Nicotine patches used in combination with e-cigarettes (with and without nicotine) for smoking cessation: a pragmatic, randomised trial.

BACKGROUND: Combination nicotine replacement therapy shows additive cessation benefits. We aimed to find out the effectiveness of combining nicotine patches with an e-cigarette (with and without nicotine) on six-month smoking abstinence. METHODS: We did a pragmatic, three-arm, parallel-group trial in New Zealand in adult smokers who were e-cigarette naive and motivated to quit smoking. Participants were recruited from the general population using national media advertising. Participants were randomly assigned (1:4:4), with the use of stratified block randomisation, to receive 14 weeks (2 weeks before the agreed quit date) of 21 mg, 24h nicotine patches, patches plus an 18 mg/L nicotine e-cigarette, or patches plus a nicotine-free e-cigarette. We advised participants to use one patch daily, with e-cigarette use as and when necessary or desired. Participants and researchers were masked to e-liquid nicotine content. We offered 6 weeks of telephone-delivered behavioural support. The primary outcome was exhaled carbon monoxide (CO)-verified continuous smoking abstinence 6 months after the agreed quit date. Primary analysis was by intention to treat, with sensitivity analysis by per protocol, treatment adherence, varying CO cutoffs, and complete case analysis. This paper presents the main analyses and is registered with ClinicalTrials.gov, NCT02521662. FINDINGS: Between March 17, 2016 and Nov 30, 2017, 1124 people were assigned to nicotine patches (patches only group, n=125), patches plus a nicotine e-cigarette (patches plus nicotine e-cigarette group, n=500), or patches plus a nicotine-free e-cigarette (patches plus nicotine-free e-cigarette group, n=499). 62 (50%) of 125 participants in the patches only group withdrew or were lost to follow-up by 6 months compared with 161 (32%) of 500 in the patches plus nicotine e-cigarette group and 162 (33%) of 499 in the patches plus nicotine-free e-cigarette group. 35 (7%) participants in the patches plus nicotine e-cigarette group had CO-verified continuous abstinence at 6 months compared with 20 (4%) in the patches plus nicotine-free e-cigarette group (risk difference [RD] 2·99 [95% CI 0·17-5·81]), and three (2%) people in the patches only group (RD 4·60 [1·11-8·09]). 18 serious adverse events occurred in 16 people in the patches plus nicotine e-cigarette group compared with 27 events in 22 people in the patches plus nicotine-free e-cigarette group and four events in three people in the patches only group. In the patches plus nicotine e-cigarette group, two life-threatening serious adverse events were reported (two separate heart attacks in the one participant). In the patches plus nicotine-free e-cigarette group, one death occurred (accidental drug overdose) and one life-threatening serious adverse event (heart attack). No significant between-group differences were noted for serious adverse events, and none were treatment-related. INTERPRETATION: Combining reduced-harm nicotine products, such as nicotine patches with a nicotine e-cigarette, can lead to a modest improvement in smoking cessation over and above that obtained from using patches plus a nicotine-free e-cigarette (or patches alone), with no indication of any serious harm in the short-term. Future e-cigarette trials should focus on their use alone or in combination with usual smoking cessation support, given issues with differential loss to follow-up and withdrawal if a usual care group is used as a comparator. FUNDING: Health Research Council of New Zealand.

Effectiveness and safety of nicotine patches combined with e-cigarettes (with and without nicotine) for smoking cessation: study protocol for a randomised controlled trial.

INTRODUCTION: Evidence indicates e-cigarettes can help people quit smoking; however, more confirmatory trials are needed. To date, no trials have evaluated the effectiveness and safety of combining nicotine patches with e-cigarettes (with and without nicotine) for smoking cessation. METHODS AND ANALYSIS: This study is a pragmatic, three-arm, community-based, single-blind, randomised trial undertaken in New Zealand. Eligible participants are daily/non-daily smokers, aged ≥18 years, naive e-cigarette users and motivated to quit smoking in the next 2 weeks. Participants (n=1809), recruited using multi-media advertising, are randomised to 14 weeks of (1) 21 mg nicotine patches (n=201); (2) 21 mg nicotine patches+18 mg/mL nicotine e-cigarette (n=804); or (3) 21 mg nicotine patches+nicotine free e-cigarette (n=804). Participants receive weekly withdrawal-oriented behavioural support calls for 6 weeks post-randomisation. The primary outcome is self-reported biochemically verified continuous abstinence (CA) at 6 months post quit-date. The primary comparison is nicotine patch + nicotine e-cigarette versus nicotine patch + nicotine free e-cigarette, and the secondary comparison is nicotine patch versus nicotine patch +nicotine e-cigarette (90% power, p=0.05, to detect an absolute difference in 6 month CA rates of 8% and 15% respectively). Secondary outcomes, collected by phone interview at quit date, then 1, 3, 6 and 12 months post-quit date, include self-reported CA, 7 day point prevalence abstinence, cigarettes per day (if smoking, or when smoking for non-daily smokers), time to relapse (if returned to smoking), belief in ability to quit, use of other cessation support, side effects/serious adverse events, treatment compliance, seeking additional support around e-cigarette use, daily use of both e-cigarettes and cigarettes, use of treatment past 14 weeks, views on treatment and recommendation to others, weight and cost-per-quitter. ETHICS AND DISSEMINATION: The Northern A Health and Disability Ethics Committee approved the trial. Findings will be disseminated through publication, conference/meeting presentations, and media. TRIAL REGISTRATION NUMBER: NCT02521662; Pre-results.

