108 smokers die every minute Facts & Numbers1.25 billion smokers Worldwide30 million smokers added every year84% of smokers live in developing countriesAfrica & Middle East (17% of World’s population) accounts for 7% of World’s total cigarette consumption8 smokers die every minuteOne-third of the world's adult population are smokers (57% of these are men, 43% are women) and each year, tobacco causes 3.5 million deaths a year, or about 10,000 deaths each day. It is predicted that in 20 years this yearly death rate from tobacco use will be more than 10 million people.Here are some worldwide alarming statistics stated by the World Heart Foundation:1.25 billion smokers Worldwide30 million new smokers are added every year84% of smokers live in developing countries.Africa & Middle East, representing 17% of World’s population, accounts for 7% of World’s total cigarette consumption.8 smokers die every minute.The picture on the right is taken from the 1996 Guinness Book of Records. It is for Stefan Sigmond, who is a 29 years old man, from Cluj in Transylvania. Stefan set a record in Bucharest on January 31st, 1996, when he smoked 800 filter-tipped western cigarettes in less than 6 minutes through a special wheel-like device, breaking his 1995 record of 750.In 1995 he ate 29 boiled eggs in 4 minutes and – separately – jumped into a lake from a 135 feet (41 meters)-high platform. He will not, however, appear in the Guinness Book of Records which now discourages gluttony and fool hardiness. AP; R 2 FebVoute J, World Heart Foundation
11Tobacco – a major health problem now and for the future A startling fact to set the scene.Tobacco is a major public health issue globally and specifically within developing countriesWHO estimates that by 2030 over 80% of tobacco related deaths will be in the developing world
12One out of two lifelong adult smokers will die from a smoking related disease. CDC. Projected smoking-related deaths among youth – United States. MMWR 1996;45(44):
13Gender-specific Smoking Prevalence Across the World 1.25 billion smokers worldwide1Sweden17%18%Iceland25%20%Canada22%17%Russian Federation60%16%Belarus53%7%France30%21%Germany37%28%US24%19%Portugal33%10%China67%2%Spain39%25%Italy33%17%Iran22%2%Mexico13%5%Egypt45%12%India47%17%Philippines41%8%Key PointsWorldwide, there are marked difference in smoking prevalence between men and womenSmoking prevalence is much lower in women (vs men) in South Africa, the Philippines, China, Iran, and PortugalSmoking prevalence is only slightly lower in women (vs men) in the US, Canada, Australia, and IcelandOverall, the prevalence of smoking in men is decliningSmoking prevalence in women is declining is some countries (US, UK, Australia, and Canada)However, smoking prevalence in women is either remaining constant or increasing in several Southern, Central, and Eastern European countriesReference1. Mackay J, Eriksen M, Shafey O. The Tobacco Atlas. Second Ed. American Cancer Society Myriad Editions Limited. Atlanta, Georgia, Also available online at:Brazil22%14%Kenya21%1%MenWomenAustralia19%16%South Africa23%8%Chile48%37%Mackay J, Eriksen M. The Tobacco Atlas. Second Ed. American Cancer Society, 2006.
