INT’L. J. PSYCHIATRY IN MEDICINE, Vol. 48(4) 325-332, 2015
CURRENT AND FUTURE TRENDS IN ELECTRONIC CIGARETTE USE
DAN MCGRAW, PHARMD MUSC Medical Center and SC College of Pharmacy Residency Program
ABSTRACT
The controversy regarding the use of electronic cigarettes as a possible modality for smoking cessation has grown in recent years. Epidemiologic surveys indicate that usage rates in both adults and adolescents have increased substantially as the popularity of these devices continues to rise. At present, there is a small but growing body of evidence studying the possible role that these “e-cigarettes” may have as a nicotine replacement tool. Much of the existing data are from observational studies and surveys which track the epidemiologic and demographic trends of e-cigarette users. More recentlypublished articles have begun to utilize randomized, experimental designs to directly compare the efficacy of e-cigarettes to active and passive controls in outcome measures such as conventional cigarette quit rates and time to relapse. Barriers to widespread adoption of e-cigarette use as a smoking cessation modality include a lack of long-term safety and toxicology data, a lack of standardization of devices, and a debate regarding whether devices can be marketed for both social nicotine use, as well as nicotine replacement. A possible role of e-cigarettes that has not yet been explored is in the primary prevention of conventional cigarette use among young adults that are smoking-naïve. (Int’l. J. Psychiatry in Medicine 2014;48:325-332)
Key Words: nicotine, replacement, e-cig, smoking, cessation 325 Ó 2015, The Author(s) doi: http://dx.doi.org/10.2190/PM.48.4.g ijpm.sagepub.com
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INTRODUCTION In the last decade, the popularity of electronic cigarettes, or “e-cigarettes,” as both a recreational device and smoking cessation aid has continued to rise. The controversy regarding the use of e-cigarettes as a possible modality for smoking cessation has grown in recent years, as well. At present, there is a small but growing body of research studying the possible role that e-cigarettes may have as a nicotine replacement tool. Much of the existing data are from observational studies and surveys which track the epidemiologic and demographic trends of e-cigarette users. More recently-published articles have begun to utilize randomized, experimental designs to directly compare the efficacy of e-cigarettes to active and passive controls in outcome measures such as conventional cigarette quit rates and time to relapse. As prevalence continues to increase, patients and healthcare professionals alike are searching for answers regarding the safety and efficacy of electronic cigarettes. If asked by patients about e-cigarettes for smoking cessation, many providers may endorse their use under the assumption that they cannot possibly be as unsafe as conventional cigarettes. Until recently, however, providers have had no data to support such a recommendation. A possible role of e-cigarettes that has not yet been explored is in the primary prevention of conventional cigarette use among young adults that are smoking-naïve. E-cigarettes differ from conventional nicotine replacement aids in that people who are smoking-naïve do not use nicotine gum or patches. In contrast, nearly 10% of teenage e-cigarette smokers have never used a conventional cigarette before. It would appear that e-cigarettes are in a unique position as agents that replace the novelty of cigarette use among youths rather than the nicotine. As the use of e-cigarettes among young people continues to rise, future observational and epidemiologic studies may see a corresponding reduction in the rates of conventional cigarette use. METHODS The Medline database was utilized using search terms “electronic cigarette” [All Fields] OR “e-cigarette” [All Fields] OR “e-cig” [All Fields]. No publication date limits were employed. This search strategy yielded 110 results; 40 of these articles were published in calendar year 2013. Four of the 110 results were randomized, controlled trials (RCTs). The majority of results were epidemiologic surveys, editorials, and reviews. Three additional articles were identified through the references provided by the articles found in the original Medline search. This article provides a review of the epidemiological trends indicated in the current literature as well as a summary of the key prospective trials that have been undertaken thus far.
