Advi s ory n ot e
Global Nicotine Reduction Strategy WHO Study Group on Tobacco Product Regulation (TobReg)
WHO Library Cataloguing-in-Publication Data Advisory note: global nicotine reduction strategy: WHO Study Group on Tobacco Product Regulation. 1.Nicotine – administration and dosage. 2.Tobacco – chemistry. 3.Smoking – prevention and control. 4.Behaviour, Addictive. 5.Tobacco Products. 6.Dose-Response Relationship, Drug. 7.Tobacco Industry. I.World Health Organization. II.WHO Study Group on Tobacco Product Regulation. ISBN 978 92 4 150932 9 (NLM classification: WM 290)
© World Health Organization 2015 All rights reserved. Publications of the World Health Organization are available on the WHO website (www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int). Requests for permission to reproduce or translate WHO publications – whether for sale or for non-commercial distribution – should be addressed to WHO Press through the WHO website (www.who.int/about/licensing/copyright_form/en/index.html). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use.
A dvis ory n ot e
Global Nicotine Reduction Strategy WHO Study Group on Tobacco Product Regulation (TobReg)
Contents Participants Acknowledgements Preface Main recommendations Significance for public health Implications for WHO programmes 5 8 10 12 13 13
Reducing the addictiveness of manufactured cigarettes by reducing their nicotine content: research needs and regulatory recommendations 15 1. Introduction 15 2. Background 16 3. Cigarettes with a reduced nicotine content 16 4. Goals of a policy to reduce addiction to cigarettes 17 5. Tobacco addictiveness factors 17 6. Establishing a performance standard for nicotine products 19 7. Feasibility of reducing nicotine 21 8. Potential behavioural and population outcomes 22 9. Policy approaches to nicotine reduction 23 10. Conclusions 27 11. Research needs 27 12. Regulatory recommendations 28 13. References 30
Participants in the seventh meeting of the WHO Study Group on Tobacco Product Regulation Rio de Janeiro, Brazil, 4–6 December 2013
Members
Dr D.L. Ashley, Director, Office of Science, Center for Tobacco Products, US Food and Drug Administration, Rockville, Maryland, United States of America Professor O.A. Ayo-Yusuf, Dean, School of Oral Health Sciences, Sefako Makgatho Health Sciences University, Pretoria, South Africa Professor A.R. Boobis, Biochemical Pharmacology, Centre for Pharmacology and Therapeutics, Department of Medicine, Imperial College, London; Director, Public Health England Toxicology Unit, Imperial College, London, United Kingdom Dr M.V . Djordjevic, Program Director/Project Officer, Tobacco Control Research Branch, Behavioral Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland, United States of America Dr N. Gray, Honorary Senior Associate, Cancer Council Victoria, Melbourne, Australia† Dr P. Gupta, Director, Healis Sekhsaria Institute for Public Health, Mumbai, India Dr S.K. Hammond, Professor of Environmental Health Sciences, School of Public Health, University of California, Berkeley, California, United States of America
5
Dr J. Henningfield, Professor (Adjunct), Behavioral Biology, The Johns Hopkins University School of Medicine; Vice President, Research, Health Policy, and Abuse Liability Pinney Associates, Bethesda, Maryland, United States of America Dr D. Hatsukami, Professor of Psychiatry, University of Minnesota, Minneapolis, Minnesota, United States of America Dr A. Opperhuizen, Director, Office for Risk Assessment and Research, Utrecht, The Netherlands Dr G. Zaatari (Chair), Professor and Chairman, Department of Pathology and Laboratory Medicine, American University of Beirut, Beirut, Lebanon
Contributors
Dr E. Akl, Associate Professor of Medicine, Department of Internal Medicine, American University of Beirut, Lebanon Dr T. Eissenberg, Professor of Psychology and Co-Director, Center for the Study of Tobacco Products, Virginia Commonwealth University, Richmond, Virginia, United States of America Dr W. Maziak, Professor and Chair, Department of Epidemiology, Florida International University; Director, Syrian Center for Tobacco Studies, Miami, Florida, United States of America Dr P. Mehrotra, Senior Programme Officer, Population Council, New Delhi, India Mr J. Morton, Senior Survey Methodologist, Global Tobacco Control Branch, Office on Smoking and Health, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America Dr A. Shihadeh, Professor of Mechanical Engineering, Faculty of Engineering and Architecture, American University of Beirut, Beirut, Lebanon
Facilitors of the WHO FCTC Conference of the Parties Working Group on Articles 9 and 10
Dr P. Altan, Tobacco Control Department, Ministry of Health, Ankara, Turkey Ms A.C. Bastos de Andrade, Head of Tobacco Products Control Department, Agência Nacional de Vigilância Sanitária, Rio de Janeiro, Brazil
6
Dr Katja Bromen, Policy Officer, Tobacco Control Team, European Commission, Directorate-General for Health and Consumers, Unit D4, Substances of Human Origin and Tobacco Control, Brussels, Belgium Mr D. Choinière, Director, Tobacco Products Regulatory Office, Controlled Substances and Tobacco Directorate, Health Canada, Ottawa, Ontario, Canada
Presenters
Dr G. Ferris Wayne, California, United States of America Dr R. Grana, Postdoctoral Fellow, Center for Tobacco Control Research and Education, University of California, San Francisco, California, United States of America Dr M. Parascandola, Epidemiologist, Tobacco Control Research Branch, Behavioral Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Maryland, United States of America Dr R. Talhout, National Institute for Public Health and Environment, Centre for Health Protection, Bilthoven, The Netherlands
Convention Secretariat of the WHO FCTC (Geneva, Switzerland)
Ms K. Brown, Programme Officer
WHO Regional Office for the Americas
Dr A. Blanco, Regional Advisor, Tobacco Control, Washington DC, United States of America
WHO Secretariat (Tobacco Free Initiative, Prevention of Noncommunicable Diseases, Geneva, Switzerland)
Ms M. Aryee-Quansah, Administrative Assistant Dr A. Peruga, Programme Manager Dr V.M. Prasad, Project Manager Ms G. Vestal, Technical Officer (Legal)
7
Acknowledgements WHO has many people to thank for the production of this WHO Study Group on Tobacco Product Regulation (TobReg) Advisory Note on Global Nicotine Reduction Strategy. Ms Gemma Vestal coordinated the production, with the supervision and support of Dr Armando Peruga and Dr Douglas Bettcher. Work on the advisory note began shortly after the fifth session of the Conference of the Parties to the WHO Framework Convention on Tobacco Control (WHO FCTC) in Seoul, Republic of Korea, 12–17 November 2012, and continued after the sixth session, in Moscow, Russian Federation, 13–18 October 2014. We thank all the members of TobReg for their full, whole-hearted dedication, time and unfailing commitment to fulfilling their mandate to advise WHO on tobacco product regulation, a highly complex area of tobacco control. As independent experts, members of TobReg serve WHO without remuneration. In response to the requests to WHO made by the Conference of the Parties at its fifth session, TobReg members provided guidance in drafting the terms of reference for commissioning a series of reviews to serve as background documents and as a basis for discussions at TobReg’s seventh meeting, held in Rio de Janeiro, Brazil, in December 2013. The TobReg recommendations on these issues were published as Technical Report Series 989 (WHO, 2015), which was presented by the DirectorGeneral of WHO to the 136th session of the Executive Board, held in Geneva, Switzerland, on 25 January to 3 February 2015. The background paper on reducing the dependence potential of manufactured cigarettes by reducing their nicotine content to levels that cannot cause or sustain addiction, which served as the basis for this advisory note, was written by Mr Geoff Ferris Wayne. It was appended as Annex 3 to Technical Report Series 989. WHO thanks Mr Wayne for the time and effort invested in writing the background paper, which was presented to TobReg in December 2013, and for continuing to
8
work with TobReg in finalizing their conclusions and recommendations on this important topic. This advisory note was finalized by Dr Dorothy Hatsukami. To ensure that WHO delivered the information requested on tobacco product regulation to the Conference of the Parties, through the Convention Secretariat, WHO and TobReg worked with the facilitators of the Working Group on Articles 9 and 10 of the WHO FCTC. Specifically, WHO acknowledges the significant reviews of this advisory note by Mr Denis Choinière of Health Canada. Administrative support throughout the years of production was provided by WHO colleagues Ms Miriamjoy Aryee-Quansah, Mr Gareth Burns, Mr Luis Madge, Ms Rosane Serrao, Ms Moira Sy, Ms Elizabeth Tecson and Atty Angeli Vigo. Special thanks go to Dr Adriana Blanco, Tobacco Control Regional Adviser, WHO Regional Office for the Americas, for ensuring a smooth TobReg meeting in Brazil. We also once again sincerely thank Ms Ana Claudia Bastos de Andrade, Agência Nacional de Vigilância Sanitária (ANVISA), Brazil, for heroically hosting the seventh meeting of TobReg in Rio de Janeiro in December 2013, while at the same time defending ANVISA from a number of lawsuits instigated by the tobacco industry. In addition, ANVISA provided much needed financial assistance to make the meeting become a reality. We also express our appreciation to the WHO editor, copy-editor and proofreader in France and to the layout and typesetter company in Portugal for their careful eye for detail and their patience with the various rounds of editing. Last but not least, WHO expresses its profound gratitude to former interns at the Tobacco Free Initiative who contributed large chunks of their internship time to the fruition of this document: Ms Aurelie Abrial, Ms Colleen Ciciora, Mr Adrian Diaz, Dr Richelle Duque, Ms Mary Law, Atty Caitlin McGowan, Ms Christina Menke, Ms Hannah Patzke and Ms Nava Shahi. It is our hope that they continue to work passionately in some aspect of tobacco control, regardless of the bright careers they follow in the future. Undoubtedly, many people to whom we are indebted are not mentioned here, because there were so many people involved in the production of this advisory note. We apologize for any omission. We therefore thank both those who are named and those who are not named. Without your assistance and support, none of this would have been possible. Thank you very much.
9
Preface The WHO Study Group on Tobacco Product Regulation (TobReg)1 is mandated to provide the WHO Director-General with scientifically sound, evidence-based recommendations for Member States about tobacco product regulation. In line with the provisions of Articles 9 and 10 of the WHO Framework Convention on Tobacco Control (WHO FCTC), TobReg identifies approaches for regulating tobacco products that pose significant public health issues and raise questions for tobacco control policy. Regulation of tobacco products is essential for tobacco control and is endorsed by the WHO FCTC in provisions of its Articles 9, 10 and 11. Regulation serves public health goals by ensuring meaningful surveillance of the manufacture, packaging, labelling and distribution of tobacco products. Scientifically based principles for implementing the provisions create synergy and mutual reinforcement of the regulatory practices described in each article. Tobacco product regulation includes regulating their contents and emissions by testing, measuring and mandating disclosure of the results and regulating their packaging and labelling. Government supervision is required for manufacture and for enforcement of regulations on the design, contents and emissions of tobacco products, as well as their distribution, packaging and labelling, with the aim of protecting and promoting public health. Chemical consumer products are usually regulated after a review of the scientific evidence on the hazards associated with them, probable exposure, patterns of use and the marketing messages of the manufacturer. Many jurisdictions require manufacturers to classify and label products according to their hazardous properties, to control the hazardous content or to limit the advertising, promotion and sponsorship of such products. 1
http://www.who.int/tobacco/industry/product_regulation/tobreg/en/, accessed 24 July 2015.
10
TobReg reviews the scientific evidence on topics related to tobacco product regulation and identifies the research necessary to fill regulatory gaps in tobacco control. It is composed of national and international scientific experts on product regulation, treatment of tobacco dependence and laboratory analysis of tobacco contents and emissions. As a formalized entity of WHO, TobReg reports to the WHO Executive Board through the Director-General to draw the attention of Member States to the Organization’s work in tobacco product regulation, which is a complex area of tobacco control. The seventh meeting of TobReg was held in Rio de Janeiro, Brazil, on 4–6 December 2013. The discussions mainly addressed the request of the Conference of the Parties of the WHO FCTC at its fifth session (Seoul, Republic of Korea, 12–17 November 2012) to WHO to: • Monitor and follow closely the evolution of new tobacco products, including products with potentially “modified risks”, and to report any relevant development to the Conference of the Parties. • Direct some of its activities towards aspects of addictiveness (or dependence liability) of both smoked and smokeless tobacco products that remain to be studied. • Monitor and research country experience and scientific developments with respect to reduced ignition propensity cigarettes. • Identify measures likely to reduce the toxicity of both smoked and smokeless tobacco products, and describe the evidence supporting the effectiveness of such measures and the experience of Parties on the matter for consideration by the Conference of the Parties. • Compile, make available to Parties and update a non-exhaustive list of the toxic contents and emissions of tobacco products, and provide advice on how such information could be best used by Parties. • Prepare draft fact sheets on measures recommended in the partial guidelines for implementation of Articles 9 and 10 of the WHO FCTC. • Continue and report on progress in validation of analytical chemical methods for testing and measuring cigarette contents and emissions. Subsequent to this request, a number of background documents were commissioned. In addition, information on the availability and regulation of novel tobacco products, smokeless tobacco products and reduced ignition propensity cigarettes was collected in a WHO survey of tobacco products sent to all Member States. Ninety countries responded, representing approximately 77% of the world’s population.
11
The WHO report to the sixth session of the WHO FCTC Conference of the Parties in October 2014 is now published (WHO, 2015). Because of the complexity of the topic of reducing the dependence potential of manufactured cigarettes by reducing their nicotine content to levels that cannot cause or sustain addiction, however, was further discussed by TobReg members for more than 18 months. The result of those discussions is encapsulated in this TobReg advisory note on a global nicotine reduction strategy.
Main recommendation
This advisory note introduces a policy of limiting the sale of cigarettes to brands with a nicotine content that is not sufficient to lead to the development and/or maintenance of addiction; they are referred to as “reduced-nicotine” cigarettes. Conventional cigarettes—even those brands that deliver low nicotine yields as measured by machine smoking under the conditions of the International Organization for Standardization (ISO)—contain addicting levels of nicotine, but the nicotine yields are reduced as a result of many design features, including ventilated filters. Users puff ISO low-nicotine-yield cigarettes more intensely (i.e. they draw larger puffs more frequently than the conditions prescribed by machines) to obtain addicting levels of nicotine. Unlike conventional cigarettes, reducednicotine cigarettes can limit the addictiveness of the product, as the low content in the tobacco filler2 cannot deliver addicting levels of nicotine. Research shows that switching from conventional to cigarettes with a nicotine content of 0.4 mg/g of cigarette tobacco filler does not significantly increase craving or withdrawal symptoms and does not result in compensatory smoking (such as more intense smoking or smoking more cigarettes per day). No specific amount of nicotine has yet been identified as the absolute threshold for addiction; however, it is likely to be equal to or possibly less than 0.4 mg/g of dry cigarette tobacco filler. The ultimate health benefits of a nicotine reduction strategy for individual smokers will require complete cessation of intake of all combusted tobacco. Population benefits will result from decreased use of combusted tobacco by current cigarette smokers and from prevention of addiction of non-smokers to cigarettes, especially among young people. To achieve the public health goal, not only product modification but also the provision of treatment will be required, including behavioural support, Cigarette tobacco filler is defined as the tobacco-containing part of a cigarette, including a blend of different tobacco types, reconstituted tobacco sheets, stems, expanded tobacco and additives. (See WHO, 2014.) 2
12
nicotine replacement and other medications, for cigarette smokers who will no longer be able to obtain adequate levels of nicotine from cigarettes. For people who switch from cigarettes to non-combusted forms of tobacco to sustain their nicotine intake, the health benefits will depend, partly, on the level of tobaccorelated toxicants delivered by the alternative products and the behaviour and duration of use of such products.
Significance for public health policies
A nicotine reduction strategy could decrease the acquisition of smoking and progression to addiction among experimenters, limit the number of cigarettes smoked by some proportion of addicted smokers and both increase the number of addicted smokers who stop smoking and reduce the number of those who relapse.
Implications for WHO programmes
Implementation of a nicotine-reduction policy should be supported by a comprehensive programme, involving: • a strategy on health communication and public education; • the absence of products with higher levels of nicotine in tobacco filler on the market; • effective, affordable, available cessation treatment that includes behavioural support, alternative forms of nicotine in products that pose a significantly lower risk for tobacco-related disease and medicines approved for treating tobacco dependence and withdrawal; • capacity to monitor the market and test tobacco products for nicotine and other constituents and emissions; and • continued research to assess: – the likelihood of use and the effects of reduced-nicotine cigarettes in non-smoking adolescents; – the likelihood that users will switch back to high-nicotine products if they are available on the market; – additional use of other types of product (e.g. smokeless tobacco products, e-cigarettes); – long-term use of reduced-nicotine cigarettes;
13
– the long-term impact of reduced-nicotine cigarettes on smoking behaviour and – comprehensive surveillance to ensure rapid detection of unintended consequences. TobReg hopes that the conclusions and recommendations contained in this advisory note will be useful to countries implementing the product regulation provisions of the WHO FCTC.
14
Reducing the addictiveness of manufactured cigarettes by reducing their nicotine content: research needs and regulatory recommendations 1. Introduction
A policy to reduce the addictiveness of tobacco by reducing its nicotine content comprises setting a maximum allowable limit on the nicotine content of all cigarettes and potentially other forms of tobacco (both combusted and noncombusted) that are available for sale, with the intention of minimizing the development and/or maintenance of nicotine addiction. The report reflects increasing scientific understanding about the population effects of cigarettes containing reduced-nicotine tobacco; it includes recommendations for policy and regulations based on the current state of science and discusses issues raised by regulatory authorities and the Conference of the Parties to the WHO Framework Convention on Tobacco Control (WHO FCTC). It is based on a background report3 commissioned by WHO (WHO, 2015), with input from the Study Group on Tobacco Product Regulation (TobReg) at its seventh meeting in Rio de Janeiro, Brazil, in December 2013.
The background report, entitled “Reducing the dependence potential of manufactured cigarettes by reducing their nicotine content to levels that cannot cause or sustain addiction”, appears as Annex 3 in WHO (2015), for further information for researchers and policy-makers. 3
15
2. Background
Addiction is a chronic, relapsing brain disease characterized by compulsive selfadministration of a drug, often despite harmful consequences (WHO, 1992; National Institute on Drug Abuse, 2014). Since the 1980s, it has been generally recognized that nicotine is the primary addicting chemical in tobacco products; by the 1990s, it was increasingly accepted that tobacco products without nicotine would not sustain addiction (Benowitz & Henningfield, 1994; Henningfield et al., 1998). The tobacco industry recognized this many years earlier and designed cigarettes to ensure that they could deliver addicting levels of nicotine despite reduced machine-estimated deliveries as measured by the ISO and United States Federal Trade Commission test methods (National Cancer Institute, 2001; WHO, 2001; WHO, 2003a). Earlier reports from TobReg and its predecessor SACTob similarly concluded that nicotine was the primary addicting chemical common to combusted and non-combusted tobacco products and that it should be regulated, with other content and design features. To date, however, TobReg has not published a clear position on reducing the addiction potential of manufactured cigarettes (WHO, 2002; WHO, 2007; WHO, 2009; WHO, 2012a). During the past decade, experimental research and modelling have been conducted to assess the potential public health impact of a policy to reduce the addictiveness of cigarettes, as discussed in this report. The results led to the current recommendation: that reducing the maximum allowable nicotine content in cigarettes to minimally addicting levels be considered a suitable strategy for reducing the demand for these products, which account for the vast majority of tobacco-attributable morbidity and mortality in most countries and regions. This report does not provide a detailed proposal of how such a policy might be enacted but rather focuses on the scientific basis for recommending this policy. It presents the conditions that might be necessary for viable enactment of such a policy and many of the challenges to be met, including unanswered research questions.
3. Cigarettes with a reduced nicotine content
In a policy to reduce the addictiveness of tobacco, the nicotine content of all cigarettes permitted for sale would be inadequate to cause or sustain addiction. Such cigarettes have been referred to as “reduced-nicotine cigarettes”, “very low nicotine content cigarettes” and “de-nicotinized cigarettes”. They are distinct from
16
reduced-yield cigarettes, which were developed in the 1970s in response to public health concern and marketed with descriptors such as “light”, “low tar” and “mild”. Those descriptions implied lower deliveries and less exposure to nicotine and other substances (commonly termed “tar”), but the products actually contained similar amounts of nicotine and delivered nicotine doses that were associated with risks for addiction and other diseases as high as those of their “full-flavoured” counterparts (National Cancer Institute, 2001; WHO, 2001; WHO, 2003a). Whereas cigarettes with a very low nicotine content cannot sustain addiction, cigarettes marketed as “reduced yield” on the basis of machine testing have been found to extend the prevalence of addiction in many populations because they are perceived as safer and are easier to inhale (Kozlowski & O’Connor, 2002).
4. Goals of a policy to reduce addiction to cigarettes
A policy to reduce the addictiveness of cigarettes has many goals: to reduce the risk that non-smokers will become addicted to cigarettes, to make it easier for smokers to quit smoking, to help prevent smokers who have quit from relapsing and, if needed, to encourage cigarette smokers to substitute a less harmful and, ideally, less addictive source of nicotine (Henningfield et al., 1998; Hatsukami et al., 2010a; Benowitz & Henningfield, 2013). Since nicotine reduction was first proposed by Benowitz and Henningfield in 1994, a number of health scientists have concluded that the approach could significantly impact public health (Gray et al., 2005; Zeller et al., 2009; Benowitz & Henningfield, 2013; Hatsukami et al., 2013a; Smith et al., 2013). The approach is consistent with Article 9 of the WHO FCTC, which calls for guidelines for regulating the contents and emissions of tobacco products (WHO, 2003b; WHO, 2012a).
5. Tobacco addictiveness factors
As discussed elsewhere and in earlier WHO reports (WHO, 2001; WHO, 2007; WHO, 2012a), nicotine is a highly addictive, potent drug, which can generate psychoactive rewarding effects even at very low doses,. Cigarettes are a particularly effective form of nicotine delivery: when smoke from a cigarette is inhaled, nicotine in the tobacco is rapidly absorbed into the lungs and carried to the brain.
17
Individual responses to nicotine, including sensitivity, are highly variable. Early exposure to nicotine (i.e. before or during adolescence) is associated with more severe dependence, greater reward and increased self-administration, suggesting that the developing brain may be more susceptible to permanent changes caused by nicotine that support addiction (Benowitz, 2008; Hatsukami et al., 2010a). Women are more strongly influenced than men by the sensory aspects of smoking and have more difficulty in quitting (Fant et al., 1996; Gritz et al., 1996; Eissenberg et al., 1999; Perkins et al., 1999; Wetter et al., 1999; Perkins et al., 2006; Perkins, 2009). Individuals with psychiatric and/or substance abuse disorders have much higher rates of nicotine dependence and have more difficulty in quitting (Ziedonis et al., 2008). The sensory characteristics of smoking (taste, aroma, tracheobronchial sensations) facilitate delivery of nicotine and come to be associated with its pharmacological effects, further reinforcing addiction (WHO, 2007; Henningfield et al., 2011; WHO, 2012a). Because non-nicotine components of tobacco are critical to the sensory experience of smoking, de-nicotinized tobacco is more effective in reducing craving and producing greater pleasure in smokers than nicotine without tobacco (Rose, 2006). Nicotine also plays a central role in the sensory composition of cigarette smoke: nicotine-containing cigarettes are consistently rated as stronger than de-nicotinized cigarettes because of the greater sensory stimulus. Some non-nicotine components of tobacco may interact chemically or have a synergistic effect (e.g. acetaldehyde) with nicotine, further potentiating its effects, or may have measurable pharmacological effects on their own. For example, various minor tobacco alkaloids reinforce self-administration by rats, and monoamine oxidase inhibitors present in tobacco smoke have been shown to increase response rates substantially when given to rats that are self-administering nicotine (Guillem et al., 2005). Thus, although drastically reducing nicotine should substantially decrease the addictiveness of tobacco for most people, a product with a very low nicotine content may still have some reinforcing effects for certain people. Expectations about the effects of a drug play an important role in determining subjective and behavioural responses to tobacco products, particularly in women (Perkins et al., 2006). Expectancy may be due to sensory stimuli produced by the product, by packaging or by other information cues. Social context also determines smoking behaviour and dependence, such as where it is permissible to use tobacco products (both legally and in terms of social norms), the cost of tobacco use both individually and to one’s family, and whether tobacco use is stigmatized in subpopulations such as by gender, religious affiliation or social status.