Evaluation of Nicotine Pharmacokinetics and Subjective Effects following Use of a Novel Nicotine Delivery System.

Introduction: Novel nicotine delivery systems represent an evolving part of the tobacco harm reduction strategy. The pharmacokinetic (PK) profile of nicotine delivered by P3L, a pulmonary nicotine delivery system, and its effects on smoking urges and craving relief in relation to Nicorette inhalator were evaluated. Methods: This open-label, ascending nicotine levels study was conducted in 16 healthy smokers. Three different nicotine delivery levels, 50, 80, and 150 µg/puff, delivered by the P3L system were evaluated consecutively on different days after the use of the Nicorette inhalator. Venous nicotine PK, subjective effects, and tolerability were assessed. Results: Geometric least-squares means for maximum plasma nicotine concentration (Cmax), generated by the mixed-effect model for exposure comparison, were 9.7, 11.2, and 9.8 ng/mL for the 50, 80, and 150 µg/puff P3L variants, respectively, compared to 6.1 ng/mL after Nicorette inhalator use. Median time from product use start to Cmax was 7.0 minutes for all P3L, compared to 30.0 minutes for the Nicorette inhalator. Craving reduction was slightly faster than with the Nicorette inhalator as assessed with the visual analog scale craving score. The mean Questionnaire of Smoking Urges -brief total scores did not differ for both products. P3L was well tolerated. Conclusions: At all three nicotine levels tested, the inhalation of the nicotine lactate aerosol delivered with the P3L provided plasma nicotine concentrations higher and faster compared to the Nicorette inhalator. The plasma nicotine concentration-time profile supports a pulmonary route of absorption for P3L compared to the oromucosal absorption of the Nicorette inhalator. Implications: The combination of nicotine and lactic acid with the P3L device shows potential over existing nicotine delivery systems by delivering nicotine with kinetics close to published data on conventional cigarettes and without exogenous carrier substances as used in current electronic nicotine delivery systems. Altogether, the PK profile, subjective effects, and safety profile obtained in this study suggest P3L is an innovative nicotine delivery product that will be acceptable to adult smokers as an alternative to cigarettes.

Estimating Demand and Cross-Price Elasticity for Very Low Nicotine Content (VLNC) Cigarettes Using a Simulated Demand Task.

Introduction: Very Low Nicotine Content (VLNC) cigarettes might be useful as part of a tobacco control strategy, but relatively little is known about their acceptability as substitutes for regular cigarettes. We compared subjective effects and demand for regular cigarettes and VLNC cigarettes, and estimated cross-price elasticity for VLNC cigarettes, using simulated demand tasks. Method: Forty New Zealand smokers sampled a VLNC cigarette and completed Cigarette Purchase Tasks to indicate their demand for regular cigarettes and VLNC cigarettes at a range of prices, and a cross-price task indicating how many regular cigarettes and VLNC cigarettes they would purchase at 0.5x, 1x, and 2x the current market price for regular cigarettes, assuming the price of VLNC cigarettes remained constant. They also rated the subjective effects of the VLNC cigarette and their usual-brand regular cigarettes. Results: Cross-price elasticity for VLNC cigarettes was estimated as 0.32 and was significantly positive, indicating that VLNC cigarettes are partially substitutable for regular cigarettes. VLNC cigarettes were rated as less satisfying and psychologically rewarding than regular cigarettes, but this was unrelated to demand or substitutability. Conclusion: VLNC cigarettes are potentially substitutable for regular cigarettes. Their availability may reduce tobacco consumption, nicotine intake and addiction; making it easier for smokers to quit. Implications: VLNC cigarettes share the behavioral and sensory components of smoking while delivering negligible levels of nicotine. Although smokers rated VLNCs as less satisfying than regular cigarettes, smokers said they would increase their consumption of VLNCs as the price of regular cigarettes increased, if VLNCs were available at a lower price. This suggests that VLNCs are partially substitutable for regular cigarettes. VLNCs can be part of an effective tobacco control strategy, by reducing nicotine dependence and improving health and financial outcomes for smokers.

