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Alcohol addiction or alcoholism is the most severe form of problem drinking. A variety of treatment methods for alcoholism are currently available that combine medications, behavioral treatment and peer support. The drugs that are currently approved by the U.S. Food and Drug Administration (FDA) for treatment of alcohol dependence are disulfiram, naltrexone and acamprosate. For many patients, however, these treatments are not effective. Evidence from a number of studies suggests that various factors, both psychosocial and economic, as well as genetic variation, are significant contributors to interindividual variation both of clinical presentation of alcohol problems and response to a given treatment. The aim of the present review is to summarize and discuss different aspects of personalized medicine of alcohol addiction. We focus on pharmacogenomics and beyond, to include the genetics and epigenetics of alcohol addiction as well as other psychosocial and even economic factors that may affect response to alcohol addiction pharmacotherapy. It is anticipated that, within the next 5-10 years, personalized medicine of alcohol addiction will be a reality and it will help reduce the burden of alcoholism from society and increase the well-being and productivity of individuals addicted to alcohol.

Fibrates are a class of medications used to treat hypercholesterolemia and dyslipidemia that target nuclear peroxisome proliferator-activated receptors (PPARs). Studies have shown the PPARα agonist fenofibrate decreases voluntary EtOH consumption however its impact on the reinforcing and motivational effects of EtOH is unknown. We evaluated the ability of fenofibrate (25, 50 and 100 mg/kg), to alter EtOH (10%, w/v) and sucrose (2%, w/v) operant self-administration in rats under a FR2 schedule of reinforcement over four days and under a progressive ratio (PR) schedule on day five of treatment. Results showed fenofibrate dose-dependently decreased EtOH self-administration under both schedules of reinforcement with the greatest effects seen after four to five days of treatment. Fenofibrate decreased responding for sucrose only under the PR schedule of reinforcement and this effect was not dose-dependent. These findings provide further evidence for fenofibrate as a potential treatment for alcohol use disorder in humans.

GABAergic signaling is involved in modulating the reinforcing properties of alcohol, and GABAB receptors have been proposed as a potential target for clinical treatment of alcoholism. The orthosteric GABAB receptor agonist baclofen has been shown to suppress operant self-administration of alcohol in animals and alcohol use in alcohol-dependent patients, but its utility is limited by a narrow therapeutic index. We tested the effects of ADX71441, a novel GABAB receptor positive allosteric modulator, on alcohol-related behaviors in rats. We first assessed the effects of ADX71441 (1, 3, 10 and 30 mg/kg, I.P.) on both non-dependent and dependent male Wistar rats trained to self-administer 20% alcohol. We then determined the effects of ADX71441 on stress-induced as well as cue-induced relapse-like behavior. Finally, we sought to identify the brain regions through which ADX71441 may act to prevent relapse-like behavior by mapping the neuronal activation induced by stress-induced reinstatement of alcohol-seeking using c-Fos immunohistochemistry. ADX71441 dose-dependently decreased alcohol self-administration of both dependent and non-dependent animals, but its potency was higher in alcohol-dependent rats. Furthermore, both cue- and stress-induced alcohol seeking were blocked by the GABAB receptor positive allosteric modulator. Finally, pretreatment with 3 mg/kg of ADX71441 before stress-induced reinstatement significantly decreased c-Fos expression in a network of brain regions implicated in stress-induced relapse, comprising the nucleus accumbens shell, the dorsal raphe nucleus and the medial prefrontal cortex. Our findings support a causal role of GABAB receptors in alcohol reinforcement and relapse to alcohol seeking. These effects are observed in the absence of significant sedative side effects. Jointly, these observations indicate that GABAB receptor positive allosteric modulators merit being tested clinically for the treatment of alcoholism. Our data also point to a potential biomarker of target engagement for early clinical studies.

The glycine transporter-1 inhibitor Org25935 is a promising candidate in a treatment concept for alcohol use disorder targeting the glycine system. Org25935 inhibits ethanol-induced dopamine elevation in brain reward regions and reduces ethanol intake in Wistar rats. This study aimed to further characterise the compound and used ethanol consumption, behavioral measures, and gene expression as parameters to investigate the effects in Wistar rats and, as pharmacogenetic comparison, Alko-Alcohol (AA) rats. Animals were provided limited access to ethanol in a two-bottle free-choice paradigm with daily drug administration. Acute effects of Org25935 were estimated using locomotor activity and neurobehavioral status. Effects on gene expression in Wistar rats were measured with qPCR. The higher but not the lower dose of Org25935 reduced alcohol intake in Wistar rats. Unexpectedly, Org25935 reduced both ethanol and water intake and induced strong CNS-depressive effects in AA-rats (withdrawn from further studies). Neurobehavioral effects by Org25935 differed between the strains (AA-rats towards sedation). Org25935 did not affect gene expression at the mRNA level in the glycine system of Wistar rats. The data indicate a small therapeutic range for the anti-alcohol properties of Org25935, a finding that may guide further evaluations of the clinical utility of GlyT-1 inhibitors. The results point to the importance of pharmacogenetic considerations when developing drugs for alcohol-related medical concerns. Despite the lack of successful clinical outcomes, to date, the heterogeneity of drug action of Org25935 and similar agents and the unmet medical need justify further studies of glycinergic compounds in alcohol use disorder.

