What is the science & review of the evidence of the smoke-free alternatives?
Dr Alice E McGee MBChB MSc ClinEd
The aim of this article is to provide an evidence review and the science behind the different smoke-free alternatives. The key different products looked at include nicotine gum, snus, nicotine pouches, e-cigarettes, aerosol heated tobacco products and heated tobacco products. There will also be some information included on the current global and regional regulatory outlook on smoke-free alternatives.
Smoke-Free Products or alternatives are products are does not combust or burn as it is the case with traditional tobacco products such as cigarettes, cigars, moassel (shisha), etc. Combusting tobacco, generates “smoke” – a highly toxic aerosol composed of solid particles and liquid droplets. By avoiding combustion, the levels of Harmful and Potentially Harmful Constituents (HPHCs) is reduced that adult smokers are exposed to when they smoke cigarettes.
Nicotine gum comes in multiple strengths but 2 mg and 4 mg strengths are the most commonly used and prescribed in clinical practice. The gum can be used every 2 hours to help with withdrawal symptoms. It’s important to note that nicotine gum is used for managing symptoms and cravings and doesn’t offer pre-loading benefits that way a nicotine patch can .
Low success rates are commonly reported when gum is used as monotherapy for NRT – with some studies reporting a success rate of about 6.2% alone vs the ‘cold turkey’ approach . However, in an American 2020 study, it was found that when used in response to desire to smoke, nicotine gum can help to prevent relapses among non-daily smokers .
Some studies have reported the use of nicotine gum in synergy with other smoke-free alternatives can prove beneficial  – especially the patch and gum combination. For example, a recent study from 2021 showed that the most common reasons given for smokers not using the patch or gum was “other,” followed by “side effects” (27.1%), and “forgot” (18.9%) .
In summary, it appears that using nicotine gum alone is not significantly associated with a successful reduction in smoking. It appears that a combination approach with another alternative is much more likely to lead to success for patients.
It’s important to note that snus is a tobacco product, which was developed from a type of dry snuff in early 18th-century Sweden. It is placed between the upper lip and gum for some time, usually about 1 hour by the user, as a form of sublabial administration. Snus is extremely popular in Sweden and Norway, and a lot of the research and data are coming from Scandinavian studies.
In terms of UK practice, the Royal College of Physicians have acknowledged its role, particularly in men, in helping to facilitate harm reduction compared to cigarette smoking  .
One of the main findings with snus use, is that dual use is very uncommon. One of the potential benefits with snus, particularly in terms of harm reduction, is that most smokers who start snus will eventually stop smoking. This figure has been reported as high as about 80% . Additionally, it has been recognized that it doesn’t act appear to act as a gateway for smoking and it appears acceptable to consumers.
There is a large potential for harm-reduction, particularly in lung cancer, heart disease and stroke risk, when compared with cigarette smoking. Further studies confirmed a negligible risk of lung cancer and low risk of stroke .
In a large USA study carried out in 2008 with over 4 million participants, snus had the highest success rate (73%) of smoking cessation amongst 11 other alternatives . A study based in New Zealand showed a preference to snus over gum in reducing the desire and impulses to smoke and also found patients reported fewer side effects, compared with nicotine. This study found that patients reported more side-effects with gum over snus .
However it is important to make patients aware that snus does contain tobacco, which can lead to cancers of the mouth and throat, gum disease and dental problems.
Nicotine pouches are a recent innovation in the nicotine replacement market. They were first introduced to the UK and other European markets (outside Scandinavia) in 2019. All major tobacco companies now sell them . They are used in a similar way to snus, as they are placed between the lip and gum to allow absorption of nicotine.
The main difference between pouches and snus is that the pouches contain nicotine extract (not processed tobacco leaf like snus). This makes them exempt from the UK and EU ban on oral tobacco. In the US, pouches are not FDA-approved – as they are not technically categorised as smokeless tobacco.
Some EU countries regulate NPs under national Tobacco Products & E-cigarettes regulations this is also the case in Switzerland. In a number of other EU countries, NPs are not regulated and fall therefore under the regulation of regular consumer goods (e.g., Sweden), however there are pending regulations in many EU countries that aim to capture NPs in the tobacco product regulations.
