Varenicline rescues nicotine-induced decrease in motivation for sucrose reinforcement.

Varenicline is one of the top medications used for smoking cessation and is often prescribed before termination of nicotine use. The effect of this combined nicotine and varenicline use on the reward system and motivation for primary reinforcement is underexplored. The goal of this study was to assess the effects of nicotine and varenicline on motivation for a food reinforcer. In Experiment 1, we first assessed the responding for sucrose after pretreatment with nicotine (0, 0.1, or 0.4 mg/kg) and varenicline (0.0, 0.1, 1.0 mg/kg) using a behavioral economics approach. The responding for sucrose was then assessed using a progressive ratio schedule of reinforcement after pretreatment with all possible combinations of nicotine and varenicline doses. In Experiment 2, rats were assessed for the consumption of sucrose in home cages after pretreatment with nicotine and varenicline. We found that (a) nicotine decreased economic demand for sucrose, (b) varenicline rescued nicotine-induced reduction in economic demand for sucrose, and (c) history of varenicline treatment predicted responding for sucrose on a progressive ratio schedule of reinforcement where rats with a history of varenicline treatment responded significantly lower for sucrose across nicotine doses than rats that had not been exposed to varenicline. The results of Experiment 2 largely confirmed that nicotine decreases motivation for sucrose using a passive consumption protocol and that varenicline rescues this effect. Overall, these findings suggest that varenicline interacts with the effects of nicotine by restoring nicotine-induced reduction in motivation for appetitive rewards.

Pharmacovigilance Assessment of Cardiac Implications of Nicotine Replacement Therapy Among Smokers.

PURPOSE: The purpose of this quantitative comparative study was to examine the possible relationship between nicotine replacement therapy (NRT) and cardiac disorder risk by comparing the rates of cardiac disorder risk of NRT with cardiac disorder risk of non-replacement drugs among smokers seeking smoking cessation. METHODS: The study used retrospective quantitative design, which involved the collection of secondary data from the adverse event reporting system (FAERS) database of the U.S Food and Drug Administration (FDA). Rates of cardiac disorder were compared between the NRT group and non- NRT (varenicline and bupropion) group. Statistical analyses involved using a 2x2 contingency table and logistic regression to calculate odds ratio (reporting odds ratio (ROR)). RESULTS AND DISCUSSION: Unadjusted ROR was 0.45 (95% confidence interval [CI] 0.28, 0.70). With age and sex as confounding factors, the smokers in the NRT group still had lower odds of having cardiac disorder risk than the non-NRT group (adjusted ROR=0.44, 95% CI 0.28, 0.70). CONCLUSION: Our study findings showed lower cardiac disorder risk with the NRT group compared to the non-NRT (varenicline and bupropion) group. While the study did not aim to undermine either using NRT or non-NRT for smoking cessation therapy to prevent smoking illness, the study results offer informed findings that could potentially improve current smoking cessation management using NRT intervention among smokers and enhance smokers' health outcome. Despite the negative signal detection of cardiac disorder risk with NRT as compared to non-NRT in final findings, we still recommend further research on the causal relationship between NRT and non-NRT and cardiac disorder risk.

Varenicline versus nicotine replacement therapy for long-term smoking cessation: an observational study using the Clinical Practice Research Datalink.

