Pharmacotherapy used for alcohol and cocaine use disorders in a CAPS-AD of Minas Gerais

Abstract Substance use disorder is one of the major social and public health problems in the world. The present study analyzed the pharmacoepidemiological profile of patients treated at the Psychosocial Treatment Center for Alcohol and Substance Use Disorders (CAPS-AD) for treatment of alcohol use disorders (AUD), cocaine use disorders (CUD) and concomitant alcohol and cocaine use disorders (A-CUD) in the city of Betim-MG. The study used quantitative and descriptive data and was based on the evaluation of medical records of patients attended from January to December 2016. After analyzing 295 medical records, the majority of study participants were male (83.7 %) with an average age of 46.26 for AUD, 28.88 for CUD and 34.29 for A-CUD. The most prescribed drugs for AUD were diazepam (54.1 %), thiamine (37 %), complex B vitamins (29.5 %), and disulfiram (2.7 %); for CUD, diazepam (26.9 %) and haloperidol (23.1 %). It should be noticed that although contraindicated by the guidelines, chlorpromazine (42.3 %, 25.3 %, 20.3 %) was prescribed for CUD, AUD, and A-CUD respectively. Knowing the pharmacoepidemiological profile of CAPS-AD patients is extremely important for making decisions regarding which medicines to make available to the population.

Treatment of opioid and alcohol withdrawal in a cohort of emergency department patients.

BACKGROUND: The safety of combining buprenorphine with a benzodiazepine or barbiturate in the treatment of concurrent alcohol and opioid withdrawal has not been well established. In this study we examine a cohort of patients treated with buprenorphine and phenobarbital or benzodiazepines for co-occurring opioid and alcohol withdrawal. METHODS: This is a retrospective cohort study of ED patients treated for opioid and alcohol withdrawal from January through December 2018. The primary outcome was unexpected airway intervention, or the administration of naloxone for respiratory depression. RESULTS: There were 16 patients treated for opioid and alcohol withdrawal. The mean age was 44.3 (standard deviation [SD] 13.1), 12 (75.0%) were male, and 8 (50.0%) of the patients were admitted to the hospital. For opioid withdrawal, six patients received intravenous buprenorphine, with doses between 0.3 mg to 1.8 mg; 12 patients received sublingual buprenorphine, with doses between 4 mg to 32 mg. For alcohol withdrawal, 10 patients received lorazepam with doses between 1 mg and 8 mg; 10 patients received phenobarbital with doses between 260 mg to 1040 mg. There were no unexpected airway interventions related to medications used for opioid or alcohol withdrawal. One patient with severe pneumonia was an expected intubation for respiratory failure. CONCLUSIONS: We describe a cohort of patients treated for opioid and alcohol withdrawal in the ED. There were no serious adverse events related to the medications used to treat opioid or alcohol withdrawal. Further work should assess optimal use of medical therapy for opioid and alcohol withdrawal and the transition to maintenance treatment for substance use disorders.

Recent findings leading to the discovery of selective dopamine D4 receptor ligands for the treatment of widespread diseases.

Since its discovery, the dopamine D4 receptor (D4R) has been suggested to be an attractive target for the treatment of neuropsychiatric diseases. Novel findings have renewed the interest in such a receptor as an emerging target for the management of different diseases, including cancer, Parkinson's disease, alcohol or substance use disorders, eating disorders, erectile dysfunction and cognitive deficits. The recently resolved crystal structures of D4R in complexes with the potent ligands nemonapride and L-745870 strongly improved the knowledge on the molecular mechanisms involving the D4R functions and may help medicinal chemists in drug design. This review is focused on the recent development of the subtype selective D4R ligands belonging to classical or new chemotypes. Moreover, ligands showing functional selectivity toward G protein activation or ß-arrestin recruitment and the effects of selective D4R ligands on the above-mentioned diseases are discussed.

A Critical Review of Alcohol Administration Guidelines in Laboratory Medication Screening Research: Is It Time to Include Treatment Seekers?

