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Pharmacology & Therapeutics Dec 2022Alcohol Use Disorder (AUD) is a multifaceted relapsing disorder that is commonly comorbid with psychiatric disorders, including anxiety. Alcohol exposure produces a... (Review)
Review
Alcohol Use Disorder (AUD) is a multifaceted relapsing disorder that is commonly comorbid with psychiatric disorders, including anxiety. Alcohol exposure produces a plethora of effects on neurobiology. Currently, therapeutic strategies are limited, and only a few treatments - disulfiram, acamprosate, and naltrexone - are available. Given the complexity of this disorder, there is a great need for the identification of novel targets to develop new pharmacotherapy. The GABAergic system, the primary inhibitory system in the brain, is one of the well-known targets for alcohol and is responsible for the anxiolytic effects of alcohol. Interestingly, GABAergic neurotransmission is fine-tuned by neuroactive steroids that exert a regulatory role on several endocrine systems involved in neuropsychiatric disorders including AUD. Mounting evidence indicates that alcohol alters the biosynthesis of neurosteroids, whereas acute alcohol increases and chronic alcohol decreases allopregnanolone levels. Our recent work highlighted that chronic alcohol-induced changes in neurosteroid levels are mediated by epigenetic modifications, e.g., DNA methylation, affecting key enzymes involved in neurosteroid biosynthesis. These changes were associated with changes in GABA receptor subunit expression, suggesting an imbalance between excitatory and inhibitory signaling in AUD. This review will recapitulate the role of neurosteroids in the regulation of the neuroendocrine system, highlight their role in the observed allostatic load in AUD, and develop a framework from mechanisms to potential pharmacotherapy.
Topics: Humans; Pregnanolone; Neurosteroids; Alcoholism; Receptors, GABA-A; Anxiety; Ethanol
PubMed: 36323379
DOI: 10.1016/j.pharmthera.2022.108299 -
Alcohol Research : Current Reviews 2022This article is part of a Festschrift commemorating the 50th anniversary of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Established in 1970, first as... (Review)
Review
This article is part of a Festschrift commemorating the 50th anniversary of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Established in 1970, first as part of the National Institute of Mental Health and later as an independent institute of the National Institutes of Health, NIAAA today is the world's largest funding agency for alcohol research. In addition to its own intramural research program, NIAAA supports the entire spectrum of innovative basic, translational, and clinical research to advance the diagnosis, prevention, and treatment of alcohol use disorder and alcohol-related problems. To celebrate the anniversary, NIAAA hosted a 2-day symposium, "Alcohol Across the Lifespan: 50 Years of Evidence-Based Diagnosis, Prevention, and Treatment Research," devoted to key topics within the field of alcohol research. This article is based on Dr. Mason's presentation at the event. NIAAA Director George F. Koob, Ph.D., serves as editor of the Festschrift.
Topics: United States; Humans; Alcoholism; National Institute on Alcohol Abuse and Alcoholism (U.S.); Alcohol Drinking; Alcohol-Related Disorders; National Institutes of Health (U.S.); Alcohol Deterrents; Naltrexone
PubMed: 36320345
DOI: 10.35946/arcr.v42.1.11 -
BMJ Open Oct 2022Opioid use disorder (OUD) is a debilitating and persistent disorder. The standard-of-care treatment is daily maintenance dosing of sublingual buprenorphine (BUP-SL) or...
Experience and response to a randomised controlled trial of extended-release injectable buprenorphine versus sublingual tablet buprenorphine and oral liquid methadone for opioid use disorder: protocol for a mixed-methods evaluation.
INTRODUCTION
Opioid use disorder (OUD) is a debilitating and persistent disorder. The standard-of-care treatment is daily maintenance dosing of sublingual buprenorphine (BUP-SL) or oral methadone (MET). Monthly, extended-release, subcutaneous injectable buprenorphine (BUP-XR) has been developed to enhance treatment effectiveness. This study aims to investigate the experiences of participants who have been offered BUP-XR (evaluation 1), health-related quality-of-life among participants who have opted to receive BUP-XR longer term (evaluation 2) and the experiences of participants allocated to receive BUP-XR or BUP-SL or MET with the offer of adjunctive personalised psychosocial intervention (evaluation 3).
