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With nicotine preloading, about 3% more people had stopped smoking at 6 months, but there was uncertainty around this effect, which may have been weakened by post-quit use of varenicline.

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Paul Aveyard 1,*, Nicola Lindson 1, Sarah Tearne 1, Rachel Adams 2, Khaled Ahmed 2, Rhona Alekna 2, Miriam Banting 2, Mike Healy 2, Shahnaz Khan 2, Gurmail Rai 2, Carmen Wood 2, Emma C Anderson 3, Alia Ataya-Williams 3, Angela Attwood 3, Kayleigh Easey 3, Megan Fluharty 3, Therese Freuler 3, Megan Hurse 3, Jasmine Khouja 3, Lindsey Lacey 3, Marcus Munafò 3, Deborah Lycett 4, Andy McEwen 5, Tim Coleman 6, Anne Dickinson 6, Sarah Lewis 6, Sophie Orton 6, Johanna Perdue 6, Clare Randall 6, Rebecca Anderson 7, Natalie Bisal 7, Peter Hajek 7, Celine Homsey 7, Hayden J McRobbie 7, Katherine Myers-Smith 7, Anna Phillips 7, Dunja Przulj 7, Jinshuo Li 8, Doug Coyle 9, Katherine Coyle 9, Subhash Pokhrel 9

1 Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
2 Primary Care Clinical Sciences, University of Birmingham, Birmingham, UK
3 School of Experimental Psychology, University of Bristol, Bristol, UK
4 Faculty of Health and Life Sciences, Coventry University, Coventry, UK
5 National Centre for Smoking Cessation and Training (NCSCT), Dorchester, UK
6 School of Medicine, University of Nottingham, Nottingham, UK
7 Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK
8 Health Sciences, University of York, York, UK
9 Institute of Environment, Health and Societies, Brunel University, Uxbridge, UK
* Corresponding author Email:

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Responses to this report

Response by Professor Paul Aveyard on 30 August 2018 at 3:55 PM
Author response

The author of the comment dated 17 August 2018 asserts that treatments for smoking cessation do not work in spite of evidence from numerous trials and Cochrane reviews of evidence to the contrary (1). The scientific basis of this case is that some observational analyses show no evidence of a benefit for users compared with non-users. Observational studies of treatment effectiveness are subject to confounding by indication- people who struggle to stop smoking are likely to seek support while those who find quitting easier are less likely to do so. This is hard to measure and adjust for. Faced with contrary trial and observational data, a more reasonable interpretation is that trials provide unbiased evidence of effectiveness while observational analyses are likely to be misleading. Trials of smoking cessation often include unsupported quitting, contrary to the assertion of the author of the comment, typically functioning as a comparison group. They consistently show that no treatment is less effective than either medication or behavioural support. That some people can quit smoking without treatment does not imply that everyone can do so (1). In light of this, it does people who smoke and struggle to quit an injustice to promote the least successful method. 1


Response by John R. Polito, JD on 17 August 2018 at 5:53 PM
Do NHS quitters need more free nicotine?

Despite a modest 17.5 percent six-month stop smoking rate, the Aveyard, Lindson, Tearne et. al. 2018 “Nicotine Preloading for Smoking Cessation” study seeks to motivate the UK NHS to increase Stop Smoking Services’ nicotine patch spending by £47 per patch quitter in order to pay for four weeks of pre-quitting patch use.[1]

Although the study’s one-year preloading rate of 14 percent is nearly identical to the 15 percent one-year normal patch use rate in Bauld 2009,[2] it’s an improvement over the disheartening 8 percent one-year findings in Dobbie 2015 and Bauld 2016.

Still, if nearly forty years of cessation research have taught us anything it’s that clinical trial findings are rarely mirrored in real-world cessation.[3][4] Real-world quitters won’t benefit from a “Russell Standard” which “allows a grace period of 2 weeks after quit day during which lapses do not count.” Nor do re-sensitized dopamine pathways normally survive this study’s allowance of “no more than five lapses thereafter.”[1]

The study’s 10ppm exhaled carbon monoxide smoking determination is extremely forgiving,[1] twice the recommended level,[5] and double the study’s pre-randomization non-smoker exclusion level.[6] Surprisingly, despite four weeks of bombarding a4b2 nicotinic receptors with substantially more nicotine than normal, the study ignores body fluid cotinine testing at any point, including pre-cessation, end of treatment, or at long-term follow-up. The neo-nicotine industry benefits and addicts suffer when, as here, cessation research ignores chemical dependence. What percentage of the 17.5 percent who blew less than 10ppm on a carboximeter had become slaves to vaping, dual use, smokeless tobacco, or had become persistent NRT users?

