Tobacco use is the leading preventable cause of death and disability in the world and shaves off years of the lives of long-term smokers. The prospect of tobacco-free, nicotine-rich cigarette use as a potential deterrent to tobacco use in the United States has become a controversial health issue since electronic cigarettes reached U.S. markets in 2007.

The "e-cigarette" (alternatively known as (E)lectronic (N)icotine (D)evice (S)ystem -- ENDS) is a battery-operated hand-held device that heats a fluid mix containing nicotine, propylene glycol, flavoring, and other chemicals allowing for direct inhalation of the vapors. Introduced in China in 2004, e-cigarettes have grossed over $3 billion dollars in revenue globally in 2013 alone, with sales forecasted to increase by a factor of 17 by 2030. (1) With hundreds of e-cigarette brands currently on the market and millions of e-cigarette users across the globe, the habit of "vaping" (the act of inhalation from an e-cigarette) is an emerged and persistent activity that is only increasing in popularity and production. E-cigarettes are here to stay.

A brief history of U.S. regulation

Amid the rise of the e-cigarette industry, the U.S. regulatory agencies were quick to take notice of the increasing use of e-cigarettes by young adults and the questionable marketing and advertising practices of e-cigarette distributors. Only recently have they been able to act on these dubious practices.

In 2008, the U.S. Food and Drug Administration (F.D.A.) attempted to classify e-cigarettes as a drug, which would imply a necessity for it to be proven safe before distribution. Prior to fully enacting this classification, the e-cigarette industry struck back with a lawsuit; subsequently this case was struck down. Two years later, the federal appeals court concluded that the F.D.A. has the right to regulate e-cigarettes as tobacco products instead of a drug. Notably, this classification does not require manufacturers and distributors to prove that e-cigarettes are safe.

In 2014, the F.D.A. proposed a rule that would give them power to authorize health warning labels and restrict sales of e-cigarettes to those 18 or older. Last week, this rule was finally issued. When it comes into effect, e-cigarette companies will be required to register with the F.D.A. and provide information regarding the ingredients and manufacturing processes of their products.(2-5)

Why should we care?

Electronic cigarettes do not combust tobacco, resulting in a substantially decreased amount of carcinogenic byproducts associated with tobacco smoking. Should smokers choose to replace regular tobacco use with electronic cigarettes, individual and population health may substantially improve. There are some data to suggest that this may be occurring. A 2014 Cochrane meta-analysis demonstrated a greater proportion of e-cigarette users reducing tobacco consumption than placebo or nicotine patch users by 8-20 fewer cigarettes. (6)

At first glance, this is compelling evidence that e-cigarettes should have an immediate place in addiction medicine. However, no studies to date have reported on the long-term impact -- good or bad -- of sustained e-cigarette use. Moreover, only two randomized controlled trials were used in the final meta-analysis.

The plot thickens: A recent systematic review and meta-analysis suggests a conflicting conclusion. The authors found lower odds of cigarette cessation among those who had used e-cigarettes compared to those who had not. (7) This meta-analysis was notably plagued with heterogeneity (i.e., large clinical and methodological diversity among the various studies reviewed) and included studies designed with inherent biases and potential confounders (observational and cross-sectional studies).

While the small amount of available research has demonstrated conflicting results regarding the reduction of tobacco products in e-cigarette smokers, they only focus on half of the risk/benefit profile. Simply put, the medical community does not have a good hold on the sustained harms of electronic cigarette use.

What are we vaping?

The quick answer is: Without regulation, we don't know. And what we do know is concerning:

1. Nicotine: Nicotine is a drug with addictive properties and potential side effects. In vitro studies have associated nicotine with cardiovascular disease and birth defects and case studies have demonstrated nicotine accidental overdose poisoning from e-cigarette use and exposure. (8)

2. Propylene glycol: Propylene glycol, used in various products from fog machines to IV medication preparations, is classified by the F.D.A. as "generally recognized as safe." However, when directly inhaled, propylene glycol has been associated with numerous adverse events including airway obstruction, headaches, dizziness, and drowsiness.(8)

3. Flavorings: A recent random sampling of flavored e-cigarettes were found to include flavoring chemicals previously associated with severe lung disease via indirect inhalation in microwave popcorn factory workers. (9)

At this point in time, no standards exist regarding the ingredients made to produce electronic cigarettes and labels may inaccurately describe the contents of liquid cartridges. One brand of e-cigarettes may carry completely different substances than another, and manufactures are not liable to publically publish ingredients or demonstrate safety in their products.