A recent UK survey has found that nicotine pouch use is concentrated among current cigarette smokers. Currently, 1 in 400 adults in the UK use the pouches. Use of nicotine pouches has increased slightly from 2020 to 2021. Pouch use is most popular in younger and middle-aged men who have smoked or are using another form of NRT .
However, there appears to be a lack of evidence for their role in successful smoking cessation . “Large gaps” in the research about pouch use has been identified – including the pharmacokinetics of nicotine pouches, the product chemistry and health & safety .
- A publication from 2021 by Azzopardi et al.  performed a chemical characterization of oral nicotine pouches and provided a risk assessment and ranking of those products on the “risk continuum”.
Their conclusion was that “Nicotine Pouches (NPs) may provide a lower toxicant-exposure source of nicotine for current smokers who seek a substitute to cigarettes, in particular for those who find NRTs ineffective. Based on their similarity to snus in physical usage, but due to the absence of tobacco, lower toxicant profile and reduced ADC, NPs may also offer fewer health risks than snus when smokers switch to using them exclusively. NP toxicant contents and estimates of exposure in comparison to other products suggest that NPs may be positioned between Swedish snus and NRTs on the tobacco and nicotine toxicant continuum.”
E-cigarettes are often referred to as vaping by the general public. Vaping products refer to e-cigarettes and e-liquids (refill containers).
There is an ongoing misconception that e-cigarettes are just as much, or more harmful than cigarette smoking in the general public . Research has shown and Public Health England has confirmed the estimates that e-cigarettes are around 95% safer than cigarette smoking .
E-cigarettes are the most popular aid used to quit smoking in the UK. There is very high awareness in the UK of e-cigarettes as a form of smoking cessation – 95% of smokers and 93% of the general population had heard of e-cigarettes (UK) . Further randomised clinical trials have shown e-cigarettes have efficacy in helping smoking cessation .
In terms of current use, current vaping prevalence among UK smokers varied between 14% and 20% across surveys . Public Health England have purported that prompting smokers to switch to e-cigarettes should be adopted as “one of the key strategies to reduce smoking related and death.” 
E-cigarettes have proven efficacy in helping with smoking cessation. In 2017, over 50,000 smokers successful quit smoking by vaping who would have otherwise continued to smoke. 27.2% of people used e-cigarettes to try and quit smoking in the UK in 2020, in contrast to 15.5% who used NRT and only 4.4% who used varenicline .
As mentioned above, e-cigarette use has been significantly affected by media and the news. Recent public health scares have led to a recent decline in UK e-cigarette use, in particular two recent international headlines, which were based on misinterpreted research findings .
This impact is demonstrated by changes in the use of e-cigarettes in surveys. It’s important to counsel patients to confirm this research and information is inaccurate. In a 2014 US survey, 82% of respondents believed vaping was safer than smoking in 2010. This figure declined to 51% in 2014 . Public Health England have confirmed there is no evidence that e-cigarette users are exposed to harmful levels of aldehydes . Most of the chemicals that are attributed to smoking-related disease are absent from e-cigarettes and the chemicals that remain present limited danger to the general public .
There has been increasing use of e-cigarettes amongst young adults. There has been concern of potential for them to act as a gateway to tobacco smoking. There is less research and evidence on effects in teens and young adults. Non-traditional smokers can become addicted to e-cigarettes. 
Heated Tobacco Products & Aerosol Heated Tobacco Products
The main difference between these two products is the difference in their functionalities. Heated tobacco products (HTPs) are often marketed as “heat not burn” products, indicating the fact that they heat tobacco and produce an aerosol, rather than burning the tobacco and producing smoke and ash, like traditional cigarettes.
Traditional HTP: around since the 1990s, where there are glass fibres surrounding a carbon tip. The consumer lights the carbon tip, heating the dried tobacco within to a temperature that does not cause the product to produce ash or burn down in size.
