Effect of an electronic nicotine delivery device (e-Cigarette) on smoking reduction and cessation: a prospective 6-month pilot study

With well over one billion smokers' worldwide, cigarette smoking is a global epidemic that poses a substantial health burden and costs [1]. This is because cigarette smoke harms several organ systems of the human body, thus causing a broad range of diseases, many of which are fatal [2, 3]. The risk of serious disease diminishes rapidly after quitting and life-long abstinence is known to reduce the risk of lung cancer, heart disease, strokes, chronic lung disease and other cancers [4, 5].

Although evidence-based recommendations indicate that smoking cessation programs are useful in helping smokers to quit [6], smoking is a very difficult addiction to break. It has been shown that approximately 80% of smokers who attempt to quit on their own, relapse within the first month of abstinence and only about 3-5% remain abstinent at 6 months [7]. Although there is little doubt that currently-marketed smoking cessation products increase the chance of committed smokers to stop smoking, they reportedly lack high levels of efficacy, especially in the real life setting [8]. Although this is known to reflect the chronic relapsing nature of tobacco dependence, the need for novel and effective approaches to smoking cessation interventions is beyond doubt.

The electronic-cigarette (e-Cigarette) is a battery-powered electronic nicotine delivery device (ENDD) resembling a cigarette designed for the purpose of nicotine delivery,where no tobacco or combustion is necessary for its operation [9] (Figure 1). Consequently, this product may be considered as a lower risk substitute for factory-made cigarettes. In addition, people report buying them to help quit smoking, to reduce cigarette consumption and to relieve tobacco withdrawal symptoms due to workplace smoking restrictions [10]. Besides delivering nicotine, e-Cigarettes may also provide a coping mechanism for conditioned smoking cues by replacing some of the rituals associated with smoking gestures (e.g. hand-to-mouth action of smoking). For this reason, e-Cigarettes may help smokers to remain abstinent during their quit attempt or to reduce cigarette consumption. A recent internet survey on the satisfaction of e-Cigarette use has reported that the device helped in smoking abstinence and improved smoking-related symptoms [11]. Under acute experimental conditions, two marketed electronic cigarette brands suppressed tobacco abstinence symptom ratings without leading to measurable levels of nicotine or CO in the exhaled breath [12]. The e-Cigarette is a very hot topic that has generated considerable global debate with authorities wanting to ban it or at least regulate it. Consequently, a formal demonstration supporting the efficacy and safety of these devices in smoking cessation and/or smoking reduction studies would be of utmost importance.

With this in mind, we designed a prospective proof-of-concept study to monitor possible modifications in the smoking habits of a group of well characterized regular smokers experimenting the most popular marketed e-Cigarette in Italy ('Categoria'; Arbi Group Srl, Milano, Italy) focusing on smoking reduction and smoking abstinence. We also monitored adverse events and measured participants' perception and acceptance of the product.

In this pilot study, we have shown for the first time that substantial and objective modifications in the smoking habits may occur in smokers using e-Cigarettes, with significant smoking reduction and smoking abstinence and no apparent increase in withdrawal symptoms. Participants were not only enthusiastic about using the e-Cigarette, but the majority (67.5%) were also able to adhere to the program and to return for the final follow-up visit at week-24 with an overall quit rate of 22.5%. Moreover, at least 50% reduction in cigarette smoking was observed in 32.5% of participants. Overall, combined reduction and smoking abstinence was shown in 55% of participants. These preliminary findings are of great significance in view of the fact that all smokers in the study were, by inclusion criteria, not interested in quitting. Although not directly comparable with classic cessation and/or reduction studies with other pharmaceutical products because of its design (the present study is not an ordinary cessation study), the results of our study are in general accordance with the findings published in the medical literature [17].

The large magnitude of this effect suggests the e-Cigarette strongly suppressed cigarette use. However, no correlations were observed between the number of nicotine cartridges/day used and the level of smoking reduction. This is not unexpected, in view of the powerful interaction between physical and behavioural dependence of smoking [18, 19] and the modest increases in blood nicotine levels measured after the use of this type of devices [20]. Therefore, it is unlikely that the observed positive effect of the e-Cigarette is due to nicotine delivery. Rather, the strong suppression of smoking in association with the absence of correlation between cartridges use and level of smoking reduction, suggests that the positive effect of the e-Cigarette may be also due to its capacity to provide a coping mechanism for conditioned smoking cues by replacing some of the rituals associated with smoking gestures (e.g. hand-to-mouth action of smoking). In agreement with this, we have recently demonstrated that nicotine free inhalators can only improve quit rates in those smokers for whom handling and manipulation of their cigarette played an important role in their ritual of smoking [21].