Objectives Disulfiram is an adjunct in the treatment of alcohol use disorders, but case reports indicate that disulfiram ethanol reactions are not always recognized in the emergency department. Our first aim is to remind of this risk with two case reports of life-threatening reactions not immediately considered by the emergency physician. The second aim is to estimate the probability that a disulfiram reaction goes unrecognized with the use of a retrospective study of patients admitted to the emergency department. Methods Clinical files of patients admitted between October 1, 2010 and September 30, 2014 to the emergency department were retrospectively screened for the key words “ethanol use” and “disulfiram”. Their diagnoses were then scored by a panel regarding the probability of an interaction. Results Seventy-nine patients were included, and a disulfiram-ethanol reaction was scored as either ‘highly likely’, ‘likely’ or ‘possible’ in 54.4% and as ‘doubtful’ or ‘certainly not present’ in 45.6% of the patients. The interrater agreement was 0.71 (95% CI: 0.64–0.79). The diagnosis was not considered or only after a delay in 44.2% of the patients with a ‘possible’ to ‘highly likely’ disulfiram interaction. One patient with a disulfiram overdose died and was considered as a ‘possible’ interaction. Discussion and conclusions A disulfiram ethanol interaction can be life threatening and failure to consider the diagnosis in the emergency department seems frequent. Prospective studies with documentation of the intake of disulfiram and evaluation of the value of acetaldehyde as a biomarker are needed to determine the precise incidence. Improving knowledge of disulfiram interactions and adequate history taking of disulfiram intake may improve the care for patients.

BackgroundSubstance use is prevalent in Canada, yet treatment is inaccessible. The Rapid Access to Addiction Medicine (RAAM) clinic opened at the University Health Network (UHN) in January 2018 as part of a larger network of addictions clinics in Toronto, Ontario, to enable timely, low barrier access to medical treatment for substance use disorder (SUD). Patients attend on a walk-in basis without requiring an appointment or referral. We describe the RAAM clinic model, including referral patterns, patient demographics and substance use patterns. Secondary outcomes include retention in treatment and changes in both self-reported and objective substance use.MethodsThe Electronic Medical Record at the clinic was reviewed for the first 26 weeks of the clinic’s operation. We identified SUD diagnoses, referral source, medications prescribed, retention in care and self-reported substance use.ResultsThe clinic saw 64 unique patients: 66% had alcohol use disorder (AUD), 39% had opiate use disorder (OUD) and 20% had stimulant use disorder. Fifty-five percent of patients were referred from primary care providers, 30% from the emergency department and 11% from withdrawal management services. Forty-two percent remained on-going patients, 23% were discharged to other care and 34% were lost to follow-up. Gabapentin (39%), naltrexone (39%), and acamprosate (15%) were most frequently prescribed for AUD. Patients with AUD reported a significant decrease in alcohol consumption at their most recent visit. Most patients (65%) with OUD were prescribed buprenorphine, and most patients with OUD (65%) had a negative urine screen at their most recent visit.ConclusionThe RAAM model provides low-barrier, accessible outpatient care for patients with substance use disorder and facilitates the prescription of evidence-based pharmacotherapy for AUD and OUD. Patients referred by their primary care physician and the emergency department demonstrated a reduction in median alcohol consumption and high rates of opioid abstinence.

Acamprosate and naltrexone are medications of proven efficacy in the treatment of alcohol dependence. In order to investigate the prescription of these drugs in outpatient routine treatment in Germany (frequency of prescription, duration, medical specialty of prescribing physician), data of a large statutory health insurance were analyzed. Persons were included who were discharged from inpatient treatment with an alcohol-related disorder among their diagnoses during a one year observation period and with no diagnosed additional substance-related disorder (apart from nicotine- and cannabis-related disorders). Thus 12.958 patients were identified (mainly male, 77.9%; at average 51.4 years [+/−12.7] of age). 44.3% of these patients were treated in a psychiatric hospital, the remaining patients in hospitals of other specialties (e. g. 9.2% in departments of surgery). During an observation period of 6 months after discharge, acamprosate or naltrexone were prescribed at least once to 98 persons (0.76% of 12.958 patients; acamprosate n=80, 0.62%; naltrexone n=18, 0.14%). 16 (0.12%) patients were prescribed acamprosate or naltrexone for more than 3 months. Half of the prescriptions were issued by general practitioners. Possible reasons for this under-prescription are lack of knowledge about the drug treatment of alcohol dependence outside of addiction psychiatry, neglect of biological aspects (including medication) regarding etiology and treatment of substance-related disorders, and stigma of patients with substance-related disorders.

Schizophrenia and schizoaffective disorder are schizophrenia spectrum disorders that cause significant disability. Among individuals who have schizophrenia or schizoaffective disorder, alcohol use disorder (AUD) is common, and it contributes to worse outcomes than for those who do not have co-occurring substance use disorder. Common neurobiological mechanisms, including dysfunction in brain reward circuitry, may explain the high rates of co-occurrence of schizophrenia and AUD or other substance use disorders. Optimal treatment combines pharmacologic intervention and other therapeutic modalities to address both the psychotic disorder and AUD. Further research on the etiology of these co-occurring disorders and on treatment of affected individuals is needed.

Introduction: Disulfiram-ethanol reaction (DER) due to acetaldehyde accumulation occurs after drinking ethanol during disulfiram therapy. DER may result in life-threatening toxicity requiring urgen...

Resurgence may be a mechanism of relapse in alcohol use disorder patients upon discharge from treatment as part of an abuse-treatment-relapse cycle. Adjunctive pharmacotherapies may be a means to facilitate behavioral treatments and block resurgence. Experiments were conducted using a model of alcohol self-administration to assess the repeatability of the elimination and resurgence of alcohol-maintained behavior and the effects of naltrexone. Experiments had three phases. In Phase 1, behavior was maintained by oral alcohol under a fixed-ratio schedule. In Phase 2, behavior was extinguished via condensed milk delivery under a differential-reinforcement-of-other-behavior (DRO) schedule. In Phase 3, the DRO schedule was eliminated. In Experiment 1, this 3-phase cycle was replicated 4 times. Across replications, response rates and dose of alcohol consumed did not differ in Phase 1, alcohol-maintained behavior was eliminated more rapidly in Phase 2, and the resurgence effect was generally stable in Phase 3. In Experiment 2, naltrexone was administered in Phase 2, Phase 3, or both Phases 2 and 3, to separate groups of rats. Naltrexone facilitated the elimination of alcohol-maintained behavior in Phase 2 and, the resurgence of alcohol-maintained behavior was reduced only for those rats that received naltrexone in both phases. Together, these experiments demonstrate that the resurgence of alcohol-maintained behavior is replicable within-subjects and, further, resurgence of alcohol-maintained behavior may be a useful model to evaluate pharmacological interventions to facilitate behavioral treatments and reduce the likelihood of relapse. Results with naltrexone support the use of medication-assisted therapy approaches to reduce relapse risk in patients. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