METHODS AND ANALYSIS
Three qualitative-quantitative (mixed-methods) evaluations embedded in a five-centre, head-to-head, randomised controlled trial of BUP-XR versus BUP-SL and MET in the UK. Evaluation 1 is a four-centre interview anchored on an OUD-related topic guide and conducted after the 24-week trial endpoint. Evaluation 2 is a two-centre interview anchored on medications for opioid use disorder-specific quality-of-life topic guide conducted among participants after 12-24 months. Evaluation 3: single-centre interview after the 24-week trial endpoint. All evaluations include selected trial clinical measures, with evaluation 2 incorporating additional questionnaires. Target participant recruitment for evaluations 1 and 2 is 15 participants per centre (n=60 and n=30, respectively). Recruitment for evaluation 3 is 15 participants per treatment arm (n=30). Each evaluation will be underpinned by theory, drawing on constructs from the behavioural model for health service use or the health-related quality-of-life model. Qualitative data analysis will be by iterative categorisation.
ETHICS AND DISSEMINATION
Study protocol, consent materials and questionnaires were approved by the London-Brighton and Sussex research ethics committee (reference: 19/LO/0483) and the Health Research Authority (IRAS project number 255522). Participants will be provided with information sheets and informed written consent will be obtained for each evaluation. Study findings will be disseminated through peer-reviewed scientific journals.
TRIAL REGISTRATION NUMBER
2018-004460-63.
Topics: Humans; Buprenorphine; Methadone; Narcotic Antagonists; Opioid-Related Disorders; Tablets; Randomized Controlled Trials as Topic
PubMed: 36270754
DOI: 10.1136/bmjopen-2022-067194 -
Frontiers in Pharmacology 2022Compounds known to be successful in the treatment of alcohol use disorder include the aversive agent, Disulfiram, the glutamatergic NMDA receptor antagonist,... (Review)
Review
Compounds known to be successful in the treatment of alcohol use disorder include the aversive agent, Disulfiram, the glutamatergic NMDA receptor antagonist, Acamprosate, and the opioid receptor antagonists, Naltrexone and Nalmefene. Although all four are effective in maintaining abstinence or reduction of alcohol consumption, only a small percentage of patients receive pharmacological treatment. In addition, many other medications have been investigated for their therapeutic potential in the treatment of alcohol use disorder. In this review we summarize and compare Baclofen, Gabapentin, Topiramate, Ondansetron, Varenicline, Aripiprazole, Quetiapine, Clozapine, Antidepressants, Lithium, Neuropeptide Y, Neuropeptide S, Corticotropin-releasing factor antagonists, Oxytocin, PF-05190457, Memantine, Ifenprodil, Samidorphan, Ondelopran, ABT-436, SSR149415, Mifepristone, Ibudilast, Citicoline, Rimonabant, Surinabant, AM4113 and Gamma-hydroxybutyrate While some have shown promising results in the treatment of alcohol use disorder, others have disappointed and should be excluded from further investigation. Here we discuss the most promising results and highlight medications that deserve further preclinical or clinical study. Effective, patient-tailored treatment will require greater understanding provided by many more preclinical and clinical studies.
PubMed: 36263121
DOI: 10.3389/fphar.2022.927703 -
Neuropsychopharmacology : Official... Feb 2023Both human and animal studies indicate that the dentate gyrus (DG) of the hippocampus is highly exploited by drug and alcohol abuse. Yet, it is poorly understood how DG...
Both human and animal studies indicate that the dentate gyrus (DG) of the hippocampus is highly exploited by drug and alcohol abuse. Yet, it is poorly understood how DG dysfunction affects addiction-related behaviors. Here, we used an animal model of alcohol use disorder (AUD) in automated IntelliCages and performed local genetic manipulation to investigate how synaptic transmission in the dorsal DG (dDG) affects alcohol-related behaviors. We show that a cue light induces potentiation-like plasticity of dDG synapses in alcohol-naive mice. This process is impaired in mice trained to drink alcohol. Acamprosate (ACA), a drug that reduces alcohol relapse, rescues the impairment of dDG synaptic transmission in alcohol mice. A molecular manipulation that reduces dDG synaptic AMPAR and NMDAR levels increases impulsive alcohol seeking during cue relapse (CR) in alcohol mice but does not affect alcohol reward, motivation or craving. These findings suggest that hindered dDG synaptic transmission specifically underlies impulsive alcohol seeking induced by alcohol cues, a core symptom of AUD.
