Acamprosate has been found to enhance rates of complete abstinence and to increase percent days abstinent (PDA) from alcohol relative to placebo treatment. As most U.S. clinical trials of acamprosate have been conducted in alcohol and other drug specialty clinics, there is a need to examine the efficacy of acamprosate in generalist settings. This study tested the efficacy of acamprosate versus placebo on the primary study outcome of PDA in the treatment of alcohol-dependent patients in a family medicine setting. Secondary study outcomes included percent heavy drinking days (%HDD) and gamma glutamyltransferase level (normal or high).
A randomized, double-blind, placebo-controlled, parallel group design of acamprosate was conducted in 2 family medicine settings (North Carolina and Wisconsin). One hundred volunteers were recruited primarily by advertisement, and participants were assigned to 666 mg (2 pills) oral acamprosate 3 times daily (1,998 mg/d) or matching placebo over a 12-week period. All participants concomitantly received 5 sessions of a brief behavioral intervention from a family/primary care physician.
No significant treatment effect of acamprosate was found on PDA or the secondary outcomes. Significant treatment goal by time interaction effects was found on PDA and %HDD. Participants who had an initial goal of abstinence versus a reduction in alcohol use improved on average over time in PDA and had less %HDD from baseline to the end of treatment.
This clinical trial did not find evidence of efficacy for acamprosate compared to placebo among alcohol-dependent individuals recruited primarily by advertisement as studied in a primary care setting. Drinking outcomes significantly improved regardless of medication condition. A goal of abstinence was significantly associated with improved drinking outcomes, suggesting that alcohol-dependent patients with such a goal may do particularly well with counseling in a family medicine setting.
"Large placebo effects are common in AUD trials, making the demonstration of significant effect sizes difficult.35 Primary care patients in the US also failed to benefit from acamprosate treatment, but exhibited a higher percentage of days abstinent during the study if they expressed a goal of abstinence at baseline.36 Meta-analysis of the European trial database, consisting primarily of middle-aged males with 7 years or more of dependence on alcohol, confirmed significant improvements in abstinence rates, percent days abstinent, and time to first drink with acamprosate treatment.33 "
[Show abstract][Hide abstract] ABSTRACT: Alcohol use disorders (AUD) continue to be a concerning health issue worldwide. Harmful alcohol use leads to 2.5 million deaths annually worldwide. Multiple options exist for the management of dependence on alcohol, not all of which are approved by drug-regulating agencies. Current practice in treating AUD does not reflect the diversity of pharmacologic options that have potential to provide benefit, and guidance for clinicians is limited. Few medications are approved for treatment of AUD, and these have exhibited small and/or inconsistent effects in broad patient populations with diverse drinking patterns. The need for continued research into the treatment of this disease is evident in order to provide patients with more specific and effective options. This review describes the neurobiological mechanisms of AUD that are amenable to treatment and drug therapies that target pathophysiological conditions of AUD to reduce drinking. In addition, current literature on pharmacologic (both approved and non-approved) treatment options for AUD offered in the United States and elsewhere are reviewed. The aim is to inform clinicians regarding the options for alcohol abuse treatment, keeping in mind that not all treatments are completely successful in reducing craving or heavy drinking or increasing abstinence.
"In another MRS study, acamprosate was found to reduce glutamate levels in anterior cingulate several weeks after abstinence (Umhau et al., 2010). Acamprosate is an FDAapproved medication for alcohol dependence that is thought to alter central glutamate neurotransmission, although its mechanism of action is not fully understood and reports on its clinical efficacy in treating alcohol dependence have been mixed (Berger et al., 2013; Mann et al., 2012; Mason and Lehert, 2012; Mann et al. 2012; Yahn et al., 2013). Likewise, studies with other therapeutics such as antiepileptics (e.g., topiramate, gabapentin, pregabalin, levetiracetam) that indirectly alter central glutamate activity have produced mixed results in terms of reducing alcohol craving/drinking (De Sousa, 2010; Guglielmo et al., 2012; Johnson and Ait-Daoud, 2010). "
[Show abstract][Hide abstract] ABSTRACT: Using a well-established model of ethanol dependence and relapse, this study examined adaptations in glutamatergic transmission in the nucleus accumbens (NAc) and their role in regulating voluntary ethanol drinking. Mice were first trained to drink ethanol in a free- choice, limited access (2 hr/day) paradigm. One group (EtOH mice) received repeated weekly cycles of chronic intermittent ethanol (CIE) exposure with intervening weeks of test drinking sessions while the remaining mice (CTL mice) were similarly treated but did not receive CIE treatment. Over repeated cycles of CIE exposure, EtOH mice exhibited significant escalation in drinking (up to ~3.5 g/kg) while drinking remained relatively stable at baseline levels (2-2.5 g/kg) in CTL mice. Using in vivo microdialysis procedures, extracellular glutamate (GLUEX) levels in the NAc were increased approximately 2-fold in EtOH mice compared to CTL mice, and this difference was observed 7 days after final CIE exposure, indicating this hyperglutamatergic state persisted beyond acute withdrawal. This finding prompted additional studies examining the effects of pharmacologically manipulating GLUEX in the NAc on ethanol drinking in the CIE model. The non-selective glutamate reuptake antagonist, TBOA, was bilaterally microinjected into the NAc and found to dose-dependently increase drinking in nondependent (CTL) mice to levels attained by dependent (EtOH) mice. TBOA also further increased drinking in EtOH mice. In contrast, reducing glutamatergic transmission in the NAc via bilateral injections of the mGluR2/3 agonist LY379268 reduced drinking in dependent (EtOH) mice to nondependent (CTL) levels while having a more modest effect in decreasing ethanol consumption in CTL mice. Taken together, these data support an important role of glutamatergic transmission in the NAc in regulating ethanol drinking. Additionally, these results indicate that ethanol dependence produces adaptations that favor elevated glutamate activity in the NAc which, in turn, promote excessive levels of ethanol consumption associated with dependence.Neuropsychopharmacology accepted article preview online, 26 September 2013. doi:10.1038/npp.2013.256.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 09/2013; 39(3). DOI:10.1038/npp.2013.256 · 7.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acamprosate (calcium acetylhomotaurine) is an amino acid modulator that has displayed efficacy in some clinical trials in reducing craving and promoting abstinence in alcohol dependent patients following detoxification. While acamprosate is safe and generally well-tolerated, not all studies have demonstrated clinical efficacy that is superior to placebo. In addition, the precise neurochemical mechanisms of action of acamprosate have still not yet been identified. In this review, we summarize current clinical data on the safety, efficacy, and pharmacokinetic properties of acamprosate, as well theories on its potential mechanism of action. We also discuss tolerability and patient preference issues and conclude with a discussion of the place of acamprosate in addiction medicine and therapy.
Substance Abuse: Research and Treatment 01/2013; 6:1-12. DOI:10.4137/SART.S9345
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