Electronic Nicotine Delivery - Wisconsin Society of ... · Multi‐criteria decision analysis from...

WISAM 2018 Annual Conference Sept. 27‐28, 2018

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Electronic Nicotine Delivery Systems

WISAM September 2018

Mary‐Anne Kowol MD

Addiction Psychiatrist, MCW

[email protected]

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Disclosures

• Nothing to disclose

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Objectives

• Describe the development of ENDS

• Describe controversies surrounding ENDS

• Describe impact on Youth

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Help or Harm?

• Impact on public health determined by 2 factors:• Toxicity/ harm

• How wide spread exposure is

• Controversies• Harm reduction vs “gateway drug”

• Quitting vs dual use vs extended use and associated health consequences

• Countries with opposing conclusions and recommendations

• Big industry vs small developers

• Science too slow to catch up on newest technical specifications

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• "I don't know of any smoker who at some point hasn't wished he didn't smoke. If we could offer an acceptable alternative for providing nicotine, I am 100 percent sure we would have a gigantic brand."1977 Lorillard letter discussing new products AP 02/26/98

"Nicotine is the most pharmacologically active constituent in tobacco smoke and is probably the most usual factor responsible for the maintenance of the smoking habit"1978 internal British‐American Tobacco Co. document by D.E. Creighton AP 04/03/98

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• "I don't know of any smoker who at some point hasn't wished he didn't smoke. If we could offer an acceptable alternative for providing nicotine, I am 100 percent sure we would have a gigantic brand."1977 Lorillard letter discussing new products AP 02/26/98

"Nicotine is the most pharmacologically active constituent in tobacco smoke and is probably the most usual factor responsible for the maintenance of the smoking habit"1978 internal British‐American Tobacco Co. document by D.E. Creighton AP 04/03/98

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Enter: ENDS/ e‐cigarettes

• 1965: 1st device resembling e‐cig by Herbert E Gilbert • 1980s: 1st heated tobacco products (HTP): “What it all comes down to is a cleaner smoke for smokers and those around them”

• 2003: 1st e‐cig product: Chinese pharmacist Hon Lik: “a way to safely stop smoking tobacco.”

• 2006/07: introduced to the US• 2009: Family Smoking Prevention and Tobacco Control Act: FDA can regulate tobacco industry

• Several countries ban sales and punish severely for selling

• 2010: Japan Tobacco International launches HTP • 2015: JUUL hits market

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• 2016: UK: 1st e‐cig on rx for cessation.

• 4/2016: Royal College of Physicians (UK) issues 200 page report

• 5/2016 : FDA’s “final deeming regulations”

• 12/2016: Surgeon General report of Youth and Young Adult e‐cigarette use: “poses a public health concern,” and calls to action to reduce e‐cig use among young people

• 12/2016: Philip Morris files a “modified risk tobacco product application” for HTP with the FDA

• 08/2017: FDA delays deadline for filing until 08/2022 for e‐cigarettes.

• 09/2017: Foundation for a Smoke Free World. Initial funding by PMI, which committed to give 80mio$ annually 8


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• 1/18: FDA declines PMI iQOS modified risk application.

• 1/2018: National Academy of Sciences and Engineering: Public Health Consequences of E‐Cigarettes

• 2018: UK Physician Health Report: Continues to be vastly supportive of e‐cig as cessation aid. Rx e‐cig update (UK): BAT passed the bat on it and nicotine inhaler

• 3/18: health groups sue FDA over delay of e‐cig regulations

• 5/2018: FDA sends warning letters to stop promoting kid friendly advertising targeting after undercover stings

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Spot the Difference:

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• 9/2018: FDA sent 1300 warning letters and civil money penalty complaints to retailers who sell ENDS illegally to minors.

• Over 500 brands and 8000 flavors. 5 brands of “big tobacco” have over 90% of market share.

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What do we know? How do we know it?

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• Opinion outpacing science which has not happened previously in tobacco research

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• Update from 2015: 3 x the size of the one considered for review

E‐cigs:

• Battery powered device that aerosolizes a liquid (e‐liquid or e‐juice) consisting of carrier material, nicotine and potentially flavors

• Carrier material usually polyethylene glycol and or vegetable glycerin

• Basic construction:

• Mouthpiece, cartridge (tank), heating element (atomizer), microprocessor, battery (Li), possibly an LED light at the end.