18
6. Establishing a performance standard for nicotine products
Various tests are available for identifying potentially addicting drugs and the dosages of the drugs that reinforce and sustain use, by producing either psychoactive effects or physical dependence and withdrawal. These tests are recommended by WHO (2006) and have been described in scientific reviews and by various regulatory agencies (Balster & Bigelow, 2003; Schuster & Henningfield, 2003; Carter et al., 2009). No single amount of nicotine can be identified as an absolute threshold for addiction in all individuals, under all circumstances and by all routes or means of administration; however, numerous studies conducted in both animals and humans confirm that there are doses above which nicotine is consistently selfadministered and below which self-administration is not observed or, in humans, results in significantly reduced dependence (Hatsukami et al., 2010a; Donny et al., 2012). The doses of nicotine necessary to produce psychoactive or discriminative effects reliably in humans and animals have also been studied (Department of Health and Human Services, 1988; Carter et al., 2009). Taken together, these and other types of studies provide a basis for setting standards for the levels of nicotine above which addiction is likely and below which addiction is less likely (Carter et al., 2009; Sofuoglu & LeSage, 2012; Benowitz & Henningfield, 2013). Smokers self-administer nicotine intravenously within a range of intake well below that from a typical cigarette, with a threshold somewhere between 0.1 and 0.4 mg of nicotine, assuming 70 kg body weight (Sofuoglu et al., 2008). Similarly, in dose–response studies, animals commonly self-administer doses of nicotine below 10 μg/kg and maintain self-administration with unit doses of as low as 3 μg/kg, equivalent to around 0.23 mg nicotine, although there is considerable individual variation in response rates at the lower end of this range (Donny et al., 2012; Smith et al., 2013). As tobacco-delivered nicotine differs substantially from intravenous nicotine, it may not be sufficient to rely on studies of intravenous nicotine self-administration to predict the potential reinforcing effects of tobacco with reduced nicotine content. Administration parameters such as the timing of dose delivery play a role in determining the pharmacology and reinforcing effects of a given dose (Sorge & Clarke, 2009). Nonetheless, the limited evidence available suggests that the nicotine threshold for self-administration of cigarette-delivered nicotine is not substantially different from that identified above. Tobacco manufacturers have used brain imaging to determine effective ranges of cigarette nicotine delivery under controlled smoking conditions (Panzano et al., 2010); the results suggest
19
a threshold for a neurophysiological effect of 0.1–0.3 mg of machine-measured smoke nicotine. The findings are also consistent with research on nicotine discrimination, which indicates that the threshold levels for discrimination are in a comparable range and do not differ for smokers and non-smokers (Hatsukami et al., 2010a). Whereas most studies in humans have been conducted among established smokers, studies in animals suggest that the threshold for acquisition of nicotine selfadministration behaviour is equal to or higher than that for maintenance of such behaviour (Donny et al., 2014). In adult rats, self-administration of low doses of nicotine is more frequent after exposure to high doses of nicotine and subsequent dose reduction than during acquisition (Smith et al., 2014). Acquisition of nicotine self-administration behaviour and dependence among adolescents may, however, be different from that among adults. Both cross-sectional and longitudinal studies indicate that young people who smoke less than daily nonetheless report the onset of dependence symptoms. Reward expectancy plays a significant role in smoking behaviour and motivation to smoke among adolescents (Kassel et al., 2007). De-nicotinized cigarettes suppress acute craving and delay the onset of ad-libitum smoking in the same way as nicotine-containing cigarettes (Rose et al., 2003; Barrett, 2010); in contrast, intravenous nicotine suppresses ad-libitum smoking to only a small extent (Rose et al., 2003). This suggests that the non-nicotine stimuli associated with smoking become conditioners, serving as cues to the smoker for anticipated nicotine delivery. The conditioning properties of tobacco smoking are acquired only after long-term prior use of nicotine-containing cigarettes. Studies in animals suggest that the conditional reinforcing properties acquired by a stimulus are a direct function of dose. This implies that stimulus control of tobacco-seeking behaviour will be most potent in people exposed to high levels of nicotine and are likely to be greatly reduced by exposure to very low nicotine, with a reduction in conditional stimuli (Palmatier et al., 2008). Variations in sensitivity to the behavioural and potentially addictive effects of nicotine have important implications for setting product performance standards for nicotine. Thus, to minimize the risk for addiction of all individuals who sample cigarettes, the maximum allowable content should be well below that which might have behavioural and addictive effects. Comprehensive surveillance and epidemiological studies will be important to determine if the performance standards set initially are effective and to assess any unintended consequences rapidly. Corrections and risk management plans can be made accordingly.
20
7. Feasibility of reducing nicotine
Currently, most conventional cigarettes contain 10–15 mg of nicotine each, of which approximately 10% is delivered in smoke, resulting in a typical systemic intake of 1–2 mg of nicotine per cigarette. Higher levels can be delivered with more intense smoking behaviour. Thus, establishing a maximum allowable limit for nicotine would require an overall reduction in nicotine intake of the order of 90–95% or more. The concentration of nicotine in tobacco is readily altered and controlled by manufacturers, for example by genetic modification, enzymatic processes or nicotine extraction, to levels approaching or exceeding this range of nicotine reduction (Wayne & Carpenter, 2009). Reduced-nicotine cigarettes are now available that contain < 1 mg nicotine per gram of tobacco and, when smoked on a standard smoking machine (ISO), have a nicotine yield of 0.03–0.1 mg, equivalent to 3–10% of the nicotine yield of standard commercial brands. Most behavioural research on nicotine reduction has been conducted with cigarettes that provide this range of nicotine in smoke. Production of cigarettes with a very low nicotine content is technically feasible. The loss of sensory impact due to reduced nicotine has been discussed as a potential technical challenge; however, the fact that commercial cigarette brands such as Next and Quest with a nicotine content of < 1 mg have been produced and that these products can substitute for conventional cigarettes and at least temporarily reduce cigarette craving provides strong evidence that the production of cigarettes with a very low nicotine content is technically feasible (Butschky et al., 1995; Rose et al, 2003; Johnson et al., 2004; Rose, 2006; Hatsukami et al., 2013b). Spectrum cigarettes, currently produced for research purposes by 22nd Century Manufacturers, have a reported level of 0.4 mg nicotine per gram of tobacco. Another concern raised with respect to nicotine reduction is that smokers will respond by altering their smoking behaviour. Evidence from clinical studies indicates, however, that smokers of products with a very low nicotine content (< 1 mg/g) do not significantly alter their behaviour from that with their usual brand, and their exposure to nicotine remains significantly reduced (Benowitz et al., 2006; Hatsukami et al., 2010b; Benowitz et al., 2012). Smokers do, however, compensate for less extreme reductions in delivered smoke nicotine (0.2–0.3 mg) (Hatsukami et al., 2010b). Moreover, for smokers not interested in quitting,
21
progressive reduction of the nicotine content of their cigarettes to 0.5 mg/g does not lead to extinction of their dependence upon follow up (Benowitz et al., 2015). The behavioural research conducted to date has been with cigarettes with reducednicotine tobacco but otherwise conventional design. Other physical and chemical parameters of cigarette construction can be manipulated to alter the basic formulation, with unknown behavioural and health consequences. Therefore, attention must continue to be paid to other product factors, in addition to nicotine delivery. Standard measures of smoke nicotine delivery do not differentiate between forms of nicotine (e.g. free-base versus protonated nicotine); comparisons of free-base nicotine delivery may provide a more accurate measure of subjective response to reduced-nicotine content products (Wayne & Carpenter, 2009).
8. Potential behavioural and population outcomes
Reduced-nicotine cigarettes can give acute subjective satisfaction (Hatsukami et al., 2010a) and immediately reduce craving in smokers (Rose et al., 2003); however, with repeated use, reduced-nicotine cigarettes give less satisfaction than those with a higher dose of nicotine (Hatsukami et al., 2013c). Clinical data indicate that withdrawal is not a common adverse consequence of reduced nicotine intake in most smokers and that significant compensation in the form of more intense smoking or more cigarettes per day is not a probable outcome at very low nicotine levels (< 1 mg) (Hatsukami et al., 2010a; Hatsukami et al., 2010b; Benowitz et al., 2012). Use of reduced-nicotine cigarettes over a long time weakens the reinforcing effects of smoking: smokers consistently report less dependence after prolonged use of such products (Donny et al., 2007; Benowitz et al., 2009; Hatsukami et al., 2010b; Benowitz et al., 2012). Reduced-nicotine cigarettes may represent a temporary coping mechanism and help smokers to achieve abstinence when they make an active attempt to quit. They may support quitting not only for smokers who seek treatment but also for smokers who have not previously expressed an interest in quitting (Benowitz et al., 2007; Benowitz et al., 2009). The effects of reduced-nicotine cigarettes on quitting may be strengthened by the addition of nicotine-based treatment, particularly in men (Vogel et al., 2014). This suggests that other forms of treatment and behavioural support may be helpful as well and should be made accessible to support the transition
22
to reduced-nicotine cigarettes as well as to people attempting complete tobacco abstinence. The health benefits of switching from cigarettes to non-combusted forms of tobacco to sustain the nicotine intake will depend partly on the level of tobacco toxicants delivered by the alternative products and how long they are used. Some people may continue to smoke cigarettes after mandated nicotine reduction, either for a strong substitution effect or because the nicotine content of the cigarettes remains above their individual threshold for reinforcement. Few studies have been conducted, however, on the uptake of reduced-nicotine cigarettes by non-smoking populations and the long-term effects of reducednicotine cigarette use; there may be little, if any, health benefit if people continue to inhale high levels of combusted tobacco emissions. People should be encouraged and supported to discontinue use of any combusted tobacco product as quickly as possible. Surveillance and other research will be required to monitor effects—desired and undesired. The literature provides no quantified estimates of the potential impact of a reduced-nicotine policy on smoking initiation among adolescents. It is theoretically possible that reduced-nicotine cigarettes could serve as “starter” products for products with a higher nicotine content, if such products were still available on the commercial market. Thus, product labelling and access restriction will remain important. Reduced-nicotine cigarettes should not be exempt from warnings about the risk for addiction, although the warnings may be somewhat different from those used on higher-nicotine products (Henningfield et al., 1994). Various models have been created to estimate the probable effects of a nicotine reduction policy; all indicate a significant positive effect on public health outcomes. No published study has provided an estimate of the probable illicit sales of conventional cigarettes with a higher nicotine content in the context of a reduced-nicotine market. Both the appeal of reduced-nicotine cigarettes and the availability and appeal of alternative forms of nicotine are likely to affect the extent of illicit sales.
9. Policy approaches to nicotine reduction
The effects of a cigarette nicotine reduction policy will depend to a significant degree on the availability, toxicity and appeal of alternative nicotine delivery systems, including other forms of combusted or non-combusted tobacco,
23
medicinal nicotine and commercial non-tobacco nicotine products, as discussed elsewhere (Henningfield et al., 1998; Benowitz & Henningfield, 2013; Department of Health and Human Services, 2014). Substitution of alternative products could have adverse health effects or maintain addiction in a significant segment of the population. Therefore, a successful nicotine reduction policy must be supported by comprehensive regulation of all tobacco- and nicotinecontaining products (Gray et al., 2005; Zeller et al., 2009; Le Houezec et al., 2011; McNeill et al., 2012; Hatsukami et al., 2013a; Benowitz et al., 2015). The goals of comprehensive regulation would be to minimize use of highly toxic nicotine-containing products, to encourage the development of less toxic nicotine delivery systems as alternatives to more toxic products and to continue to monitor and regulate the health effects of the less toxic products (Gray et al., 2005; Le Houezec et al., 2011; Benowitz & Henningfield, 2013). Policy approaches could be considered to motivate smokers who are unable to quit to substitute less hazardous forms of tobacco and nicotine use, e.g. through restrictions on access, marketing and use, in order to encourage complete cessation of use of the more toxic products. The health benefits for people who switch from cigarettes to non-combusted forms of tobacco to sustain their nicotine intake will depend partly on the level of tobacco-related toxicants delivered by the alternative products, the extent to which they continue to smoke cigarettes and how long they continue to use the products. The effects of reducing nicotine to very low levels either gradually or immediately have been evaluated in clinical studies; no adverse effect was found in either condition, indicating that neither approach poses a significant safety concern (Hatsukami et al., 2013a; Smith et al., 2013; Hatsukami et al., 2015). A gradual reduction would maintain smokers at nicotine doses more likely to support compensatory behaviour for an extended period and could theoretically enable them gradually to adapt effective compensatory behaviour to products with a low nicotine content. Therefore, an immediate reduction in nicotine, preceded by health communication strategies and public education, is the more promising approach. Product performance standards are necessary to ensure successful implementation of nicotine reduction. While a number of approaches could be considered, reducing the total nicotine available in unburnt cigarettes is the most promising, as it is both easily measured and not subject to behavioural manipulation or individual variation. Although this report addresses cigarettes, a similar regulatory approach
24
would be appropriate for other combusted and non-combusted products. Product performance standards must remain responsive to the changing marketplace (Hatsukami et al., 2012; O’Connor, 2012; Hatsukami et al., 2013a), and new products and technologies must be evaluated carefully. Commercial introduction of new products should be permitted only when they have been shown sufficiently to be associated with reduced risk, addictiveness and appeal. Whether a policy will result in a reduction in the addictiveness of cigarettes will depend partly on how effectively the risks are communicated. Mistaken beliefs about the greater safety of reduced-nicotine products could lower the likelihood of quitting and could encourage more experimentation. Implementation of smoke-free policies might provide a useful model, and public education can support compliance and ensure continued support for the law. Studies in the USA (Hatsukami et al., 2013a) have shown strong support for mandated nicotine reduction among both smokers and non-smokers, but no surveys have been reported from other parts of the world. Education of smokers and non-smokers about the health risks of tobacco without nicotine, the relative harm of different products and opportunities for treatment is critical. The marketing of tobacco and nicotine products will have to be strongly regulated (McNeill et al., 2012; Hatsukami et al., 2013a). Although the evidence is inconclusive, various models have indicated that setting a maximum allowable nicotine content will sharply increase the number of smokers who want to quit (Tengs et al., 2005; Morrison, 2013). Many smokers are likely to seek nicotine replacement or behavioural therapy to aid cessation or to obtain relief from withdrawal symptoms. Effective, affordable treatment offered by health care professionals and coverage by insurance programmes will be invaluable in ensuring the success of the policy, as will individualized services to populations in whom the adverse effects may be more severe, such as those with psychiatric disorders. Wide availability of pharmacotherapy and treatment might not only reduce the discomfort associated with smoking reduced-nicotine cigarettes but might also lead to a substantial reduction in cigarette smoking and possibly to cessation of use of all tobacco and nicotine products by some or many current smokers (Zeller et al., 2009; O’Connor, 2012; Benowitz & Henningfield, 2013). The appeal of alternative tobacco products, such as oral and smokeless tobacco, waterpipes, pipes and cigars, may increase, as they may substitute for conventional cigarettes more effectively than reduced-nicotine cigarettes; however, few data are available. This prospect must be included in any assessment of the health effects of
25
existing and new products that could serve such a purpose. Extending a nicotine reduction policy to other combusted products or possibly non-combusted tobacco products should be considered. Electronic nicotine delivery devices and other products designed expressly to replicate the act of smoking may present viable alternatives; in some countries, however, if they are marketed as cessation aids, they would first have to be proven safe and effective in clinical trials (Department of Health and Human Services, 2014; WHO, 2014b). Reduced availability of conventional cigarettes as a consequence of adoption of a maximum allowable limit for the nicotine content of all cigarettes might increase the demand of addicted smokers for contraband conventional cigarettes. Minimizing sales of illicit cigarette will require effective surveillance of wide-scale organized smuggling and other types of illegal trade, such as in bootlegged and counterfeit products (Joossens & Raw, 2008). Unregulated combusted tobacco, such as roll-your-own, could be substituted for manufactured cigarettes. Other areas of potential concern include use of both reduced-nicotine cigarettes and nicotine delivery devices, use of pH modification or additives to increase the impact and pharmacological effect of manufactured products and unanticipated behavioural changes, such as deeper inhalation or increased or more frequent long-term use of reduced-nicotine cigarettes. The production of more appealing alternative nicotine products is likely to serve as a check on these unintended market outcomes (Benowitz & Henningfield, 2013; Hatsukami et al., 2013a). An adequate surveillance system would allow regulators to monitor the impact of tobacco products on the prevalence, initiation and harm of smoking and to address unintended outcomes (Hatsukami et al., 2013a). Mandatory reporting of all nicotine and tobacco products, as described in the partial guidelines to implementing Articles 9 and 10 of the WHO FCTC (WHO, 2012b), are a necessary condition for adequate surveillance. Mandatory reporting should include the physical design (tobacco weight, nicotine concentration, filter ventilation), the tobacco and added constituents, the emissions of combusted products and measures of possible abuse (Carter et al., 2009; Hatsukami et al., 2012; McNeill et al., 2012). The complexity of tobacco products and the knowledge required to assess toxicological effects, the possibility of abuse and other outcomes may be barriers for some Parties. A global data repository would facilitate tobacco product regulation and surveillance worldwide, would ease the burden on regulators by providing access to analysed data and global comparisons, and would provide information to national regulators, with recommendations in an easily understandable form (McNeill et al., 2012).
26
10. Conclusions
There is clear evidence that reducing the nicotine content of cigarettes to a very low level can reduce their dependence potential. The maximum nicotine content of cigarettes that leads to dependence is likely to vary individually and is possibly lower for young people. Thus, the maximum nicotine content should be as low as is technically feasible. At present, that level would appear to be 0.4 mg nicotine per gram of cigarette tobacco filler.4 Compensatory smoking has been observed with highly ventilated cigarettes but not with cigarettes with a nicotine content of 0.4 mg per gram of cigarette tobacco filler. The evidence indicates that setting a maximum allowable nicotine content for all cigarettes could: • reduce acquisition of smoking and progression to addiction; • reduce the prevalence of smoking in a proportion of addicted smokers as a result of behavioural extinction; • increase the rate of quitting and reduce the number of smokers who relapse; and • increase the development, availability and use of alternative forms of nicotine, e.g. smokeless tobacco products, nicotine aerosol products and medicinal nicotine, which have potential adverse health effects, including maintenance of addiction, but less than those of combusted products or conventional cigarettes.
11. Research needs
Major research projects, including clinical trials, are under way and are providing relevant information for implementing an approach to reducing the addictiveness of cigarettes. The research priorities include: • the probable use and effects of reduced-nicotine cigarettes in non-smoking adolescents, non-smoking adults5 and non-dependent smokers (i.e. light In the working group report FCTC/COP/5/9, dated 17 July 2012, reference is made to commercial cigarettes containing 0.03 mg nicotine. This measure refers to the smoke nicotine yield, which is only a fraction (in this case, approximately 10%) of the nicotine contained in unburnt cigarette tobacco. Spectrum cigarettes, produced for research by 22nd Century Manufacturers, have a reported content of 0.4 mg nicotine per gram of tobacco. 5 As administering reduced nicotine cigarettes to tobacco-naive humans is unethical, studies on animals or indirect ways of assessing the impact on non-smokers will have to be considered. 4
27
• • • • •
•
or occasional smokers who experience minimal withdrawal symptoms yet continue to smoke);6 potential use of reduced-nicotine products as “starters” or “gateway” products by adolescents, leading to use of other forms of nicotine or drugs; the effects of reduced-nicotine cigarettes in populations at risk, such as people with moderate or severe depression or other comorbid conditions; the comparative health risks of smoking reduced-nicotine cigarettes and conventional cigarettes, including in special sub-populations (e.g. women of reproductive age); long-term use of reduced-nicotine cigarettes and the long-term impact on smoking behaviour and health outcomes, including cancer; comparison of the long-term public health effects of reduced-nicotine cigarettes and of alternative non-combusted forms of nicotine (e.g. some smokeless tobacco products with reduced tobacco-specific nitrosamines or electronic nicotine and non-nicotine delivery systems); and surveillance and epidemiology to assess any unintended consequences, including on health, and to guide modification of the policy and supporting strategies.
12. Regulatory recommendations
• Mandated reductions in nicotine to minimally addictive levels should be supported by comprehensive regulation of all nicotine- and tobaccocontaining products. • Mandated reductions in nicotine to minimally addictive levels must be part of comprehensive tobacco control, including increased taxes on cigarettes, comprehensive smoking bans, anti-smoking educational campaigns and graphic warning labels or plain packaging. • Mandated reductions in nicotine to minimally addictive levels might be considered for all combusted products because of the overwhelming A subset of light or occasional smokers consumes five or fewer cigarettes per day and appears to smoke primarily for the positive reinforcing effects of nicotine (Benowitz, 2008). These smokers use cigarettes mainly in association with specific activities, such as after meals or with alcohol, and less in response to negative affect; they may be more reactive to smoking cues (Watson et al., 2010). Although these occasional smokers experience minimal or no withdrawal symptoms, many have difficulty in quitting, suggesting a form of dependence that is distinct from that of everyday smokers. 6
28
toxicity associated with combustion and to minimize substitution of reduced-nicotine cigarettes for other combusted products. • The original proposal for nicotine reduction (Benowitz & Henningfield, 1994) urged a gradual reduction over many years. More recent scientific evidence suggests that an immediate reduction in the intake of nicotine below the established product performance standard, preceded by health communication strategies and public education, is a better approach, for practical reasons. There is no scientific basis for concluding that a onetime reduction is more or less likely to be associated with unintended consequences than gradual reduction. • Health professionals must be taught to communicate the risks, once they are known, and ensure compliance with and support for the law. The availability of effective, affordable cigarette cessation treatment, alternative forms of nicotine, optimal medicinal forms of nicotine and other approved treatments and medicines for tobacco dependence and withdrawal will help dependent smokers who experience adverse effects or withdrawal symptoms. • The potential adverse health effects and increased use of alternative nicotine products must be weighed against the benefits of a reduction in cigarette consumption. The health benefits for people who switch from conventional cigarettes to non-combusted forms of tobacco to sustain their nicotine intake will partly depend, however, on the level of tobaccorelated toxicants delivered by such alternative products, the extent to which people continue to smoke some cigarettes and how long they continue to use such products. • A strategy to reduce the addictiveness of tobacco is not recommended in the absence of developed capacity for market surveillance and product testing. Countries without an adequate infrastructure to ensure a comprehensive approach to nicotine reduction should carefully consider increasing that capacity before implementing such a strategy.
29
13. References Balster RL, Bigelow GE (2003) Guidelines and methodological reviews concerning drug abuse liability assessment. Drug Alcohol Depend 70(3 Suppl):S13–40. Barrett SP (2010) The effects of nicotine, denicotinized tobacco, and nicotine-containing tobacco on cigarette craving, withdrawal, and self-administration in male and female smokers. Behav Pharmacol 21:144–52. Benowitz NL (2008) Clinical pharmacology of nicotine: implications for understanding, preventing, and treating tobacco addiction. Clin Pharmacol Ther 83:531–41. Benowitz NL, Henningfield JE (1994) Establishing a nicotine threshold for addiction. The implications for tobacco regulation. N Engl J Med 331:123–5. Benowitz NL, Henningfield JE (2013) Reducing the nicotine content to make cigarettes less addictive. Tob Control 22(Suppl 1):i14–7. Benowitz NL, Jacob P 3rd, Herrera B (2006) Nicotine intake and dose response when smoking reduced-nicotine content cigarettes. Clin Pharmacol Ther 80:703–14. Benowitz NL, Hall SM, Stewart S, Wilson M, Dempsey D, Jacob P 3rd (2007) Nicotine and carcinogen exposure with smoking of progressively reduced nicotine content cigarette. Cancer Epidemiol Biomarkers Prev 16:2479–85. Benowitz NL, Dains KM, Hall SM, Syewart S, Wilson M, Dempsey D, et al. (2009) Progressive commercial cigarette yield reduction: biochemical exposure and behavioral assessment. Cancer Epidemiol Biomarkers Prev 18:876–83. Benowitz NL, Dains KM, Hall SM, Syewart S, Wilson M, Dempsey D, et al. (2012) Smoking behavior and exposure to tobacco toxicants during 6 months of smoking progressively reduced nicotine content cigarettes. Cancer Epidemiol Biomarkers Prev 21:761–9. Benowitz NL, Nardone N, Dains KM, Hall SM, Stewart S, Dempsey D, et al. (2015) Effect of reducing the nicotine content of cigarettes on smoking behavior and tobacco smoke toxicant exposure: 2-year follow up. Addiction. doi: 10.1111/add.12978. Butschky M, Bailey D, Henningfield JE, Pickworth WB (1995) Smoking without nicotine delivery decreases withdrawal in 12-hour abstinent smokers. Pharmacol Biochem Behav 50:91–96. Carter LP, Stitzer ML, Henningfield JE, O’Connor RJ, Cummings KM, Hatsukami DK (2009) Abuse liability assessment of tobacco products including potential reduced exposure products. Cancer Epidemiol Biomarkers Prev 18:3241–62.