BACKGROUND: Smoking is the leading avoidable cause of illness and premature mortality. The first-line treatments for smoking cessation are nicotine replacement therapy and varenicline. Meta-analyses of experimental studies have shown that participants allocated to the varenicline group were 1.57 times (95% confidence interval 1.29 to 1.91 times) as likely to be abstinent 6 months after treatment as those allocated to the nicotine replacement therapy group. However, there is limited evidence about the effectiveness of varenicline when prescribed in primary care. We investigated the effectiveness and rate of adverse events of these medicines in the general population. OBJECTIVE: To estimate the effect of prescribing varenicline on smoking cessation rates and health outcomes. DATA SOURCES: Clinical Practice Research Datalink. METHODS: We conducted an observational cohort study using electronic medical records from the Clinical Practice Research Datalink. We extracted data on all patients who were prescribed varenicline or nicotine replacement therapy after 1 September 2006 who were aged ≥ 18 years. We investigated the effects of varenicline on smoking cessation, all-cause mortality and cause-specific mortality and hospitalisation for: (1) chronic lung disease, (2) lung cancer, (3) coronary heart disease, (4) pneumonia, (5) cerebrovascular disease, (6) diabetes, and (7) external causes; primary care diagnosis of myocardial infarction, chronic obstructive pulmonary disease, depression, or prescription for anxiety; weight in kg; general practitioner and hospital attendance. Our primary outcome was smoking cessation 2 years after the first prescription. We investigated the baseline differences between patients prescribed varenicline and patients prescribed nicotine replacement therapy. We report results using multivariable-adjusted, propensity score and instrumental variable regression. Finally, we developed methods to assess the relative bias of the different statistical methods we used. RESULTS: People prescribed varenicline were healthier at baseline than those prescribed nicotine replacement therapy in almost all characteristics, which highlighted the potential for residual confounding. Our instrumental variable analysis results found little evidence that patients prescribed varenicline had lower mortality 2 years after their first prescription (risk difference 0.67, 95% confidence interval -0.11 to 1.46) than those prescribed nicotine replacement therapy. They had similar rates of all-cause hospitalisation, incident primary care diagnoses of myocardial infarction and chronic obstructive pulmonary disease. People prescribed varenicline subsequently attended primary care less frequently. Patients prescribed varenicline were more likely (odds ratio 1.46, 95% confidence interval 1.42 to 1.50) to be abstinent 6 months after treatment than those prescribed nicotine replacement therapy when estimated using multivariable-adjusted for baseline covariates. Patients from more deprived areas were less likely to be prescribed varenicline. However, varenicline had similar effectiveness for these groups. CONCLUSION: Patients prescribed varenicline in primary care were more likely to quit smoking than those prescribed nicotine replacement therapy, but there was little evidence that they had lower rates of mortality or morbidity in the 4 years following the first prescription. There was little evidence of heterogeneity in effectiveness across the population. FUTURE WORK: Future research should investigate the decline in prescribing of smoking cessation products; develop an optimal treatment algorithm for smoking cessation; use methods for using instruments with survival outcomes; and develop methods for comparing multivariable-adjusted and instrumental variable estimates. LIMITATIONS: Not all of our code lists were validated, body mass index and Index of Multiple Deprivation had missing values, our results may suffer from residual confounding, and we had no information on treatment adherence. TRIAL REGISTRATION: This trial is registered as NCT02681848. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 9. See the NIHR Journals Library website for further project information.

Smoking is the number one avoidable cause of ill health and death. Experiments suggest that more smokers will quit after being given the drug varenicline than with any other smoking cessation treatment. However, most of the experiments used to license varenicline had a relatively short follow-up (< 1 year) and did not necessarily recruit participants who were representative of smokers seen in a general practice in the UK, who tend to be older, are sicker and more likely to have neuropsychiatric illnesses. In this study, we investigated the outcomes of 287,079 patients prescribed varenicline or nicotine replacement therapy (e.g. nicotine patches and gum). We followed each patient for up to 4 years after they received their prescriptions and matched their data to information on deaths from the Office for National Statistics and hospital admissions. We investigated how often these patients subsequently attended their general practitioner, and how often they received a diagnosis of myocardial infarction, chronic obstructive pulmonary disease, depression or anxiety in primary care. We found that patients who were prescribed varenicline were much more likely to quit smoking up to 4 years after they received treatment and subsequently attended their general practitioner less frequently. These findings were robust across the three different analysis methods we used. We also found that patients prescribed varenicline were much less likely to be ill or to die than those prescribed nicotine replacement therapy. However, these results may be because the patients who were prescribed varenicline were much healthier before they received the prescription. Therefore, these differences in health are unlikely to be caused by taking varenicline or quitting smoking. In conclusion, varenicline helped patients quit smoking, but there was little causal evidence that prescribing patients varenicline causally reduced rates of mortality or morbidity compared with prescribing nicotine replacement therapy.

Nicotine preloading for smoking cessation: the Preloading RCT.