Who is vaping?

Current tobacco smokers are not the only cohort of individuals using electronic cigarettes.

A random-sample repeated survey between 2010-2013 found that 20% of current e-cigarette users had either never smoked or were former smokers. (10) Another prospective observational study found that among teens who had never used tobacco, exposure to e-cigarettes increased the likelihood of future use of tobacco products. (11) Although uncontrolled and preliminary, these studies imply that electronic cigarette use has the potential to both function as a gateway for those who were previously nicotine-naïve to nicotine addiction and also maintain nicotine addiction in former smokers.

Do no harm

Our current understanding of electronic cigarette use has significant knowledge gaps regarding safety, efficacy, and superiority of e-cigarettes as pharmacotherapy for tobacco cessation or reduction. Perhaps in future e-cigarettes will be an integral facet to harm-reduction in addiction medicine -- we should not discount this possibility and encourage it if found safe and effective through more extensive research. But until then, the use of e-cigarettes for the purpose of tobacco cessation is currently not approved nor supported by evidence and should be seen as "beyond off-label" by clinicians.

There are seven different forms of pharmacotherapy currently approved by the F.D.A. and demonstrated through rigorous research to be at least somewhat effective and safe for the treatment for tobacco addiction. Until we know more about the sustained risks and benefits of electronic cigarettes, clinicians should discourage all electronic cigarette use for tobacco-naive patients and, for the majority of current smokers, focus on standard-of-care practices for treating tobacco addiction.

Written as an independent opinion piece for One Medical Group

Citations:

1. Conference of the Parties to the WHO Framework Conventionon Tobacco Control Sixth session: Provisional agenda item 4.4.2 Moscow, Russian Federation,13-18 October 2014 link

2. McMillen RC, Gottlieb MA, Winickoff JP. e-Cigarettes-The Roles of Regulation and Clinicians. JAMA Intern Med. 2015 Oct 1;175(10):1603-4. link

3. Bartter T. Electronic Cigarettes: Aggregate Harm.Ann Intern Med. 2015 Jul 7;163(1):59-60. link

4. Ebbert JO, Agunwamba AA, Rutten LJ. Counseling patients on the use of electronic cigarettes. Mayo Clin Proc. 2015 Jan;90(1):128-34. link

5. Tavernise, S. F.D.A. Imposes Rules for E-Cigarettes in a Landmark Move. New York Times 2016 link

6. McRobbie H, Bullen C, Hartmann-Boyce J, Hajek P. Electronic cigarettes for smoking cessation and reduction. Cochrane Database Syst Rev. 2014. link

7. Kalkhoran, Sara et al. E-cigarettes and smoking cessation in real-world and clinical settings: a systematic review and meta-analysis
The Lancet Respiratory Medicine 0:0 Published Online: 14 January 2016 link

8. Jerry JM, Collins GB, Streem D. E-cigarettes: Safe to recommend to patients? Cleve Clin J Med. 2015 Aug;82(8):521-6. link

9. Allen JG, Flanigan SS, LeBlanc M, Vallarino J, MacNaughton P, Stewart JH, Christiani DC. Flavoring Chemicals in E-Cigarettes: Diacetyl, 2,3-Pentanedione, and Acetoin in a Sample of 51 Products, Including Fruit-, Candy-, and Cocktail-Flavored E-Cigarettes. Environ Health Perspect. 2015 Dec 8. link

10. McMillen RC, Gottlieb MA, Shaefer RM, Winickoff JP, Klein JD. Trends in Electronic Cigarette Use Among U.S. Adults: Use is Increasing in Both Smokers and Nonsmokers. Nicotine Tob Res. 2015 Oct;17(10):1195-202. link

11. Leventhal AM, Strong DR, Kirkpatrick MG, Unger JB, Sussman S, Riggs NR, Stone MD, Khoddam R, Samet JM, Audrain-McGovern J. Association of Electronic Cigarette Use With Initiation of Combustible Tobacco Product Smoking in Early Adolescence. JAMA. 2015 Aug 18;314(7):700-7. link

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Brian Secemsky, M.D.

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