30
Department of Health and Human Services (1988) The health consequences of smoking: nicotine addiction. A report of the Surgeon General. Rockville, Maryland: Department of Health and Human Services, Public Health Service, Centers for Disease Control, Office on Smoking and Health; 1988 Department of Health and Human Services (2014) The health consequences of smoking—50 years of progress: a report of the Surgeon General. Rockville, Maryland; 874. Donny EC, Houtsmuller E, Stitzer ML (2007) Smoking in the absence of nicotine: behavioral, subjective and physiological effects over 11 days. Addiction 102:324–34. Donny EC, Taylor TG, Le Sage MG, Levin M, Buffalari DM, Joel D, et al. (2012) Impact of tobacco regulation on animal research: new perspectives and opportunities. Nicotine Tob Res 14:1319–38. Donny, E.C., Hatsukami, D.K., Benowitz, N.L., Sved, A.F., Tidey, J.W., Cassidy, R.N. (2014) Reduced nicotine product standards for combustible tobacco: Building an empirical basis for effective regulation. Preventive Medicine, epub ahead of print June 23. Eissenberg T, Adams C, Riggins EC 3rd, Likness M (1999) Smokers’ sex and the effects of tobacco cigarettes: subject-rated and physiological measures. Nicotine Tob Res 1:317–24. Fant RV, Everson D, Dayton G, Pickworth WB, Henningfield JE (1996) Nicotine dependence in women. J Am Med Women Assoc 51:19–20, 22–4, 28. Gray N, Henningfield JE, Benowitz NL, Connolly GN, Dresler C, Fagerstrom K, et al. (2005) Toward a comprehensive long term nicotine policy. Tob Control 14:161–5. Gritz ER, Nielsen IR, Brooks LA (1996) Smoking cessation and gender: the influence of physiological, psychological, and behavioral factors. J Am Med Women Assoc 51:35–42. Guillem K1, Vouillac C, Azar MR, Parsons LH, Koob GF, Cador M, et al. (2005) Monoamine oxidase inhibition dramatically increases the motivation to self-administer nicotine in rats. J Neurosci 25:8593–600. Hatsukami DK, Perkins KA, Le Sage MG, Ashley DL, Henningfield JE, Benowitz NL, et al. (2010a) Nicotine reduction revisited: science and future directions. Tob Control 19:e1–10. Hatsukami DK, Hertsgaard LA, Vogel RI, Jensen JA, Murphy SE, Hecht SS, et al. (2010b) Reduced nicotine content cigarettes: effects on toxicant exposure, dependence and cessation. Addiction 105:343–55. Hatsukami DK, Biener L, Leischow SJ, Zeller MR (2012) Tobacco and nicotine product testing. Nicotine Tob Res 14:7–17.
31
Hatsukami DK, Benowitz NL, Donny E, Henningfield J, Zeller M (2013a) Nicotine reduction: strategic research plan. Nicotine Tob Res 15:1003–13. Hatsukami DK, Hertsgaard LA, Vogel RI, Jensen JA, Murphy SE, Hecht SS, et al. (2013b) Reduced nicotine content cigarettes and nicotine patch. Cancer Epidemiol Biomarkers Prev 22:1015– 24. Hatsukami DK, Heishman SJ, Vogel RI, Denlinger RL, Roper-Batker AN, Mackowick KM, et al. (2013c) Dose response effects of Spectrum research cigarettes. Nicotine Tob Res 15:1113–21. Hatsukami DK, Donny EC, Koopmeiners JS, Benowitz NL (2015) Compensatory smoking from gradual and immediate reduction in cigarette nicotine content. Cancer Epidemiol Biomarkers Prev 24:472–6. Henningfield JE, Kozlowski LT Benowitz NL (1994) A proposal to develop meaningful labeling for cigarettes. J Am Med Assoc 272:312–4. Henningfield JE, Benowitz NL, Slade J, Houston TP, Davis RM, Deitchman SD (1998) Reducing the addictiveness of cigarettes. Council on Scientific Affairs, American Medical Association. Tob Control 7:281–93. Henningfield JE, Hatsukami DK, Zeller M, Peters E (2011) Conference on abuse liability and appeal of tobacco products: conclusions and recommendations. Drug Alcohol Depend 116:1–7. Johnson MW, Bickel WK, Kirshenbaum AP (2004) Substitutes for tobacco smoking: a behavioral economic analysis of nicotine gum, denicotinized cigarettes, and nicotine-containing cigarettes. Drug Alcohol Depend 74:253–64. Joossens L, Raw M (2008) Progress in combating cigarette smuggling: controlling the supply chain. Tob Control 17:399–404. Kassel JD, Evatt DP, Greenstein JE, Wardle MC, Yates MC, Veilleux JC (2007) The acute effects of nicotine on positive and negative affect in adolescent smokers. J Abnorm Psychol 116:543–53. Kozlowski LT, O’Connor RJ (2002) Cigarette filter ventilation is a defective design because of misleading taste, bigger puffs, and blocked vents. Tob Control 11(Suppl 1):I40–50. Le Houezec J, McNeill A, Britton J (2011) Tobacco, nicotine and harm reduction. Drug Alcohol Rev 30:119–23. McNeill A, Hammond D, Gartner C (2012) Whither tobacco product regulation? Tob Control 21:221–6. Morrison B (2013) Modeling the benefits of a nicotine standard for tobacco products sold in Canada (abstract). In: Benefit–cost analysis for evidence-based decision making, Sixth Annual Conference and Meeting of the Society for Benefit-Cost Analysis. Seattle, Washington: Society
32
for Benefit-Cost Analysis, Evans School of Public Affairs, University of Washington (http:// benefitcostanalysis.org/system/files/SBCA14_Program_Book_Final2.pdf). National Cancer Institute (2001) Risks associated with smoking cigarettes with low tar machinemeasured yields of tar and nicotine (Monograph 13). Bethesda, Maryland. National Institute on Drug Abuse (2014) Media guide: The science of drug abuse and addiction: the basics. Bethesda, Maryland (http://www.drugabuse.gov/publications/media-guide/sciencedrug-abuse-addiction-basics, accessed 24 July 2015). O’Connor RJ (2012) Non-cigarette tobacco products: what have we learnt and where are we headed? Tob Control 21:181–90. Palmatier MI, Coddington SB, Liu X, Donny EC, Caggiula AR, Sved AF (2008) The motivation to obtain nicotine-conditioned reinforcers depends on nicotine dose. Neuropharmacology 55:1425–30. Panzano VC, Wayne GF, Pickworth WB, Connolly GN (2010) Human electroencephalography and the tobacco industry: a review of internal documents. Tob Control 19:153–9. Perkins KA (2009). Sex differences in nicotine reinforcement and reward: influences on the persistence of tobacco smoking. In: Bevins R,,Caggiula R, Eds. The motivational impact of nicotine and its role in tobacco use. New York: Springer-Verlag: 143–69. Perkins KA, Donny E, Caggiula AR (1999) Sex differences in nicotine effects and self-administration: review of human and animal evidence. Nicotine Tob Res 1:301–15. Perkins KA, Doyle T, Ciccocioppo M, Conklin C, Sayette M, Caggiula A (2006) Sex differences in the influence of nicotine dose instructions on the reinforcing and self-reported rewarding effects of smoking. Psychopharmacology 184:600–7. Rose JE (2006) Nicotine and nonnicotine factors in cigarette addiction. Psychopharmacology 184:274–85. Rose JE, Behm FM, Westman EC, Bates JE, Salley A (2003) Pharmacologic and sensorimotor components of satiation in cigarette smoking. Pharmacol Biochem Behav 76:243–50. Schuster CR, Henningfield J (2003) Conference on abuse liability assessment of CNS drugs. Drug Alcohol Depend 70(3 Suppl):S1–4. Smith TT, Levin ME, Schassburger RL, Buffalari DM, Sved AF, Donny EC (2013) Gradual and immediate nicotine reduction result in similar low-dose nicotine self-administration. Nicotine Tob Res 15:1918–25. Smith TT, Schassburger RL, Buffalan DM, Sved AF, Donny EC (2014) Low-dose nicotine selfadministration is reduced in adult male rats naive to high doses of nicotine: implications for
33
nicotine product standards. Exp Clin Psychopharmacol 22:453–9. Sofuoglu M, LeSage MG (2012) The reinforcement threshold for nicotine as a target for tobacco control. Drug Alcohol Depend 125:1–7. Sofuoglu M, Yoo S, Hill KP, Mooney M (2008) Self-administration of intravenous nicotine in male and female cigarette smokers. Neuropsychopharmacology 33:715–20. Sorge RE, Clarke PB (2009) Rats self-administer intravenous nicotine delivered in a novel smokingrelevant procedure: effects of dopamine antagonists. J Pharmacol Exp Ther 330:633–40. Tengs TO, Ahmad S, Savage JM, Moore R, Gage E (2005) The AMA proposal to mandate nicotine reduction in cigarettes: a simulation of the population health impacts. Prev Med 40:170–80. Vogel RI, Hertsgaard LA, Dermody SS, Luo X, Moua L, Allen S, et al. (2014) Sex differences in response to reduced nicotine content cigarettes. Addict Behav 39:1197–204. Watson NL, Carpenter MJ, Saladin ME, Gray KM, Upadhyaya HP (2010) Evidence for greater cue reactivity among low-dependent vs. high-dependent smokers. Addict Behav 35:673–7. Wayne GF, Carpenter CM (2009) Tobacco industry manipulation of nicotine dosing. Handb Exp Pharmacol 192:457–85. Wetter DW, Kenford SL, Smith SS, Fiore MC, Jorenby DE, Baker TB (1999) Gender differences in smoking cessation. J Consult Clin Psychol 67:555–62. WHO (1992) International classification of diseases and related health problems, 10th rev. Geneva. WHO (2001) Advancing knowledge on regulating tobacco products. Geneva: Tobacco Free Initiative (http://www.who.int/tobacco/media/en/OsloMonograph.pdf). WHO (2002) SACTob recommendation on nicotine and the regulation in tobacco and non-tobacco products. Geneva: Scientific Advisory Committee on Tobacco Product Regulation, Tobacco Free Initiative (http://apps.who.int/iris/handle/10665/42780). WHO (2003a) SACTob conclusions on health claims derived from ISO/FTC method to measure cigarette yield. Geneva: Scientific Advisory Committee on Tobacco Product Regulation, Tobacco Free Intitiative (http://www.who.int/tobacco/global_interaction/tobreg/en/iso_ ftc_en.pdf) WHO (2003b) Framework Convention on Tobacco Control. Geneva: Tobacco Free Initiative (http://www.who.int/fctc/en/). WHO (2006) WHO Expert Committee on Drug Dependence: Thirty-fourth report. Geneva (WHO Technical Report Series, No. 942). WHO (2007) The scientific basis of tobacco product regulation. Geneva (WHO Technical Report Series, No. 945).
34
WHO (2009) The scientific basis of tobacco product regulation. Third report of a WHO study group. Geneva (WHO Technical Report Series, No. 955). WHO (2012a) The scientific basis of tobacco product regulation. Fourth report of a WHO study group. Geneva (WHO Technical Report Series, No. 967). WHO (2012b) Partial guidelines for implementation of Articles 9 and 10 of the WHO Framework Convention on Tobacco Control. Geneva: Tobacco Free Initiative (http://www.who.int/fctc/ guidelines/adopted/article_9and10/en). WHO (2014a) Standard operating procedure for determination of nicotine in cigarette tobacco filler. Geneva (WHO TobLabNet Official Method SOP 04). WHO (2014b) Electronic nicotine delivery systems. In: Report of the Sixth Session of the Conference of the Parties to the WHO Framework Convention on Tobacco Control (FCTC/ COP/6/10 Rev.1). Geneva: Tobacco Free Initiative. WHO (2015) The scientific basis of tobacco product regulation. Fifth report of a WHO study group. Geneva (WHO Technical Report Series, No. 989). Zeller M, Hatsukami D (2009) The strategic dialogue on tobacco harm reduction: a vision and blueprint for action in the US. Tob Control 18:324–32. Ziedonis D, Hitsman B, Beckham JC, Zvolensky M, Adler LE, Audrain-McGovern J, et al. (2008) Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res 10:1691–715.
35
This advisory note presents the conclusions and recommendations of the members of the WHO Study Group on Tobacco Product Regulation (TobReg) on a policy for limiting the sale of cigarettes to brands with a nicotine content that is not sufficient to lead to the development and/or maintenance of addiction. Initial discussions began at the seventh meeting of TobReg, which was held in December 2013; discussions subsequently continued for more than 18 months because of the complexity and sensitivity of the topic. One of the main conclusions was that no specific amount of nicotine has yet been identified as the absolute threshold for addiction; however, it is likely to be equal to or possibly less than 0.4 mg/g of dry cigarette tobacco filler. The following topics are also covered in the advisory note: • Cigarettes with a reduced nicotine content • Goals of a policy to reduce addiction to cigarettes • Tobacco addictiveness factors • Establishing a performance standard for nicotine products • Feasibility of reducing nicotine • Potential behavioural and population outcomes • Policy approaches to nicotine reduction The conclusions reached by TobReg and recommendations and research needs are discussed at the end of the advisory note.
World Health Organization Tobacco Free Initiative Avenue Appia 20, 1211 Geneva 27, Switzerland Tel: +41 22 791 21 26 Fax: +41 22 791 48 32 tfi@who.int http://tobacco.who.int
本书英文版于 2015 年由世界卫生组织 出版， 书名为： （World Health Organization） Advisory note: global nicotine reduction strategy: WHO Study Group on Tobacco Product Regulation (TobReg) © World Health Organization 2015 世界卫生组织（World Health Organization）授权中国科技出版传媒股份有限公 司（科学出版社）翻译出版本书中文版。中文版的翻译质量和对原文的忠实性 完全由科学出版社负责。当出现中文版与英文版不一致的情况时，应将英文版 视作可靠和有约束力的版本。 中文版《咨询说明：全球烟碱降低策略》 © World Health Organization 2016 如翻译或复制世界卫生组织的健康信息产品，无论是以营利为目的的销售还是 非营利性的发行，都必须事先联系 WHO Press (Email: permissions@who.int) 以获 得许可。
咨询说明
全球烟碱降低策略 WHO烟草制品管制研究小组
图字：01-2016-0190 号 内 容 简 介 本咨询说明由 WHO 烟草制品管制研究小组（TobReg）成员提供， 作为一项政策，其目的是将烟草销售控制在那些烟碱含量不足以导致和 / 或维持成瘾的卷烟品牌。最初的讨论开始于 2013 年 12 月举行的 TobReg 第七次会议，随后由于该议题的复杂性和敏感性，讨论一直持续了 18 个 月以上。主要结论之一是虽然还没有明确的烟碱含量被确定为成瘾的绝 对阈值，但是，它很可能等于或可能小于 0.4 mg/g 干燥卷烟烟丝 。本咨 询说明也包括以下议题：①降低烟碱含量的卷烟；②降低烟草致瘾性政 策的目标；③烟草致瘾性的因素；④建立烟碱产品的绩效标准；⑤降低 烟碱的可行性；⑥潜在的行为和人群后果；⑦降低烟碱的政策性措施。 TobReg 已给出结论，并且在咨询说明的结尾讨论了研究需求和监管建议。 本咨询说明会引起吸烟与健康、烟草化学以及公共卫生学等诸多领域 研究人员的兴趣，可以为从事烟草科学研究的科技工作者和烟草管制研究 的决策者提供权威性参考，还对烟草企业的生产实践有重要的指导作用 。 图书在版编目(CIP)数据 咨询说明： 全球烟碱降低策略/WHO烟草制品管制研究小组著； 胡清源 等译. —北京： 科学出版社， 2016.3 书名原文： Advisory note: global nicotine reduction strategy: WHO Study Group on Tobacco Product Regulation （TobReg） ISBN 978-7-03-047797-2 I. ①咨… II. ①W… ②胡… III. ①烟草制品 – 管制–研究 – 世界 IV. ①D588 中国版本图书馆CIP数据核字(2016)第055342号 责任编辑：刘 冉 / 责任校对：彭 涛 责任印制：徐晓晨 / 封面设计：铭轩堂
北京教图印刷有限公司 印刷 科学出版社发行 各地新华书店经销 * 2016年3月第 一 版 开本：890×1240 A5 2016年3月第一次印刷 印张：3 1/4 字数：100 000
定价：60.00元 ( 如有印装质量问题，我社负责调换 )
目 录 WHO TobReg 第七次会议······································································ 1 致谢 ·········································································································· 5 前言 ·········································································································· 9 主要建议··········································································································· 11 对公共卫生政策的意义················································································· 12 对 WHO 方案的启示····················································································· 12
通过降低烟碱含量来降低卷烟的致瘾性： 研究需求和监管建议 ····································································· 15 1. 引言················································································································ 15 2. 背景················································································································ 15 3. 降低烟碱含量的卷烟················································································· 16 4. 降低卷烟致瘾性政策的目标···································································· 17 5. 烟草致瘾性的因素····················································································· 18 6. 建立烟碱产品的绩效标准········································································ 19 7. 降低烟碱的可行性····················································································· 22 8. 潜在的行为和人群后果············································································· 23 9. 降低烟碱的政策性措施············································································· 25 10. 结论·············································································································· 28 11. 研究需求····································································································· 29 12. 监管建议····································································································· 30
参考文献 ································································································ 33
·i·
CONTENTS Participants in the seventh meeting of the WHO Study Group on Tobacco Product Regulation ····················································· 43 Acknowledgements ··············································································· 47 Preface··················································································································· 51 Main recommendation····················································································· 54 Significance for public health policies····························································· 56 Implications for WHO programmes······························································ 56
Reducing the addictiveness of manufactured cigarettes by reducing their nicotine content: research needs and regulatory recommendations·········59 1. Introduction··································································································· 59 2. Background···································································································· 60 3. Cigarettes with a reduced nicotine content················································· 61 4. Goals of a policy to reduce addiction to cigarettes····································· 62 5. Tobacco addictiveness factors······································································ 63 6. Establishing a performance standard for nicotine products·············································65 7. Feasibility of reducing nicotine···································································· 68 8. Potential behavioural and population outcomes······································· 71 9. Policy approaches to nicotine reduction····················································· 73 10. Conclusions·································································································· 78 11. Research needs····························································································· 79 12. Regulatory recommendations···································································· 81
References············································································································· 85 ·iii·
WHO TobReg 第七次会议 巴西里约热内卢，2013 年 12 月 4~6 日 参加者 D. L. Ashley 博士，美国食品药品管理局（马里兰州罗克维尔）烟草制 品中心科学办公室主任 O. A. Ayo-Yusuf 教授，Sefako Makgatho 卫生科学大学（南非比勒陀利亚） 口腔卫生科学学院院长 A. R. Boobis 教授，英国伦敦帝国学院医学系药理学与治疗学中心生化 药理学专业；伦敦帝国学院公共卫生英格兰毒理学课题组组长 M. V. Djordjevic 博士，美国国家癌症研究所（美国马里兰州贝塞斯达） 癌症控制与人口科学部烟草控制研究课题组项目负责人 N. Gray 博士，维多利亚癌症委员会（澳大利亚墨尔本）高级荣誉合伙 人 P. Gupta 博士，Healis Sekhsaria 公共卫生研究所（印度孟买）所长 S. K. Hammond 博士，加利福尼亚大学伯克利分校（美国加利福尼亚州 伯克利）公共卫生学院环境卫生学教授 J. Henningfield 博士，约翰·霍普金斯大学医学院行为生物学兼职教授； Pinney 协会（美国马里兰州贝塞斯达）研究与健康政策部副总裁 D. Hatsukami 博士，明尼苏达大学（美国明尼苏达州明尼阿波利斯）精 神病学教授 A. Opperhuizen 博士，荷兰乌得勒支省风险评估与研究办公室主任 ·1·
咨询说明： 全球烟碱降低策略
G. Zaatari 博士， WHO 烟草制品管制研究小组主席 ； 贝鲁特美国大学 （黎 巴嫩贝鲁特）病理学与实验医学教授 撰稿人 E. Akl 博士，贝鲁特美国大学（黎巴嫩贝鲁特）内科医学系医学专业副 教授 T. Eissenberg 博士，弗吉尼亚联邦大学（美国弗吉尼亚州里士满）烟草 制品研究中心心理学教授，联合主任 W. Maziak 博士，佛罗里达国际大学（美国佛罗里达州迈阿密）流行病 学系教授，系主任；叙利亚烟草研究中心主任 P. Mehrotra 博士，印度人口委员会（印度新德里）高级项目主管 J. Morton 先生，美国疾病控制与预防中心（美国佐治亚州亚特兰大） 吸烟与健康办公室全球烟草控制分部高级调查方法学家 A. Shihadeh 博士，贝鲁特美国大学（黎巴嫩贝鲁特）工程和建筑学院 机械工程系教授 WHO FCTC 缔约方大会第 9 条和第 10 条工作组协调员 P. Altan 博士，土耳其卫生部（土耳其安卡拉省）烟草控制司 A. C. Bastos de Andrade 女士，巴西国家卫生监督管理局（巴西里约热内 卢）烟草制品控制司司长 Katja Bromen 博士，欧盟健康与消费者理事会（比利时布鲁塞尔）D4 单元人类起源物质与烟草控制组政策官员 D. Choinière 先生，加拿大卫生部（加拿大安大略省渥太华）控制物质 与烟草理事会烟草制品管制办公室主任
·2·
WHO TobReg 第七次会议
发言人 G. Ferris Wayne 博士，美国加利福尼亚州 R. Grana 博士，加利福尼亚大学（美国加利福尼亚州圣弗朗西斯科） 烟草控制研究与教育中心博士后 M. Parascandola 博士，美国国家癌症研究所（美国马里兰州）癌症控制 与人口科学部行为研究项目烟草控制研究课题组流行病学专业 R. Talhout 博士，荷兰国家公共卫生与环境研究所（荷兰比尔特霍芬） 健康防护中心 WHO FCTC 公约秘书处（瑞士日内瓦） K. Brown 女士，项目官员 WHO 美洲地区办公室 A. Blanco 博士，烟草控制地区顾问，美国华盛顿特区 WHO 秘书处（非传染性疾病预防处无烟草行动组，瑞士日内瓦） M. Aryee-Quansah 女士，行政助理 A. Peruga 博士，计划理事 V. M. Prasad 博士，项目理事 G. Vestal 女士，技术官员（法律）
·3·
致 谢 WHO 烟草制品管制研究小组（TobReg） 关于全球烟碱降低策 略的咨询说明要感谢很多人。本咨询说明在 Armando Peruga 博士和 Douglas Bettcher 博士的监督和支持下，由 Gemma Vestal 女士负责协 调出版。 咨询说明工作始于 2012 年 11 月 12~17 日在韩国首尔举行的世 界卫生组织《烟草控制框架公约》（WHO FCTC）第五次缔约方会 议之后不久， 直到 2014 年 10 月 13~18 日在俄罗斯莫斯科举行的第 六次会议之后，这个工作仍然在继续。 我们衷心地感谢 TobReg 所有成员全心奉献， 始终如一地履行 就烟草制品管制这一烟草控制中相当复杂的领域向 WHO 提供建议 的承诺。作为独立专家，TobReg 成员为 WHO 服务是没有报酬的。 为了响应 WHO 第五次缔约方会议的决议，TobReg 成员受委托为参 考条款的起草提供指导， 这一系列资料作为 2013 年 12 月在巴西里 约热内卢举行的 TobReg 第七次会议的背景资料和讨论依据。TobReg 关于这些议题的建议作为 WHO 技术报告系列 989*（WHO，2015） 发布， 于 2015 年 1 月 25 日至 2 月 3 日期间由世界卫生组织总干事 在瑞士日内瓦召开的第 136 次会议中呈交执行委员会。 Geoff Ferris Wayne 先生撰写了一份关于通过降低烟碱含量水平 使其不能引起或者维持成瘾性，以此来降低卷烟潜在依赖性的背景 * 该报告中文版《烟草制品管制科学基础报告：WHO 研究组第五份报告》由胡清源、 侯宏卫等翻译，科学出版社出版。—译注
·5·
咨询说明： 全球烟碱降低策略
文件， 成为本咨询说明的基础。 这份背景文件的内容见 WHO 技术 报告系列 989 的附录 3。WHO 衷心感谢 Wayne 先生投入宝贵的时 间和精力用于背景文件的撰写， 该背景文件于 2013 年 12 月递交给 TobReg， 同时也要感谢 Wayne 先生能够继续与 TobReg 协作完成该 重要议题的结论和建议。本咨询说明最后由 Dorothy Hatsukami 博士 完成。 为了确保 WHO 能够通过秘书处将烟草制品管制所要求的相关 信息更好地提交给缔约方会议，WHO、TobReg 与世界卫生组织《烟 草控制框架公约》缔约方大会第 9 条和第 10 条工作组协调员进行协 作。WHO 特别感谢加拿大卫生部的 Denis Choinière 先生关于咨询 说明的重要评论。 感 谢 WHO 同 事 Miriamjoy Aryee-Quansah 女 士、Gareth Burns 先 生、Luis Madge 先 生、Rosane Serrao 女 士、Moira Sy 女 士、 Elizabeth Tecson 女士及 Angeli Vigo 律师在行政上的支持。 特 别 感 谢 WHO 美 洲 地 区 办 公 室 烟 草 控 制 地 区 顾 问 Adriana Blanco 博士为确保 TobReg 会议在巴西顺利召开所做的工作。 还要 感谢巴西国家卫生监督管理局（ANVISA） 的 Ana Claudia Bastos de Andrade 女士在 ANVISA 被烟草公司提起数起诉讼的同时， 勇敢地 主持了 2013 年 12 月在里约热内卢召开的 TobReg 第七次会议。此外， ANVISA 提供了大量财政援助使得这次会议得以顺利进行。 我们也衷心感谢在法国的 WHO 编辑、技术编辑和校对人员以 及在葡萄牙的设计和排版人员耐心细致的工作。 最后但同样重要的，WHO 感谢无烟草行动组的前实习生们把 大量时间贡献给了本咨询说明的成果，他们分别是 Aurelie Abrial 女 士、Colleen Ciciora 女 士、Adrian Diaz 先 生、Richelle Duque 博 士、 ·6·
致
谢
Mary Law 女 士、Caitlin McGowan 律 师、Christina Menke 女 士、 Hannah Patzke 女士和 Nava Shahi 女士。 不管他们在未来从事什么 光明的职业，我们都希望他们能够在烟草控制的相关方面继续努力 工作。 毫无疑问，因为有太多的人参与了本咨询说明工作，有很多人 我们在这里没有提及。我们为任何遗漏而道歉。我们同时感谢那些 没有被提及的人。没有你们的帮助和支持，就没有这份咨询说明。 非常感谢你们。
·7·
前 言 世界卫生组织（WHO）烟草制品管制研究小组（TobReg）13已被 授权向 WHO 总干事提供科学合理的、 基于证据的、 关于成员国烟 草管制的建议。为了与 WHO《烟草控制框架公约》（FCTC）中第 9 条和第 10 条规定相符合，TobReg 要确定管制烟草制品的方法，主 要针对形成重大公共卫生问题和引起烟草控制政策难题的这些烟草 产品。 烟草制品的管制是非常有必要的， 并且获得了 WHO FCTC 中 第 9 条、 第 10 条和第 11 条规定的支持。 监管要通过确保烟草制品 生产、 包装、 标识和销售的有效监督来更好地服务于公众健康的目标。 要以科学性为基本原则执行每一条款所描述的管制措施，形成协同 及相互增强的作用。 烟草制品的管制包括通过测试、测量以及强制披露测试结果来 监管成分及释放物，以及监管包装和标识。烟草制品的生产及设计、 成分、释放物以及销售、包装、标识的法规的强制执行需要政府进 行监管，其主要目的是保护和促进公众健康。 化学消费品的监管通常需要在审查与其相关的危害、可能的暴 露、使用方式和制造商市场信息的科学依据后进行。许多司法管辖 区要求制造商根据其危害特性对产品进行分类和标识，以控制有害 成分或限制产品的广告、促销和赞助。
1
http://www.who.int/tobacco/industry/product_regulation/tobreg/en/, accessed 24 July 2015.
