Nicotine preloading for smoking cessation: the Preloading RCT

Abstract

BackgroundNicotine 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.ObjectivesTo 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.DesignOpen-label randomised controlled trial with examination of mediation and a cost-effectiveness analysis.SettingNHS smoking cessation clinics.ParticipantsPeople seeking help to stop smoking.InterventionsNicotine 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 measuresThe 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.ResultsIn 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.LimitationsThe open-label design could partially account for the mediation results. Outcome assessment could not be blinded but was biochemically verified.ConclusionsUse 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 registrationCurrent Controlled Trials ISRCTN33031001.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 22, No. 41. See the NIHR Journals Library website for further project information.

Extending varenicline preloading to 6 weeks facilitates smoking cessation: A single-site, randomised controlled trial

“…The cyclic repetition of this mechanism during a 6-week period could have weakened the learnt association between reinforcement and smoking, facilitating cessation. This analysis is supported by the above study of Aveyard and colleagues [16], showing that changes in abstinence were mediated mainly by a reduction in the drive to smoke before and after smoking cessation, and by a reduction in smoke intake. The present findings also support…”

“…The present findings considerably strengthen the existing evidence for a unified mechanism of preloading and support the view that the benefits of pre-treatment are not specific to varenicline. In the largest trial of nicotine preloading published to date, Aveyard and colleagues [16] found an increase in long-term abstinence after 4 weeks of preloading with a nicotine patch followed by standard cessation therapy. Interestingly, in the initial analysis, the nicotine preloading benefit was undermined because it reduced the use of varenicline in the post-quit treatment; however, when the results were adjusted for the use of post-quit varenicline, the effect of nicotine preloading was larger than the unadjusted value and was statistically significant.…”

“…The drive to smoke was evaluated using the MPSS-craving subscale (MPSS-C, items 8 and 9), alone or in combination, and the MPSS-mood subscale (MPSS-M, items 1À7). Also, aversion was determined by the occurrence of nausea and through the aversion subscale of the mCEQ [16].…”

Intraoperative cell salvage for obstetrics: a prospective randomized controlled clinical trial

“…At present, some medical institutions around the world have carried out autologous blood recovery from amniotic fluid in the operation field after delivery and placenta separation and filtration of white blood cells without leading to obvious puerperal complications [ 13 ]. Although the technique has been confirmed to be safe by multiple studies with large clinical sample sizes [ 14 ], its promotion has currently encountered some taboos. For example, pregnant patients with malignant tumours and patients with sickle cell anaemia were excluded.…”

Nicotine replacement therapy: A friend or foe

“…It increases the rate of quitting and is assumed that nicotine preloading is reasonably effective in tobacco cessation; however, the data are limited. [ 8 39 ]…”