BACKGROUND Initial evidence that OPRM1 genotype moderates the clinical response to naltrexone has not been replicated in prospective clinical trials. However, the use of traditional statistical analyses and clinical endpoints might limit sensitivity for studying pharmacogenetic associations, whereas the use of intensive daily assessments and person-centered analytic methods might increase sensitivity. This study leveraged person-centered analyses and daily measures of alcohol use, craving, and medication adherence to investigate OPRM1 as a moderator of changes in clinical outcomes during naltrexone treatment. METHODS Treatment-seeking participants with alcohol use disorder (n = 58; Mage = 38 years; 71% male) provided daily cell phone reports of craving and consumption while taking naltrexone as part of a mobile health trial. Daily medication adherence was measured remotely using electronic pill cap recordings. Multilevel modeling and multilevel structural equation modeling analyses evaluated the hypotheses that OPRM1 genotype would moderate prospective reductions in daily alcohol use and craving, and would also moderate within-person associations of daily adherence with same-day craving and consumption. RESULTS OPRM1 genotype moderated the association of daily adherence with reduced same-day consumption (p = 0.007) and craving (p = 0.06), with these associations being stronger for participants with the 118G variant. OPRM1 genotype did not moderate changes in craving and consumption over time. CONCLUSIONS These findings suggest that high-density assessments and person-centered analytic approaches, including modeling within-person variation in medication adherence, could be advantageous for pharmacogenetic studies.

Compared to other medical disorders, including other brain diseases, the number of medications approved for alcohol use disorder (AUD) is very small. Disulfiram, naltrexone (oral and long-acting), and acamprosate are approved by the US Food and Drug Administration (FDA) to treat patients with AUD. These medications are also approved in other countries, including in Europe, where the European Medicines Agency (EMA) also approved nalmefene for AUD. Furthermore, baclofen was recently approved for AUD in France. These approved medications have small effect sizes, which are probably the consequence of the fact that they only work for some patients, yet a personalized approach to match the right medication with the right patient is still in its infancy. Therefore, research is needed to expand the armamentarium of medications that clinicians can use to treat their patients, as well as to better develop personalized approaches. This book chapter reviews other medications, beyond those approved by the FDA, that have shown efficacy in clinical trials, as well as medications which are still in the early stages of evaluation in human studies.

BACKGROUND: The nociceptin/orphanin FQ opioid peptide (NOP) receptor and its endogenous ligand N/OFQ have been implicated in the regulation of drug and alcohol use disorders. In particular, evidence demonstrated that NOP receptor activation blocks reinforcing and motivating effects of alcohol across a range of behavioral measures, including alcohol intake, conditioned place preference and vulnerability to relapse. METHODS: Here, we show the effects of pharmacological activation and inhibition of NOP receptors on binge-like alcohol consumption, as measured by the “drinking in the dark” (DID) model in C57BL/6J mice. RESULTS: We found that two potent and selective NOP agonists AT-202 (0, 0.3, 1, 3 mg/kg) and AT-312 (0, 0.3, 1 mg/kg) did not affect binge alcohol drinking at doses that do not affect locomotor activity. AT-202 also failed to alter DID behavior when administered to mice previously exposed to chronic alcohol treatment with an alcohol-containing liquid diet. Conversely, treatment with either the high affinity NOP receptor antagonist SB-612111 (0, 3, 10, 30 mg/kg) or the selective antagonist LY2817412 (0, 3, 10, 30 mg/kg) decreased binge drinking. SB-612111 was effective at all doses examined, LY2817412 was effective at 30 mg/kg. Consistently, NOP receptor knockout mice consumed less alcohol compared to wild type. SB-612111 reduced DID and increased sucrose consumption at doses that do not appear to affect locomotor activity. However, the high dose of SB-612111 (30 mg/kg) reduced alcohol intake but failed to inhibit preference in a two-bottle choice DID model that can assess moderate alcohol intake. CONCLUSIONS: The present results suggest that NOP receptor inhibition rather than activation may represent a valuable approach for treatment of alcohol use disorders characterized by excessive alcohol consumption such as binge drinking.

We describe a case of disulfiram-ethanol reaction in a patient presenting with altered mental status. The patient was found to be profoundly hypotensive, requiring multiple vasopressor agents. As the symptoms associated with disulfiram reaction are non-specific, it is important to maintain a high level of suspicion for drug reaction when caring for the undifferentiated altered and hypotensive patient.

We present the preliminary data in an ongoing open-label safety and tolerability proof of concept study exploring the potential role for 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in treating patients with alcohol use disorder. At this stage, seven participants have completed the full 8-week MDMA-assisted psychotherapy course, including two therapy sessions each with MDMA. This paper focuses on the safety and tolerability of the therapeutic course for the first four participants to complete treatment. Longer-term outcomes of drinking behaviour will be presented later when the full project data are published. Results show all four participants have successfully tolerated the treatment. There have been no serious adverse events related to MDMA, no unexpected physiological responses to the MDMA sessions or changes to blood results or electrocardiograms, measured before and after the 8-week course. We conclude that the treatment is well- tolerated and are making plans to expand the project into a randomised placebo-controlled study.