BACKGROUND: Nicotine preloading means using nicotine replacement therapy prior to a quit date while smoking normally. The aim is to reduce the drive to smoke, thereby reducing cravings for smoking after quit day, which are the main cause of early relapse. A prior systematic review showed inconclusive and heterogeneous evidence that preloading was effective and little evidence of the mechanism of action, with no cost-effectiveness data. OBJECTIVES: To assess (1) the effectiveness, safety and tolerability of nicotine preloading in a routine NHS setting relative to usual care, (2) the mechanisms of the action of preloading and (3) the cost-effectiveness of preloading. DESIGN: Open-label randomised controlled trial with examination of mediation and a cost-effectiveness analysis. SETTING: NHS smoking cessation clinics. PARTICIPANTS: People seeking help to stop smoking. INTERVENTIONS: Nicotine preloading comprised wearing a 21 mg/24 hour nicotine patch for 4 weeks prior to quit date. In addition, minimal behavioural support was provided to explain the intervention rationale and to support adherence. In the comparator group, participants received equivalent behavioural support. Randomisation was stratified by centre and concealed from investigators. MAIN OUTCOME MEASURES: The primary outcome was 6-month prolonged abstinence assessed using the Russell Standard. The secondary outcomes were 4-week and 12-month abstinence. Adverse events (AEs) were assessed from baseline to 1 week after quit day. In a planned analysis, we adjusted for the use of varenicline (Champix®; Pfizer Inc., New York, NY, USA) as post-cessation medication. Cost-effectiveness analysis took a health-service perspective. The within-trial analysis assessed health-service costs during the 13 months of trial enrolment relative to the previous 6 months comparing trial arms. The base case was based on multiple imputation for missing cost data. We modelled long-term health outcomes of smoking-related diseases using the European-study on Quantifying Utility of Investment in Protection from Tobacco (EQUIPT) model. RESULTS: In total, 1792 people were eligible and were enrolled in the study, with 893 randomised to the control group and 899 randomised to the intervention group. In the intervention group, 49 (5.5%) people discontinued preloading prematurely and most others used it daily. The primary outcome, biochemically validated 6-month abstinence, was achieved by 157 (17.5%) people in the intervention group and 129 (14.4%) people in the control group, a difference of 3.02 percentage points [95% confidence interval (CI) -0.37 to 6.41 percentage points; odds ratio (OR) 1.25, 95% CI 0.97 to 1.62; p = 0.081]. Adjusted for use of post-quit day varenicline, the OR was 1.34 (95% CI 1.03 to 1.73; p = 0.028). Secondary abstinence outcomes were similar. The OR for the occurrence of serious AEs was 1.12 (95% CI 0.42 to 3.03). Moderate-severity nausea occurred in an additional 4% of the preloading group compared with the control group. There was evidence that reduced urges to smoke and reduced smoke inhalation mediated the effect of preloading on abstinence. The incremental cost-effectiveness ratio at the 6-month follow-up for preloading relative to control was £710 (95% CI -£13,674 to £23,205), but preloading was dominant at 12 months and in the long term, with an 80% probability that it is cost saving. LIMITATIONS: The open-label design could partially account for the mediation results. Outcome assessment could not be blinded but was biochemically verified. CONCLUSIONS: Use of nicotine-patch preloading for 4 weeks prior to attempting to stop smoking can increase the proportion of people who stop successfully, but its benefit is undermined because it reduces the use of varenicline after preloading. If this latter effect could be overcome, then nicotine preloading appears to improve health and reduce health-service costs in the long term. Future work should determine how to ensure that people using nicotine preloading opt to use varenicline as cessation medication. TRIAL REGISTRATION: Current Controlled Trials ISRCTN33031001. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 41. See the NIHR Journals Library website for further project information.

Smoking Cessation for Smokers Not Ready to Quit: Meta-analysis and Cost-effectiveness Analysis.

CONTEXT: To provide a systematic review and cost-effectiveness analysis on smoking interventions targeting smokers not ready to quit, a population that makes up approximately 32% of current smokers. EVIDENCE ACQUISITION: Twenty-two studies on pharmacological, behavioral, and combination smoking-cessation interventions targeting smokers not ready to quit (defined as those who reported they were not ready to quit at the time of the study) published between 2000 and 2017 were analyzed. The effectiveness (measured by the number needed to treat) and cost effectiveness (measured by costs per quit) of interventions were calculated. All data collection and analyses were performed in 2017. EVIDENCE SYNTHESIS: Smoking interventions targeting smokers not ready to quit can be as effective as similar interventions for smokers ready to quit; however, costs of intervening on this group may be higher for some intervention types. The most cost-effective interventions identified for this group were those using varenicline and those using behavioral interventions. CONCLUSIONS: Updating clinical recommendations to provide cessation interventions for this group is recommended. Further research on development of cost-effective treatments and effective strategies for recruitment and outreach for this group are needed. Additional studies may allow for more nuanced comparisons of treatment types among this group.

Assessment of Risk Evaluation and Mitigation Strategies (REMS) for varenicline (Chantix): A multistage patient survey.

