A Membrane\u2010Centric Plasma Lipidomic Signature of Response to Long\u2010Acting Naltrexone in Alcohol Use Disorder

BackgroundPrimary care provider skills such as screening, longitudinal monitoring, and medication management are generalizable to prescribing alcohol use disorder (AUD) pharmacotherapy. The association between primary care engagement (i.e., longitudinal utilization of primary care services) and prescribing of AUD pharmacotherapy is unknown.MethodsWe examined a 5-year (2010–2014) retrospective cohort of patients with AUD, 18 years and older, at an urban academic medical center in the Bronx, NY, USA. Our main exposure was level of primary care engagement (no primary care, limited primary care, and engaged with primary care) and our outcome was any AUD pharmacotherapy prescription within 2 years of AUD diagnosis. Using multivariable logistic regression, we examined the association between primary care engagement and pharmacotherapy prescribing, accounting for demographic and clinical factors.ResultsOf 21,159 adults (28.9% female) with AUD, 2.1% (n = 449) were prescribed pharmacotherapy. After adjusting for confounders, the probability of receiving an AUD pharmacotherapy prescription for patients with no primary care was 1.61% (95% CI 1.39, 1.84). The probability of AUD pharmacotherapy prescribing was 2.56% (95% CI 2.06, 3.06) for patients with limited primary care and 2.89% (95% CI 2.44, 3.34%) for patients engaged with primary care.ConclusionsThe percentage of AUD patients prescribed AUD pharmacotherapy was low; however, primary care engagement was associated with a higher, but modest, probability of receiving a prescription. Efforts to increase primary care engagement among patients with AUD may translate into increased AUD pharmacotherapy prescribing; however, strategies to increase prescribing across health care settings are needed.

