Varenicline OTC Trial on Efficacy and Safety.

INTRODUCTION: Varenicline helps people who smoke quit at rates 2-3 times greater than placebo. Currently in the U.S., varenicline is not available over the counter (OTC). In this study, we assessed the safety and efficacy of 1mg and 0.5mg varenicline as an OTC medication for smoking cessation in comparison to placebo. METHODS: This randomized, double-blind, placebo-controlled study was performed at two clinical sites in the United States of n=313 people. The treatment period was 12 weeks. During the COVID pandemic, the protocol was modified to allow remote participation; verification of smoking status was via breath carbon monoxide levels for in-person visits and mailed urine cotinine kits for the remote participants. RESULTS: There was no difference in biologically confirmed continuous abstinence by condition between Weeks 8-12; however, the odds of biologically confirmed point prevalence abstinence were higher for those in the 1mg b.i.d. condition than for those in the placebo condition at Week 12 (OR 3.39; 95% CI 1.49, 7.71), and were higher for those assigned to the 1.0mg b.i.d. condition than the 0.5mg b.i.d. condition at Week 12 (OR 2.37; 95% CI 1.11, 5.05). Adverse events were modest, and as expected (vivid dreams and nausea in the medication conditions). CONCLUSIONS: The results are suggestive that varenicline is safe and effective as an OTC medication.

Cytisinicline for Smoking Cessation: A Randomized Clinical Trial.

Importance: Cytisinicline (cytisine) is a plant-based alkaloid that, like varenicline, binds selectively to α4ß2 nicotinic acetylcholine receptors, which mediate nicotine dependence. Although not licensed in the US, cytisinicline is used in some European countries to aid smoking cessation, but its traditional dosing regimen and treatment duration may not be optimal. Objective: To evaluate the efficacy and tolerability of cytisinicline for smoking cessation when administered in a novel pharmacokinetically based dosing regimen for 6 or 12 weeks vs placebo. Design, Setting, and Participants: A 3-group, double-blind, placebo-controlled, randomized trial (ORCA-2) compared 2 durations of cytisinicline treatment (6 or 12 weeks) vs placebo, with follow-up to 24 weeks, among 810 adults who smoked cigarettes daily and wanted to quit. It was conducted at 17 US sites from October 2020 to December 2021. Interventions: Participants were randomized (1:1:1) to cytisinicline, 3 mg, 3 times daily for 12 weeks (n = 270); cytisinicline, 3 mg, 3 times daily for 6 weeks then placebo 3 times daily for 6 weeks (n = 269); or placebo 3 times daily for 12 weeks (n = 271). All participants received behavioral support. Main Outcomes and Measures: Biochemically verified continuous smoking abstinence for the last 4 weeks of cytisinicline treatment vs placebo (primary) and from end of treatment to 24 weeks (secondary). Results: Of 810 randomized participants (mean age, 52.5 years; 54.6% female; mean of 19.4 cigarettes smoked daily), 618 (76.3%) completed the trial. For the 6-week course of cytisinicline vs placebo, continuous abstinence rates were 25.3% vs 4.4% during weeks 3 to 6 (odds ratio [OR], 8.0 [95% CI, 3.9-16.3]; P < .001) and 8.9% vs 2.6% during weeks 3 to 24 (OR, 3.7 [95% CI, 1.5-10.2]; P = .002). For the 12-week course of cytisinicline vs placebo, continuous abstinence rates were 32.6% vs 7.0% for weeks 9 to 12 (OR, 6.3 [95% CI, 3.7-11.6]; P < .001) and 21.1% vs 4.8% during weeks 9 to 24 (OR, 5.3 [95% CI, 2.8-11.1]; P < .001). Nausea, abnormal dreams, and insomnia occurred in less than 10% of each group. Sixteen participants (2.9%) discontinued cytisinicline due to an adverse event. No drug-related serious adverse events occurred. Conclusions and Relevance: Both 6- and 12-week cytisinicline schedules, with behavioral support, demonstrated smoking cessation efficacy and excellent tolerability, offering new nicotine dependence treatment options. Trial Registration: ClinicalTrials.gov Identifier: NCT04576949.

