-
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 -
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 2021The misuse of alcohol in the United States continues to take a large toll on society, resulting in the deaths of about 88,000 Americans per year. Moreover, it is... (Review)
Review
The misuse of alcohol in the United States continues to take a large toll on society, resulting in the deaths of about 88,000 Americans per year. Moreover, it is estimated that nearly 14.6 million Americans currently meet diagnostic criteria for current alcohol use disorder (AUD). However, very few individuals receive treatment, with an even smaller portion receiving medications approved by the U.S. Food and Drug Administration (FDA) for the treatment of AUD, despite scientifically rigorous evidence showing the benefits of combining medication approved for treating AUD with evidence-based behavioral therapy. These benefits include higher rates of abstinence and less risk of relapse to heavy drinking, with associated improvements in medical and mental health and in quality of life. This review provides an overview of FDA-approved medications and "off-label" drugs for the treatment of AUD. The article emphasizes that AUD medical advice and prescription recommendations should come from professionals with training in the treatment of AUD and that treatment plans should consider medication in conjunction with evidence-based behavioral therapy. Finally, this review notes the limited number of medications available and the continued need for the development of new pharmacotherapies to optimize AUD recovery goals.
Topics: Acamprosate; Alcoholism; Humans; Naltrexone; Pharmaceutical Preparations; Quality of Life; United States
PubMed: 34113531
DOI: 10.35946/arcr.v41.1.07 -
World Journal of Psychiatry Sep 2019Substance use disorders (SUDs) are a growing problem among older adults. Acamprosate, disulfiram, and naltrexone are United States Food and Drug Administration (referred...
Substance use disorders (SUDs) are a growing problem among older adults. Acamprosate, disulfiram, and naltrexone are United States Food and Drug Administration (referred to as FDA) approved for the treatment of alcohol use disorder, and buprenorphine is approved for the treatment of opiate use disorder among adults. However, the data on the use of these medications for the treatment of SUDs among older adults are unclear from randomized controlled trials (referred to as RCTs). A review of the literature indicates that there are only two RCTs that evaluated the use of pharmacologic agents for SUDs among older adults (≥ 50 years). One trial evaluated the use of naltrexone when compared to placebo for the treatment of alcohol use disorder among individuals, 50-70 years in age. The other trial evaluated the use of naltrexone or placebo as adjuncts with sertraline in the treatment of alcohol use disorder among individuals older than 55 years in age. Both trials indicated that the use of naltrexone reduced the rates of relapse among older adults with alcohol use disorder. However, we did not identify any RCTs that studied the use of buprenorphine, acamprosate, or disulfiram for SUDs among older adults. Based on available evidence, it would be safe to conclude that limited data indicate some efficacy for naltrexone in the treatment of alcohol use disorder among older adults. However, data from controlled trials on the use of other medications that are FDA approved for the treatment of SUDs among younger adults are nonexistent among older adults with SUDs.
PubMed: 31559148
DOI: 10.5498/wjp.v9.i5.78 -
Journal of Clinical Medicine May 2021We tested the hypothesis that poor adherence is associated with a greater risk of alcohol-caused mortality and morbidities within the first year of discontinuing this...
OBJECTIVES
We tested the hypothesis that poor adherence is associated with a greater risk of alcohol-caused mortality and morbidities within the first year of discontinuing this medication.
MATERIALS AND METHODS
A retrospective cohort study of 3319 individuals who received acamprosate in the East of Scotland in a 10-year period was conducted using a health informatics approach with record linkage of dispensing data, hospital utilization (SMR) and General Register Office of Scotland (GROS) data. The primary outcome was adherence between one to six months after initiating acamprosate medication. The secondary outcome was all-cause morbidities and mortality.
RESULTS
Of the total 3319 individuals identified, a good adherence index of >80% was found in 59% of those prescribed acamprosate after three months and 6% after six months. There were significant linear trends of poorer adherence with increased risk of alcohol-caused mortality (Hazard Ratio, HR 1.2), medical morbidities especially neoplasm (HR 4.1) and poisoning (HR 1.4), and psychiatric morbidities especially stress (HR 35.1), psychotic (HR 5.6) and neurotic disorders, and directly alcohol induced conditions (7.4 HR) after adjustment for other factors within a one-year period of initiation of acamprosate treatment.