·9·
咨询说明： 全球烟碱降低策略
TobReg 审查对烟草制品管制相关议题的科学依据，并确定填补 烟草控制监管空白的研究需求。TobReg 由国际上在烟草制品监管、 烟碱依赖治疗以及烟草制品成分及释放物实验室分析领域的科学家 组成。 作为 WHO 的一个正式实体，TobReg 通过总干事向 WHO 执 行委员会报告， 提请成员国对 WHO 在烟草制品管制这一烟草控制 复杂领域的工作引起重视。 TobReg 第七次会议于 2013 年 12 月 4~6 日在巴西里约热内卢举 行。 讨论主要涉及 2012 年 11 月 12~17 日在韩国首尔召开的 WHO FCTC 第五次缔约方会议的决议要求： • 密切监测和跟踪新型烟草制品的发展，包括潜在“改进风险”
的产品，并向缔约方会议报告相关的进展。 • 针对有烟和无烟烟草制品成瘾性（或依赖性）方面的问题仍
然有待研究。 • 监控和研究关于降低引燃倾向卷烟的国家经验及科学发展。 • 确定可能降低有烟和无烟烟草制品有害性的方法，并对缔约
方会议审议事项中的有关措施的有效性和缔约方的经验进行 说明。 • 编制一份烟草制品有害性成分和释放物的非详尽清单，以供
缔约方使用，对其进行更新，并提供如何使这些信息在缔约 方被最有效使用的相关建议。 • 准备一份部分指导原则中推荐措施的概况介绍草案，以便推
进 WHO FCTC 第 9 条和第 10 条的实施。 • 继续开展并报告测试和测量卷烟成分和释放物的分析化学方
法的确认的进程。 随后针对这一要求，委托撰写多份背景文件。此外，新型烟草 ·10·
前
言
制品、无烟烟草制品、降低引燃倾向卷烟的可利用性及监管信息被 收集于 WHO 烟草制品调查报告，并发送给所有成员国。90 个国家 作出了回应，约占世界人口的 77%。 世界卫生组织关于 2014 年 10 月举行的第六次 WHO FCTC 缔约 方会议的报告已经公布（WHO，2015）。由于通过降低烟碱含量至 不会引起或维持成瘾性的水平来降低卷烟依赖性这个议题的复杂性， TobReg 成员进一步讨论了 18 个月以上。 这些讨论的结果概括在此 份 TobReg 关于全球烟碱降低策略的咨询说明中。
主 要 建 议 本咨询说明介绍了一项政策 —将烟草销售限制在那些烟碱含 量不足以导致和 / 或维持成瘾的卷烟品牌； 这些卷烟被称作降低烟 碱含量的卷烟。传统卷烟，即使是那些在国际标准化组织（ISO）条 件下检测的低烟碱含量的卷烟，也含有成瘾水平烟碱；但是由于通 风滤嘴等许多设计功能，降低了烟碱释放量。那么，吸烟者会更加 深度地抽吸 ISO 条件下的低烟碱释放量卷烟（即相较于吸烟机设定 的条件，他们会更加频繁地深度抽吸），以便获得上瘾的烟碱水平。 2 中低含量不到致 不同于传统的卷烟，降低烟碱含量的卷烟由于烟丝 4
瘾水平的烟碱，能够限制产品上瘾。研究表明，从传统的卷烟转换 为烟丝烟碱低于或等于 0.4 mg/g 的卷烟并不会显著增加渴求或戒断 症状， 同时也不会导致补偿抽吸 （如深度抽吸或每天吸烟支数增加） 。 2 卷烟烟丝被定义为卷烟中含烟草的部分，它包括不同类型烟叶、再造烟草薄片、
烟梗，膨胀烟丝及添加剂的混合物（WHO，2014）。
·11·
咨询说明： 全球烟碱降低策略
然而还没有明确的烟碱含量被认定为成瘾的绝对阈值，但是，它很 可能是等于或小于 0.4 mg/g 烟丝干重。对吸烟者个体来说，烟碱降 低策略的最终健康益处是要求吸烟者完全戒除摄入所有燃烧型烟草 制品。人群益处来自于吸烟者降低燃烧型烟草制品的使用量和预防 非吸烟者特别是年轻人产生烟瘾。为了实现公共卫生目标，不仅需 要产品的改进，而且需要提供治疗，包括行为支持、烟碱替代品和 其他药物等，对吸烟者来说将不再能够从卷烟中获得足够的烟碱水 平。对于那些从卷烟转换到非燃烧形式的烟草制品来维持他们的烟 碱摄入量的人来说，健康益处将部分取决于替代产品中烟草相关的 有害成分和吸烟行为，以及使用这些产品的时间。
对公共卫生政策的意义 烟碱降低策略能够降低试验者的吸烟数量和成瘾发展，限制成 瘾吸烟者的吸烟数量，并且增加停止吸烟的成瘾者的数量，减少复 吸的成瘾者的数量。
对 WHO 方案的启示 采取一个全面的方案来支持降低烟碱政策的实施，包括： • 健康传播与公共教育的策略研究； • 市场上没有卷烟烟丝中烟碱含量较高的产品； • 包括行为支持在内的有效的、负担得起的、可得到的戒断治 ·12·
前
言
疗，具有显著降低烟草相关疾病风险的烟碱替代形式产品， 以及批准治疗烟草依赖和戒断药物； • 监测市场和测试烟草制品中的烟碱和其他成分及释放物的能
力； • 持续研究以评估：
—在非吸烟青少年中使用的可能性和降低烟碱卷烟的影响； —如果吸烟者可以在市场上获得高烟碱水平的产品，他们转 向这些产品的可能性； —其他类型产品的额外使用（如使用无烟烟草制品、电子卷 烟等）； —降低烟碱含量卷烟的长期使用； —降低烟碱含量卷烟对于吸烟行为的长期影响； —全面监督以确保对意外后果的迅速监测。 世界卫生组织烟草制品管制研究小组 (TobReg) 希望包含在本 咨询说明中的结论和建议将对世界卫生组织《烟草控制框架公约》 （WHO FCTC）各成员国实施烟草制品管制政策有所帮助。
·13·
通过降低烟碱含量来降低卷烟的 致瘾性：研究需求和监管建议 1. 引 言 通过降低烟碱含量来降低烟草制品致瘾性的策略包括：针对可 供出售的所有卷烟或潜在的其他形式的烟草制品（包括燃烧型和非 燃烧型） 设置烟碱含量的最大允许上限， 最大限度地降低引发和 / 或维持烟碱成瘾的可能性。本报告呈现了关于降低烟碱含量的卷烟 对人群影响的越来越多的科学认识。它包括政策建议和基于科学现 状的法规，以及由监管部门和世界卫生组织《烟草控制框架公约》 （WHO FCTC） 的缔约方会议提出的讨论意见。 它是基于被 WHO 委托的背景报告 3（WHO，2015），以及世界卫生组织烟草制品管制 研究小组（TobReg）在它的第七次会议（巴西里约热内卢，2013 年 12 月）所提供的资料。
2. 背 景 成瘾是一种慢性复发性脑疾病，具有强迫性自身给药的特征， 3 该背景报告题为“通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟
产品的依赖性”，见 WHO（2015）中的附录 3，为研究人员和决策者提供进一步信息。
·15·
咨询说明： 全球烟碱降低策略
常常不顾危害性的后果 (WHO, 1992；National Institute on Drug Abuse, 2014)。自 20 世纪 80 年代，普遍认为烟碱是烟草制品中主要的致瘾 性化学物质； 到 20 世纪 90 年代， 人们越来越认为不含烟碱的烟草 制品不会维持成瘾 (Benowitz & Henningfield, 1994; Henningfield, et al., 1998)。 烟草行业早在许多年前就认识到这一点，从而设计卷烟以确 保它们能递送致瘾水平的烟碱量，尽管按国际标准化组织和美国联 邦贸易委员会的测试方法，吸烟机估计的递送量是降低的（National Cancer Institute, 2001; WHO, 2001; WHO, 2003a）。来自 TobReg 及其 前身 SACTob 的早前报告同样认为，对于燃烧型和非燃烧型烟草制品， 烟碱是主要的成瘾性化学物质，它应当与其他成分和设计特性一起被 管制。然而，到目前为止，TobReg 在降低卷烟制品的成瘾潜力方面尚 未发表明确的立场 (WHO, 2002; WHO, 2007; WHO, 2009; WHO, 2012a)。 在过去的十年间，如本报告中讨论的，已经进行了实验研究和 建模以评估降低卷烟致瘾性政策潜在的公众健康影响。这个结果导 向当前的建议：降低烟碱含量的最高允许上限以实现最小成瘾水平被 认为是减少对烟草制品需求的一个适用策略，那些烟草制品在大多数 国家和地区导致了很高的以烟草为主因的发病率和死亡率。本报告不 提供关于如何制定这样一个政策的详细建议，而是更专注于推荐这一 政策的科学基础。它呈现了有效执行这一政策可能的必要条件和可能 遇到的诸多挑战，包括尚未回答的研究性问题。
3. 降低烟碱含量的卷烟 在一个降低烟草成瘾性的政策中，所有允许出售的卷烟的烟碱 ·16·
通过降低烟碱含量来降低卷烟的致瘾性：研究需求和监管建议
含量应该不足以引起或维持成瘾。这种卷烟被称为“降低烟碱含量 的卷烟”，“ 极低烟碱含量的卷烟” 以及“ 去烟碱的卷烟”。 它们 有别于“ 降低释放量的卷烟”， 此概念形成于 20 世纪 70 年代， 作 为对公众健康关注的回应，在市场上被描述为“淡的”，“低焦油” 和“温和的”。这些描述暗示了烟碱和其他物质（通常指“焦油”） 更低的递送量和更少的暴露量， 但产品实际上含有类似数量的烟碱， 释放的烟碱剂量与成瘾和其他疾病风险有关，并且风险与“全香型” 的 等 同 品 同 样 高 (National Cancer Institute, 2001; WHO, 2001; WHO, 2003a)。 极低烟碱含量的卷烟不会维持成瘾， 而基于吸烟机测试的 作为“降低释放量”销售的卷烟，被发现实际上在许多人群中增加 了成瘾的流行，因为它们被认为更安全且更易于被吸入 (Kozlowski & O’ Connor, 2002)。
4. 降低卷烟致瘾性政策的目标 降低卷烟致瘾性政策有很多目标： 降低非吸烟者发展成为卷 烟成瘾者的风险， 使吸烟者能够更早戒烟， 防止已经戒烟的吸烟 者复吸， 如果需要的话， 鼓励吸烟者替换至一种危害更低、 理想 情况下致瘾性更低的烟碱来源 (Henningfield et al., 1998; Hatsukami et al., 2010a; Benowitz & Henningfield, 2013)。 自 从 1994 年 Benowitz 和 Henningfield 首次提出降低烟碱策略， 很多卫生领域的科学家得 出结论， 该方法能显著影响公众健康 (Gray et al., 2005; Zeller et al., 2009; Benowitz & Henningfield, 2013; Hatsukami et al., 2013a; Smith et al., 2013)。 该方法与 WHO FCTC 第 9 条是一致的， 而 WHO FCTC ·17·
咨询说明： 全球烟碱降低策略
被认为是管制烟草制品成分和释放物的指南 (WHO, 2003b; WHO, 2012a)。
5. 烟草致瘾性的因素 正 如 在 其 他 地 方 讨 论 的， 在 早 期 WHO 的 报 告 (WHO, 2001; WHO, 2007; WHO, 2012a) 中，烟碱是一种高度致瘾的、强效的药物， 即使非常低的剂量也可以产生精神奖赏的效应。卷烟是烟碱递送的 一种特别有效的形式：当来自卷烟的烟气被吸入时，烟草中的烟碱 很快被肺部吸收，并运送到大脑。 不同个体对烟碱的反应，包括灵敏度，有很大差异。早期（即 在青春期以前或在青春期 ） 暴露于烟碱， 可能与更严重的依赖、 更大的奖励和增加自身给药相关， 表明发育中的大脑可能更容易 受 到 诱 导 成 瘾 的 烟 碱 的 永 久 性 改 变 (Benowitz, 2008; Hatsukami et al., 2010a)。 女性比男性更强烈地受到吸烟的感官方面的影响， 因 而 戒 烟 难 度 更 大 (Fant et al., 1996; Gritz et al., 1996; Eissenberg et al., 1999; Perkins et al., 1999; Wetter et al., 1999; Perkins et al., 2006; Perkins, 2009)。有精神和 / 或物质滥用障碍的个体有高得多的烟碱依赖率， 并且戒烟难度更大 (Ziedonis et al., 2008)。 吸烟的感观特征（ 味道， 香味， 气管的感受 ） 促进了烟碱的 递送， 加上与其药理学效应相关， 会进一步加强成瘾 (WHO, 2007; Henningfield et al., 2011; WHO, 2012a)。 因为烟草的非烟碱成分对吸 烟的感官体验是至关重要的，去烟碱的烟草与无烟草的烟碱相比， 能更有效地降低对吸烟的渴求， 带给吸烟者更多的愉悦感 (Rose, ·18·
通过降低烟碱含量来降低卷烟的致瘾性：研究需求和监管建议
2006)。烟碱在卷烟烟雾的感官构成中也起着主要作用：由于其更强 烈的感官刺激， 含有烟碱的卷烟一直被认为比去烟碱的卷烟更强烈。 烟草中的一些非烟碱成分可能存在化学地相互作用或与烟碱有 协同效应（如乙醛），从而进一步增强烟碱的作用，或者可能它们 自身有显著的药理效应。例如，各种烟草次要生物碱加强大鼠的自 身给药，在烟草烟雾中的单胺氧化酶抑制剂已被证明对于正在进行 烟碱自我给药的大鼠，能显著增加反应速率 (Guillem et al., 2005)。因 此， 尽管大大降低烟碱对于大多数人来说应该能显著降低烟草成瘾性， 但一个极低烟碱含量的产品仍然可能对某些人有一定的强化作用。 对药物作用的期待在决定对烟草制品的主观和行为反应中发挥 了重要作用，特别是对妇女 (Perkins et al., 2006)。期待可能是由于产 品带来的感官刺激产生，可通过包装或其他信息暗示。社会环境也 决定了吸烟行为和依赖性， 如允许使用烟草制品 （法律和社会规范） ， 个人和所在家庭使用烟草的成本，以及烟草的使用是否会在亚群中 受到歧视，如性别、宗教信仰或社会地位。
6. 建立烟碱产品的绩效标准 许多测试可通过产生精神效应或生理上的依赖和戒断来确定 潜在的成瘾药物及其加强和维持使用的剂量。 这些测试被 WHO （2006）推荐，已经由各种监管机构在科学评论中描述过 (Balster & Bigelow, 2003; Schuster & Henningfield, 2003; Carter et al., 2009)。并非 单一数量的烟碱能够被认定为所有个体、在所有情况下、经由所有 的给药途径成瘾的绝对阈值；不过，大量的动物和人体研究证实， ·19·
咨询说明： 全球烟碱降低策略
存在这么一个剂量，当高于这个剂量时，烟碱被持续进行自我给药， 而低于这个剂量时，没有观察到自我给药行为，或者，在人群中， 导致依赖性显著降低 (Hatsukami et al., 2010a; Donny et al., 2012)。在 人和动物中， 产生精神或判别力影响所需的烟碱剂量也被研究过 (Department of Health and Human Services, 1988; Carter et al., 2009)。 综上，这些及其他类型的研究为烟碱水平的设定标准提供了一个科 学基础，高于这个标准水平，成瘾是可能的，而低于这个标准水平， 成瘾则不太可能 (Carter et al., 2009; Sofuoglu & LeSage, 2012; Benowitz & Henningfield, 2013)。 吸烟者（ 假设 70 kg 体重） 通过静脉自我注射低于传统单只卷 烟烟碱含量的一系列剂量的烟碱， 在 0.1~0.4 mg 烟碱范围内存在一 个阈值 (Sofuoglu et al., 2008)。 类似地， 在剂量 - 效应研究中， 动物 烟碱自我给药的剂量通常在 10 μg/kg 以下，维持自我给药的单位剂 量低至 3 μg/kg， 相当于 0.23 mg 的烟碱， 尽管在这个范围的下限响 应率存在相当大的个体差异 (Donny et al., 2012; Smith et al., 2013)。 由于烟草递送的烟碱与静脉注射的烟碱有很大的不同，可能不 足以依靠静脉注射烟碱的自我给药研究，来预测降低烟碱含量的烟 草制品的潜在强化效应。给药参数如剂量递送时间在确定药理学及 一个给定剂量的加强效应方面是有作用的 (Sorge & Clarke, 2009)。 尽管如此， 有限的证据表明， 通过卷烟递送烟碱的自我给药方式 下烟碱的阈值与上述的研究并没有本质的不同。 烟草生产商已经 使用脑成像技术来确定控制吸烟条件下卷烟烟碱递送的有效范围 (Panzano, et al., 2010)；这些结果表明烟碱神经生理学效应阈值为吸 烟机测定的 0.1~0.3 mg 烟气烟碱。该结果与烟碱识别研究结果相一 致，显示出识别阈值水平处于可比的范围，且吸烟者和非吸烟者之 ·20·
通过降低烟碱含量来降低卷烟的致瘾性：研究需求和监管建议
间无差异 (Hatsukami et al., 2010a)。 然而大多数人群研究是在已成瘾的吸烟者中进行的研究，动物 研究表明，自身给药获取烟碱行为的阈值等于或高于维持此行为的 值 (Donny et al., 2014)。在成年大鼠中，高剂量的烟碱暴露后，低剂 量烟碱的自身给药是更加频繁的，随后剂量减少，低于高剂量烟碱 暴露期 (Smith et al., 2014)。 然而， 青少年的烟碱自身给药行为和依 赖性与成年人不同。尽管如此，横向和纵向研究表明，非每日吸烟 的年轻人也出现了依赖症状。奖赏预期在青少年吸烟行为和动机中 起着重要作用 (Kassel et al., 2007)。 与抽吸含有烟碱的卷烟一样，抽吸去烟碱卷烟会抑制严重性渴 求以及延迟随意吸烟的开始 (Rose et al., 2003; Barrett, 2010) ； 相 反 ， 静 脉 注 射 烟 碱 仅 能 在 很 小 程 度 上 抑 制 随 意 吸 烟 (Rose et al., 2003) 。 这表明 ， 与吸烟相关的非烟碱刺激是一个调节器 ， 为吸 烟者预期烟碱传递提供暗示 。 只有曾长期使用含有烟碱的卷烟 ， 才会获得吸烟的调节特性 。 动物研究表明 ， 通过刺激获得调节强 化特性是剂量的直接作用 。 这意味着 ， 控制烟草寻求行为的刺激 对暴露于高水平烟碱的人群将是最有效的 ， 并且随着条件刺激减 少 ， 极低烟碱暴露很可能大大降低烟草寻求行为 （ Palmatier et al., 2008 ）。 对行为上的和潜在的烟碱成瘾影响的敏感性变化对制定产品的 烟碱绩效标准具有重要意义。因此，为了最大限度地降低所有尝试 卷烟者个体上瘾的风险，最大允许含量应低于可能产生行为上的和 成瘾影响的剂量。全面监测和流行病学研究将在确定最初设定的绩 效标准是否有效、快速评估任何意外的后果方面发挥重要作用。还 应相应地作出修正和风险管理计划。 ·21·
咨询说明： 全球烟碱降低策略
7. 降低烟碱的可行性 目前， 大多数的传统卷烟每支含有 10~15 mg 的烟碱， 其中约 10% 传递到烟气中，一般从每支卷烟产生 1~2 mg 的烟碱总摄入量。 更深度的吸烟行为可递送更高水平的烟碱。因此，建立许可的烟碱 最大限量需要总共减少 90%~95% 或更多的烟碱摄入量。 烟草中烟碱的含量易于被制造商改变和控制， 例如转基因、 酶处理或烟碱萃取， 达到接近或超过这个烟碱降低幅度 (Wayne & Carpenter, 2009)。 现有的烟碱低于 1 mg/g 烟丝的卷烟， 当在标准吸 烟机条件（ISO） 下抽吸时， 烟碱的释放量为 0.03~0.1 mg， 相当于 标准商业品牌 3%~10% 的烟碱释放量。大部分关于降低烟碱的行为 研究已经使用这一烟气烟碱范围的卷烟。 生产烟碱含量很低的卷烟在技术上是可行的。降低烟碱造成的 感官作用的损失已作为潜在的技术挑战被讨论；但事实上，商业卷 烟品牌如“Next”和“Quest”中烟碱含量已小于 1 mg/g 烟草，这些 产品可以代替传统的卷烟或至少暂时性地减少卷烟渴求，为生产烟 碱含量很低的卷烟的技术可行性提供了强有力的证据 (Butschky et al., 1995; Rose et al., 2003; Johnson et al., 2004; Rose, 2006; Hatsukami et al., 2013b)。目前，二十二世纪公司生产的用于研究目的的“光谱”卷烟， 据报道每克烟草中烟碱含量为 0.4 mg。 另一个关于降低烟碱的担忧是吸烟者会通过改变他们的吸烟 行为作出反应。然而，临床研究的证据表明，吸烟者抽吸烟碱含量 非常低的产品（<1 mg/g） 没有显著改变他们抽吸常用品牌时的行 ·22·
通过降低烟碱含量来降低卷烟的致瘾性：研究需求和监管建议
为，而他们的烟碱暴露量显著降低 (Benowitz et al., 2006; Hatsukami et al., 2010b; Benowitz et al., 2012)。然而，当烟气烟碱递送水平（0.2~0.3 mg） 不是极其显著降低时， 吸烟者存在补偿抽吸 (Hatsukami et al., 2010b)。 此外， 随访对戒烟不感兴趣的吸烟者， 逐步减少卷烟烟碱 含量到 0.5 mg/g 不会使其依赖性消失（Benowitz et al., 2015）。 迄今为止开展行为研究使用的是降低烟碱的卷烟而不是传统 设计的卷烟。 可以控制卷烟构成的其他物理和化学参数来改变基 本配方 ， 可能产生未知的行为和健康影响 。 因此 ， 必须继续注意 除了烟碱传递之外其他的产品因素 。 烟气烟碱的标准测量方法是 不 区 分 烟 碱 形 态 的 （ 如 游 离 态 与 质 子 化 的 烟 碱 ）； 比 较 游 离 态 烟碱的传递可能对降低烟碱产品主观反应的测量更准确 (Wayne & Carpenter, 2009).
