Pharmacotherapy For Alcohol Use Disorder Research Articles

Alcohol use disorder pharmacotherapy and treatment in primary care (ADaPT-PC) trial: Impact on identified barriers to implementation

Background: A minority of individuals meeting diagnostic criteria for alcohol use disorders (AUD) receive any type of formal treatment. Developing options for AUD treatment within primary care settings is imperative to increase treatment access. A multi-faceted implementation intervention including provider and patient education, clinician reminders, development of local champions and ongoing facilitation was designed to enhance access to AUD pharmacotherapy in primary care settings at three large Veterans Health Administration (VHA) facilities. This qualitative study compared pre-implementation barriers to post-implementation barriers identified via provider interviews to identify those barriers addressed and not addressed by the intervention to better understand the limited impact of the intervention. Methods: Following the nine-month implementation period, primary care providers at the three participating facilities took part in qualitative interviews to collect perceptions regarding which pre-implementation barriers had and had not been successfully addressed by the intervention. Participants included 20 primary care providers from three large VHA facilities. Interviews were coded using common coding techniques for qualitative data using the Consolidated Framework for Implementation Research (CFIR) codebook. Summary reports were created for each CFIR construct for each facility and the impact of each CFIR construct on implementation was coded as positive, neutral, or negative. Results: Some barriers identified during pre-implementation interviews were no longer identified as barriers in the post-implementation interviews. These included Relative Advantage, Relative Priority, and Knowledge & Beliefs about the Innovation. However, Compatibility, Design Quality & Packaging, and Available Resources remained barriers at the end of the implementation period. No substantial new barriers were identified. Conclusions: The implementation intervention appears to have been successful at addressing barriers that could be mitigated with traditional educational approaches. However, the intervention did not adequately address structural and organizational barriers to implementation. Recommendations for enhancing future interventions are provided.

Reducing effect of the novel positive allosteric modulator of the GABAB receptor, COR659, on binge-like alcohol drinking in male mice and rats.

Binge drinking (BD) is a widespread drinkingpattern that may contribute to promote the development of alcohol use disorder (AUD). The comprehension of its neurobiological basis and the identification of molecules that may prevent BD are critical. Preclinical studies demonstrated that positive allosteric modulators (PAMs) of the GABAB receptor effectively reduced, and occasionally suppressed, the reinforcing and motivational properties of alcohol in rodents, suggesting their potential use as pharmacotherapy for AUD, including BD. Recently, we demonstrated that COR659, a novel GABAB PAM, effectively reduced (i) alcohol drinking under the 2-bottle choice regimen, (ii) alcohol self-administration under both fixed and progressive ratio schedules of reinforcement, and (iii) cue-induced reinstatement of alcohol-seeking behavior in Sardinian alcohol-preferring (sP) rats. The present study investigated whether the "anti-alcohol" properties of COR659 extend to binge-like drinking in rodents. COR659 was tested on the "drinking in the dark" (DID) paradigm in C57BL/6J mice and the 4-bottle "alcohol [10%, 20%, 30% (v/v)] versus water" choice regimen with limited and unpredictable access to alcohol in sP rats. Acute administration of non-sedative doses of COR659 (10, 20, and 40 mg/kg; i.p.) effectively and selectively suppressed the intake of intoxicating amounts of alcohol (> 2 g/kg) consumed by C57BL/6J mice and sP rats exposed to these binge-like drinking experimental procedures. The present data demonstrate the ability of COR659 to suppress binge-like drinking in rodents and strengthen the hypothesis that GABAB PAMs may represent a potentially effective pharmacotherapy for alcohol misuse.

Management of alcohol use disorder in patients with cirrhosis in the setting of liver transplantation.

