JUUL In The Crown? Emerging Nicotine Delivery Systems Douglas E Jorenby, PhD Professor of Medicine, Center for Tobacco Research and Intervention UW School of Medicine and Public Health 14 Feb 2019

I have received research grant support from the US Food and Drug Administration, the National Cancer Institute, and the National Heart, Lung, and Blood Institute.

Objectives Today’s goals are to: Understand multiple generations of ENDS technology and the implications for use; Be able to critically evaluate harm reduction/dual use claims regarding ENDS; Learn how product flavorings and developmental factors may place adolescents at increased risk.

Drug Delivery Mission Parameters Easy to use Available in many environments Variable dosing Low latency to drug onset

First Generation Disposable

First/Second Generation Rechargeable

Second Generation Vape pen

Second Generation Tank systems

Second Generation Mod systems

Third Generation Resembles a USB drive Minimal vapor cloud Pod units Nicotine salt-based delivery system

Imitation is the sincerest form of marketing Vuse Alto Pod System Kit- Key Features Pod mod system from Vuse Includes a mixed pack of Alto Pods Pod flavors: Original, Menthol, Mixed Berry, Rich Tobacco

Suorin ‘Til You Drop

Less Than Meets The Eye Images courtesy of ClearWay MN Forest…. ….or Trees? Images courtesy of ClearWay MN

New Challenges Evolving technology Improved nicotine delivery New form factors/difficult identification Change in output

So Why Should We Care? Vaping is safe, right?

Context Matters “However, the absolute magnitude of any risk attributable to e-cigarette use is likely to be very small in absolute terms, and hence substantially smaller than that arising from tobacco smoking.” Royal College of Physicians, Nicotine Without Smoke. 28 April 2016.

An Alternate View Conclusion 5-1. There is conclusive evidence that in addition to nicotine, most e-cigarette products contain and emit numerous potentially toxic substances. Conclusion 14-1. There is conclusive evidence that e-cigarette devices can explode and cause burns and projectile injuries. Such risk is significantly increased when batteries are of poor quality, stored improperly, or modified by users. Conclusion 14-2. There is conclusive evidence that intentional or accidental exposure to e-liquids (from drinking, eye contact, or dermal contact) can result in adverse health effects including but not limited to seizures, anoxic brain injury, vomiting, and lactic acidosis. Conclusion 14-3. There is conclusive evidence that intentionally or unintentionally drinking or injecting e-liquids can be fatal. National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. https://doi.org/10.17226/24952

An Alternate View Conclusion 5-4. There is substantial evidence that e-cigarette aerosol contains metals. The origin of the metals could be the metallic coil used to heat the e-liquid, other parts of the e-cigarette device, or e-liquids. Product characteristics and use patterns may contribute to differences in the actual metals and metal concentrations measured in e- cigarette aerosol. Conclusion 7-1.There is substantial evidence that e-cigarette aerosols can induce acute endothelial cell dysfunction, although the long-term consequences and outcomes on these parameters with long-term exposure to e-cigarette aerosol are uncertain. Conclusion 7-2.There is substantial evidence that components of e-cigarette aerosols can promote formation of reactive oxygen species/oxidative stress. Although this supports the biological plausibility of tissue injury and disease from long-term exposure to e-cigarette aerosols, generation of reactive oxygen species and oxidative stress induction is generally lower from e-cigarettes than from combustible tobacco cigarette smoke. Conclusion 10-4.There is substantial evidence that some chemicals present in e- cigarette aerosols (e.g., formaldehyde, acrolein) are capable of causing DNA damage and mutagenesis. This supports the biological plausibility that long-term exposure to e- cigarette aerosols could increase risk of cancer and adverse reproductive outcomes. Whether or not the levels of exposure are high enough to contribute to human carcinogenesis remains to be determined. National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. https://doi.org/10.17226/24952

E-cigarettes help people stop smoking. So Why Should We Care? E-cigarettes help people stop smoking.

