The New Nicotine Pouch Category: A Tobacco Harm Reduction Tool?

Nicotine pouches to be put under the upper lip are a new category of products that are being rapidly developed and marketed as consumer goods with little research or regulatory oversight. We have identified research gaps in assessing their harm and benefit potential, and possible regulatory science approaches to inform the policies that can allow a maximization of the category's public health potential while minimizing unintended consequences. Implications: This commentary presents a potential blueprint for a comprehensive assessment of the nicotine pouches category. Data from the proposed research areas can better inform the regulatory policy decisions around the category, with the aim to maximize the category's tobacco harm reduction potential while minimizing unintended harms.

Can alternative nicotine products put the final nail in the smoking coffin?

This review describes the evolution of smoking prevalence in countries with relatively high adoption of alternative nicotine products such as e-cigarettes, heated tobacco, and snus compared to neighboring countries where these products are less prevalent. The data indicate that countries with high adoption of alternative nicotine products have been able to achieve lower smoking rates. The findings suggest that adoption of alternative nicotine products may help in reduce smoking prevalence faster than traditional tobacco control measures solely focused on prevention and cessation.

Pharmacokinetic Comparison of a Novel Non-tobacco-Based Nicotine Pouch (ZYN) With Conventional, Tobacco-Based Swedish Snus and American Moist Snuff.

INTRODUCTION: The single-dose pharmacokinetics (PK) of a novel, non-tobacco-based nicotine pouch, ZYN, 3 and 6 mg, were compared with 8 mg General snus (part 1) and ZYN 8 mg was compared with 18 mg Longhorn moist snuff (part 2). The present study demonstrates the characteristics of three strengths of a novel tobacco-free oral snus, ZYN, viz. the extraction of nicotine from the oral cavity and its uptake into the systemic blood circulation. Comparison is made to Swedish General snus and American Longhorn moist snuff and from literature 4 mg Nicorette gum and mean of 13 brands of e-cigarettes. AIMS AND METHODS: A single-dose randomized crossover design was used. In vivo extraction and PK parameters were determined. RESULTS: Part 1. The AUCinf of ZYN 3 mg was 27% smaller than that of 8 mg General and the AUCinf of ZYN 6 mg was 34% larger than that of 8 mg General. Less nicotine was extracted from ZYN 3 mg (1.5 mg) and more from ZYN 6 mg (3.5 mg) than from 8 mg General (2.4 mg). The extracted fractions of nicotine for both ZYN products (56% and 59%) were significantly larger than for 8 mg General (32%). RESULTS: Part 2. Close to identical plasma nicotine curves, AUCinf and Cmax were found for ZYN 8 mg and Longhorn Natural 18 mg moist snuff. The extracted amount of nicotine from ZYN 8 mg (3.8 mg) was larger than the amount extracted from Longhorn Natural 18 mg (3.0 mg), but smaller than the extracted amount of nicotine from General 2 × 8 mg snus pouches (5.0 mg). The extracted fraction of nicotine for ZYN 8 mg (50%) was larger than for Longhorn Natural (19%) and General 2 × 8 mg snus pouches (33%). CONCLUSIONS: The two higher doses of ZYN (6 and 8 mg) deliver nicotine as quickly and to a similar extent as existing smokeless products, with no significant adverse effects.

Initial Information on a Novel Nicotine Product.