8. 潜在的行为和人群后果 降低烟碱含量的卷烟可以给予吸烟者强烈的主观满足 (Hatsukami et al., 2010a) 并且立即降低渴求（Rose et al., 2003）；然而 重复使用降低烟碱含量的卷烟的满足感少于使用那些高剂量烟碱的 卷烟 （Hatsukami et al., 2013c） 。 临床资料表明， 对于大多数吸烟者来说， 戒断不是减少烟碱摄入量常见的不利后果，而是以更深度方式吸烟 的显著补偿或每天抽吸更多极低烟碱水平卷烟 (< 1 mg)(Hatsukami et al., 2010a; Hatsukami et al., 2010b; Benowitz et al., 2012)。 长期使用降低烟碱含量的卷烟会削弱吸烟强化作用：吸烟者在 长期使用低烟碱卷烟后产生更少的依赖 (Donny et al., 2007; Benowitz ·23·
咨询说明： 全球烟碱降低策略
et al., 2009; Hatsukami et al., 2010b; Benowitz et al., 2012)。 当 吸 烟 者 主动戒烟时， 降低烟碱含量的卷烟可能是暂时性的应对方法， 帮 助他们进行戒烟。不仅是那些尝试戒烟的烟民，也包括以前对戒烟 没有兴趣的吸烟者， 他们都可能会支持戒烟 (Benowitz et al., 2007; Benowitz et al., 2009)。 降低烟碱含量卷烟对戒烟的作用可通过加入烟碱的治疗方法来 加强，特别是对于男性 (Vogel et al., 2014)。这表明其他形式的治疗和 行为支持可能也是有益的，除了彻底戒烟之外，应支持转抽降低烟 碱含量的卷烟。从卷烟转换到非燃烧型烟草以维持烟碱的摄入量对 健康的益处将部分取决于替代产品烟草有害物质的传递水平和使用 时间。强制降低烟碱后，无论是出于强替代效应还是由于卷烟烟碱 含量仍保持在他们的个人强化阈值之上，有些人可能会继续吸烟。 然而，已通过非吸烟人群和使用降低烟碱含量的卷烟的长期影响对 降低烟碱含量的卷烟的摄入量开展了少量研究。如果人们持续吸入 高水平的燃烧型烟草释放物，几乎不可能对健康有益处。应该鼓励 和支持人们尽可能快地停止使用任何燃烧型烟草制品。需要监测和 其他研究来监控期望的和不期望的效果。 文献没有提供降低烟碱政策对青少年开始吸烟潜在影响的量化 评估。降低烟碱含量的卷烟可以作为“初吸者”产品替代更高烟碱 含量的产品，如果后者在市场上仍然可获得，在理论上这是可能的。 因此，产品标识和购买限制仍很重要。降低烟碱含量的卷烟不应该 被免除成瘾风险的警语，虽然可能会与更高烟碱含量产品的警语有 所不同 (Henningfield et al., 1994)。 已经建立了多种模型来评估烟碱降低政策可能的影响；所有结 果都显示对公众健康有显著的积极影响。已发表的研究不能提供对 ·24·
通过降低烟碱含量来降低卷烟的致瘾性：研究需求和监管建议
降低烟碱背景下，市场非法销售较高烟碱含量传统卷烟的可能性的 评估。降低烟碱含量的卷烟的吸引力、可用性和烟碱替代产品的吸 引力有可能影响非法销售程度。
9. 降低烟碱的政策性措施 卷烟烟碱降低政策的影响主要取决于替代性烟碱传递系统 （包括如前所述的其他形式的燃烧型、非燃烧型烟草，医用烟碱和 商业非卷烟烟碱产品 ） 的可用性、 有害性和吸引力的显著程度。 (Henningfield et al., 1998; Benowitz & Henningfield, 2013; Department of Health and Human Services, 2014)。 对于很大一部分人群来说， 替代 产品可能会对健康有不利的影响或维持成瘾的状态。因此，在对所 有烟草制品和含有烟碱的产品进行全面监管的支持下，降低烟碱政 策才能成功 (Gray et al., 2005; Zeller et al., 2009; Le Houezec et al., 2011; McNeill et al., 2012; Hatsukami et al., 2013a; Benowitz et al., 2015)。全面 监管的目标是尽量减少使用有害性高的烟碱产品，鼓励发展有害性 低的烟碱传输系统作为有害产品替代品，继续监控和监管低有害性 产品对健康的影响 (Gray et al., 2005; Le Houezec et al., 2011; Benowitz & Henningfield, 2013)。 政策性措施可以激励不能戒烟的吸烟者使用危害较少的烟草和 烟碱产品，例如通过限制购买、销售和使用，鼓励完全停止使用更 有害的产品。人们从卷烟转换到非燃烧形式的烟草来维持他们的烟 碱摄入， 对健康的益处部分取决于烟草相关的有害物质的传递水平， 在一定程度上取决于他们继续抽吸卷烟和继续使用该产品的时间。 ·25·
咨询说明： 全球烟碱降低策略
临床研究已经评估过逐步或立即降低烟碱到非常低水平的影响， 两者都没有发现有负面影响，表明两者都不存在显著的安全性担忧 (Hatsukami et al., 2013a; Smith et al., 2013; Hatsukami et al., 2015)。逐渐 降低可能使吸烟者在更可能有补偿行为的烟碱剂量持续更长时间， 理论上可以使他们逐渐适应低烟碱含量产品实际的补偿行为。 因此， 首先进行健康宣传策略和公共教育，然后采取立即降低烟碱的方法 是比较理想的方案。 产品绩效标准对确保成功实施降低烟碱的策略是必要的。尽管 许多方法可以考虑， 降低未燃烧烟支中可利用的总烟碱是最理想的， 因为这既容易测量，又不受行为操控或个体差异的影响。尽管本报 告主要讨论卷烟，但类似的监管方法也适用于其他燃烧型和非燃烧 型产品。 产品绩效标准必须适应不断变化的市场 (Hatsukami et al., 2012; O’ Connor, 2012; Hatsukami et al., 2013a)，同时要谨慎评估新产 品和新技术。只有当新型烟草制品被充分证明具有低风险、低成瘾 性和低吸引力时，才可以进行商业化。 政策能否降低烟草制品成瘾性，将部分取决于如何有效地宣传 沟通风险。人们对于风险更低的烟草制品的过分信赖，可能会导致 戒烟率的降低甚至使更多的人尝试吸烟。实行禁烟政策可以提供一 种有用的模型，同时加强相关的公共教育可以确保相关法律的执行 和持续支持。美国的研究表明 (Hatsukami et al., 2013a) ，吸烟者和非 吸烟者都强烈支持强制降低烟碱含量，但对于其他国家没有相关的 调查。无论对于吸烟人群还是非吸烟人群，告知其烟草制品除了烟 碱以外的危害、 不同烟草制品的相对危害和治疗机会是至关重要的。 对于市场上的烟草和烟碱产品，必须要严格监管 (McNeill et al., 2012; Hatsukami et al., 2013a)。 ·26·
通过降低烟碱含量来降低卷烟的致瘾性：研究需求和监管建议
尽管现阶段还不能下定论，但各种研究模型表明，对烟草制品 设置一个允许的最高烟碱含量，会导致想要戒烟的人大幅增加 (Tengs et al., 2005; Morrison, 2013)。许多吸烟者倾向于使用烟碱替代品或者 行为疗法来戒烟或减轻戒断症状带来的不适。医疗保健专业人员提 供有效的、负担得起的治疗和保险计划的覆盖率，对政策的成功实 行将起到不可估量的作用，如对不利影响可能会更严重的人群（比 如有精神性紊乱的）提供个性化服务。对一些吸烟者的研究表明， 有效的药物疗法不仅可能减缓吸烟者因为烟碱含量下降而带来的不 适， 同时也可以大幅度地降低吸烟者对所有烟碱产品的依赖 (Zeller et al., 2009; O’ Connor, 2012; Benowitz & Henningfield, 2013)。 一些烟草替代产品（如口含烟、无烟烟草、水烟、雪茄）的吸 引力可能会增加，因为它们可能比降低烟碱含量的卷烟更有效地替 代传统卷烟，尽管并没有足够的证据表明这一观点。在对现有的和 新的烟草制品健康影响进行评估的时候必须考虑到这种可能。应考 虑将烟碱降低政策延伸到其他燃烧型或非燃烧型烟草制品上。电子 烟碱传输装置和其他明显模拟吸烟动作的产品现阶段可以作为可行 的替代产品；然而在某些国家，电子烟作为一种戒烟辅助品，销售 之前必须首先提供其安全性和临床治疗效果的评估 (Department of Health and Human Services, 2014; WHO; 2014b)。 所有卷烟中烟碱含量采用最大允许限量减少了传统卷烟的可用 性，可能会增加对传统卷烟上瘾的烟民的需求。为了最大限度地减 少非法卷烟，就需要有效措施监管大规模的烟草走私和控制其他的 非法渠道，如非法制造和冒牌生产烟草制品 (Joossens & Raw, 2008)。 一些未经监管的燃烧型烟草制品，如手工制作的雪茄，可能会成为 市售卷烟的替代品。其他一些方面也有问题值得关注，包括在低烟 ·27·
咨询说明： 全球烟碱降低策略
碱卷烟和电子烟中， 改变 pH 或添加剂来增加烟草制品的劲头或者 效果， 也会带来一些意料之外的吸烟习惯的改变， 比如更深度地抽吸， 或者更频繁或更长时间地吸食低烟碱卷烟。生产更具吸引力的替代 烟碱产品很可能成为这些意想不到的市场结果的绊脚石 (Benowitz & Henningfield, 2013; Hatsukami et al., 2013a)。 一个足够完善的监管机制将能够使监管者监督烟草制品的流行 性、 吸烟的开始及其危害， 并能处理意外的后果 (Hatsukami et al., 2013a)。世界卫生组织《烟草控制框架公约》第 9 条和第 10 条的部 分实施指南 (WHO, 2012b) 指出，为了实现完善的监管机制，贯彻执 行强制报告所有的烟碱和烟草制品的制度是必不可少的。需要强制 报告的内容有：物理设计参数（烟草重量、烟碱含量、滤嘴通风）， 烟草和添加剂成分， 燃烧型产品的释放物以及可能的滥用评估 (Carter et al., 2009; Hatsukami et al., 2012; McNeill et al., 2012)。烟草制品的复 杂性、评估有害性效应的必要知识、滥用的可能性以及其他一些意 想不到的结果，成为了令缔约方困扰的问题。建立一个全球共享的 数据库可以促进烟草制品的规范化和监管全球化，可以通过提供数 据和进行全球化的比较减轻监管部门的负担，也可以将信息以一种 更为易于理解的形式提供给国家监管部门 (McNeill et al., 2012)。
10. 结 论 有证据清楚地表明，将卷烟中的烟碱含量降低至一个非常低的 值可以减少其烟碱依赖的可能性。能够产生依赖性的卷烟中的最大 烟碱含量因人而异，且该值对于年轻人来说更低。因此，尽量降低最 ·28·
通过降低烟碱含量来降低卷烟的致瘾性：研究需求和监管建议
大烟碱含量从技术上来说是可行的。目前，该值似乎为每克卷烟烟丝 含有 0.4 mg 烟碱。4 在高度通风的卷烟中已经观察到补偿抽吸行为， 但在烟碱含量为每克卷烟烟丝 0.4 mg 的卷烟中没有观察到补偿抽吸 行为。 证据表明，对所有卷烟设置一个最高允许烟碱含量可以： • 减少对烟碱的需求从而避免成瘾； • 减少部分成瘾吸烟者的吸烟率，进而使这种行为消失； • 增加戒烟人数，同时降低复吸者比例； • 加速研制和使用烟碱替代品，例如无烟烟草、烟碱气溶胶产
品和医用烟碱， 尽管此类产品有着如烟碱依赖等潜在副作用， 但是其危害要小于传统卷烟和燃烧型烟草制品。
11. 研 究 需 求 包括临床试验在内的主要研究课题正在为实行降低卷烟致瘾性 的方法提供相关信息。研究重点包括： • 非吸烟青少年、非吸烟成年人 5 以及无烟碱依赖的吸烟者 ( 如
4
引自工作小组在 2012 年 7 月 17 日提出的报告 FCTC/COP/5/9， 即每支卷烟中含
有 0.03 mg 的烟碱。该值参考了卷烟烟气中的烟碱含量，实际上仅仅是一根未燃烧卷烟中 烟碱含量的一小部分（实际上，大约为真实值的 10 %）。对二十二世纪公司生产的某种 用于研究目的的“光谱”卷烟进行测量，得出的结果是每克烟草含有 0.4 mg 的烟碱。 5 由于用未接触过烟草的人群做低烟碱卷烟危害评估是不道德的，所以需要考虑通 过动物试验或间接方式评价低烟碱卷烟对非吸烟人群的影响。
·29·
咨询说明： 全球烟碱降低策略
轻度或偶尔吸烟者曾有过轻微的戒断症状，并且再次吸烟）6 使用低烟碱卷烟的可能性及其效果； • 低烟碱卷烟成为青少年的“初吸品”或者“尝试吸烟途径”
的潜在可能性，会导致其他形式的烟碱成瘾； • 低烟碱烟草制品对某些人群存在一定的风险，如有中度或严
重抑郁症或其他共存性疾病状况的人； • 低烟碱卷烟和传统卷烟对健康影响的比较，包括对特殊的人
群（如生育期妇女）； • 长期吸食低烟碱卷烟对吸烟习惯和健康状况的长期影响，包
括对癌症的影响； • 比较长期使用低烟碱卷烟和非燃烧型烟碱替代产品间（比如
一些烟草特有亚硝胺成分更低的无烟烟草制品，或者含有和 不含有烟碱的电子烟）的长期公众健康效应； • 通过监测和流行病学研究方法来评估任何意外后果，比如对
健康的影响，从而指导修正政策和支持发展策略。
12. 监 管 建 议 • 强制降低烟碱到最低致瘾水平，需要对全部烟碱制品和烟草
6
一部分轻度或偶尔吸烟者每天吸烟数低于五支，而且他们的吸烟动机可能是出于
烟碱的强化效应 (Benowitz, 2008)。这些吸烟者抽烟行为总是和其他一些行为联系在一起， 比如饭后或饮酒时，且在消极情绪下抽烟的情况相对少一些；这类吸烟者更易对吸烟的暗 示敏感 (Watson et al., 2010)。尽管这类吸烟者很少甚至不会有戒断反应，但他们当中很多 人也难以戒烟，他们被认为有着与那些天天吸烟的人不同的独特的烟草依赖。
·30·
通过降低烟碱含量来降低卷烟的致瘾性：研究需求和监管建议
产品进行综合监管作为支撑。 • 强制降低烟碱到最低致瘾水平，必须成为全面监管烟草的手
段之一，其他还有提高烟草税率、全面禁烟、反烟教育活动 和标识或包装上的图片警示。 • ·强制降低烟碱到最低致瘾水平， 可考虑用于所有燃烧型产品，
由于燃烧可以产生很大的毒性，并尽量减少低烟碱烟草制品 代替其他燃烧型产品。 • 最初降低烟碱的提议 (Benowitz & Henningfield, 1994) 建议花
费多年时间逐步降低烟碱水平。更多的最新科学依据表明， 在将烟碱摄入量直接降低到既定产品绩效标准以下之前，出 于实践性原因，需要健康传播策略和公众教育一次性将烟碱 降低到标准以下和逐步降低烟碱浓度到底哪个更可能导致意 料之外的后果，没有科学结论。 • 健康专业人员必须学会风险意识的传播， 一旦他们了解风险，
则会确保对法律的遵守和支持。有效且廉价的戒烟治疗、烟 碱替代品、烟碱最佳给药剂型，以及其他一些得到批准的治 疗烟碱成瘾的药物将会帮助正在遭受戒断症状和不良反应的 卷烟依赖人群。 • 烟碱替代产品的消耗量增长及其带来的副作用必须与传统燃
烧型烟草制品的消耗降低来进行权衡。然而，对于那些从抽 吸传统卷烟转变为使用非燃烧型烟草产品来维持烟碱摄入的 人来说，对健康的影响在一定程度上取决于这些烟碱替代品 的有害性、是否继续抽吸传统卷烟以及持续使用烟碱替代品 的时间长短。
·31·
咨询说明： 全球烟碱降低策略
• 为了实现减少烟草制品致瘾性的策略， 需要足够的市场监
管能力和产品检测能力。 没有足够的基础设施来保障降低 烟碱综合措施的国家， 在执行这项政策前应认真考虑增强 能力。
·32·
参 考 文 献 Balster RL, Bigelow GE (2003) Guidelines and methodological reviews concerning drug abuse liability assessment. Drug Alcohol Depend 70(3 Suppl):S13–40. Barrett SP (2010) The effects of nicotine, denicotinized tobacco, and nicotine-containing tobacco on cigarette craving, withdrawal, and self-administration in male and female smokers. Behav Pharmacol 21:144–52. Benowitz NL (2008) Clinical pharmacology of nicotine: implications for understanding, preventing, and treating tobacco addiction. Clin Pharmacol Ther 83:531–41. Benowitz NL, Henningfield JE (1994) Establishing a nicotine threshold for addiction. The implications for tobacco regulation. N Engl J Med 331:123–5. Benowitz NL, Henningfield JE (2013) Reducing the nicotine content to make cigarettes less addictive. Tob Control 22(Suppl 1):i14–7. Benowitz NL, Jacob P 3rd, Herrera B (2006) Nicotine intake and dose response when smoking reduced-nicotine content cigarettes. Clin Pharmacol Ther 80:703–14. Benowitz NL, Hall SM, Stewart S, Wilson M, Dempsey D, Jacob P 3rd (2007) Nicotine and carcinogen exposure with smoking of progressively reduced nicotine content cigarette. Cancer Epidemiol Biomark·33·
咨询说明： 全球烟碱降低策略
ers Prev 16:2479–85. Benowitz NL, Dains KM, Hall SM, Syewart S, Wilson M, Dempsey D, et al. (2009) Progressive commercial cigarette yield reduction: biochemical exposure and behavioral assessment. Cancer Epidemiol Biomarkers Prev 18:876–83. Benowitz NL, Dains KM, Hall SM, Syewart S, Wilson M, Dempsey D, et al. (2012) Smoking behavior and exposure to tobacco toxicants during 6 months of smoking progressively reduced nicotine content cigarettes. Cancer Epidemiol Biomarkers Prev 21:761–9. Benowitz NL, Nardone N, Dains KM, Hall SM, Stewart S, Dempsey D, et al. (2015) Effect of reducing the nicotine content of cigarettes on smoking behavior and tobacco smoke toxicant exposure: 2-year follow up. Addiction. doi: 10.1111/add.12978. Butschky M, Bailey D, Henningfield JE, Pickworth WB (1995) Smoking without nicotine delivery decreases withdrawal in 12-hour abstinent smokers. Pharmacol Biochem Behav 50:91–96. Carter LP, Stitzer ML, Henningfield JE, O’Connor RJ, Cummings KM, Hatsukami DK (2009) Abuse liability assessment of tobacco products including potential reduced exposure products. Cancer Epidemiol Biomarkers Prev 18:3241–62. Department of Health and Human Services (1988) The health consequences of smoking: nicotine addiction. A report of the Surgeon General. Rockville, Maryland: Department of Health and Human Services, Public Health Service, Centers for Disease Control, Office on Smoking and Health; 1988 ·34·
参 考 文 献
Department of Health and Human Services (2014) The health consequences of smoking—50 years of progress: a report of the Surgeon General. Rockville, Maryland; 874. Donny EC, Houtsmuller E, Stitzer ML (2007) Smoking in the absence of nicotine: behavioral, subjective and physiological effects over 11 days. Addiction 102:324–34. Donny EC, Taylor TG, Le Sage MG, Levin M, Buffalari DM, Joel D, et al. (2012) Impact of tobacco regulation on animal research: new perspectives and opportunities. Nicotine Tob Res 14:1319–38. Donny, E.C., Hatsukami, D.K., Benowitz, N.L., Sved, A.F., Tidey, J.W., Cassidy, R.N. (2014) Reduced nicotine product standards for combustible tobacco: Building an empirical basis for effective regulation. Preventive Medicine, epub ahead of print June 23. Eissenberg T, Adams C, Riggins EC 3rd, Likness M (1999) Smokers’ sex and the effects of tobacco cigarettes: subject-rated and physiological measures. Nicotine Tob Res 1:317–24. Fant RV, Everson D, Dayton G, Pickworth WB, Henningfield JE (1996) Nicotine dependence in women. J Am Med Women Assoc 51:19-20, 22-4, 28. Gray N, Henningfield JE, Benowitz NL, Connolly GN, Dresler C, Fagerstrom K, et al. (2005) Toward a comprehensive long term nicotine policy. Tob Control 14:161-5. Gritz ER, Nielsen IR, Brooks LA (1996) Smoking cessation and gender: the influence of physiological, psychological, and behavioral factors. J Am Med Women Assoc 51:35–42. ·35·
咨询说明： 全球烟碱降低策略
Guillem K1, Vouillac C, Azar MR, Parsons LH, Koob GF, Cador M, et al. (2005) Monoamine oxidase inhibition dramatically increases the motivation to self-administer nicotine in rats. J Neurosci 25:8593–600. Hatsukami DK, Perkins KA, Le Sage MG, Ashley DL, Henningfield JE, Benowitz NL, et al. (2010a) Nicotine reduction revisited: science and future directions. Tob Control 19:e1–10. Hatsukami DK, Hertsgaard LA, Vogel RI, Jensen JA, Murphy SE, Hecht SS, et al. (2010b) Reduced nicotine content cigarettes: effects on toxicant exposure, dependence and cessation. Addiction 105:343–55. Hatsukami DK, Biener L, Leischow SJ, Zeller MR (2012) Tobacco and nicotine product testing. Nicotine Tob Res 14:7–17. Hatsukami DK, Benowitz NL, Donny E, Henningfield J, Zeller M (2013a) Nicotine reduction: strategic research plan. Nicotine Tob Res 15:1003–13. Hatsukami DK, Hertsgaard LA, Vogel RI, Jensen JA, Murphy SE, Hecht SS, et al. (2013b) Reduced nicotine content cigarettes and nicotine patch. Cancer Epidemiol Biomarkers Prev 22:1015–24. Hatsukami DK, Heishman SJ, Vogel RI, Denlinger RL, Roper-Batker AN, Mackowick KM, et al. (2013c) Dose response effects of Spectrum research cigarettes. Nicotine Tob Res 15:1113–21. Hatsukami DK, Donny EC, Koopmeiners JS, Benowitz NL (2015) Compensatory smoking from gradual and immediate reduction in cigarette nicotine content. Cancer Epidemiol Biomarkers Prev 24:472–6. Henningfield JE, Kozlowski LT Benowitz NL (1994) A proposal to develop meaningful labeling for cigarettes. J Am Med Assoc 272:312–4. ·36·
参 考 文 献
Henningfield JE, Benowitz NL, Slade J, Houston TP, Davis RM, Deitchman SD (1998) Reducing the addictiveness of cigarettes. Council on Scientific Affairs, American Medical Association. Tob Control 7:281–93. Henningfield JE, Hatsukami DK, Zeller M, Peters E (2011) Conference on abuse liability and appeal of tobacco products: conclusions and recommendations. Drug Alcohol Depend 116:1–7. Johnson MW, Bickel WK, Kirshenbaum AP (2004) Substitutes for tobacco smoking: a behavioral economic analysis of nicotine gum, denicotinized cigarettes, and nicotine-containing cigarettes. Drug Alcohol Depend 74:253–64. Joossens L, Raw M (2008) Progress in combating cigarette smuggling: controlling the supply chain. Tob Control 17:399–404. Kassel JD, Evatt DP, Greenstein JE, Wardle MC, Yates MC, Veilleux JC (2007) The acute effects of nicotine on positive and negative affect in adolescent smokers. J Abnorm Psychol 116:543–53. Kozlowski LT, O’Connor RJ (2002) Cigarette filter ventilation is a defective design because of misleading taste, bigger puffs, and blocked vents. Tob Control 11(Suppl1): I40–50. Le Houezec J, McNeill A, Britton J (2011) Tobacco, nicotine and harm reduction. Drug Alcohol Rev 30:119–23. McNeill A, Hammond D, Gartner C (2012) Whither tobacco product regulation? Tob Control 21:221–6. Morrison B (2013) Modeling the benefits of a nicotine standard for tobacco products sold in Canada (abstract). In: Benefit–cost analysis for evidence-based decision making, Sixth Annual Conference and ·37·
咨询说明： 全球烟碱降低策略
Meeting of the Society for Benefit-Cost Analysis. Seattle, Washington: Society for Benefit-Cost Analysis, Evans School of Public Affairs, University of Washington (http://benefitcostanalysis.org/system/files/ SBCA14_Program_Book_Final2.pdf). National Cancer Institute (2001) Risks associated with smoking cigarettes with low tar machine-measured yields of tar and nicotine (Monograph 13). Bethesda, Maryland. National Institute on Drug Abuse (2014) Media guide: The science of drug abuse and addiction: the basics. Bethesda, Maryland (http://www. drugabuse.gov/publications/media-guide/science-drug-abuse-addiction-basics, accessed 24 July 2015). O’ Connor RJ (2012) Non-cigarette tobacco products: what have we learnt and where are we headed? Tob Control 21:181-90. Palmatier MI, Coddington SB, Liu X, Donny EC, Caggiula AR, Sved AF (2008) The motivation to obtain nicotine-conditioned reinforcers depends on nicotine dose. Neuropharmacology 55:1425–30. Panzano VC, Wayne GF, Pickworth WB, Connolly GN (2010) Human electroencephalography and the tobacco industry: a review of internal documents. Tob Control 19:153-9. Perkins KA (2009). Sex differences in nicotine reinforcement and reward: influences on the persistence of tobacco smoking. In: Bevins R, Caggiula R, Eds. The motivational impact of nicotine and its role in tobacco use. New York: Springer-Verlag: 143–69. Perkins KA, Donny E, Caggiula AR (1999) Sex differences in nicotine effects and self-administration: review of human and animal evidence. ·38·
参 考 文 献
Nicotine Tob Res 1:301–15. Perkins KA, Doyle T, Ciccocioppo M, Conklin C, Sayette M, Caggiula A (2006) Sex differences in the influence of nicotine dose instructions on the reinforcing and self-reported rewarding effects of smoking. Psychopharmacology 184:600–7. Rose JE (2006) Nicotine and nonnicotine factors in cigarette addiction. Psychopharmacology 184:274–85. Rose JE, Behm FM, Westman EC, Bates JE, Salley A (2003) Pharmacologic and sensorimotor components of satiation in cigarette smoking. Pharmacol Biochem Behav 76:243–50. Schuster CR, Henningfield J (2003) Conference on abuse liability assessment of CNS drugs. Drug Alcohol Depend 70(3 Suppl):S1–4. Smith TT, Levin ME, Schassburger RL, Buffalari DM, Sved AF, Donny EC (2013) Gradual and immediate nicotine reduction result in similar low-dose nicotine self-administration. Nicotine Tob Res 15:1918–25. Smith TT, Schassburger RL, Buffalan DM, Sved AF, Donny EC (2014) Low-dose nicotine self-administration is reduced in adult male rats naive to high doses of nicotine: implications for nicotine product standards. Exp Clin Psychopharmacol 22:453–9. Sofuoglu M, LeSage MG (2012) The reinforcement threshold for nicotine as a target for tobacco control. Drug Alcohol Depend 125:1–7. Sofuoglu M, Yoo S, Hill KP, Mooney M (2008) Self-administration of intravenous nicotine in male and female cigarette smokers. Neuropsychopharmacology 33:715–20. Sorge RE, Clarke PB (2009) Rats self-administer intravenous nicotine de·39·
咨询说明： 全球烟碱降低策略
livered in a novel smoking-relevant procedure: effects of dopamine antagonists. J Pharmacol Exp Ther 330:633–40. Tengs TO, Ahmad S, Savage JM, Moore R, Gage E (2005) The AMA proposal to mandate nicotine reduction in cigarettes: a simulation of the population health impacts. Prev Med 40:170–80. Vogel RI, Hertsgaard LA, Dermody SS, Luo X, Moua L, Allen S, et al. (2014) Sex differences in response to reduced nicotine content cigarettes. Addict Behav 39:1197–204. Watson NL, Carpenter MJ, Saladin ME, Gray KM, Upadhyaya HP (2010) Evidence for greater cue reactivity among low-dependent vs. high-dependent smokers. Addict Behav 35:673–7. Wayne GF, Carpenter CM (2009) Tobacco industry manipulation of nicotine dosing. Handb Exp Pharmacol 192:457–85. Wetter DW, Kenford SL, Smith SS, Fiore MC, Jorenby DE, Baker TB (1999) Gender differences in smoking cessation. J Consult Clin Psychol 67:555–62. WHO (1992) International classification of diseases and related health problems, 10th rev. Geneva. WHO (2001) Advancing knowledge on regulating tobacco products. Geneva: Tobacco Free Initiative (http://www.who.int/tobacco/media/en/ OsloMonograph.pdf). WHO (2002) SACTob recommendation on nicotine and the regulation in tobacco and non-tobacco products. Geneva: Scientific Advisory Committee on Tobacco Product Regulation, Tobacco Free Initiative (http://apps.who.int/iris/handle/10665/42780). ·40·
参 考 文 献