Current estimates of the prevalence of chronic pancreatitis, one of the most common causes of exocrine pancreatic insufficiency, are in the range of 3-10 per 100,000 people in many parts of the world. Alcohol consumption is a very important risk factor for exocrine pancreatic insufficiency and is involved in nearly half of all cases. The main hypothesis regarding the role of chronic alcohol consumption in pancreatitis is that there must be additional environmental or genetic risk factors involved for ongoing damage to occur. Treatment of patients with alcohol-related exocrine pancreatic insufficiency is complex, as the patient has two concomitant pathologies, alcohol-use disorder (AUD) and exocrine pancreatic insufficiency/chronic pancreatitis. Alcohol abstinence is the starting point for treatment, although even this along with the most advanced therapies allow only a slowdown in progression rather than restoration of function. This position paper of the Italian Association for the Study of the Pancreas and the Italian Society of Alcohology provides an overview of the pathogenesis of alcohol-related pancreatitis and discuss diagnostic issues. Treatment options for both exocrine pancreatic insufficiency/chronic pancreatitis (with a focus on pancreatic enzyme replacement therapy) and AUD (acamprosate, disulfiram, oral naltrexone, long-acting injectable naltrexone, sodium oxybate, nalmefene, baclofen, and psychosocial interventions) are also reviewed.

Importance: According to recent studies, only a small proportion of alcoholics in the system for addiction treatment receive expedited treatment [Rehm et al.: Sucht 2014;60:93–105] and that those who are untreated are at risk of harmful and dependent alcohol consumption. This is associated with significantly negative effects on morbidity, mortality, and quality of life [Kraus et al.: Sucht 2010;56:337–347]. As a result, not only individuals and their environment suffer but there is also a health economic impact. Objective: How often do patients with a primary or secondary diagnosis of alcohol dependence who have been discharged from inpatient treatment receive anticraving medication in the follow-up period of 6 months? Design, Setting, and Participants: Based on data from a statutory health insurance in Germany, 12,958 patients were investigated regarding alcohol dependence, rates for readmission to hospital, and prescription of anticraving drugs. In addition, outpatient and inpatient treatment costs were calculated. Main Outcomes and Measures: There will be an examination of how often anticraving medications are prescribed and what the economic consequences are. Results: Two hundred and eighty-eight (2.22%) patients received anticraving medication, 98 (0.76%) in the first 6 months after inpatient treatment. Fifty-nine of the 288 patients were monitored with a pre- and postcomparison over a 90-day period. Inpatient treatment fell from 0.83 times (±1.10) during the 3 months afterward to 0.79 (±1.01). On average, the duration of an inpatient stay before anticraving treatment (n = 29) was 17.34 days (±14.37), with an average cost of EUR 4,142.70 (±2,721.28). Among the anticraving treatment group, this fell to 14.03 days (±9.96) with an average cost of EUR 3,685.43 (±2,307.67). Overall, the average outpatient and inpatient treatment costs dropped from EUR 1,533.88 before treatment to EUR 1,462.76 after treatment. If this is extrapolated to the whole group, it leads to between EUR 921,500 and EUR 6.6 million saving for a health insurance company. Conclusion: Anticraving medications are hardly ever prescribed. Their routine use could reduce hospital readmission rates and save on health-care costs.

INTRODUCTION: Alcohol use disorder (AUD) is a highly prevalent; costly economically, socially, and interpersonally; and grossly undertreated disorder. The low rate of utilization of pharmacological treatments with demonstrated efficacy is particularly noteworthy. This is due, in part, to the modest efficacy of the medications approved to treat the disorder. One approach to increasing the utility and safety of these medications is to use precision medicine, which seeks to identify patients for whom specific medications are likely to have the most robust therapeutic effects and the fewest adverse effects. AREAS COVERED: Here we review the current literature on the pharmacogenetics of AUD treatment. We cover both laboratory studies and clinical trials that have provided valuable insights into the mechanisms and value of precision-based care for AUD. We discuss studies of genetic moderators for personalizing pharmacotherapy with medications approved by regulatory agencies in the United States and Europe and those that are used off-label to treat AUD. EXPERT OPINION: Pharmacotherapy can be a useful component of AUD treatment. Currently, the evidence regarding genetic predictors of medication efficacy is very limited. Thus, precision medicine is not yet ready for widespread clinical implementation. Further research is needed to identify candidate genetic variants that moderate the response to both established and novel medications in development for this goal to be achieved. The growing availability of large-scale, longitudinal datasets that enable the synthesis of genetic and electronic health record data could provide important opportunities to develop this area of research.

Naltrexone (NTX) has been widely studied for the treatment of alcohol use disorder with overall support for its efficacy. The mechanisms of action of naltrexone are thought to involve attenuation of the hedonic effects of alcohol and potentiation of its aversive effects. In order to provide a quantitative estimate of the effects of naltrexone on subjective response to alcohol, the aims of this meta-analytic review are to examine the effects of naltrexone across four domains of subjective response. Meta-analyses of naltrexone effects on alcohol craving (k=16, N=686), stimulation (k=15, N=675), sedation (k=18, N=777), and negative mood (k=9, N=281) suggested that under laboratory conditions and compared with placebo, naltrexone reduces craving (Hedges g=-0.252; SE=0.054; 95% CI, -0.375 to -0.130; P&nbsp

To report dispensing of disulfiram, naltrexone, antidepressants and quetiapine for New Zealanders diagnosed with alcohol use disorder.The Pharmaceutical Collection is the national dispensing database for medications in New Zealand. PRIMHD is the national mental health and addiction service database. Dispensing data was extracted from the Pharmaceutical Collection and merged with diagnostic data from PRIMHD to report pharmacological treatment of alcohol use disorders in New Zealand.In 2014, there were 5,004 individuals diagnosed with an alcohol use disorder by mental health and addiction services. Four hundred and eighty-nine individuals also received a major depressive disorder diagnosis. 2.1% of the group with alcohol use disorder were dispensed disulfiram and 0.7% were dispensed naltrexone. Treatment with antidepressants (12.7%) and quetiapine (5.6%) was more common. In the group with comorbid alcohol use disorder and depression, 2% were dispensed disulfiram, 0.2% were dispensed naltrexone, 27.4% were dispensed antidepressants and 11.2% were dispensed quetiapine.Overall rates of dispensing were relatively low. Antidepressants followed by quetiapine were the most common treatments. In contrast, disulfiram and naltrexone were only used for a minority of clients. This suggests inadequate and poorly targeted pharmacological treatments are used for the treatment of alcohol use disorders in New Zealand.