Pharmacotherapy of Alcohol Use Disorders in the Veterans Health Administration

Heavy-Drinking Smokers: Pathophysiology and Pharmacologic Treatment Options

As hepatology providers, we assemble a toolbox of interventions to treat acute and chronic liver diseases with a goal to prevent fibrosis progression, HCC, and hepatic decompensation while also improving the quality of life and survival of our patients (Figure 1). This toolbox has been built based on our experiences during clinical training and the practice of routine patient care. We are comfortable with a diverse set of tools, from antivirals to immunosuppressive medications, vasoactive medications to beta-blockers, as well as performing interventions such as endoscopy, banding, paracentesis, and liver biopsies. Hepatology providers have accepted that in the setting of chronic liver disease, we are primarily responsible for prescribing interventions, which treat the underlying liver insult and follow-up on outcomes and side effects using a multidisciplinary approach. Yet, when it comes to the management of alcohol use disorder (AUD) in the setting of alcohol-associated liver disease (ALD), our discipline seems to have made an exception. Although treatment of AUD has been identified as a quality metric in the care of patients with liver disease,1 rates of AUD treatment in those with ALD are astonishingly low,2,3 and current societal recommendations are to refer elsewhere for AUD management once identified.4,5 Why has this culture evolved among hepatology providers? Is it a lack of knowledge and/or comfort in AUD treatment? Do patients with AUD and their providers have difficulty accessing the tools when needed? Importantly, can social stigma and sociocultural considerations influence patient participation in AUD treatment? The answer is all of the above.FIGURE 1: The hepatology toolbox—how do we include alcohol use disorder treatment?.DESPITE THE BENEFIT, TREATMENT OF AUD IN ALD RARELY HAPPENS It is universally agreed that alcohol abstinence is the cornerstone of ALD management, as it is associated with improved liver-related outcomes3 and is cost-effective and even cost-saving in those with ALD cirrhosis.6 Yet despite this, 2 large cohort studies of individuals with AUD and ALD cirrhosis have shown that only ~15% receive AUD behavioral therapy and a mere 1% receive pharmacotherapy.2,3 Why are AUD treatment rates so low? To begin, data have suggested that apart from psychiatry and addiction medicine, physicians receive minimal training in AUD identification and management and do not feel equipped to treat it. Surveys by GI/hepatology providers suggest that almost all screen universally for frequency and quality of alcohol consumption; however, almost half never/rarely screen for AUD, and 70% never/rarely prescribe AUD therapy.7 The most common provider-perceived barriers to prescribing AUD pharmacotherapy were lack of training, unfamiliarity, and lack of time. Other studies have identified patient-perceived barriers, including lack of apparent benefit to treatment, financial and insurance obstacles, and access to transportation.8 However, in addition to these hurdles, other patient-related barriers are faced disproportionately by those most vulnerable in society. SOCIOCULTURAL AND EQUITY CONSIDERATIONS INFLUENCING DELIVERY OF AUD/ALD THERAPY A significant proportion of individuals with AUD/ALD are from historically underrepresented racial/ethnic, sex/gender, and sociocultural groups9 and those vulnerable in their social determinants of health, creating additional barriers to AUD treatment (Figure 2). These disparities are complex and historically rooted in patterns of systemic discrimination and socioeconomic disadvantage.10 Overall, AUD treatment is most effective as a combination of pharmacologic and behavioral interventions, yet most studies evaluating AUD treatment underrepresent those of diverse cultural, racial/ethnic, and sex/gender backgrounds and have not been designed to address important dimensions of diversity. In considering those vulnerable in social determinants of health, pharmacologic treatments require public and/or private insurance to cover costs, while in addition to cost, behavioral therapy also requires significant time and social resources to participate. These include the ability to take time from work in those employed and/or the ability to delay home obligations if caring for dependents. Individuals must also secure transportation and be in proximity to AUD behavioral treatment, or if able to be delivered remotely, have access to technological resources for participation. Finally, culturally and linguistically appropriate AUD services are required to provide safe and equitable access to AUD treatment to all but are not universally accessible. Moving forward, these important aspects of diversity will need to be considered in the development and delivery of AUD services.FIGURE 2: Barriers to alcohol use disorder treatment in vulnerable populations.SPECIAL CONSIDERATIONS FOR WOMEN AND YOUTHS Women and youths have been identified as populations experiencing a disproportionate increase in harm from AUD/ALD and have emerged as priority groups in need of AUD treatment.11,12 Women and youths with AUD have a high prevalence of co-morbid mental health conditions and have experienced mental, physical, and/or sexual abuse, which can impact participation and outcomes of treatment. Although outcomes of AUD treatment are comparable between sexes, women are less likely to receive treatment than men.12 Unique factors among women that can influence participation in AUD treatment include issues surrounding motherhood, such as the need for childcare to participate and perceived or experienced social stigma creating fear of the involvement of child protective services if AUD is disclosed.12 Further, no AUD pharmacotherapy has been shown to be safe for women who are pregnant or breastfeeding, limiting treatment options during this time. Similarly, for youths, no pharmacotherapies are FDA-approved to treat AUD in those ≤18 years of age, and no trials of AUD treatment among youths with ALD have been conducted. Despite the knowledge that most adults with AUD began using alcohol during the teenage years, the majority of efforts developed to treat AUD have not focused on identification and intervention during adolescence, which may be a key time for behavioral change. Further, the delivery of AUD behavioral therapy for youths is best if the family and caregivers partake, which again will be dependent on the ability of not only the individuals but also their social circle to participate. POTENTIAL SOLUTIONS Several provider, hospital, research, and societal solutions to address barriers in AUD management in ALD are outlined in Figure 3. On an individual GI/Hepatology provider level, the universal implementation of standardized screening tools for AUD to all patients with ALD at the time of the first clinical encounter should be straightforward to implement. In addition to this, the delivery of an AUD pharmacotherapy curriculum to GI/Hepatology trainees, nurses, and clinicians could empower them with the knowledge and skills to initiate AUD pharmacotherapy among their ALD patients. This would be especially important in settings where access to addiction medicine is limited. From a hospital level, providing language and transportation services to facilitate access to AUD behavioral therapy would be specifically helpful to engage vulnerable populations. Further, universal and quick access to inpatient and outpatient addiction medicine consultative services, social work, and psychiatry are essential. From an academic level, the development of studies, which evaluate AUD treatment and outcomes among those with advanced ALD, are needed in addition to the inclusion of previously understudied and vulnerable populations as outlined above. From a society level, it is vital to address the stigma attached to a diagnosis of AUD to empower patients to seek appropriate help without worry about judgment or discrimination. This could involve public education campaigns that emphasize AUD as a disease as opposed to a personal choice and highlight how appropriate treatment of AUD can lead to disease remission and improve other alcohol-associated harms including ALD.FIGURE 3: Potential solutions to address disparities in AUD treatment among those with ALD. Abbreviations: ALD, alcohol-associated liver disease; AUD, alcohol use disorder.CONCLUSIONS AND FUTURE CONSIDERATIONS AUD is a preventable cause of liver-related morbidity and mortality, and AUD treatment is associated with improved outcomes, especially among those with ALD. Yet the use of AUD treatment in those with ALD is discouragingly low due to the paucity of well-executed clinical trials and patient and provider barriers, with additional unique barriers faced by underrepresented and vulnerable members of society. As hepatology providers caring for these patients, our discipline needs to begin gathering AUD treatment tools to put in our toolbox. Importantly, these tools will need to incorporate considerations surrounding stigma, culture, diversity, and equity in order to provide the best care for our diverse patient population.

