E-Cigarettes & Heated Tobacco Products:Latest Developments

Robert M. Anthenelli, M.D.

Professor and Interim Chair

Director, Pacific Treatment and Research Center

Department of Psychiatry

University of California, San Diego, Health Sciences

Acknowledgements

• Dr. Anthenelli’s research is supported by:

– National Institute on Alcohol Abuse and Alcoholism (NIAAA) Award # R44 AA024643

– UCOP Tobacco-Related Disease Research Program Award# T29IPO379

– National Institute on Drug Abuse (NIDA) Award# UO1 DA041731

– NIAAA’s Collaborative Study on the Genetics of Alcoholism Award # U10 AA008401

– …and thanks to Lindsay Gomez and Dr. Natassia Gaznick for help with slides and visuals

Disclosures

• Consulting Agreements: Astraea Therapeutics; Pfizer

• Other Research Support: Pfizer (drug supply for UCOP TRDRP Award # T29IPO379)

• Discussion of Off-Label Drug Use: Electronic nicotine delivery systems (ENDS) and Heated Tobacco Products (HTPs) are not U.S. FDA-approved for smoking cessation

• The opinions expressed in this talk are Dr. Anthenelli’s own and do not necessarily reflect the views of the University of California

Objectives

• Examine the rapid growth of electronic nicotine delivery systems (ENDS) aka E-cigarettes and Heated Tobacco Products (HTPs) aka Heat-not-Burn Tobacco Products

• Describe evolution of e-cigarettes and Heat-not-Burn (HnB) Tobacco Products

• Discuss evidence whether they aid smoking cessation

• Describe alarming trend of greater use in teens

• Describe the effects of nicotine on the brain’s reward circuit and how that contributes to an addicted brain

Global Trends and Projections for Tobacco Use 1990-2025

First, the good news…

• For 2000-2010, smoking prevalence ↓ in 72% of countries in men and 87% of countries in women

But, the bad news…

• Only 21% of countries for men and 49% for women are on track to achieve targeta reductions

• Smoking burden projected to shift geographically

• Estimated 1.1 billion smokers in 2025

aWHO target 30% relative reduction in tobacco smoking from baseline 2010 to 2025 (i.e., 2% reduction per year). From Bilano V et al. Lancet 2015; 385: 966-976

While Smoking Combustible Cigarettes Is On The Decline, Use of ENDS is Increasing

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Global E-Cigarette Market Projections

a Compound Annual Growth Rate (CAGR) estimate = 23.8%

b CAGR estimate = 8.3%

a https://www.askthetrainer.com/global-trends-in-e-cigarette-use/ accessed October 9, 2019; bhttps://www.mordorintelligence.com/industry-reports/global-e-cigarettes-market-industry accessed October 9, 2019

Current Use (2013-2017) of Nicotine Vaping Products from 14 International Tobacco Control Policy Evaluation Project (ITC Project)

Gravely S. et al. Addiction 2019

Electronic Cigarettes (E-cigarettes)

• Battery-operated nicotine delivery devices gaining popularity as a ‘safer’ alternative to smoking conventional tobacco cigarettes

• Generally comprised of 3 components

– A cartridge holding a liquid solution containing nicotine, flavorants and other chemicals

– A heating device (vaporizer)

– A power source (usually a battery)

McKenna LA Jr. National Fire Data Center; U.S. Fire Administration

First Generation“Cig-a-likes”

Small lithium batteryCartridge with atomizer

limited flavor assortments

Second Generation“Vape pens”

Improved lithium batteryAdjustable voltage

Refillable cartridges

Third Generation“Mods”

Largest lithium batteryAdjustable voltage/wattage

Various shapes/sizes

E-Cigarette Designs Have Evolved

Adapted from Farsalinos and Polasa. Ther Adv Drug Saf 2014; 5: 67-86

Authors, Year

# of Subjects

Intervention Length of Intervention

Outcome Significant Differences?

Bullen, et al,2013

N = 657 E-cig vs. nicotine patch vs. placebo e-cig

13 weeks Modestly increased smoking abstinence at 6 months in e-cig users as compared to patch or placebo

No

Caponnetto et al, 2013

N = 300 2 levels of nicotine e-cigarette vs. no nicotine e-cigarette

12 weeks Reduction in expired CO levels and reported #cigs/day across all study groups vs. baseline use

p < .001

Adriaens et al, 2014

N = 48 E-cig vs. smoking as usual

8 weeks Reduction in cigarettes per day throughout 8 week study, but no difference at 8 monthfollow up

p < 0.001 at 8 weeks; not significant at 8 months

Tseng et al, 2016 N = 99 E-cig vs. placebo e-cig

3 weeks Greater reduction in the number of cigarettes smoked per day in users of e-cigs with nicotine

p = .025

Meier et al, 2016

N = 24 E-cig vs placebo e-cig crossover

3 weeks No reduction in cigarettes per day

No

Are e-Cigarettes Effective Smoking Cessation Aids?