15Smoking and coronary artery disease HistoryEpidemiologyCV EffectsImportance of Cessation
16Smoking: Leading Preventable Cause of Disease and Death1 CancerLung (#1)Leukemia (AML, ALL, CLL)2-4Oral cavity/pharynxLaryngealEsophagealStomachPancreaticKidneyBladderCervicalOtherAdverse surgical outcomes/wound healingHip fracturesLow-bone densityCataractPeptic ulcer disease in Helicobacter pylori-positive patientsReproductiveLow-birth weightPregnancy complicationsReduced fertilitySIDSCardiovascularIschemic heart disease (#2) Stroke – vascular dementia5Peripheral vascular disease6Abdominal aortic aneurysmRespiratoryCOPD (#3)PneumoniaPoor asthma controlKey PointsSmoking has been causally linked to a host of cardiovascular, respiratory, reproductive, and other conditions, as well as many types of cancerThese diseases affect smokers of all ages, but …Increases in a smoker’s age correlate with increased frequency of smoking-related diseasesBackgroundIn 2004, the US Surgeon General published a report on the health effects of active smoking1, focusing specifically on the evidence for a causal relationship between smoking and disease and death. According to the research summarised in the report, many serious conditions are caused by smoking, including cardiovascular, respiratory, reproductive, and other conditions, as well as cancer affecting diverse areas and organs of the body. In addition to the widely known consequences of lung cancer and respiratory disease, smoking has been causally linked to such diverse morbidities as low-bone density, nuclear cataract, bladder cancer, and reduced fertility. Other studies have linked smoking to vascular dementia5 and peripheral arterial disease.7 These conditions can affect young and middle-aged smokers and, in general, as a smoker’s age increases, the frequency of smoking-caused diseases rises.ReferencesSurgeon General’s Report. The Health Consequences of Smoking; 2004.Sandler DP, et al. J Natl Cancer Inst. 1993;85:Crane MM, et al. Cancer Epidemiol Biomarkers Prev. 1996;5:Miligi L, et al. Am J Ind Med. 1999;36:60-69.Roman GC. Cerebrovasc Dis. 2005;20:Willigendael EM, et al. J Vasc Surg. 2004;40:AML = acute myeloid leukemia; ALL = acute lymphocytic leukemia; CLL = chronic lymphocytic leukemia;COPD = chronic obstructive pulmonary disease; SIDS = sudden infant death syndrome.Surgeon General’s Report. The Health Consequences of Smoking; 2004.Sandler DP, et al. J Natl Cancer Inst. 1993;85:Crane MM, et al. Cancer Epidemiol Biomarkers Prev. 1996;5:Miligi L, et al. Am J Ind Med. 1999;36:60-69.Roman GC. Cerebrovasc Dis. 2005;20:Willigendael EM, et al. J Vasc Surg. 2004;40:
17Published 2004 The INTERHEART Study Finding: Nine potentially modifiable risk factors are strongly associated with AMI worldwide
18INTERHEART: Smoking and MI Odds of myocardial infarction24816OR (99% CI)> #cigarettes smoked per day
20Cardiovascular Risk Factors 8422 Men Age Followed for 72,011 person-yearsSmoking > 1 ppdWeight > 129% ideal vs < 112%Cholesterol > 268 vs < 219Systolic BP > 150 vs < 130Diastolic BP > 94 vs < 80Relative Risk of Major Coronary EventsThere are also interactions between risk factors.The Pooling Project Research Group. J Chron Dis 1978;31:
21WHO top ten causes of death3 Smoking Is Related To 5 of the Top 10 Leading Causes of Death Worldwide11 in 10 adult deaths are smoking-related2500,000,000 people alive today will die from smoking-related causes2WHO top ten causes of death3Smoking has been found to be causally related to 5 of the top 10 leading causes of death worldwide. These 5– Ischemic Heart Disease, Cerebrovascular disease, COPD, Lung Cancer, Stomach Cancer – are highlighted in orange in the graph above.Note – the graph displays overall numbers of deaths, which includes but is not limited to those that are directly attributable to smoking.ReferencesUS Department of Health and Human Services. The Health Consequences of Smoking. A Report of the Surgeon General. Atlanta, Ga: Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2004.The World Bank Curbing the epidemic: governments and the economics of tobacco control. Washington, D.C.World Health Organization. World Health Report: 2003: Shaping the Future.Causes Related to Smoking1. Surgeon General’s Report, World Bank, World Health Organization, 2003.