BackgroundDespite the high prevalence of alcohol use disorders (AUDs), in 2016, only 7.8% of individuals meeting diagnostic criteria received any type of AUD treatment. Developing options for treatment within primary care settings is imperative to increase treatment access. As part of a trial to implement AUD pharmacotherapy in primary care settings, this qualitative study analyzed pre-implementation provider interviews using the Consolidated Framework for Implementation Research (CFIR) to identify implementation barriers.MethodsThree large Veterans Health Administration facilities participated in the implementation intervention. Local providers were trained to serve as implementation/clinical champions and received external facilitation from the project team. Primary care providers received a dashboard of patients with AUD for case identification, educational materials, and access to consultation from clinical champions. Veterans with AUD diagnoses received educational information in the mail. Prior to the start of implementation activities, 24 primary care providers (5–10 per site) participated in semi-structured interviews. Transcripts were analyzed using common coding techniques for qualitative data using the CFIR codebook Innovation/Intervention Characteristics, Outer Setting, Inner Setting, and Characteristics of Individuals domains. Number and type of barriers identified were compared to quantitative changes in AUD pharmacotherapy prescribing rates.ResultsFour major barriers emerged across all three sites: complexity of providing AUD pharmacotherapy in primary care, the limited compatibility of AUD treatment with existing primary care processes, providers’ limited knowledge and negative beliefs about AUD pharmacotherapy and providers’ negative attitudes toward patients with AUD. Site specific barriers included lack of relative advantage of providing AUD pharmacotherapy in primary care over current practice, complaints about the design quality and packaging of implementation intervention materials, limited priority of addressing AUD in primary care and limited available resources to implement AUD pharmacotherapy in primary care.ConclusionsCFIR constructs were useful for identifying pre-implementation barriers that informed refinements to the implementation intervention. The number and type of pre-implementation barriers identified did not demonstrate a clear relationship to the degree to which sites were able to improve AUD pharmacotherapy prescribing rate. Site-level implementation process factors such as leadership support and provider turn-over likely also interacted with pre-implementation barriers to drive implementation outcomes.

Over the past decade, research into pharmacotherapy for alcohol use disorder (AUD) has significantly expanded. Three medications—naltrexone (including its extended-release (XR formulation, Vivitrol®), acamprosate, and disulfiram—are Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved for alcohol use disorder treatment. In some European regions, baclofen, nalmefene, and sodium oxybate are also approved for alcohol use disorder treatment. Despite their widespread use, variability in clinical outcomes underscores the need for more tailored treatment strategies. Several emerging medications show promise for treating alcohol use disorder. Among the numerous neurotransmitter systems identified for novel drug development, the most promising compounds modulate the functions of opioids, glutamate (with or without gamma-aminobutyric acid), and serotonin. Other potential therapeutic agents target systems involved in sleep, appetite, stress response, and neuroplasticity. While more research is needed to confirm the efficacy of these agents in larger clinical trials, they represent an exciting new avenue for alcohol use disorder treatment. In summary, while established treatments for alcohol use disorder remain essential, there is a growing need for more personalized approaches. These strategies should address not only alcohol-related reward mechanisms but also symptoms of withdrawal, cravings, depression, cognitive processing, and sleep disturbances. The exploration of new pharmacotherapies offers hope for improved outcomes, with treatment tailored to each individual’s unique needs.