Curiosity and intentions to use myblu e-cigarettes and an examination of the 'gateway' theory: Data from cross-sectional nationally representative surveys.

Encouraging adult smokers who are uninterested or unwilling to quit, and would otherwise continue to smoke, to transition to potentially less harmful nicotine products such as electronic nicotine delivery systems (ENDS) may positively impact population health. However, counterbalancing this benefit is the societal concern that ENDS may be used by never smokers and youth and serve as a 'gateway' into cigarette smoking. Data were analysed from two independent surveys of the prevalence and perceptions of myblu ENDS use in the United States. Total sample size was 22,232 young adults and 23,264 adults. Being curious to use myblu was 1.6-2.0 times more likely in young adult current smokers than young adult never smokers. This likelihood was 2.8 times greater for adult current smokers compared with adult never smokers in the perceptions survey, while in the prevalence survey, there was no difference between adult current and never smokers. Intentions to use myblu were significantly greater in young adult current smokers compared with young adult never smokers in both surveys and in adults in the prevalence survey. In all surveys and age cohorts, 124 of 45,496 participants (0.1% of the total survey population) reported first using myblu prior to smoking cigarettes and went on to become established smokers. Curiosity and intentions to use myblu were generally higher in current smokers compared with never smokers. There was minimal evidence to suggest the existence of a 'gateway' effect to established cigarette smoking among never-smoking myblu users.

Examination of the impact of myblu electronic nicotine delivery system e-liquid nicotine strength on self-reported measures of dependence.

BACKGROUND: Greater nicotine delivery is associated with higher nicotine concentrations in electronic nicotine delivery system (ENDS) liquids. However, there is a current debate as to whether this leads to increased dependence and mitigates ENDS public health potential. METHODS: Self-reported dependence among users of myblu ENDS containing different nicotine concentrations was examined with data from a multiwave cross-sectional survey of US young adults and adults. Questions examined responses related to dependence measures and participants' most often used myblu ENDS nicotine concentration (low: 0%, 1% and 1.2%; medium: 2%, 2.4% and 2.5%; or high: 3.6% and 4%). RESULTS: A global general linear model using nicotine concentration, age and days myblu that was used in the past 30 revealed a significant difference in PROMIS scores among nicotine concentration groups (F = 4.07, p = 0.02). However, pairwise comparisons to examine which specific groups differed significantly from others showed no significant differences. Logistic regression demonstrated that strong past 30-day cravings to use myblu among participants using high or medium nicotine concentrations were not significantly different from those using a low concentration (ORs 0.66 [0.42, 1.03], p = 0.07 and 0.95 [0.49, 1.82], p = 0.98, respectively). Time to daily first use for high or medium nicotine concentration users was not significantly different from those using a low concentration (ORs 0.89 [0.70, 1.14], p = 0.35 and 0.84 [0.57, 1.25], p = 0.40, respectively). CONCLUSIONS: Use of myblu ENDS with different nicotine concentrations is not associated with differing levels of dependence. Our findings contradict the notion that high ENDS e-liquid nicotine levels generate increased dependence.

A Multicenter, Double-Blind, Randomized, Placebo-Controlled Phase 2b Trial of Cytisinicline in Adult Smokers (The ORCA-1 Trial).

