At the core of alcoholism is the pathologically increased motivation to consume alcohol at the expense of natural rewards with disregard for adverse consequences. naltrexone and acamprosate represent the first generation of modern pharmacotherapies that target this pathology.
Alcoholism is a chronic relapsing disease. The features that define it as such, including gene-environment interactions, behaviors, and social determinants, are comparable to those that define type 2 diabetes, hypertension, or asthma as chronic relapsing diseases.1 The 2 pharmacotherapies for alcoholism that have been approved over the past decade, naltrexone (NTX) and acamprosate (ACMP), may not have sufficient effect size, yet they are incredibly important. They disprove the common notion that "you can't cure chemical dependence with a chemical," while giving us pharmacologic probes into disease mechanisms that, in an iterative process, help target these and future treatments to the appropriate patient, ultimately increasing effect size.
At the core of alcoholism is the pathologically increased motivation to consume alcohol at the expense of natural rewards with disregard for adverse consequences. NTX and ACMP represent the first generation of modern pharmacotherapies that target this pathology. This action is fundamentally different from that of disulfiram, which makes alcohol intake unpleasant and potentially dangerous through the accumulation of acetaldehyde.
Disulfiram effects are only seen with supervised administration, reflecting that this compound does not target the motivation to consume alcohol. Given a chance, patients avoid using disulfiram and consequently relapse. Furthermore, since disulfiram does not target pathophysiology, it cannot teach us anything about pathophysiology. On the other hand, disulfiram may have useful effects in another addictive disorder, namely, cocaine dependence. Carroll and associates2 found that by inhibiting dopamine-ß-hydroxylase, disulfiram blocks the synthesis of central norepinephrine. This attenuates the rewarding properties of cocaine use by inhibit- ing inputs to the ventral tegmental area from the locus caeruleus.
Clinical outcomes in alcoholism will not be radically altered overnight by the arrival of any single drug but rather by the cumulative effect over time of compounds that target a range of mechanisms. It is therefore encouraging that the fundamental shift brought about by NTX and ACMP does not stop with these compounds. A second generation of pharmacotherapies, already approved for other indications, is slowly working its way through the development pipeline. If these pharmacotherapies are determined to be effective and safe for treating alcoholism, these agents can quickly be brought to market and used in clinical settings to treat this disease. Finally, a third generation of compounds may be further away; nevertheless, there is considerable excitement because the compounds reflect fundamental advances in the science of alcohol dependence.
THE FIRST GENERATION
NTX is an example of successful translational work. Seminal animal data3 were followed by evidence for clinical efficacy in alcoholism more than a decade ago.4 Meta-analyses of the numerous subsequent trials clearly demonstrate efficacy of this agent.5,6 The findings of the recent Combining Medications and Behavioral Interventions for Alcoholism (COMBINE) trial are in line with this conclusion.7 In the meta-analysis, short-term NTX treatment decreased relapse with an odds ratio (OR) of 0.64, and a number needed to treat (NNT) for preventing relapse of about 7. This is lower than for many established medical treatments, such as hypertension treatments to prevent cardiovascular events, where the NNT ranges between 29 and 86.8 NTX also improved retention in treatment, as well as secondary variables such as craving.
It is frequently argued that pharmacotherapies for alcoholism can only be adjuncts to behavioral treatment. However, in the short term, NTX is not more effective when given with an intensive behavioral treatment than with a minimal behavioral treatment.5,6 The COMBINE trial yielded similar results.7 On the other hand, intensive behavioral treatment does seem to augment the efficacy of NTX in the longer term. It is possible that the main action of behavioral treatments is to improve patient compliance, a critical variable in determining treatment success.9 Another method of achieving this is through the administration of a depot preparation, the efficacy of which was recently elegantly demonstrated.10 (Vivitrol is a once-a-month injectable depot preparation that was approved by the FDA in April 2006, and it seems to be well tolerated.)
