Parkinson’s Drug Shows Promise when used for Alcohol Dependence

December 14, 2011 (Scottsdale, Arizona) — Inhibition of the catechol O-methyl-transferase (COMT) enzyme, which decreases synaptic dopamine levels, may be a novel and effective way to fight alcohol dependence, new research suggests.

In a small, open-label study of 25 psychiatric outpatients with AD, 88% of the participants showed anti-craving effects after taking the COMT-inhibitor entacapone (Comtan, Orion Corp.) for 12 weeks.

In addition, entacapone, which was given along with routinely used psychiatric medication, was not associated with any serious treatment-related adverse effects.

“This is the first study of its kind to show COMT inhibition as a potential pharmacological method of combatting alcohol craving,” principal investigator Rahim Shafa, MD, scientific director at MetroWest CNS Research Center in Natick, Massachusetts.

“For decades, a need has been recognized for a tolerable, non–habit forming compound to balance out the hypodopaminergic state of drug craving. In our study population, entacapone was effective to counteract both cue craving and ordinary mental craving, which is usually a product of nostalgia from getting high,” note the investigators.

They add that entacapone was also effective in alleviating alcoholic post-withdrawal dysphoria.

“I would like us to start thinking out of the box about how the reward system operates. That will help us to open up some new avenues for treatment of craving across the board,” said Dr. Shafa.

The results were presented here at the American Academy of Addiction Psychiatry (AAAP) 22nd Annual Meeting & Symposium.

Call for New Medications

The researchers note that of the 18 million Americans who had alcohol problems between 2001 and 2002, only 10% sought treatment, and fewer than 5% received pharmacotherapy.

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) “strongly recommends adjunctive pharmacotherapy to the conventional treatment methods and calls for new medication to improve the high relapse rate,” write the investigators.

The COMT-inhibitor entacapone is approved by the US Food and Drug Administration (FDA) to treat Parkinson’s disease in conjunction with carbidopa-levodopa products.

At the 2008 AAAP Annual Meeting, Dr. Shafa presented results of a pilot study showing that more than half of its entacapone-treated patients achieved abstinence from marijuana use.

“COMT is one of the enzymes in the synaptic cleft that degrades available dopamine. By manipulating the enzyme in that study population, we hoped to remove the desire to seek marijuana. And that was the same principle we applied to this study — manipulate COMT to remove the desire for alcohol,” explained Dr. Shafa.

“Basically, we think that craving is a state of low dopamine. When dopamine levels go down in addicted people once drugs are out of their system, that creates a thirst for the drug.”

According to data from the 2009 National Survey on Drug Use and Health, adults with a mental disorder are 4 times more likely to also develop AD than those without a mental disorder.

However, Dr. Shafa noted that conventional anti-craving pharmacological studies often exclude participants with major mental illness. He added that past research has suggested that patients with schizophrenia and bipolar disorder who also have alcohol dependence or another substance use disorder often have high expression of COMT in their genes.

For this study, the investigators enrolled 25 adult psychiatric outpatients (64% men) with alcohol dependence who had “exhausted standard available pharmacologic treatments.”

All participants received entacapone for 12 weeks, in addition to their normal psychiatric medications. The average daily dose of entacapone treatment was 1600 mg.

A serial alcohol ethyl glucuronide urine test and patient interview were used to measure relapse. Abstinence for at least a 4-week period or significantly decreased craving during the first 4 weeks of treatment was considered evidence of overall improvement on the Clinical Global Impression (CGI) scale.

Alternative Treatment Strategy

Results showed that a significant percentage of the participants had improved anti-craving effects (88%, P < .05) by the end of the study.

Of these, 10 were considered “very much improved” on the CGI scale (improvement for all 3 months; mean age, 44.5 years), 3 were “much improved” (improvement for just 2 months; mean age, 41 years), 9 were “slightly improved” (improvement for just 1 month; mean age, 32.5 years), and 3 had no change (mean age, 28.3 years). All 3 of the nonresponders were male.

The 10 “very much improved” patients chose to continue treatment for an extra 6 months and “none had a relapse,” reported Dr. Shafa.

Treatment-related adverse events included palpitation (1 participant), nausea (2 participants), and urine discoloration (all 25 participants).

“Classic pharmacologic treatment of alcohol craving is based on the effect of alcohol on opiate receptor, its interaction with the glutamate system, or its metabolism at the liver,” write the investigators.

“Consideration of dopamine pathway offers an alternative treatment strategy, which could be used independently or potentially combined with one of the above classic approaches, based on more research,” they add.

Dr. Shafa noted that further double blind, placebo-controlled studies are needed to reexamine this concept and to “shed more light” on the situation.

“Still, the advantage of this was that it did not cause many side effects, as you would expect from a Parkinson’s medicine. This was especially important because we were able to give it to mentally ill patients who were able to also continue taking their own medicines.”

Dr. Shafa reported that he is now conducting studies using the same treatment for sugar and chocolate craving.

“Of Considerable Interest”

“I’m really interested in pharmacotherapy for alcohol. Having tried everything else, anything that comes along that might have potential is of considerable interest,” said Jan Campbell, MD, professor of psychiatry at the University of Kansas School of Medicine in Kansas City.

“It also looks like this treatment does not exacerbate comorbid psychiatric disorders, and that’s even more important,” added Dr. Campbell, who was not involved with the research.

She also noted that it looked as though entacapone was very well tolerated.

“It didn’t cause somnolence or weight gain, which are 2 effects we often find. And it’s FDA approved, which means it’s available and on the market. So that’s another plus,” said Dr. Campbell.

“There are all kinds of other things that are potentially on the market, but it’ll probably be a long time before they really get out there.”

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