INTRODUCTION: Cytisinicline (known as cytisine), a nicotinic acetylcholine receptor partial agonist, is a smoking cessation aid currently marketed in Central and Eastern Europe using a 1.5-mg/tablet 25-day downward titration schedule. No prior studies have evaluated other doses or administration schedules. This study evaluated the effects of a higher dosage and simplified dosing schedule on drug efficacy and tolerability. METHODS: ORCA-1 was a double-blind, randomized, placebo-controlled clinical trial that provided cytisinicline or placebo tablets plus behavioral support for 25 days. Adult smokers (>10 cigarettes daily) committed to quitting smoking were randomized to compare 2 cytisinicline doses (1.5 mg and 3 mg) versus placebo, and 2 administration schedules [downward titration versus 3 times daily (TID)]. Primary outcome was a reduction in expected cigarettes smoked at end of treatment; secondary outcomes were biochemically confirmed 7-day abstinence at Week 4 and continuous abstinence from Weeks 5 to 8. RESULTS: Among 254 participants, those in cytisinicline arms (regardless of dose or schedule) had greater reductions in cigarettes smoked versus placebo, with differences observed in 3 cytisinicline arms statistically significant versus placebo. All cytisinicline arms had statistically significantly higher abstinence rates at Week 4 versus placebo. Both cytisinicline arms using TID schedules had statistically significantly higher continuous abstinence rates from Weeks 5 to 8 compared with placebo. Participants in the cytisinicline 3-mg TID arm had the highest abstinence rate. There were no safety concerns with either 1.5-mg or 3-mg cytisinicline. CONCLUSION: Based on simpler dose scheduling, excellent tolerability, and best-continued abstinence rate, cytisinicline 3-mg TID was selected for future Phase 3 studies. IMPLICATIONS: Although the 1.5-mg 25-day titration schedule has been marketed in Central and Eastern Europe for decades, this study explored using a higher dosage and a simplified dosing schedule for impact on cytisinicline efficacy and tolerability. Based on these results, a Phase 3 program was initiated using cytisinicline 3-mg tablets on a TID schedule for potential market approval in the United States.

Efficacy and Safety of a Nicotine Mouth Spray for Smoking Cessation: A Randomized, Multicenter, Controlled Study in a Naturalistic Setting.

BACKGROUND: Nicotine replacement therapy (NRT) has been demonstrated to be an effective pharmacological treatment for smoking cessation, and most types of NRT have been approved as over-the-counter (OTC) medications. In an effort to create a fast-acting, flexible, and discreet NRT, a nicotine mouth spray (NMS) has been developed. This study was designed to assess the efficacy and safety of NMS in a naturalistic setting in the United States. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 26-week study in 1198 smokers motivated to quit. The study was designed to resemble an OTC environment, and thus included limited intervention, limited motivational screening, and no behavioral support. The primary efficacy endpoint was carbon monoxide-verified, self-reported continuous abstinence from smoking from week 2 until week 6. The safety of NMS was assessed by measuring vital signs, visual mouth inspection, and collection of subject-reported adverse events (AEs). RESULTS: The percentage of subjects with carbon monoxide-verified continuous abstinence from week 2 to week 6 was statistically significantly greater in the NMS group compared with the placebo group (5.0% vs. 2.5%, p = .021). Statistically significant treatment effects for the NMS were maintained throughout the 26-week period. The study medications were generally well tolerated. The severity of AEs was similar for both treatment groups, and most AEs were of mild or moderate severity. CONCLUSIONS: These study results demonstrate that the NMS is an effective and safe smoking cessation option for smokers motivated to quit, even in a naturalistic setting and without behavioral support. IMPLICATIONS: This study demonstrated the safety, efficacy, and acceptability of an NMS in an OTC environment with no behavioral counseling or support. It provides an additional option for smokers motivated to quit. TRIAL REGISTRATION: ClinicalTrials.gov (number NCT02355665).

Changing patterns of first e-cigarette flavor used and current flavors used by 20,836 adult frequent e-cigarette users in the USA.

