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Invited Commentary
Substance Use and Addiction
October 20, 2020

Is Nicotine Reduction in Cigarettes Enough?

Author Affiliations
  • 1Department of Social and Behavioral Sciences, School of Global Public Health, New York University, New York, New York
  • 2Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, United Kingdom
JAMA Netw Open. 2020;3(10):e2019367. doi:10.1001/jamanetworkopen.2020.19367

In July 2017, the US Food and Drug Administration (FDA) announced a proposal to limit all cigarettes to those with very low nicotine content (VLNC) as a key part of the comprehensive plan for nicotine regulation. The objectives of that plan are to promote smoking cessation in existing adult smokers and to help keep those who are experimenting, especially young people, from progressing to persistent smoking.1 For more than a decade, the FDA has funded research on the use of VLNC cigarettes among the general population of smokers. Higgins et al2 examined the changes in consumption of VLNC cigarettes in 3 groups drawn from vulnerable populations: individuals with affective disorders, those with opioid use disorder, and women with socioeconomic disadvantage. These populations have disproportionately high rates of smoking and low rates of cessation and warrant special attention as a matter of social justice as well as health. Paid volunteers were randomized to receive experimental cigarettes with normal nicotine content or cigarettes with 2 levels of VLNC. After a week of smoking to establish a baseline, participants were given their assigned cigarettes for 12 weeks. Participants received twice the number of baseline cigarettes used to allow for the possibility they might smoke more. However, participants in the VLNC groups often used their own brand of cigarettes, despite instructions not to do so, complicating interpretation of results. The primary outcome was that those in the 2 VLNC groups smoked about 5 to 7 cigarettes less per day than control participants. There were small decreases in carbon monoxide and nicotine dependence in the VLNC groups, but, importantly, there was no difference in smoking cessation. The suggested conclusion of the study by Higgins et al2 is that “reducing nicotine content of cigarettes to low levels has the potential to benefit populations that are vulnerable to tobacco use, addiction, and smoking-attributable morbidity and mortality.”

Is this strong policy statement warranted by the findings in this study? We think not. The main finding—a modest within-trial reduction in cigarette consumption—does not support the objectives of the comprehensive plan for nicotine regulation at a national level. The ability of the VLNC intervention to promote smoking cessation was specifically tested at week 12 when participants were offered $100 to abstain from smoking for 24 hours, a modest goal given that most smokers who abstain for 24 hours relapse, and smokers do not get such offers in real life. The VLNC intervention did not result in smoking cessation.2 This raises serious questions about the conclusion that a VLNC cigarette policy alone would promote smoking cessation or reduce morbidity and mortality. The health benefits of VLNC cigarettes remain unclear. Reductions in the level of NNAL (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol), a biomarker for tobacco smoke carcinogens, were small, and 1 group (opioid users) experienced an increase in the level of NNAL.2

To effectively support policy change, research that considers the broad context of the whole FDA strategic plan is required.1 Areas to be considered include evidence from implementation studies of real-world use rather than ideal conditions, unintended negative consequences associated with VLNC cigarettes, complex market forces, evolving safer nicotine products, complex user behaviors, and even black markets. Consideration of black markets is particularly useful when attempting to make nicotine, which is an avidly sought-after commodity for over 30 million smokers in the US and 1 billion smokers worldwide, so much harder to obtain in legitimate cigarette products.3

Any VLNC cigarette policy needs to be considered—as the FDA intended—as just 1 part of a broader initiative to move nicotine seekers completely away from smoking deadly combusted cigarettes. Cigarettes with VLNC are at best half of the policy. The FDA put it plainly the “new tobacco strategy has two primary parts: reducing the addictiveness of combustible cigarettes while recognizing and clarifying the role that potentially less harmful tobacco products could play in improving public health.”1(p1112)

The second part of the FDA’s comprehensive nicotine plan is making available substantially less harmful products by which nicotine can be delivered without the toxic effects of tobacco smoke. The most common way of using nicotine without smoke, indeed without tobacco, is nicotine vaping (e-cigarettes), which decreases exposure to harmful chemicals,3,4 emits no carbon monoxide, may facilitate the switch from cigarettes to medicinal nicotine or nicotine products without smoke,3,4 can complement the use of VLNC cigarettes,5 and may accelerate saving smoker’s lives.3,4 It is encouraging to note that the FDA has recently authorized a modified-risk marketing order for a product that heats but does not burn tobacco and will be reviewing the safety of other nicotine vaping products in the near future, allowing for clearer communication to the public that smokeless nicotine product use may be associated with lower exposure to harmful chemicals. In terms of smoking behavior, to encourage more smokers to switch from deadly cigarettes to medicinal nicotine or nicotine products without smoke, it is essential to correct misperceptions among the public, health care clinicians, and policy makers who believe that nicotine is the most harmful component of smoking. The FDA has stated that “Nicotine, though not benign, is not directly responsible for the tobacco-caused cancer, lung disease and heart disease that kill hundreds of thousands of Americans each year.”1(p1112)

