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