DISCUSSION AND CONCLUSIONS
Further exploratory studies using this digitalized approach should be encouraged in order to capture role of compliance to acamprosate and other types of medication that are known to reduce relapse into alcohol dependence and its direct relationship to mortality and morbidities in this population.
PubMed: 34068243
DOI: 10.3390/jcm10102102 -
Brain Sciences Mar 2022Although Alcohol Use Disorder (AUD) is highly prevalent worldwide, treating this condition remains challenging. Further, potential treatments for AUD do not fully... (Review)
Review
BACKGROUND
Although Alcohol Use Disorder (AUD) is highly prevalent worldwide, treating this condition remains challenging. Further, potential treatments for AUD do not fully address alcohol-induced neuroadaptive changes. Understanding the effects of pharmacotherapies for AUD on the human brain may lead to tailored, more effective treatments, and improved individual clinical outcomes.
OBJECTIVES
We systematically reviewed the literature for studies investigating pharmacotherapies for AUD that included neuroimaging-based treatment outcomes. We searched the PubMed, Scielo, and PsycINFO databases up to January 2021.
STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS
Eligible studies included those investigating pharmacotherapies for AUD and employing functional magnetic resonance imaging (fMRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and/or proton magnetic resonance spectroscopy (H-MRS).
STUDY APPRAISAL AND SYNTHESIS METHODS
Two independent reviewers screened studies' titles and abstracts for inclusion. Data extraction forms were shared among all the authors to standardize data collection. We gathered information on the following variables: sample size; mean age; sociodemographic and clinical characteristics; alcohol use status; study design and methodology; main neuroimaging findings and brain-regions of interest (i.e., brain areas activated by alcohol use and possible pharmacological interactions); and limitations of each study.
RESULTS
Out of 177 studies selected, 20 studies provided relevant data for the research topic. Findings indicate that: (1) Acamprosate and gabapentin may selectively modulate limbic regions and the anterior cingulate cortex; (2) Naltrexone and disulfiram effects may involve prefrontal, premotor, and cerebellar regions; (3) Pharmacotherapies acting on glutamate and GABA neurotransmission involve primarily areas underpinning reward and negative affective states, and; (4) Pharmacotherapies acting on opioid and dopamine systems may affect areas responsible for the cognitive and motor factors of AUD.
LIMITATIONS
Most of the studies were focused on naltrexone. A small number of studies investigated the action of disulfiram and gabapentin, and no neuroimaging studies investigated topiramate. In addition, the time between medication and neuroimaging scans varied widely across studies.
CONCLUSIONS
We identified key-brain regions modulated by treatments available for AUD. Some of the regions modulated by naltrexone are not specific to the brain reward system, such as the parahippocampal gyrus (temporal lobe), parietal and occipital lobes. Other treatments also modulate not specific regions of the reward system, but play a role in the addictive behaviors, including the insula and dorsolateral prefrontal cortex. The role of these brain regions in mediating the AUD pharmacotherapy response warrants investigation in future research studies.
PubMed: 35326342
DOI: 10.3390/brainsci12030386 -
British Journal of Pharmacology Jul 2022Acamprosate is an anti-craving drug used for the pharmacotherapy of alcohol use disorder (AUD). However, only some patients achieve optimal therapeutic outcomes. This...
BACKGROUND AND PURPOSE
Acamprosate is an anti-craving drug used for the pharmacotherapy of alcohol use disorder (AUD). However, only some patients achieve optimal therapeutic outcomes. This study was designed to explore differences in metabolomic profiles between patients who maintained sobriety and those who relapsed, to determine whether those differences provide insight into variation in acamprosate treatment response phenotypes.
EXPERIMENTAL APPROACH
We previously conducted an acamprosate trial involving 442 AUD patients, and 267 of these subjects presented themselves for a 3-month follow-up. The primary outcome was abstinence. Clinical information, genomic data and metabolomics data were collected. Baseline plasma samples were assayed using targeted metabolomics.