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RESULTS A survey conducted by the Office on Smoking and Health within the U.S. Centers for Disease Control and Prevention found that, as of 2011, 1 in 5 adult smokers have tried e-cigarettes at least once. Additionally, the report stated that use of e-cigarettes nearly doubled from 2010 to 2011 [1]. Perhaps more alarming, a second survey conducted by the same agency among adolescents and teenagers found similar trends in use of e-cigarettes. Specifically, overall use of e-cigarettes has increased from 3.3% to 6.8% in 6-12 graders from 2011 to 2012 (p < 0.05). Use among high school-age teens saw the largest overall increase, from 4.7% to 10.0% over the same time period (p < 0.05) [2]. In recently published articles regarding the use of e-cigarettes, there has been a trend in increasing strength of study design. Until recently, much of the available data was derived from cross-sectional surveys and observational studies. In the past few years, there have been several attempts at randomized, controlled trials and there are several more in progress with results yet to be published. The results of a Czech survey conducted by Kralikova and colleagues were published in CHEST in 2013 [3]. The study represents some of the earliest information available regarding the proportion of cigarette smokers who become regular users of e-cigarettes. A total of 1,738 smokers of conventional cigarettes were included in the survey. Participants were asked a series of questions regarding their e-cigarette use and attitudes toward e-cigarettes. Nearly 50% of those surveyed reported trying e-cigarettes at least once; of that group, 18.3% are regular users and 14% daily users of e-cigarettes. Of the 152 subjects classified as regular e-cigarette users, 101 (66%) reported the desire to reduce or discontinue conventional cigarette use as motivation. The authors concluded that nearly 20% of smokers who try e-cigarettes become regular users, and factors such as age, gender, level of addiction, and individual perceptions may influence this progression. They caution the medical community that more safety and efficacy data will be needed in the event that e-cigarettes replace conventional cigarette use on a wider scale. Another survey published in 2013 was conducted by Dawkins et al. to measure the attitudes and behaviors of e-cigarette users [4]. A total of 1,347 participants from 33 different countries took the online survey. Survey participants were current e-cigarette users; 83% described themselves as ex-cigarette smokers and 16% stated that they were current cigarette smokers. The investigators aimed to assess the demographic characteristics of e-cigarette users, the nature of e-cigarette use, and the positive and negative effects of use as reported by e-cigarette users. Of the patients that were labeled “current smokers,” 55% reported that e-cigarette use has led to a dramatic decrease in tobacco consumption and 70% reported a dramatic reduction in tobacco cravings. The authors concluded that a large contingent of e-cigarette consumers use these devices as a method for quitting smoking, some with a high degree of success. The reduction
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in tobacco consumption may be attributed to the reduced tobacco cravings, few side effects, and overall high levels of satisfaction among e-cigarette users who participated. In 2013, Polosa and colleagues published the results of an uncontrolled, prospective cohort study that followed 40 smokers who were given e-cigarettes as nicotine replacement for 24 months [5]. Primary efficacy endpoints were > 50% self-reported cigarette/day reduction compared to baseline; > 80% self-reported cigarette/day reduction compared to baseline; and self-reported abstinence from smoking. The self-reported results were confirmed by commensurate reduction in carbon monoxide exhaled in breath (eCO) for each of the outcomes of interest. The authors found that 40% of participants had decreased cigarette use by > 50% (p < 0.001) at the 24-month mark, including five participants who had achieved complete abstinence (p = 0.042). Additionally, 28% of patients decreased cigarette use by > 80% (p = 0.012). The treatments were well-tolerated and those side effects commonly seen in smoking cessation studies (e.g., depression, anxiety, insomnia, irritability) were largely absent among the participants. In February 2013, Caponnetto and colleagues published the results of the first large-scale long-term randomized trial to study the efficacy and safety of e-cigarettes as nicotine replacement therapy [6]. The ECLAT trial randomized 300 smokers that did not intend on quitting into three treatment arms: 1) a high-nicotine content e-cigarette group; 2) a high-nicotine content followed by low nicotine-content e-cigarette group; and 3) a control group which included no e-cigarette use. Subjects utilized their assigned treatment for 12 weeks and were followed for a total of 12 months. Investigators assessed complete cigarette abstinence and a reduction of daily cigarette use by > 50% as primary endpoints, measured by self-reporting and eCO objective measures. A significant reduction in median cigarette per day use was seen in all three treatment assignments (p < 0.0001). Between-group comparisons were not statistically significant at week 52 and the authors stated that, in large part, no significant differences were observed between groups in cigarette reduction or overall quitting rates. Of note, the study revealed that quit rates in the two combined e-cigarette groups compared with the control group were significantly higher (14% vs. 4%, p = 0.008 at week 12; 11% vs. 4%, p = 0.04 at week 52). One of the primary weaknesses ascribed to the ECLAT trial is the lack of a true comparator group as there was no placebo or active control used in the study design. Subsequently, a New Zealand-based trial conducted by Bullen and colleagues compared e-cigarettes to nicotine patches and a placebo-containing e-cigarette device [7]. A total of 657 smokers who wished to quit were randomized 4:4:1 into one of the three treatment arms. The primary endpoint was sustained cigarette abstinence 6 months after quit date, assessed by subject self-reporting and confirmatory eCO measurements. Statistical significance was not achieved in comparing the primary outcome between the two treatment groups (p = 0.46). Cigarette abstinence at 1-month post quit date did favor e-cigarettes, however