WHO (2003a) SACTob conclusions on health claims derived from ISO/ FTC method to measure cigarette yield. Geneva: Scientific Advisory Committee on Tobacco Product Regulation, Tobacco Free Intitiative (http://www.who.int/tobacco/global_interaction/tobreg/en/iso_ftc_ en.pdf) WHO (2003b) Framework Convention on Tobacco Control. Geneva: Tobacco Free Initiative (http://www.who.int/fctc/en/). WHO (2006) WHO Expert Committee on Drug Dependence: Thirty-fourth report. Geneva (WHO Technical Report Series, No. 942). WHO (2007) The scientific basis of tobacco product regulation. Geneva (WHO Technical Report Series, No. 945). WHO (2009) The scientific basis of tobacco product regulation. Third report of a WHO study group. Geneva (WHO Technical Report Series, No. 955). WHO (2012a) The scientific basis of tobacco product regulation. Fourth report of a WHO study group. Geneva (WHO Technical Report Series, No. 967). WHO (2012b) Partial guidelines for implementation of Articles 9 and 10 of the WHO Framework Convention on Tobacco Control. Geneva: Tobacco Free Initiative (http://www.who.int/fctc/guidelines/adopted/ article_9and10/en). WHO (2014a) Standard operating procedure for determination of nicotine in cigarette tobacco filler. Geneva (WHO TobLabNet Official Method SOP 04). WHO (2014b) Electronic nicotine delivery systems. In: Report of the Sixth ·41·
咨询说明： 全球烟碱降低策略
Session of the Conference of the Parties to the WHO Framework Convention on Tobacco Control (FCTC/COP/6/10 Rev.1). Geneva: Tobacco Free Initiative. WHO (2015) The scientific basis of tobacco product regulation. Fifth report of a WHO study group. Geneva (WHO Technical Report Series, No. 989). Zeller M, Hatsukami D (2009) The strategic dialogue on tobacco harm reduction: a vision and blueprint for action in the US. Tob Control 18:324–32. Ziedonis D, Hitsman B, B eckham JC, Zvolensky M, Adler LE, Audrain-McGovern J, et al. (2008) Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res 10:1691–715.
·42·
Participants in the seventh meeting of the WHO Study Group on Tobacco Product Regulation Rio de Janeiro, Brazil , 4–6 December 2013 Members Dr D.L. Ashley, Director, Office of Science, Center for Tobacco Products, US Food and Drug Administration, Rockville, Maryland, United States of America Professor O.A. Ayo-Yusuf, Dean, School of Oral Health Sciences, Sefako Makgatho Health Sciences University, Pretoria, South Africa Professor A.R. Boobis, Biochemical Pharmacology, Centre for Pharmacology and Therapeutics, Department of Medicine, Imperial College, London; Director, Public Health England Toxicology Unit, Imperial College, London, United Kingdom Dr M.V. Djordjevic, Program Director/Project Officer, Tobacco Control Research Branch, Behavioral Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland, United States of America Dr N. Gray, Honorary Senior Associate, Cancer Council Victoria, Melbourne, Australia ·43·
Advisory Note: Global Nicotine Reduction Strategy
Dr P. Gupta, Director, Healis Sekhsaria Institute for Public Health, Mumbai, India Dr S.K. Hammond, Professor of Environmental Health Sciences, School of Public Health, University of California, Berkeley, California, United States of America Dr J. Henningfield, Professor (Adjunct), Behavioral Biology, The Johns Hopkins University School of Medicine; Vice President, Research, Health Policy, and Abuse Liability Pinney Associates, Bethesda, Maryland, United States of America Dr D. Hatsukami, Professor of Psychiatry, University of Minnesota, Minneapolis, Minnesota, United States of America Dr A. Opperhuizen, Director, Office for Risk Assessment and Research, Utrecht, The Netherlands Dr G. Zaatari (Chair), Professor and Chairman, Department of Pathology and Laboratory Medicine, American University of Beirut, Beirut, Lebanon Contributors Dr E. Akl, Associate Professor of Medicine, Department of Internal Medicine, American University of Beirut, Lebanon Dr T. Eissenberg, Professor of Psychology and Co-Director, Center for the Study of Tobacco Products, Virginia Commonwealth University, Richmond, Virginia, United States of America Dr W. Maziak, Professor and Chair, Department of Epidemiology, Florida International University; Director, Syrian Center for Tobacco Studies, ·44·
Participants in the seventh meeting of the WHO Study Group on Tobacco Product Regulation
Miami, Florida, United States of America Dr P. Mehrotra, Senior Programme Officer, Population Council, New Delhi, India Mr J. Morton, Senior Survey Methodologist, Global Tobacco Control Branch, Office on Smoking and Health, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America Dr A. Shihadeh, Professor of Mechanical Engineering, Faculty of Engineering and Architecture, American University of Beirut, Beirut, Lebanon Facilitors of the WHO FCTC Conference of the Parties Working Group on Articles 9 and 10 Dr P. Altan, Tobacco Control Department, Ministry of Health, Ankara, Turkey Ms A.C. Bastos de Andrade, Head of Tobacco Products Control Department, Agência Nacional de Vigilância Sanitária, Rio de Janeiro, Brazil Dr Katja Bromen, Policy Officer, Tobacco Control Team, European Commission, Directorate-General for Health and Consumers, Unit D4, Substances of Human Origin and Tobacco Control, Brussels, Belgium Mr D. Choinière, Director, Tobacco Products Regulatory Office, Controlled Substances and Tobacco Directorate, Health Canada, Ottawa, Ontario, Canada
·45·
Advisory Note: Global Nicotine Reduction Strategy
Presenters Dr G. Ferris Wayne, California, United States of America Dr R. Grana, Postdoctoral Fellow, Center for Tobacco Control Research and Education, University of California, San Francisco, California, United States of America Dr M. Parascandola, Epidemiologist, Tobacco Control Research Branch, Behavioral Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Maryland, United States of America Dr R. Talhout, National Institute for Public Health and Environment, Centre for Health Protection, Bilthoven, The Netherlands Convention Secretariat of the WHO FCTC (Geneva, Switzerland) Ms K. Brown, Programme Officer WHO Regional Office for the Americas Dr A. Blanco, Regional Advisor, Tobacco Control, Washington DC, United States of America WHO Secretariat (Tobacco Free Initiative, Prevention of Noncommunicable Diseases, Geneva, Switzerland) Ms M. Aryee-Quansah, Administrative Assistant Dr A. Peruga, Programme Manager Dr V.M. Prasad, Project Manager Ms G. Vestal, Technical Officer (Legal) ·46·
Acknowledgements WHO has many people to thank for the production of this WHO Study Group on Tobacco Product Regulation (TobReg) Advisory Note on Global Nicotine Reduction Strategy. Ms Gemma Vestal coordinated the production, with the supervision and support of Dr Armando Peruga and Dr Douglas Bettcher. Work on the advisory note began shortly after the fifth session of the Conference of the Parties to the WHO Framework Convention on Tobacco Control (WHO FCTC) in Seoul, Republic of Korea, 12–17 November 2012, and continued after the sixth session, in Moscow, Russian Federation, 13–18 October 2014. We thank all the members of TobReg for their full, whole-hearted dedication, time and unfailing commitment to fulfilling their mandate to advise WHO on tobacco product regulation, a highly complex area of tobacco control. As independent experts, members of TobReg serve WHO without remuneration. In response to the requests to WHO made by the Conference of the Parties at its fifth session, TobReg members provided guidance in drafting the terms of reference for commissioning a series of reviews to serve as background documents and as a basis for discussions at TobReg’s seventh meeting, held in Rio de Janeiro, Brazil, in December 2013. The TobReg recommendations on these issues were published as Technical Report Series 989 (WHO, 2015), which was presented by the ·47·
Advisory Note: Global Nicotine Reduction Strategy
Director- General of WHO to the 136th session of the Executive Board, held in Geneva, Switzerland, on 25 January to 3 February 2015. The background paper on reducing the dependence potential of manufactured cigarettes by reducing their nicotine content to levels that cannot cause or sustain addiction, which served as the basis for this advisory note, was written by Mr Geoff Ferris Wayne. It was appended as Annex 3 to Technical Report Series 989. WHO thanks Mr Wayne for the time and effort invested in writing the background paper, which was presented to TobReg in December 2013, and for continuing to work with TobReg in finalizing their conclusions and recommendations on this important topic. This advisory note was finalized by Dr Dorothy Hatsukami. To ensure that WHO delivered the information requested on tobacco product regulation to the Conference of the Parties, through the Convention Secretariat, WHO and TobReg worked with the facilitators of the Working Group on Articles 9 and 10 of the WHO FCTC. Specifically, WHO acknowledges the significant reviews of this advisory note by Mr Denis Choinière of Health Canada. Administrative support throughout the years of production was provided by WHO colleagues Ms Miriamjoy Aryee-Quansah, Mr Gareth Burns, Mr Luis Madge, Ms Rosane Serrao, Ms Moira Sy, Ms Elizabeth Tecson and Atty Angeli Vigo. Special thanks go to Dr Adriana Blanco, Tobacco Control Regional Adviser, WHO Regional Office for the Americas, for ensuring a smooth TobReg meeting in Brazil. We also once again sincerely thank Ms Ana ·48·
Acknowledgements
Claudia Bastos de Andrade, Agência Nacional de Vigilância Sanitária (ANVISA), Brazil, for heroically hosting the seventh meeting of TobReg in Rio de Janeiro in December 2013, while at the same time defending ANVISA from a number of lawsuits instigated by the tobacco industry. In addition, ANVISA provided much needed financial assistance to make the meeting become a reality. We also express our appreciation to the WHO editor, copy-editor and proofreader in France and to the layout and typesetter company in Portugal for their careful eye for detail and their patience with the various rounds of editing. Last but not least, WHO expresses its profound gratitude to former interns at the Tobacco Free Initiative who contributed large chunks of their internship time to the fruition of this document: Ms Aurelie Abrial, Ms Colleen Ciciora, Mr Adrian Diaz, Dr Richelle Duque, Ms Mary Law, Atty Caitlin McGowan, Ms Christina Menke, Ms Hannah Patzke and Ms Nava Shahi. It is our hope that they continue to work passionately in some aspect of tobacco control, regardless of the bright careers they follow in the future. Undoubtedly, many people to whom we are indebted are not mentioned here, because there were so many people involved in the production of this advisory note. We apologize for any omission. We therefore thank both those who are named and those who are not named. Without your assistance and support, none of this would have been possible. Thank you very much.
·49·
Preface The WHO Study Group on Tobacco Product Regulation (TobReg) 1is mandated to provide the WHO Director-General with scientifically sound, evidence-based recommendations for Member States about tobacco product regulation. In line with the provisions of Articles 9 and 10 of the WHO Framework Convention on Tobacco Control (WHO FCTC), TobReg identifies approaches for regulating tobacco products that pose significant public health issues and raise questions for tobacco control policy. Regulation of tobacco products is essential for tobacco control and is endorsed by the WHO FCTC in provisions of its Articles 9, 10 and 11. Regulation serves public health goals by ensuring meaningful surveillance of the manufacture, packaging, labelling and distribution of tobacco products. Scientifically based principles for implementing the provisions create synergy and mutual reinforcement of the regulatory practices described in each article. Tobacco product regulation includes regulating their contents and emissions by testing, measuring and mandating disclosure of the results and regulating their packaging and labelling. Government supervision is required for manufacture and for enforcement of regulations on the 3
1
http://www.who.int/tobacco/industry/product_regulation/tobreg/en/, accessed 24 July 2015.
·51·
Advisory Note: Global Nicotine Reduction Strategy
design, contents and emissions of tobacco products, as well as their distribution, packaging and labelling, with the aim of protecting and promoting public health. Chemical consumer products are usually regulated after a review of the scientific evidence on the hazards associated with them, probable exposure, patterns of use and the marketing messages of the manufacturer. Many jurisdictions require manufacturers to classify and label products according to their hazardous properties, to control the hazardous content or to limit the advertising, promotion and sponsorship of such products. TobReg reviews the scientific evidence on topics related to tobacco product regulation and identifies the research necessary to fill regulatory gaps in tobacco control. It is composed of national and international scientific experts on product regulation, treatment of tobacco dependence and laboratory analysis of tobacco contents and emissions. As a formalized entity of WHO, TobReg reports to the WHO Executive Board through the Director-General to draw the attention of Member States to the Organization’ s work in tobacco product regulation, which is a complex area of tobacco control. The seventh meeting of TobReg was held in Rio de Janeiro, Brazil, on 4–6 December 2013. The discussions mainly addressed the request of the Conference of the Parties of the WHO FCTC at its fifth session (Seoul, Republic of Korea, 12–17 November 2012) to WHO to: • Monitor and follow closely the evolution of new tobacco products,
including products with potentially “modified risks”, and to report any relevant development to the Conference of the Parties. ·52·
Preface
• Direct some of its activities towards aspects of addictiveness
(or dependence liability) of both smoked and smokeless tobacco products that remain to be studied. • Monitor and research country experience and scientific
developments with respect to reduced ignition propensity cigarettes. • Identify measures likely to reduce the toxicity of both smoked and
smokeless tobacco products, and describe the evidence supporting the effectiveness of such measures and the experience of Parties on the matter for consideration by the Conference of the Parties. • Compile, make available to Parties and update a non-exhaustive
list of the toxic contents and emissions of tobacco products, and provide advice on how such information could be best used by Parties. • Prepare draft fact sheets on measures recommended in the partial
guidelines for implementation of Articles 9 and 10 of the WHO FCTC. • Continue and report on progress in validation of analytical
chemical methods for testing and measuring cigarette contents and emissions. Subsequent to this request, a number of backg round documents were commissioned. In addition, information on the availability and regulation of novel tobacco products, smokeless tobacco products and reduced ignition propensity cigarettes was collected in a WHO survey of tobacco products sent to all Member States. Ninety countries responded, ·53·
Advisory Note: Global Nicotine Reduction Strategy
representing approximately 77% of the world’ s population. The WHO report to the sixth session of the WHO FCTC Conference of the Parties in October 2014 is now published (WHO, 2015). Because of the complexity of the topic of reducing the dependence potential of manufactured cigarettes by reducing their nicotine content to levels that cannot cause or sustain addiction, however, was further discussed by TobReg members for more than 18 months. The result of those discussions is encapsulated in this TobReg advisory note on a global nicotine reduction strategy.
Main recommendation This advisory note introduces a policy of limiting the sale of cigarettes to brands with a nicotine content that is not sufficient to lead to the development and/or maintenance of addiction; they are referred to as “reduced-nicotine” cigarettes. Conventional cigarettes—even those brands that deliver low nicotine yields as measured by machine smoking under the conditions of the International Organization for Standardization (ISO)—contain addicting levels of nicotine, but the nicotine yields are reduced as a result of many design features, including ventilated filters. Users puff ISO low-nicotine-yield cigarettes more intensely (i.e. they draw larger puffs more frequently than the conditions prescribed by machines) to obtain addicting levels of nicotine. Unlike conventional cigarettes, reduced- nicotine cigarettes can limit the addictiveness of the product, ·54·
Preface
as the low content in the tobacco filler 2 cannot deliver addicting levels of nicotine. Research shows that switching from conventional to cigarettes with a nicotine content of 0.4 mg/g of cigarette tobacco filler does not significantly increase craving or withdrawal symptoms and does not result in compensatory smoking (such as more intense smoking or smoking more cigarettes per day). No specific amount of nicotine has yet been identified as the absolute threshold for addiction; however, it is likely to be equal to or possibly less than 0.4 mg/g of dry cigarette tobacco filler. The ultimate health benefits of a nicotine reduction strategy for individual smokers will require complete cessation of intake of all combusted tobacco. Population benefits will result from decreased use of combusted tobacco by current cigarette smokers and from prevention of addiction of non-smokers to cigarettes, especially among young people. To achieve the public health goal, not only product modification but also the provision of treatment will be required, including behavioural support,nicotine replacement and other medications, for cigarette smokers who will no longer be able to obtain adequate levels of nicotine from cigarettes. For people who switch from cigarettes to non-combusted forms of tobacco to sustain their nicotine intake, the health benefits will depend, partly, on the level of tobacco- related toxicants delivered by the alternative products and the behaviour and duration of use of such products.
4
2 Cigarette tobacco filler is defined as the tobacco-containing part of a cigarette, including a blend of different tobacco types, reconstituted tobacco sheets, stems, expanded tobacco and additives. (See WHO, 2014.)