Human laboratory studies play an important role in alcohol use disorder (AUD) medication development. Medications that are found to be safe and effective during human laboratory screening will then move to more expensive clinical trials in patient populations. Given the gatekeeping role of human laboratory studies in the medication development pipeline, it is critical that these studies accurately forecast how pharmacotherapies will perform under true-to-life clinical conditions. On the other hand, the design of these studies also must adhere to ethical guidelines: certain aspects of clinical reality cannot be incorporated into screening studies because doing so might place the participant at risk for harm or breach other ethical guidelines. Conventions exist that guide the resolution of these conflicting ideals. This article considers the practice of recruiting non-treatment-seeking heavy drinkers to participate in laboratory screening studies. By convention, volunteers are excluded from laboratory screening studies that involve alcohol administration if they are deemed "treatment seeking," meaning that they recently stopped drinking or are motivated to do so. Although this common practice may reduce risk to participants, findings may not accurately predict medication effects on treatment seekers. Indeed, there is empirical evidence that treatment seekers differ from nontreatment seekers in their responses to medications (Neuropsychopharmacology 2017a; 42: 1776; Am J Drug Alcohol Abuse 2017b; 43: 703; J Psychiatr Res 2006; 40: 383). Here, we argue for the importance of recruiting treatment seekers for this research due to their qualitative difference from nontreatment seekers. We argue that these individuals should be the default population in human laboratory medication screening studies. We conclude by discussing 2 case examples of medication experiments led by our research groups that involved administering medications to treatment seekers.

Gabapentin for Alcohol-Related Disorders: Critical Appraisal of the Symptom-Driven Approach.

Gabapentin, available as gabapentin and as the prodrug gabapentin enacarbil, is an approved treatment for partial seizures, postherpetic neuralgia, and the restless legs syndrome. Gabapentin has been studied for diverse off-label indications, including alcohol use disorder (AUD). Meta-analyses of randomized controlled trials (RCTs) suggest that gabapentin reduces the severity of alcohol withdrawal symptoms (AWS) as well as the percentage of heavy drinking days in persons with AUD; however, the magnitude of benefit is small, and no benefits are apparent for other drinking outcomes. Furthermore, a recent, large RCT found an extended-release formulation of gabapentin enacarbil ineffective for a wide range of drinking and other outcomes in patients with AUD. Some research suggests that gabapentin may improve drinking outcomes specifically in AUD patients with higher levels of AWS; this may be a result of gabapentin-associated reduction in AWS, precluding AWS-triggered continued drinking. In this context, a recent, large RCT found that gabapentin reduced heavy drinking and increased abstinence, and that these findings were apparent only in patients with higher levels of AWS during the 2 weeks before randomization; disconcertingly, gabapentin appeared to worsen drinking outcomes in the patients with low AWS. Whereas these findings support the conjecture that gabapentin could be considered indicated in AUD patients with high AWS, problems with this RCT and with its findings limit the applicability of the findings to everyday clinical practice. These problems are discussed in detail. It is concluded that, in line with the recommendations of a recent treatment guideline, gabapentin may be considered for patients with AUD only if first line drugs such as naltrexone and acamprosate cannot be used. It may also be worth examining benefits with gabapentin in AUD associated with chronic pain, anxiety, and chronic insomnia because gabapentin is suggested to attenuate these syndromes.

Pharmacological interventions for antisocial personality disorder.