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(23.2% vs. 15.9%, p = 0.03). Relapse rates were notably high for both groups as most subjects relapsed within 50 days of their quit date. The e-cigarette group was associated with a higher percentage of adverse events than the nicotine patch group, including a higher rate of serious adverse events such as hospital admission and prolonged hospital length of stay. Studies investigating the efficacy of e-cigarettes have yielded conflicting results. Trials with weaker study design tended to be more supportive of e-cigarette use compared to those with an experimental design. For example, the Polosa trial, though small and uncontrolled, concluded that e-cigarettes conferred statistically significant benefit in all primary efficacy endpoints. However, when compared against conventional nicotine replacement therapy as in the Bullen study, e-cigarettes fared no better or worse than nicotine patches in terms of 6-month cigarette abstinence. Thus, while the existing literature offers suggestions of smoking cessation efficacy, the data need to be corroborated with larger controlled studies. Additional barriers to widespread adoption of e-cigarette use as a smoking cessation modality include a lack of long-term safety and toxicology data, a lack of standardization of devices, and a debate regarding whether devices can be marketed for both social nicotine use as well as nicotine replacement. The main safety concerns regarding e-cigarette use include the collective uncertainty regarding standardization of e-cigarette ingredients and the lack of long-term adverse event data. To date, there are no published studies evaluating the long-term health effects of e-cigarettes. In 2009, the Food and Drug Administration (FDA) conducted a chemical analysis of the ingredients of two leading e-cigarette products [8]. The analysis included a total of 19 individual samples. Their intent was to quantify the amount of nicotine contained in each product as well as measure the amounts of other known toxins. They found that several impurities thought to be harmful to humans and commonly found in cigarettes were also found in the e-cigarettes (e.g., cotinine, myosamine, anabasine). The analysis also revealed the presence of known carcinogens such as N-nitroso-anabasine in several of the samples. The FDA noted that, due to the design of the analysis, this data cannot be used to draw conclusions pertaining to the ingredients of all e-cigarettes nor can human safety data be extrapolated from the information garnered. Cobb et al. conducted a series of chemical assays to determine amount of nicotine and other excipients were included in three commercially available e-cigarette products [9]. The authors reported that the nicotine content in the devices tested was much lower than advertised. This study also confirmed the conclusion reached by the FDA analysis that toxic impurities and nitrosamines are indeed present in e-cigarette cartridges. As the sample of products was modest and details regarding methodology lacking, it is difficult to generalize the results to the larger e-cigarette market. Additionally, these assays were conducted in 2010 and the results may not account for the mechanical and chemical changes that may have occurred within the industry since then.
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An FDA representative published a summary of adverse events attributable to electronic cigarettes in 2012 [10]. The report describes the system that the FDA and the Center for Tobacco Products (CTP) employs to solicit voluntary adverse event reporting from consumers and health professionals regarding tobacco products. Electronic cigarettes were added to the list of products to monitor after the first adverse event report concerning e-cigarettes was submitted in 2008. At the time of publication, the CTP had received 47 adverse event reports, 8 of which were considered serious. The serious events included pneumonia, heart failure, hypotension, chest pain, tachycardia, vision loss, disorientation, seizure, and 2nd degree burns due to a device explosion. The author notes that, due to the nature in which these instances were reported and collected, no causal relationship can be drawn that implicates e-cigarette use. A systematic review of published studies regarding safety and toxicology profiles of electronic cigarettes was published in 2014 [11]. A total of 97 studies were included in the analysis. The purpose of the review was to assess the level hazard that e-cigarettes pose to users and compare those results to those that are already known about conventional cigarettes. The authors concluded that e-cigarettes are “by far” a safer alternative to conventional cigarettes for those individuals who are already regular smokers. It was noted in the review that while toxic chemicals have been detected in e-cigarette vapor, the levels are much lower compared to those found in tobacco smoke and that the risks of toxicity in e-cigarette users have been exaggerated.
DISCUSSION The CDC report on teenage and adolescent use of e-cigarettes revealed an interesting trend. While an estimated 1.78 million teens have tried e-cigarettes as of 2012, nearly 10% (~160,000) had no prior exposure to conventional cigarettes [2]. The CDC has also found that the rate of conventional cigarette use among adolescents has decreased from 2009 to 2011 [12]. The application of this information by healthcare professionals is limited by the paucity of knowledge regarding e-cigarette safety. It has been suggested that the increase of e-cigarette use among this age group could be detrimental due to the effects that early nicotine exposure can have on developing teenage brains [13]. It has also been suggested that e-cigarettes could act as a “gateway” to conventional cigarette use and addiction, though this concern has not yet been substantiated. An alternative theory that should be explored is that these trends among youth may indicate a possible role of e-cigarettes in the primary prevention of tobacco use. Teenagers that may otherwise go on to use conventional cigarettes could be diverted from doing so through the use of e-cigarettes. To date, no studies have been conducted to validate such a radical theory and the existing CDC data do not provide enough information to draw this conclusion.