BACKGROUND: Understanding the role that flavors play in the population's use of e-cigarettes and the impact that flavored e-cigarette products have on the population's use of more harmful tobacco products, like conventional cigarettes, has been identified by the US Food and Drug Administration (FDA) as a public health research priority. The purpose of the study was to assess the first e-cigarette flavor and current e-cigarette flavors used by a large non-probabilistic sample of adult frequent users of e-cigarettes in the USA and assess how flavor preferences vary by cigarette smoking status and time since first e-cigarette purchase. METHODS: An online survey assessed the first e-cigarette flavor and current e-cigarette flavors used by a non-probabilistic sample of 20,836 adult frequent e-cigarette users in the USA. Differences in e-cigarette flavor preferences between current smokers, former smokers, and never-smokers and trends in the first flavor used across time of e-cigarette use initiation were assessed. RESULTS: The majority (n = 15,807; 76.4%) of sampled frequent e-cigarette users had completely substituted e-cigarettes for conventional cigarettes-"switchers"-and were currently using rechargeable, refillable vaping devices. Among them, the proportion of first e-cigarette purchases that were fruit-flavored increased from 17.8% of first purchases made before 2011 to 33.5% of first purchases made between June 2015 and June 2016. Tobacco-flavored first purchases almost halved during this time (46.0% pre-2011 to 24.0% between 2015 and 2016). Fruit/fruit beverage (73.9 to 82.9% of sampled users), dessert/pastry (63.5 to 68.5% of sampled users), and candy, chocolate, or sweets (48.7 to 53.4% of sampled users) were the most popular currently used e-cigarette flavors. Tobacco and menthol flavors, the two most popular flavors for initiating e-cigarette use prior to 2013, now rank as the 5th and 6th most popular currently used e-cigarette flavors, respectively. CONCLUSIONS: Adult frequent e-cigarette users in the USA who have completely switched from smoking cigarettes to using e-cigarettes are increasingly likely to have initiated e-cigarette use with non-tobacco flavors and to have transitioned from tobacco to non-tobacco flavors over time. Restricting access to non-tobacco e-cigarette flavors may discourage smokers from attempting to switch to e-cigarettes.

Nicotine Lozenges in the Relief of Behaviorally Provoked Craving.

OBJECTIVES: Environmental cues may precipitate nicotine cravings in smokers. We present 2 studies exploring the efficacy of nicotine mini lozenges to reduce nicotine craving in smokers following behavioral provocation. METHODS: Healthy smokers aged ≥18 years enrolled. In Study 1, participants were stratified by number of cigarettes smoked daily; Study 2 enrolled only heavy smokers. After an abstinence period, participants engaged in behavioral provocation to induce nicotine craving before receiving a nicotine mini lozenge (Study 1: 1.5 mg or 4 mg; Study 2: 4 mg) or matching placebo. Craving was assessed using a 100-mm visual analogue scale, and safety was monitored. RESULTS: In Study 1, neither nicotine mini lozenge dose significantly reduced craving in smokers versus placebo. In Study 2, 4-mg nicotine mini lozenges significantly reduced craving scores 5 minutes post-treatment (least-square mean [LSM] change from baseline: -41.8; 95% confidence interval [CI]: -45.8, -37.7) versus placebo (-25.9; 95% CI: -30.0, -21.8; p < .001). Adverse events were infrequent, mild in intensity, and more common with the 4-mg nicotine mini lozenges. CONCLUSIONS: Behaviorally provoked nicotine craving can be significantly and safely reduced in heavy/high-dependency smokers with 4-mg nicotine mini lozenges.

Comparison of nicotine oral soluble film and nicotine lozenge on efficacy in relief of smoking cue-provoked acute craving after a single dose of treatment in low dependence smokers.

RATIONALE: Pilot study results suggested that a new form of nicotine oral soluble film relieved smoking cue-provoked acute craving faster than nicotine lozenge or gum. The new nicotine film may provide smokers another choice to relieve acute craving. OBJECTIVES: This study compared the efficacy of the 2.5 mg nicotine oral soluble film to 2 mg nicotine lozenge for acute relief of smoking cue-provoked craving. METHODS: A randomized, open label, active comparator controlled, parallel group study was conducted with 322 smokers enrolled. After 4 h of abstinence from smoking, eligible subjects were exposed to smoking cues as provocation. Immediately after the post-provocation baseline craving assessment using a 0-100 mm visual analogue scale (VAS), subjects took a randomized single dose of either the 2.5 mg nicotine film or the 2 mg nicotine lozenge. Craving assessments were completed at 50 s, 3 min, 5 min, 7 min, 15 min, 20 min, 25 min and 30 min after drug administration. RESULTS: Both treatments reduced cue-induced craving and had similar maximum effects on craving relief. However, the 2.5 mg nicotine film relieved cue-induced craving to a greater degree than the 2 mg nicotine lozenge at 50 s (mean difference: -4.9, p = 0.014), 3 min (mean difference: -6.7, p = 0.011), and 5 min (mean difference: -5.6, p = 0.049) post-treatment. CONCLUSIONS: The study confirmed the results from the pilot study. The 2.5 mg nicotine film relieved cue-provoked craving much quicker than the 2 mg nicotine lozenge while both having similar maximum effects. Nicotine film could be useful to provide quick craving relief for low dependence smokers.