Alcohol use disorders (AUDs) can lead to unemployment, yet they remain undertreated. Pharmacotherapies may strengthen labour market attachment but are underused. This study investigates the association between AUD pharmacotherapy use and the risk of becoming unemployed among individuals with an AUD diagnosis in Sweden. A longitudinal register-based study was conducted, using the Swedish Work, Illness and labour market Participation (SWIP) cohort, restricted to gainfully employed individuals between 16 and 60 years with a first-time AUD diagnosis in Sweden between 2006 and 2019 (n=77 503). The exposure was AUD pharmacotherapy use. The outcome was the first unemployment spell (≥90 consecutive days) that occurred after the first-time AUD diagnosis (2006-2020). Covariates included sociodemographic characteristics, comorbidities and unemployment history. The association between pharmacotherapy use and unemployment was examined using Cox regression models. Of the cohort, 42.8% used AUD pharmacotherapy and 15 098 individuals became unemployed during the observation period (median 7.1 years, IQR 3.3-10.6 years). Relative to those with AUD who did not use any pharmacotherapy, an inverse association between the use of AUD pharmacotherapy and unemployment incidence was observed (adjusted HR (aHR): 0.86; 95% CIs 0.82 to 0.89). AUD pharmacotherapy may decrease the risk of long-term unemployment. The findings further underscore the importance of pharmacotherapy treatment to sustain work ability and promote a healthy workforce.

Although classic psychedelic medications have shown promise in the treatment of alcohol use disorder (AUD), the efficacy of psilocybin remains unknown. To evaluate whether 2 administrations of high-dose psilocybin improve the percentage of heavy drinking days in patients with AUD undergoing psychotherapy relative to outcomes observed with active placebo medication and psychotherapy. In this double-blind randomized clinical trial, participants were offered 12 weeks of manualized psychotherapy and were randomly assigned to receive psilocybin vs diphenhydramine during 2 day-long medication sessions at weeks 4 and 8. Outcomes were assessed over the 32-week double-blind period following the first dose of study medication. The study was conducted at 2 academic centers in the US. Participants were recruited from the community between March 12, 2014, and March 19, 2020. Adults aged 25 to 65 years with a DSM-IV diagnosis of alcohol dependence and at least 4 heavy drinking days during the 30 days prior to screening were included. Exclusion criteria included major psychiatric and drug use disorders, hallucinogen use, medical conditions that contraindicated the study medications, use of exclusionary medications, and current treatment for AUD. Study medications were psilocybin, 25 mg/70 kg, vs diphenhydramine, 50 mg (first session), and psilocybin, 25-40 mg/70 kg, vs diphenhydramine, 50-100 mg (second session). Psychotherapy included motivational enhancement therapy and cognitive behavioral therapy. The primary outcome was percentage of heavy drinking days, assessed using a timeline followback interview, contrasted between groups over the 32-week period following the first administration of study medication using multivariate repeated-measures analysis of variance. A total of 95 participants (mean [SD] age, 46 [12] years; 42 [44.2%] female) were randomized (49 to psilocybin and 46 to diphenhydramine). One participant (1.1%) was American Indian/Alaska Native, 3 (3.2%) were Asian, 4 (4.2%) were Black, 14 (14.7%) were Hispanic, and 75 (78.9%) were non-Hispanic White. Of the 95 randomized participants, 93 received at least 1 dose of study medication and were included in the primary outcome analysis. Percentage of heavy drinking days during the 32-week double-blind period was 9.7% for the psilocybin group and 23.6% for the diphenhydramine group, a mean difference of 13.9%; (95% CI, 3.0-24.7; F1,86 = 6.43; P = .01). Mean daily alcohol consumption (number of standard drinks per day) was also lower in the psilocybin group. There were no serious adverse events among participants who received psilocybin. Psilocybin administered in combination with psychotherapy produced robust decreases in percentage of heavy drinking days over and above those produced by active placebo and psychotherapy. These results provide support for further study of psilocybin-assisted treatment for AUD. ClinicalTrials.gov Identifier: NCT02061293.

Addiction as a Coping Response: Hyperkatifeia, Deaths of Despair, and COVID-19.