Although dry cough and mouth ulcers can be associated with withdrawal effects, typical withdrawal symptoms of smoking cessation trials with drugs for nicotine dependence were not reported during the course of the study. It is possible that the e-Cigarette by providing a coping mechanism for conditioned smoking cues could mitigate withdrawal symptoms associated with smoking reduction and smoking abstinence. In contrast from other ENDDs such as Eclipse (which is known to generate substantial level of eCO) [22], e-Cigarettes use does not lead to increased eCO levels [12]. In the present study, the smoking reduction with 'Categoria' e-Cigarette use was associated to a substantial decrease in the level of eCO. The most frequent adverse events were mouth irritation, throat irritation and dry cough, but all appeared to wane spontaneously with time. These are likely to be secondary to exposure to propylene glycol mist generated by the e-Cigarette's atomizer. Propylene glycol is a low toxicity compound widely used as a food additive and in pharmaceutical preparations. Exposure to propylene glycol mist may occur from smoke generators in discotheques, theatres, and aviation emergency training and is known to cause ocular, mouth, throat, upper airway irritation and cough [23, 24]. Dizziness was often reported by participants at the beginning of the study and can be brought about by the hyperventilation associated to the greater puffing time with the e-Cigarette. Alternatively, the dizziness as well as other reported adverse events such as nausea and headaches may be due to nicotine overuse. The substantial reduction in the frequency of dizziness observed by the end of the study may be due to the improved familiarisation with the puffing technique and/or to the overall reduction in nicotine use. Therefore, the 'Categoria'" e-Cigarette can be seen as a safe way to smoke although larger and longer studies will be required for a full assessment of its adverse events.

The 'Categoria' e-Cigarette rated high scores for a range of subjective ratings of user preferences suggesting that the product was functioning as an adequate cigarette substitute. Hence, participants were more likely to recommend the e-Cigarette to friends or relatives. Conversely, as would be expected the perception and acceptance of the product by those who failed to remain abstinent or to reduce smoking was poor and these individuals were unlikely to recommend the e-Cigarette. We cannot exclude that technical problems (particularly those who went unreported) and difficulty of use (it takes time to familiarize with the puffing technique) could have affected the number of lost to follow-up and failures. Although the overall participants' perception and acceptance of the product was good, its ease of use could be improved. Technical defects could be reduced by increasing manufacturing standards, providing a recharge lasting at least 24 hours, reducing the weight of the device and substituting the hard plastic mouthpiece. These latter two suggestions would improve device acceptability for certain common rituals of cigarette smoking, e.g. keeping the cigarette between lips.

Harm-reduction strategies are aimed at reducing the adverse health effects of tobacco use in individuals unable or unwilling to quit. Reducing the number of cig/day is one of several kinds of harm reduction strategies [25]. It is uncertain whether substantial smoking reduction in smokers using the e-Cigarette will translate in health benefits, but a number of studies have analyzed the ability of smoking reduction to lower health risks and have reported some reductions in cardiovascular risk factors and lung cancer mortality [26‐28]. Moreover, reduction in cigarette smoking by e-Cigarette may well increase motivation to quit as indicated by a substantial body of evidence showing that gradually cutting down smoking can increase subsequent smoking cessation among smokers [15, 29‐32]. While not the treatment of choice, reduced smoking strategies might be considered for recalcitrant smokers unwilling to quit, as in the case of our study population.

There are some limitations in our study. Firstly, this was a small uncontrolled study, hence the results observed may be due to a chance finding and not to a true effect; consequently the results should be interpreted with caution. However, it would have been quite problematic to have a placebo arm in such a study. Secondly, 32.5% of the participants failed to attend their final follow-up visit, but this is not unexpected in a smoking cessation study. Thirdly, because of its unusual design (smokers not willing to quit, e-Cigarettes were used throughout the entire study period) this is not an ordinary cessation study and therefore direct comparison with other smoking cessation products cannot be made. Fourthly, failure to complete the study and smoking cessation failures could be due to occurrence of technical defects for the e-Cigarette. However, this could not be assessed with confidence in the present study. Lastly, assessment of withdrawal symptoms in our study was not rigorous. Withdrawal was assessed at each visit by simply asking about the presence/absence of irritability, restlessness, difficulty concentrating, increased appetite/weight gain, depression or insomnia. It is likely that this way of collecting information is liable to recall bias. Therefore, the reported lack of withdrawal symptoms in the study participants should be considered with caution.

Current smoking cessation interventions can increase the chance of quitting in committed smokers who are already motivated and prepared to stop smoking [33], but a broader range of interventions are needed in order to bring more smokers into treatment and increase the numbers who are motivated to make quit attempts. Although not formally regulated as a pharmaceutical product, the e-Cigarette can help smokers to remain abstinent or reduce their cigarette consumption. By replacing tobacco cigarettes, the e-cigarette can only save lives.

Here we show for the first time that e-Cigarettes can substantially decrease cigarette consumption without causing significant side effects in smokers not intending to quit. However, large and carefully conducted RCTs will be required before a definite answer about the efficacy and safety of these devices can be formulated. Some of these trials are now in progress in Italy [34‐36] and New Zealand [37] and hopefully they will be able to confirm and expand the preliminary observations reported in the present article.