NTX taps into the known action of ethanol in a logical manner. Ethanol administration leads to release of endogenous opioids with a downstream effect that activates mesolimbic dopamine release, a substrate for pleasurable drug effects.11 Based on this role of endogenous opioids in ethanol reward, NTX would be expected to benefit persons with a disease that is mostly characterized by craving for the pleasurable effects of alcohol, or what has recently been labeled "reward craving."12 This is in agreement with observations that predictors of NTX efficacy are being male, having high levels of craving, and having a family history that is positive for alcoholism.10,13,14
It is a major concern that NTX is not made available to many patients who need it. Even addiction medicine specialists prescribe it to only 13% of their patients who are alcohol-dependent, citing concerns about compliance or affordability. In fact, however, prescription rates can be predicted by physicians' knowledge about NTX.15
A progressive recruitment of a hyperglutamatergic state is at the core of 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 is a serotonin (5-HT3) antagonist, approved for use in chemotherapy-induced nausea. 5-HT3 receptors are present on terminals of mesolimbic dopaminergic 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 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.
Topiramate is an antiepileptic agent with a complex pharmacology that includes antiglutamatergic effects.33 Two clinical studies showed topiramate to decrease alcohol use34 and reduce negative consequences of drinking.35 In this case, the preclinical literature is very limited and not consistent with the human data.36 It is presently difficult to assess whether topiramate will provide a useful addition to the treatment of alcoholism, since mechanistic understanding at the preclinical level is largely lacking, as is independent confirmation of clinical efficacy. Also, clinical management and tolerability are more challenging with topiramate than with current medications because it may cause language impairments (verbal fluency and word-finding difficulties).37,38
THE THIRD GENERATION
Animal models that reflect important aspects of alcoholism are a major catalyst for bringing about novel therapeutics. These models include genetically determined high alcohol preference, binge/intoxication type of drinking typical of early stages of alcoholism, neuroadaptive processes that evolve over time to recruit negative affect and increased sensitivity to stress and other such factors, and alcohol-associated cues that trigger relapse. The first compounds with documented clinical efficacy have initiated a bootstrapping process to evaluate the ability of animal models to predict clinically relevant outcomes.39,40
Using these models, more than a dozen novel mechanisms are currently being explored as candidates for new treatments. Two of these deserve particular mention because of their extensive preclinical validation and because molecules exist with potential for clinical development.
First, extensive animal work predicts that the predominant brain receptor for endogenous cannabinoids, the CB1 receptor, is a promising treatment target for alcoholism.41-44 A CB1 antagonist, rimonabant, has recently shown efficacy in reducing obesity and associated metabolic risk factors in the Rimonabant in Obesity studies.45 Rimonabant has recently been approved for treatment of the metabolic syndrome in Europe, and FDA approval is expected. Clinical efficacy for alcoholism by this or other CB1 antagonists remains to be demonstrated. A concern is a dose-dependent incidence of depressive symptoms observed with rimonabant. This may not be an issue in the treatment of obesity, since those effects are largely mediated by CB1 receptors in the liver46 and can be achieved with doses that yield low central receptor occupancy. However, therapeutic efficacy in alcoholism will require central actions. A decisive issue is, therefore, whether a dose window can be found in which this can be achieved with an acceptable tolerability and safety profile.
Second, corticotropin-releasing hormone (CRH) has long been known to mediate behavioral stress effects through extrahypothalamic mechanisms largely independent of its endocrine actions.47 More recently, it has become clear that the CRH system is recruited following a prolonged history of dependence and this system accounts for the long-term increase in negative affect and stress sensitivity in this state, as well as the up-regulated motivation to consume alcohol.48 Antagonists for the CRH1 subtype of CRH receptors selectively reduce alcohol self-administration in postdependent animals, but not in animals without a history of dependence.49 This reflects the fact that extrahypothalamic CRH systems are generally quiescent under baseline, unstressed conditions, in turn promising an attractive tolerability and safety profile for drugs that target them. Efforts to develop antagonists for the CRH1 receptor have long been frustrating, but important breakthroughs are currently being made.
Effective medications are now available for alcoholism, and additional breakthroughs are expected in the next decade. A major challenge is to deliver these treatments to patients.
US taxpayers fund alcohol research with almost half a billion dollars a year. This is an investment unparalleled by any other country and one that generates wonderful science. As inspiring as it is to be part of this effort, one has to ask the question: what point is there in investing in developing new treatments when those already available are not reaching patients who need them?