BACKGROUND AND OBJECTIVES: This is the first study to assess the appeal and interest among adults in a new consumer tobacco product, ZYN. We also describe ZYN users, patterns of use, and reasons for use. METHODS: Two data sets, consisting of a ZYN-naive consumer panel (n = 5179) and ZYN users (n = 1266), were provided by Swedish Match North America. Descriptive, cross-sectional analyses and logistic regression assessed the perceptions of and likelihood of buying ZYN in the consumer panel and the characteristics of ZYN users. RESULTS: The majority of current smokeless tobacco (ST) users in the consumer panel found that ZYN was moderately-extremely appealing, while never and former tobacco users indicated much less interest; the former were more likely to buy ZYN than other groups. The highest percentage of ZYN users were former tobacco users (43%); very few were never users (4%). The most popular reason for using ZYN was "Less harmful to my health than other tobacco products," followed by "ease of use." DISCUSSION AND CONCLUSIONS: Nonusers of tobacco had very little interest in ZYN. ST users are not only more interested and likely to buy ZYN than other tobacco users, they were the largest group of regular users. SCIENTIFIC SIGNIFICANCE: The first assessment of a new nicotine product, ZYN, suggests that current and former tobacco users may perceive ZYN as a reduced-risk product. ZYN potentially could be used as a smoking/tobacco-cessation aid based on reasons of current users. (Am J Addict 2020;00:00-00).

Associations of Proposed Relative-Risk Warning Labels for Snus With Perceptions and Behavioral Intentions Among Tobacco Users and Nonusers.

INTRODUCTION: The US Food and Drug Administration can require changes in warning statements for modified risk tobacco products. We report an independent analysis of a consumer perception survey sponsored by Swedish Match as part of a Modified Risk Tobacco Product application to change warning labels for Swedish snus products. METHODS: The survey exposed each of 4324 daily exclusive cigarette smokers, 1033 daily smokeless tobacco users, 1205 daily other tobacco users, 726 former users, and 5915 triers/never users to one of four current warnings and two proposed relative-risk labels (No tobacco product is safe, but this product presents lower risks to health than cigarettes, or No tobacco product is safe, but this product presents substantially lower risks to health than cigarettes) for snus. Descriptive and logistic regression analyses examined four outcomes: believability, harmfulness, motivation to use, and intention to buy snus. RESULTS: Compared with the current not-safe-alternative warning, adult tobacco users who viewed the proposed labels perceived them as less believable, perceived snus as less harmful and were more likely to use and buy snus. The proposed labels had no impact on former smokers' likelihood to use and buy snus; triers/never users viewing the substantially lower risk label were more likely to buy snus. CONCLUSIONS: Tobacco users viewing the proposed labels perceived snus as less harmful than cigarettes and may be more likely to use and buy snus. If labeling changes lead to increased snus use and cigarette reduction or abstinence, public health may benefit. If the opposite occurs, public health could suffer.

Time to First Use Among Daily Smokers and Smokeless Tobacco Users.

INTRODUCTION: Time to the first cigarette after waking up in the morning is the most validated measure of dependence among smokers, and its complement is also a good indicator of dependence for smokeless tobacco (ST) users. However, no studies have directly compared these measures. METHODS: We used a multivariate logistic regression model to compare the time to first use (TTFU) of cigarettes and ST among white men 18+ years of age who were daily users in the 2003 Tobacco Use Supplement of the Current Population Survey. Smokers were classified as light (1-14 cigarettes per day [cpd]), moderate (15-24 cpd), and heavy (25+ cpd) and ST users were classified as former smokers or exclusive users. RESULTS: There was no difference in TTFU within 5min between light smokers and exclusive ST users (Odds ratio [OR] = 1.3, CI = 0.95-1.7), but the latter were less likely to use tobacco within 30min (OR = 0.75, CI = 0.62-0.89). ST former smokers were more likely than light smokers to have a TTFU within 5min (OR = 1.5, CI = 1.1-2.0) but not within 30min. Moderate and heavy smokers had significantly higher odds of TTFU within both time points than light smokers. CONCLUSION: Compared to light smokers, the likelihood of TTFU within 5min was similar among exclusive ST users and was slightly higher among ST former smokers, offering some support for the Fagerström-Eissenberg hypothesis that the dependence level of cigarettes is higher than that of ST.

Predictors of success for smoking cessation at the workplace: a longitudinal study.

