the dynamic modulation of cardiovascular responses to eliciting cues. Investigation of treatment responses using psychophysiological techniques may elucidate baclofen's mechanisms of action, and identify subgroups amenable to treatment.

Brain GABA levels are reduced in alcoholic liver disease: A proton magnetic resonance spectroscopy study.

BACKGROUND AND AIMS: Baclofen, a selective γ-aminobutyric acid (GABA)B receptor agonist, has emerged as a potential treatment for alcohol use disorder with much unexplained variation in response to treatment efficacy and dose regimen. Several positive studies include patients with alcoholic liver disease (ALD) and/or history of heavy drinking. The aim of this paper was to examine the association of cortical GABA+ concentration with severity of liver disease (including markers of liver injury) and other clinical characteristics in alcohol patients. METHODS: Proton magnetic resonance spectroscopy (1 H-MRS), from the parietal lobe, was analyzed to yield absolute concentration of GABA in 24 alcohol-dependent individuals. Diagnosis of ALD, markers of liver injury, severity of liver disease (Model for End-Stage Liver Disease [MELD]), and alcohol history were assessed. Covariates included concurrent medication, age, and recent alcohol consumption. RESULTS: Multiple linear regression revealed that GABA+ concentration was significantly predicted by MELD scores (F = 5.02, R2  = 0.59, P = 0.01; MELD: B = -0.63, P = 0.02), when controlling for covariates concurrent medication, age, and recent alcohol consumption. CONCLUSION: Severity of ALD is associated with lower cortical concentrations of GABA+. These results may explain variations in response to the GABAB agonist, baclofen, in the alcohol-dependent population.

Brain N-Acetyl Aspartate and associations with cognitive impairment in alcohol dependent patients.

Introduction: Chronic alcohol consumption has been observed to be associated with a range of cognitive impairments that impact on treatment management. In this spectroscopy study, we examined the association of N-Acetyl Aspartate (NAA), a marker of neuronal integrity, and cognitive impairment in alcohol dependent patients.Method: Using in vivo proton magnetic resonance spectroscopy (1H-MRS), we examined brain metabolite levels in 31 alcohol dependent individuals. 1H-MRS from the parietal lobe were analyzed to yield absolute concentrations of NAA. Alcohol history, neurocognitive function including Clock Drawing Test (CDT), Mini Mental State Exam (MMSE), Trial Making Test (TMT) and Balloon Analogue Risk Task (BART) were also assessed. Covariates included concurrent medication, age and recent alcohol consumption.Results: There were statistically significant bivariate associations between NAA and the variables age, CDT and BART (r = -.45, P = 01; r = -.53, P = .01; r = .49, P = .02) respectively) but there were no statistically significant associations with other measures of cognitive function. Controlling for age, concurrent medication and recent alcohol consumption, multiple linear regression revealed a negative association between parietal NAA (Model: F = 6.96, R2 = .66, P = .001) and CDT scores (B = -.35, P = .03), a positive association with BART scores (B = .47, P = .02).Conclusion: These results demonstrate that in alcohol dependent patients lower NAA/Cr is associated with reduced cognitive functioning and increased risk-taking.

Executive Functioning Moderates Responses to Appetitive Cues: A Study in Severe Alcohol Use Disorder and Alcoholic Liver Disease.

AIM: To examine subjective and psychophysiological responses to appetitive cues during an alcohol cue reactivity task, and its relation to alcoholic liver disease and assess whether executive functioning is associated with appropriate regulation of cue-elicited responses in individuals with severe alcohol use disorder (AUD). METHODS: Seventeen treatment-seeking alcoholic liver disease patients and a control group of treatment-seeking severe AUD participants completed neuropsychological executive functioning measures (Stroop task; Trail-making test) and the cue reactivity task, whereby control (water) and alcohol beverage cues were presented, followed by respective recovery periods. Subjective alcohol craving and heart rate variability were recorded across the task. RESULTS: Overall cue reactivity and consequent recovery after cue offset during the cue reactivity task was observed, and alcoholic liver disease participants demonstrated a reduced overall recovery effect. Better Stroop performance related to greater overall and alcohol-specific cue reactivity within the control AUD group, and alcoholic liver disease participants showed dysfunctional activity regardless of executive functioning performance. No group differences in recovery effects according to executive functioning performance were seen. CONCLUSION: Among patients with AUD, having alcoholic liver disease seems to reduce overall regulation of responses to eliciting cues. Executive functioning moderated the magnitude of responses during cue exposures in our AUD sample overall; having alcoholic liver disease did not appear to affect regulation related to executive functioning during recovery.

