Are contemporary e-cigarette efficient at delivering nicotine?

This is a question to which the research and development team of the Big Tobacco company, British American Tobacco, tried to answer by studying blood nicotine levels. Dr Ian Fearon, Principal Scientist and Head of Clinical Research for British American Tobacco’s Research and Development Department in Southampton (UK) carried out a survey of smokers recently initiated to e-cigarettes and experienced vapers.

This issue is also a concern raised by the European Commission when elaborating the revised TPD. They required e-cigarette manufacturers to ensure a continuous delivery of nicotine and the guarantee that the product are efficient at doing so. This is a point that Dr Konstantinos Farsalinos explored in a previous article.

Potential nicotine delivery and its effective uptake by individuals, two different approaches

The rationale is that laboratory machine puffing or mathematical modelling studies generally give an indication of the potential nicotine delivery from an e-cigarette but effective nicotine uptake by an individual can only be accurately determined by blood sampling in clinical studies.

The BAT researchers showed that nicotine levels in blood were heterogenous and demonstrate that nicotine delivery was uneven, not only between products but also among participants using the same products and even between experienced and rookie vapers.

Same protocol but two different cohorts

The scientific article combines the results of two studies conducted (Study 1) in Belfast (UK) and (Study 2) in Los Angeles (CA, USA). While the British participants were current smokers who don’t generally use e-cigarettes (rookie vapers), American ones were current experienced vapers who only smoke occasionally and use second generation devices.

Table 1: Study products used in each study (Fearon et al., 2016).

The experimental protocol is detailed in the text and group specificities are described in their Table 1. The protocol involves the use of BAT e-vapor products and combustible cigarettes. The careful reader can immediately notice hat the two combustible tobacco cigarettes were not comparable in term of nicotine content, the British one (JPS Blue by Imperial Brands, 1.0 mg nicotine/cigarette) being stronger than the US one (Marlboro ultralight by Philip Morris, 0.5 mg nicotine/cigarette). The Vype vPro ePen and the Nicolites were the second and first generation devices, respectively.

Figure 1: Plasma nicotine levels in smokers smoking a cigarette or
using an e-cigarette

Study 1 (N=22) was conducted as a a part-randomized, part blinded, crossover study. Participants were smokers and the protocol consisted in a medical check during Visit 1, after 12 h of total abstinence with respect to nicotine to determine baseline conditions, and a Visit 2, two days after, during which e-cigarette and cigarette tests were conducted. Figure 1 shows the average nicotine blood level for e-cigarette users and vapers with time from study 1.

Study 2 (N=18) was conducted as a part-randomized, open-label, crossover study. Participants were regular users of second generation e-cigarettes and occasional smokers. During the two visits, they were asked to follow the protocole. Figure 4 shows the average nicotine blood level for e-cigarette users and vapers in the study 2.

Authors’ remarks regarding the selection of participants

The authors argue that the choice of the cohort may affect the results obtained for a similar e-cigarette which is supported by the fact that the elevation of blood nicotine levels during e-cigarette use was greater for experienced vapers when compared to rookie vapers and under more realistic conditions ad libitum use. Therefore, the design of future nicotine pharmacokinetic studies would require the standardization of protocoles with respect to participant careful selection. However, it would be considered unethical to submit non-smokers to some protocols implying smoking cigarettes, as well as submitting non-smokers to vaping tests.

“Urge to smoke”, satisfaction and nicotine delivery

The BAT researchers remain cautious with the conclusions of their study. It is however possible to interpret the results in more details, and that is what we try to do below.

Figure 3: Changes in smoking urges over time in participants smoking a
cigarette or using a Vype vPro ePen in Study 1.