The prevalence of alcohol use disorder (AUD) has been steadily increasing over the past decade. In parallel, alcohol-associated liver disease (ALD) has been increasing at an alarming rate, especially among young patients. Data suggest that most patients with ALD do not receive AUD therapy. Although liver transplantation is the only curative therapy for end-stage ALD, transplant candidacy is often a matter of debate given concerns about patients being under-treated for AUD and fears of post-transplantation relapse affecting the allograft. In this Review, we discuss diagnosis, predictors and effects of relapse, behavioural therapies and pharmacotherapies, and we also propose an integrative, multidisciplinary and multimodality approach for treating AUD in patients with cirrhosis, especially in the setting of liver transplantation. Notably, this approach takes into account the utility of AUD pharmacotherapy in patients on immunosuppressive medications and those with renal impairment after liver transplantation. We also propose a comprehensive and objective definition of relapse utilizing contemporary biomarkers to guide future clinical trials. Future research using the proposed approach and definition is warranted with the goal of optimizing AUD treatment in patients with cirrhosis, the transplant selection process and post-transplantation care of patients with AUD.

Neurobeachin, a promising target for use in the treatment of alcohol use disorder.

Hazardous, heavy drinking increases risk for developing alcohol use disorder (AUD), which affects ~7% of adult Americans. Thus, understanding the molecular mechanisms promoting risk for heavy drinking is essential to developing more effective AUD pharmacotherapies than those currently approved by the FDA. Using genome-wide bisulfate sequencing, we identified DNA methylation (DNAm) signals within the nucleus accumbens core (NAcC) that differentiate nonheavy and heavy ethanol-drinking rhesus macaques. One differentially DNAm region (D-DMR) located within the gene neurobeachin (NBEA), which promotes synaptic membrane protein trafficking, was hypermethylated in heavy drinking macaques. A parallel study identified a similar NBEA D-DMR in human NAcC that distinguished alcoholic and nonalcoholic individuals. To investigate the role of NBEA in heavy ethanol drinking, we engineered a viral vector carrying a short hairpin RNA (shRNA) to reduce the expression of NBEA. Using two murine models of ethanol consumption: 4 days of drinking-in-the-dark and 4 weeks of chronic intermittent access, the knockdown of NBEA expression did not alter average ethanol consumption in either model. However, it did lead to a significant increase in the ethanol preference ratio. Following withdrawal, whole-cell patch clamp electrophysiological experiments revealed that Nbea knockdown led to an increase in spontaneous excitatory postsynaptic current amplitude with no alteration in spontaneous inhibitory postsynaptic currents, suggesting a specific role of NBEA in trafficking of glutamatergic receptors. Together, our findings suggest that NBEA could be targeted to modulate the preference for alcohol use.

Pharmacotherapy for alcohol use disorders – Unequal provision across sociodemographic factors and co-morbid conditions. A cohort study of the total population in Sweden

BackgroundPharmacotherapy for alcohol use disorders (AUD) is effective. However, knowledge about utilization of, and patient characteristics associated with prescriptions is scarce. The aim is to investigate prescriptions of pharmacotherapy for AUD in Sweden across time, sociodemographics, domicile and comorbid conditions. MethodThis is a national cohort study, comprising 132 733 adult patients with AUD diagnosis between 2007 and 2015. The exposure variables were age, sex, income, education, family constellation, domicile, origin, concurrent psychiatric and somatic co-morbid diagnoses. Logistic regression analyses were used to obtain odds ratios (OR) for any filled prescription of AUD pharmacotherapy; Acamprosate, Disulfiram, Naltrexone or Nalmefene during 12 months after AUD diagnosis. ResultsDuring the study period, the proportion of individuals who received pharmacotherapy ranged between 22.80 and 23.94 % (χ2(64) = 72.00, p = .23). Female sex, age 31–45, higher education and income, living in a big city, co-habiting and born in Sweden, bar Norway, Denmark and Iceland, were associated with higher odds of pharmacotherapy. Concurrent somatic diagnosis was associated with lower odds of pharmacotherapy but psychiatric diagnosis higher (aOR = 0.61 95 % CI 0.59−0.63 and aOR = 1.61 95 % CI 1.57−1.66 respectively). ConclusionsPharmacotherapy for AUD is underutilized. The proportion of individuals with a prescription did not change between 2007 and 2015. Provision of treatment is unequal across different groups in society, where especially older age, lower income and education, and co-morbid somatic diagnosis were associated with lower odds of prescription. There is a need to develop treatment provision, particularly for individuals with co-morbid somatic conditions.