KEY RESULTS
Baseline plasma arginine, threonine, α-aminoadipic acid and ethanolamine concentrations were associated with acamprosate treatment outcomes and baseline craving intensity, a measure that has been associated with acamprosate treatment response. We next applied a pharmacometabolomics-informed genome-wide association study (GWAS) strategy to identify genetic variants that might contribute to variations in plasma metabolomic profiles that were associated with craving and/or acamprosate treatment outcome. Gene expression data for induced pluripotent stem cell-derived forebrain astrocytes showed that a series of genes identified during the metabolomics-informed GWAS were ethanol responsive. Furthermore, a large number of those genes could be regulated by acamprosate. Finally, we identified a series of single nucleotide polymorphisms that were associated with acamprosate treatment outcomes.
CONCLUSION AND IMPLICATIONS
These results serve as an important step towards advancing our understanding of disease pathophysiology and drug action responsible for variation in acamprosate response and alcohol craving in AUD patients.
Topics: Acamprosate; Alcohol Deterrents; Alcohol Drinking; Alcoholism; Ethanol; Genome-Wide Association Study; Humans; Taurine
PubMed: 35016259
DOI: 10.1111/bph.15795 -
Cureus Apr 2024Background Alcohol use disorder (AUD) is one of the most common substance use disorders globally. It is a chronic mental illness characterized by frequent...
Background Alcohol use disorder (AUD) is one of the most common substance use disorders globally. It is a chronic mental illness characterized by frequent relapses. Hence, preventing relapse is one of the most important aspects of the management of patients with AUD. Aims This study aimed to compare the role of acamprosate and baclofen as anti-craving agents in patients diagnosed with AUD. Settings and design This was a 12-week interventional follow-up study conducted in the Department of Psychiatry of S N Medical College, a tertiary care teaching hospital in Agra, Uttar Pradesh, India. Methods and materials Patients with AUD were enrolled in the study. Following medical management of alcohol withdrawal symptoms, patients were alternately assigned to receive either acamprosate or baclofen and were then followed up for 12 weeks. Measures to compare the effectiveness of the two medications were craving as measured using the Penn Alcohol Craving Scale (PACS), days to first alcohol consumption, days to relapse, number of drinks consumed at one occasion, number of patients who completed the study, and number of patients who remained abstinent throughout the duration of the study. Descriptive statistics were used to present the data while unpaired t-test and Fisher's exact test were used to compare the two groups. Results A total of 63 patients were enrolled in the study. Following medical management of alcohol withdrawal symptoms for one week, 50 (79.37%) patients were retained in the study. Hence, these 50 patients were assigned to treatment with either acamprosate or baclofen alternately in a 1:1 ratio. Only 32 (64%) of the patients who were started on these medications completed the study and were available for analysis at the end of 12 weeks. Acamprosate-treated patients were found to have less severe cravings (p < 0.01) for alcohol at the end of the study and also had consumed less number of drinks on a single occasion (p < 0.05). For other variables being considered in the study, namely, days to first alcohol consumption, days to relapse to previous drinking pattern, number of patients who dropped from the study versus those who completed the study, and those who were abstinent versus those who relapsed, no statistically significant difference was noted. Conclusion Acamprosate-treated patients had significantly lesser cravings for alcohol and consumed a lesser number of drinks on one occasion compared to baclofen-treated patients in this 12-week study.
PubMed: 38741835
DOI: 10.7759/cureus.58174 -
Journal of Hepatology Jun 2021Alcohol use treatment such as medication-assisted therapies (MATs) and counseling are available and effective in promoting alcohol abstinence. We sought to explore the...
BACKGROUND & AIMS
Alcohol use treatment such as medication-assisted therapies (MATs) and counseling are available and effective in promoting alcohol abstinence. We sought to explore the cost-effectiveness of different alcohol use treatments among patients with compensated alcohol-related cirrhosis (AC).