Embodied in FDA’s modeling study,6 which predicted that 8.5 million smokers’ lives could be saved by reducing the levels of nicotine in cigarettes, is the need to implement both parts of the comprehensive nicotine regulation plan. Harm reduction keeps the focus squarely where it should be: on reducing the severe disease burden and mortality associated with smoking.1,3-6 The FDA plan accepts that many smokers may not want or be able to achieve complete nicotine abstinence, but they do not have to die from the method of nicotine delivery. The perfect public health outcome would be for people who are already using any form of nicotine to stop all use and abstain for their lifetime or, better still, never to start. But a pragmatic public health approach requires that realistic alternatives to de facto nicotine prohibition be considered.3 Cigarettes are by far the most popular yet deadly route of nicotine administration. Safer alternatives are now available along the FDA nicotine harm continuum.1,3,4 Years of robust evidence are available for the use of nicotine replacement therapy (NRT) as a safe way to deliver clean nicotine. But after more than 25 years, NRT has not become a viable vehicle for displacing smoking at a scale to impact the population, partly because of inadequate nicotine delivery and its unattractive and expensive medicinal positioning in the market. Far more smokers try to quit by vaping nicotine than with NRT.3,4 Many former smokers enjoy vaping nicotine and report its advantages.7,8 They find vaping nicotine to be a reasonable and safer substitute for smoking.4,9 Informed by rigorous evidence reviews, the United Kingdom endorses harm reduction (including vaped nicotine e-cigarettes) as part of a comprehensive tobacco control plan.4

Whereas other fields have accepted that continued safer use of a psychoactive drug may help avoid more serious harm (eg, methadone maintenance in people dependent on opiates) the tobacco control field is not quite there yet. The combination of VLNC in deadly combusted cigarettes with the availability of adequate alternative nicotine delivery products holds promise to rapidly reduce smoking, which remains the leading cause of premature death in the US.10 The time has come to rethink nicotine use. The lives of 1 billion smokers worldwide are at stake.

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Article Information

Published: October 20, 2020. doi:10.1001/jamanetworkopen.2020.19367

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Abrams DB et al. JAMA Network Open.

Corresponding Author: David B. Abrams, PhD, School of Global Public Health, New York University, 715 Broadway, 12th Floor, New York, NY 10003 (da94@nyu.edu).

Conflict of Interest Disclosures: Dr Abrams reported receiving grants and non-financial support from Westat, the National Longitudinal Survey of Tobacco Use-PATH, and the National Institutes of Health/National Institute on Drug Abuse outside of the submitted work. No other disclosures were reported.