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The basis for recommending e-cigarettes to individuals who are currently addicted to conventional cigarettes is weak due to the infancy of requisite efficacy/ safety data. Further, e-cigarettes are largely unregulated by the FDA unlike nicotine replacement aids and, as a result, divergent marketing strategies may exist [14]. The traditional goal of nicotine replacement therapies such as patches and gum is to wean the patient off of all sources of nicotine completely. It is unlikely that members of the $1 billion-a-year e-cigarette industry share that intent. A more realistic view is that e-cigarette companies wish to maintain their customers’ nicotine use as a permanent cigarette replacement. At present, due to the lack of long-term efficacy and safety data as well as the unregulated status that e-cigarette companies currently hold, it may be imprudent to recommend these devices to patients. However, an alternative stance that some providers may hold is that e-cigarettes are no worse than conventional cigarettes. Many clinicians may reasonably presume that, while their long-term risks are not established, e-cigarettes probably pose a much lower public health burden than conventional cigarettes. As a result, some may feel comfortable recommending their use on those grounds alone despite the lack of evidence supporting this claim. Though presently inconclusive, the body of evidence supporting electronic cigarettes for smoking cessation continues to grow. Providers must weigh the risks and benefits that each individual patient may be expected to encounter should e-cigarettes be used as a smoking-cessation tool. A fascinating trend to watch is the effect that e-cigarette use will have on smoking rates among adolescents and young adults, particularly in those who are smoking-naïve.
REFERENCES 1. King B, Alam S, Promoff G, Arrazola R, Dube S. Awareness and ever use of electronic cigarettes among U.S. adults, 2010-2011. Nicotine and Tobacco Research 2013; 15(9):1623-1627. 2. Corey C, Wang B, Johnson S, Apelberg B, Husten C. Electronic cigarette use among middle and high school students – United States, 2011-2012. Mortality and Morbidity Weekly Report 2013;62(35):729-730. 3. Kralikova E, Novak J, West O, Kmetova A, Hajek P. Do e-cigarettes have the potential to compete with conventional cigarettes? A survey of conventional cigarette smokers’ experiences with e-cigarettes. Chest 2013;144(5):1609-1614. 4. Dawkins L, Turner J, Roberts A, Soar K. “Vaping” profiles and preferences: An online survey of electronic cigarette users. Addiction 2013;108(6):1115-1125. 5. Polosa R, Morjaria J, Caponnetto P, et al. Effectiveness and tolerability of electronic cigarette in real life: A 24-month prospective observational study. Internal Emergency Medicine 2014;9(5):537-546. 6. Caponnetto P, Campagna D, Cibella F, et al. Efficiency and safety of an electronic cigarette (ECLAT) as tobacco cigarettes substitute: A prospective 12-month randomized control design study. PLoS ONE 2013;8(6):e66317.
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7. Bullen C, Howe C, Laugesen M, et al. Electronic cigarettes for smoking cessation: A randomized control trial. Lancet 2013;382(9905):1629-1637. 8. Westenberger B. Memo: Evaluation of e-cigarettes. Center for Drug Evaluation and Research, Division of Pharmaceutical Analysis, St. Louis, MO, May 2009. 9. Cobb N, Byron M, Abrams D, Shields P. Novel nicotine delivery systems and public health: The rise of the e-cigarette. American Journal of Public Health 2010;10(2):2340-2342. 10. Chen, I. Letter: FDA summary of adverse events on electronic cigarettes. Nicotine and Tobacco Research 2013;15(2):615-616. 11. Konstantinos E, Polosa R. Safety evaluation and risk assessment of electronic cigarettes as tobacco cigarette substitutes: A systematic review. Therapeutic Advances in Drug Safety 2014;5(2):67-86. 12. Centers for Disease Control and Prevention. Current tobacco use among middle and high school students – United States, 2011. Mortality and Morbidity Weekly Report 2012;61:581-585. 13. Dwyer J, McQuown S, Leslie F. The dynamic effects of nicotine on the developing brain. Pharmacology Therapy 2009;122:125-139. 14. Riker C, Lee K, Darville A, Hahn E. E-cigarettes: Promise or peril? Nursing Clinics of North American 2012;47(1):159-171.