• Atomizer: heating element, wicking material

• Activated either manually or by inhaling

• Temp roughly 100‐250C (?) 14


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“Vaping” needs to be learned:

• Vapors differentiate between Mouth‐to‐lung hits and Direct‐lung‐inhalation

• Puff time is longer, requires more forceful suction

• Power of the battery controls amount of vapor produced if the wicking supply is adequate. If not, there will be “dry puffs”

• Sub‐ohming: huge puff volumes (>1000ml), huge liquid consumption per puff (can be more then 30 mg/puff), similar temp of evaporation, more expensive, need to lower nicotine content

• Cloud‐chasing as a hobby

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Further developments:

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Further development (around 2014):

• Increasingly adjustable, high tech elements, safety features• Can be made from stainless steel and pyrex glass, contain very little plastic• Stops “dry puffs”, burning or overheating.

• Sub‐ohm/ low ohm devices: included by some in this categorization

• Higher power devices: lower nicotine concentration needs, double amount of liquid

• Unclear if this increases absorption of harmful/ potentially harmful constituents

• Chemicals in vapor differ substantially across manufacturers, devices, cartridges, puff volume and puff to puff.

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“Stealth vaping”

This image cannot currently be displayed. Internet full of adviceon how to hide vaping

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“Mod pods”:

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JUUL “the apple of vaping”

• Liked for:• Sleek design

• Inconspicuous

• Not much visible vape production

• Easily chargeable

• Easy refill

• No need to press buttons or tinker around

• High nicotine content

• There’s an app for that

• Claiming damage and giving serial # to company will give you a replacement, no questions asked

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Pod vape: all‐in‐one system, closed system, prefilled cartridges

JUUL

• Nicotine content: more like traditional cigarettes, about 2‐10 x of most free‐base nicotine in e‐cig products

• delivers nicotine up to 2.7 times faster than other e‐cigarettes.

• equivalent to ~ 20 combustible cigarettes.

• combination of salt‐based nicotine and other additives: satisfying experience even at high nicotine concentrations

• Nicotine salts: benzoic acid + nicotine base. Per JUUL, resembles more the nicotine in the leaf. Less irritating, vaporizes at lower temp. Great for smaller devices with lower power, not just for JUUL

• Unclear if nicotine salts deliver drug more rapidly than other formulation.

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JUUL

• 37% youth and young adults knew that the product always contains nicotine.

• 68% of ENDS market share at this point

• Interesting marketing: mainly internet display, even cut down from 2015‐2016. Targeted Twitter, Instagram. Youtube presence.

• Online fora research: high underage usage, offers of discret shipping, tips for how to hide underage use, exchange of serial # that are still under warranty to get “replacements.”

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Tobacco Heating Products/ Heat‐not‐burn devices

• Heat‐not‐burn products: heats tobacco leaves to 500‐600F

• Japan (no e‐cigarettes): 3.7% in 2017

• Per PMI: could cut tobacco‐related deaths by 90,000 during the next 2 decades.

• FDA and PMI data on exclusive use vary substantially

• Has 2 chips inside and Bluetooth accessory• Data use, marketing and privacy concerns

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Heat‐not‐burn device

• Nicotine aerosol: 70% to 84% of reference cigarettes.

• Claims:

• no combustion but has been found, produces vapor, also CO

• iQOS delivers only 10% of toxic substances as CC.

• FDA found higher levels of acrolein, formaldehyde, and benz(a)pyrene than reported by the company. (Still sig lower than in cigs)

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Cannabis vaping:

Dry weed vaporizer

Oil vaporizer

Desk vaporizer26


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Cannabis vaping:

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Nicotine absorption

28JUUL

Tobacco Heating system 2.2


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Public Health England Report (2015) and Royal College of Physicians report (2016):

• E‐cigs around 95% less harmful then smoking

• E‐cigs appear to be effective when used as cessation aid• Acknowledges concern re youth smoking initiation; only temporary cessation

• Likely to cause harm: COPD, cancer, cardiovasc disease et al increase

• However RCP concludes recommending promoting e‐cigs, NRT and non‐tobacco nicotine products as widely as possible as substitute for smoking in the UK

• PHE said: “Although not without risk, the overall risk of harm is estimated at less than 5% of that from smoking tobacco; the risk of cancer has been calculated to be less than 1%.”

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Multi‐criteria decision analysis from which the quote “e‐cigarettes are 95% less harmful than combustible tobacco” derives:This is NOT about toxicity!

National Academies of Science, Engineering, and Medicine 2018• Looked @ potential benefits and harms of e‐cigarettes.• “contains fewer numbers and lower levels of toxicants than smoke from combustible tobacco cigarettes” with

• “limited evidence that e‐cigarettes may be effective aids to promote smoking cessation.”

• “substantial evidence that e‐cigarette use increases the risk of ever using combustible tobacco cigarettes among youth and young adults” and

• “moderate evidence that e‐cigarette use increases the frequency and intensity of subsequent combustible tobacco cigarette smoking.”

• Open ? will e‐cigs undermine or advance public health?• Attractiveness to youth (like JUUL) will define the answer.