References
1.
Gottlieb  S, Zeller  M.  A Nicotine-Focused Framework for Public Health.   N Engl J Med. 2017;377(12):1111-1114. doi:10.1056/NEJMp1707409 PubMedGoogle ScholarCrossref
2.
Higgins  ST, Tidey  JW, Sigmon  SC,  et al.  Changes in cigarette consumption with reduced nicotine–content cigarettes among smokers with psychiatric conditions or socioeconomic disadvantage: 3 randomized clinical trials.   JAMA Netw Open. 2020;3(10):e2019311. doi:10.1001/jamanetworkopen.2020.19311Google Scholar
3.
Fairchild  A, Healton  C, Curran  J, Abrams  D, Bayer  R.  Evidence, alarm, and the debate over e-cigarettes.   Science. 2019;366(6471):1318-1320. doi:10.1126/science.aba0032 PubMedGoogle ScholarCrossref
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McNeill A, Brose L, Calder R, Bauld L, Robson D. Vaping in England: an evidence update including mental health and pregnancy, March 2020. a report commissioned by Public Health England. Accessed August 31, 2020. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/869401/Vaping_in_England_evidence_update_March_2020.pdf
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Benowitz  N, Donny  E, Hatsukami  D.  Reduced nicotine content cigarettes, e-cigarettes and the cigarette end game.   Addiction. 2017;112(1):6-7. doi:10.1111/add.13534PubMedGoogle ScholarCrossref
6.
Apelberg  BJ, Feirman  SP, Salazar  E,  et al.  Potential public health effects of reducing nicotine levels in cigarettes in the United States.   N Engl J Med. 2018;378(18):1725-1733. doi:10.1056/NEJMsr1714617 PubMedGoogle ScholarCrossref
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Abrams  DB, Glasser  AM, Villanti  AC, Pearson  JL, Rose  S, Niaura  RS.  Managing nicotine without smoke to save lives now: Evidence for harm minimization.   Prev Med. 2018;117:88-97. doi:10.1016/j.ypmed.2018.06.010PubMedGoogle ScholarCrossref
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Notley  C, Ward  E, Dawkins  L, Holland  R.  User pathways of e‐cigarette use to support long term tobacco smoking relapse prevention: a qualitative analysis. Published online August 15 , 2020.  Addiction. doi:10.1111/add.15226Google Scholar
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Notley  C, Ward  E, Dawkins  L, Holland  R.  The unique contribution of e-cigarettes for tobacco harm reduction in supporting smoking relapse prevention.   Harm Reduct J. 2018;15(1):31. doi:10.1186/s12954-018-0237-7 PubMedGoogle ScholarCrossref
10.
National Center for Chronic Disease Prevention and Health Promotion US Office on Smoking and Health.  The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Centers for Disease Control and Prevention; 2014.
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    1 Comment for this article
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    Reply from Higgins, Tidey, Sigmon, Heil, Gaalema et al.
    Stephen Higgins |
    On behalf of my coauthors, I welcome this opportunity to reply to the commentary by Abrams and Notley on our article. First, Abrams and Notley argue that a U.S. national policy of nicotine reduction alone is not enough to reduce the terrible public-health burden of cigarette smoking. They contend that to be effective the policy must be embedded in the broad context of the FDA’s Nicotine-focused Framework detailed in Gottlieb and Zeller’s 2017 NEJM report. We agree and indicated such while citing that same Gottlieb and Zeller report in our Discussion section, noting: “The goal of reducing nicotine content in cigarettes to very low levels is to eventually eliminate all use of combusted cigarettes. Ideally, current smokers would eventually quit, but some may be unable or unwilling to totally quit nicotine use. Individuals with OUD have low rates of quitting even compared to other vulnerable populations and thus may be overrepresented among those unable/unwilling to quit nicotine. Migrating these individuals to exclusive use of non-combusted sources of nicotine may be a more achievable harm-reduction goal than complete nicotine abstinence.”

    Second, Abrams and Notley noted that we reported non-adherence with very low nicotine content (VLNC) cigarettes among our study participants and reductions in cigarettes per day (CPD) rather than quitting. While VLNC non-adherence adds complexity, there is also important scientific information to be gleaned from that complexity. As an example, use of non-study cigarettes decreased across weeks in all three populations suggesting that non-adherence was at least in part associated with product transition and as such may be a time-limited phenomenon for many (see e-Figure 1). As another example, non-adherence was greater among those with OUD compared to those with affective disorders or socioeconomic disadvantage underscoring the potential importance of providing non-combusted sources of nicotine to those who are uninterested or unwilling to completely quit nicotine use. Indeed, we are currently conducting follow-up RCTs in these same vulnerable populations testing whether availability of e-cigarettes and flavored e-liquids moderates the effects of VLNC cigarettes on total CPD—a sensitive marker of the relative reinforcing effects of smoking. While Abrams and Notley suggest that the magnitude of reduction in CPD was trivial, we disagree. The mean decreases in total CPD at the 0.4 and 2.4 mg/g doses represented reductions of 28.4% and 22.1% of control levels, respectively, were of sufficient magnitude to reduce dependence severity, and were biochemically verified by breath CO in all three populations and by urine cotinine and NNAL in two of the three populations. We also found that VLNC use increased mean number of days without smoking during the study and the proportion of individuals who reported a quit attempt during the trials. Moreover, those effects were observed in study participants explicitly recruited from vulnerable populations not currently planning to quit—an important inclusion criterion that protects against confounding changes in smoking due to preexisting plans with reductions in smoking due to the experimental manipulations. Importantly, these results also demonstrated that effects of VLNCs on cigarette reduction observed in smokers from the general population extend to more vulnerable populations underscoring the potential for broad reach.
    CONFLICT OF INTEREST: None Reported
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