Topics: Mice; Humans; Animals; Dentate Gyrus; Ethanol; Synaptic Transmission; Alcoholism; Recurrence
PubMed: 36182989
DOI: 10.1038/s41386-022-01464-5 -
Frontiers in Pharmacology 2022Acamprosate is an anti-craving drug used in alcohol use disorder (AUD) pharmacotherapy. However, only a subset of patients achieves optimal treatment outcomes. The...
Acamprosate is an anti-craving drug used in alcohol use disorder (AUD) pharmacotherapy. However, only a subset of patients achieves optimal treatment outcomes. The identification of predictive biomarkers of acamprosate treatment response in patients with AUD would be a substantial advance in addiction medicine. We designed this study to use proteomics data as a quantitative biological trait as a step toward identifying inflammatory modulators that might be associated with acamprosate treatment outcomes. The NIAAA-funded Mayo Clinic Center for the Individualized Treatment of Alcoholism study had previously recruited 442 AUD patients who received 3 months of acamprosate treatment. However, only 267 subjects returned for the 3-month follow-up visit and, as a result, had treatment outcome information available. Baseline alcohol craving intensity was the most significant predictor of acamprosate treatment outcomes. We performed plasma proteomics using the Olink target 96 inflammation panel and identified that baseline plasma TNF superfamily member 10 (TNFSF10) concentration was associated with alcohol craving intensity and variation in acamprosate treatment outcomes among AUD patients. We also performed RNA sequencing using baseline peripheral blood mononuclear cells from AUD patients with known acamprosate treatment outcomes which revealed that inflammation-related pathways were highly associated with relapse to alcohol use during the 3 months of acamprosate treatment. These observations represent an important step toward advancing our understanding of the pathophysiology of AUD and molecular mechanisms associated with acamprosate treatment response. In conclusion, applying omics-based approaches may be a practical approach for identifying biologic markers that could potentially predict alcohol craving intensity and acamprosate treatment response.
PubMed: 36120372
DOI: 10.3389/fphar.2022.986238 -
The Mental Health Clinician Aug 2022At a Veterans Affairs Medical Center (VAMC), a clinical pharmacist practitioner (CPP) was added to an inpatient addiction triage team in August 2019 to provide education...
INTRODUCTION
At a Veterans Affairs Medical Center (VAMC), a clinical pharmacist practitioner (CPP) was added to an inpatient addiction triage team in August 2019 to provide education and recommendations regarding medications for alcohol use disorder (MAUD) and opioid use disorder (MOUD). Before the addition of the CPP, missed opportunities for MAUD and MOUD education and prescribing prior to discharge on non-psychiatric units were observed.
METHODS
This was a single-center, single-site, retrospective, observational cohort study with a primary objective to compare initiation rates of MAUD/MOUD 12 months before and after the addition of the CPP to the addiction triage team. Secondary end points included 90-day medication possession ratio, 1- and 3-month emergency department visit rates, 1- and 3-month hospital readmission rates, and opioid education and naloxone distribution interventions for eligible patients with a diagnosis of opioid use disorder.
RESULTS
Both statistically and clinically significant improvements in MAUD/MOUD initiation rates were found in the CPP intervention group compared with the historical control group (26.3% vs 4%, < .0001). Although secondary end points within this review were not found to be statistically significant, improvements were seen in the CPP intervention group compared with the historical control group related to medication possession ratio, and emergency department and hospital readmission rates.
DISCUSSION
This study highlights the potential utility of a CPP to an inpatient addiction triage team to improve MAUD/MOUD prescribing rates in appropriate patients prior to discharge. Overall, the introduction of a CPP to an inpatient addiction triage team was feasible, well received by interprofessional team members, and required limited additional resources.
PubMed: 36071740
DOI: 10.9740/mhc.2022.08.219 -
Addiction Biology Sep 2022Acamprosate (Campral® - calcium-bis[N-acetylhomotaurinate]) is one of few available pharmacotherapies for individuals suffering from alcohol use disorder. Previously,...