Nicotine blood levels and short-term smoking reduction with an electronic nicotine delivery system.

OBJECTIVES: To evaluate nicotine delivery from the NJOY® King Bold Electronic Nicotine Delivery System (ENDS) and its short-term potential for smoking reduction or cessation. METHODS: One week of ad libitum use was followed by measurements of plasma nicotine, heart rate, and craving and withdrawal after 12 hours of nicotine abstinence in 25 adult smokers not interested in quitting. RESULTS: After 5 minutes of use, blood nicotine levels increased by a mean of 3.5 ng/mL (p < .001), heart rate increased, and craving was reduced by 55%. Cigarettes per day were reduced by 39% during the test week, and perceptions of use for reduction or cessation were positive. CONCLUSIONS: The NJOY® King Bold ENDS delivers nicotine and led to short-term smoking reduction.

Varenicline versus bupropion SR or placebo for smoking cessation: a pooled analysis.

OBJECTIVES: To evaluate varenicline's efficacy for smoking cessation versus bupropion SR and placebo and to explore whether factors typically predictive of abstinence influence varenicline's efficacy versus placebo, as measured by the week 9-12 continuous abstinence rate (CAR9-12). METHODS: Smokers in 2 randomized, placebo-controlled trials received varenicline 1 mg BID (n=696), bupropion SR 150 mg BID (n=671), or placebo (n=685) for 12 weeks. Nontreatment followup lasted 40 weeks. RESULTS: CAR(9-12) was greater for varenicline (44.0%) versus bupropion SR (29.7%; P<0.0001) and placebo (17.7%; P<0.0001). CAR(9-12) for varenicline versus placebo was not affected by age, gender, or nicotine dependence level. CONCLUSIONS: Varenicline was more efficacious than bupropion SR or placebo. Varenicline's efficacy versus placebo was not influenced by factors predictive of abstinence.

Update on pharmacologic options for smoking cessation treatment.

Although the proportion of the adult population in the United States that smokes has decreased steadily, the rate of successful quit attempts is still low. Smokers develop nicotine dependence that resembles other addictions, and may require multiple attempts and long-term treatment to sustain abstinence. Currently available first-line agents for smoking cessation therapy include nicotine replacement therapy, which is available in several formulations, including transdermal patch, gum, nasal spray, inhaler, and lozenge; bupropion, an atypical antidepressant; and varenicline, a partial agonist of the alpha(4)beta(2) nicotinic acetylcholine receptor that was recently developed and approved specifically for smoking cessation therapy. Second-line agents are nortriptyline, a tricyclic antidepressant agent, and clonidine, an antihypertensive drug. With the exception of varenicline, which has been shown to offer significant improvement in abstinence rates over bupropion, all of the available treatments appear similarly effective. However, the adverse event profiles of nortriptyline and clonidine make them more appropriate for second-line therapy, when first-line treatments have failed or are not tolerated. Rimonabant, a cannabinoid-1 receptor antagonist that was being developed for smoking cessation, received a nonapprovable letter from the FDA in 2006 and there is no further information as to whether development for this indication is continuing for this agent. Nicotine vaccines are under investigation and offer promise, especially for relapse prevention. Ultimately, selection of pharmacologic agent should be based on the patient's comorbidities and preferences, as well as on the agent's adverse event profile.

Pharmacokinetics, safety and efficacy from randomized controlled trials of 1 and 2 mg nicotine bitartrate lozenges (Nicotinell).