BACKGROUND: Antisocial personality disorder (AsPD) is associated with rule-breaking, criminality, substance use, unemployment, relationship difficulties, and premature death. Certain types of medication (drugs) may help people with AsPD. This review updates a previous Cochrane review, published in 2010. OBJECTIVES: To assess the benefits and adverse effects of pharmacological interventions for adults with AsPD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, 13 other databases and two trials registers up to 5 September 2019. We also checked reference lists and contacted study authors to identify studies. SELECTION CRITERIA: Randomised controlled trials in which adults (age 18 years and over) with a diagnosis of AsPD or dissocial personality disorder were allocated to a pharmacological intervention or placebo control condition. DATA COLLECTION AND ANALYSIS: Four authors independently selected studies and extracted data. We assessed risk of bias and created 'Summary of findings tables' and assessed the certainty of the evidence using the GRADE framework. The primary outcomes were: aggression; reconviction; global state/global functioning; social functioning; and adverse events. MAIN RESULTS: We included 11 studies (three new to this update), involving 416 participants with AsPD. Most studies (10/11) were conducted in North America. Seven studies were conducted exclusively in an outpatient setting, one in an inpatient setting, and one in prison; two studies used multiple settings. The average age of participants ranged from 28.6 years to 45.1 years (overall mean age 39.6 years). Participants were predominantly (90%) male. Study duration ranged from 6 to 24 weeks, with no follow-up period. Data were available from only four studies involving 274 participants with AsPD. All the available data came from unreplicated, single reports, and did not allow independent statistical analysis to be conducted. Many review findings were limited to descriptive summaries based on analyses carried out and reported by the trial investigators. No study set out to recruit participants on the basis of having AsPD; many participants presented primarily with substance abuse problems. The studies reported on four primary outcomes and six secondary outcomes. Primary outcomes were aggression (six studies) global/state functioning (three studies), social functioning (one study), and adverse events (seven studies). Secondary outcomes were leaving the study early (eight studies), substance misuse (five studies), employment status (one study), impulsivity (one study), anger (three studies), and mental state (three studies). No study reported data on the primary outcome of reconviction or the secondary outcomes of quality of life, engagement with services, satisfaction with treatment, housing/accommodation status, economic outcomes or prison/service outcomes.   Eleven different drugs were compared with placebo, but data for AsPD participants were only available for five comparisons. Three classes of drug were represented: antiepileptic; antidepressant; and dopamine agonist (anti-Parkinsonian) drugs. We considered selection bias to be unclear in 8/11 studies, attrition bias to be high in 7/11 studies, and performance bias to be low in 7/11 studies. Using GRADE, we rated the certainty of evidence for each outcome in this review as very low, meaning that we have very little confidence in the effect estimates reported. Phenytoin (antiepileptic) versus placebo One study (60 participants) reported very low-certainty evidence that phenytoin (300 mg/day), compared to placebo, may reduce the mean frequency of aggressive acts per week (phenytoin mean = 0.33, no standard deviation (SD) reported; placebo mean = 0.51, no SD reported) in male prisoners with aggression (skewed data) at endpoint (six weeks). The same study (60 participants) reported no evidence of difference between phenytoin and placebo in the number of participants reporting the adverse event of nausea during week one (odds ratio (OR) 1.00, 95% confidence interval (CI) 0.06 to 16.76; very low-certainty evidence). The study authors also reported that no important side effects were detectable via blood cell counts or liver enzyme tests (very low-certainty evidence). The study did not measure reconviction, global/state functioning or social functioning. Desipramine (antidepressant) versus placebo One study (29 participants) reported no evidence of a difference between desipramine (250 to 300 mg/day) and placebo on mean social functioning scores (desipramine = 0.19; placebo = 0.21), assessed with the family-social domain of the Addiction Severity Index (scores range from zero to one, with higher values indicating worse social functioning), at endpoint (12 weeks) (very low-certainty evidence). Neither of the studies included in this comparison measured the other primary outcomes: aggression; reconviction; global/state functioning; or adverse events. Nortriptyline (antidepressant) versus placebo One study (20 participants) reported no evidence of a difference between nortriptyline (25 to 75 mg/day) and placebo on mean global state/functioning scores (nortriptyline = 0.3; placebo = 0.7), assessed with the Symptom Check List-90 (SCL-90) Global Severity Index (GSI; mean of subscale scores, ranging from zero to four, with higher scores indicating greater severity of symptoms), at endpoint (six months) in men with alcohol dependency (very low-certainty evidence). The study measured side effects but did not report data on adverse events for the AsPD subgroup. The study did not measure aggression, reconviction or social functioning. Bromocriptine (dopamine agonist) versus placebo One study (18 participants) reported no evidence of difference between bromocriptine (15 mg/day) and placebo on mean global state/functioning scores (bromocriptine = 0.4; placebo = 0.7), measured with the GSI of the SCL-90 at endpoint (six months) (very low-certainty evidence). The study did not provide data on adverse effects, but reported that 12 patients randomised to the bromocriptine group experienced severe side effects, five of whom dropped out of the study in the first two days due to nausea and severe flu-like symptoms (very low-certainty evidence). The study did not measure aggression, reconviction and social functioning. Amantadine (dopamine agonist) versus placebo The study in this comparison did not measure any of the primary outcomes. AUTHORS' CONCLUSIONS: The evidence summarised in this review is insufficient to draw any conclusion about the use of pharmacological interventions in the treatment of antisocial personality disorder. The evidence comes from single, unreplicated studies of mostly older medications. The studies also have methodological issues that severely limit the confidence we can draw from their results. Future studies should recruit participants on the basis of having AsPD, and use relevant outcome measures, including reconviction.