METHODS
We simulated a cohort of patients with compensated AC receiving care from a hepatology clinic over their lifetimes. We estimated costs (in 2017 US$) and benefits in terms of quality-adjusted life years (QALYs) gained from healthcare and societal perspectives. Transition probabilities, costs, and health utility weights were taken from the literature. Treatment effects of FDA-approved MATs (acamprosate and naltrexone) and non-FDA approved MATs (baclofen, gabapentin, and topiramate) and counseling were based on a study of employer-insured patients with AC. We calculated incremental cost-effectiveness ratios (ICERs) and performed one-way and probabilistic sensitivity analyses to understand the impact of parameter uncertainty.
RESULTS
Compared to a do-nothing scenario, MATs and counseling were found to be cost-saving from a healthcare perspective, which means that they provide more benefits with less costs than no intervention. Compared to other interventions, acamprosate and naltrexone cost the least and provide the most QALYs. If the effectiveness of MATs and counseling decreased, these interventions would still be cost-effective based on the commonly used $100,000 per QALY gained threshold. Several sensitivity and scenario analyses showed that our main findings are robust.
CONCLUSIONS
Among patients with compensated AC, MATs and counseling are extremely cost-effective, and in some cases cost-saving, interventions to prevent decompensation and improve health. Health policies (e.g. payer reimbursement) should emphasize and appropriately compensate for these interventions.
LAY SUMMARY
Alcohol use treatments, including physician counseling and medication-assisted therapies (MATs), improve the outcomes of patients with compensated alcohol-related cirrhosis, though use and access have remained suboptimal. In this study, we found that counseling and MATs are extremely cost-effective, and in some cases cost-saving, interventions to help patients with alcohol-related cirrhosis abstain from alcohol and improve their health. Wider use of these interventions should be encouraged.
Topics: Acamprosate; Aged; Alcohol Deterrents; Alcoholism; Cohort Studies; Cost-Benefit Analysis; Female; Health Care Costs; Humans; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Naltrexone; Quality-Adjusted Life Years; Treatment Outcome
PubMed: 33326815
DOI: 10.1016/j.jhep.2020.12.004 -
Scientific Reports Oct 2023Alcohol misuse accounts for a sizeable proportion of the global burden of disease, and Campral (acamprosate; calcium-bis-(N-acetylhomotaurinate)) is widely used as...
Alcohol misuse accounts for a sizeable proportion of the global burden of disease, and Campral (acamprosate; calcium-bis-(N-acetylhomotaurinate)) is widely used as relapse prevention therapy. The mechanism underlying its effect has in some studies been attributed to the calcium moiety and not to the N-acetylhomotaurine part of the compound. We recently suggested that the dopamine elevating effect of acamprosate is mediated both by N-acetylhomotaurine and calcium in a glycine receptor dependent manner. Here we aimed to explore, by means of in vivo microdialysis, if our previous study using local administration was functionally relevant and if systemic administration of the sodium salt of N-acetylhomotaurine (sodium acamprosate; 200 mg/kg, i.p.) enhanced the effects of calcium chloride (CaCl; 73.5 mg/kg, i.p.) on nucleus accumbens (nAc) dopamine and/or taurine levels in male Wistar rats. In addition, we investigated the impact of regular acamprosate and the combination of CaCl and N-acetylhomotaurine on the alcohol deprivation effect (ADE). Finally, we assessed if N-acetylhomotaurine potentiates the ethanol-intake reducing effect of CaCl in a two-bottle choice voluntary ethanol consumption model followed by an ADE paradigm. Systemic administration of regular acamprosate, sodium acamprosate and CaCl all trended to increase nAc dopamine whereas the combination of CaCl and sodium acamprosate produced a significant increase. Sodium acamprosate elevated extracellular taurine levels without additional effects of CaCl. Ethanol intake was significantly reduced by systemic administration of CaCl without additional effects of the combination of CaCl and sodium acamprosate. Both acamprosate and CaCl combined with sodium acamprosate blocked the ADE following acute treatment. The data presented suggest that CaCl and N-acetylhomotaurine act in concert on a neurochemical level, but calcium appears to have the predominant effect on ethanol intake.
Topics: Rats; Male; Animals; Acamprosate; Ethanol; Rats, Wistar; Calcium; Calcium Chloride; Dopamine; Taurine; Sodium
PubMed: 37857829
DOI: 10.1038/s41598-023-45167-3