Use of pharmacotherapy for alcohol use disorder in Manitoba, Canada: A whole-population cohort study.

ObjectiveUpdate the evidence on use of pharmacotherapy for alcohol use disorder in a Canadian population.MethodsUsing whole-population administrative data from Manitoba, Canada, we identified all residents age 12+ who were first diagnosed with alcohol use disorder between April 1, 1996 and March 31, 2015, and compared characteristics of those who filled a prescription for naltrexone, acamprosate or disulfiram at least once during that period to those who did not fill a prescription for an alcohol use disorder medication.ResultsOnly 1.3% of individuals with alcohol use disorder received pharmacotherapy (62.3% of prescriptions were for naltrexone, 39.4% for acamprosate, 7.5% for disulfiram). Most prescriptions came from family physicians in urban alcohol use disorder (53.6%) and psychiatrists (22.3%). Individuals were more likely to fill a prescription for alcohol use disorder medication if they lived in an urban vs rural environment (OR 2.25; 95% CI 1.83–2.77) or had a mood/anxiety disorder diagnosis vs no diagnosis (OR 2.40, 95% CI 1.98–2.90) in the five years before being diagnosed with alcohol use disorder.ConclusionDespite established evidence for the effectiveness of pharmacotherapy for alcohol use disorder, these medications continue to be profoundly underutilized in Canada.

Effectiveness of spironolactone dispensation in reducing weekly alcohol use: a retrospective high-dimensional propensity score-matched cohort study.

There is a need to increase the armamentarium of pharmacotherapies for alcohol use disorder (AUD). Recent research suggests that mineralocorticoid receptor (MR) antagonism via spironolactone may represent a novel pharmacological treatment for AUD. We conducted a pharmacoepidemiologic retrospective cohort study (June 1, 2014 to May 31, 2018) to examine whether spironolactone dispensation (≥90 continuous days), for any indication, is associated with changes in weekly alcohol use about 6 months later. We compared 523 spironolactone-treated adults and 2305 untreated adults, matched on high-dimensional propensity scores created from a set of predefined (sociodemographic and health characteristics, diagnoses, and service utilization) and empirical electronic health record-derived covariates. The sample was 57% female and 27% non-White with a mean age of 59.2 years (SD = 19.3). Treated patients reduced their weekly alcohol use by 3.50 drinks (95% CI = -4.22, -2.79), while untreated patients reduced by 2.74 drinks (95% CI = -3.22, -2.26), yielding a significant difference of 0.76 fewer drinks (95% CI = -1.43, -0.11). Among those who drank >7 drinks/week at baseline, treated patients, compared to untreated patients, reported a greater reduction in weekly alcohol use by 4.18 drinks (95% CI = -5.38, -2.97), while there was no significant difference among those who drank less. There was a significant dose-response relationship between spironolactone dosage and change in drinks/week. Pending additional evidence on its safety and efficacy in individuals with AUD, spironolactone (and MR blockade, at large) may hold promise as a pharmacotherapy for AUD.

How prescribing available pharmacotherapies for alcohol use disorder can impact the healthcare system: A retrospective quality improvement study.

Alcohol use disorder is a multifactorial undertreated chronic disorder influenced by genetic, psychological, and environmental factors. Numerous pharmacotherapies are available and effective but are underutilized in healthcare. The purpose of this retrospective quality improvement study is to determine the impact of education sessions on the availability and efficacy of medications (focusing on Naltrexone) to treat alcohol use disorder in the healthcare system. Control charts were implemented to monitor the system change in two comparable urban areas. Dispensing rates increased at three points after a series of presentations. The first increase from baseline was 2.47 times, the second 3.7, and the third 4.81. Coinciding with these, weekly visits to the emergency department also decreased by 35% and stabilized at a 15% reduction. It was also observed that alcohol use disorder hospital admission rates decreased by 21%, but bounced back once the education sessions ended. Combined with counselling, pharmacotherapies can be effective in combating alcohol use disorder, while potentially reducing demands on the healthcare system.