Predicting Short-Term Uptake of Electronic Cigarettes: Effects of Nicotine, Subjective Effects, and Simulated Demand.

Introduction: E-cigarettes have potential to support tobacco cessation or reduction, but how nicotine content affects smokers' subjective perceptions and use of e-cigarettes, rather than tobacco, is unclear. Method: Thirty-five adult daily smokers who had not previously tried e-cigarettes were recruited from two cities in New Zealand in 2016-2017. Smokers were given four e-cigarette cartridges (0, 6, 12, and 18 mg nicotine) in a randomized, blinded order over four 2-week periods. Daily cigarette smoking and e-cigarette use was monitored using ecological momentary analysis and participants completed the modified Cigarette Evaluation Questionnaire after each 2-week period. Results: Mean cigarettes per day decreased by 37% (9.69 to 6.09) when e-cigarettes were available relative to baseline (p = .008). Nicotine-containing cartridges (>0 mg) were associated with greater use (p = .023) and craving reduction (p = .026) than 0 mg. Alleviation of withdrawal symptoms (p = .048) and taste and enjoyment factors (p = .039) predicted e-cigarette use. Conclusion: Availability of e-cigarettes reduced cigarette smoking behavior regardless of nicotine content, and e-cigarette use was greater with nicotine-containing cartridges. First-time users' e-cigarette use can be predicted using subjective ratings and more research is required to clarify the effect of nicotine content on subjective perceptions and use. Implications: For low-moderate dependence smokers, availability of e-cigarettes may reduce cigarette smoking behavior regardless of nicotine content, but the availability of nicotine-containing cartridges may promote greater e-cigarette use. First response to trialing e-cigarettes is an important factor in determining subsequent experimental and possibly longer-term use.

Reduced tobacco consumption, improved diet and life expectancy for 1988-1998: analysis of New Zealand and OECD data.

AIM: We compared changes in tobacco consumption and diet in relation to changes in life expectancy in 1988-1998 in 22 OECD (Organisation for Economic Cooperation and Development) countries. METHOD: Between 1985 and 1995 using regression analysis we estimated differences in tobacco consumption per adult and the differences in the sum of atherogenic and thrombogenic indices against life expectancy. Each index was derived from the various fats per gram of food from standard texts, and from the annual measurements of fat in the food balance sheets of each country. RESULTS: In 1985-1995, New Zealand showed the largest decrease in tobacco consumption per adult (41%) and the greatest decrease (except for Switzerland) in the sum of atherogenic and thrombogenic indices (17%) as a measure of diet. New Zealand ranked first for life expectancy increases from 1988-1998 for men (3.2 years), women (2.8 years) and both sexes combined. Regression analyses revealed that increases in life expectancy across the OECD for males, but not females, were strongly associated with decreases in tobacco consumption, with a weaker effect of diet improvement. CONCLUSION: These results suggest that reduced tobacco consumption in 1985-1995 likely contributed to New Zealand's gains in life expectancy from 1988-1998.

Changes to smoking habits and addiction following tobacco excise tax increases: a comparison of Maori, Pacific and New Zealand European smokers.

OBJECTIVE: To compare changes in smoking habit and psychological addiction in Maori/Pacific and NZ European smokers in response to two annual excise tax increases from 2012 to 2014. METHODS: Smokers from New Zealand cities completed questionnaires at three time points before and after two excise tax increases. RESULTS: There were no significant differences in cigarettes per day or psychological addiction at baseline, but a linear decline in both measures was observed in Maori/Pacific and NZ European smokers. Cigarettes per day reduced at a greater rate for Maori/Pacific than NZ European smokers but dependence did not. CONCLUSION: Results indicated that Maori/Pacific smokers' demand for cigarettes may be more price sensitive than NZ European smokers. Implications for Public Health: Tobacco excise tax may be particularly effective for Maori/Pacific smokers and may contribute to reductions in smoking-related health inequalities in NZ.

Gender differences in satisfaction ratings for nicotine electronic cigarettes by first-time users.