Direct reprint requests to: Current and Future Trends in Electronic Cigarette Use Dan McGraw, PharmD PGY-2 Psychiatric Pharmacy Resident MUSC Medical Center and SC College of Pharmacy Residency Program 280 Calhoun Street, MSC 132 Charleston, SC 29425-1320 e-mail: [email protected]
CURRENT AND FUTURE TRENDS IN ELECTRONIC CIGARETTE USE
DAN MCGRAW, PHARMD MUSC Medical Center and SC College of Pharmacy Residency Program
ABSTRACT
The controversy regarding the use of electronic cigarettes as a possible modality for smoking cessation has grown in recent years. Epidemiologic surveys indicate that usage rates in both adults and adolescents have increased substantially as the popularity of these devices continues to rise. At present, there is a small but growing body of evidence studying the possible role that these “e-cigarettes” may have as a nicotine replacement tool. Much of the existing data are from observational studies and surveys which track the epidemiologic and demographic trends of e-cigarette users. More recentlypublished articles have begun to utilize randomized, experimental designs to directly compare the efficacy of e-cigarettes to active and passive controls in outcome measures such as conventional cigarette quit rates and time to relapse. Barriers to widespread adoption of e-cigarette use as a smoking cessation modality include a lack of long-term safety and toxicology data, a lack of standardization of devices, and a debate regarding whether devices can be marketed for both social nicotine use, as well as nicotine replacement. A possible role of e-cigarettes that has not yet been explored is in the primary prevention of conventional cigarette use among young adults that are smoking-naïve. (Int’l. J. Psychiatry in Medicine 2014;48:325-332)
Key Words: nicotine, replacement, e-cig, smoking, cessation 325 Ó 2015, The Author(s) doi: http://dx.doi.org/10.2190/PM.48.4.g ijpm.sagepub.com
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INTRODUCTION In the last decade, the popularity of electronic cigarettes, or “e-cigarettes,” as both a recreational device and smoking cessation aid has continued to rise. The controversy regarding the use of e-cigarettes as a possible modality for smoking cessation has grown in recent years, as well. At present, there is a small but growing body of research studying the possible role that e-cigarettes may have as a nicotine replacement tool. Much of the existing data are from observational studies and surveys which track the epidemiologic and demographic trends of e-cigarette users. More recently-published articles have begun to utilize randomized, experimental designs to directly compare the efficacy of e-cigarettes to active and passive controls in outcome measures such as conventional cigarette quit rates and time to relapse. As prevalence continues to increase, patients and healthcare professionals alike are searching for answers regarding the safety and efficacy of electronic cigarettes. If asked by patients about e-cigarettes for smoking cessation, many providers may endorse their use under the assumption that they cannot possibly be as unsafe as conventional cigarettes. Until recently, however, providers have had no data to support such a recommendation. A possible role of e-cigarettes that has not yet been explored is in the primary prevention of conventional cigarette use among young adults that are smoking-naïve. E-cigarettes differ from conventional nicotine replacement aids in that people who are smoking-naïve do not use nicotine gum or patches. In contrast, nearly 10% of teenage e-cigarette smokers have never used a conventional cigarette before. It would appear that e-cigarettes are in a unique position as agents that replace the novelty of cigarette use among youths rather than the nicotine. As the use of e-cigarettes among young people continues to rise, future observational and epidemiologic studies may see a corresponding reduction in the rates of conventional cigarette use. METHODS The Medline database was utilized using search terms “electronic cigarette” [All Fields] OR “e-cigarette” [All Fields] OR “e-cig” [All Fields]. No publication date limits were employed. This search strategy yielded 110 results; 40 of these articles were published in calendar year 2013. Four of the 110 results were randomized, controlled trials (RCTs). The majority of results were epidemiologic surveys, editorials, and reviews. Three additional articles were identified through the references provided by the articles found in the original Medline search. This article provides a review of the epidemiological trends indicated in the current literature as well as a summary of the key prospective trials that have been undertaken thus far.