Aerosol HTP: US FDA authorized since 2019 – has 2 components: an electronic heating device and tobacco sticks (dried tobacco wrapped in paper). The consumer inserts the stick into the device, which penetrates the tobacco stick with a ceramic blade (covered in glass). This then heats the tobacco to a temperature sufficient to create an aerosol.
HTPs heat processed tobacco leaf, which lets consumers inhale nicotine directly into their lungs. They still contain tobacco and so do not help users stop tobacco use. A systematic review performed in 2021 shows they can lead to harm reduction in terms of causing chronic diseases including cardiovascular and pulmonary disease, when compared to traditional cigarette smoking, but further research is required as they still contain toxicants and cause harm . They potentially can increase oxidative stress in the respiratory system and cause an increased number of respiratory tract infections through their effect of larger microbial adherence to the respiratory tract .
Another large systematic review conducted in 2022 (including 13 studies, 11 of which were RCTs) showed there was insufficient evidence in the role of HTPs in smoking cessation . This study also identified the need for further investigation of the risks of adverse events caused by HTPs in comparison to cigarette smoking and e-cigarette use, but the team did confirm that there was moderate proof that HTP consumers have lower exposure to carcinogens and toxic chemicals than cigarette smokers . The team found that “independently funded research on the effectiveness and safety of HTPs is needed.”
Summary of Different Smoke-Free Alternatives
|Agent||Tobacco||Nicotine||Route of admin.|
|Heated tobacco product||Y||Y||Inhalation|
|Aerosol heated tobacco product||Y||Y||Inhalation|
Gulf Cooperation Council Regulatory Outlook on Smoke-Free Alternatives:
4 countries in the GCC have regulated smoke-free products: the UAE, Kuwait, KSA and Bahrain. These countries’ regulations covers requirements for safety, ingredients, also warnings required to be placed on the packages of e-cigarettes and heated tobacco products. On top, these regulations’ requirements are different from the regulations applied on traditional tobacco products such as cigarettes. The health warning statements for cigarettes are related to the harms of smoking and the smoking related diseases (text plus pictures) while the warning for smoke-free products are only for nicotine being not-risk -free and causes addiction (only text warning no pictures).
United Arab Emirates (2019): Adoption of Technical Regulation ESMA 50:30 titled “Electronic Nicotine Products (equivalents of traditional tobacco products)
Kuwait (2020): Ministerial Decree by the Ministry of Commerce to adopt the UAE Technical Regulation for Electronic Nicotine Products
Saudi Arabia (KSA) (2020): Adoption of Technical Regulation SFDA 50:50 titled “Electronic Liquids and Heated Tobacco Products for Smoking” by the Saudi FDA
Bahrain (2021): Adoption of Technical Regulation BH:2 titled “Electronic Nicotine Products (equivalents of traditional tobacco products)
Global Regulatory Outlook on Smoke-Free Alternatives
EU in 2014: The EU Tobacco Products Directive distinguishes Novel Tobacco Products as a separate product category from conventional tobacco products
USA in 2017: the U.S. FDA announced a new strategic plan to address smoking by increasing restrictions on cigarettes and by allowing “greater flexibility” for alternative non-combusted products.
The U.S. takes an evidence-based approach to new products, requiring manufacturers to provide extensive information, including scientific studies and market research, for the FDA to verify that placing the product on the market is “appropriate for the protection of the public health.” U.S. law also allows manufacturers to submit applications for the FDA to evaluate whether a tobacco product may be sold for use to reduce harm or the risk of tobacco-related disease. This is the Modified Risk Tobacco Product Application (MRTPA) process.
According to then-FDA Commissioner Scott Gottlieb, “Envisioning a world where cigarettes would no longer create or sustain addiction, and where adults who still need or want nicotine could get it from alternative and less harmful sources, needs to be the cornerstone of our efforts.”
New Zealand: In 2018, the Ministry of Health recognized the role vaping products could play in achieving New Zealand’s smoke-free target of 5% smoking incidence by 2025 and has since run communication campaigns encouraging adult smokers to consider vaping to quit smoking.
