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Genetic Linkage

Taking a Chance on Chantix

After 60+ years of smoking, my mother-in-law’s lungs were surely a toxic wasteland, yet nothing would make her quit. By the time that studies from the 1950s finally led to warning messages on cigarette packages in the 1960s, too many nicotine molecules had bombarded neuron receptors in her brain’s nucleus accumbens, for far too long. She, like millions of others, was hooked. Not even the death of her husband from lung cancer was enough to get her to quit.

My mother-in-law has been lucky. The right genotype has kept cancer at bay, and her alveoli are apparently tough enough to keep the inevitable emphysema beneath the diagnostic radar. But she didn’t escape peripheral vascular disease and atherosclerosis, and when numb feet kept her from driving and my husband and I refused to get her cancer sticks, she bribed our kids to do it. It’s a tough addiction.

And then she had a heart attack.

Again, she was lucky. No crushing chest pain, but a textbook case of symptoms seen in women: shortness of breath, sudden weakness and fatigue, and a cold sweat. After a stint in the cardiac wing and choosing drugs over bypass, she was released with a handful of prescriptions. One of them was for Chantix, to help her quit smoking. It was a month-long prescription with online support, which she never called.

We’d encountered Chantix the year before, shortly after the drug had been FDA approved, but then she’d turned it down. Pre-heart attack, she didn’t think she needed it. And I was on her side because the physician offering it dismissed my admittedly obnoxious attempt to determine whether or not he actually knew anything about what he was prescribing so enthusiastically.

“A drug to stop the craving. Interesting. How does it work?”

A dirty look from the man in white. “I don’t know. The drug rep was just here.”

“Well, wouldn’t it bind at a nicotinic receptor in the nucleus accumbens and prevent dopamine release?”

“I have no idea,” he muttered. “But it will help her quit.”

Chantix, aka varenicline, indeed binds part of the nicotinic receptor, blocking the pleasurable release of dopamine that fuels many addictions. Nefariously, these receptors not only sit elsewhere in the brain, but also on lung cells, where they bind carcinogens, explaining how smoking is addictive and sets the stage for cancer at the same time, in genetically susceptible individuals. Nicotinic receptors are in other organ systems, too. And that’s the trouble with receptors and the drugs that interact with them. They sometimes lurk in places other than where you want to target them, possibly causing adverse events. For Chantix, reports of AEs began to accumulate almost as soon as doctors began writing prescriptions.

• 11/20/07: An FDA Early Communication About an Ongoing Safety Review reports "serious neuropsychiatric symptoms”

• 5/16/08: FDA adds info on suicidal ideation and actions to prescribing literature and a patient medication guide

• 7/1/09: FDA slaps on a boxed warning, the most serious labeling, of possible behavioral changes.

It’s unclear to me how one can distinguish whether those behavioral changes – hostility, aggression, agitation, depression, and threats to do oneself in if a smoke cannot be had – are due to the smoking cessation aid, or to smoking cessation itself. But the continuing trickle of AE reports must have been serious enough to warrant attention.

• 7/2010: FDA orders Chantix manufacturer Pfizer to resubmit adverse event reports that were “initially sent to the Agency in a way that did not allow for comprehensive evaluation,” whatever that means.

• 5/19/11: FDA reports several new studies: Pfizer’s doing a postmarketing clinical trial to reconsider safety, while observational studies start at the Veteran’s Administration and the Department of Defense.

It’s a good thing Chantix was hauled through further trials, because they turned up another risk – that the aid that stops the smoking that causes cardiovascular disease (CVD), can itself worsen or even cause it.

• 6/16/11: Yet another safety announcement from FDA adds shortness of breath, chest pain, and leg pain to the list of what to watch out for when taking the drug. The warning is for patients who already have CVD.

This at first mind-boggling finding makes a certain sense. First, post-marketing surveillance often turns up adverse events (remember Vioxx?) simply because the numbers grow. If something’s rare, more individuals must be surveyed to see it. And it’s logical that the AEs will hit a body part at the center of the indication.

But wait!

• 7/4/11: A study in the Canadian Medical Association Journal finds that Chantix increases, ever so slightly, risk of CVD in people who don’t already have it! Said Sonal Singh, lead author, “People should be concerned. They don’t need Chantix to quit and this is another reason to consider avoiding Chantix altogether.”

The studies aren’t perfect. Some are meta analyses, lumping old studies done different ways. And the risk numbers aren’t huge. In the 6/16/11 news release, for Chantix users with CVD, 2% had a nonfatal heart attack, compared to .9% for those taking placebo. In the 7/4/11 study, the increased risk of CVD was 72%, for young men. Still, the dangers make one wonder if there isn’t a better way.

Coincidentally, a paper published in online Lancet just as the Canadian Chantix study appeared introduced just such a method – texting.

In the txt2stop experiment, Caroline Free and colleagues at the London School of Hygiene and Tropical Medicine randomly assigned 5,800 smokers wanting to quit to receive either of two types of frequent text messages: a specific strategy for how to get through a craving, or placebo messages merely thanking them. At follow-up, saliva tests caught the liars.

The smokers receiving the motivational messages were twice as likely to quit smoking. Concludes Dr. Free, “Text messages are a very convenient way for smokers to receive support to quit. People described txt2stop as having a ‘friend’ encouraging them. It helped people resist the temptation to smoke.” Texting to quit is cheap enough for many more people to use than a pricey drug that brings those nasty adverse effects, if only rarely.

Chantix does work, either by plugging up receptors or by exerting a powerful placebo effect, or both. My mother-in-law never smoked another cigarette after that heart attack four years ago, but I think it was sheer fear that did it. And that’s why I’m hopeful that the new scare photos on cigarette packages will ultimately make risky stop-smoking drugs unnecessary.

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