Following overnight abstinence of at least 12 hours, craving for cigarettes was quantified among study 1 smokers thanks to a “urge to smoke” questionnaire. In both cases, smoking and vaping, the craving score significantly decreased after less than 6 minutes of use (1 puff/30s), almost the same time as required for the blood to show its highest concentration in nicotine (Cmax). With the cigarette, the score stabilized in the higher range in a stationary-like phase as nicotine remained high in blood. Neo-vapers reached a score level similar to rooted smokers after a delay of ±2 minutes but with much less nicotine in their body: The overall gain in nicotine was smaller among neo-vapers (Δ≅1.5) than with rooted smokers (Δ≅10).

Are smokers more anxious about receiving their dose with the Vype ePen vPro than with a cigarette?

Maybe, but what finally is the most important for the satisfaction of vapers, to substantially decrease the score with time or to compare their scores with rooted smokers?

The overall decrease in craving score during the experiment (Δ≅3) is comparable for each category but with a nicotine gain almost one order of magnitude lower, one can reasonably think that a second generation e-cigarette must be able to fulfil a smoker’s need with the added value of releasing less nicotine and to the blood and less toxic compounds to the body than a combustible cigarette for the same physiological effect.

Figure 2: Plasma nicotine levels in smokers smoking a cigarette or using an e-cigarette ad libitum in study 1.

With a use of the Vype ePen vPro ad libitum, the nicotine blood level remained lower than for smokers. However, the fluctuations of the score in time, pronounced with the cigarette, were dampened with the e-cigarette likely able to deliver a more constant dose.

Figure 4: Plasma nicotine levels in e-cigarette users smoking a cigarette or using one of the two different e-cigarettes.

Among experienced vapers (Figure 4), the use of a first generation (Nicolites) doesn’t create a nicotine uptake comparable to a cigarette. The pattern observed with a second generation e-cigarette is almost identical as smoking a Marlboro light stick. The fact that the nicotine yield in blood of a UK smoker is also much higher than a US smoker is much likely imputable to the quality of the cigarette (strong JPS versus Marlboro light).

Nevertheless, compared to Study 1, the nicotine yield in blood of experienced vapers using a second generation e-cigarette is much higher (∼7 ng/ml) than with smokers using the same device (∼2 ng/ml) and evokes different vaping behaviors. Unfortunately, the study didn’t take into consideration the volume of e-liquide consumed during the experiment.

The behavior of vapers is an important parameter to consider in future studies

If the vaping pattern theory was confirmed, mouth-to-lung (MTL) vaping which characterizes neo-vapers would give way to a more advanced vaping mode called direct-lung inhalation (DL), among experienced vapers. A closer look at the settings reveals that neo-vapers in Study 1 used their Vype ePen vPro at 4.55 W while the output power reached 5.6 W in the second study (Figure 1). At higher power, more e-liquid is vaporized per puff, which increases the delivery of nicotine to the blood.

Downward effects or raising power are first a greater exposure to harmful or potentially harmful (HPH) compounds contained in the e-vapor (aldehydes, furans). Secondly, with more heat produced (a simple application of the Joule law), the same e-liquid is more likely to yield more HPH compounds. And thirdly, the probability of gunking up the coil increases, which constitutes an extra source of HPH compounds during the Maillard reaction.

This study also confirms, after Dr Farsalinos’ conclusions, that vaping with a second generation device like the Vype ePen vPro may provide enough comfort for a regular smoker to be successful in switch to vaping without the need to relapse with smoking.

A fast and efficient nicotine delivery is also what is put forward by Philip Morris (PMI) to make the promotion of their new Heat not Brun cigarette, iQOS. BAT’s Glo and iFuse are the major concurrents of PMI’s iQOS in this sector and about to be launched in Japan, like PMI did successfully before trying to conquer the American market.

Fearon, I. M., Eldridge, A., Gale, N., Shepperd, C. J., McEwan, M., Camacho, O. M., … & Proctor, C. J. (2017). E-cigarette Nicotine Delivery: Data and Learnings from Pharmacokinetic Studies. American Journal of Health Behavior, 41(1), 16-32.

More readings about patterns and their potential issues:

What do scientists think about vaping? – Konstantinos Farsalinos at Vapexpo 2016, Paris