Receipt of evidence-based alcohol-related care in a national sample of transgender patients with unhealthy alcohol use: Overall and relative to non-transgender patients

Background/objectiveEvidence-based alcohol-related care–brief intervention for all patients with unhealthy alcohol use and specialty addictions treatment and/or pharmacotherapy for patients with alcohol use disorder (AUD)–should be routinely offered. Transgender persons may be particularly in need of alcohol-related care, given common experiences of social and economic hardship that may compound the adverse effects of unhealthy alcohol use. We examined receipt of alcohol-related care among transgender patients compared to non-transgender patients in a large national sample of Veterans Health Administration (VA) outpatients with unhealthy alcohol use. MethodsWe extracted electronic health record data for patients from all VA facilities who had an outpatient visit 10/1/09–7/31/17 and a documented positive screen for unhealthy alcohol use (AUDIT-C ≥ 5). We identified transgender patients with a validated approach using transgender-related diagnostic codes. We fit modified Poisson models, adjusted for demographics and comorbidities, to estimate the average predicted prevalence of brief intervention (documented 0–14 days following most recent positive screening), specialty addictions treatment for AUD (documented 0–365 days following screening), and filled prescriptions for medications to treat AUD (documented 0–365 days following screening) for transgender patients, and compared to that of non-transgender patients. ResultsAmong transgender Veterans with unhealthy alcohol use (N = 1392), the adjusted prevalence of receiving brief intervention was 75.4% (95% CI 72.2–78.5), specialty addictions treatment for AUD was 15.7% (95% CI 13.7–17.7), and any AUD pharmacotherapy was 19.0% (95% CI 17.1–20.8). Receipt of brief intervention did not differ for transgender relative to non-transgender patients (Prevalence Ratio [PR] 1.01, 95% CI 0.98–1.04, p = 0.574). However, transgender patients were more likely to receive specialty addictions treatment (PR 1.24, 95% CI 1.12–1.37, p < 0.001) and pharmacotherapy (PR 1.16, 95% CI 1.06–1.28, p = 0.002). ConclusionsFindings suggest the majority of transgender VHA patients with unhealthy alcohol use receive brief intervention, though a quarter still do not. Nonetheless, rates of specialty addictions treatment and pharmacotherapy are low overall, although transgender patients may be receiving this care at greater rates than non-transgender patients. Further research is needed to investigate these findings and to increase receipt of evidence-based care overall.

Pilot randomized placebo-controlled clinical trial of high-dose gabapentin for alcohol use disorder.

Despite advances in the development of pharmacotherapy for alcohol use disorder (AUD), there remains a need for medications that can be administered to actively drinking outpatients to promote a reduction in harmful alcohol consumption. The primary aim of this pilot study was to determine whether high-dose gabapentin (3600mg/daily) is more effective than placebo in reducing harmful alcohol consumption in outpatients with AUD. Forty patients (27 men) who met DSM-IV-TR criteria for alcohol dependence and reporting at least 4heavy drinking days (HDD) per week were recruited at a single site. Participants were actively drinking at study entry and received double-blind gabapentin (3600mg/day; n=19) or placebo (n=20) for 8weeks. Study medication was titrated over 5days and administered in three divided doses (1200mg three times per day). The proportion of HDD (primary outcome) and percent days abstinent (PDA; secondary outcome) were analyzed using generalized longitudinal mixed models with the predictors being study arm, week, study arm by week interaction, and corresponding baseline drinking measure. There was a significant interaction between study arm and week for the proportion of HDD per week, F (7, 215)=3.33, p=0.002 . There was also a significant interaction between study arm and week for PDA per week, F (7, 215)=3.11, p=0.004. The overall retention rate was 67.5% with no significant difference in time-to-dropout between treatment groups. There were no serious adverse events. No participants were removed from the trial due to the development of moderate-to-severe alcohol withdrawal (CIWA-Ar≥13). Gabapentin treatment rapidly titrated to a dosage of 3600mg/day is associated with a reduction in the proportion of HDD per week and an increase in PDA per week in actively drinking outpatients with AUD. High-dose gabapentin is potentially a feasible approach to treating AUD and deserving of further study.