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RESULTS A survey conducted by the Office on Smoking and Health within the U.S. Centers for Disease Control and Prevention found that, as of 2011, 1 in 5 adult smokers have tried e-cigarettes at least once. Additionally, the report stated that use of e-cigarettes nearly doubled from 2010 to 2011 [1]. Perhaps more alarming, a second survey conducted by the same agency among adolescents and teenagers found similar trends in use of e-cigarettes. Specifically, overall use of e-cigarettes has increased from 3.3% to 6.8% in 6-12 graders from 2011 to 2012 (p < 0.05). Use among high school-age teens saw the largest overall increase, from 4.7% to 10.0% over the same time period (p < 0.05) [2]. In recently published articles regarding the use of e-cigarettes, there has been a trend in increasing strength of study design. Until recently, much of the available data was derived from cross-sectional surveys and observational studies. In the past few years, there have been several attempts at randomized, controlled trials and there are several more in progress with results yet to be published. The results of a Czech survey conducted by Kralikova and colleagues were published in CHEST in 2013 [3]. The study represents some of the earliest information available regarding the proportion of cigarette smokers who become regular users of e-cigarettes. A total of 1,738 smokers of conventional cigarettes were included in the survey. Participants were asked a series of questions regarding their e-cigarette use and attitudes toward e-cigarettes. Nearly 50% of those surveyed reported trying e-cigarettes at least once; of that group, 18.3% are regular users and 14% daily users of e-cigarettes. Of the 152 subjects classified as regular e-cigarette users, 101 (66%) reported the desire to reduce or discontinue conventional cigarette use as motivation. The authors concluded that nearly 20% of smokers who try e-cigarettes become regular users, and factors such as age, gender, level of addiction, and individual perceptions may influence this progression. They caution the medical community that more safety and efficacy data will be needed in the event that e-cigarettes replace conventional cigarette use on a wider scale. Another survey published in 2013 was conducted by Dawkins et al. to measure the attitudes and behaviors of e-cigarette users [4]. A total of 1,347 participants from 33 different countries took the online survey. Survey participants were current e-cigarette users; 83% described themselves as ex-cigarette smokers and 16% stated that they were current cigarette smokers. The investigators aimed to assess the demographic characteristics of e-cigarette users, the nature of e-cigarette use, and the positive and negative effects of use as reported by e-cigarette users. Of the patients that were labeled “current smokers,” 55% reported that e-cigarette use has led to a dramatic decrease in tobacco consumption and 70% reported a dramatic reduction in tobacco cravings. The authors concluded that a large contingent of e-cigarette consumers use these devices as a method for quitting smoking, some with a high degree of success. The reduction
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in tobacco consumption may be attributed to the reduced tobacco cravings, few side effects, and overall high levels of satisfaction among e-cigarette users who participated. In 2013, Polosa and colleagues published the results of an uncontrolled, prospective cohort study that followed 40 smokers who were given e-cigarettes as nicotine replacement for 24 months [5]. Primary efficacy endpoints were > 50% self-reported cigarette/day reduction compared to baseline; > 80% self-reported cigarette/day reduction compared to baseline; and self-reported abstinence from smoking. The self-reported results were confirmed by commensurate reduction in carbon monoxide exhaled in breath (eCO) for each of the outcomes of interest. The authors found that 40% of participants had decreased cigarette use by > 50% (p < 0.001) at the 24-month mark, including five participants who had achieved complete abstinence (p = 0.042). Additionally, 28% of patients decreased cigarette use by > 80% (p = 0.012). The treatments were well-tolerated and those side effects commonly seen in smoking cessation studies (e.g., depression, anxiety, insomnia, irritability) were largely absent among the participants. In February 2013, Caponnetto and colleagues published the results of the first large-scale long-term randomized trial to study the efficacy and safety of e-cigarettes as nicotine replacement therapy [6]. The ECLAT trial randomized 300 smokers that did not intend on quitting into three treatment arms: 1) a high-nicotine content e-cigarette group; 2) a high-nicotine content followed by low nicotine-content e-cigarette group; and 3) a control group which included no e-cigarette use. Subjects utilized their assigned treatment for 12 weeks and were followed for a total of 12 months. Investigators assessed complete cigarette abstinence and a reduction of daily cigarette use by > 50% as primary endpoints, measured by self-reporting and eCO objective measures. A significant reduction in median cigarette per day use was seen in all three treatment assignments (p < 0.0001). Between-group comparisons were not statistically significant at week 52 and the authors stated that, in large part, no significant differences were observed between groups in cigarette reduction or overall quitting rates. Of note, the study revealed that quit rates in the two combined e-cigarette groups compared with the control group were significantly higher (14% vs. 4%, p = 0.008 at week 12; 11% vs. 4%, p = 0.04 at week 52). One of the primary weaknesses ascribed to the ECLAT trial is the lack of a true comparator group as there was no placebo or active control used in the study design. Subsequently, a New Zealand-based trial conducted by Bullen and colleagues compared e-cigarettes to nicotine patches and a placebo-containing e-cigarette device [7]. A total of 657 smokers who wished to quit were randomized 4:4:1 into one of the three treatment arms. The primary endpoint was sustained cigarette abstinence 6 months after quit date, assessed by subject self-reporting and confirmatory eCO measurements. Statistical significance was not achieved in comparing the primary outcome between the two treatment groups (p = 0.46). Cigarette abstinence at 1-month post quit date did favor e-cigarettes, however