BackgroundThe role of pharmacotherapy for alcohol use disorder (AUD) in mitigating COPD exacerbations remains underexplored. This study aims to evaluate the impact of AUD pharmacotherapy on COPD-related clinical outcomes.MethodsA retrospective cohort study was conducted on 635 COPD patients with comorbid AUD. Patients were categorized into two groups based on whether they received medication for AUD (MAUD group) or not (no-MAUD group). Data on demographics, COPD severity, exacerbation rates, and AUD treatment were extracted from electronic medical records.ResultsIndividuals in the MAUD group (n=229) exhibited a substantially reduced frequency of COPD exacerbations when compared to those in the non-MAUD group (n=406), with a significant difference observed (P<0.001). Additionally, the MAUD group experienced a longer duration before the first exacerbation event (P<0.001).ConclusionPharmacotherapy for AUD appears to have a protective effect against the occurrence of COPD exacerbations and improved clinical outcomes in patients with comorbid AUD. These findings suggest that AUD treatment should be considered as part of a comprehensive management strategy for COPD patients with AUD.

Pharmacotherapy can be an important part of the continuum of care for alcohol use disorder (AUD). The Swedish universal health-care system emphasizes provision of care to marginalized groups. The primary aim was to test associations of neighborhood deprivation and disadvantaged social status with receipt of AUD pharmacotherapy in this context. Data from linked population registers were used to follow an open cohort over 7years. Sweden. Alcohol-related ICD-10 codes reported for all hospitalizations in the Swedish Hospital Discharge Register and all clinic/office visits in the Outpatient Care Register between 2005 and 2012 were used to identify 62 549 cases with AUD. The primary outcome was any AUD pharmacotherapy (naltrexone, disulfiram, acamprosate, nalmefene) picked up by patients between 2005 and 2012 (versus none), based on the Swedish Prescribed Drug Register. Neighborhood deprivation was defined using aggregated data from the Total Population Register; indicators of disadvantaged social status (income, education, country of origin) also came from this source. Approximately half the cases (53.7%) picked up one or more AUD pharmacotherapy prescriptions. In adjusted models, people living in neighborhoods with moderate [odds ratio (OR)=0.90, 95% confidence interval (CI)=0.86, 0.95] or high levels of deprivation (OR=0.75, 95% CI=0.70, 0.79) compared with low deprivation, those with lower incomes (for example, lowest quartile: OR=0.70, 95% CI=0.66, 0.73 compared with highest) and less education (for example, <10years: OR=0.82, 95% CI=0.78, 0.85 compared with 12+ years) and people born outside Sweden (OR=0.74, 95% CI=0.71, 0.78 compared with Swedish-born) were significantly less likely to pick up a prescription for AUD pharmacotherapy during the study period. There appear to be socio-economic disparities in the receipt of pharmacotherapy for alcohol use disorder in Sweden.

Alcohol consumption affects sleep both in healthy populations and in patients with alcohol use disorder (AUD). However, sleep has typically not been considered within AUD pharmacotherapy trials. We used data from a completed gabapentin clinical treatment trial to explore the medication's effect on patient-rated insomnia measured by a standard insomnia rating (Insomnia Severity Index [ISI]) and whether this influenced gabapentin's effects on alcohol consumption. This study included 90 individuals with current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition AUD criteria reporting current or past alcohol withdrawal. Participants were assigned to placebo or gabapentin (up to 1200 mg/day) for a 16-week randomized controlled trial with percent heavy drinking days (PHDD) and percent abstinent days (PDA) as outcomes. Utilizing mixed-effects models, this study assessed medication effects on ISI over the trial. We then examined the interaction of baseline ISI and medication on drinking. Finally, given our previous finding of alcohol withdrawal influencing gabapentin efficacy, we added change in ISI as a potential "moderator" of the interaction of medication effects and alcohol withdrawal on drinking. Sleep (ISI) improved more in those treated with gabapentin (60.6% reduction) compared with placebo (37.8% reduction; P = 0.013). Higher baseline ISI predicted drinking in gabapentin-treated individuals (lower PHDD [ P = 0.026] and higher (PDA [ P = 0.047]). ISI was an independent predictor of PHDD decrease and PDA increase ( P < 0.001; P = 0.002), but this did not significantly moderate gabapentin's effectiveness. Although gabapentin positively impacts both alcohol use and sleep, its effect on drinking is not fully dependent on sleep improvement, implying a direct biological mechanism on alcohol use.