World Health Organization risk drinking levels as a treatment outcome measure in topiramate trials.

Although abstinence has traditionally been considered the only suitable outcome for alcohol treatment, reduced drinking is also associated with improved functioning and medical and psychiatric outcomes. The World Health Organization (WHO) risk drinking levels (RDLs) have been shown to be valid outcome measures in treatment trials for alcohol use disorder (AUD). We conducted a secondary analysis of two 12-week, randomized controlled trials (RCTs), in which a total of 308 individuals with problematic alcohol use received topiramate or placebo treatment. We compared the utility of the WHO RDLs with other treatment outcomes, including self-reported measures of alcohol consumption, alcohol-related problems, and quality of life, and the biomarker gamma-glutamyltransferase. Topiramate treatment was associated with small effect sizes for both a 1-level (d=0.26) and a 2-level (d=0.19) reduction in WHO RDL, effects that were not significant after correction for multiple comparisons. No heavy drinking days, one of the outcome measures recommended by the US Food and Drug Administration for alcohol medication registration trials, also exhibited a small effect (0.21), while an effect size for abstinence could not be calculated. There were medium effects of topiramate on continuous measures of percent heavy drinking days (d=0.49) and alcohol-related problems (d=0.41). Topiramate is an efficacious pharmacotherapy for AUD. Although continuous measures of drinking and alcohol-related problems yielded larger effect sizes than the WHO RDLs, the latter nonetheless provide a categorical alternative for use in both clinical care and pharmacotherapy trials.

Negative allosteric modulation of metabotropic glutamate receptor 5 attenuates alcohol self-administration in baboons

Many of the behavioral symptoms that define alcohol use disorder (AUD) are thought to be mediated by amplified glutamatergic activity. As a result, previous preclinical studies have investigated glutamate receptor inhibition as a potential pharmacotherapy for AUD, particularly the metabotropic glutamate receptor 5 (mGlu5). In rodents, mGlu5 negative allosteric modulators (NAMs) have been shown to decrease alcohol self-administration. However, their effect on non-human primates has not previously been explored. To bridge this gap, the effects of mGlu5 NAM pretreatment on sweetened alcohol (8% w/v in diluted KoolAid) self-administration in female baboons were evaluated. Two different mGlu5 NAMs were tested: 1) 3-2((-Methyl-4-thiazolyl) ethynyl) pyridine (MTEP) which was administered at a dose of 2 mg/kg IM; and 2) auglurant (N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide), a newly developed NAM, which was tested under two different routes (0.001, 0.01, 0.03, 0.1 mg/kg IM and 0.1, 0.3, 1.0 mg/kg PO). MTEP decreased both fixed ratio and progressive ratio responding for sweetened alcohol. Auglurant, administered IM, decreased alcohol self-administration at doses that did not affect self-administration of an alcohol-free sweet liquid reward (0.01 to 0.1 mg/kg). Oral administration of auglurant was not effective in decreasing alcohol self-administration. Our results extend positive findings from rodent studies on mGlu5 regulation of alcohol drinking to female baboons and further strengthen the rationale for targeting mGlu5 in clinical trials for AUD.

A meta-regression of methodological features that predict the effects of medications on the subjective response to alcohol.

Alcohol administration paradigms have been used for early efficacy testing of novel compounds for alcohol use disorder (AUD). There has been an ongoing debate about sample characteristics and methodological features that affect the likelihood of detecting an early efficacy signal for AUD medications. We conducted a meta-regression to test whether the drinking level of the study sample and the peak breath alcohol concentration (BrAC) in the alcohol administration study predict the efficacy of AUD pharmacotherapies on the subjective responses to alcohol. We computed the effects of 21 medications on alcohol-induced stimulation, sedation, negative mood, and craving during alcohol administration in49studies. Meta-regression analyses indicated a significant and positive effect of pre-study drinks per month on alcohol-induced stimulation (β=0.142, p<0.0001), such that as drinking increases, the benefit of medication over placebo decreases. There was an effect of drinks per month on negative mood (β=-0.164, p=0.0248), such that at higher levels of drinks per month, the effects of medications on negative mood are stronger. For sedation, there was an effect of peak BrAC (β=0.119, p=0.0002), such that at low levels of peak BrAC, the effects of medication on sedation were null. For craving, there was a peak BrAC×drinks per month interaction such that at low levels of BrAC, a heavier drinking sample is required to detect the effects of medication on craving. Sensitivity analyses comparing naltrexone studies and non-naltrexone studies suggested that naltrexone was less sensitive to drinks per month across subjective response domains. These analyses show that design features are critical in studies that test the effects of medications on the subjective responses to alcohol. By specifying the significance and directionality of these effects, as well as the specific points in BrAC or drinks per month at which medication effects are detectable, the study offers recommendations for design features of alcohol administration studies that aim to inform AUD medication development.