BACKGROUND: The effectiveness of worksite interventions to reduce smoking is debatable. OBJECTIVES: A comprehensive smoking cessation intervention was implemented in a community of more than 17,000 employees at three different health care companies. The primary endpoint was abstinence at 24 months (self-reported and confirmed by exhaled carbon monoxide ≤ 6 parts per million). Predictors of long-term abstinence were analysed by multivariable regression analysis. METHODS: The study was designed as an investigator-initiated and investigator-driven, open, multicentre, cohort study; 887 smokers were enrolled in the programme. The intervention included intensive individual counselling as well as nicotine replacement and/or bupropion according to individual preferences. Re-interventions for relapse were offered during the 24-month follow-up. RESULTS: The abstinence rate was 37% at 24 months and did not differ among the various medication groups (p > 0.05 for all). Predictors of successful cessation were higher age (odds ratio, OR 1.47, 95% confidence interval, CI 1.08-2.00, p < 0.01), breathlessness on exertion (OR 2.26, 95% CI 1.1-4.9, p = 0.03), and a higher educational level (OR 1.81, 95% CI 1.06-3.09, p = 0.03). Higher Fagerström (OR 0.76, 95% CI 0.59-0.97, p < 0.01) and craving scores (OR 0.75, 95% CI 0.63-0.89, p < 0.01), chronic sputum production (OR 0.52, 95% CI 0.31-0.87, p = 0.01) and use of antidepressants (OR 0.54, 95% CI 0.32-0.91, p = 0.02) were associated with ongoing smoking. CONCLUSION: A comprehensive smoking cessation intervention at the workplace achieves high, stable, long-term abstinence rates. Elderly, well-educated employees with breathlessness on exertion have higher odds of quitting smoking. In contrast, those with high physical dependency and more intense craving, and those reporting use of antidepressant medication or sputum production have poorer chances to quit.

Estimating the harms of nicotine-containing products using the MCDA approach.

BACKGROUND: An international expert panel convened by the Independent Scientific Committee on Drugs developed a multi-criteria decision analysis model of the relative importance of different types of harm related to the use of nicotine-containing products. METHOD: The group defined 12 products and 14 harm criteria. Seven criteria represented harms to the user, and the other seven indicated harms to others. The group scored all the products on each criterion for their average harm worldwide using a scale with 100 defined as the most harmful product on a given criterion, and a score of zero defined as no harm. The group also assessed relative weights for all the criteria to indicate their relative importance. FINDINGS: Weighted averages of the scores provided a single, overall score for each product. Cigarettes (overall weighted score of 100) emerged as the most harmful product, with small cigars in second place (overall weighted score of 64). After a substantial gap to the third-place product, pipes (scoring 21), all remaining products scored 15 points or less. INTERPRETATION: Cigarettes are the nicotine product causing by far the most harm to users and others in the world today. Attempts to switch to non-combusted sources of nicotine should be encouraged as the harms from these products are much lower.

Niccine®, a nicotine vaccine, for relapse prevention: a phase II, randomized, placebo-controlled, multicenter clinical trial.

INTRODUCTION: A nicotine vaccine could prevent relapse to smoking by hindering blood nicotine from reaching the brain. Niccine® is a nicotine hapten tetanus-toxoid conjugate vaccine. The present study evaluated the clinical efficacy of Niccine for tobacco smoking relapse prevention. METHODS: Cigarette smokers (n = 355) aged 25-50 years were enrolled in a randomized, double-blind, parallel group 1-year trial encompassing 16 visits and 16 telephone calls. Niccine 40 µg or placebo was administered on Days 0, 28, 56, 90, 150, and 210. Between Days 56-98, subjects were treated with varenicline to aid cessation, targeted for Day 70. Only individuals abstinent between Days 90-98 (n = 265) were allowed to continue to 1 year (n = 219). Relapse to smoking was defined as >5 cigarettes within 7 days or since the last contact, or smoking on >5 occasions within 7 days or since the last contact. RESULTS: At 1 year, nonrelapse was 43.3% in the Niccine versus 51.1% in the placebo groups (difference = -7.9%; 95% CI = -20.6% to 4.9%). There was no benefit of Niccine on smoking status at 6 or 9 months, exhaled carbon monoxide levels, time to relapse, abstinence, withdrawal symptoms, or smoking reinforcement. Nicotine antibody levels increased (mean = 1.34 µg/ml; SD = 2.84 µg/ml) in the Niccine group, but were not related to relapse. Adverse events except hypersensitivity and compensatory smoking did not differ between groups. CONCLUSIONS: This nicotine vaccine appeared well tolerated but did not influence trajectories of relapse possibly because of insufficient antibody levels or lack of efficacy of the vaccine concept for relapse prevention.