Evidence suggests that spironolactone, a nonselective mineralocorticoid receptor (MR) antagonist, modulates alcohol seeking and consumption. Therefore, spironolactone may represent a novel pharmacotherapy for alcohol use disorder (AUD). In this study, we tested the effects of spironolactone in a mouse model of alcohol drinking (drinking-in-the-dark) and in a rat model of alcohol dependence (vapor exposure). We also investigated the association between spironolactone receipt for at least 60 continuous days and change in self-reported alcohol consumption, using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), in a pharmacoepidemiologic cohort study in the largest integrated healthcare system in the US. Spironolactone dose-dependently reduced the intake of sweetened or unsweetened alcohol solutions in male and female mice. No effects of spironolactone were observed on drinking of a sweet solutionwithout alcohol, food or water intake, motor coordination, alcohol-induced ataxia, or blood alcohol levels. Spironolactone dose-dependently reduced operant alcohol self-administration in dependent and nondependent male and female rats. In humans, a greater reduction in alcohol consumption was observed among those who received spironolactone, compared to propensity score-matched individuals who did not receive spironolactone. The largest effects were among those who reported hazardous/heavy episodic alcohol consumption at baseline (AUDIT-C ≥ 8) and those exposed to ≥ 50 mg/day of spironolactone. These convergent findings across rodent and human studies demonstrate that spironolactone reduces alcohol use and support the hypothesis that this medication may be further studied as a novel pharmacotherapy for AUD.

Introduction Alcohol use disorder (AUD) is prevalent and recognized as a chronic, relapsing disorder. Even though effective treatment options are available, AUD is strongly undertreated. As adjuvant treatment strategies accompanying psychosocial treatments, pharmacological strategies can increase the efficacy of AUD treatment options. Areas covered After giving a brief update of epidemiology, neurobiology and treatment rationales for AUD, the review outlines pharmacological interventions against the background of current evidence. These include approved substances like naltrexone, nalmefene, acamprosate and disulfiram, second line medications like topiramate, baclofen and varenicline and novel approaches like hallucinogens. The review refers to the primary database on pharmacotherapies for AUD and to findings from pairwise and network meta-analyses. It illustrates effects of pharmacotherapies for AUD on different outcomes and assesses risks and benefits of treatment strategies. Search has been conducted in PubMed using the substance name or related categories (such as anti-craving or relapse prevention) as key words. Expert opinion Improved understanding of AUDs neurocircuitry expands the range of available pharmacotherapeutic strategies for supporting abstinence and drinking reduction. Pharmacotherapies for AUD can be improved by understanding differences in treatment response. Matching different treatment approaches to individual needs can challenge the view of alcohol dependence as a lifelong disorder.

ABSTRACTBackground: Although there is a growing literature examining organizational characteristics and medication adoption, little is known about service delivery differences between specialty treatment organizations that have and have not adopted pharmacotherapy for alcohol use disorder (AUD). This study compares adopters and nonadopters across a range of treatment services, including levels of care, availability of tailored services for specific populations, treatment philosophy and counseling orientations, and adoption of comprehensive wraparound services. Methods: In-person interviews were conducted with program leaders from a national sample of 372 organizations that deliver AUD treatment services in the United States. Results: About 23.6% of organizations had adopted at least 1 AUD medication. Organizations offering pharmacotherapy were similar to nonadopters across many measures of levels of care, tailored services, treatment philosophy, and social services. The primary area of difference between the 2 groups was for services related to health problems other than AUD. Pharmacotherapy adopters were more likely to offer primary medical care, medications for smoking cessation, and services to address co-occurring psychiatric conditions. Conclusions: Service delivery differences were modest between adopters and nonadopters of AUD pharmacotherapy, with the exception of health-related services. However, the greater adoption of health-related services by organizations offering AUD pharmacotherapy represents greater medicalization of treatment, which may mean these programs are more strongly positioned to respond to opportunities for integration under health reform.