Despite effective therapies for smoking cessation, most smokers find quitting difficult and most successful quitters relapse. Considerable evidence supports a genetic risk for nicotine dependence; however, less is known about the pharmacogenetics of smoking cessation. In the first pharmacogenetic investigation of the efficacy of varenicline and bupropion, we examined whether genes important in the pharmacodynamics and pharmacokinetics of these drugs and nicotine predict medication efficacy and adverse events. Subjects participated in randomized, double-blind, placebo-controlled smoking cessation clinical trials, comparing varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, with bupropion, a norepinephrine/dopamine reuptake inhibitor, and placebo. Primary analysis included 1175 smokers of European ancestry, and 785 single nucleotide polymorphisms from 24 genes, representing 254 linkage disequilibrium (LD) bins (genes included nAChR subunits, additional varenicline-specific genes, and genes involved in nicotine or bupropion metabolism). For varenicline, continuous abstinence (weeks 9–12) was associated with multiple nAChR subunit genes (including CHRNB2, CHRNA5, and CHRNA4) (OR=1.76; 95% CI: 1.23–2.52) (p<0.005); for bupropion, abstinence was associated with CYP2B6 (OR=1.78; 95% CI: 1.27–2.50) (p<0.001). Incidence of nausea was associated with several nAChR subunit genes (OR=0.50; 95% CI: 0.36–0.70) (p<0.0001) and time to relapse after quitting was associated with HTR3B (HR=1.97; 95% CI: 1.45–2.68) (p<0.0001). These data provide evidence for multiple genetic loci contributing to smoking cessation and therapeutic response. Different loci are associated with varenicline vs bupropion response, suggesting that additional research may identify clinically useful markers to guide treatment decisions.
Importance Some cigarette smokers may not be ready to quit immediately but may be willing to reduce cigarette consumption with the goal of quitting. Objective To determine efficacy and safety of varenicline for increasing smoking abstinence rates through smoking reduction. Design, Setting, and Participants Randomized, blinded, placebo-controlled, multinational clinical trial with a 24-week treatment period and 28-week follow-up conducted between July 2011 and July 2013 at 61 centers in 10 countries. 1510 cigarette smokers not willing or able to quit smoking within the next month but willing to reduce smoking and make a quit attempt within the next 3 months recruited through advertising. Interventions Twenty-four weeks of varenicline titrated to 1 mg twice daily or placebo with reduction target of ≥ 50% in number of cigarettes smoked by 4 weeks and ≥ 75% by 8 weeks and a quit attempt by 12 weeks. Main Outcome Measures Primary efficacy endpoint was carbon monoxide (CO)-confirmed self-reported abstinence during weeks 15-24. Secondary outcomes were CO-confirmed self-reported abstinence rate for weeks 21-24 and weeks 21-52. Results The varenicline group (N = 760) had significantly higher continuous abstinence rates during weeks 15-24 versus placebo (N = 750) (32.1% vs 6.9%; risk difference (RD) 25.2%; 95% CI 21.4%, 29.0%; relative risk (RR) = 4.6; 95% CI 3.5, 6.1). The varenicline group had significantly higher continuous abstinence rates versus placebo during weeks 21-24 (37.8% vs 12.5%; RD 25.2%; 95 CI 21.1%, 29.4%; RR 3.0; 95% CI 2.4, 3.7) and weeks 21-52 (27.0% vs 9.9%; RD 17.1%; 95% CI 13.3%, 20.9%; RR 2.7; 95% CI 2.1, 3.5). Serious adverse events occurred in 3.7% and 2.2% of the varenicline and placebo groups, respectively (P = 0.07). Conclusions and Relevance Among cigarette smokers not willing or able to quit within the next month but willing to reduce cigarette consumption and make a quit attempt in the next 3 months, use of varenicline for 24 weeks compared with placebo significantly increased smoking cessation rates through 6 months of follow up. Varenicline offers a treatment option for smokers whose needs are not addressed by clinical guidelines recommending abrupt smoking cessation. Trial Registration www.clinicaltrials.gov (NCT01370356): https://clinicaltrials.gov/ct2/results?term=NCT01370356&Search=Search
Chronic pain substantially impacts patient function and quality of life and is a burden to society at large in terms of increased health care utilization and loss of productivity. As a result, there is an increasing recognition of chronic pain as a public health crisis. However, there remains wide variability in clinical practices related to the prevention, assessment, and treatment of chronic pain. Certain fundamental aspects of chronic pain are often neglected including the contribution of the psychological, social, and contextual factors associated with chronic pain. Also commonly overlooked is the importance of understanding the likely neurobiological mechanism(s) of the presenting pain and how they can guide treatment selection. Finally, physicians may not recognize the value of using electronic medical records to systematically capture data on pain and its impact on mood, function, and sleep. Such data can be used to monitor onset and maintenance of treatments effects at the patient level and evaluate costs at the systems level. In this review we explain how these factors play a critical role in the development of a coordinated, evidence-based treatment approach tailored to meet specific needs of the patient. We also discuss some practical approaches and techniques that can be implemented by clinicians in order to enhance the assessment and management of individuals with chronic pain in primary care settings. ARTICLE HISTORY
Chronic pain conditions impose a substantial burden on the healthcare system, with musculoskeletal conditions associated with the highest overall costs. Costs appeared to be primarily related to use of outpatient services. This type of research supports integrated delivery systems as a source for assessing opportunities to improve patient outcomes and lower the costs for chronic pain patients.
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