Medication-assisted behavior treatment for alcohol use disorder (AUD) holds promise to enhance the efficacy of medication and of behavior therapy when administered individually. The present study examines the treatment benefit of combined outpatient naltrexone (NTX) treatment with Alcoholics Anonymous Facilitation (AAF) behavior therapy, in the context of OPRM1 genotype. The minor OPRM1 Asp40 G-allele has been associated with greater positive reinforcing effects of alcohol consumption and greater alcohol craving, suggesting that individuals carrying the OPRM1 G allele may have an improved naltrexone response. Twenty patients, including 7 G-allele carriers, received 90 days of naltrexone with medication support and dispensing sessions, and ten AAF behavior therapy sessions. During treatment and the eight-week posttreatment follow-up, an overall increase in percent days abstinent was observed for the sample as a whole, but G-allele carriers reported relatively heavier drinking relative to other subjects. These findings suggest that this enhanced medication-assisted behavior treatment is a promising therapeutic combination, and mirror other recent findings that G-allele carriers may require more intensive treatment.

BACKGROUND: Nalfurafine is the first clinically approved kappa-opioid receptor (KOP-r) agonist as an anti-pruritus 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 (two-bottle choice, 24-h 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 five-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 multi-dosing 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.

Alcohol use is a common contributor to medical disease and a leading cause of preventable death. Because brief interventions for unhealthy alcohol use are effective, and because risk factors for unhealthy alcohol use are not always immediately identifiable, universal screening is recommended for adults. For patients who screen positive, physicians should assess further to diagnose alcohol use disorder, determine risk of withdrawal symptoms, and recommend an appropriate level of treatment. Outcomes of alcohol use disorder management are improved with evidence-based psychosocial therapy, but there is no support for preferring one specific evidence-based therapy over another. Disulfiram, acamprosate, and naltrexone are medication-assisted treatment options approved by the Food and Drug Administration. Baclofen, topiramate, and gabapentin are off-label options that may be effective; they should be considered second-line treatment because of limited research.

The mechanisms behind relapse to ethanol intake in recovering alcoholics are still unclear. The negative reinforcing effects contributing to ethanol addiction, including relapse, are considered to be partly driven by the kappa-opioidergic system. As the kappa-opioidergic system interacts with the mesolimbic reward pathway, the aim of the study was to clarify the role of nucleus accumbens shell kappa-opioidergic mechanisms in relapse to ethanol intake by using the alcohol deprivation effect (ADE) paradigm. The ADE is defined as a transient increase in voluntary ethanol intake after a forced period of abstinence. Male Long-Evans rats were trained to voluntarily consume 10% (v/v) ethanol solution. Ethanol access and deprivation cycles were initiated after stable ethanol intake baselines had been reached and bilateral guide cannulas had been implanted above the nucleus accumbens shell. One cycle consisted of 10 days of 90 min access to ethanol followed by 6 days of ethanol deprivation. The ADE was measured in the beginning of a new cycle. Rats received JDTic, a selective kappa-antagonist, either subcutaneously (10 mg/kg) or intra-accumbally (15 mu g/site) or, as a reference substance, systemic naltrexone (0.3 mg/kg) before ethanol re-access, and the effects on the ADE were evaluated. Systemic and intra-accumbal JDTic significantly attenuated the ADE on the first day of ethanol re-access, as did systemic naltrexone. Additionally, naltrexone decreased ethanol intake levels. These results suggest that nucleus accumbens shell kappa-opioidergic mechanisms may have a role in mediating relapse to ethanol intake. Additionally, kappa-antagonism could be a valuable adjunct in ethanol relapse prevention. (C) 2019 Elsevier B.V. and ECNP. All rights reserved.

Current directions in medication development for alcohol use disorder (AUD) emphasize the need to identify novel molecular targets and efficiently screen new compounds aimed at those targets. Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor and was recently found to reduce alcohol intake in rats by ∼50%. To advance medication development for AUD, the present study consists of a randomized, crossover, double-blind, placebo-controlled laboratory study of IBUD in nontreatment-seeking individuals with current (ie, past month) mild-to-severe AUD. This study tested the safety, tolerability, and initial human laboratory efficacy of IBUD (50 mg b.i.d.) on primary measures of subjective response to alcohol as well as secondary measures of cue- and stress-induced changes in craving and mood. Participants (N=24) completed two separate 7-day intensive outpatient protocols that included daily visits for medication administration and testing. Upon reaching a stable target dose of IBUD (or matched placebo), participants completed a stress-exposure session (day 5; PM), an alcohol cue-exposure session (day 6; AM), and an i.v. alcohol administration session (day 6; PM). Participants stayed overnight after the alcohol administration, and discharge occurred on day 7 of the protocol. Medication conditions were separated by a washout period that was ⩾7 days. IBUD was well tolerated; however, there were no medication effects on primary measures of subjective response to alcohol. IBUD was associated with mood improvements on the secondary measures of stress exposure and alcohol cue exposure, as well as reductions in tonic levels of craving. Exploratory analyses revealed that among individuals with higher depressive symptomatology, IBUD attenuated the stimulant and mood-altering effects of alcohol as compared with placebo. Together, these findings extend preclinical demonstrations of the potential utility of IBUD for the treatment of AUD and suggest that depressive symptomatology should be considered as a potential moderator of efficacy for pharmacotherapies with neuroimmune effects, such as IBUD.