·55·
Advisory Note: Global Nicotine Reduction Strategy
Significance for public health policies A nicotine reduction strategy could decrease the acquisition of smoking and progression to addiction among experimenters, limit the number of cigarettes smoked by some proportion of addicted smokers and both increase the number of addicted smokers who stop smoking and reduce the number of those who relapse.
Implications for WHO programmes Implementation of a nicotine-reduction policy should be supported by a comprehensive programme, involving: • a strategy on health communication and public education; • the absence of products with higher levels of nicotine in tobacco
filler on the market; • effective, affordable, available cessation treatment that includes
behavioural support, alternative forms of nicotine in products that pose a significantly lower risk for tobacco-related disease and medicines approved for treating tobacco dependence and withdrawal; • capacity to monitor the market and test tobacco products for
nicotine and other constituents and emissions; and ·56·
Preface
• continued research to assess:
— the likelihood of use and the effects of reduced-nicotine cigarettes in non-smoking adolescents; — the likelihood that users will switch back to high-nicotine products if they are available on the market; — additional use of other types of product (e.g. smokeless tobacco products, e-cigarettes); — long-term use of reduced-nicotine cigarettes; — the long-term impact of reduced-nicotine cigarettes on smoking behaviour and — comprehensive surveillance to ensure rapid detection of unintended consequences. TobReg hopes that the conclusions and recommendations contained in this advisory note will be useful to countries implementing the product regulation provisions of the WHO FCTC.
·57·
Reducing the addictiveness of manufactured cigarettes by reducing their nicotine content: research needs and regulatory recommendations 1. Introduction A policy to reduce the addictiveness of tobacco by reducing its nicotine content comprises setting a maximum allowable limit on the nicotine content of all cigarettes and potentially other forms of tobacco (both combusted and non- combusted) that are available for sale, with the intention of minimizing the development and/or maintenance of nicotine addiction. The report reflects increasing scientific understanding about the population effects of cigarettes containing reduced-nicotine tobacco; it includes recommendations for policy and regulations based on the current state of science and discusses issues raised by regulatory authorities and the Conference of the Parties to the WHO Framework Convention on
·59·
Advisory Note: Global Nicotine Reduction Strategy
Tobacco Control (WHO FCTC). It is based on a background report
3
commissioned by WHO (WHO, 2015), with input from the Study Group on Tobacco Product Regulation (TobReg) at its seventh meeting in Rio de Janeiro, Brazil, in December 2013.
2. Background Addiction is a chronic, relapsing brain disease characterized by compulsive self-administration of a drug, often despite harmful consequences (WHO, 1992; National Institute on Drug Abuse, 2014). Since the 1980s, it has been generally recognized that nicotine is the primary addicting chemical in tobacco products; by the 1990s, it was increasingly accepted that tobacco products without nicotine would not sustain addiction (Benowitz & Henningfield, 1994; Henningfield et al., 1998). The tobacco industry recognized this many years earlier and designed cigarettes to ensure that they could deliver addicting levels of nicotine despite reduced machine-estimated deliveries as measured by the ISO and United States Federal Trade Commission test methods (National Cancer Institute, 2001; WHO, 2001; WHO, 2003a). Earlier reports from TobReg and its predecessor SACTob similarly concluded that nicotine was the primary addicting chemical common to combusted and non3 The background report, entitled “Reducing the dependence potential of manufactured cigarettes by reducing their nicotine content to levels that cannot cause or sustain addiction”, appears as Annex 3 in WHO (2015), for further information for researchers and policy-makers.
·60·
Reducing the addictiveness of manufactured cigarettes by reducing their nicotine content: research needs and regulatory recommendations
combusted tobacco products and that it should be regulated, with other content and design features. To date, however, TobReg has not published a clear position on reducing the addiction potential of manufactured cigarettes (WHO, 2002; WHO, 2007; WHO, 2009; WHO, 2012a). During the past decade, experimental research and modelling have been conducted to assess the potential public health impact of a policy to reduce the addictiveness of cigarettes, as discussed in this report. The results led to the current recommendation: that reducing the maximum allowable nicotine content in cigarettes to minimally addicting levels be considered a suitable strategy for reducing the demand for these products, which account for the vast majority of tobacco-attributable morbidity and mortality in most countries and regions. This report does not provide a detailed proposal of how such a policy might be enacted but rather focuses on the scientific basis for recommending this policy. It presents the conditions that might be necessary for viable enactment of such a policy and many of the challenges to be met, including unanswered research questions.
3. Cigarettes with a reduced nicotine content In a policy to reduce the addictiveness of tobacco, the nicotine content of all cigarettes permitted for sale would be inadequate to cause or sustain addiction. Such cigarettes have been referred to as “reducednicotine cigarettes”, “very low nicotine content cigarettes” and “de·61·
Advisory Note: Global Nicotine Reduction Strategy
nicotinized cigarettes”. They are distinct from reduced-yield cigarettes, which were developed in the 1970s in response to public health concern and marketed with descriptors such as “light”, “low tar” and “mild”. Those descriptions implied lower deliveries and less exposure to nicotine and other substances (commonly termed “ tar ” ), but the products actually contained similar amounts of nicotine and delivered nicotine doses that were associated with risks for addiction and other diseases as high as those of their “full-flavoured” counterparts (National Cancer Institute, 2001; WHO, 2001; WHO, 2003a). Whereas cigarettes with a very low nicotine content cannot sustain addiction, cigarettes marketed as “reduced yield” on the basis of machine testing have been found to extend the prevalence of addiction in many populations because they are perceived as safer and are easier to inhale (Kozlowski & O’ Connor, 2002).
4. Goals of a policy to reduce addiction to cigarettes A policy to reduce the addictiveness of cigarettes has many goals: to reduce the risk that non-smokers will become addicted to cigarettes, to make it easier for smokers to quit smoking, to help prevent smokers who have quit from relapsing and, if needed, to encourage cigarette smokers to substitute a less harmful and, ideally, less addictive source of nicotine (Henningfield et al., 1998; Hatsukami et al., 2010a; Benowitz & Henningfield, 2013). Since nicotine reduction was first proposed by ·62·
Reducing the addictiveness of manufactured cigarettes by reducing their nicotine content: research needs and regulatory recommendations
Benowitz and Henningfield in 1994, a number of health scientists have concluded that the approach could significantly impact public health (Gray et al., 2005; Zeller et al., 2009; Benowitz & Henningfield, 2013; Hatsukami et al., 2013a; Smith et al., 2013). The approach is consistent with Article 9 of the WHO FCTC, which calls for guidelines for regulating the contents and emissions of tobacco products (WHO, 2003b; WHO, 2012a).
5. Tobacco addictiveness factors As discussed elsewhere and in earlier WHO reports (WHO, 2001; WHO, 2007; WHO, 2012a), nicotine is a highly addictive, potent drug, which can generate psychoactive rewarding effects even at very low doses. Cigarettes are a particularly effective form of nicotine delivery: when smoke from a cigarette is inhaled, nicotine in the tobacco is rapidly absorbed into the lungs and carried to the brain. Individual responses to nicotine, including sensitivity, are highly variable. Early exposure to nicotine (i.e. before or during adolescence) is associated with more severe dependence, greater reward and increased self-administration, suggesting that the developing brain may be more susceptible to permanent changes caused by nicotine that support addiction (Benowitz, 2008; Hatsukami et al., 2010a). Women are more strongly influenced than men by the sensory aspects of smoking and have more difficulty in quitting (Fant et al., 1996; Gritz et al., 1996; Eissenberg et al., 1999; Perkins et al., 1999; Wetter et al., 1999; Perkins et al., 2006; ·63·
Advisory Note: Global Nicotine Reduction Strategy
Perkins, 2009). Individuals with psychiatric and/or substance abuse disorders have much higher rates of nicotine dependence and have more difficulty in quitting (Ziedonis et al., 2008). The sensory characteristics of smoking (taste, aroma, tracheobronchial sensations) facilitate delivery of nicotine and come to be associated with its pharmacological effects, further reinforcing addiction (WHO, 2007; Henningfield et al., 2011; WHO, 2012a). Because non-nicotine components of tobacco are critical to the sensory experience of smoking, de-nicotinized tobacco is more effective in reducing craving and producing greater pleasure in smokers than nicotine without tobacco (Rose, 2006). Nicotine also plays a central role in the sensory composition of cigarette smoke: nicotine-containing cigarettes are consistently rated as stronger than de-nicotinized cigarettes because of the greater sensory stimulus. Some non-nicotine components of tobacco may interact chemically or have a synergistic effect (e.g. acetaldehyde) with nicotine, further potentiating its effects, or may have measurable pharmacological effects on their own. For example, various minor tobacco alkaloids reinforce self-administration by rats, and monoamine oxidase inhibitors present in tobacco smoke have been shown to increase response rates substantially when given to rats that are self-administering nicotine (Guillem et al., 2005). Thus, although drastically reducing nicotine should substantially decrease the addictiveness of tobacco for most people, a product with a very low nicotine content may still have some reinforcing effects for certain people. ·64·
Reducing the addictiveness of manufactured cigarettes by reducing their nicotine content: research needs and regulatory recommendations
Expectations about the effects of a drug play an important role in determining subjective and behavioural responses to tobacco products, particularly in women (Perkins et al., 2006). Expectancy may be due to sensory stimuli produced by the product, by packaging or by other information cues. Social context also determines smoking behaviour and dependence, such as where it is permissible to use tobacco products (both legally and in terms of social norms), the cost of tobacco use both individually and to one’ s family, and whether tobacco use is stigmatized in subpopulations such as by gender, religious affiliation or social status.
6. Establishing a performance standard for nicotine products Various tests are available for identifying potentially addicting drugs and the dosages of the drugs that reinforce and sustain use, by producing either psychoactive effects or physical dependence and withdrawal. These tests are recommended by WHO (2006) and have been described in scientific reviews and by various regulatory agencies (Balster & Bigelow, 2003; Schuster & Henningfield, 2003; Carter et al., 2009). No single amount of nicotine can be identified as an absolute threshold for addiction in all individuals, under all circumstances and by all routes or means of administration; however, numerous studies conducted in both animals and humans confirm that there are doses above which nicotine is consistently self-administered and below which self-administration is not observed or, in humans, results in significantly reduced dependence (Hatsukami et ·65·
Advisory Note: Global Nicotine Reduction Strategy
al., 2010a; Donny et al., 2012). The doses of nicotine necessary to produce psychoactive or discriminative effects reliably in humans and animals have also been studied (Department of Health and Human Services, 1988; Carter et al., 2009). Taken together, these and other types of studies provide a basis for setting standards for the levels of nicotine above which addiction is likely and below which addiction is less likely (Carter et al., 2009; Sofuoglu & LeSage, 2012; Benowitz & Henningfield, 2013). Smokers self-administer nicotine intravenously within a range of intake well below that from a typical cigarette, with a threshold somewhere between 0.1 and 0.4 mg of nicotine, assuming 70 kg body weight (Sofuoglu et al., 2008). Similarly, in dose–response studies, animals commonly self-administer doses of nicotine below 10 μg/kg and maintain selfadministration with unit doses of as low as 3 μg/kg, equivalent to around 0.23 mg nicotine, although there is considerable individual variation in response rates at the lower end of this range (Donny et al., 2012; Smith et al., 2013). As tobacco-delivered nicotine differs substantially from intravenous nicotine, it may not be sufficient to rely on studies of intravenous nicotine self-administration to predict the potential reinforcing effects of tobacco with reduced nicotine content. Administration parameters such as the timing of dose delivery play a role in determining the pharmacology and reinforcing effects of a given dose (Sorge & Clarke, 2009). Nonetheless, the limited evidence available suggests that the nicotine threshold for selfadministration of cigarette-delivered nicotine is not substantially different from that identified above. Tobacco manufacturers have used brain ·66·
Reducing the addictiveness of manufactured cigarettes by reducing their nicotine content: research needs and regulatory recommendations
imaging to determine effective ranges of cigarette nicotine delivery under controlled smoking conditions (Panzano et al., 2010); the results suggest a threshold for a neurophysiological effect of 0.1–0.3 mg of machinemeasured smoke nicotine. The findings are also consistent with research on nicotine discrimination, which indicates that the threshold levels for discrimination are in a comparable range and do not differ for smokers and non-smokers (Hatsukami et al., 2010a). Whereas most studies in humans have been conducted among established smokers, studies in animals suggest that the threshold for acquisition of nicotine self-administration behaviour is equal to or higher than that for maintenance of such behaviour (Donny et al., 2014). In adult rats, self-administration of low doses of nicotine is more frequent after exposure to high doses of nicotine and subsequent dose reduction than during acquisition (Smith et al., 2014). Acquisition of nicotine selfadministration behaviour and dependence among adolescents may, however, be different from that among adults. Both cross-sectional and longitudinal studies indicate that young people who smoke less than daily nonetheless report the onset of dependence symptoms. Reward expectancy plays a significant role in smoking behaviour and motivation to smoke among adolescents (Kassel et al., 2007). De-nicotinized cigarettes suppress acute craving and delay the onset of ad-libitum smoking in the same way as nicotine-containing cigarettes (Rose et al., 2003; Barrett, 2010); in contrast, intravenous nicotine suppresses ad-libitum smoking to only a small extent (Rose et al., 2003). This suggests that the non-nicotine stimuli associated with smoking ·67·
Advisory Note: Global Nicotine Reduction Strategy
become conditioners, serving as cues to the smoker for anticipated nicotine delivery. The conditioning properties of tobacco smoking are acquired only after long-term prior use of nicotine-containing cigarettes. Studies in animals suggest that the conditional reinforcing properties acquired by a stimulus are a direct function of dose. This implies that stimulus control of tobacco-seeking behaviour will be most potent in people exposed to high levels of nicotine and are likely to be greatly reduced by exposure to very low nicotine, with a reduction in conditional stimuli (Palmatier et al., 2008). Variations in sensitivity to the behavioural and potentially addictive effects of nicotine have important implications for setting product performance standards for nicotine. Thus, to minimize the risk for addiction of all individuals who sample cigarettes, the maximum allowable content should be well below that which might have behavioural and addictive effects. Comprehensive surveillance and epidemiological studies will be important to determine if the performance standards set initially are effective and to assess any unintended consequences rapidly. Corrections and risk management plans can be made accordingly.
7. Feasibility of reducing nicotine Currently, most conventional cigarettes contain 10–15 mg of nicotine each, of which approximately 10% is delivered in smoke, resulting in a typical systemic intake of 1–2 mg of nicotine per cigarette. Higher levels ·68·
Reducing the addictiveness of manufactured cigarettes by reducing their nicotine content: research needs and regulatory recommendations
can be delivered with more intense smoking behaviour. Thus, establishing a maximum allowable limit for nicotine would require an overall reduction in nicotine intake of the order of 90–95% or more. The concentration of nicotine in tobacco is readily altered and controlled by manufacturers, for example by genetic modification, enzymatic processes or nicotine extraction, to levels approaching or exceeding this range of nicotine reduction (Wayne & Carpenter, 2009). Reduced-nicotine cigarettes are now available that contain < 1 mg nicotine per gram of tobacco and, when smoked on a standard smoking machine (ISO), have a nicotine yield of 0.03–0.1 mg, equivalent to 3–10% of the nicotine yield of standard commercial brands. Most behavioural research on nicotine reduction has been conducted with cigarettes that provide this range of nicotine in smoke. Production of cigarettes with a very low nicotine content is technically feasible. The loss of sensory impact due to reduced nicotine has been discussed as a potential technical challenge; however, the fact that commercial cigarette brands such as Next and Quest with a nicotine content of < 1 mg have been produced and that these products can substitute for conventional cigarettes and at least temporarily reduce cigarette craving provides strong evidence that the production of cigarettes with a very low nicotine content is technically feasible (Butschky et al., 1995; Rose et al, 2003; Johnson et al., 2004; Rose, 2006; Hatsukami et al., 2013b). Spectrum cigarettes, currently produced for research purposes by 22nd Century Manufacturers, have a reported level of 0.4 mg nicotine per gram of tobacco. ·69·
Advisory Note: Global Nicotine Reduction Strategy
Another concern raised with respect to nicotine reduction is that smokers will respond by altering their smoking behaviour. Evidence from clinical studies indicates, however, that smokers of products with a very low nicotine content (< 1 mg/g) do not significantly alter their behaviour from that with their usual brand, and their exposure to nicotine remains significantly reduced (Benowitz et al., 2006; Hatsukami et al., 2010b; Benowitz et al., 2012). Smokers do, however, compensate for less extreme reductions in delivered smoke nicotine (0.2–0.3 mg) (Hatsukami et al., 2010b). Moreover, for smokers not interested in quitting, progressive reduction of the nicotine content of their cigarettes to 0.5 mg/g does not lead to extinction of their dependence upon follow up (Benowitz et al., 2015). The behavioural research conducted to date has been with cigarettes with reduced-nicotine tobacco but otherwise conventional design. Other physical and chemical parameters of cigarette construction can be manipulated to alter the basic formulation, with unknown behavioural and health consequences. Therefore, attention must continue to be paid to other product factors, in addition to nicotine delivery. Standard measures of smoke nicotine delivery do not differentiate between forms of nicotine (e.g. free-base versus protonated nicotine); comparisons of free-base nicotine delivery may provide a more accurate measure of subjective response to reduced-nicotine content products (Wayne & Carpenter, 2009).
·70·
Reducing the addictiveness of manufactured cigarettes by reducing their nicotine content: research needs and regulatory recommendations
8. Potential behavioural and population outcomes Reduced-nicotine cigarettes can give acute subjective satisfaction (Hatsukami et al., 2010a) and immediately reduce craving in smokers (Rose et al., 2003); however, with repeated use, reduced-nicotine cigarettes give less satisfaction than those with a higher dose of nicotine (Hatsukami et al., 2013c). Clinical data indicate that withdrawal is not a common adverse consequence of reduced nicotine intake in most smokers and that significant compensation in the form of more intense smoking or more cigarettes per day is not a probable outcome at very low nicotine levels (< 1 mg) (Hatsukami et al., 2010a; Hatsukami et al., 2010b; Benowitz et al., 2012). Use of reduced-nicotine cigarettes over a long time weakens the reinforcing effects of smoking: smokers consistently report less dependence after prolonged use of such products (Donny et al., 2007; Benowitz et al., 2009; Hatsukami et al., 2010b; Benowitz et al., 2012). Reduced-nicotine cigarettes may represent a temporary coping mechanism and help smokers to achieve abstinence when they make an active attempt to quit. They may support quitting not only for smokers who seek treatment but also for smokers who have not previously expressed an interest in quitting (Benowitz et al., 2007; Benowitz et al., 2009). The effects of reduced-nicotine cigarettes on quitting may be strengthened by the addition of nicotine-based treatment, particularly in ·71·
Advisory Note: Global Nicotine Reduction Strategy
men (Vogel et al., 2014). This suggests that other forms of treatment and behavioural support may be helpful as well and should be made accessible to support the transition to reduced-nicotine cigarettes as well as to people attempting complete tobacco abstinence. The health benefits of switching from cigarettes to non-combusted forms of tobacco to sustain the nicotine intake will depend partly on the level of tobacco toxicants delivered by the alternative products and how long they are used. Some people may continue to smoke cigarettes after mandated nicotine reduction, either for a strong substitution effect or because the nicotine content of the cigarettes remains above their individual threshold for reinforcement. Few studies have been conducted, however, on the uptake of reducednicotine cigarettes by non-smoking populations and the long-term effects of reduced-nicotine cigarette use; there may be little, if any, health benefit if people continue to inhale high levels of combusted tobacco emissions. People should be encouraged and supported to discontinue use of any combusted tobacco product as quickly as possible. Surveillance and other research will be required to monitor effects—desired and undesired. The literature provides no quantified estimates of the potential impact of a reduced-nicotine policy on smoking initiation among adolescents. It is theoretically possible that reduced-nicotine cigarettes could serve as “starter” products for products with a higher nicotine content, if such products were still available on the commercial market. Thus, product labelling and access restriction will remain important. Reduced-nicotine cigarettes should not be exempt from warnings about the risk for addiction, although the warnings may be somewhat different ·72·
Reducing the addictiveness of manufactured cigarettes by reducing their nicotine content: research needs and regulatory recommendations
from those used on higher-nicotine products (Henningfield et al., 1994). Various models have been created to estimate the probable effects of a nicotine reduction policy; all indicate a significant positive effect on public health outcomes. No published study has provided an estimate of the probable illicit sales of conventional cigarettes with a higher nicotine content in the context of a reduced-nicotine market. Both the appeal of reduced-nicotine cigarettes and the availability and appeal of alternative forms of nicotine are likely to affect the extent of illicit sales.
9. Policy approaches to nicotine reduction The effects of a cigarette nicotine reduction policy will depend to a significant degree on the availability, toxicity and appeal of alternative nicotine delivery systems, including other forms of combusted or noncombusted tobacco, medicinal nicotine and commercial non-tobacco nicotine products, as discussed elsewhere (Henningfield et al., 1998; Benowitz & Henningfield, 2013; Department of Health and Human Services, 2014). Substitution of alternative products could have adverse health effects or maintain addiction in a significant segment of the population. Therefore, a successful nicotine reduction policy must be supported by comprehensive regulation of all tobacco- and nicotinecontaining products (Gray et al., 2005; Zeller et al., 2009; Le Houezec et al., 2011; McNeill et al., 2012; Hatsukami et al., 2013a; Benowitz et al., 2015). The goals of comprehensive regulation would be to minimize use of ·73·
Advisory Note: Global Nicotine Reduction Strategy
highly toxic nicotine-containing products, to encourage the development of less toxic nicotine delivery systems as alternatives to more toxic products and to continue to monitor and regulate the health effects of the less toxic products (Gray et al., 2005; Le Houezec et al., 2011; Benowitz & Henningfield, 2013). Policy approaches could be considered to motivate smokers who are unable to quit to substitute less hazardous forms of tobacco and nicotine use, e.g. through restrictions on access, marketing and use, in order to encourage complete cessation of use of the more toxic products. The health benefits for people who switch from cigarettes to non-combusted forms of tobacco to sustain their nicotine intake will depend partly on the level of tobacco-related toxicants delivered by the alternative products, the extent to which they continue to smoke cigarettes and how long they continue to use the products. The effects of reducing nicotine to very low levels either gradually or immediately have been evaluated in clinical studies; no adverse effect was found in either condition, indicating that neither approach poses a significant safety concern (Hatsukami et al., 2013a; Smith et al., 2013; Hatsukami et al., 2015). A gradual reduction would maintain smokers at nicotine doses more likely to support compensatory behaviour for an extended period and could theoretically enable them gradually to adapt effective compensatory behaviour to products with a low nicotine content. Therefore, an immediate reduction in nicotine, preceded by health communication strategies and public education, is the more promising approach. ·74·
Reducing the addictiveness of manufactured cigarettes by reducing their nicotine content: research needs and regulatory recommendations
Product performance standards are necessary to ensure successful implementation of nicotine reduction. While a number of approaches could be considered, reducing the total nicotine available in unburnt cigarettes is the most promising, as it is both easily measured and not subject to behavioural manipulation or individual variation. Although this report addresses cigarettes, a similar regulatory approach would be appropriate for other combusted and non-combusted products. Product performance standards must remain responsive to the changing marketplace (Hatsukami et al., 2012; O’ Connor, 2012; Hatsukami et al., 2013a), and new products and technologies must be evaluated carefully. Commercial introduction of new products should be permitted only when they have been shown sufficiently to be associated with reduced risk, addictiveness and appeal. Whether a policy will result in a reduction in the addictiveness of cigarettes will depend partly on how effectively the risks are communicated. Mistaken beliefs about the greater safety of reducednicotine products could lower the likelihood of quitting and could encourage more experimentation. Implementation of smoke-free policies might provide a useful model, and public education can support compliance and ensure continued support for the law. Studies in the USA (Hatsukami et al., 2013a) have shown strong support for mandated nicotine reduction among both smokers and non-smokers, but no surveys have been reported from other parts of the world. Education of smokers and non-smokers about the health risks of tobacco without nicotine, the relative harm of different products and ·75·
Advisory Note: Global Nicotine Reduction Strategy
opportunities for treatment is critical. The marketing of tobacco and nicotine products will have to be strongly regulated (McNeill et al., 2012; Hatsukami et al., 2013a). Although the evidence is inconclusive, various models have indicated that setting a maximum allowable nicotine content will sharply increase the number of smokers who want to quit (Tengs et al., 2005; Morrison, 2013). Many smokers are likely to seek nicotine replacement or behavioural therapy to aid cessation or to obtain relief from withdrawal symptoms. Effective, affordable treatment offered by health care professionals and coverage by insurance programmes will be invaluable in ensuring the success of the policy, as will individualized services to populations in whom the adverse effects may be more severe, such as those with psychiatric disorders. Wide availability of pharmacotherapy and treatment might not only reduce the discomfort associated with smoking reduced-nicotine cigarettes but might also lead to a substantial reduction in cigarette smoking and possibly to cessation of use of all tobacco and nicotine products by some or many current smokers (Zeller et al., 2009; O’ Connor, 2012; Benowitz & Henningfield, 2013). The appeal of alternative tobacco products, such as oral and smokeless tobacco, waterpipes, pipes and cigars, may increase, as they may substitute for conventional cigarettes more effectively than reducednicotine cigarettes; however, few data are available. This prospect must be included in any assessment of the health effects of existing and new products that could serve such a purpose. Extending a nicotine reduction policy to other combusted products or possibly non-combusted tobacco ·76·
Reducing the addictiveness of manufactured cigarettes by reducing their nicotine content: research needs and regulatory recommendations
products should be considered. Electronic nicotine delivery devices and other products designed expressly to replicate the act of smoking may present viable alternatives; in some countries, however, if they are marketed as cessation aids, they would first have to be proven safe and effective in clinical trials (Department of Health and Human Services, 2014; WHO, 2014b). Reduced availability of conventional cigarettes as a consequence of adoption of a maximum allowable limit for the nicotine content of all cigarettes might increase the demand of addicted smokers for contraband conventional cigarettes. Minimizing sales of illicit cigarette will require effective surveillance of wide-scale organized smuggling and other types of illegal trade, such as in bootlegged and counterfeit products (Joossens & Raw, 2008). Unregulated combusted tobacco, such as roll-your-own, could be substituted for manufactured cigarettes. Other areas of potential concern include use of both reduced-nicotine cigarettes and nicotine delivery devices, use of pH modification or additives to increase the impact and pharmacological effect of manufactured products and unanticipated behavioural changes, such as deeper inhalation or increased or more frequent long-term use of reduced-nicotine cigarettes. The production of more appealing alternative nicotine products is likely to serve as a check on these unintended market outcomes (Benowitz & Henningfield, 2013; Hatsukami et al., 2013a). An adequate surveillance system would allow regulators to monitor the impact of tobacco products on the prevalence, initiation and harm of smoking and to address unintended outcomes (Hatsukami et al., ·77·
Advisory Note: Global Nicotine Reduction Strategy
2013a). Mandatory reporting of all nicotine and tobacco products, as described in the partial guidelines to implementing Articles 9 and 10 of the WHO FCTC (WHO, 2012b), are a necessary condition for adequate surveillance. Mandatory reporting should include the physical design (tobacco weight, nicotine concentration, filter ventilation), the tobacco and added constituents, the emissions of combusted products and measures of possible abuse (Carter et al., 2009; Hatsukami et al., 2012; McNeill et al., 2012). The complexity of tobacco products and the knowledge required to assess toxicological effects, the possibility of abuse and other outcomes may be barriers for some Parties. A global data repository would facilitate tobacco product regulation and surveillance worldwide, would ease the burden on regulators by providing access to analysed data and global comparisons, and would provide information to national regulators, with recommendations in an easily understandable form (McNeill et al., 2012).
