Abstract
Background: Smoking is the biggest cause of preventable death in industrialised countries. Quit rates after use of current Nicotine Replacement Therapy (NRT) are low. Animal studies suggest nicotine is more rewarding when it is delivered rapidly to the brain, and human clinical trials of the current NRT that delivers nicotine to the brain most rapidly (nicotine nasal spray), demonstrate quit rates are improved if it is used in combination with nicotine transdermal patches. However, nicotine nasal spray is aversive and other rapid nicotine delivery systems are required. The lung is the most rapid delivery route to the brain; however, inhalation of nicotine is aversive, and delivery of substances to the lung is technically difficult. In 2008, when these trials were designed, apart from bench-top nebulisers, waterpipes, cigarettes, and some electronic cigarettes, no device was capable of pulmonary nicotine delivery. Nicotine mouthsprays are amongst the most rapid NRT at delivering nicotine to the brain and may be more tolerable than nasal spray.
Objectives:
1. Develop a nicotine pressurised metered-dose inhaler (pMDI).
2. Test the long-term abstinence rates of active nicotine mouthspray plus active patch, and of active nicotine inhaler plus active patch, compared to placebo plus active patch.
Methods:
1. Double-blind, Randomised Controlled Trial (RCT) of active nicotine mouthspray and active nicotine patch cf. placebo mouthspray plus active nicotine patch (ZAP).
2. A cross-over, non-randomised, open-label, pharmacokinetic, pharmacodynamic, and tolerability trial of a free-base nicotine pressurised metered-dose inhaler (pMDI).
3. A cross-over, non-randomised, open-label, pharmacodynamic, preference and tolerability trial of free-base nicotine, and nicotine lactate, and the effects of flavouring, delivered by pMDI.
4. Double-blind, RCT of active nicotine lactate pMDI and active patch cf. placebo pMDI plus active nicotine patch (INHALE).
Results: Ten smokers enrolled in the pharmacokinetic trial, which showed that nicotine was delivered, at least in part, via the lung, and rapidly quenched urges to smoke.
ZAP enrolled 1,423 smokers. Nicotine mouthspray plus nicotine patch, significantly increased abstinence to six months cf. placebo and nicotine patch (15.5% vs 10.6%; p=0.006). The prolonged twelve-month abstinence was 10.1% with the active combination cf. 7.1% (p=0.045). At all follow-up time-points urges to smoke reduced significantly compared to baseline in both active and control groups, and this reduction was significantly greater in the active cf. control group. Withdrawal scores reduced at all follow-ups compared to the one-month visit in both groups, with no significant difference between groups after Bonferroni correction. The variables recorded before randomisation that were statistically significant predictors of lower rates of abstinence after Bonferroni correction were Māori ethnicity; enrolment at a Māori community trial site; previous use of NRT, and higher scores of the Social/Environmental Goads scale of the brief-WISDM psychological battery. Pre-randomisation variables significantly predictive of higher odds of abstinence were being 50 years or older; having started smoking daily aged sixteen years or older; how prepared subjects’ felt they were to handle stress without smoking; the number of subjects’ personal acquaintances who have quit.
Six variables measured after randomisation statistically decreased abstinence after Bonferroni correction: MNWS Craving score at one-, three-, and six-months post-target quit date; MNWS Negative Affect score at three-months post-target quit date; and brief-QSU total score at one- and three-months post-target quit date. Eleven variables recorded post-randomisation predicted increase abstinence: having quit on or before the target quit date; fully completed the record of CPD for the first fortnight of the trial, strongly wanting to continue trying to quit or remain abstinent and continue to participate in the trial (recorded the day after the target quit date); being highly confident that one will quit/stay abstinent (measured a day after the target quit date); how well subjects reported they were coping with their urges to smoke reported a day after the target quit date;, and how much Zonnic subjects reported using a day after the target quit date. Of the eight Likert scales conceived by the author, none predicted abstinence after Bonferroni correction for sixteen comparisons, while one was significant after correction for eight comparisons.
Twelve smokers enrolled in the preference trial; menthol nicotine lactate was tolerable.
Five-hundred-and-two smokers enrolled in INHALE. Prolonged six-months abstinence rates were 78/246 (31.71%) vs. 46/256 (17.97%), p=0.00042 in the active and control group, respectively. Subjects in the active group had a significantly greater reduction in their brief Questionnaire of Smoking Urges (QSU) scores at baseline cf. the control group, and continued to have lower scores at the one-, three- and six-month follow-ups in the active- compared to control-group. Subjects in the two groups had similar nicotine withdrawal scores (MNWS scores) at all timepoints except the active group had significantly lower scores at three- and six-months. Of the ten variables recoded at baseline that were analysed as a potential predictor of prolonged abstinence, only FTND was statistically significant, albeit, weakly significant. At every follow-up beyond a week after baseline, the number of days the inhalers were used predicted abstinence in both groups. Favourable scores on the Cigarette Evaluation Questionnaire scales used to rate the inhalers, predicted abstinence at many follow-ups for many of the scales.
Although, in the active groups, abstinence rates were significantly higher in INHALE cf. ZAP, the trials were underpowered to find a significant difference in the ORs of abstinence between the trials. In both trials, the sensory qualities of the rapid-acting NRT and its placebo equivalent, had a significant bearing on abstinence, and subject who correctly guessed their treatment assignment had higher abstinence than those who guessed incorrectly or were unsure.
Conclusions: The combination of nicotine patches and each of two rapid nicotine delivery devices assisted more smokers to quit smoking than use of nicotine patch and placebo. Further research is required to reduce the aversive sensory effects of nicotine mouthsprays and inhalers, and to find effective methods to encourage smokers to use these therapies regularly to replace the roles of smoking.