BACKGROUND: The use of nicotine replacement therapy (NRT) can almost double the chances of success for smokers to quit. Nevertheless, there is still a considerable number of cessation attempts that are made without any treatment. This novel oral formulation, (lozenge containing nicotine bitartrate dihydrate) has been developed to enlarge the offer for efficient smoking cessation drug therapies, assuming that increasing treatment options will bring more smokers to find the support they personally need to stop smoking. METHODS: Three pharmacokinetic (PK), one safety and two efficacy studies were carried out with Nicotinell lozenges. PK trials were: (1) a single-dose, three-way crossover study comparing 1 and 2 mg lozenges with 2 mg nicotine gum; (2) a multiple-dose, two-way crossover study comparing 1 mg lozenge with 2 mg gum; (3) a multiple-dose, three-way crossover study comparing 1 and 2 mg lozenges with 4 mg gum. Safety trial: (4) a single dose study to assess the safety of swallowing up to 12 lozenges containing 1 mg nicotine. Efficacy trials: two efficacy studies in (5) France and (6) the USA, including more than 900 smokers followed-up for up to one year, conducted with the 1 mg lozenge. RESULTS: The results of the individual PK trials showed that the 1 mg Nicotinell lozenge is bioequivalent to 2 mg polacrilex gum, as demonstrated by similar blood PK parameters (tmax, Cmax, AUC). The 2 mg lozenge was found to deliver quantities of nicotine that were intermediate between those delivered by 2 and 4 mg polacrilex gum. The short-term efficacy of the 1 mg lozenge in comparison with placebo was also demonstrated with significantly more subjects continuously abstinent from smoking with active lozenges on week 6 in two different populations: moderate to heavy smokers (FTND between 4 and 7) OR = 1.72 [95% CI: 1.05-2.80]; heavy to very heavy smokers (FTND 6 and over) OR = 2.87 [95% CI: 1.18-6.97]. Nicotinell lozenges were found to be safe with mainly mild and reversible adverse events. The safety of the 1 mg lozenge formulation, even when misused was also demonstrated. CONCLUSION: The data presented in this review demonstrate high nicotine bioavailability, excellent safety profile and proven short-term efficacy of Nicotinell lozenges. At nominal equivalent doses 1 and 2 mg Nicotinell lozenges were shown to deliver larger amounts of bioavailable nicotine compared to the nicotine polacrilex gum. According to the data developed here, the systemic exposure to nicotine could be ranked: 4 mg polacrilex gum > 2 mg Nicotinell lozenge > 1 mg Nicotinell lozenge = 2 mg polacrilex gum.Adverse events observed during the clinical trials were mild or moderate in severity, transient and completely reversible. With respect to efficacy in smoking cessation, significantly higher continuous abstinence rates were achieved with lozenge compared to placebo. In conclusion, Nicotinell lozenges offer a valuable addition to the therapeutic armamentarium available for smoking cessation.

Hollywood quits--behind the scenes of a Hollywood-based smoking cessation program.

OBJECTIVES: To develop, implement, and assess the efficacy of a comprehensive, evidence-based smoking cessation program for entertainment industry workers and their families. METHODS: Study participants were recruited from 5 outpatient medical clinics and a worksite setting. Tobacco use data were collected during the initial counseling visit and at 6-month follow-up. Univariate and multivariate regressions were used in analysis. RESULTS: More than 50% of participants (n=470) self-reported 7-day abstinence at follow-up. The majority of participants used combination cessation medications, with more than 50% still using at least 1 medication at 6 months. CONCLUSIONS: This evidence-based smoking cessation program using behavioral counseling and combination pharmacotherapy was successful with entertainment industry workers.

Maximizing smoking cessation in clinical practice: pharmacologic and behavioral interventions.

Clinicians are in a unique position to reduce cardiovascular morbidity and mortality by helping their patients quit smoking. At each visit, clinicians should document smoking status, provide strong and clear advice to quit, and recommend and prescribe pharmacotherapy for patients who are motivated to quit, which can double the odds of success. Effective pharmacotherapies include nicotine replacement, bupropion, and varenicline, which was recently approved by the Food and Drug Administration. Behavioral counseling to develop a quit plan and extended follow-up are critical to maximize quit rates but are rarely provided by clinicians due to time constraints and lack of expertise. As an alternative, the authors recommend referral to telephone quitlines that provide no-cost behavioral counseling by specialists. Hospitals should implement systemwide procedures to ensure that smokers are identified at admission and trained staff is available to provide smoking cessation consults that include a minimum of 20 minutes of inpatient counseling with follow-up for at least 1 month.

Smoking cessation with varenicline, a selective alpha4beta2 nicotinic receptor partial agonist: results from a 7-week, randomized, placebo- and bupropion-controlled trial with 1-year follow-up.