Medication Utilization for Alcohol Use Disorder in a Commercially Insured Population.

OBJECTIVE: Examine patterns of alcohol use disorder (AUD) medication use and identify factors associated with prescription fill among commercially insured individuals with an index AUD visit. DESIGN: Using 2008-2018 claims data from a large national insurer, estimate days to first AUD medication using cause-specific hazards approach to account for competing risk of benefits loss. PARTICIPANTS: Aged 17-64 with ≥ 1 AUD visit. MAIN MEASURE: Days to AUD medication fill. KEY RESULTS: A total of 13.3% of the 151,128 with an index visit filled an AUD prescription after that visit, while 69.8% lost benefits before filling and 17.0% remained enrolled but did not fill (median days observed = 305). Almost half (46.3%) of those who filled a prescription received substance use disorder (SUD) inpatient care within 7 days before the fill, and 63.4% received SUD outpatient care. Likelihood of medication use was higher for those aged 26-35, 36-45, and 46-55 years relative to 56-64 years (e.g., 26-35: hazard ratio = 1.29 [95% confidence interval 1.23-1.36]); those diagnosed with moderate/severe AUD (2.05 [1.98-2.12]), co-occurring opioid use disorder (OUD) (1.33 [1.26-1.39]), or severe mental illness (1.31 [1.27-1.35]); those with a chronic alcohol-related diagnosis (1.08 [1.04-1.12]); and those whose index visit was in an inpatient/emergency department (1.27 [1.23-1.31]) or intermediate care setting (1.13 [1.07-1.20]) relative to outpatient. Likelihood of use was higher in later years relative to 2008 (e.g., 2018:2.02 [1.89-2.15]) and higher for those who received the majority of AUD care in a practice with a psychiatrist/addiction medicine specialist (1.13 [1.10-1.16]). Likelihood of use was lower for those diagnosed with a SUD other than AUD or OUD (0.88 [0.85-0.92]), those with an acute alcohol-related condition (0.79 [0.75-0.84]), and males (0.71 [0.69-0.73]). CONCLUSIONS: While AUD medication use increased and was more common among individuals with greater severity, few patients who could benefit from medications are using them. More efforts are needed to identify and treat individuals in non-acute care settings earlier in their course of AUD.

Alcohol and the Hospitalized Patient.

Alcohol use is a common social and recreational activity in our society. Misuse of alcohol can lead to significant medical comorbidities that can affect essentially every organ system and lead to high health care costs and utilization. Heavy alcohol use across the spectrum from binge drinking and intoxication to chronic alcohol use disorder can lead to high morbidity and mortality both in the long and short term. Recognizing and treating common neurologic, gastrointestinal, and hematological manifestations of excess alcohol intake are essential for those who care for hospitalized patients. Withdrawal is among the most common and dangerous sequela associated with alcohol use disorder.

Role of the treatment environment in the effects of aripiprazole on ethanol-induced behavioral sensitization and conditioned place preference in female mice.