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Flavors = toxicants??

• FDA does not regulate the flavors

• About 8000 flavors: Consists of water +/‐ etoh + chemical additives

• “flavor only” might contain nicotine!

• Approved for safe oral intake but what’s the impact when inhaled?• Diacetyl: buttery flavor, linked to severe respiratory disease (popcorn lung: bronchiolitis obliterans), is found in 75% of favored e‐cigs and refill liquids

• Cytotoxicity to human and mouse stem cells due to flavors. • Cinnamon worst offender

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Should flavors be banned?

• 1 study suggested (discrete choice experiment):

• Ban menthol cigarettes only

• Reason: greatest reduction in choice of cigarettes (5.2%), with increase of 3.8% in e‐cigs

• In contrast: • Banning e‐cig flavors while allowing menthol in cigs:

• Results in greatest increase in cig uptake: 8.3%. • Ban on all flavors:• Increase “opting out the most (5.2%), but would increase cig choice (2.7%) and decrease e‐cig choice (‐7.9%)

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Health Effects:

• No or minimal impact on other physiological measures (exhaled CO, weight, blood counts)

• Reduced blood pressure, improved lung function, improved disease symptoms (COPD/ asthma), increased HR, association with MI (??)

• Improved memory, nicotine withdrawal reversal

• Very low 2nd hand exposure with unclear health outcomes

• Increased anti‐inflammatory response, oxidative stress on cells, increased apoptosis and necrosis. nicotine levels not correlated. VG and PG not cytotoxic. Overall much less cytotoxic than cigs

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Dependence: ENDS vs Cigs

• ¾ of e‐cig users consider self addicted.• 1/3 former smokers who vape daily perceive dependence on ENDS as strong as or stronger than on cigs

• E‐cigs: sig longer time‐to‐first‐use after waking

• Cig smokers more likely to consider themselves as addicted, have strong cravings and find it difficult to refrain from using where prohibited.

• Keep in mind: data is on older models!

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E‐cig: adults

• 2016: ≥18• 15.4% ever use e‐cigarette

• 3.2% current use e‐cigarettes

• 2015:• Recent former smoker: 22%

• Former smoker: 2.3%

• Dual use: 25% smokers vape, 60% vapers smoke

• 11% vapers were never smokers (mostly 18‐24 yo group)

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UK’s e‐cig population study: about quitting

• UK: cross‐sectional household surveys ≥ 16yo, quarterly data 06‐2016• Prevalence of e‐cigs in current smokers and during quit attempt were used to predict quit success and rate of quit attempts.

• Success rate of quit attempt increased by 0.098% (95%CI 0.064‐0.132)and 0.058%(0.038‐0.078) for every 1% increase in e‐cig use prevalence in smokers. No clear association with rate of attempts. Negative association between e‐cig use during recent quit attempt and use of NRT obtained on rx.

• Example: With quit attempts at 32.5% of 8mio smokers (2015), and prevalence of e‐cig use in quit attempt at 36%, this equates to 54,288 addlshort to medium term quitters compared to no e‐cig use. Estimating 2/3 relapse, they project 18,000 long term quitters.

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US population survey results:

• 5 waves from Current Population Survey‐Tobacco Use Supplement

• ~160,000 people included• Asked for cigs, e‐cigs, quit attempts, quit for 3 ms

• E‐cig users more likely to attempt 65% vs 40%, and to quit 8.2% vs 4.2%

• Overall population cessation rate for 2014/5 sig higher than for 2010‐11 and higher for other ys. (5.6% vs ~4.4%)

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Answer to studies with + results:

• Kalkhoran et al Lancet Respiratory medicine 2016: “real‐world” setting.

• Critique: studies did not compare e‐cig intervention with no‐eciguse intervention. Studies in which all participants use an e‐cig demonstrate much higher quit rate.

• Long‐term and cross‐sectional studies that compared e‐cigs w no or proven intervention:

• e‐cigs reduce quit rates by 28%.

• 1 explanation for lower quitting rate w e‐cigs: it’s a freely available consumer product. Some data show OTC NRT much less effective than rx’ed NRT or meds + counseling.

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WHO commissioned systematic review and meta‐analysis 2016:• Assessed impact of ENDS vs no cessation aid or alternative cessation aids on long‐term tobacco use among cigarette smokers, regardless of whether users were using them as part of quitting attempt

• 3 RTCs (1007 participants) and 9 longitudinal cohort studies (13,115 participants)

• GRADE approach

• 2 RCT results: possible increase in tobacco cessation (RR 2.03 CI 0.94‐4.38 p0.07 low certainty evidence) with ENDS use

• Imprecision and missing outcome data, no blinding

• 3rd RTC data failed to show difference after RR was calculated

• Long. Studies: possible increase in cessation: OR 0.74, CI 0.55 to 1.00 p=0.051 very low certainty) with ENDS use

• Missing outcome data, imprecision in assessment of prognostic factors and outcomes

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Conclusion e‐cigs smoking cessation:

• Head to head studies unlikely to happen: would require Investigational New Drug approval by the FDA (not sure how likely companies will be requesting this!)