BACKGROUND: Currently available smoking cessation therapies have limited success rates. Varenicline tartrate is a novel, selective nicotinic receptor partial agonist developed specifically for smoking cessation. This study evaluated the efficacy, tolerability, and safety of 3 varenicline doses for smoking cessation. Bupropion hydrochloride was included as an active control. METHODS: A phase 2, multicenter, randomized, double-blind, placebo-controlled study of healthy smokers (18-65 years old). Subjects were randomized to varenicline tartrate, 0.3 mg once daily (n = 128), 1.0 mg once daily (n = 128), or 1.0 mg twice daily (n = 127), for 6 weeks plus placebo for 1 week; to 150-mg sustained-release bupropion hydrochloride twice daily (n = 128) for 7 weeks; or to placebo (n = 127) for 7 weeks. RESULTS: During the treatment phase, the continuous quit rates for any 4 weeks were significantly higher for varenicline tartrate, 1.0 mg twice daily (48.0%; P<.001) and 1.0 mg once daily (37.3%; P<.001), than for placebo (17.1%). The bupropion rate was 33.3% (P = .002 vs placebo). The carbon monoxide-confirmed continuous quit rates from week 4 to week 52 were significantly higher in the varenicline tartrate, 1.0 mg twice daily, group compared with the placebo group (14.4% vs 4.9%; P = .002). The bupropion rate was 6.3% (P = .60 vs placebo). Discontinuation owing to treatment-emergent adverse events was 15.9% for bupropion, 11.2% to 14.3% for varenicline, and 9.8% for placebo. No dose-related increases occurred in adverse events for varenicline. CONCLUSIONS: Varenicline tartrate demonstrated both short-term (1 mg twice daily and 1 mg once daily) and long-term efficacy (1 mg twice daily) vs placebo. Varenicline was well tolerated and may provide a novel therapy to aid smoking cessation.

Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist, varenicline, for smoking cessation.

BACKGROUND: The selective nicotinic acetylcholine receptor partial agonist, varenicline tartrate, represents a novel type of therapy for smoking cessation. This study evaluated the efficacy, safety, and tolerability of 4 varenicline dose regimens, 2 with progressive dosing over the first week (eg, titrated) and 2 with a fixed dosing schedule (eg, non-titrated), for promoting smoking cessation. METHODS: This multicenter, double-blind, placebo-controlled study randomized healthy smokers (aged 18-65 years) to varenicline tartrate, 0.5 mg twice daily nontitrated (n = 129), 0.5 mg twice daily titrated (n = 130), 1.0 mg twice daily nontitrated (n = 129), 1.0 mg twice daily titrated (n = 130), or placebo (n = 129) for 12 weeks to aid in smoking cessation. A 40-week follow-up period assessed long-term efficacy. The primary efficacy measures were the carbon monoxide-confirmed 4-week continuous quit rates by pooled dosage group for weeks 4 through 7 and 9 through 12 and the continuous abstinence rates for weeks 9 through 52. RESULTS: Weeks 9 through 12 continuous quit rates were greater in the 1.0-mg group (49.4%) and the 0.5-mg group (44.0%) vs placebo (11.6%; P<.001 vs both doses). Weeks 9 through 52 abstinence rates were greater in the 1.0-mg group (22.4%; P<.001) and the 0.5-mg group (18.5%; P<.001) vs placebo (3.9%). Varenicline was generally well tolerated, with nausea occurring in 16% to 42% of varenicline-treated subjects. Reports of nausea were lower for the titrated vs nontitrated dosing and infrequently led to medication discontinuation. CONCLUSION: Varenicline tartrate, 0.5 mg and 1.0 mg twice daily, is efficacious for smoking cessation.

Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial.