Aims To compare post-treatment alcohol use between those who use cannabis and those who abstain during treatment for alcohol use disorders (AUD); and to examine potential cannabis use thresholds by comparing post-treatment alcohol use between four frequency groups of cannabis users relative to abstainers. Design Secondary analyses of the Combined Pharmacotherapies and Behavioral Interventions (COMBINE) Study, a randomized control trial of AUD treatments. The current study compares longitudinal drinking data between those who used cannabis versus those who abstained during COMBINE treatment. Setting The COMBINE Study treatments were delivered on an out-patient basis for 16 weeks. The current analyses include 206 cannabis users and 999 cannabis abstainers. Participants All participants met diagnosis of primary alcohol dependence (n = 1383). Measurements Primary exposures were any cannabis use and quartiles of cannabis use (Q1: 1–4 use days during treatment, Q2: 5–9 days, Q3: 10–44 days, Q4: 45–112 days). Outcomes were percentage of days abstinent from alcohol (PDA), drinks per drinking day (DPDD) and percentage of heavy drinking days (PHD), all measured at treatment end and 1 year post-treatment. Findings Compared with no cannabis use, any cannabis use during treatment was associated with 4.35% [95% confidence interval (CI) = –8.68, −0.02], or approximately 4 fewer alcohol abstinent days at the end of treatment. This association weakened by 1 year post-treatment (95% CI = –9.78, 0.54). Compared with no cannabis use, only those in the second quartile of cannabis use (those who used once or twice per month during treatment) had 8.81% (95% CI = –17.00, −0.63), or approximately 10 fewer days alcohol abstinent at end of treatment, and 11.82% (95% CI = –21.56, −2.07), or approximately 13 fewer alcohol abstinent days 1 year post-treatment. Neither any cannabis use nor quartiles were associated with DPDD or PHD at either time-point. Conclusions Among individuals in alcohol treatment, any cannabis use (compared with none) is related to a significantly lower percentage of days abstinent from alcohol post-treatment, although only among those who used cannabis once or twice per month.

Disulfiram (tetraethylthiuram disulfide) has been used for the treatment of alcohol dependence. An axonal sensory-motor polyneuropathy with involvement of cranial pairs due to disulfiram is exceedingly rare. The authors report a unique case of an extremely severe axonal polyneuropathy involving cranial nerves that developed within weeks after a regular dosage of 500 mg/day disulfiram. To the authors best knowledge, such a severe and rapidly-progressive course has never been described with disulfiram dosages of only 500 mg/day.

Chenhui Wang,1,2,* Jiebing Yang,1,3,* Haobo Han,3 Jiawen Chen,3 Yudi Wang,3 Quanshun Li,3 Yanbo Wang1 1Department of Urology, First Hospital of Jilin University, 2Innovative Drug Research Centre, School of Pharmacy, Chongqing University, Chongqing, 3Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun, People’s Republic of China *These authors contributed equally to this work Abstract: In this study, poly(lactic-co-glycolic acid) (PLGA) was used as a carrier to construct disulfiram-loaded porous microparticle through the emulsion solvent evaporation method, using ammonium bicarbonate as a porogen. The microparticle possessed highly porous surface, suitable aerodynamic diameter for inhalation (8.31±1.33 µm), favorable drug loading (4.09%±0.11%), and sustained release profile. The antiproliferation effect of release supernatant was detected through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay using non-small-cell lung cancer A549 as a model, with only 13.3% of cell viability observed for the release supernatant at 7 days. The antiproliferation mechanism was elucidated to be associated with the enhanced induction of cell apoptosis and cell cycle arrest at S phase through flow cytometry and Western blotting analysis. Finally, wound healing and transwell migration assay showed that they could efficiently inhibit the cell migration. These results demonstrated that disulfiram-loaded porous PLGA microparticle could achieve favorable antitumor efficiency, implying the potential of treating non-small-cell lung cancer in a pulmonary administration. Keywords: disulfiram, poly(lactic-co-glycolic acid), porous microparticle, non-small-cell lung cancer, antiproliferation, antimigration

Although the precise drug mechanism of action of acamprosate remains unclear, its antidipsotropic effect is mediated in part through glutamatergic neurotransmission. We evaluated the effect of 4 weeks of acamprosate treatment in a cohort of 13 subjects with alcohol dependence (confirmed by a structured interview, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) on proton magnetic resonance spectroscopy glutamate levels in the midline anterior cingulate cortex (MACC). We compared levels of metabolites with a group of 16 healthy controls. The Pennsylvania Alcohol Craving Scale was used to assess craving intensity. At baseline, before treatment, the mean cerebrospinal fluid-corrected MACC glutamate (Glu) level was significantly elevated in subjects with alcohol dependence compared with controls (P = 0.004). Four weeks of acamprosate treatment reduced glutamate levels (P = 0.025), an effect that was not observed in subjects who did not take acamprosate. At baseline, there was a significant positive correlation between cravings, measured by the Pennsylvania Alcohol Craving Scale, and MACC (Glu) levels (P = 0.019). Overall, these data would suggest a normalizing effect of acamprosate on a hyperglutamatergic state observed in recently withdrawn patients with alcohol dependence and a positive association between MACC glutamate levels and craving intensity in early abstinence. Further research is needed to evaluate the use of these findings for clinical practice, including monitoring of craving intensity and individualized selection of treatment with antidipsotropic medications in subjects with alcohol dependence.