INTRODUCTION: Nicotine electronic cigarettes (NECs) are becoming increasingly popular as a potentially safer alternative to tobacco but little is known regarding their subjective effects, including possible gender differences. METHOD: Participants were New Zealand smokers with no intention to quit (N = 357) and whom had never used an NEC. During an interview in November-December 2012, participants sampled an NEC and rated it and their own-brand tobacco for satisfaction on a 10-point visual analogue scale. Participants were contacted again in February-March 2013 after a 10% increase in the tobacco excise tax on 1 January 2013. RESULTS: Overall participants rated NECs 83.3% as satisfying as own-brand tobacco. Females rated NECs more highly than males. Of those who agreed to be re-interviewed (n = 227), 37.8% said they had cut back or made a change in their smoking habit and 7% had quit in February-March 2013. NEC satisfaction ratings predicted changes in smoking habit and reductions in nicotine dependence after controlling for covariates including demographic variables, factory-made vs. roll-your-own tobacco preference, and addiction scores. CONCLUSION: Smokers' first impressions of NECs were very favourable, and were correlated with readiness to change after a tobacco tax increase. NECs appear to be particularly attractive for female smokers, and their use may help to improve the efficacy of nicotine replacement therapy for women.

Nicotine and toxicant yield ratings of electronic cigarette brands in New Zealand.

AIMS: To analyse electronic cigarette (EC) brands available in New Zealand for nicotine and toxicant yield ratings. METHOD: Fourteen EC brands were analysed before and after nicotine exhaustion for nicotine and nine for major toxicants. Concentration of nicotine and aldehydes in vapour was measured and compared with the nicotine and aldehydes in the smoke of a Marlboro cigarette. RESULTS: ECs labelled as high strength (16-18+ mg nicotine) contained 5-46 mg nicotine. Nicotine EC brands yielded 19-93 mcg nicotine per puff compared to 147 mcg per puff for Marlboro cigarettes, and emitted 200 times less toxic aldehydes (acetaldehyde, formaldehyde and acrolein) than Marlboro cigarette smoke. Compared with the first generation EC, study ECs emitted 73% less aldehydes. Diethylene and monoethylene glycol were not detected in vapour. CONCLUSION: ECs available in New Zealand in 2013 exposed users to higher levels of nicotine than in older brands but lower than cigarettes, and to far lower levels of toxicants than cigarettes and earlier ECs, indicating potential as safer substitutes for tobacco.

Assessing the Temporal Stability of a Cigarette Purchase Task After an Excise Tax Increase for Factory-Made and Roll-Your-Own Smokers.

INTRODUCTION: Cigarette purchase tasks (CPTs) are used increasingly to measure simulated demand curves for tobacco. However, there is currently limited information about the temporal stability of demand curves obtained from these tasks. METHOD: We interviewed a sample (N = 210) of smokers in New Zealand both before and after a 10% increase in the tobacco excise tax that took effect on January 1, 2013. Participants were interviewed in November-December 2012 (wave 1) and February-March 2013 (wave 2). At each interview, participants completed a high-resolution CPT with 64 prices ranging from NZ $0.00 to NZ $5.00/cigarette, and questionnaires regarding their smoking habit. RESULTS: Roll-your-own smokers had higher levels of nicotine dependence and tobacco demand based on CPT responses than factory-made smokers. Although demand curves for waves 1 and 2 were similar, intentions to purchase cigarettes were significantly less at wave 2 for three prices (NZ $0.85, NZ $0.90, and NZ $0.95) that were just higher than the actual price after the tax increase, for both roll-your-own and factory-made smokers. Measures of elasticity (α) derived from Hursh and Silberberg's model were significantly greater at wave 2 than wave 1, and there was a significant reduction in smoking habit as measured by cigarettes/day and the Fagerström Test for Nicotine Dependence at wave 2. CONCLUSIONS: Purchase tasks can discriminate between smokers based on their tobacco preference, and although results are relatively stable over time, they depend on contextual factors such as the current real price for tobacco.

Predicting decreases in smoking with a cigarette purchase task: evidence from an excise tax rise in New Zealand.