The MoH statement mentions: “Expert opinion is that vaping products are much less harmful than smoking tobacco but not completely harmless. A range of toxicants have been found in vapour including some cancer-causing agents but, in general, at levels much lower than found in cigarette smoke or at levels that are unlikely to cause harm. Smokers switching to vaping products are highly likely to reduce the risks to their health and those around them.”
Vaping products are exempted from some of the restrictions applied to smoked tobacco products.
According to New Zealand’s Ministry of Health official position on vaping, available on their website, the Government considers vaping products to have the potential to make a contribution to the country’s smoke-free 2025 goal and could disrupt the significant inequities that are present.
Legislation enacted in 2020 to regulate vaping products (e-cigarettes and heated tobacco devices) aimed to achieve a careful balance—preventing initiation by youth and non-smokers, while also recognizing that vaping products are less harmful than smoked tobacco products, and that smokers should be supported to switch if they do not quit. One of its stated purposes, enshrined in the law itself, is to “support smokers to switch to significantly less harmful products.”
Greece: In 2019, the Greek Government presented the National Action Plan against Smoking that strengthens and supports the actual implementation of the anti-smoking law (L. 4633/2019). The Plan is based on four pillars, including the “The assessment and regulation of novel tobacco products under a harm-reduction strategic approach”.
Portugal: The Tobacco Law (which entered into force in 2018) recognizes harm reduction for smokers who do not quit: “…., and exclusively to adult smokers that are not successful with cessation therapies, about the existence of alternatives that are acknowledged by the Directorate-General of Health, as of entailing harm and risk reduction.”
The Greek Government legislated the fourth pillar in July 2020 stating the objective “of achieving maximum harm reduction for active and passive smokers with the aid of new technologies is added to the policies of prevention at a young age, the cessation of smoking and the protection from passive smoking”. Law 4715/2020 established Tobacco Harm Reduction as an additional tool for addressing smoking, recognizing the right of citizens to access information about special properties of certain tobacco products such as non-combusted tobacco products and the communication of reduced-risk messages subject to a strict procedure of scientific assessment led by a specialized committee.
The Key Messages for Clinical Practice
Stopping cigarette smoking is the goal, and the smoke-free alternatives are still improvements in harm reduction. It’s important to emphasize this to patients. However, it is also important to choose reputable brands where possible. It appears that any of the smoke-free alternatives are better than traditional cigarette smoking. Quitting in a supported way is highly important. The support of smoke-free alternatives in their smoking cessation journey. There is high quality evidence that nicotine replacement therapy works . The quitting rate is increased by 50 to 60% with their use.
“Provision of more intense levels of support, although beneficial in facilitating the likelihood of quitting, is not essential to the success of NRT.” 
Unwanted side-effects (chest pain and palpitations) are rare, and serious adverse events extremely rare  when using nicotine replacement products. It is important to make patients aware of potential side-effects, but often these are not that common. Patients can always switch to a different method.
Every patient is unique. There are so many factors to consider about each patient. These include their lifestyle, career, wishes, what they’ve tried before and their support levels. Patients can mix and match and vary their choice of smoke-free alternative depending on the variability in their week, for example, when at work they could use nicotine patches and use e-cigarettes at the weekend. Having this versatility and variability will help success rates in patients and allow them to have flexibility in their smoking cessation journey.
This market is continuously expanding, and new products are constantly coming to the market. It is highly important clinicians keep up to date on the latest evidence available to counsel patients well. Using a combined approach of at least 2 nicotine replacement options will produce better outcomes .
It is important patients have follow-up or check-ins to ensure they continue to reduce or quit their cigarette consumption. It is very important to remember the role of behavioural and psychological support in this journey for patients and to help them support maintaining the changes they are making .
For example, in the UK, the NHS have implemented a Stop Smoking Service. This allows patients to enrol for support and prescriptions from their local pharmacy which has helped boost participation. Further interventions to help support patients who are quitting smoking include counselling, hypnotherapy and support groups.
What does this mean for the future?
- E-cigarettes remain the most popular choice at present in the UK, and have increasing popularity in the UAE.
- This review highlights the need for further independent research especially into nicotine pouches and HTPs. There is still a lot unknown about these products, especially in terms of short-term and long-term health risks, making it especially difficult to counsel patients on these methods.
