Efficacy of bupropion and varenicline genetic markers in choosing pharmacological treatment for smoking cessation, and implications for combining drugs: A randomized controlled trial - GENTSMOKING.

INTRODUCTION: Smoking cessation is the best strategy for reducing tobacco-related morbimortality. The goal of this randomized controlled trial was to test whether using the genetically favorable markers to choose a smoking cessation drug treatment (precision medicine) was superior to using the most effective drug (varenicline) in terms of abstinence rates. Additionally, combination therapy was tested when monotherapy failed. METHODS: This partially blind, single-center study randomized (1:1) 361 participants into two major groups. In the genetic group (n=184), CYP2B6 rs2279343 (genotype AA) participants started treatment with bupropion, and CHRNA4 rs1044396 (genotype CT or TT) participants started treatment with varenicline; when genetic favorable to both, participants started treatment with bupropion, and when favorable to neither, on both drugs. In the control group (n=177), participants started treatment with varenicline, regardless of genetic markers. Drug treatment lasted 12 weeks. Efficacy endpoints were abstinence rates at Weeks 4, and Weeks 8-12, biochemically validated by carbon monoxide in exhaled air. Participants who did not achieve complete abstinence at Week 4, regardless of group, were given the choice to receive combination therapy. RESULTS: Abstinence rates were 42.9% (95% CI: 36-64) in the control group versus 30.4% (95% CI: 23-37) in the genetic group at Week 4 (p=0.01); and 74% (95% CI: 67-80) versus 52% (95% CI: 49-64) at Week 12 (p<0.001), respectively. The strategy of combining drugs after Week 4 increased abstinence rates in both groups and the significant difference between genetic and control groups was maintained. CONCLUSIONS: Results show that using these selected genetic markers was inferior to starting treatment with varenicline (control group), which is currently the most effective smoking cessation drug; moreover, the addition of bupropion in cases of varenicline monotherapy failure improves the efficacy rate until the end of treatment. CLINICAL TRIAL IDENTIFIER: NCT03362099.

Does deep TMS really works for smoking cessation? A prospective, double blind, randomized, sham controlled study.

INTRODUCTION: A substantial proportion of smokers wishing to quit do not stop smoking when using current therapies to aid cessation. Magnetic pulses to specific brain areas designated as transcranial magnetic stimulation may modulate brain activity and thereby change chemical dependencies. Deep transcranial magnetic stimulation (dTMS) with the H4 coil stimulates neuronal pathways in the lateral prefrontal cortex and insula bilaterally, areas involved in tobacco addiction. OBJECTIVE: To evaluate the efficacy and safety of dTMS with T4 coil in smoking cessation. METHODS: In a double blind, controlled clinical trial, adult smokers of at least 10 cigarettes/day were randomized to active (n = 50) versus sham dTMS (n = 50). The protocol involved up to 21 sessions administered over up to 12 weeks. Tobacco use was monitored by self-report and confirmed by expired air monoximetry (at each dTMS visit) and blood cotinine (at the screening visit and at the end of sessions). Participants completed abstinence, mood and cognition scales at determined timepoints during follow-up. RESULTS: In the intention to-treat-analysis, the cessation rate of the intervention and control groups was 14.0%. The reported side effects were as expected for this procedure. Although there were no serious adverse events, three participants were withdrawn according to safety criteria. CONCLUSION: Active treatment with dTMS H4 coil was safe but not effective for smoking cessation.

Cue restricted smoking increases quit rates with varenicline.

INTRODUCTION: Varenicline effectively helps smokers quit by reducing withdrawal symptoms and blocking the reward of smoking. However, most quitters return to smoking within one year. 'Cue Restricted Smoking' is a behavioral technique designed to increase quit rates by asking smokers attempting to quit to restrict smoking to the standing position, while alone, in an isolated area facing a wall, with the cigarette as the only stimulus. METHODS: Using retrospective clinic records we compared quit rates in 281 smokers (50% males) instructed in the cue restricted smoking cessation method during 2016-2018 to quit rates in 324 smokers (46% males) advised to completely stop smoking on the target quit date which we previously used during 2011-2014. All were prescribed varenicline for 12 weeks alone, with the addition of bupropion if needed after 4 weeks. Follow-up consisted of behavioral support at 4-6 visits during active drug treatment and telephone counselling at 24 and 52 weeks. The smoking cessation rate was confirmed with exhaled carbon monoxide at the clinic visit at 12 weeks and only by telephone at 52 weeks. RESULTS: The mean age of smokers was 49 years in both groups and the number of cigarettes smoked daily was similar (18/day in the cue restricted vs 19/day in the target quit day group). The smoking cessation rate at 12 weeks was 75% in the cue restricted versus 45% in the target quit day group (relative risk, RR=1.8; 95% CI: 1.4-2.2, p<0.001). At 52 weeks the quit rate was 65% vs 34%, respectively (RR=1.9; 95% CI: 1.5-2.4, p<0.001). CONCLUSIONS: Cue restricted smoking was associated with a substantially increased chance of quitting compared with standard advice during treatment with varenicline. These results should be further studied in a randomized controlled trial.