BACKGROUND: Evidence suggests that aripiprazole, a partial dopamine D2 and serotonin 5-HT1A receptor agonist and 5-HT2A receptor antagonist, show significant efficacy in reducing alcohol use. We have previously demonstrated that treatment with aripiprazole blocked the reinstatement of cocaine-induced behavioral sensitization in a context-dependent manner, suggesting that the treatment environment may modulate the therapeutic effects of aripiprazole. The present study aimed to evaluate the effects of treatment with aripiprazole on ethanol-induced behavioral sensitization and conditioned place preference in female mice, and the role of the treatment environment in those effects. METHODS: Adult female mice were either sensitized with ethanol injections in the open-field apparatus, or conditioned with ethanol in the conditioned place preference (CPP) apparatus. Animals were then treated with vehicle or 0.1 mg/kg aripiprazole paired to the test environment (open-field or CPP apparatus) or not (home-cage treatments) for 4 alternate days, and the subsequent expression of behavioral sensitization or CPP to ethanol was evaluated during or following an ethanol re-exposure, respectively. RESULTS: Repeated treatment with aripiprazole attenuated the expression of ethanol-induced behavioral sensitization regardless of the treatment environment. Treatment with aripiprazole was only effective at preventing the reinstatement of ethanol-induced CPP when paired with the ethanol-associated environment, but not when administered in the home-cage. CONCLUSIONS: The present findings corroborate previous studies suggesting the effectiveness of aripiprazole for the treatment of alcohol use disorder. Our results also point to an important role of the treatment environment in the therapeutic effects of aripiprazole in rodent models of ethanol abuse.

Titrated baclofen for high-risk alcohol consumption: a randomized placebo-controlled trial in out-patients with 1-year follow-up.

BACKGROUND AND AIMS: Baclofen is a promising drug for treating patients with alcohol-related disorders. Nevertheless, the first randomized clinical trials (mainly with target doses) reported inconsistent efficacy, possibly because of the effective dose widely varying between patients. The Bacloville study aimed to test the efficacy of titrated baclofen for achieving low-risk alcohol consumption. DESIGN: Twelve-month multicenter pragmatic double-blind randomized clinical trial from June 2012 to June 2014. SETTING: Sixty-two French primary care centers. PARTICIPANTS: Out-patients with high-risk alcohol consumption (> 40 g/day for women and > 60 g/day for men). INTERVENTION AND COMPARATOR: Patients were randomly assigned (1 : 1 ratio) to receive titrated baclofen up to 300 mg/day or placebo for 12 months. Switching to open-label baclofen was allowed in cases of perceived inefficacy. MEASUREMENTS: The primary outcome defined success as no or low-risk alcohol consumption (≤ 20 g/day for women and ≤ 40 g/day for men) during the last month of the 1-year follow up, with patients who switched to open-label baclofen classified as failures. FINDINGS: A total of 320 patients were randomized, 162 to baclofen and 158 to placebo (consumption 129 g/day in both arms). Discontinuation rates were 30 and 34% in the baclofen and placebo arms, respectively, and return rates of the last-month diaries were 42 and 34%, respectively. Primary success rates were 57 and 36% in the baclofen and placebo arms, respectively [difference: 21 percentage points, 95% confidence interval (CI) = 8-34, P = 0.003]. When switchers were not classified as failures unless they failed, the success rates were 62 versus 55% (difference: 6 percentage points, 95% CI = -7 to 20). Over 12 months, daily consumption differed between both arms (11 g less in the baclofen arm), as did the number of abstinence days (3.3 days more in the baclofen arm). Adverse events were more frequent with baclofen than placebo and were mostly drowsiness, fatigue and insomnia. Serious adverse events occurred in 85 (seven deaths) and 36 (three deaths) patients with baclofen and placebo, respectively. CONCLUSIONS: Baclofen was more effective than placebo in reducing alcohol consumption to low-risk levels. The number of adverse events and more serious adverse events was greater with baclofen than placebo.

Safety of nalmefene for the treatment of alcohol use disorder: an update.

Introduction: Reduced drinking has been debated as a treatment goal for heavy drinking alcohol-dependent patients, in whom treatment based on abstinence is not always an option. Nalmefene was the first drug approved by the European Medicines Agency (2013) with the indication of reduced drinking in high drinking risk level alcohol-dependent patients. Six years after its introduction in Europe, data from clinical experience can be compared with those from preclinical studies and pivotal registration studies to evaluate what nalmefene has added to the treatment of AUD.Areas covered: Systematic review of efficacy and safety data of nalmefene use in humans from preclinical, phase III and phase IV studies, including systematic reviews, meta-analyses, cost-effectiveness analyses, and other secondary analyses.Expert opinion: Nalmefene introduces a paradigm change in the treatment of AUD that makes it appealing to patients that are reluctant to embrace abstinence, and facilitate patient-centered care in heavy users. However, information regarding safety data in special populations (e.g., patients with alcohol-related diseases, pregnancy, psychiatric disease), and direct comparisons with other potential drugs for alcohol reduction are further needed. Despite the promising role of nalmefene, there are still some factors that limit its wide prescription further than in specialized settings.