BACKGROUND: Tobacco excise taxes are known to be effective in reducing smoking at the population level, but less research has examined how individual smokers respond to changes in tax policy. We ask whether price elasticities for individual smokers, derived from simulated demand curves obtained with a cigarette purchase task (CPT), can predict changes in smoking after a tax increase. METHOD: Smokers (N=357) were recruited from four New Zealand cities and interviewed before and after a 10% tobacco excise tax increase. RESULTS: Simulated demand curves from the CPT were curvilinear and well described by an exponential model. Smokers reported significant reductions in cigarettes/day and addiction scores at Wave 2 (n=226). Local elasticities derived from the demand curves significantly predicted decreases in cigarettes/day after controlling for covariates. CONCLUSIONS: Elasticities from simulated demand curves can predict decreases in consumption for individual smokers after an excise tax increase. Understanding individual differences in tobacco demand curves may help to predict how different groups of smokers will respond to price increases.

Abrupt nicotine reduction as an endgame policy: a randomised trial.

OBJECTIVE: To determine if smokers unmotivated to quit reduce usual cigarette consumption when cigarettes priced according to nicotine content are made available. METHODS: Randomised, parallel-group, trial (ACTRN12612000914864) undertaken in Wakatipu/Central Otago, New Zealand. Dependent adult daily smokers unmotivated to quit were randomly allocated to an intervention group provided with 12 weeks supply of free very low nicotine content (VLNC) cigarettes, or to a control group, who were free to purchase their usual cigarette brand over the same period. The primary outcome was change from baseline in the daily mean number of usual cigarettes smoked over the previous week, measured at 12 weeks. Secondary outcomes at 6 and 12 weeks included cigarettes smoked per week (also measured at weeks 1-6 and 9), salivary cotinine, tobacco dependence, smoking satisfaction/craving, behavioural addiction to smoking, autonomy over smoking, motivation to stop, price at which participants would purchase VLNC cigarettes, quitting and adverse events. RESULTS: Thirty-three smokers were randomised (17 intervention, 16 control). A NZ$15 price differential (per pack of 20) based on nicotine content led to a halving in the mean number of cigarettes smoked per day over the previous week, a reduction in tobacco dependence and an increase in quitting. Intervention participants smoked a similar total number of cigarettes (usual plus VLNC) as those in the control group, exposing them to a similar level of toxicants. CONCLUSIONS: Smokers unmotivated to quit reduce their usual cigarette consumption (and thus nicotine exposure) when VLNC cigarettes are made available at a significantly reduced price.

Estimating cross-price elasticity of e-cigarettes using a simulated demand procedure.

INTRODUCTION: Our goal was to measure the cross-price elasticity of electronic cigarettes (e-cigarettes) and simulated demand for tobacco cigarettes both in the presence and absence of e-cigarette availability. METHOD: A sample of New Zealand smokers (N = 210) completed a Cigarette Purchase Task to indicate their demand for tobacco at a range of prices. They sampled an e-cigarette and rated it and their own-brand tobacco for favorability, and indicated how many e-cigarettes and regular cigarettes they would purchase at 0.5×, 1×, and 2× the current market price for regular cigarettes, assuming that the price of e-cigarettes remained constant. RESULTS: Cross-price elasticity for e-cigarettes was estimated as 0.16, and was significantly positive, indicating that e-cigarettes were partially substitutable for regular cigarettes. Simulated demand for regular cigarettes at current market prices decreased by 42.8% when e-cigarettes were available, and e-cigarettes were rated 81% as favorably as own-brand tobacco. However when cigarettes cost 2× the current market price, significantly more smokers said they would quit (50.2%) if e-cigarettes were not available than if they were available (30.0%). CONCLUSION: Results show that e-cigarettes are potentially substitutable for regular cigarettes and their availability will reduce tobacco consumption. However, e-cigarettes may discourage smokers from quitting entirely as cigarette price increases, so policy makers should consider maintaining a constant relative price differential between e-cigarettes and tobacco cigarettes.

Whole tobacco smoke extracts to model tobacco dependence in animals.

Smoking tobacco is highly addictive and a leading preventable cause of death. The main addictive constituent is nicotine; consequently it has been administered to laboratory animals to model tobacco dependence. Despite extensive use, this model might not best reflect the powerful nature of tobacco dependence because nicotine is a weak reinforcer, the pharmacology of smoke is complex and non-pharmacological factors have a critical role. These limitations have led researchers to expose animals to smoke via the inhalative route, or to administer aqueous smoke extracts to produce more representative models. The aim was to review the findings from molecular/behavioural studies comparing the effects of nicotine to tobacco/smoke extracts to determine whether the extracts produce a distinct model. Indeed, nicotine and tobacco extracts yielded differential effects, supporting the initiative to use extracts as a complement to nicotine. Of the behavioural tests, intravenous self-administration experiments most clearly revealed behavioural differences between nicotine and extracts. Thus, future applications for use of this behavioural model were proposed that could offer new insights into tobacco dependence.