The Pearson Center for Alcoholism and Addiction Research and Molecular and Integrative Neurosciences Department, The Scripps Research Institute, 10550 North Torrey Pines Road, TPC-5, La Jolla, CA 92037, United States.
This is the first US study to evaluate the clinical efficacy of acamprosate (Campral), a newly FDA-approved medication for maintaining abstinence in patients with alcohol dependence following alcohol withdrawal. We compared effects of the standard 2 g dose (n=258) and an exploratory 3 g dose of acamprosate (n=83) versus placebo (n=260), and evaluated drug safety in a double-blind, placebo-controlled 6-month trial conducted in 21 outpatient clinics across the US. Participants were 601 volunteers with current alcohol dependence recruited primarily by advertisement. All patients concomitantly received eight sessions of brief manual-guided counseling (www.alcoholfree.info). The main outcome measure was the percentage of alcohol-free days over the 6-month study. Self-report was validated by breath alcohol concentration, gamma-glutamyltransferase (GGT) and collateral informant interviews. The percentage of abstinent days did not differ significantly across groups in a priori analysis (54.3% for placebo, 56.1% for 2 g, 60.7% for 3 g). Post-hoc analysis controlling for baseline variables and treatment exposure found acamprosate was associated with a significantly higher percentage of abstinent days than placebo (52.3% for placebo, 58.2% for 2 g, 62.7% for 3 g; P=0.01), with an even greater effect in the subgroup of 241 patients having a baseline goal of abstinence (58.1% for placebo, 70.0% for 2 g, 72.5% for 3 g; P=0.02). There were no deaths or serious drug-related adverse events. The US study findings suggest that acamprosate is safe and well tolerated in a broadly inclusive sample of alcoholics and appears effective in populations of patients motivated to have a treatment goal of abstinence.
"Glial sodium dependent transporters , GLAST ( EAAT1 ) and GLT1 ( EAAT2 ) , in particular GLT1 , are responsible for at least 90% of extracellular glutamate removal ( For review , see Anderson and Swanson , 2000 ) . Impaired glu - tamate uptake due to dysfunction or downregulation of EAAT2 results in several neurological disorders , including Amyotrophic Lateral Sclerosis ( ALS ) , Alzheimer ' s disease , epilepsy , ischemia and hepatic encephalopathy ( Maragakis and Rothstein , 2006 ) . Importantly , we have previously demonstrated that chronic exposure to alcohol results in significant down - regulation of GLT1 expression in the Acb and / or PFC in P rats ( Sari and Sreemantula , 2012 ; Sari et al . "
[Show abstract][Hide abstract] ABSTRACT: Alcoholism is a serious public health concern that is characterized by the development of tolerance to alcohol's effects, increased consumption, loss of control over drinking and the development of physical dependence. This cycle is often times punctuated by periods of abstinence, craving and relapse. The development of tolerance and the expression of withdrawal effects, which manifest as dependence, have been to a great extent attributed to neuroadaptations within the mesocorticolimbic and extended amygdala systems. Alcohol affects various neurotransmitter systems in the brain including the adrenergic, cholinergic, dopaminergic, GABAergic, glutamatergic, peptidergic, and serotonergic systems. Due to the myriad of neurotransmitter and neuromodulator systems affected by alcohol, the efficacies of current pharmacotherapies targeting alcohol dependence are limited. Importantly, research findings of changes in glutamatergic neurotransmission induced by alcohol self- or experimenter-administration have resulted in a focus on therapies targeting glutamatergic receptors and normalization of glutamatergic neurotransmission. Glutamatergic receptors implicated in the effects of ethanol include the ionotropic glutamate receptors (AMPA, Kainate, and NMDA) and some metabotropic glutamate receptors. Regarding glutamatergic homeostasis, ceftriaxone, MS-153, and GPI-1046, which upregulate glutamate transporter 1 (GLT1) expression in mesocorticolimbic brain regions, reduce alcohol intake in genetic animal models of alcoholism. Given the hyperglutamatergic/hyperexcitable state of the central nervous system induced by chronic alcohol abuse and withdrawal, the evidence thus far indicates that a restoration of glutamatergic concentrations and activity within the mesocorticolimbic system and extended amygdala as well as multiple memory systems holds great promise for the treatment of alcohol dependence.