Alcohol Use Disorder among General Hospital Medical Inpatients

Objectives: We sought to examine alcohol use disorder (AUD) among general hospital medical inpatients with respect to identification, service utilization, and initiation of medication-assisted treatment. Methods: We performed a retrospective chart review for all adult inpatients over one full calendar year. Subjects were separated into two categories: patients with chart documentation of an AUD diagnosis and those without such documentation. We extracted from the electronic health record and analyzed information on demographics, service utilization, and treatment initiation of medication-assisted treatment for AUD such as naltrexone, disulfiram, or acamprosate. Results: The study revealed three main findings: 1) Less than one percent of patients discharged from the hospital in one full calendar year had an identified AUD diagnosis. 2) Patients with an AUD diagnosis had a significantly higher number of emergency department (ED) visits and longer hospital length of stay (LOS) but did not have significantly higher 30-day hospital readmissions, compared to patients with no AUD diagnosis. 3) Among patients diagnosed with AUD, only 1.8% received FDA-approved medication-assisted treatment for AUD. Conclusions: The AUD identification rate we detected was markedly lower than prevalence rates reported in the literature. Patients who were identified with AUD had higher counts of ED visits and longer LOS. Initiation rates of medication-assisted treatment for AUD were low. The study findings suggest that concerted efforts are needed to improve detection and diagnosis of AUD in order to support the delivery of effective AUD treatment including the initiation of evidence-based pharmacotherapy for AUD in the general hospital setting.

Efficacy and tolerability of baclofen in a U.S. community population with alcohol use disorder: a dose-response, randomized, controlled trial

Identification of new medications for alcohol use disorder (AUD) is important for improving treatment options. Baclofen, a GABAB agonist, has been identified as a potential pharmacotherapy for AUD. In a 16-week double-blind, randomized, placebo-controlled trial, we investigated 30 and 90 mg/day of baclofen compared to placebo and examined effects of dose, sex, and level of pretreatment drinking. One hundred and twenty participants with DSM-IV alcohol dependence (age 46.1 (sd = 10.1) years, 51.7% male) were randomized after exclusion for unstable medical/psychiatric illness and/or dependence on drugs other than nicotine. Seventy-three participants completed the trial. A main effect of baclofen was found [%HDD (F(2,112) = 4.16, p = 0.018, d = 0.51 95%CI (0.06–0.95), 13.6 fewer HDD) and %ABST (F(2,112) = 3.68, p = 0.028, d = 0.49 95%CI (0.04–0.93), 12.9 more abstinent days)] and was driven by the 90 mg/day dose. A sex × dose interaction effect was present for both %HDD (F(2,110) = 5.48, p = 0.005) and %ABST (F(2,110) = 3.19, p = 0.045). Men showed a marginally positive effect for 90 mg/day compared to PBO (%HDD t(110) = 1.88, p = 0.063, d = 0.36 95%CI (−0.09–0.80), 15.8 fewer HDD days; %ABST t(110) = 1.68 (p = 0.096, d = 0.32 95%CI (−0.12–0.76), 15.7 more ABST)) with no effect for 30 mg/day. Women showed a positive effect for 30 mg/day (%HDD, t(110) = 3.19, p = 0.002, d = 0.61 95%CI (0.16–1.05), 26.3 fewer HDD days; %ABST t(110) = 2.73, p = 0.007, d = 0.52 95%CI (0.07–0.96), 25.4 more ABST days) with marginal effects for 90 mg/day on %ABST (p = 0.06) with drop-outs/dose reduction from sedative side-effects of 59% in women at 90 mg/day compared to 5% for men. These findings support the hypothesis that baclofen has efficacy in AUD and suggest that dose and sex be further explored as potential moderators of baclofen response and tolerability.