The purpose of this study was to compare the naturalistic outcomes of individuals with alcohol or opioid use problems who were treated with extended-release naltrexone (XR-NTX) to those treated with psychosocial treatment only and also to those treated with other medication-assisted therapies in Missouri during 2010 to 2011. We analyzed intake and discharge data collected as part of SAMHSA's Treatment Episode Data Set assessments. Patients who received XR-NTX during their treatment episode were compared, for those reporting alcohol (but not opioids) as their problem ( N =21,137), to those who received oral naltrexone, acamprosate, and psychosocial treatment only, and for those who reported opioids as a problem ( N =8996), to those receiving oral naltrexone, buprenorphine/naloxone, and psychosocial treatment only. Group differences were adjusted using propensity score weighting, with propensity scores derived from 18 intake variables. For the alcohol sample, patients who received XR-NTX vs. the oral naltrexone group had superior composite outcomes on a measure combining abstinence, self-help participation, employment, and arrests. For the opioid sample, XR-NTX was found to have significantly better outcomes than oral naltrexone on the composite outcome measure. For both the alcohol and opioid samples, the group that received XR-NTX stayed in treatment longer vs. psychosocial treatment only. In the opioid sample, those receiving buprenorphine/naloxone remained in treatment longer than those receiving XR-NTX.

The mesolimbic dopamine (DA) system plays a key role in drug reinforcement and is involved in the development of alcohol addiction. Manipulation of the DAergic system represents a promising strategy to control drug-seeking behavior. Previous studies on 2-amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-Phen) showed in vivo effects as a DA-ergic modulator. This study was aimed at investigate DA-Phen effects on operant behavior for alcohol seeking behavior, during reinstatement following subsequent periods of alcohol deprivation. For this purpose, male Wistar rats were tested in an operant paradigm of self-administration; behavioral reactivity and anxiety like-behavior during acute abstinence were evaluated. A characterization of DA-Phen CNS targeting by its quantification in the brain was also carried out. Our findings showed that DA-Phen administration was able to reduce relapse in alcohol drinking by 50% and reversed the alterations in behavioral reactivity and emotionality observed during acute abstinence. In conclusion, DA-Phen can reduce reinstatement of alcohol drinking in an operant-drinking paradigm following deprivation periods and reverse abstinence-induced behavioral phenotype. DA-Phen activity seems to be mediated by the modulation of the DAergic transmission. However further studies are needed to characterize DA-Phen pharmacodynamic and pharmacokinetic properties, and its potential therapeutic profile in alcohol addiction.

We recently described that the anti-apoptotic AMPK-related kinase, SNARK, promotes transforming growth factor (TGF)-β signaling in hepatocellular carcinoma (HCC) cells, as a potentially new therapeutic target. Here we explored FDA-approved drugs inhibiting the enzymatic activity of SNARK, using an in vitro luminescence kinase assay system. Interestingly, the long-used anti-alcoholism drug disulfiram (DSF), also known as Antabuse, emerged as the top hit. Enzymatic kinetics analyses revealed that DSF inhibited SNARK kinase activity in a noncompetitive manner to ATP or phosphosubstrates. Comparative in vitro analyses of DSF analogs indicated the significance of the disulfide bond-based molecular integrity for the kinase inhibition. DSF suppressed SNARK-promoted TGF-β signaling and demonstrated anti-HCC effects. The chemical and enzymatic findings herein reveal novel pharmacological effects of and use for DSF and its derivatives, and could be conducive to prevention and inhibition of liver fibrosis and HCC.

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

Aims Neither the predictive value of early continuous abstinence in alcohol use disorder (AUD) or the point at which this effect may emerge has been evaluated. This analysis of the Combined Pharmacotherapies and Behavioral Interventions (COMBINE) clinical trial evaluated whether abstinence early in treatment was a predictor of longer term abstinence. Methods Participants who stated a goal of total abstinence ( N = 954) were dichotomized into Early Abstainer vs. Nonabstainers and were compared on a variety of drinking outcome measures that are frequently used in clinical trial evaluations of alcohol treatment strategies, as a function of duration of early continuous abstinence. Results Significant differences existed for every outcome. Early Abstinence was significantly associated with fewer drinks per drinking day, number of drinking and number of heavy drinking days, and longer time to first drinking and first heavy drinking day. Effects were evident within the first week. The magnitude of all effects increased as the duration of early abstinence (1–4 weeks) increased, though the size of increase varied across the outcomes. Conclusions These data provide evidence that drinking at the beginning of alcohol treatment is significantly and robustly associated with drinking throughout and at the end of a clinical trial treatment for AUD. Early drinking may be a useful early index to identify whether patients are responding positively to a treatment strategy, and provides a useful method for tailoring treatment to patients that is consistent with a personalized medicine approach.

Cannabinoids are still classified as illegal psychoactive drugs despite their broad and increasingly acknowledged therapeutic potential. These substances are most famous for their wide recreational use, particularly among young adults to either alter the state of consciousness, intensify pleasure induced by other psychoactive substances or as an alternative to the previously abused drugs. It is important to emphasize that cannabinoids are often taken together with a variety of medications intended for the treatment of alcohol use disorder (AUD) or alcohol withdrawal syndrome (AWS). These medications include disulfiram, acamprosate, and naltrexone. In this paper, we summarize recent advances in the knowledge of possible beneficial effects and interactions between cannabinoids and drugs commonly used for treatment of AUD and AWS either comorbid or existing as a separate disorder.