Frontiers in Neuroscience 04/2015; 9:144. DOI:10.3389/fnins.2015.00144 · 3.66 Impact Factor
"However, the efficacy of these medications is only approved for use in patients who are abstinent at the start of treatment. Although the clinical trials in the US have shown controversial, insignificant, and unsuccessful results7,8, the NIH has continually invested much effort and funding in clinical trials, which indicates some hope rather than no hope. However, the NIH nevertheless declared that there is an urgent need for the development of new and more effective medication (http://grants1.nih.gov/grants/guide/pa-files/PA-10-100.html). "
[Show abstract][Hide abstract] ABSTRACT: Alcohol use disorders (AUD) are defined as alcohol abuse and alcohol dependence, which create large problems both for society and for the drinkers themselves. To date, no therapeutic can effectively solve these problems. Understanding the underlying mechanisms leading to AUD is critically important for developing effective and safe pharmacological therapies. Benzodiazepines (BZs) are used to reduce the symptoms of alcohol withdrawal syndrome. However, frequent use of BZs causes cross-tolerance, dependence, and cross-addiction to alcohol. The FDA-approved naltrexone and acamprosate have shown mixed results in clinical trials. Naltrexone is effective to treat alcohol dependence (decreased length and frequency of drinking bouts), but its severe side effects, including withdrawal symptoms, are difficult to overcome. Acamprosate showed efficacy for treating alcohol dependence in European trials, but two large US trials have failed to confirm the efficacy. Another FDA-approved medication, disulfiram, does not diminish craving, and it causes a peripheral neuropathy. Kudzu is the only natural medication mentioned by the National Institute on Alcohol Abuse and Alcoholism, but its mechanisms of action are not yet established. It has been recently shown that dihydromyricetin, a flavonoid purified from Hovenia, has unique effects on GABAA receptors and blocks ethanol intoxication and withdrawal in alcoholic animal models. In this article, we review the role of GABAA receptors in the treatment of AUD and currently available and potentially novel pharmacological agents.
"Naltrexone is an opioid antagonist that reduces the reward properties of and cravings for alcohol . Acamprosate reduces cravings and has been found to be efficacious in maintaining, but perhaps not producing, abstinence . While disulfiram may be more familiar to clinicians than naltrexone or acamprosate, some clinical practice guidelines do not recommend disulfiram as a first-line pharmacological treatment because of significant toxicity risks and limited evidence of effectiveness . "
[Show abstract][Hide abstract] ABSTRACT: As a quality improvement metric, the US Veterans Health Administration (VHA) monitors the proportion of patients with alcohol use disorders (AUD) who receive FDA approved medications for alcohol dependence (naltrexone, acamprosate, and disulfiram). Evidence supporting the off-label use of the antiepileptic medication topiramate to treat alcohol dependence may be as strong as these approved medications. However, little is known about the extent to which topiramate is used in clinical practice. The goal of this study was to describe and examine the overall use, facility-level variation in use, and patient -level predictors of topiramate prescription for patients with AUD in the VHA.
Using national VHA administrative data in a retrospective cohort study, we examined time trends in topiramate use from fiscal years (FY) 2009--2012, and predictors of topiramate prescription in 375,777 patients identified with AUD (ICD-9-CM codes 303.9x or 305.0x) treated in 141 VHA facilities in FY 2011.
Among VHA patients with AUD, rates of topiramate prescription have increased from 0.99% in FY 2009 to 1.95% in FY 2012, although substantial variation across facilities exists. Predictors of topiramate prescription were female sex, young age, alcohol dependence diagnoses, engagement in both mental health and addiction specialty care, and psychiatric comorbidity.
Veterans Health Administration facilities are monitored regarding the extent to which patients with AUD are receiving FDA-approved pharmacotherapy. Not including topiramate in the metric, which is prescribed more often than acamprosate and disulfiram combined, may underestimate the extent to which VHA patients at specific facilities and overall are receiving pharmacotherapy for AUD.
Addiction science & clinical practice 07/2013; 8(1-1):12. DOI:10.1186/1940-0640-8-12
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