• Cessation overall seems more likely with higher nicotine level and more frequent e‐cig use

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Adolescents: Monitoring the Future 2017

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• Vaping overall: 2016: 13% 2017: 17% overall

• Nicotine in past month:• 12th graders: 11% ‐ 24% daily (≥20 occasions)

• Cannabis in past month• 12th graders: 10%

• Flavors only: 21%

• JUUL: • 8% of youth and young adults past 30 days

Concern regarding youth and ENDS

• E‐cig may confer public harm if their use leads to

• a substantially greater number of youth who initiate cig smoking compared with the number of youth who would have initiated cig smoking in the absence of e‐cigs

• or greater number of youth who currently smoke compared with the number of youth who would have currently smoked in the absence of e‐cigs.

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Monitoring the Future data on e‐cig – cig progression 2015:• 4 x the incidence of past 12ms smoking for youth who vaped at baseline

• Remained significant after controlling for confounders. • Reported smoking level: ‘once or twice’ in past 12 months

• Even amongst the people who perceived highest risk, recent vaping at baseline strongly predicted incidence of cigarette smoking in the following year.

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Youth and Young Adults: e‐cig/ cig association

• Systematic review and meta‐analysis 2017:

• Strong and consistent evidence of association between initial e‐cigarette use and subsequent cigarette smoking initiation, as well as between past 30‐day e‐cig use and subsequent past 30‐day cig use

• 6959 unique studies, 9 met inclusion criteria, comprising 17,389 adolescents and young adults (14‐30 ys)

• Looked at baseline never smokers:

• Pooled probabilities of cig use: • 23% for baseline ever e‐cig use and 7.2% for baseline never e‐cig use• 21.5% for baseline past 30‐day e‐cig user and 4.6% for baseline never e‐cig user.

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• After adjustments (demographics, psychosocial, behavioral risk for cig smoking) pooled odds ratio for subsequent cig smoking initiation:

• 3.5 (CI 2.38‐5.16) for ever vs never e‐cig use,

• 4.28 (CI 2.52‐7.27) for past 30‐day ecig ever vs non‐past 30‐day e‐cig use at baseline

• After controlling for heterogeneity: supported the results even more.

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• e‐cig use not merely a marker for high risk for smoking adolescents:

• Canadian study (9‐11th grade): After 2 ys: among non‐susceptible never smokers: 45% vs 13.5% baseline e‐cig vs non‐e‐cig tried a cig.

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Youth and Young Adult: e‐cig cig progression

• Studies followed mainly early phase of smoking initiation, question remained for likelihood to progress to established smoking

• Results from another look at the PATH survey (12‐17yo) showed:

• Ever e‐cig use predicted current established smoking (≥100 cigs) (adjusted OR 1.80; CI 1.04 ‐3.12) but did not reach statistical sig for established smoking and past 30‐day smoking but the direction of evidence pointed strongly in that direction

• Only 1 Hawaiian study with lack of correlation e‐cig use and subsequent change in smoking frequency among baseline every cig users

• Per a study of 10 LA schools: higher nicotine concentration may increase subsequent frequency and intensity of smoking and vaping

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E‐cigarette and future cannabis use

• Longitudinal study (PATH Population Assessment of Tobacco and Health)

• 1 year follow up

• Baseline never cb, ever e‐cig users had increased likelihood of cannabis in the past year. (almost double)

• Significant interaction with age, younger adolescents sig more likely to use and with heavier use.

• Study from 10 LA public schools found an OR of ~3.6 for initiation and current cb use for ever e‐cig use after 24 ms.

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Youth and Young Adults

• Critique by pro‐e‐cig researchers:

• Miscoding “use” for “experimentation” inflate that numbers

• Experimentation with e‐cigarettes is now associated with an accelerated rate of decline in smoking among youths

• Most studies don’t ask about model of ENDS, nor content. Evidence does not support conclusion that e‐cigs are a gateway to smoking: CC smoking has fallen to historic low. This would be nearly impossible to explain if e‐cigs were causing substantial number of youths to start smoking. Vaping culture is helping to displace a smoking culture.

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Conclusion for ENDS

• Moving target:

• Motivation for ENDS use might continue to change and influence quit rates.

• ENDS specifications change all aspects of research.

• Clear evidence:

• Nicotine (and cannabis) is (are) addictive.

• As long as it can be sold, it will.

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Thank you!

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