From Gaznick NV and Anthenelli RM. Current Psychiatry, 2017; 16(5): 31-39

The Largest RCT To Date

• Compared 2nd-Gen Refillable E-Cig versus NRT (incl. combo)

• 886 adult smokers; U.K. NHS stop-smoking service– 75% failed NRT in past

– 42% had also tried e-cigs

• 1º efficacy outcome = abstinence at 52 wk

• Among quitters, also examined n(%) of those still using e-cigs versus NRT

Hajek P et al. NEJM 2019; 380(7): 629-637.

E-Cigs versus NRT as Cessation Aids

• Combustible Cig Abstinence at 52 wk

– E-Cigs = 18%, NRT = 9%

• Combustible Cig Abstainers still using product

– E-Cigs = 80%, NRT = 9%; RR = 1.83; 95% CI = 1.3-2.6

– Thus, Substituted Dependence

• Most frequent adverse events

– Nausea: NRT = 38%, E-Cig = 31%

– Throat or Mouth Irritation: NRT = 51%, E-Cig = 65%

Hajek P et al. NEJM 2019; 380(7): 629-637.

So What’s the Harm in Harm Reduction? Percentage of U.S. Middle-Schoolers

Using Tobacco Products -- NYTS 2011-2015

NYTS = National Youth Tobacco Survey. U.S. Department of Health and Human Services. E-cigarette use among youth and young adults. A report of the Surgeon General, 2016.

ENDs Being Used by Teenagers and Transitional Age Youth: Percentage of U.S. High-Schoolers

Using Tobacco Products -- NYTS 2011-2015

NYTS = National Youth Tobacco Survey. U.S. Department of Health and Human Services. E-cigarette use among youth and young adults. A report of the Surgeon General, 2016.

The Advent of High-Tech, Pod-Based E-Cigs

• Trade names: JUUL, Suorin Air, EnviiFITT, MYLE

• Smaller, concealable; mimics USB flash drive

• Delivers nicotine at concentrations akin to cigarettes

• JUUL flavor pods produce less harsh aerosol but high plasma nicotine concentrations

• Flavors, sleek high-tech design, and misperceptions that safe attract youth smokers

Current e-cigarette use among middle and high school students increased markedly

between 2017-2018 in the U.S.

Cullen KA et al. MMWR. Nov. 16, 2018; 67(45): 1276-1277

The Market for Pod-Based e-Cigarettes

• Juul Labs Inc. flavored products make up > 80% of sales

• Was on track for $2 Billion in sales in 2019 before CDC warning of lung injury associated with vaping

• Altria Group invested $12.8 Billion in JLI in 2018; $38 billion valuation (35% stake)

• Federal (White House), State (MA, MI), County, City (San Francisco), Commercial (Walmart) regulatory actions planned Maloney J. The Wall Street Journal; Wednesday, September 25, 2019: B1-B2

U.S. Outbreak of Vaping-Induced Lung Injury

• As of November 5 -- Over 2000 cases reported across 49 states with 39 deaths and counting

• 70% are men; median age = 24 years

• Patients typically present with hypoxemia following several days to a few weeks of respiratory symptoms

• Most (>80%) have reported using e-cigs containing cannabinoids, with or without nicotine, but some cases involve only nicotine e-cigs

• No single device or compound identified

• E-cig fluids have been shown to contain at least 6 groups of potentially toxic compounds: nicotine, carbonyls, volatile organic compounds (such as benzene and toluene), particles, trace metal elements according to flavor, and bacterial endotoxins and fungal glucans

https://www.cdc.gov/tobacco/basic information/e-cigarettes/severe-lung-disease.html accessed November 7, 2019; Schier et al MMWR 2019;68(36):787-790; Christiani NEJM 2019

Heated Tobacco Products (HTPs)• aka Heat-not-Burn (HnB) Tobacco Products

• Heat tobacco at lower temperatures using battery-powered electronic heating elements

• Inhalable nicotine aerosol

• ‘Authentic tobacco taste'

• Latest effort at ‘safer cigarette’