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329
(23.2% vs. 15.9%, p = 0.03). Relapse rates were notably high for both groups as most subjects relapsed within 50 days of their quit date. The e-cigarette group was associated with a higher percentage of adverse events than the nicotine patch group, including a higher rate of serious adverse events such as hospital admission and prolonged hospital length of stay. Studies investigating the efficacy of e-cigarettes have yielded conflicting results. Trials with weaker study design tended to be more supportive of e-cigarette use compared to those with an experimental design. For example, the Polosa trial, though small and uncontrolled, concluded that e-cigarettes conferred statistically significant benefit in all primary efficacy endpoints. However, when compared against conventional nicotine replacement therapy as in the Bullen study, e-cigarettes fared no better or worse than nicotine patches in terms of 6-month cigarette abstinence. Thus, while the existing literature offers suggestions of smoking cessation efficacy, the data need to be corroborated with larger controlled studies. Additional barriers to widespread adoption of e-cigarette use as a smoking cessation modality include a lack of long-term safety and toxicology data, a lack of standardization of devices, and a debate regarding whether devices can be marketed for both social nicotine use as well as nicotine replacement. The main safety concerns regarding e-cigarette use include the collective uncertainty regarding standardization of e-cigarette ingredients and the lack of long-term adverse event data. To date, there are no published studies evaluating the long-term health effects of e-cigarettes. In 2009, the Food and Drug Administration (FDA) conducted a chemical analysis of the ingredients of two leading e-cigarette products [8]. The analysis included a total of 19 individual samples. Their intent was to quantify the amount of nicotine contained in each product as well as measure the amounts of other known toxins. They found that several impurities thought to be harmful to humans and commonly found in cigarettes were also found in the e-cigarettes (e.g., cotinine, myosamine, anabasine). The analysis also revealed the presence of known carcinogens such as N-nitroso-anabasine in several of the samples. The FDA noted that, due to the design of the analysis, this data cannot be used to draw conclusions pertaining to the ingredients of all e-cigarettes nor can human safety data be extrapolated from the information garnered. Cobb et al. conducted a series of chemical assays to determine amount of nicotine and other excipients were included in three commercially available e-cigarette products [9]. The authors reported that the nicotine content in the devices tested was much lower than advertised. This study also confirmed the conclusion reached by the FDA analysis that toxic impurities and nitrosamines are indeed present in e-cigarette cartridges. As the sample of products was modest and details regarding methodology lacking, it is difficult to generalize the results to the larger e-cigarette market. Additionally, these assays were conducted in 2010 and the results may not account for the mechanical and chemical changes that may have occurred within the industry since then.
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An FDA representative published a summary of adverse events attributable to electronic cigarettes in 2012 [10]. The report describes the system that the FDA and the Center for Tobacco Products (CTP) employs to solicit voluntary adverse event reporting from consumers and health professionals regarding tobacco products. Electronic cigarettes were added to the list of products to monitor after the first adverse event report concerning e-cigarettes was submitted in 2008. At the time of publication, the CTP had received 47 adverse event reports, 8 of which were considered serious. The serious events included pneumonia, heart failure, hypotension, chest pain, tachycardia, vision loss, disorientation, seizure, and 2nd degree burns due to a device explosion. The author notes that, due to the nature in which these instances were reported and collected, no causal relationship can be drawn that implicates e-cigarette use. A systematic review of published studies regarding safety and toxicology profiles of electronic cigarettes was published in 2014 [11]. A total of 97 studies were included in the analysis. The purpose of the review was to assess the level hazard that e-cigarettes pose to users and compare those results to those that are already known about conventional cigarettes. The authors concluded that e-cigarettes are “by far” a safer alternative to conventional cigarettes for those individuals who are already regular smokers. It was noted in the review that while toxic chemicals have been detected in e-cigarette vapor, the levels are much lower compared to those found in tobacco smoke and that the risks of toxicity in e-cigarette users have been exaggerated.
DISCUSSION The CDC report on teenage and adolescent use of e-cigarettes revealed an interesting trend. While an estimated 1.78 million teens have tried e-cigarettes as of 2012, nearly 10% (~160,000) had no prior exposure to conventional cigarettes [2]. The CDC has also found that the rate of conventional cigarette use among adolescents has decreased from 2009 to 2011 [12]. The application of this information by healthcare professionals is limited by the paucity of knowledge regarding e-cigarette safety. It has been suggested that the increase of e-cigarette use among this age group could be detrimental due to the effects that early nicotine exposure can have on developing teenage brains [13]. It has also been suggested that e-cigarettes could act as a “gateway” to conventional cigarette use and addiction, though this concern has not yet been substantiated. An alternative theory that should be explored is that these trends among youth may indicate a possible role of e-cigarettes in the primary prevention of tobacco use. Teenagers that may otherwise go on to use conventional cigarettes could be diverted from doing so through the use of e-cigarettes. To date, no studies have been conducted to validate such a radical theory and the existing CDC data do not provide enough information to draw this conclusion.