Neurometabolite Levels in Alcohol Use Disorder Patients During Baclofen Treatment and Prediction of Relapse to Heavy Drinking.

Background and Aims: Baclofen, a GABAB agonist, is used as a treatment for alcohol dependence. We aimed to examine brain metabolites following administration of baclofen or placebo in alcohol dependent individuals enrolled in a randomized placebo-controlled trial. Methods: Participants included 31 alcohol dependent individuals (recent drinking: N = 16; and abstinent: N = 15) who had received daily baclofen (BAC 30-75 mg = 20) or placebo (PL = 11) for at least 2 weeks (average 17 days). Using in vivo proton magnetic resonance spectroscopy (1H-MRS), spectra from the right parietal lobe were analyzed to obtain measures of GABA, Glutamate (Glu), Glutathione (GSH) and N-Acetyl Apartate (NAA) 120 min following administration of PL or BAC. Results: When weighting alcohol dependent participants according to recent alcohol consumption (within 24 h), there were significant differences between BAC and PL on parietal concentrations of GSH (p < 0.01) and NAA (p < 0.05). Multiple linear regression revealed a significant predictive effect of GSH on heavy drinking days at 12 weeks follow-up (Model: F = 14.28, R2 = 0.85; GSH: B = -1.22, p = 0.01) and also percentage days abstinent at 12 weeks follow-up (Model: F = 6.50, R2 = 0.72; GSH: B = 0.99, p = 0.06). Conclusion: Our data provide preliminary evidence that the effect of baclofen may be mediated by increased parietal concentrations of the antioxidant GSH and NAA in recently drinking alcohol dependent patients. GSH/Cr levels were also predictive of improved drinking outcomes in the trial and suggests a role for neural oxidative stress in alcohol use disorder.

Socioeconomic and geographic disparities in access to pharmacotherapy for alcohol dependence.

A higher rate of alcohol-attributable morbidity and mortality exists in remote and socioeconomically disadvantaged regions of Australia. This study aimed to explore the dispensing pattern of pharmacotherapy for alcohol dependence across these groups. A retrospective cohort study of patients (aged 15-84) dispensed acamprosate or naltrexone (July 2009-June 2013) was conducted. Observed dispensing rates were obtained for 541 local government areas (LGA) of Australia. Expected dispensing was based on national rates and age standardized to each LGA. Mean dispensing ratios (observed to expected) for each medicine over the period were calculated for remoteness and socioeconomic disadvantaged groups. For both medications, the mean dispensing ratio significantly differed across geographical groups and across socioeconomic groups (p's<0.05). For naltrexone and acamprosate, respectively, the mean dispensing ratio in remote areas was 6 and 9 times less than for the major cities. The mean dispensing ratio for both medications in the most socially disadvantaged areas was approximately 5 times less than that of the most disadvantaged areas. Our data highlight geographical and socioeconomic disparities in Australia regarding access to pharmacological treatment for alcohol use disorder. Targeted strategies aimed at bridging the gap of accessibility for relapse prevention medications are required.

National trends in alcohol pharmacotherapy: Findings from an Australian claims database.

BACKGROUND: Although the efficacy of alcohol pharmacotherapy has been widely investigated, little is known about real-world prescription patterns. Population-based dispensing data can provide an understanding of prescription patterns and characteristics of treatment in nonexperimental settings. METHODS: A retrospective cohort study of patients (aged 15-84) treated with acamprosate or naltrexone between July 2009 and June 2013 was conducted using dispensing claims from the Australian Pharmaceutical benefits Scheme Database. Only individuals with prescriptions from September 2009 onwards were included. RESULTS: We identified 61,904 individuals (40% female, 32% in 35-44 age bracket,) with a total number of 198,247 dispensings. There were 23,452 naltrexone-treated and 38,452 acamprosate-treated patients. For naltrexone, 42% of initial dispenses were followed by a second dispense with only 25% receiving at least 3 months of treatment. For acamprosate, 28% of dispenses were followed by a third dispense with only 15% receiving at least 3 months of treatment. Patients in older age groups were more likely to be dispensed a repeat script than those in younger age groups (e.g., for the 75-84 vs 15-24 age bracket OR's=2.27 and 2.98 for naltrexone and acamprosate respectively). CONCLUSION: Current national guidelines in Australia recommend alcohol pharmacotherapy for a minimum period of 3 months yet only 15-25% are receive this duration of treatment. Naltrexone-treated patients were more likely to return for a second and third dispense than acamprosate-treated patients. Prevalence and prescribing patterns change with age.