Drug May Aid in Alcohol Dependence, but Safety Concerns Linger

Fran Lowry

June 06, 2013

Varenicline (Chantix, Pfizer Inc), currently approved by the US Food and Drug Administration (FDA) to aid smoking cessation, shows a signal that it may also help in the treatment of alcohol dependence, new research suggests. However, concerns linking the drug to an increased risk for suicidal thoughts and cardiovascular events linger.

A proof-of-concept study conducted by researchers at the National Institutes of Health showed that varenicline significantly reduced alcohol consumption and craving in alcohol-dependent individuals.

"Varenicline does appear to help reduce drinking in alcohol-dependent individuals, at least in some of them," lead investigator Raye Z. Litten, PhD, associate director of the Division of Treatment and Recovery Research, National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, Maryland, told Medscape Medical News.

"We did see a significant decrease in heavy drinking, at least 22%, so there appears to be, at least in our trial, a signal in terms of reducing drinking. Of course, we would like to see this reproduced in larger studies of longer duration, and perhaps try to identify the patients who respond to the compound," Dr. Litten said.

"Drinking and smoking often co-occur, and given their genetic and neurochemical similarities, it's not really a surprise that a drug that helps to stop smoking would also work for treating alcohol problems," he said.

The study was published online May 30 in the Journal of Addiction Medicine.

Lingering Concerns

Varenicline, which was approved by the FDA in 2006 to aid smoking cessation, has since been found to increase suicidal thoughts and cardiovascular risk.

In 2009, the FDA required that a boxed warning highlighting the risk for serious mental health events, including changes in behaviour, depressed mood, hostility and suicidal thoughts, be placed in the prescribing information for varenicline.

As reported by Medscape Medical News, the study of more than 13,000 cases of adverse events involving smoking cessation products during a 13-year period showed that the vast majority of the reports of suicidal behavior and depression — 90% — were linked to varenicline. Bupropion and nicotine replacement products were responsible for the remaining 7% and 3%, respectively.

At that time, Curt D. Furberg, MD, PhD, professor of public health sciences at Wake Forest Baptist Medical Center in Winston-Salem, North Carolina, and a study coinvestigator, told Medscape Medical News, "Ideally, I think it should come off the market, but that is not realistic. So a more realistic recommendation is to restrict its use."

Dr. Furberg added that although there currently is an FDA boxed warning about the risk for suicidal behaviors and depression with varenicline, the warning should be revised to say that varenicline has the highest risk compared with other cessation treatments.

In 2011, after reports of a link between varenicline and an increased cardiovascular risk in heart patients began to emerge, the FDA approved an updated drug label highlighting a small increased risk for certain cardiovascular adverse events in individuals with cardiovascular disease.

As reported by Medscape Medical News, the FDA warning came after a meta-analysis of 15 studies found that 0.31% of 4190 patients treated with varenicline had a major adverse cardiovascular event vs 0.21% of 2812 patients treated with placebo.

Although the event rates were low and not statistically significant when compared with placebo, the FDA stated, "the data were analyzed many different ways and consistently showed a higher occurrence of events in patients using Chantix, which makes it seem more likely that it is related to the drug and not purely a chance finding."

Dr. Raye Litten

"We did not see any significant changes in suicidal thought, mood changes, hostility, aggression, but again, the study population numbered 200, and we excluded people who had suicidal tendencies and major depression," Dr. Litten said.

"Nor did we see anything that would contradict the package insert the way it is right now. The main side effects we saw were nausea, abnormal dreams, and constipation."

One Drug Does Not Fit All

In the multicenter trial, the investigators randomly assigned 200 alcohol-dependent adults to receive varenicline or placebo each day for 13 weeks.

The dose of varenicline was titrated during the first week to 2 mg/day, which was maintained throughout the remainder of the study. All study participants also received a computerized behavioral therapy intervention. They were recruited through newspaper, radio, and television ads.

The study participants had reported drinking 28 drinks per week for women or 35 drinks per week for men prior to the study, per the Timeline Followback interview. The women reported drinking at least 4 drinks and the men 5 drinks a day on most days.

"These were functional alcoholics. The majority, some 73%, were employed. They did not have a comorbid depression or substance abuse disorder," Dr. Litten said.

The primary outcome, weekly percent heavy drinking days, was significantly lower in the varenicline group than in the placebo group (37.9 vs 48.4, P = .03).

The varenicline group also had significantly fewer drinks per day (4.4 vs 5.3, respectively; P = .03), fewer drinks per drinking day (5.8 vs 6.8, respectively; P = .03), and lower percent of very heavy drinking days (17.6% vs 26.1%, respectively; P = .047) than the group receiving placebo.

The varenicline group also had less alcohol craving compared with the placebo group, with a Penn Alcohol Craving Scale (PACS) score of 9.9 vs 11.6 (P = .01).

However, varenicline did not alter the percent of abstinence, which was similar between the groups (P = .81); the percent of patients with no heavy drinking days (P = .50); or the percent of days abstinent (P = .29).

Smokers and nonsmokers derived similar benefit with varenicline. Additionally, the researchers noted that varenicline's effects were comparable to those seen in studies of naltrexone and acamprosate, 2 of the medications already approved by the FDA for the treatment of alcohol dependence.

"There is so much heterogeneity in the alcohol-dependent population, and this is one of the challenges for coming up with treatments. No one treatment works for everybody," Dr. Litten said.

"We now have 4 drugs approved by the FDA for the treatment of alcohol dependence, and when they work, it's pretty dramatic for a lot of patients. But they don't work in everybody, and that is why we continue to explore other medications. If one doesn't work, we can try another one, and there are behavioral therapies that can be used in combination, such as Alcoholics Anonymous.

"We like to have all these possibilities for clinicians to choose from. It gives a better chance of finding one that will work, a little bit like antidepressants," he said.

New Treatment Option

Commenting on the study for Medscape Medical News, Frances Levin, MD, professor of psychiatry at Columbia University School of Medicine in New York City, president of the American Academy of Addiction Psychiatry, and new chair of the American Psychiatric Association's Council on Addiction Psychiatry, said that although the study results need to be replicated, "it's exciting that varenicline would be useful not just for smoking but for alcohol dependence and that it works in smokers and nonsmokers. It opens a new avenue of potential treatment options for this population."

Dr. Levin agreed that having a choice of such medications is beneficial.

"Not every medication works for every person, and the goal, as the article said, is to figure out who will benefit most from this new approach. Having various options is crucial because although, for example, naltrexone can be very helpful, it's not a panacea, it doesn't work for everybody.

"Similarly disulfiram, although I use it and a lot of clinicians do, has its limitations in terms of compliance. So this is a very nice new potential option. It's obviously not FDA approved for this indication, but I think it's an interesting way to go now, and I was happy to see the study."

The study was supported by the National Institute on Alcohol Abuse and Alcoholism. Dr. Litten and Dr. Levin report no relevant financial relationships.

J Addict Med. Published online May 30, 2013. Abstract

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