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.

Insurance coverage and utilization of nicotine patches after receipt of a prescription.

Introduction: Changes in reimbursement policy have made nicotine replacement therapy (NRT) much more available, but little is known about what happens to patients after they receive their prescription. This study describes rates of successfully filling prescriptions for NRT and its association with type of insurance. Methods: We identified 224 patients who received a prescription for NRT during an outpatient visit to an academic medical center between January 1st 2016 and February 10th 2017. We conducted telephone surveys to assess whether they tried to fill their prescriptions and if so, determine the effects of insurance type on the ability to successfully fill the prescription. Results: Of 117 patients completing the survey, 23 (19.6%) did not attempt to fill and 6 (5.1%) had no insurance. Of the 90 patients with insurance who attempted to fill their prescription, 67 (74.4%) were successful and 23 (25.6%) were unsuccessful in obtaining medications. Success varied by insurance with successful fills ranging from 34 (87.2%) of those with commercial insurance, 24 (70.6%) with Medicaid, to 9 (52.9%) with Medicare. Of 37 participants living with another smoker, 31 (83.7%) wanted an NRT prescription specifically for their partner; several volunteered that they had shared patches with their partner. Conclusions: Despite widespread coverage for NRT, many patients may still encounter difficulties in getting their prescriptions filled. Some tobacco users might also benefit from getting NRT prescriptions for their partners that smoke.

Using REDCap for ambulatory assessment: Implementation in a clinical trial for smoking cessation to augment in-person data collection.

BACKGROUND: The use of ambulatory assessment to study behavior and physiology in daily life is becoming more common, yet barriers to implementation remain. Limitations in budget, time, and expertise may inhibit development or purchase of dedicated ambulatory assessment software. Research Electronic Data Capture (REDCap) is widely used worldwide, offering a cost-effective and accessible option for implementing research studies. OBJECTIVES: To present a step-by-step guideline on how to implement ambulatory assessment using REDCap and provide preliminary evidence of feasibility. METHODS: Feasibility and acceptability data are presented for randomized participants (N ranged from 19 to 36, depending on analysis) from an ongoing 8-week smoking cessation pharmacological clinical trial (ClinicalTrials.gov Identifier: NCT02737358). Participants (N = 36; 50% female) completed up to three ambulatory assessment surveys per day, depending on the phase of the study. These included self-report and video confirmation of smoking biomarkers and medication adherence. RESULTS: Participants completed 74.8% of morning reports (86.6% for study completers), 73.8% of videos confirming smoking biomarkers, and 70.4% of videos confirming medication adherence. Study completers reported that the REDCap assessments were easy to use, and 78.9% of participants preferred the REDCap assessments to traditional, paper measures. CONCLUSIONS: These data from a pharmacological trial suggest feasibility of remote data collection using REDCap. As REDCap functionality is continually evolving, it is likely that options for collecting ambulatory assessment data via this platform will progressively improve allowing for greater individualization of assessment scheduling for enhancing data collection in clinical trials.

Cost-effectiveness analysis of smoking cessation interventions using cell phones in a low-income population.

BACKGROUND: The prevalence of cigarette smoking is significantly higher among those living at or below the federal poverty level. Cell phone-based interventions among such populations have the potential to reduce smoking rates and be cost-effective. METHODS: We performed a cost-effectiveness analysis of three smoking cessation interventions: Standard Care (SC) (brief advice to quit, nicotine replacement therapy and self-help written materials), Enhanced Care (EC) (SC plus cell phone-delivered messaging) and Intensive Care (IC) (EC plus cell phone-delivered counselling). Quit rates were obtained from Project ACTION (Adult smoking Cessation Treatment through Innovative Outreach to Neighborhoods). We evaluated shorter-term outcomes of cost per quit and long-term outcomes using cost per quality-adjusted life year (QALY). RESULTS: For men, EC cost an additional $541 per quit vs SC; however, IC cost an additional $5232 per quit vs EC. For women, EC was weakly dominated by IC-IC cost an additional $1092 per quit vs SC. Similarly, for men, EC had incremental cost-effectiveness ratio (ICER) of $426 per QALY gained vs SC; however, IC resulted in ICER of $4127 per QALY gained vs EC. For women, EC was weakly dominated; the ICER of IC vs SC was $1251 per QALY gained. The ICER was below maximum acceptable willingness-to-pay threshold of $50 000 per QALY under all alternative modelling assumptions. DISCUSSION: Cell phone interventions for low socioeconomic groups are a cost-effective use of healthcare resources. Intensive Care was the most cost-effective strategy both for men and women. TRIAL REGISTRATION NUMBER: NCT00948129; Results.

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.

Using Bioinformatics to Treat Hospitalized Smokers: Successes and Challenges of a Tobacco Treatment Service.

BACKGROUND: Hospitals face increasing regulations to provide and document inpatient tobacco treatment, yet few blueprint data exist to implement a tobacco treatment service (TTS). METHODS: A hospitalwide, opt-out TTS with three full-time certified counselors was developed in a large tertiary care hospital to proactively treat smokers according to Chronic Care Model principles and national treatment guidelines. A bioinformatics platform facilitated integration into the electronic health record to meet evolving Centers for Medicare & Medicaid Services meaningful use and Joint Commission standards. TTS counselors visited smokers at the bedside and offered counseling, recommended smoking cessation medication to be ordered by the primary clinical service, and arranged for postdischarge resources. RESULTS: During a 3.5-year span, 21,229 smokers (31,778 admissions) were identified; TTS specialists reached 37.4% (7,943), and 33.3% (5,888) of daily smokers received a smoking cessation medication order. Adjusted odds ratios (AORs) of receiving a chart order for smoking cessation medication during the hospital stay and at discharge were higher among patients the TTS counseled > 3 minutes and recommended medication: inpatient AOR = 7.15 (95% confidence interval [CI] = 6.59-7.75); discharge AOR = 5.3 (95% CI = 4.71-5.97). As implementation progressed, TTS counseling reach and medication orders increased. To assess smoking status ≤ 1 month postdischarge, three methods were piloted, all of which were limited by low follow-up rates (4.5%-28.6%). CONCLUSION: The TTS counseled approximately 3,000 patients annually, with increases over time for reach and implementation. Remaining challenges include the development of strategies to engage inpatient care teams to follow TTS recommendations, and patients postdischarge in order to optimize postdischarge smoking cessation.