Reduction in Drinking was Associated With Improved Clinical Outcomes in Women With HIV Infection and Unhealthy Alcohol Use: Results From a Randomized Clinical Trial of Oral Naltrexone Versus Placebo.

BACKGROUND: Alcohol consumption is associated with poor health outcomes in women living with HIV (WLWH), but whether medication can help to reduce drinking in non-treatment-seeking women or whether reduction in drinking improves HIV outcomes is unclear. We conducted a randomized clinical trial (RCT) of daily oral naltrexone (50 mg) versus placebo in WLWH who met criteria for current unhealthy alcohol use. METHODS: WLWH with current unhealthy alcohol use (>7 drinks/wk or >3 drinks/occasion) were randomly assigned to daily oral naltrexone 50 mg (n = 96) or placebo (n = 98) for 4 months. Drinking outcomes, including the proportion of women who reduced (

Distinct functions of endogenous cannabinoid system in alcohol abuse disorders.

Δ9 -tetrahydrocannabinol, the principal active component in Cannabis sativa extracts such as marijuana, participates in cell signalling by binding to cannabinoid CB1 and CB2 receptors on the cell surface. The CB1 receptors are present in both inhibitory and excitatory presynaptic terminals and the CB2 receptors are found in neuronal subpopulations in addition to microglial cells and astrocytes and are present in both presynaptic and postsynaptic terminals. Subsequent to the discovery of the endocannabinoid (eCB) system, studies have suggested that alcohol alters the eCB system and that this system plays a major role in the motivation to abuse alcohol. Preclinical studies have provided evidence that chronic alcohol consumption modulates eCBs and expression of CB1 receptors in brain addiction circuits. In addition, studies have further established the distinct function of the eCB system in the development of fetal alcohol spectrum disorders. This review provides a recent and comprehensive assessment of the literature related to the function of the eCB system in alcohol abuse disorders.

Primary care engagement is associated with increased pharmacotherapy prescribing for alcohol use disorder (AUD).

BACKGROUND: Primary 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. METHODS: We 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. RESULTS: Of 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. CONCLUSIONS: The 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.

Prospects for pharmacotherapies to treat alcohol use disorder: an update on recent human studies.

PURPOSE OF REVIEW: The aim of this study was to provide an update on medication development efforts for alcohol use disorder (AUD) by reviewing recently published (past 2 years) human studies that evaluated medications' effects on alcohol-related outcomes. RECENT FINDINGS: Forty-five publications were found suitable for this review. A variety of compounds have been tested in the past 2 years as potential pharmacological options for AUD, including medications that act on multiple targets (topiramate, aripiprazole, quetiapine), calcium channels (gabapentin), gamma-Aminobutyric acid receptors (baclofen, diazepam), glutamate receptors (ifenprodil, memantine, glycine), nicotinic acetylcholine receptors (varenicline, mecamylamine), α1 adrenergic receptors (prazosin, doxazosin), neuroendocrine pathways (oxytocin, a vasopressin receptor 1b antagonist, a ghrelin receptor inverse agonist) and others (samidorphan, ibudilast, N-acetylcysteine, citoline). Important findings and limitations regarding the effects of these medications on alcohol-related outcomes are discussed. SUMMARY: There is a critical need to increase the armamentarium of medications for AUD. Human laboratory studies may help screen and prioritize promising targets and compounds before running large clinical trials. Given the complexity of AUD and the heterogeneity of afflicted patients, future studies should also investigate potential moderators and predictors of response to each pharmacological intervention.