CONTEXT: The alpha4beta2 nicotinic acetylcholine receptors (nAChRs) are linked to the reinforcing effects of nicotine and maintaining smoking behavior. Varenicline, a novel alpha4beta2 nAChR partial agonist, may be beneficial for smoking cessation. OBJECTIVE: To assess efficacy and safety of varenicline for smoking cessation compared with sustained-release bupropion (bupropion SR) and placebo. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, parallel-group, placebo- and active-treatment-controlled, phase 3 clinical trial conducted at 19 US centers from June 19, 2003, to April 22, 2005. Participants were 1025 generally healthy smokers (> or =10 cigarettes/d) with fewer than 3 months of smoking abstinence in the past year, 18 to 75 years old, recruited via advertising. INTERVENTION: Participants were randomly assigned in a 1:1:1 ratio to receive brief counseling and varenicline titrated to 1 mg twice per day (n = 352), bupropion SR titrated to 150 mg twice per day (n = 329), or placebo (n = 344) orally for 12 weeks, with 40 weeks of nondrug follow-up. MAIN OUTCOME MEASURES: Primary outcome was the exhaled carbon monoxide-confirmed 4-week rate of continuous abstinence from smoking for weeks 9 through 12. A secondary outcome was the continuous abstinence rate for weeks 9 through 24 and weeks 9 through 52. RESULTS: For weeks 9 through 12, the 4-week continuous abstinence rates were 44.0% for varenicline vs 17.7% for placebo (odds ratio [OR], 3.85; 95% confidence interval [CI], 2.70-5.50; P<.001) and vs 29.5% for bupropion SR (OR, 1.93; 95% CI, 1.40-2.68; P<.001). Bupropion SR was also significantly more efficacious than placebo (OR, 2.00; 95% CI, 1.38-2.89; P<.001). For weeks 9 through 52, the continuous abstinence rates were 21.9% for varenicline vs 8.4% for placebo (OR, 3.09; 95% CI, 1.95-4.91; P<.001) and vs 16.1% for bupropion SR (OR, 1.46; 95% CI, 0.99-2.17; P = .057). Varenicline reduced craving and withdrawal and, for those who smoked while receiving study drug, smoking satisfaction. No sex differences in efficacy for varenicline were observed. Varenicline was safe and generally well tolerated, with study drug discontinuation rates similar to those for placebo. The most common adverse events for participants receiving active-drug treatment were nausea (98 participants receiving varenicline [28.1%]) and insomnia (72 receiving bupropion SR [21.9%]). CONCLUSION: Varenicline was significantly more efficacious than placebo for smoking cessation at all time points and significantly more efficacious than bupropion SR at the end of 12 weeks of drug treatment and at 24 weeks. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00141206.

Smoking reduction in the Lung Health Study.

We examined the ability of smokers who failed to quit smoking in the Lung Health Study to reduce the number of cigarettes per day and maintain this reduction and whether reduction predicted increased or decreased future cessation. In the Lung Health Study, among smokers with early lung disease who wished to stop smoking, 3923 were randomized to a special intervention of counseling and nicotine gum for smoking cessation and to bronchodilator therapy or placebo. Among the 1722 who were still smoking at the first year follow-up, 27% smoked the same, 43% smoked 1%-49% fewer, and 30% smoked at least 50% fewer cigarettes per day. Reduction in cigarettes per day was accompanied by reduction in expired-air carbon monoxide. About half of the less-than-50% reducers and one-fifth of the at-least-50% reducers maintained or exceeded this reduction over the next 4 years. Reduction was associated with nicotine gum use. Greater reduction at year 1 predicted more quit attempts in year 2 but not more point prevalence abstinence at year 2 nor more quits or abstinence between years 2 and 5. We conclude that reduction can be maintained but such reduction neither predicts an increased nor decreased probability of future cessation.

Comparative testing of 5 nicotine systems: initial use and preferences.

OBJECTIVE: To test initial reactions to 5 nicotine treatments (NRTs: 2 and 4 mg gum, inhaler, nasal spray, tablet) in a crossover study (n=41). METHODS: Subjects used each medication on arising (1/2 day) and resumed smoking each afternoon. Subjects rated (individually) and ranked (comparatively) treatments on use, reinforcement, withdrawal, craving, and preferences. RESULTS: Overall preferences: inhaler (49%), 4 mg gum (24%), 2 mg gum (10%), 2 mg tablet (10%), nasal spray (7%). Overall results were consistent with ratings and rankings of individual characteristics of drugs. CONCLUSION: Subjects had varied reactions to NRTs that may affect initiation of cessation.