The Effects of N-Acetylcysteine on the Rat Mesocorticolimbic Pathway: Role of mGluR5 Receptors and Interaction with Ethanol.

N-acetylcysteine (NAC) is a prodrug that is marketed as a mucolytic agent and used for the treatment of acetaminophen overdose. Over the last few decades, evidence has been gathered that suggests the potential use of NAC as a new pharmacotherapy for alcohol use disorder (AUD), although its mechanism of action is already being debated. In this paper, we set out to assess both the potential involvement of the glutamate metabotropic receptors (mGluR) in the possible dual effect of NAC administered at two different doses and NAC’s effect on ethanol-induced activation. To this aim, 30 or 120 mg/kg of NAC was intraperitoneally administered to rats with the presence or absence of the negative allosteric modulator of mGluR5 (MTEP 0.1 mg/kg). Thereafter, the cFOS IR-cell expression was analyzed. Secondly, we explored the effect of 120 mg/kg of NAC on the neurochemical and behavioral activation induced by intra-VTA ethanol administration (150 nmol). Our results showed that the high NAC dose stimulated cFOS expression in the NAcc, and that this effect was suppressed in the presence of MTEP, thus suggesting the implication of mGluR5. Additionally, high doses could attenuate the ethanol-induced increase in cFOS-expression in the NAcc, probably due to a phenomenon based on the long-term depression of the MSNs. Additional experiments are required to corroborate our hypothesis.

An open-label pilot study of pregabalin pharmacotherapy for alcohol use disorder

ABSTRACT Background: There is a need for alcohol use disorder (AUD) pharmacotherapy that can be administered to actively drinking outpatients. Pregabalin, a gabapentoid anticonvulsant, has preliminary evidence supporting effects on alcohol withdrawal and AUD. Objectives: To evaluate the safety, tolerability, and optimal dosing of pregabalin for treating AUD. Methods: In an open-label, 8-week, outpatient trial of eighteen adults (nine women) with AUD, participants were titrated to 600 mg/day (or the maximum tolerated dose) over 3 weeks and then maintained for 5 weeks. Results: The majority (11/14, 78.6%) of participants with at least one-week of medication exposure achieved a maximum dose of 600 mg/day. Mean retention was 6.8 weeks (SD = 2.6). Eighty percent (12/15) of participants with post-enrollment data reported any adverse effects during the trial; and for those reporting adverse effects the most common were drowsiness (33.3%, 4/12), and fogginess (25%, 3/12), dizziness (25%, 3/12), and insomnia (25%, 3/12). Two participants discontinued study medication due to adverse effects and one had a dose reduction. Mean Heavy Drinking Days (HDD)/week decreased significantly by 3.43 days (SD = 2.47; median (IQR) = 4.00 (1.00 to 5.50)); Wilcoxon signed rank test statistic ((S) = 49.5, p = .0006). Mean proportion of HDD significantly decreased on average by 48.7% (SD = 35.1%; median (IQR) = 57.1% (14.3% to 78.6%)). The proportion of abstinent days increased significantly on average by 36.1% (SD = 35.0%; median (IQR) = 17.9% (14.3% to 75.0%); S = 49.5, p = .0005). Conclusions: Pregabalin treatment of AUD appears to be safe and well tolerated in doses up to 600 mg per day. Trial Registration: clinicaltrials.gov identifier: NCT03256253

Ibudilast, a neuroimmune modulator, reduces heavy drinking and alcohol cue-elicited neural activation: a randomized trial

