Improving the success of treating tobacco smokers.

Despite decades of progress in the public health fight to reduce tobacco use, smoking remains the leading preventable cause of death in theUnited States.1 For the approximately 40 million US smokers left, the epidemiological evidence is clear: they will benefit from stopping smoking no matter how long they have smoked.1 Effective treatments to help smokers quit are available, but patients still struggle to become tobacco free.2 Most physicians now consider addressing patients’ tobacco use to be part of their job, but doing so can be a challenge. How can we change this picture? At the population level, the outcome of treating any disease can be improved by finding a better treatment or by expanding the reach of treatments that already exist. Both apply to treatingsmokers.Wehaveeffective treatments;however, they are imperfect, andmost smokers do not use themwhen they try to quit. Almost 70% of smokers say that theywant to quit smoking;more thanhalf say that they tried todo so in the past year, but onlyone-thirdusedany tobacco cessation treatment in that attempt.3 This is a gap that physicians couldhelp bridge. Routine brief advice from a physician increases the chance that a smoker will make a quit attempt.2 We fall short inensuring that thesmokersmaking thoseeffortsuse the treatments that could help them succeed.We can do this by building team-based systems of care into the routine work flow of office practice rather than relying on the physician’s actions alone. Essentially, it means building a chronic disease management model for treating tobacco users.4 A second strategy to improve outcomes is to identify better tobacco cessation treatments. The existing treatments improve a smoker’s chance of success, but even the best approach—a combinationof pharmacotherapy and counseling— typically produces long-term abstinence rates of only 25% to 30% after any single quit attempt.2 This is better than the estimated 6% success rate of smokers who try to quit without treatment, but it leaves plenty of room for improvement.3 Despite ongoing efforts to improve treatment, no new smoking cessationaid isnearingUSFoodandDrugAdministration (FDA) approval, to my knowledge. With no new drug on the horizon, research is exploring whether we could improve the effectiveness of our existing medications. For example, we are still learning how to optimize the dose and delivery of nicotine replacement therapy (NRT), although the first product, nicotine gum, reached the US market in 1988. Manufacturers have since developed new products (patch, lozenge, nasal spray, and oral inhaler) and tweaked their formulations to enhance consumer appeal. Investigators learned that using an individual product often fails to fully suppress a smoker’s cigarette cravings or nicotine withdrawal symptoms. They achieved higher quit rates by combining NRT products, specifically by pairing the skin patch, a long-acting slow-onset product, with a rapiddelivery short-acting product such as the lozenge, gum, inhaler, or nasal spray. The latter product is used as needed for withdrawal symptom control by a smoker wearing the patch. Combination NRT has outperformed single NRT agents in clinical trials and is endorsed in national clinical guidelines.2 It is a better way to use NRT, and it provides physicians with a new option to offer to smokers who may have already failed with a single NRT product. Another strategy to improve treatment efficacy is to combine drugs with different mechanisms of action, much as we do in treating hypertension or diabetes mellitus. Two recent studies5,6 tested themarginal benefit and tolerability of combining varenicline with another active drug, either bupropionhydrochlorideornicotinepatch.Bothstudies foundsome improvement over varenicline use alone, although replication is warranted. Combining bupropion and NRT has generated equivocal results, but the combination is used clinically when individual products fail. Acommonquestionfacedbyphysicians iswhat todowhen smokers do not respond to the standard dosage of a drug. Should they increase the dose or switch to a different drug? Randomized clinical trial evidence to guide this decision is rarely available. A study7 in the current issue of JAMA Internal Medicine provides this evidence for varenicline, a firstline FDA-approved smoking cessation aid that is a partial agonist at the α4β2 nicotinic receptor. Hajek and colleagues7 asked the followingquestion: if the standard dosage of varenicline does not appear to be working,will increasing thedose improve cessation success andbe tolerable to the patient? They answered the question with an ingeniousdouble-blind randomizedplacebo-controlled clinical trial design. Smokerswhowanted toquit started takingvarenicline tartrate in the standardway, increasing thedose from 0.5 to 2 mg/d during the first week to minimize nausea, the most common adverse effect. Ten days after beginning varenicline use and well before the target quit date on day 21, smokers were asked if they had noticed any nausea or any of the changes that varenicline users usually experience before quitting (reducedenjoymentofsmokingorsmokingfewercigarettes per day). Only thosewho tolerated the standarddosage but forwhom the drug did not appear to have any effectwere enrolled in the actual trial. They were randomly assigned to continue the standard dosage or to increase it incrementally before the quit day, reaching a dose of 5mg/d if tolerated. The drug was taken for an additional 12 weeks after the quit day, and outcomes were measured at that point. Smokers were closely monitored for adverse effects and for nicotine withdrawal symptoms, and they concurrently received a moderate amount of psychosocial support to aid quitting. The results of the study7 were clear, if disappointing. Increasing the varenicline dose in apparent nonresponderswas Related article page 266 Research Original Investigation Increasing Varenicline Dose in Smokers