Dependence on tobacco and nicotine products: a case for product-specific assessment.

The International Classification of Diseases and the Diagnostic and Statistical Manual for diagnosing tobacco/nicotine dependence emphasize the dependence-producing drug nicotine. These diagnostic tools have been challenged on grounds of poor predictive validity, and they do not differentiate across various forms of nicotine-containing products. In fact, nicotine-containing products (e.g., tobacco cigarettes, smokeless tobacco [ST], waterpipe, electronic cigarettes [ECIGs], and nicotine replacement [NR] products) have very different characteristics both in terms of sensory and behavioral involvement and also in pharmacokinetic and pharmacodynamic effects. For example, a cigarette and a nicotine patch are very different on almost every one of these dimensions. When ability to stop using a nicotine/tobacco product is used as a criterion for dependence, success rates vary considerably across products: Tobacco cigarette cessation is more difficult than ST cessation that in turn is more difficult than NR product cessation. Based on these results, we hypothesize that there is a continuum of dependence as much as there is a continuum of harm, with tobacco cigarettes and NR products on opposite ends of both continua and other products (waterpipe and ECIGs) somewhere in between. In order to capture more precisely the dependence produced by both nicotine and its administration forms, product-specific instruments may be required. The pros and cons of this approach are discussed.

Snus as a smoking cessation aid: a randomized placebo-controlled trial.

INTRODUCTION: Snus is a low-nitrosamine smokeless product that appears to be safer than other smokeless products. Evidence indicates that snus has been used as an effective smoking cessation aid in Scandinavia. No randomized controlled trial has directly tested the efficacy of snus for smoking cessation. METHODS: This randomized, double-blind, placebo-controlled multicentre trial tested the efficacy of snus for smoking cessation. Of the 250 subjects, 125 were randomized to active or placebo snus sachets. Subjects were followed up through 28 weeks after randomization. In total, 5 clinical visits and 8 telephone contacts were scheduled. Primary outcome measure was biologically verified continuous smoking abstinence from Week 6 through 28. RESULTS: The continuous abstinence rate during Weeks 6-28 in the snus and placebo groups was 4.0% and 1.6% (odds ratio [OR]: 2.5, 95% CI: 0.4-27), respectively. The point prevalence abstinence rate at 6 weeks was 18.4% in the snus group versus 8.8% in the placebo group (OR: 2.3, 95% CI: 1.1-5.0, p = .03). At Week 28, the difference in favor of the snus group was not statistically significant (12.8% vs. 7.2%, OR: 1.9, 95% CI: 0.8-4.4). Snus was generally well tolerated. Treatment-related adverse events that were more common in the snus group were generally mild and included nausea, dyspepsia, gingivitis, hiccups, and dizziness. CONCLUSIONS: Although the cessation rates generally were low and, at 28 weeks, did not differ between active and placebo, early quit rates suggested that snus was superior and with similar effect sizes to those with nicotine replacement. These results suggest that snus needs to be further researched as a smoking cessation treatment.

The Fagerström Test for Nicotine Dependence as a predictor of smoking abstinence: a pooled analysis of varenicline clinical trial data.