PURPOSE: To evaluate the Risk Evaluation and Mitigation Strategies (REMS) for varenicline by assessing patients' understanding of the varenicline medication guide (MG) at pre-specified time points: 18 months, 3 years, and 7 years after the REMS approval. METHODS: Self-administered surveys were mailed to people who received varenicline based on a pharmacy dispensing. Survey questions assessed understanding of potential risks outlined in the MG: neuropsychiatric symptoms, skin reactions, allergic reactions, and cardiovascular risks. Crude and weighted analyses were conducted. RESULTS: The response to the survey overall was between 18% and 19%. Among responders, approximately 90% recalled receiving the MG, and at least 80% read all or part of it. At least 88% correctly identified neuropsychiatric symptoms as potential medication effects, while 41% did so for skin reactions, 53% for allergic reactions, and 82% for cardiovascular risks. Patients who read the MG had a high proportion of correct responses to the risk comprehension questions. CONCLUSIONS: A large majority of patients who were dispensed varenicline recalled receiving the MG and were able to correctly recall neuropsychiatric and cardiovascular risks in all 3 surveys. The varenicline MG may be an effective tool for patient education.

Modelling a budgetary impact analysis for funding drug-based smoking cessation therapies for patients with major depressive disorder in Spain.

BACKGROUND: Smoking is associated with high healthcare resource utilisation and cost to society. Patients with major depressive disorder (MDD) exhibit high susceptibility to nicotine dependence. Varenicline, bupropion and nicotine replacement therapy are all indicated for smoking cessation; however funding by the Spanish national health system (SNHS) is limited. We modelled a budgetary impact analysis (BIA) to estimate the impact of the SNHS funding drug-based therapies for smoking cessation in smokers with MDD. METHODS: The BIA compared the current unfunded scenario versus a funded scenario (varenicline, bupropion, nicotine replacement therapy combined with medical follow-up and counselling) using the Spanish SNHS and societal perspectives. The BIA design was a hybrid model using a decision tree algorithm (population size: smokers with MDD) and Markov chains (smoking cessation attempts) over a 5-year horizon. Smoking cessation drug efficacy was derived from clinical trials, and smoking cessation costs avoided were taken from an analysis of the Spanish National Health Survey. Results were shown as incremental cost savings. Scenarios and threshold univariate sensitivity analyses tested model robustness. RESULTS: The funded scenario resulted in an increase of 43,478 cessation attempts and 8930 fewer smokers after 5 years compared to the unfunded scenario. The cost of funding was €25.3 million and costs avoided were €26.5 million. There was a cumulative 5-year incremental cost saving of €1.2 million to Spanish society. Results were robust using alternative scenarios. CONCLUSIONS: Funding smoking cessation drugs in patients with MDD is of economic benefit to Spain and could produce net savings from the third year of implementation.

Re-treatment with varenicline is a cost-effective aid for smoking cessation.

OBJECTIVE: One quit attempt with varenicline has been found to be a cost-effective smoking cessation intervention. The purpose of this study was to analyze varenicline's cost-effectiveness in patients who relapse during or after the first treatment. A comparison was made between re-treatment schema with varenicline and re-treatment schema with bupropion, NRT and unaided cessation, and treatment once with varenicline in a Finnish context. METHODS: The two-quit version of BENESCO Markov model was used to follow a cohort of smokers making up to two quit attempts over a lifetime. The abstinence rates of the interventions were derived from a Cochrane review. Gender- and age-specific data on the incidence and prevalence of five smoking-related diseases were included in the model. Quality-adjusted life-years, total expected costs, and the lifetime cumulative incidence of smoking-related morbidities and mortality were the primary outcomes evaluated. RESULTS: The study cohort comprised 116,533 smokers who were willing to make a quit attempt. In the lifetime simulation, re-treatment with varenicline yielded 6,150-20,250 extra quitters, depending on the comparator. Among these quitters it was possible to prevent 899-2,972 additional cases of smoking-related diseases, and 395-1,307 deaths attributable to smoking. Re-treatment with varenicline resulted in cost savings of up to 54.9 million Euros. Re-treatment with varenicline dominated all the other smoking cessation interventions used in the analysis. Sensitivity analysis supported the robustness of the base case results. LIMITATIONS: The analysis did not consider adverse events, and included only five major smoking-related diseases, which is a conservative approach, and probably leads to under-estimation of cost-effectiveness of cessation interventions. Furthermore, assumptions of constant relative risks for smoking-related diseases for each smoking status and the proxy values used as efficacy estimates of second quit attempts for other interventions than varenicline are limitations. CONCLUSIONS: A second quitting effort with varenicline is economically justifiable.