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The basis for recommending e-cigarettes to individuals who are currently addicted to conventional cigarettes is weak due to the infancy of requisite efficacy/ safety data. Further, e-cigarettes are largely unregulated by the FDA unlike nicotine replacement aids and, as a result, divergent marketing strategies may exist [14]. The traditional goal of nicotine replacement therapies such as patches and gum is to wean the patient off of all sources of nicotine completely. It is unlikely that members of the $1 billion-a-year e-cigarette industry share that intent. A more realistic view is that e-cigarette companies wish to maintain their customers’ nicotine use as a permanent cigarette replacement. At present, due to the lack of long-term efficacy and safety data as well as the unregulated status that e-cigarette companies currently hold, it may be imprudent to recommend these devices to patients. However, an alternative stance that some providers may hold is that e-cigarettes are no worse than conventional cigarettes. Many clinicians may reasonably presume that, while their long-term risks are not established, e-cigarettes probably pose a much lower public health burden than conventional cigarettes. As a result, some may feel comfortable recommending their use on those grounds alone despite the lack of evidence supporting this claim. Though presently inconclusive, the body of evidence supporting electronic cigarettes for smoking cessation continues to grow. Providers must weigh the risks and benefits that each individual patient may be expected to encounter should e-cigarettes be used as a smoking-cessation tool. A fascinating trend to watch is the effect that e-cigarette use will have on smoking rates among adolescents and young adults, particularly in those who are smoking-naïve.
REFERENCES 1. King B, Alam S, Promoff G, Arrazola R, Dube S. Awareness and ever use of electronic cigarettes among U.S. adults, 2010-2011. Nicotine and Tobacco Research 2013; 15(9):1623-1627. 2. Corey C, Wang B, Johnson S, Apelberg B, Husten C. Electronic cigarette use among middle and high school students – United States, 2011-2012. Mortality and Morbidity Weekly Report 2013;62(35):729-730. 3. Kralikova E, Novak J, West O, Kmetova A, Hajek P. Do e-cigarettes have the potential to compete with conventional cigarettes? A survey of conventional cigarette smokers’ experiences with e-cigarettes. Chest 2013;144(5):1609-1614. 4. Dawkins L, Turner J, Roberts A, Soar K. “Vaping” profiles and preferences: An online survey of electronic cigarette users. Addiction 2013;108(6):1115-1125. 5. Polosa R, Morjaria J, Caponnetto P, et al. Effectiveness and tolerability of electronic cigarette in real life: A 24-month prospective observational study. Internal Emergency Medicine 2014;9(5):537-546. 6. Caponnetto P, Campagna D, Cibella F, et al. Efficiency and safety of an electronic cigarette (ECLAT) as tobacco cigarettes substitute: A prospective 12-month randomized control design study. PLoS ONE 2013;8(6):e66317.
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7. Bullen C, Howe C, Laugesen M, et al. Electronic cigarettes for smoking cessation: A randomized control trial. Lancet 2013;382(9905):1629-1637. 8. Westenberger B. Memo: Evaluation of e-cigarettes. Center for Drug Evaluation and Research, Division of Pharmaceutical Analysis, St. Louis, MO, May 2009. 9. Cobb N, Byron M, Abrams D, Shields P. Novel nicotine delivery systems and public health: The rise of the e-cigarette. American Journal of Public Health 2010;10(2):2340-2342. 10. Chen, I. Letter: FDA summary of adverse events on electronic cigarettes. Nicotine and Tobacco Research 2013;15(2):615-616. 11. Konstantinos E, Polosa R. Safety evaluation and risk assessment of electronic cigarettes as tobacco cigarette substitutes: A systematic review. Therapeutic Advances in Drug Safety 2014;5(2):67-86. 12. Centers for Disease Control and Prevention. Current tobacco use among middle and high school students – United States, 2011. Mortality and Morbidity Weekly Report 2012;61:581-585. 13. Dwyer J, McQuown S, Leslie F. The dynamic effects of nicotine on the developing brain. Pharmacology Therapy 2009;122:125-139. 14. Riker C, Lee K, Darville A, Hahn E. E-cigarettes: Promise or peril? Nursing Clinics of North American 2012;47(1):159-171.
Direct reprint requests to: Current and Future Trends in Electronic Cigarette Use Dan McGraw, PharmD PGY-2 Psychiatric Pharmacy Resident MUSC Medical Center and SC College of Pharmacy Residency Program 280 Calhoun Street, MSC 132 Charleston, SC 29425-1320 e-mail: [email protected]