INTRODUCTION: We explored the relationship between the Fagerström Test for Nicotine Dependence (FTND) and smoking abstinence rates in 10 randomized, double-blind placebo-controlled Phase 2-4 varenicline studies. METHODS: Participants were adult smokers (≥10 cigarettes/day) who were motivated to quit. Efficacy end points included continuous abstinence rate (CAR) for weeks 9-24 analyzed, by baseline FTND and Heaviness of Smoking Index (HSI) scores, and treatment. Data were analyzed using logistic regression models. RESULTS: Overall, 2,763 varenicline (M [SD] FTND score: 5.6 [2.2]) and 2,229 placebo subjects (5.5 [2.1]) were included in the analysis. An increase of one unit in baseline FTND or HSI score decreased the odds of abstinence at Week 24 by 11% (odds ratio [OR] 0.89, 95% CI 0.86-0.92, p < .0001) and 18% (OR 0.82, 95% CI 0.79-0.87, p < .0001), respectively. Treatment had a significant impact on CAR 9-24: odds of abstinence were increased threefold for varenicline versus placebo (OR 3.3, 95% CI 2.8-3.8, p < .0001). There was no interaction between treatment and FTND (p = .98) or HSI score (p = .97) for CAR 9-24. The HSI score predicted abstinence outcome as effectively as the FTND score. CONCLUSION: Abstinence rates decreased with increasing dependence scores. There was no interaction between treatment and baseline FTND or HSI score, suggesting that they have no effect on the efficacy of varenicline versus placebo. These results also suggest that the HSI may be as effective at predicting smoking cessation outcome as the whole FTND questionnaire.

Enhanced didactic methods of smoking cessation training for medical students--a randomized study.

BACKGROUND: It is essential that medical students are adequately trained in smoking cessation. A web-based tobacco abstinence training program might supplement or replace traditional didactic methods. METHODS: One-hundred and forty third-year medical students were all provided access to a self-directed web-based learning module on smoking cessation. Thereafter, they were randomly allocated to attend 1 of 4 education approaches: (a) web-based training using the same tool, (b) lecture, (c) role playing, and (d) supervised interaction with real patients. RESULTS: Success of the intervention was measured in an objective structured clinical examination. Scores were highest in Group 4 (35.9 ± 8.7), followed by Groups 3 (35.7 ± 6.5), 2 (33.5 ± 9.4), and 1 (28.0 ± 9.6; p = .007). Students in Groups 4 (60.7%) and 3 (57.7%) achieved adequate counseling skills more frequently than those in Groups 2 (34.8%) and 1 (30%; p = .043). There was no difference in the scores reflecting theoretical knowledge (p = .439). Self-assessment of cessation skills and students' satisfaction with training was significantly better in Groups 3 and 4 as compared with 1 and 2 (p < .001 and p = .006, respectively). CONCLUSIONS: Role playing and interaction with real patients are equally efficient and both more powerful learning tools than web-based learning with or without a lecture.

Efficacy of varenicline to prompt quit attempts in smokers not currently trying to quit: a randomized placebo-controlled trial.

INTRODUCTION: Nicotine replacement therapy to aid smoking reduction increases the probability of a future quit attempt among smokers not currently planning to quit smoking. We tested whether varenicline, a partial nicotine agonist, would also increase future quit attempts. METHODS: This randomized, placebo-controlled trial recruited 218 smokers who were interested in quitting but had no plans to quit in the next month. Participants used varenicline (2 mg/day) or placebo for 2-8 weeks plus received brief counseling on methods to reduce cigarettes/day. The primary measure was the incidence of a quit attempt within 6 months of study entry. Secondary measures were point prevalence abstinence, motivation to stop smoking, and reduction in cigarettes/day. RESULTS: Varenicline increased the incidence of a quit attempt more than placebo at the Nebraska site (73% vs. 41%; p < .001) but not at the Vermont site (45% vs. 51%; p = .45). Varenicline increased most other measures of quit attempts, motivation and abstinence, independent of site. The beneficial effects of varenicline in quit attempts appeared to be mediated by greater reductions in cigarettes/day, dependence, craving, and cigarette satisfaction. Varenicline had a greater effect on quit attempts in less-dependent smokers, in minority smokers, and in those who had less prior cessation or reduction activity. Adverse events were minimal. CONCLUSIONS: Varenicline increased quit attempts in smokers who are not currently trying to quit at one of the two study sites and improved most all secondary outcomes independent of site. This appeared to be due to decreasing cigarettes/day and level of dependence.

