Almost 70 percent of U.S. smokers want to quit, according to a Centers for Disease Control and Prevention survey, but each year only a small percentage of those who try to kick the habit succeed. Even among smokers who are prescribed a smoking-cessation medication, quit rates range from just 7 percent to 30 percent, one review found.
Researchers are working to help health-care providers improve those rates by figuring out which patients will respond best to which medications. They've found that a biomarker called the nicotine metabolite ratio—measured by a simple blood or saliva test—can help determine which of the two main types of FDA-approved smoking-cessation medications will work best for an individual smoker.
"Our goal is to understand how we can modify the use of existing medications in ways that make them more effective," says Robert Schnoll, PhD, a psychologist and associate professor in the department of psychiatry at the University of Pennsylvania.
He and his colleagues have found, for example, that people whose bodies metabolize nicotine more quickly do better on varenicline, a dopamine agonist that can reduce cigarette cravings. Slow metabolizers, on the other hand, do just as well with nicotine-replacement therapy (like a nicotine patch)—a far less expensive medication that generally has fewer side effects.
Now, researchers are working to better understand the reward pathways in the brain that may underlie the differences between faster (sometimes called "normal") metabolizers and slower ones, and to move their findings from the laboratory to clinician's offices, where more patients can benefit from them.
From liver to brain
The nicotine metabolite ratio is simply a measure of how quickly a person's body breaks down nicotine. One of the primary drivers of that process is a liver enzyme called CYP2A6. By looking at the ratio of a longer-lasting CYP2A6 metabolite called cotinine to a shorter-lasting one called 3'-hydroxycotinine, the nicotine metabolite ratio can indicate whether a person is a slower nicotine metabolizer or a faster one.
Neal Benowitz, MD, and colleagues at the University of California, San Francisco, and University of Toronto first developed the nicotine metabolite ratio test more than a decade ago. In a series of studies, they found that the ratio is related to smokers' smoking behavior. Normal metabolizers—who likely need to take in more nicotine to maintain the same level in the body—smoke more cigarettes per day (Clinical Pharmacology and Therapeutics, 2006), inhale larger volumes of smoke (Cancer Epidemiology, Biomarkers and Prevention, 2011) and smoke their first cigarette earlier each day, on average, than slow metabolizers do.
Building on that work, researchers began studying how the nicotine metabolite ratio might affect smokers' ability to quit and reaction to smoking-cessation medications.
In a randomized prospective study published in 2015, University of Pennsylvania psychologist Caryn Lerman, PhD, and University of Toronto pharmacology professor Rachel Tyndale, PhD, with Schnoll, Benowitz and other colleagues, assigned 1,246 smokers (662 slow metabolizers and 584 normal metabolizers) to receive either the nicotine patch, varenicline or a placebo treatment. Immediately after the treatment and at a six-month follow-up, they found that normal metabolizers were much more successful with varenicline (22 percent remained abstinent after six months) than the patch (13.6 percent). Among slow metabolizers, however, there was no significant difference between the two treatments (The Lancet Respiratory Medicine, 2015).
The researchers also found that slow metabolizers had more side effects (including nausea, insomnia and diarrhea) on varenicline than on the patch, but that normal metabolizers did not.
That means using the nicotine metabolite ratio to sort smokers into slow versus normal metabolizers could help smokers minimize side effects and maximize their chances of quitting when choosing medication.
Why does it work? Researchers aren't yet entirely sure, but brain-imaging studies are beginning to provide some answers. They suggest that the rate at which people metabolize nicotine may, over years of smoking, lead to differences in the brains of normal- and slow-metabolizing smokers that could affect behavior.
In one study, Eliot Stein, PhD, chief of the Neuroimaging Research Branch at the National Institute on Drug Abuse (NIDA) intramural research program, used fMRI to image the brains of 23 smokers and 23 nonsmokers—all of whom were temporarily abstinent from cigarettes before the experiment—while they anticipated a reward in a game. Half of the participants were normal metabolizers and half were slow (Tyndale, who collaborated on the research, measured this by testing their genotype, because different variants of the CYP2A6 gene are associated with being a slow versus normal metabolizer). The researchers found that for nonsmokers, there were no differences between the normal and slow metabolizers in how the brain responded to the game. But among smokers, those with the "slow" CYP2A6 variant had less response in the ventral striatum, an area of the brain related to reward, than those with the "normal" gene (Biological Psychiatry, 2016).
"This is important because … it suggests that these smokers have changed their brains in a very specific way, not just by smoking but by the interaction of smoking and having a different genotype," Stein says.
From lab to clinic
This kind of personalized medicine may be the future of treatment, but there are several hurdles to overcome before health-care providers can ask patients to take a blood test before they try to quit smoking. First, while NIDA is funding some commercial development, so far there are no commercial test kits for the nicotine metabolite ratio, explains Tyndale.
Second, she says, more work is needed to ensure the findings apply in community settings outside a clinical trial—including in patients such as pregnant women and those with serious mental illness or opiate dependency.
Finally, Schnoll and other researchers have also applied for funding for a study that would introduce nicotine metabolite ratio testing into primary-care practices to evaluate how it affects the doctor's prescribing rate and patients' medication utilization and quit rates.
"Right now, for a variety of clinical problems, you see your physician, and then you're asked to give blood, and then the results are reported back to your physician," he says. "That's the model we are looking to emulate."