Imagine daily life as a 35 year-old actively feeding nicotine addict. Imagine experiencing a yearning and hunger for more nicotine, 10, 15 or 20 times daily. Imagine researchers behaving as though, arguably, the greatest harm of all - a permanent brain wanting disorder and mental illness - isn’t worthy of any post-study follow-up questions to determine whether nicotine dependence had been arrested or remained active and serviced by alternative delivery.

If as found by West and colleagues, that “NRT bought over the counter was associated with a lower odds of abstinence (odds ratio, 0.68; 95% CI, 0.49-0.94),”[3] at what point will UK cessation researchers apply their skills to analyzing the giant turkey in the room, abrupt nicotine cessation?

Chapman and MacKenzie refer to it as “global research neglect,” the fact that “two-thirds to three-quarters of ex-smokers stop unaided” yet “91.3% of recent intervention studies focused on assisted cessation.”[8]

If serious about cessation, what logic is there in ignoring how the vast majority of UK nicotine addicts arrest their dependence? NHS leadership should be demanding science-based answers to three fundamental questions:

  1. Were the more than 200 placebo-controlled NRT trials blind as claimed or could 3 to 4 times as many placebo group members correctly declare their assignment as could not, and could they do so within 24-48 hours of quitting (peak withdrawal)?
  2. If nearly impossible to randomize replacement nicotine expectations versus abrupt nicotine cessation expectations, in what clinical trial did smokers wanting and expecting to quit nicotine use cold turkey go head-to-head against smokers wanting and expecting weeks or months of free replacement nicotine?
  3. What are the keys to successful abrupt nicotine cessation, and can they be easily and inexpensively taught and mastered?

John R. Polito, JD Nicotine Cessation Educator

References: 1. Aveyard P, Lindson N, Tearne S, Adams R, Ahmed K, Alekna R, Banting M, Healy M, Khan S, Rai G, Wood C, Anderson EC, Ataya-Williams A, Attwood A, Easey K, Fluharty M, Freuler T, Hurse M, Khouja J, Lacey L, Munafò M, Lycett D, McEwen A, Coleman T, Dickinson A, Lewis S, Orton S, Perdue J, Randall C, Anderson R, Bisal N, Hajek P, Homsey C, McRobbie HJ, Myers-Smith K, Phillips A, Przulj D, Li J, Coyle D, Coyle K, Pokhrel S. Nicotine preloading for smoking cessation: the Preloading RCT. Health Technol Assess. 2018 Aug;22(41):1-84. doi: 10.3310/hta22410. PMID: 30079863 Full text: National Institute Health Research 2. Bauld L, Bell K, McCullough L, Richardson L, Greaves L. The effectiveness of NHS smoking cessation services: a systematic review. J Public Health (Oxf). 2010 Mar;32(1):71-82. doi: 10.1093/pubmed/fdp074. Epub 2009 Jul 28. Pubmed: 19638397 3. Kotz, D, Brown J, West R. Prospective Cohort Study of the Effectiveness of Smoking Cessation Treatments Used in the “Real World” Mayo Clinic Proceedings, Oct. 2014, Volume 89, Issue 10 , 1360 – 1367. PMC: 4194355 4. Weaver SR, Huang J, Pechacek TF, Heath JW, Ashley DL, Eriksen MP. Are electronic nicotine delivery systems helping cigarette smokers quit? Evidence from a prospective cohort study of U.S. adult smokers. PLoS One. 2018 Jul 9;13(7):e0198047. doi: 10.1371/journal.pone.0198047. eCollection 2018. PMC: 6037369 5. Chatrchaiwiwatana S, Ratanasiri A. Exhaled carbon monoxide levels among tobacco smokers by age. Southeast Asian J Trop Med Public Health. 2017 Mar;48(2):429-37. PMID: 29642305 6. Lindson-Hawley N1, 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. PMC 4223826 7. Dobbie F, Hiscock R, Leonardi-Bee J, Murray S, Shahab L, Aveyard P, Coleman T, McEwen A, McRobbie H, Purves R, Bauld L. Evaluating Long-term Outcomes of NHS Stop Smoking Services (ELONS): a prospective cohort study. Health Technol Assess. 2015 Nov;19(95):1-156. doi: 10.3310/hta19950. PMC 4781027 8. Chapman S, MacKenzie R. The global research neglect of unassisted smoking cessation: causes and consequences. PLoS Med. 2010 Feb 9;7(2):e1000216. doi: 10.1371/journal.pmed.1000216. PMC 2817714


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