Combination of Clinically Utilized Kappa-Opioid Receptor Agonist Nalfurafine With Low-Dose Naltrexone Reduces Excessive Alcohol Drinking in Male and Female Mice.

BACKGROUND: Nalfurafine is the first clinically approved kappa-opioid receptor (KOP-r) agonist as an antipruritus drug with few side effects in humans (e.g., sedation, depression, and dysphoria). No study, however, has been done using nalfurafine on alcohol drinking in rodents or humans. METHODS: We investigated whether nalfurafine alone or in combination with mu-opioid receptor (MOP-r) antagonist naltrexone changed excessive alcohol drinking in male and female C57BL/6J (B6) mice subjected to a chronic intermittent-access drinking paradigm (2-bottle choice, 24-hour access every other day) for 3 weeks. Neuronal proopiomelanocortin enhancer (nPE) knockout mice with brain-specific deficiency of beta-endorphin (endogenous ligand of MOP-r) were used as a genetic control for the naltrexone effects. RESULTS: Single administration of nalfurafine decreased alcohol intake and preference in both male and female B6 mice in a dose-dependent manner. Pretreatment with nor-BNI (a selective KOP-r antagonist) blocked the nalfurafine effect on alcohol drinking, indicating a KOP-r-mediated mechanism. Pharmacological effects of a 5-dosing nalfurafine regimen were further evaluated: The repeated nalfurafine administrations decreased alcohol consumption without showing any blunted effects, suggesting nalfurafine did not develop a tolerance after the multidosing regimen tested. Nalfurafine did not produce any sedation (spontaneous locomotor activity), anhedonia-like (sucrose preference test), anxiety-like (elevated plus maze test), or dysphoria-like (conditioned place aversion test) behaviors, suggesting that nalfurafine had few side effects. Investigating synergistic effects between low-dose naltrexone and nalfurafine, we found that single combinations of nalfurafine and naltrexone, at doses lower than individual effective dose, profoundly decreased excessive alcohol intake in both sexes. The effect of nalfurafine on decreasing alcohol consumption was confirmed in nPE-/- mice, suggesting independent mechanisms by which nalfurafine and naltrexone reduced alcohol drinking. CONCLUSION: The clinically utilized KOP-r agonist nalfurafine in combination with low-dose naltrexone has potential in alcoholism treatment.

Using clinical decision support through the electronic medical record to increase prescribing of high-dose parenteral thiamine in hospitalized patients with alcohol use disorder.

BACKGROUND: Patients with alcohol use disorder (AUD) are at an increased risk of developing Wernicke's encephalopathy (WE), a devastating and difficult diagnosis caused by thiamine deficiency. Even as AUD is present in up to 25% of hospitalized patients on medical floors, appropriate thiamine supplementation in the hospital setting remains inadequate. These patients are particularly susceptible to thiamine deficiency and subsequent WE due to both their alcohol use and active medical illnesses. The electronic medical record (EMR) has become ubiquitous in health care systems and can be used as a tool to improve the care of hospitalized patients. METHODS: As a quality improvement initiative, we implemented a medication order panel in the EMR with autopopulated orders for thiamine dosing to increase the appropriate use of high-dose parenteral thiamine (HPT) for hospitalized patients with AUD. We conducted a retrospective cohort study of all inpatients with AUD who received an Addiction Psychiatry Consult Service consult three months before and after the EMR change. We compared the proportion of patients receiving HPT prior to consultation (primary outcome) and the length of stay (secondary outcome) between the historical control group and the EMR intervention group. RESULTS: Patients in the EMR intervention group were significantly more likely to receive HPT than the historical control group (20.2% vs. 2.7%, p < 0.0001). This difference remained statistically significant when adjusted for potential confounders (OR: 9.89, 95% CI: [2.77, 35.34], p = 0.0004). There was a trend towards statistical significance that the intervention group had a higher likelihood of being prescribed any thiamine (76.6% vs. 64.6%, p = 0.06) and had a shorter length of stay (median (IQR): 3.8 (2.4, 7.0) vs. 4.6 (2.9, 7.8) days, p = 0.06). CONCLUSION: These results indicate that providing autopopulated thiamine order panels for patients with AUD can be an effective method for specialty services to increase appropriate care practices without additional education or training for providers. Further research should consider the clinical outcomes of increasing HPT for patients with AUD.