- The importance of further review of the current regulations in place is also needed – this may affect snus use in the future.
- There has been a recent emergence and focus on new alternatives, including nicotine salt therapy and potential for nicotine inhalers.
- It is likely further alternatives will develop in the future – it is essential that clinicians review these and are aware of all options available to their patients.
- Journal Addictive Behaviours, Nov 2006. https://www.cdc.gov/tobacco/campaign/tips/quit-smoking/quit-smoking-medications/how-to-use-quit-smoking-medicines/how-to-use-nicotine-gum.html Accessed 4th October 2022.
- Lindson-Hawley N, Coleman T, Docherty G, Hajek P, Lewis S, Lycett D, McEwen A, McRobbie H, Munafò MR, Parrott S, Aveyard P. Nicotine patch preloading for smoking cessation (the preloading trial): study protocol for a randomized controlled trial. Trials. 2014 Jul 22;15:296. doi: 10.1186/1745-6215-15-296. PMID: 25052334; PMCID: PMC4223826.
- Shiffman S, Ferguson SG, Mao J, Scholl SM, Hedeker D, Tindle HA. Effectiveness of nicotine gum in preventing lapses in the face of temptation to smoke among non-daily smokers: a secondary analysis. Addiction. 2020 Nov;115(11):2123-2129. doi: 10.1111/add.15083. Epub 2020 May 14. PMID: 32285979.
- Hébert ET, Bhushan T, Ra CK, Frank-Pearce S, Alexander AC, Cole AB, Kendzor DE, Businelle MS. Daily use of nicotine replacement medications is related to daily smoking status: An ecological momentary assessment study. Drug Alcohol Depend. 2021 Dec 1;229(Pt A):109161. doi: 10.1016/j.drugalcdep.2021.109161. Epub 2021 Oct 29. PMID: 34775184; PMCID: PMC8671265.
- Royal College of Physicians. Nicotine without smoke: tobacco harm reduction. 2016. https://www.rcplondon.ac.uk/projects/outputs/nicotine-without-smoke-tobacco-harm-reduction-0. Accessed 2nd October 2022.
- Royal College of Physicians. Harm reduction in nicotine addiction: helping people who can’t quit. 2007. https://cdn.shopify.com/s/files/1/0924/4392/ files/harm-reduction-nicotine-addiction.pdf?15599436013786148553.
- Ramström L, Borland R, Wikmans T. Patterns of smoking and snus use in sweden: implications for public health. Int J Environ Res Public Health. 2016;13:E1110.
- Asplund K, Nasic S, Janlert U, Stegmayr B. Smokeless tobacco as a possible risk factor for stroke in men – a nested case-control study. Stroke. 2003;34:1754–9.
- Rodu B, Phillips CV. Switching to smokeless tobacco as a smoking cessation method: evidence from the 2000 National Health Interview Survey. Harm Reduct J. 2008;5:18. (USA 2008)
- Caldwell B, Burgess C, Crane J. Randomized crossover trial of the acceptability of snus, nicotine gum, and Zonnic therapy for smoking reduction in heavy smokers. Nicotine Tob Res. 2010;12:179–83.
- Stanfill S, Tran H, Tyx R, et al.. Characterization of total and unprotonated (free) nicotine content of nicotine pouch products. Nicotine Tob Res.2021;23(9):1590–1596.
- Tattan-Birch H, Jackson SE, Dockrell M, Brown J. Tobacco-free Nicotine Pouch Use in Great Britain: A Representative Population Survey 2020-2021. Nicotine Tob Res. 2022 Aug 6;24(9):1509-1512. doi: 10.1093/ntr/ntac099. PMID: 35417551; PMCID: PMC9356773.
- Patwardhan S,Fagerström K. The New Nicotine Pouch Category: A Tobacco Harm Reduction Tool?, Nicotine & Tobacco Research, Volume 24, Issue 4, April 2022, Pages 623–625, https://doi.org/10.1093/ntr/ntab198
- West R, et al., Electronic cigarettes: what we know so far. Briefing report to UK All-Party Parliamentary Group on Pharmacy. 2014
- Action on Smoking and Health (ASH). Use of e-cigarettes (vapes) among adults in Great Britain. 2021.