Acamprosate (Campral® - calcium-bis[N-acetylhomotaurinate]) is one of few available pharmacotherapies for individuals suffering from alcohol use disorder. Previously, we suggested that acamprosate reduces ethanol intake by increasing dopamine in the nucleus accumbens (nAc), thereby partly substituting for alcohol's dopamine releasing effect. An experimental study suggested the calcium moiety of acamprosate to be the active component of the drug and to mediate the relapse preventing effect. The aim of the present study was to, by means of reversed in vivo microdialysis, elucidate if the dopamine elevating properties of acamprosate are mediated by N-acetylhomotaurine or by the calcium moiety. Male rats were equipped with a microdialysis probe in the nAc and received acute local treatment with regular acamprosate (CaAcamp 0.5 mM), calcium chloride (CaCl 0.5 mM), sodium acamprosate (NaAcamp 0.5-1 mM), the glycine receptor (GlyR) antagonist strychnine (Stry 20 μM), or vehicle. In all experiments, extracellular levels of dopamine and taurine were examined. We found that local perfusion with both CaAcamp and CaCl increased dopamine levels in a GlyR-dependent manner. NaAcamp did not influence dopamine levels, but concomitant administration with CaCl resulted in an additive dopamine output compared to the drugs administrated alone. We also found CaAcamp and the combination of CaCl and NaAcamp to increase accumbal taurine levels, suggesting that CaAcamp may act indirectly on GlyRs via taurine release. The present results indicate that both N-acetylhomotaurine and the calcium moiety of acamprosate have dopamine elevating properties within the nAc and that, in this respect, these substances are beneficial in combination.
Topics: Acamprosate; Animals; Calcium; Calcium Chloride; Dopamine; Male; Microdialysis; Nucleus Accumbens; Rats; Rats, Wistar; Receptors, Glycine; Sodium; Taurine
PubMed: 36001425
DOI: 10.1111/adb.13224 -
Trials Aug 2022Sublingual tablet buprenorphine (BUP-SL) and oral liquid methadone (MET) are the daily, standard-of-care (SOC) opioid agonist treatment medications for opioid use...
Extended-release pharmacotherapy for opioid use disorder (EXPO): protocol for an open-label randomised controlled trial of the effectiveness and cost-effectiveness of injectable buprenorphine versus sublingual tablet buprenorphine and oral liquid methadone.
BACKGROUND
Sublingual tablet buprenorphine (BUP-SL) and oral liquid methadone (MET) are the daily, standard-of-care (SOC) opioid agonist treatment medications for opioid use disorder (OUD). A sizable proportion of the OUD treatment population is not exposed to sufficient treatment to attain the desired clinical benefit. Two promising therapeutic technologies address this deficit: long-acting injectable buprenorphine and personalised psychosocial interventions (PSI). This study will determine (A) the effectiveness and cost-effectiveness - monthly injectable, extended-release (BUP-XR) in a head-to-head comparison with BUP-SL and MET, and (B) the effectiveness of BUP-XR with adjunctive PSI versus BUP-SL and MET with PSI. Safety, retention, craving, substance use, quality-adjusted life years, social functioning, and subjective recovery from OUD will be also evaluated.
METHODS
This is a pragmatic, multi-centre, open-label, parallel-group, superiority RCT, with a qualitative (mixed-methods) evaluation. The study population is adults. The setting is five National Health Service community treatment centres in England and Scotland. At each centre, participants will be randomly allocated (1:1) to BUP-XR or SOC. At the London study co-ordinating centre, there will also be allocation of participants to BUP-XR with PSI or SOC with PSI. With 24 weeks of study treatment, the primary outcome is days of abstinence from non-medical opioids during study weeks 2-24 combined with up to 12 urine drug screen tests for opioids. For 90% power (alpha, 5%; 15% inflation for attrition), 304 participants are needed for the BUP-XR versus SOC comparison. With the same planning parameters, 300 participants are needed for the BUP-XR and PSI versus SOC and PSI comparison. Statistical and health economic analysis plans will be published before data-lock on the Open Science Framework. Findings will be reported in accordance with the Consolidated Standards of Reporting Trials and Consolidated Health Economic Evaluation Reporting Standards.
DISCUSSION
This pragmatic randomised controlled trial is the first evaluation of injectable BUP-XR versus the SOC medications BUP-SL and MET, with personalised PSI. If there is evidence for the superiority of BUP-XR over SOC medication, study findings will have substantial implications for OUD clinical practice and treatment policy in the UK and elsewhere.
TRIAL REGISTRATION
EU Clinical Trials register 2018-004460-63.
Topics: Adult; Analgesics, Opioid; Buprenorphine; Cost-Benefit Analysis; Delayed-Action Preparations; Humans; Methadone; Multicenter Studies as Topic; Narcotic Antagonists; Opioid-Related Disorders; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; State Medicine; Tablets
PubMed: 35986418
DOI: 10.1186/s13063-022-06595-0