Closing Perspective on the Special Issue on JUUL.

Objective: This article provides an overview of this theme issue of the American Journal of Health Behavior dedicated to electronic nicotine delivery systems (ENDS), with a special focus on JUUL. Methods: The author summarizes key findings from included papers and offers an evaluative perspective on ENDS as tools for smoking cessation versus the prospect of their appeal to previous non-smokers. Results: Delineation of certain metrics (eg, defining who is a smoker) and clarification about an acceptable level of unintended consequences weighed against harm reduction confound conclusions about the public health role of ENDS/JUUL. Conclusion: Until agreement on key definitions and performance of well-controlled studies, a system that promotes ENDS/JUUL use among smokers but discourages their use by never-smokers is a regulatory challenge.

Varenicline: mode of action, efficacy, safety and accumulated experience salient for clinical populations.

Objective: Varenicline, a selective partial agonist of the α4ß2 nicotinic acetylcholine receptor, is a smoking cessation pharmacotherapy that more than doubles the chance of quitting smoking at 6 months compared with placebo. This article reviews salient knowledge of the discovery, pharmacological characteristics, and the efficacy and safety of varenicline in general and in specific populations of smokers and provides recommendations to support use in clinical practice.Methods: Literature searches for varenicline were conducted using PubMed, with date limitations of 2000-2018 inclusive, using search terms covering the discovery, mechanism of action, pharmacokinetics, efficacy and safety in different populations of smokers, alternative quit approaches and combination therapy. Selection of safety and efficacy data was limited to clinical trials, meta-analyses and observational studies.Results: Standard administration of varenicline is efficacious in helping smokers to quit, including smokers with cardiovascular disease and chronic obstructive pulmonary disease. Furthermore, varenicline efficacy may be improved with pre-loading, a gradual quitting approach for smokers unwilling or unable to quit abruptly, and extended treatment in smokers who have recently quit to help maintain abstinence. Initial concerns regarding the association of varenicline with increased risk of neuropsychiatric and cardiovascular adverse events have been disproven after extensive clinical evaluations, and the benefit-risk profile of varenicline is considered favorable.Conclusions: Varenicline is efficacious and safe for all adult smokers with a range of clinical characteristics. Evidence suggests that approaches offering greater flexibility in timing and duration of treatment may further extend treatment efficacy and clinical reach.

A comparison of the Fagerström Test for Nicotine Dependence and smoking prevalence across countries.

AIMS: To examine the correlation between the Fagerström Test for Nicotine Dependence (FTND) score and smoking prevalence across countries. DESIGN: Cross-sectional study. SETTING: Fifteen studies from 13 countries with FTND score data. PARTICIPANTS: Samples of smokers were identified through systematic literature searches, web queries and colleagues. Smokers were considered representative of their country's smoking population if they were drawn from population-based sources, were not seeking smoking cessation treatment and did not have significant comorbidities. Smoking prevalence data were derived from the study itself or the country's population rate of daily smoking for the study year. MEASUREMENTS: A Pearson correlation coefficient was used to examine the direction and magnitude of the correlation between FTND score and smoking prevalence across countries. FINDINGS: FTND scores ranged from 2.8 to 4.6. Smokers in Germany and Norway had the lowest FTND scores, while smokers in Sweden and the United States had the highest FTND scores. The prevalence of daily smoking in these countries was very different: 37% and 30% in Germany and Norway, 19% and 16% in the United States and Sweden, respectively. An inverse correlation towards higher FTND scores in countries with lower smoking prevalence was found (r=-0.73, P=0.001). Current smokers had higher FTND scores than former smokers. CONCLUSIONS: The significant inverse correlation between FTND score and smoking prevalence across countries and higher FTND score among current smokers supports the idea that remaining smokers may be hardening. Less dependent smokers may quit more easily and remaining dependent smokers may need more intensive treatment.