• U.S. FDA granted IQOS® Pre-Market Approval as cigarette, but not as Modified Risk Tobacco Product

• Reduced exposure to toxicants

Modified from Glantz SA TobControl 2018; 27: s1-s6; Lempert & Glantz TobControl 2018; 27: s118-s125

Marketed Heated Tobacco Products

Brand Company Year Launched Countries

glo iFuse;glo

British American Tobacco

20152016

6 including Japan, Canada,

South Korea

PloomTECH Japan Tobacco International

2016 Japan, Switzerland

lila KT & G Corp 2017 South Korea

IQOS Phillip Morris International

2014 ~30 including Spain,

South Korea, USA (limited)

Modified from Bialous & Glantz Tob Control 2018; 27: s111-s117; Glantz SA Tob Control 2018; 27: s1-s6. alil (“a little is a lot”)

The Philip Morris International IQOS Charger, Holder and Heet-Stick (tobacco stick)

from Glantz SA. Tob Control 2018;27:s1-s6; ©2018 by BMJ Publishing Group Ltd

Lessons Learned: Combustible Tobacco’s Addiction Potential

Lifetime prevalence of DEPENDENCE

overall: 26% in men and 23% in womena

among one-time users: 33% in men and 31% in womena

among daily users: as high as 90%

Among last year users of alcohol, tobacco, cannabis and cocaine, TOBACCO USERS WERE MORE LIKELY TO BE NICOTINE DEPENDENT (28%) than alcohol (5.2%), cannabis (8.2%) or cocaine (11.6%) usersb

aNational Comorbidity Study (DSM-III-R)bNational Household Survey on Drug Abuse; Kandel D et al. Drug Alcohol Depend 1997

Combustible Cigarettes: The Model Nicotine Delivery System

• Inhaled route of administration

• Lungs → arterial blood → brain (10-20 secs.)

• Rapid elimination & distribution to peripheral tissues

• Rapid onset/offset → frequent re-administration

Venous Blood Nicotine Concentrations After Smoking a Cigarette vs. Various Forms of NRT

Mitrouska I et al. Pulmonary Pharmacology & Therapeutics 2007

Blood Nicotine Concentrations Vary Based On E-Liquid Nicotine Concentrations and Device &

Approach or Surpass Combustibles

Ramôa CP et al. Tob Control 2016; 25: e6-e9.

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Nicotine Hijacks Nicotinic ACh Receptors

Picciotto, Marina; Emerging Neuronal Nicotinic Receptor Targets; SRNT 9th Annual Meeting, Feb. 2003, New Orleans, LA

Brain Saturation of nAChRs -- High-Dose Vaping Equivalent to Combustible Cigarette Smoking!

Baldassari SR et al. Nicotine Tob Res. April 21, 2017; 430

Too Much of a Bad Thing: How Nicotine Receptors Adapt to Too Much Nicotine

The Metabolism of Nicotine - www.chm.bris.ac.uk/motm/nicotine/E-metabolisme.html accessed October 09, 2019

Up-Regulation of nAChRs with Chronic Cigarette Smoking

Brody AL et al. Intl J Neuropsychopharmacology 2013

Likely Effects of Chronic Vaping

They’ll Learn to Vape: Nicotine enhances brain mechanisms undergirding

memory formation; vaping gets yoked to environmental cues (e.g., drinking)

They’ll Want to Vape: Nicotine modulates activity of dopamine in the

brain’s reward center; vaping behavior reinforced

They’ll Need to Vape or Smoke: Chronic nicotine use up-regulates

nicotinic acetylcholine receptors (nAChRs)

- nAChR activity returns when nicotine absent (e.g., person quits vaping or smoking)

- Increased receptor number and activity contribute to nicotine withdrawal dysphoria;

Vaper / smoker relapses to “feel normal” again

Summary on E-Cigarettes

• Probably ‘safer’ than conventional cigarettes, but insufficient information available regarding long-term use and health risks

• Vapor contains nicotine which is highly addictive and other potentially harmful chemicals

• Modest evidence for potential use as aid to smoking cessation, but really more a harm reduction tool providing substituted dependence

• Current e-cig use among middle and high school students increased alarmingly between 2017-18

Read More About It

• National Academies of Sciences, Engineering, and Medicine, 2018. Public health consequences of e-cigarettes, Washington, DC: The National Academies Press. doi:https//doi.org/10.17226/24952

• Gaznick NV and Anthenelli RM. E-cigarettes and vapes: do they work for smoking cessation and should we be recommending their use? Current Psychiatry, 2017; 16(5): 31-39.