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Vol. LXII, No. 10
May 14, 2010

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Pharmacogenomics and Alcoholism
Why Meds Work for Some People, but Not for Others

On the front page...

You can add alcoholism to the growing list of conditions that may be addressed with medication, depending on a patient’s genetic topography.

That was the message delivered recently in a lecture by NIAAA clinical director Dr. Markus Heilig, who studied the effect—or lack thereof—of the drug naltrexone (an opioid antagonist commonly used in the treatment of drug addiction) on a person’s wired desire to reach for a drink. It appears as though people struggling with alcoholism for whom naltrexone is an effective treatment possess a particular genetic variant. That variant is worked on by the drug to stymie its push to make the body want alcohol.


  Dr. Markus Heilig  
  Dr. Markus Heilig  

This could be huge news for clinicians who work daily with alcoholics desperate to get sober, something Heilig said would be welcome in the field.

“It’s difficult not to be impressed by the progress that’s been made in basic neuroscience in the last 40 years,” he said. “There’s been an explosion of understanding of brain function, but you walk out into the clinic and it’s as if time stood still.”

While effective in its own right, much of today’s current treatment emphasis has been on behavioral therapy, with clinicians seeking to integrate medication as part of treatment, but never really knowing why a drug could work wonders in some patients and not help others.

Heilig, who studies alcoholism and anxiety disorders as chief of the Laboratory of Clinical and Translational Studies, felt compelled to unravel this mysterious disparity in effectiveness. He started with a simple theory.

“If patients respond differently,” he said, “maybe they are different [physiologically]. In the age of the mapped genome and personalized medicine, this is not difficult to imagine.”

Heilig explained that the brain is similar to a parliament, with the voting of pleasure receptors and cleared or blocked pathways determining a yes or no vote.

“That voting will determine whether or not the behavior is turned on,” he said. “It’s even more complex than the U.S. Congress.”

Research shows that in the early phases of alcoholism, people drink because it is pleasurable—the body tells the mind that drinking is rewarding. Heilig wanted to determine why the medicinal blunting of the circuitry that rewards intake of alcohol worked for some patients but not for others. He decided to focus on male subjects because alcoholism in men and women tends to express differently and studies show naltrexone works much better in men than in women.

Heilig studied mice, rats and rhesus macaques and, going on a hunch that genetics are at work in this equation, he turned up some curious results. He found that in people who possess a specific genetic variant, this chemical pleasure reward is much more pronounced because when alcohol is consumed, their bodies release a swell of dopamine that heightens the physical connection to drinking. This intense reward only prompts the body to want more alcohol, continuing the cycle and strengthening the chemical connection. In people without the variant, their bodies’ dopamine release was nonexistent.

Heilig says, “Over time, the addicted brain transitions from ‘reward craving’ to ‘relief craving.’ If you keep drinking, it will push your brain into a pathological pattern of anxiety.”

Heilig says, “Over time, the addicted brain transitions from ‘reward craving’ to ‘relief craving.’ If you keep drinking, it will push your brain into a pathological pattern of anxiety.”

In cases of people with the mutation, naltrexone works to block the reward cascade of dopamine following the consumption of alcohol. With no dopamine reward, the body has less reason to want a drink, so the patient can more easily walk away from alcohol. In people without this genetic switch flipped on, naltrexone is not an effective intervention tool.

Unfortunately, this finding is only one part of the puzzle. While naltrexone can help many people in the early stages of addiction when the body still believes it’s being rewarded for drinking, it isn’t nearly as effective once the brain has turned a corner in its addiction.

“Over time, the addicted brain transitions from ‘reward craving’ to ‘relief craving,’” Heilig said. “If you keep drinking, it will push your brain into a pathological pattern of anxiety.”

Instead of the body wanting alcohol because it feels good, it wants it because not having alcohol will make the body feel bad. That’s what scientists call a “negatively reinforced drug craving”—the body must have the chemical fix or it will suffer withdrawal symptoms.

In tests, naltrexone isn’t particularly effective in helping with the relief stage, nor is it able to help curb the sense of anxiety that is felt by all alcoholics when placed under stress. This anxiousness often causes people to relapse into drinking to relieve anxiety.

Heilig said there are currently several stress-related mechanisms that seem promising for inclusion in treatment strategies, though none is quite ready for prime time. He said that like human beings themselves, each treatment plan will be as individual as the patient.

“There will never be a silver bullet,” he predicted. NIHRecord Icon

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