Markus Heilig, clinical director at the National Institutes on Alcohol Abuse and Alcoholism, succinctly sums up the problem with treating alcoholics with drugs: "Why would you want to take a drug that is taking away pleasurable sensations?" he asked BioWorld Today.

Apparently a lot of addicts ask themselves the same thing - to the point that Alkermes Inc., of Cambridge, Mass., has developed a once-a-month formulation of its drug Vivitrol (naltrexone) to improve compliance. Nevertheless, naltrexone is used only by a small fraction of those who might benefit from it. Heilig hopes to help develop drugs that can reach a larger segment of the patient population; "My hope, and my challenge, is to change the clinical scene," he said.

To reach those patients, Heilig is focusing on another aspect of drugs than their pleasures: the fact that the kick from drugs does not last forever. Sooner or later, using a drug - illegal or legal - stops feeling good.

Ironically, though, that usually does not get addicts to stop. It does change the reasons for using, though. "In the absence of the drug, you feel miserable, and that creates its own incentive to drink," Heilig said, adding that the shift for the reasons to drink "really hasn't been appreciated by addiction researchers."

Heilig's research has focused on the transition to late-stage alcoholism, and along with colleagues, he found, that the neurotransmitter corticotropin-releasing hormone, or CRH, and its receptor play a large role in this transition.

CRH antagonists have also been tested to treat depression and anxiety, but "it's been very difficult to get compounds that have drug-like properties," Heilig said.

Now, in the March 7, 2007, Journal of Neuroscience, Heilig and his colleagues at Lilly Research Laboratories, the University of Toronto in Canada, and the University of Camerino in Italy, describe such a drug-like CRH blocker, called MTIP.

In behavioral experiments, MTIP reversed the anxiety-producing effects of alcohol withdrawal both in rats with a genetic propensity towards alcoholism and in those that became addicted through repeated cycles of alcohol use and withdrawal, while having no effect on more moderate alcohol use in nonaddicted rats. The combination of favorable chemical properties and their behavioral results led the scientists to conclude the compound "should be developed for clinical use in alcoholism."

A recent paper in Science garnered a lot of interest for its suggestion that the cravings accompanying dug addiction were due to activity of the insula; smokers who had brain damage that included this brain structure no longer craved cigarettes.

Heilig said that though the Science paper marked an important advance in understanding addiction, from the point of view of drug development it offered no practical guidance.

In fact, he noted, "sometimes you are worse off with localized delivery, because you don't know what the effect of exposing the entire central nervous system will be." And such systemwide activation is what patients will experience at the end of the day.

Viral vectors could, in principle, be used to target certain anatomical regions, but are currently at a stage of development that has researchers proceeding with extreme caution, even in fatal diseases such as cancer. And the methods used for targeted delivery in animals are not going to fly in the clinic "We are not going to drill holes into people's skulls and microinject stuff," Heilig said.