Ethical and Practical Considerations in Removing Black Box Warnings from Drug Labels.

Boxed warnings-also known as "black box" warnings-can be a powerful tool in communicating drug risks to physicians and patients. The overall number of boxed warnings has grown in recent years as the US Food and Drug Administration (FDA) has approved more drugs on the basis of limited pre-marketing information and as new safety issues for marketed drugs have been identified. Two recent manufacturers' petitions to remove boxed warnings on the drugs rosiglitazone (Avandia) and varenicline (Chantix) have led to divergent FDA decisions and revealed different considerations involved in boxed warning imposition and removal. For ethical and practical reasons, the FDA is justified in applying a higher standard for boxed warning removal than for imposition, as removal of a boxed warning may have unintended effects on physician and patient behavior. However, no guidelines on boxed warning removal currently exist. To promote safe use of approved prescription drugs, the FDA should adopt a uniform and transparent process governing decisions to impose or remove boxed warnings.

What are the effects of varenicline compared with nicotine replacement therapy on long-term smoking cessation and clinically important outcomes? Protocol for a prospective cohort study.

INTRODUCTION: Smoking is a major avoidable cause of ill-health and premature death. Treatments that help patients successfully quit smoking have an important effect on health and life expectancy. Varenicline is a medication that can help smokers successfully quit smoking. However, there are concerns that it may cause adverse effects, such as increase in the occurrence of depression, self-harm and suicide and cardiovascular disease. In this study we aim to examine the effects of varenicline versus other smoking cessation pharmacotherapies on smoking cessation, health service use, all-cause and cause-specific mortality and physical and mental health conditions. METHODS: In this project we will investigate the effects of varenicline compared to nicotine replacement therapies on: (1) long-term smoking cessation and whether these effects differ by area level deprivation; and (2) the following clinically-important outcomes: rate of general practice and hospital attendance; all-cause mortality and death due to diseases of the respiratory system and cardiovascular disease; and a primary care diagnosis of respiratory illness, myocardial infarction or depression and anxiety. The study is based on a cohort of patients prescribed these smoking cessation medications from the Clinical Practice Research Datalink (CPRD). We will use three methods to overcome confounding: multivariable adjusted Cox regression, propensity score matched Cox regression, and instrumental variable regression. The total expected sample size for analysis will be at least 180,000. Follow-up will end with the earliest of either an 'event' or censoring due to the end of registration or death. ETHICS AND DISSEMINATION: Ethics approval was not required for this study. This project has been approved by the CPRD's Independent Scientific Advisory Committee (ISAC). We will disseminate our findings via publications in international peer-reviewed journals and presentations at international conferences.

Homeless Clients Benefit From Smoking Cessation Treatment Delivered by a Homeless Persons' Program.

INTRODUCTION: Few homeless programs offer smoking cessation treatment. This study examined the feasibility, acceptability, and effectiveness of a smoking cessation treatment model delivered by staff of a homeless persons' program. METHODS: Fourteen nurses from Melbourne's Royal District Nursing Service Homeless Persons' Program recruited 49 clients into a 12-week program offering weekly nurse-delivered smoking cessation appointments with intermittent carbon monoxide measurements, doctor-prescribed free nicotine patch, bupropion or varenicline, and Quitline phone support. Surveys were completed at program enrolment, end of program (EoP, 3 months) and 6 months post-enrolment. RESULTS: Clients attended on average 6.7 nurse-delivered appointments. Most used pharmacotherapy (69%, n = 34) and Quitline (61%, n = 30, average 8.4 calls among users). Using all-cases analyses 29% had made a quit attempt by EoP; 24-hour point prevalence abstinence rates were 6% at EoP and 4% at 6 months (no participants achieved sustained cessation), and 29% reported 50% consumption reduction at 6 months, the latter positively associated with increased Quitline use. Tobacco consumption and money spent on tobacco halved by EoP with similar levels maintained at 6 months. Discarded butt smoking reduced. Using within-subjects analyses, all participants reported either the same or less symptoms of anxiety at EoP compared to baseline and 92% reported the same or less depressive symptoms. CONCLUSIONS: Integrating nurse support with readily accessible cessation interventions (government subsidized pharmacotherapy plus Quitline) was feasible and acceptable. While quit rates were low, treatment benefits included harm-reduction (reduced consumption and butt smoking), significant financial savings, and psychological benefits (improved or stable mood).