- Huang J, Feng B, Weaver SR, Pechacek TF, Slovic P, Eriksen MP. Changing Perceptions of Harm of e-Cigarette vs Cigarette Use Among Adults in 2 US National Surveys From 2012 to 2017. JAMA Netw Open.2019;2(3):e191047. doi:10.1001/jamanetworkopen.2019.1047
- Hajek P, Phillips-Waller A, Przulj D, Pesola F, Myers Smith K, Bisal N, Li J, Parrott S, Sasieni P, Dawkins L, Ross L, Goniewicz M, Wu Q, McRobbie HJ. A Randomized Trial of E-Cigarettes versus Nicotine-Replacement Therapy. N Engl J Med. 2019 Feb 14;380(7):629-637. doi: 10.1056/NEJMoa1808779. Epub 2019 Jan 30. PMID: 30699054.
- https://www.gov.uk/government/publications/vaping-in-england-evidence-update-march-2020/vaping-in-england-2020-evidence-update-summary Date accessed: 6th October 2022
- McNeill A, Brose LS, Calder R, Simonavicius E and Robson D (2021). Vaping in England: An evidence update including vaping for smoking cessation, February 2021: a report commissioned by Public Health England. London: Public Health England.
- West R, Brown J, and Beard E. Trends in electronic cigarette use in England. University College London, Smoking Toolkit Study, 2014.
- Tan AS and Bigman CA. E-cigarette awareness and perceived harmfulness: prevalence and associations with smoking-cessation outcomes. Am J Prev Med, 2014. 47(2): p. 141-9.
- McNeill A, Brose LS, Calder R, Simonavicius E, and Robson D. (2021). Vaping in England: An evidence update including vaping for smoking cessation, February 2021: a report commissioned by Public Health England. London: Public Health England.
- Znyk M, Jurewicz J, Kaleta D. Exposure to Heated Tobacco Products and Adverse Health Effects, a Systematic Review. Int J Environ Res Public Health. 2021 Jun 21;18(12):6651. doi: 10.3390/ijerph18126651. PMID: 34205612; PMCID: PMC8296358.
- Tattan-Birch H, Hartmann-Boyce J, Kock L, Simonavicius E, Brose L, Jackson S, Shahab L, Brown J. Heated tobacco products for smoking cessation and reducing smoking prevalence. Cochrane Database Syst Rev. 2022 Jan 6;1(1):CD013790. doi: 10.1002/14651858.CD013790.pub2. PMID: 34988969; PMCID: PMC8733777.
- Hartmann-Boyce J, Chepkin SC, Ye W, Bullen C, Lancaster T. Nicotine replacement therapy versus control for smoking cessation. Cochrane Database Syst Rev. 2018 May 31;5(5):CD000146. doi: 10.1002/14651858.CD000146.pub5. PMID: 29852054; PMCID: PMC6353172.
- Walker N, Parag V, Verbiest M, Laking G, Laugesen M, Bullen C. Nicotine patches used in combination with e-cigarettes (with and without nicotine) for smoking cessation: a pragmatic, randomised trial. Lancet Respir Med. 2020 Jan;8(1):54-64. doi: 10.1016/S2213-2600(19)30269-3. Epub 2019 Sep 9. PMID: 31515173.
- Fiore MC, Smith SS, Jorenby DE, Baker TB. The effectiveness of the nicotine patch for smoking cessation. A meta-analysis. JAMA. 1994 Jun 22-29;271(24):1940-7. PMID: 8201739.
- New Zealand Ministry of Health: https://www.health.govt.nz/our-work/preventative-health-wellness/tobacco-control/vaping-smokefree-environments-and-regulated-products/position-statement-vaping
- Azzopardi D, Liu C, Murphy J. Chemical characterization of tobacco-free “modern” oral nicotine pouches and their position on the toxicant and risk continuums. 2021
- July 17th 2022 https://www.thenationalnews.com/health/2022/07/17/e-cigarettes-used-by-one-in-five-uae-university-students-study-finds/