TORONTO/PHILADELPHIA – In a first-of-its-kind randomized clinical trial, researchers from the Centre for Addiction and Mental Health (CAMH) and collaborators have shown the benefits of a personalized approach to smoking treatment, based on how quickly smokers break down nicotine in their bodies.
Nearly 70 percent of smokers who try to quit smoking relapse within one week. Researchers have long theorized that some individuals may be genetically programmed to have an easier time quitting than others, but have been unable to provide guidance on the most successful approach – nicotine patch versus prescription pills, for instance.
“In this new trial, we’ve shown that it is possible to optimize quit rates for smokers, while minimizing side effects, by selecting treatment based on whether people break down nicotine slowly or normally,” says study co-lead Dr. Rachel Tyndale, senior scientist in CAMH’s Campbell Family Mental Health Research Institute and a professor of Pharmacology & Toxicology and Psychiatry at the University of Toronto.
The multi-site study was published online in The Lancet Respiratory Medicine. Dr. Tony George, CAMH Chief of Schizophrenia, led the clinical study at the CAMH site.
“Normal” metabolizers of nicotine were significantly more likely to remain abstinent from smoking after treatment with the drug varenicline (Chantix, manufactured by Pfizer) compared to the nicotine patch, at the end of treatment and 6 months later. “Slow” metabolizers, on the other hand, could benefit the most from the nicotine patch, the authors suggest. Varenicline was just as effective as nicotine patch for “slow” metabolizers, but it led to more side effects than the patch.
“This is a much-needed, genetically-informed biomarker that could be translated into clinical practice,” said co-lead Dr. Caryn Lerman, a professor of Psychiatry and director of the Center for Interdisciplinary Research on Nicotine Addiction at the University of Pennsylvania. “Matching a treatment choice based on the rate at which smokers metabolize nicotine could be a viable strategy to help guide choices for smokers and ultimately improve quit rates.”
The difference between slow and normal metabolizers is how long nicotine stays in the body after quitting. Nicotine levels drop more quickly in normal metabolizers, putting them at risk to succumb to cravings and relapse. But they are also more likely to be helped by medications such as varenicline, which can increase levels of the “feel-good” hormone dopamine and reduce cravings.
In the clinical trial, 1,246 smokers seeking treatment were categorized as either slow metabolizers (662) or normal metabolizers (584). They were randomized to receive one of the following for 11 weeks: the nicotine patch plus a placebo pill; varenicline plus placebo patch; or both placebo pill and patch. All received behavioral counselling. The trial was conducted at four academic medical centres: the Perelman School of Medicine at the University of Pennsylvania, CAMH and the University of Toronto, the State University of New York at Buffalo, and MD Anderson Cancer Center.
Participants’ status as either a normal or slow metabolizer was based on a measure called the nicotine metabolite ratio (NMR). NMR is the ratio of two chemical products of nicotine, which break down at different rates based on different genetic versions of CYP2A6, a liver enzyme. Participants’ smoking behaviour was assessed at the end of treatment, and six and 12 months later.
Among normal metabolizers, nearly 40 percent taking varenicline were still abstaining from smoking at the end of treatment, compared to 22 percent on the nicotine patch. The quit rates, as expected based on the difficulty of prolonged quitting success, decreased at six and 12 months, but the overall pattern of response for both normal and slow metabolizers on the patch and varenicline remained.
“Our data suggest that treating normal metabolizers with varenicline, and slow metabolizers with the nicotine patch could provide a practical clinical approach. What’s more, extending the duration of these treatments beyond 11 weeks could potentially sustain the benefit of tailored treatment,” according to the authors.
Smoking rates in North America have fallen substantially since the 1960s, but nearly 1.8 million Ontario adults and students still report smoking, according to recent CAMH surveys. Worldwide, about six million people die every year from smoking-related diseases, and $200 billion is spent on tobacco-related health care costs.
“These findings support the use of the nicotine metabolite ratio as a genetically informed biomarker to guide treatment choices,” said Dr. Tyndale, “and also underscore the notion that tobacco dependence is a heterogeneous condition and that smoking cessation treatments are not equally effective for all smokers.”
The work was conducted under the Pharmacogenomics Research Network—Pharmacogenetics of Nicotine Addiction Treatment Research Group, funded primarily through the National Institutes of Health (National Institute on Drug Abuse, National Cancer Institute, National Institute of General Medical Sciences, and the National Human Genome Research Institute; U01-DA20830). Pfizer provided active varenicline and placebo pills at no cost. Pfizer had no input on study design, data analysis or the writing of the manuscript.