Alcohol use disorders (AUD) cause significant morbidity and mortality worldwide, but pharmacological treatments for them are underused, despite evidence of efficacy. Acamprosate, naltrexone, nalmefene and disulfiram are all approved in one or more region for the treatment of alcohol use disorders. Baclofen currently has a temporary indication in France. Safety considerations for using psychopharmacological treatments in this patient group include the impact of concurrent alcohol consumption at high levels, multiple physical comorbidities which may interfere with pharmacological effects, distribution and metabolism, and concomitant medication for the treatment of comorbid physical and psychiatric conditions. The five drugs, including an extended-release injectable suspension of naltrexone, have different safety profiles which need to be balanced with the objective of treatment (initiation or continuation of abstinence, or reduction of drinking), individual patient preferences and comorbid conditions. Appropriate treatment will be based on the unique risk- benefit profile in each case.

Background and Aims Craving for alcohol is thought to be a predictor of alcohol use, particularly in the near future. The assessment of craving in clinical practice requires brief, simple measures that can be implemented routinely. This study tested whether greater alcohol craving was associated with a higher likelihood of alcohol use in the subsequent week. Design The COMBINE Study (Combining Medications and Behavioral Interventions for Alcohol Dependence) was a large, multi-site clinical trial of treatment for alcohol dependence. Participants were randomized (stratified by site) to one of nine treatment conditions involving combinations of pharmacotherapy and psychotherapy. Craving was assessed every other week throughout the treatment period. Setting Substance use disorder treatment settings at 11 academic sites across the United States. Participants Participants from the COMBINE Study (n = 1370) with available craving data. Measurements Craving was assessed using the three-item self-report Craving Scale. Drinking was assessed using the Timeline Followback method, and was defined as alcohol use in each study week. Findings There was an average of 5.8 (of a possible seven) observation pairs per participant. Craving was associated strongly with alcohol use in the following week [B = 0.27, standard error (SEB) = 0.06, Wald χ2 = 43.34, odds ratio (OR) = 1.31, 95% confidence interval (CI) = 1.16, 1.47, P

Background This study evaluated the extent to which the addition of disulfiram and contingency management for adherence and abstinence (CM), alone and in combination, might enhance the effects of cognitive behavioral therapy (CBT) for cocaine use disorders. Methods Factorial randomized double blind (for medication condition) clinical trial where CBT served as the platform and was delivered in weekly individual sessions in a community-based outpatient clinic. 99 outpatients who met DSM-IV criteria for current cocaine dependence were assigned to receive either disulfiram or placebo, and either CM or no CM. Cocaine and other substance use was assessed via a daily calendar with thrice weekly urine sample testing for 12 weeks with a one-year follow-up (80% interviewed at one year). Results The primary hypothesis that CM and disulfiram would produce the best cocaine outcomes was not confirmed, nor was there a main effect for disulfiram. For the primary outcome (percent days of abstinence, self report), there was a significant interaction, with the best cocaine outcomes were seen for the combination of CM and placebo, with the two groups assigned to disulfiram associated with intermediate outcomes, and poorest cocaine outcome among those assigned to placebo and no CM. The secondary outcome (urinalysis) indicated a significant effect favoring CM over no CM but the interaction effect was not significant. One year follow-up data indicated sustained treatment effects across conditions. Conclusions CM enhances outcomes for CBT treatment of cocaine dependence, but disulfiram provided no added benefit to the combination of CM and CBT.

To evaluate costs and health outcomes of nalmefene plus psychosocial support, compared with psychosocial intervention alone, for reducing alcohol consumption in alcohol-dependent patients, specifically focusing on societal costs related to productivity losses and crime. A Markov model was constructed to model costs and health outcomes of the treatments over 5 years. Analyses were conducted for nalmefene’s licensed population: adults with both alcohol dependence and high or very high drinking-risk levels (DRLs) who do not require immediate detoxification and who have high or very high DRLs after initial assessment. The main outcome measure was cost per quality-adjusted life-year (QALY) gained as assessed from a UK societal perspective. Alcohol-attributable productivity loss, crime and health events occurring at different levels of alcohol consumption were taken from published risk-relation studies. Health-related and societal costs were drawn from public data and the literature. Data on the treatment effect, as well as baseline characteristics of the modelled population and utilities, came from three pivotal phase 3 trials of nalmefene. Nalmefene plus psychosocial support was dominant compared with psychosocial intervention alone, resulting in QALYs gained and reduced societal costs. Sensitivity analyses showed that this conclusion was robust. Nalmefene plus psychosocial support led to per-patient reduced costs of £3324 and £2483, due to reduced productivity losses and crime events, respectively. Nalmefene is cost effective from a UK societal perspective, resulting in greater QALY gains and lower costs compared with psychosocial support alone. Nalmefene demonstrates considerable public benefits by reducing alcohol-attributable productivity losses and crime events in adults with both alcohol dependence and high or very high DRLs who do not require immediate detoxification and who have high or very high DRLs after initial assessment.

Polysubstance abuse of alcohol and nicotine has been overlooked in our understanding of the neurobiology of addiction and especially in the development of novel therapeutics for its treatment. Estimates show that as many as 92% of people with alcohol use disorders also smoke tobacco. The health risks associated with both excessive alcohol consumption and tobacco smoking create an urgent biomedical need for the discovery of effective cessation treatments, as opposed to current approaches that attempt to independently treat each abused agent. The lack of treatment approaches for alcohol and nicotine abuse/dependence mirrors a similar lack of research in the neurobiology of polysubstance abuse. This review discusses three critical needs in medications development for alcohol and nicotine co-abuse: (1) the need for a better understanding of the clinical condition (i.e. alcohol and nicotine polysubstance abuse), (2) the need to better understand how these drugs interact in order to identify new targets for therapeutic development and (3) the need for animal models that better mimic this human condition. Current and emerging treatments available for the cessation of each drug and their mechanisms of action are discussed within this context followed by what is known about the pharmacological interactions of alcohol and nicotine. Much has been and will continue to be gained from studying comorbid alcohol and nicotine exposure.