10. Conclusions There is clear evidence that reducing the nicotine content of cigarettes to a very low level can reduce their dependence potential. The maximum nicotine content of cigarettes that leads to dependence is likely to vary individually and is possibly lower for young people. Thus, the maximum nicotine content should be as low as is technically feasible. At present, that level would appear to be 0.4 mg nicotine per gram of cigarette tobacco ·78·
Reducing the addictiveness of manufactured cigarettes by reducing their nicotine content: research needs and regulatory recommendations
filler. 4 Compensatory smoking has been observed with highly ventilated cigarettes but not with cigarettes with a nicotine content of 0.4 mg per gram of cigarette tobacco filler. The evidence indicates that setting a maximum allowable nicotine content for all cigarettes could: • reduce acquisition of smoking and progression to addiction; • reduce the prevalence of smoking in a proportion of addicted
4
smokers as a result of behavioural extinction; • increase the rate of quitting and reduce the number of smokers
who relapse; and • increase the development, availability and use of alternative forms
of nicotine, e.g. smokeless tobacco products, nicotine aerosol products and medicinal nicotine, which have potential adverse health effects, including maintenance of addiction, but less than those of combusted products or conventional cigarettes.
11. Research needs Major research projects, including clinical trials, are under way and
4
In the working group report FCTC/COP/5/9, dated 17 July 2012, reference is made to
commercial cigarettes containing 0.03 mg nicotine. This measure refers to the smoke nicotine yield, which is only a fraction (in this case, approximately 10%) of the nicotine contained in unburnt cigarette tobacco. Spectrum cigarettes, produced for research by 22nd Century Manufacturers, have a reported content of 0.4 mg nicotine per gram of tobacco.
·79·
Advisory Note: Global Nicotine Reduction Strategy
are providing relevant information for implementing an approach to reducing the addictiveness of cigarettes. The research priorities include: • the probable use and effects of reduced-nicotine cigarettes in non-
smoking adolescents, non-smoking adults and non-dependent smokers (i.e. light or occasional smokers who experience minimal withdrawal symptoms yet continue to smoke); 6
5
• potential use of reduced-nicotine products as “ starters” or
“gateway” products by adolescents, leading to use of other forms of nicotine or drugs; • the effects of reduced-nicotine cigarettes in populations at risk,
such as people with moderate or severe depression or other comorbid conditions; • the comparative health risks of smoking reduced-nicotine
cigarettes and conventional cigarettes, including in special subpopulations (e.g. women of reproductive age); • long-term use of reduced-nicotine cigarettes and the long-term
impact on smoking behaviour and health outcomes, including 5 As administering reduced nicotine cigarettes to tobacco-naive humans is unethical,
studies on animals or indirect ways of assessing the impact on non-smokers will have to be considered. 6 A subset of light or occasional smokers consumes five or fewer cigarettes per day and appears to smoke primarily for the positive reinforcing effects of nicotine (Benowitz, 2008). These smokers use cigarettes mainly in association with specific activities, such as after meals or with alcohol, and less in response to negative affect; they may be more reactive to smoking cues (Watson et al., 2010). Although these occasional smokers experience minimal or no withdrawal symptoms, many have difficulty in quitting, suggesting a form of dependence that is distinct from that of everyday smokers.
·80·
Reducing the addictiveness of manufactured cigarettes by reducing their nicotine content: research needs and regulatory recommendations
cancer; • comparison of the long-term public health effects of reduced-
nicotine cigarettes and of alternative non-combusted forms of nicotine (e.g. some smokeless tobacco products with reduced tobacco-specific nitrosamines or electronic nicotine and nonnicotine delivery systems); and • surveillance and epidemiology to assess any unintended
consequences, including on health, and to guide modification of the policy and supporting strategies.
12. Regulatory recommendations • Mandated reductions in nicotine to minimally addictive levels
should be supported by comprehensive regulation of all nicotineand tobacco-containing products. • Mandated reductions in nicotine to minimally addictive levels
must be part of comprehensive tobacco control, including increased taxes on cigarettes, comprehensive smoking bans, antismoking educational campaigns and graphic warning labels or plain packaging. • Mandated reductions in nicotine to minimally addictive levels
might be considered for all combusted products because of the overwhelming toxicity associated with combustion and to minimize substitution of reduced-nicotine cigarettes for other ·81·
Advisory Note: Global Nicotine Reduction Strategy
combusted products. • The original proposal for nicotine reduction (Benowitz &
Henningfield, 1994) urged a gradual reduction over many years. More recent scientific evidence suggests that an immediate reduction in the intake of nicotine below the established product performance standard, preceded by health communication strategies and public education, is a better approach, for practical reasons. There is no scientific basis for concluding that a one-time reduction is more or less likely to be associated with unintended consequences than gradual reduction. • Health professionals must be taught to communicate the risks,
once they are known, and ensure compliance with and support for the law. The availability of effective, affordable cigarette cessation treatment, alternative forms of nicotine, optimal medicinal forms of nicotine and other approved treatments and medicines for tobacco dependence and withdrawal will help dependent smokers who experience adverse effects or withdrawal symptoms. • The potential adverse health effects and increased use of
alternative nicotine products must be weighed against the benefits of a reduction in cigarette consumption. The health benefits for people who switch from conventional cigarettes to noncombusted forms of tobacco to sustain their nicotine intake will partly depend, however, on the level of tobacco-related toxicants delivered by such alternative products, the extent to which people continue to smoke some cigarettes and how long they continue to ·82·
Reducing the addictiveness of manufactured cigarettes by reducing their nicotine content: research needs and regulatory recommendations
use such products. • A strategy to reduce the addictiveness of tobacco is not
recommended in the absence of developed capacity for market surveillance and product testing. Countries without an adequate infrastructure to ensure a comprehensive approach to nicotine reduction should carefully consider increasing that capacity before implementing such a strategy.
·83·
References Balster RL, Bigelow GE (2003) Guidelines and methodological reviews concerning drug abuse liability assessment. Drug Alcohol Depend 70(3 Suppl):S13–40. Barrett SP (2010) The effects of nicotine, denicotinized tobacco, and nicotine-containing tobacco on cigarette craving, withdrawal, and self-administration in male and female smokers. Behav Pharmacol 21:144–52. Benowitz NL (2008) Clinical pharmacology of nicotine: implications for understanding, preventing, and treating tobacco addiction. Clin Pharmacol Ther 83:531–41. Benowitz NL, Henningfield JE (1994) Establishing a nicotine threshold for addiction. The implications for tobacco regulation. N Engl J Med 331:123–5. Benowitz NL, Henningfield JE (2013) Reducing the nicotine content to make cigarettes less addictive. Tob Control 22(Suppl 1):i14–7. Benowitz NL, Jacob P 3rd, Herrera B (2006) Nicotine intake and dose response when smoking reduced-nicotine content cigarettes. Clin Pharmacol Ther 80:703–14. Benowitz NL, Hall SM, Stewart S, Wilson M, Dempsey D, Jacob P 3rd (2007) Nicotine and carcinogen exposure with smoking of progressively reduced nicotine content cigarette. Cancer Epidemiol Biomark·85·
Advisory Note: Global Nicotine Reduction Strategy
ers Prev 16:2479–85. Benowitz NL, Dains KM, Hall SM, Syewart S, Wilson M, Dempsey D, et al. (2009) Progressive commercial cigarette yield reduction: biochemical exposure and behavioral assessment. Cancer Epidemiol Biomarkers Prev 18:876–83. Benowitz NL, Dains KM, Hall SM, Syewart S, Wilson M, Dempsey D, et al. (2012) Smoking behavior and exposure to tobacco toxicants during 6 months of smoking progressively reduced nicotine content cigarettes. Cancer Epidemiol Biomarkers Prev 21:761–9. Benowitz NL, Nardone N, Dains KM, Hall SM, Stewart S, Dempsey D, et al. (2015) Effect of reducing the nicotine content of cigarettes on smoking behavior and tobacco smoke toxicant exposure: 2-year follow up. Addiction. doi: 10.1111/add.12978. Butschky M, Bailey D, Henningfield JE, Pickworth WB (1995) Smoking without nicotine delivery decreases withdrawal in 12-hour abstinent smokers. Pharmacol Biochem Behav 50:91–96. Carter LP, Stitzer ML, Henningfield JE, O’Connor RJ, Cummings KM, Hatsukami DK (2009) Abuse liability assessment of tobacco products including potential reduced exposure products. Cancer Epidemiol Biomarkers Prev 18:3241–62. Department of Health and Human Services (1988) The health consequences of smoking: nicotine addiction. A report of the Surgeon General. Rockville, Maryland: Department of Health and Human Services, Public Health Service, Centers for Disease Control, Office on Smoking and Health; 1988 ·86·
References
Department of Health and Human Services (2014) The health consequences of smoking—50 years of progress: a report of the Surgeon General. Rockville, Maryland; 874. Donny EC, Houtsmuller E, Stitzer ML (2007) Smoking in the absence of nicotine: behavioral, subjective and physiological effects over 11 days. Addiction 102:324–34. Donny EC, Taylor TG, Le Sage MG, Levin M, Buffalari DM, Joel D, et al. (2012) Impact of tobacco regulation on animal research: new perspectives and opportunities. Nicotine Tob Res 14:1319–38. Donny, E.C., Hatsukami, D.K., Benowitz, N.L., Sved, A.F., Tidey, J.W., Cassidy, R.N. (2014) Reduced nicotine product standards for combustible tobacco: Building an empirical basis for effective regulation. Preventive Medicine, epub ahead of print June 23. Eissenberg T, Adams C, Riggins EC 3rd, Likness M (1999) Smokers’ sex and the effects of tobacco cigarettes: subject-rated and physiological measures. Nicotine Tob Res 1:317–24. Fant RV, Everson D, Dayton G, Pickworth WB, Henningfield JE (1996) Nicotine dependence in women. J Am Med Women Assoc 51:19–20, 22–4, 28. Gray N, Henningfield JE, Benowitz NL, Connolly GN, Dresler C, Fagerstrom K, et al. (2005) Toward a comprehensive long term nicotine policy. Tob Control 14:161–5. Gritz ER, Nielsen IR, Brooks LA (1996) Smoking cessation and gender: the influence of physiological, psychological, and behavioral factors. J Am Med Women Assoc 51:35–42. ·87·
Advisory Note: Global Nicotine Reduction Strategy
Guillem K1, Vouillac C, Azar MR, Parsons LH, Koob GF, Cador M, et al. (2005) Monoamine oxidase inhibition dramatically increases the motivation to self-administer nicotine in rats. J Neurosci 25:8593–600. Hatsukami DK, Perkins KA, Le Sage MG, Ashley DL, Henningfield JE, Benowitz NL, et al. (2010a) Nicotine reduction revisited: science and future directions. Tob Control 19:e1–10. Hatsukami DK, Hertsgaard LA, Vogel RI, Jensen JA, Murphy SE, Hecht SS, et al. (2010b) Reduced nicotine content cigarettes: effects on toxicant exposure, dependence and cessation. Addiction 105:343–55. Hatsukami DK, Biener L, Leischow SJ, Zeller MR (2012) Tobacco and nicotine product testing. Nicotine Tob Res 14:7–17. Hatsukami DK, Benowitz NL, Donny E, Henningfield J, Zeller M (2013a) Nicotine reduction: strategic research plan. Nicotine Tob Res 15:1003–13. Hatsukami DK, Hertsgaard LA, Vogel RI, Jensen JA, Murphy SE, Hecht SS, et al. (2013b) Reduced nicotine content cigarettes and nicotine patch. Cancer Epidemiol Biomarkers Prev 22:1015–24. Hatsukami DK, Heishman SJ, Vogel RI, Denlinger RL, Roper-Batker AN, Mackowick KM, et al. (2013c) Dose response effects of Spectrum research cigarettes. Nicotine Tob Res 15:1113–21. Hatsukami DK, Donny EC, Koopmeiners JS, Benowitz NL (2015) Compensatory smoking from gradual and immediate reduction in cigarette nicotine content. Cancer Epidemiol Biomarkers Prev 24:472–6. Henningfield JE, Kozlowski LT Benowitz NL (1994) A proposal to develop meaningful labeling for cigarettes. J Am Med Assoc 272:312–4. ·88·
References
Henningfield JE, Benowitz NL, Slade J, Houston TP, Davis RM, Deitchman SD (1998) Reducing the addictiveness of cigarettes. Council on Scientific Affairs, American Medical Association. Tob Control 7:281–93. Henningfield JE, Hatsukami DK, Zeller M, Peters E (2011) Conference on abuse liability and appeal of tobacco products: conclusions and recommendations. Drug Alcohol Depend 116:1–7. Johnson MW, Bickel WK, Kirshenbaum AP (2004) Substitutes for tobacco smoking: a behavioral economic analysis of nicotine gum, denicotinized cigarettes, and nicotine-containing cigarettes. Drug Alcohol Depend 74:253–64. Joossens L, Raw M (2008) Progress in combating cigarette smuggling: controlling the supply chain. Tob Control 17:399–404. Kassel JD, Evatt DP, Greenstein JE, Wardle MC, Yates MC, Veilleux JC (2007) The acute effects of nicotine on positive and negative affect in adolescent smokers. J Abnorm Psychol 116:543–53. Kozlowski LT, O’Connor RJ (2002) Cigarette filter ventilation is a defective design because of misleading taste, bigger puffs, and blocked vents. Tob Control 11(Suppl 1):I40–50. Le Houezec J, McNeill A, Britton J (2011) Tobacco, nicotine and harm reduction. Drug Alcohol Rev 30:119–23. McNeill A, Hammond D, Gartner C (2012) Whither tobacco product regulation? Tob Control 21:221–6. Morrison B (2013) Modeling the benefits of a nicotine standard for tobacco products sold in Canada (abstract). In: Benefit–cost analysis for evidence-based decision making, Sixth Annual Conference and ·89·
Advisory Note: Global Nicotine Reduction Strategy
Meeting of the Society for Benefit-Cost Analysis. Seattle, Washington: Society for Benefit-Cost Analysis, Evans School of Public Affairs, University of Washington (http://benefitcostanalysis.org/system/files/ SBCA14_Program_Book_Final2.pdf). National Cancer Institute (2001) Risks associated with smoking cigarettes with low tar machine- measured yields of tar and nicotine (Monograph 13). Bethesda, Maryland. National Institute on Drug Abuse (2014) Media guide: The science of drug abuse and addiction: the basics. Bethesda, Maryland (http://www. drugabuse.gov/publications/media-guide/science- drug-abuse-addiction-basics, accessed 24 July 2015). O’ Connor RJ (2012) Non-cigarette tobacco products: what have we learnt and where are we headed? Tob Control 21:181–90. Palmatier MI, Coddington SB, Liu X, Donny EC, Caggiula AR, Sved AF (2008) The motivation to obtain nicotine-conditioned reinforcers depends on nicotine dose. Neuropharmacology 55:1425–30. Panzano VC, Wayne GF, Pickworth WB, Connolly GN (2010) Human electroencephalography and the tobacco industry: a review of internal documents. Tob Control 19:153–9. Perkins KA (2009). Sex differences in nicotine reinforcement and reward: influences on the persistence of tobacco smoking. In: Bevins R, Caggiula R, Eds. The motivational impact of nicotine and its role in tobacco use. New York: Springer-Verlag: 143–69. Perkins KA, Donny E, Caggiula AR (1999) Sex differences in nicotine effects and self-administration: review of human and animal evidence. ·90·
References
Nicotine Tob Res 1:301–15. Perkins KA, Doyle T, Ciccocioppo M, Conklin C, Sayette M, Caggiula A (2006) Sex differences in the influence of nicotine dose instructions on the reinforcing and self-reported rewarding effects of smoking. Psychopharmacology 184:600–7. Rose JE (2006) Nicotine and nonnicotine factors in cigarette addiction. Psychopharmacology 184:274–85. Rose JE, Behm FM, Westman EC, Bates JE, Salley A (2003) Pharmacologic and sensorimotor components of satiation in cigarette smoking. Pharmacol Biochem Behav 76:243–50. Schuster CR, Henningfield J (2003) Conference on abuse liability assessment of CNS drugs. Drug Alcohol Depend 70(3 Suppl):S1–4. Smith TT, Levin ME, Schassburger RL, Buffalari DM, Sved AF, Donny EC (2013) Gradual and immediate nicotine reduction result in similar low-dose nicotine self-administration. Nicotine Tob Res 15:1918–25. Smith TT, Schassburger RL, Buffalan DM, Sved AF, Donny EC (2014) Low-dose nicotine self- administration is reduced in adult male rats naive to high doses of nicotine: implications for nicotine product standards. Exp Clin Psychopharmacol 22:453–9. Sofuoglu M, LeSage MG (2012) The reinforcement threshold for nicotine as a target for tobacco control. Drug Alcohol Depend 125:1–7. Sofuoglu M, Yoo S, Hill KP, Mooney M (2008) Self-administration of intravenous nicotine in male and female cigarette smokers. Neuropsychopharmacology 33:715–20. Sorge RE, Clarke PB (2009) Rats self-administer intravenous nicotine de·91·
Advisory Note: Global Nicotine Reduction Strategy
livered in a novel smoking- relevant procedure: effects of dopamine antagonists. J Pharmacol Exp Ther 330:633–40. Tengs TO, Ahmad S, Savage JM, Moore R, Gage E (2005) The AMA proposal to mandate nicotine reduction in cigarettes: a simulation of the population health impacts. Prev Med 40:170–80. Vogel RI, Hertsgaard LA, Dermody SS, Luo X, Moua L, Allen S, et al. (2014) Sex differences in response to reduced nicotine content cigarettes. Addict Behav 39:1197–204. Watson NL, Carpenter MJ, Saladin ME, Gray KM, Upadhyaya HP (2010) Evidence for greater cue reactivity among low-dependent vs. high-dependent smokers. Addict Behav 35:673–7. Wayne GF, Carpenter CM (2009) Tobacco industry manipulation of nicotine dosing. Handb Exp Pharmacol 192:457–85. Wetter DW, Kenford SL, Smith SS, Fiore MC, Jorenby DE, Baker TB (1999) Gender differences in smoking cessation. J Consult Clin Psychol 67:555–62. WHO (1992) International classification of diseases and related health problems, 10th rev. Geneva. WHO (2001) Advancing knowledge on regulating tobacco products. Geneva: Tobacco Free Initiative (http://www.who.int/tobacco/media/en/ OsloMonograph.pdf). WHO (2002) SACTob recommendation on nicotine and the regulation in tobacco and non-tobacco products. Geneva: Scientific Advisory Committee on Tobacco Product Regulation, Tobacco Free Initiative (http://apps.who.int/iris/handle/10665/42780). ·92·
References
WHO (2003a) SACTob conclusions on health claims derived from ISO/ FTC method to measure cigarette yield. Geneva: Scientific Advisory Committee on Tobacco Product Regulation, Tobacco Free Intitiative (http://www.who.int/tobacco/global_interaction/tobreg/en/iso_ ftc_ en.pdf) WHO (2003b) Framework Convention on Tobacco Control. Geneva: Tobacco Free Initiative (http://www.who.int/fctc/en/). WHO (2006) WHO Expert Committee on Drug Dependence: Thirty-fourth report. Geneva (WHO Technical Report Series, No. 942). WHO (2007) The scientific basis of tobacco product regulation. Ge neva (WHO Technical Report Series, No. 945). WHO (2009) The scientific basis of tobacco product regulation. Third report of a WHO study group. Geneva (WHO Technical Report Series, No. 955). WHO (2012a) The scientific basis of tobacco product regulation. Fourth report of a WHO study group. Geneva (WHO Technical Report Series, No. 967). WHO (2012b) Partial guidelines for implementation of Articles 9 and 10 of the WHO Framework Convention on Tobacco Control. Geneva: Tobacco Free Initiative (http://www.who.int/fctc/ guidelines/adopted/ article_9and10/en). WHO (2014a) Standard operating procedure for determination of nicotine in cigarette tobacco filler. Geneva (WHO TobLabNet Official Method SOP 04). WHO (2014b) Electronic nicotine delivery systems. In: Report of the Sixth ·93·
Advisory Note: Global Nicotine Reduction Strategy
Session of the Conference of the Parties to the WHO Framework Convention on Tobacco Control (FCTC/ COP/6/10 Rev.1). Geneva: Tobacco Free Initiative. WHO (2015) The scientific basis of tobacco product regulation. Fifth report of a WHO study group. Geneva (WHO Technical Report Series, No. 989). Zeller M, Hatsukami D (2009) The strategic dialogue on tobacco harm reduction: a vision and blueprint for action in the US. Tob Control 18:324–32. Ziedonis D, Hitsman B, B eckham JC, Zvolensky M, Adler LE, Audrain-McGovern J, et al. (2008) Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res 10:1691–715.
·94·