Originally published in MedPage Today

by Kristina Fiore, MedPage Today Staff Writer

Contrary to information that led the FDA and other regulatory agencies to release warnings about varenicline (Chantix), a new study has found “no clear evidence” of a relationship between the risk of suicide and the smoking-cessation drug.

Both varenicline and bupropion (Zyban), another drug used in smoking cessation programs, were associated with a 12% and 17% increased risk, respectively, of self-harm compared with people who used a nicotine replacement product, but the confidence intervals were wide and straddled 1.00, David Gunnell, PhD, of the University of Bristol in the U.K., and colleagues reported online in British Medical Journal.

The limited study power “means we cannot rule out either a halving or a twofold increase in risk,” the researchers said.

Adverse event reports have sparked growing concern that varenicline may be associated with an increased risk of suicide.

Regulatory agencies worldwide have issued warnings on use of the drug, and last July, the FDA required boxed warnings on both varenicline and bupropion.

However, the researchers said, few large population studies have been done to assess the risk. Further, they said, assessing risk is challenging because of the need to control for confounders such as previous disease and smoking habits.

People who smoke already have a two- to- threefold increased risk of suicide, since smoking is common among people with psychiatric illness, they said. Also, it’s possible that [smoking] “has a beneficial effect on psychiatric symptoms, such as anxiety, that may be lost with smoking cessation,” the researchers added.

And last March, a study in the Journal of General Internal Medicine found that varenicline didn’t increase the risk of depressive symptoms.

So to clarify the issue, the researchers conducted a cohort study of 80,660 patients ages 18 to 95 who were prescribed a new course of any smoking cessation product — nicotine replacement products, bupropion, or varenicline — between Sept. 1, 2006 and May 31, 2008.

In general, patients prescribed bupropion or varenicline were less likely than those on nicotine products to have a history of psychiatric consultation, alcohol misuse, use of psychotropic medication, or self harm or suicidal thoughts.

There were 166 episodes of nonfatal self-harm, two suicides — both in the nicotine replacement group — and 37 episodes of suicidal thoughts.

The incidence of self-harm was 533.1 per 100,000 person-years in patients on varenicline, 498.7 for those on bupropion, and 751.7 for nicotine replacement products.

The researchers found “no clear evidence” that varenicline was associated with an increased risk of suicide or nonfatal self-harm. However, they said they could not rule out a twofold increased risk “on the basis of the upper limit of the 95% confidence interval.”

Those confidence limits were 0.67 to 1.88 for varenicline and 0.59 to 2.32 for bupropion.

Varenicline was also associated with a 43% increased risk of suicidal thoughts compared with nicotine replacement products, but, again, the confidence intervals were wide and straddled 1.00 (95% CI 0.53 to 2.85).

The researchers said such evidence is consistent with all possibilities — “a large protective effect, no effect, or a large adverse effect.”

Yet they cautioned that suicidal thoughts are under-recorded in the General Practice Research Database, from which they took their data.

The study may also have been limited in its power, since there were only 18 episodes of self-harm reported in the varenicline group, the researchers said.

Still, they concluded, in light of the “possible increased risk of suicide associated with these drugs and their increasing popularity, further investigation of their effect on suicide risk is required in other databases and through secondary analysis of all adverse event reporting in relevant clinical trials.”

Visit MedPageToday.com for more smoking news.