Strategies to increase implementation of pharmacotherapy for alcohol use disorders: a structured review of care delivery and implementation interventions.

BACKGROUND: Effective medications for treating alcohol use disorders (AUD) are available but underutilized. Multiple barriers to their provision have been identified, and optimal strategies for addressing and overcoming barriers to use of medications for AUD treatment remain elusive. We conducted a structured review of published care delivery and implementation studies evaluating interventions that aimed to increase medication treatment for patients with AUD to identify interventions and component strategies that were most effective. METHODS: We reviewed literature through May 2018 and used networking to identify intervention studies with AUD medication receipt reported as a primary or secondary outcome. Studies were identified as care delivery studies, characterized by patient-level recruitment and willingness to be randomized to candidate treatment options, and implementation studies, characterized by inclusion of all patients treated at sites involved in the study. Each identified study was independently coded by two investigators for strategies used, guided by a published taxonomy of implementation strategies. All authors reviewed coding discrepancies and revised codes based on consensus. After reaching internal consensus, we solicited feedback from lead investigators on studies to code additional strategies. We reviewed implementation strategies used across studies to assess their relationship with medication receipt, as well as alcohol use outcomes, as available. RESULTS: Nine studies were identified: four RCTs of care delivery interventions, four quasi-experimental evaluations of large-scale implementation interventions, and one quasi-experimental evaluation of a targeted single-site implementation intervention. Implementation strategies used were variable across studies; no strategy was universally used. Effects of the interventions on receipt of AUD pharmacotherapy and alcohol use outcomes also varied. Three of four care delivery interventions resulted in increased receipt of AUD medications, but only one of these three improved alcohol use outcomes. One large-scale and one single-site implementation intervention were associated with increased AUD medication receipt, and these studies did not assess alcohol use outcomes. Patterns of implementation strategies did not clearly distinguish studies that successfully increased use of pharmacotherapy versus those that did not. CONCLUSIONS: Our review did not reveal strategies most effective for implementing AUD medications. Interventions designed to overcome identified barriers may have missed the mark, or differences in the intensity or targets of strategies may matter more than differences in strategies. Further research is needed to understand effective implementation methods and to better understand patient-level perspective, preferences and barriers to receipt of medications.

Potential of GABAB Receptor Positive Allosteric Modulators in the Treatment of Alcohol Use Disorder.

The orthosteric γ-aminobutyric acidB (GABAB) receptor agonist baclofen is currently considered a therapeutic option for alcohol use disorder (AUD); however, the safety profile of baclofen is a concern, thus arousing interest in the positive allosteric modulators (PAMs) of the GABAB receptor (GABAB PAMs), a new class of ligands expected to possess a better safety profile. The present paper summarizes the several lines of experimental evidence indicating the ability of GABAB PAMs to inhibit multiple alcohol-motivated behaviors in rodents. All GABAB PAMs tested to date have invariably been reported to reduce, or even suppress, excessive alcohol drinking, relapse- and binge-like drinking, operant oral alcohol self-administration, reinstatement of alcohol seeking, and alcohol-induced locomotor stimulation and conditioned place preference in rats and mice. The use of validated animal models of several aspects of AUD confers translational value to these findings. The reducing effects of GABAB PAMs on alcohol-motivated behaviors (1) occurred at doses largely lower than those inducing sedation, suggesting that GABAB PAMs may possess, if compared with baclofen, a higher therapeutic index and a more favorable safety profile, and (2) were often not associated with reductions on other non-drug consummatory behaviors. Additional findings with therapeutic potential were (1) the lack of tolerance, after repeated treatment, to the reducing effect of GABAB PAMs on alcohol drinking and self-administration; (2) the efficacy of GABAB PAMs after intragastric administration; and (3) the ability of GABAB PAMs to selectively potentiate the suppressing effect of baclofen on alcohol self-administration. The recent transition of the first GABAB PAMs to the initial steps of clinical testing makes investigation of the efficacy of GABAB PAMs in AUD patients a feasible option.