Cochrane Review Based upon two RCTs Participants using an EC were more likely to have abstained from smoking for at least six months compared with participants using placebo EC (RR 2.29, 95% CI 1.05 to 4.96; placebo 4% versus EC 9%; 2 studies; 662 participants. GRADE: low). The one study that compared EC to nicotine patch found no significant difference in six-month abstinence rates, but the confidence intervals do not rule out a clinically important difference (RR 1.26, 95% CI 0.68 to 2.34; 584 participants. GRADE: very low). Hartmann-Boyce J, et al. Cochrane Database of Systematic Reviews. 2016

Population Survey Results “The adjusted odds of quitting smoking were lower for those that used ENDS at baseline (9.4%, 95% CI = 5.22%-16.38%; AOR = 0.30, 95% CI = 0.13–0.72) compared to smokers who did not use at ENDS (18.9%, 95% CI = 14.24%-24.68%). Smokers who used ENDS daily at some point during the study period were also less likely to quit smoking than nonusers (AOR = 0.17; 95% CI = 0.04–0.82).” Weaver SR, Huang J, Pechacek TF, Heath JW, Ashley DL, Eriksen MP (2018) Are electronic nicotine delivery systems helping cigarette smokers quit? Evidence from a prospective cohort study of U.S. adult smokers, 2015–2016. PLoS ONE 13(7): e0198047

Breaking News! N=886 “The 1-year abstinence rate was 18.0% in the e-cigarette group, as compared with 9.9% in the nicotine-replacement group (relative risk, 1.83; 95% confidence interval [CI], 1.30 to 2.58; P<0.001).” Conducted in three UK NHS service sites between 2015 and 2018 Hajek P, Phillips-Waller A, Przulj D, et al. A randomized trial of e-cigarettes versus nicotine-replacement therapy. N Engl J Med. DOI: 10.1056/NEJMoa1808779.

Pros and Cons Large study with randomized assignment to treatment Relevant real-world comparison Biochemical confirmation Decent follow-up rate (78.8% at 12 mos.) No placebo control Weekly behavioral support from trained staff Non-trivial crossover use of products 80% of quitters vaping at 1 year (vs. 9% NRT) Used 2nd generation devices

Vaping is a harm reduction strategy. So Why Should We Care? Vaping is a harm reduction strategy.

Pop Quiz Remember the conclusions of the Academies of Sciences, Engineering, and Medicine. While vaping may cause less harm, it is not harmless.

The Proof of the Pudding….

More Pudding

And More

Marketing Is Effective Data from WI Dept of Health Services, Youth Tobacco Survey 2018, P-01624 (Rev 01/2019)

Gateway Effects “The positive association between baseline vaping and follow-up smoking frequency was stronger among baseline nonsmokers (n = 2966; OR, 2.51; 95% CI, 2.30-2.75) than baseline infrequent (n = 63; OR, 1.47; 95% CI, 0.98-2.23) and frequent (n = 53; OR, 1.06; 95% CI, 0.72-1.55) smokers (P < .001 for interaction; Table 1 and Table 2). Similar trends were found for smoking heaviness (Table 1).” Leventhal AM, et al. JAMA. 2016;316:1918-1920. A recent meta-analysis concluded that adolescents who first tried e-cigarettes were 3.6 times more likely to be smoking at follow-up. Soneji S, Barrington-Trimis JL, Wills TA, et al. Association between initial use of e-cigarettes and subsequent cigarette smoking among adolescents and young adults: a systematic review and meta-analysis. JAMA Pediatr. 2017;171(8):788–797

Dual Use 59% of e-cigarette users (as of 2015) are actually dual users (vaping + smoking) Centers for Disease Control and Prevention. QuickStats: Cigarette smoking status among current adult e-cigarettes users by age group - National Health Interview Survey, United States, 2015. 2016. https://www.cdc.gov/mmwr/volumes/65/wr/mm6542a7.htm

Tobacco Specific Nitrosamines Shahab L, et al. Annals of Internal Medicine. 2017;166:390-400.

Carbon Monoxide Jorenby DE, et al. Drug and Alcohol Dependence. 2017;170:93-101.

Public Health Implications E-cigarette use has eclipsed traditional smoking Marketing provides attractive flavors and reinforces lowered perceptions of risk Early use increases risk of dependence and progression to smoking Dual use is very common among adults

Summary ENDS technology is evolving rapidly While vaping may cause less harm, it is not harmless Marketing (particularly of non-tobacco flavors) increases youth adoption Early vaping more than triples risk of progression to smoking Dual use carries significant health risks

https://ctri.wisc.edu/providers/e-cigs-and-vaping/ Additional Resources https://ctri.wisc.edu/providers/e-cigs-and-vaping/