A progressive recruitment of a hyperglutamatergic state is at the core of alcohol(Drug information on alcohol) dependence.16 ACMP, a functional glutamate antagonist, normalizes the progressive recruitment of elevated extracellular glutamate that occurs with repeated cycles of intoxication and withdrawal.17,18 Accordingly, it selectively blocks dependence-induced drinking of ethanol in experimental animals, while leaving intake in subjects that do not have a history of dependence unaffected.19
Two recent American studies failed to find efficacy of ACMP,7,20 but its clinical efficacy is robustly supported by meta-analyses.5,21 Analysis of 17 European studies including 4087 persons found that ACMP improved continuous abstinence rates at 6 months compared with placebo, with an OR of 1.47 and an NNT of 7.5. Similar to the effect of NTX, ACMP had a modest beneficial effect on retention. The discrepancy between the European and American studies may appear puzzling. However, patients in the American studies were recruited through newspaper advertisements rather than from clinical populations and had much lower disease severity than those in the European trials.
Additional exclusion criteria may be a contributing factor. For example, patients in the COMBINE study who were recruited through newspaper ads and excluded if they had any significant psychiatric comorbidities or other substance use disorders, had an average alcohol consumption of approximately 120 g/d. In an elegant European study addressing some of the same questions, patients were recruited from a clinical population of 2 Hamburg hospitals, and exclusions were kept to a necessary minimum. In this study, average consumption was around 250 g/d.22 Of interest, while the 2 studies were in agreement on demonstrating the efficacy of NTX, the former study failed to find evidence for efficacy of ACMP, while the latter did find such evidence despite its lower sample size. Animal studies demonstrate selective effects of ACMP only following a prolonged history and high degree of dependence. Efficacy of ACMP in more severely addicted populations and the lack thereof in less severely addicted patients is therefore in agreement with the animal studies.
Based on its mechanism of action, a widely held hypothesis is that ACMP might preferentially target protracted abstinence and associated relief craving12 resulting from neuroadaptations following a history of dependence.12,16
THE SECOND GENERATION
Ondansetron(Drug information on ondansetron)
Ondansetron is a serotonin (5-HT3) antagonist, approved for use in chemotherapy-induced nausea. 5-HT3 receptors are present on terminals of mesolimbic dopamine(Drug information on dopamine)rgic neurons involved in natural and drug reward, and they modulate the release of dopamine from these terminals. The first human trial with this compound was carried out in Oxford, England, and appropriately employed consumption of a pint of lager as the laboratory drinking paradigm. It found that pretreatment with ondansetron significantly attenuated subjective pleasurable effects and decreased the subjective desire to drink.23 A small subsequent study supported the efficacy of ondansetron.24
This was followed by a study that not only documented the drug's efficacy in alcoholism but also pointed to the target population.25 Patients were stratified by age at onset, based on an a priori prediction that those with early onset and a family history positive for alcoholism would be selectively responsive to ondansetron. This phenotype closely approximates that described as type 2 alcoholism.26 A reduction of drinking was indeed found in early-onset patients but not in those with late onset. Reduced self-reported drinking was accompanied by a decrease in carbohydrate deficient transferring, an objective biomarker of heavy alcohol use. This has since been independently replicated.27 A secondary analysis indicated that ondansetron reduced subjective craving in subjects with early-onset, but not with late-onset.28 Ondansetron appears safe and well tolerated. Based on its mechanism of action and available clinical data, its optimal patient population probably overlaps with that of NTX.
Baclofen, an agonist at γ-aminobutyric acid receptors, has long been on the market for use in spasticity. Its development for alcoholism is also an example of translation from preclinical work. It was first shown that baclofen(Drug information on baclofen) reduced withdrawal and ethanol consumption in genetically selected alcohol-preferring rats.29 This was rapidly followed by preliminary human efficacy data in a small open-label safety and tolerability study.30 The preclinical and clinical data have since accumulated in parallel, and they appear to be consistent.31 In a small randomized controlled trial, baclofen reduced several measures of alcohol intake and decreased craving and anxiety.32 A larger study is under way at the University of North Carolina. For now, baclofen appears to hold some promise, although further studies are needed. One concern with baclofen is its sedative properties and potential for interactions with ethanol. This may well be a pharmacodynamic class effect that could invalidate this mechanism as a treatment principle in general.