Ibudilast, a neuroimmune modulator which selectively inhibits phosphodiesterases (PDE)-3, -4, -10, and -11, and macrophage migration inhibitory factor (MIF), shows promise as a novel pharmacotherapy for alcohol use disorder (AUD). However, the mechanisms of action underlying ibudilast’s effects on the human brain remain largely unknown. Thus, the current study examined the efficacy of ibudilast to improve negative mood, reduce heavy drinking, and attenuate neural reward signals in individuals with AUD. Fifty-two nontreatment-seeking individuals with AUD were randomized to receive ibudilast (n = 24) or placebo (n = 28). Participants completed a 2-week daily diary study during which they filled out daily reports of their past day drinking, mood, and craving. Participants completed an functional magnetic resonance imaging (fMRI) alcohol cue-reactivity paradigm half-way through the study. Ibudilast did not have a significant effect on negative mood (β = −0.34, p = 0.62). However, ibudilast, relative to placebo, reduced the odds of heavy drinking across time by 45% (OR = 0.55, (95% CI: 0.30, 0.98)). Ibudilast also attenuated alcohol cue-elicited activation in the ventral striatum (VS) compared to placebo (F(1,44) = 7.36, p = 0.01). Alcohol cue-elicited activation in the VS predicted subsequent drinking in the ibudilast group (F(1,44) = 6.39, p = 0.02), such that individuals who had attenuated ventral striatal activation and took ibudilast had the fewest number of drinks per drinking day in the week following the scan. These findings extend preclinical and human laboratory studies of the utility of ibudilast to treat AUD and suggest a biobehavioral mechanism through which ibudilast acts, namely, by reducing the rewarding response to alcohol cues in the brain leading to a reduction in heavy drinking.

Acamprosate—an Anti-Craving Drug for Alcohol Use Disorder (AUD) Pharmacotherapy: Plasma Metabolomics Signatures are Associated With Alcohol Craving Intensity and Acamprosate Treatment Response

Acamprosate is an anti-craving drug used for the pharmacotherapy of alcohol use disorder (AUD). However, acamprosate’s mechanism(s) of action during the treatment of AUD remains unclear, and only some patients achieve optimal therapeutic outcomes. The present study was designed to explore the differences in metabolomic profiles between patients who maintained sobriety and those who relapsed. It also sought to determine whether those differences might provide insight into the mechanisms involved in the variations in acamprosate treatment response phenotypes.

Characterizing the Variation of Alcohol Cessation Pharmacotherapy in Primary Care.

Alcohol use disorder (AUD) imposes a high mortality and economic burden. Effective treatment is available, though underutilized. Describe trends in AUD pharmacotherapy, variation in prescribing, and associated patient factors. Retrospective cohort using electronic health records from 2010 to 2019. Primary care patients from 39 clinics in Ohio and Florida with diagnostic codes for alcohol dependence or abuse plus social history indicating alcohol use. PCPs in family or internal medicine with at least 20 AUD patients. Pharmacotherapy for AUD (naltrexone, acamprosate, and disulfiram), abstinence from alcohol, patient demographics, and comorbidities. Generalized linear mixed models were used to identify patient factors associated with prescriptions and the association of pharmacotherapy with abstinence. We identified 13,250 patients; average age was 54 years, 66.9% were male, 75.0% were White, and median household income was $51,776 per year. Over 10 years, the prescription rate rose from 4.4 to 5.6%. Patients who were Black (aOR 0.74; 95% CI 0.58, 0.94) and insured by Medicare versus commercial insurance (aOR 0.61; 95% CI 0.48, 0.78) were less likely to be treated. Higher median household income ($10,000 increment, aOR 1.06; 95% CI 1.03, 1.10) and Medicaid versus commercial insurance (aOR 1.52; 95% CI 1.24, 1.87) were associated with treatment. Receiving pharmacotherapy was associated with subsequent documented abstinence from alcohol (aOR 1.60; 95% CI 1.33, 1.92). We identified 236 PCPs. The average prescription rate was 3.6% (range 0 to 24%). The top decile prescribed to 14.6% of their patients. The bottom 4 deciles had no prescriptions. Family physicians had higher rates of pharmacotherapy than internists (OR 1.50; 95% CI 1.21, 1.85). Medications for AUD are infrequently prescribed, but there is considerable variation among PCPs. Increasing the use of pharmacotherapy by non-prescribers may increase abstinence from alcohol.