22How does smoking induce ACS ? PlateletViscosityfunctionEndothelialfunctionCoagulationCollagen(PAI-1)MacrophagesInflammation(hs-CRP, cytokine,chemokine)MMPsSmoothLDL-Cmuscle cellsHDL-CTG
26Tobacco associated mortality in Mumbai (Bombay) India Tobacco associated mortality in Mumbai (Bombay) India. Results of the Bombay Cohort StudyGupta PC, Pednekar MS, Parkin DM, Sankaranarayanan RBackground Little is known about the excess mortality from forms of tobacco use other than cigarette smoking that are widely prevalent in India, such as bidi smoking and the various forms of smokeless tobacco use. We report on absolute and relative risks of mortality among various kinds of ever tobacco users vs never-users in the city of Mumbai, India. (n=99570)Results The adjusted relative risk was 1.37 (95% CI 1.23–1.53) for (men) cigarette smokers and 1.64 (95% CI 1.47–1.81) for bidi smokers, with a significant dose–response relationship for number of bidis or cigarettes smoked. Women were essentially smokeless tobacco users; the adjusted relative risk was 1.25 (95% CI 1.15–1.35).Conclusions Bidi is no less hazardous than cigarette smoking, and smokeless tobacco use may also result in significantly increased mortality.Intl J Epidemiol 2005;43(6):
27Smokeless tobacco and health in India and South Asia Prakash C. GUPTA, Cecily S. RAYAbstract: South Asia is a major producer and net exporter of tobacco. Over one-third of tobacco consumed regionally is smokeless. Traditional forms like betel quid, tobacco with lime and tobacco tooth powder are commonly used and the use of new products is increasing, not only among men but also among children, teenagers, women of reproductive age, medical and dental students and in the South Asian diaspora. Smokeless tobacco users studied prospectively in India had age-adjusted relative risks for premature mortality of 1.2–1.96 (men) and 1.3 (women). Current male chewers of betel quid with tobacco in case-control studies in India had relative risks of oral cancer varying between 1.8–5.8 and relative risks for oesophageal cancer of 2.1–3.2. Oral submucous fibrosis is increasing due to the use of processed areca nut products, many containing tobacco. Pregnant women in India who used smokeless tobacco have a threefold increased risk of stillbirth and a two- to threefold increased risk of having a low birthweight infant. In recent years, several states in India have banned the sale, manufacture and storage of gutka, a smokeless tobacco product containing areca nut. In May 2003 in India, the Tobacco Products Bill 2001 was enacted to regulate the promotion and sale of all tobacco products. In two large-scale educational interventions in India, sizable proportions of tobacco users quit during 5–10 years of follow-up and incidence rates of oral leukoplakia measured in one study fell in the intervention cohort. Tobacco education must be imparted through schools, existing government health programmes and hospital outreach programmes.Respirology 2003;8(4):419-31
28Tobacco consumption is a major source of mortality and morbidity in India. Studies have shown contradictory results regarding smokeless tobacco use as a cardiovascular risk factor, but many show conclusive connection.2003 Study of adults males in a rural village in Haryana, northern India (chosen randomly)
29Prevalence of tobacco use in study population (N=443): Non-user of tobacco %Smokeless tobacco user (exclusive) 21%Smoker of tobacco (exclusive) 33%Both smoker and smokeless tobacco user 19.4%Exclusive ST User N=93 (21%)Non User of tobacco N=118 (26.6%)P valueMean body weight (kg)51.8 ±10.453.2 ±12.50.386Family history of HTN5.4% (n=5)6.77% (n=8)0.779Regular exercise12.9% (n=12)11.8% (n=14)0.835Mean systolic BP (mmHg)139.2 ±17.4135.7 ±18.80.16Mean diastolic BP (mmHg)86.8 ±11.582.6 ±11.50.01Systolic HTN prevalence43% (n=40)36.4% (n=43)0.39Diastolic HTN prevalence40.9% (n=38)22.9% (n=27)0.0018Conclusion: Smokeless tobacco consumption is associated in this population with increased prevalence of high blood pressure, which is an indicator of increased disposition to major adverse cardiac events.Pandey A etal. Tobacco Induced Diseases 2009; 5:15
30smokeless tobaccoWith smoke-free laws, smokeless tobacco (ST) products are being marketed as smoking substitutes: snuff, chewing tobacco, spitless pouched moist snuff, compressed tobacco lozenges.A recent US study found no reduction in smoking rates among people using ST as replacement, although a previous (2006) Swedish study showed an overall country reduction in smoking with increased overall ST consumption.
31Global Common Smokeless Tobacco Products North AmericaChewing tobacco: loose leaf, plug, twist, iq’mik Snuff (spit tobacco): moist, dry Snus (drier moist snuff) Oral compressed tobacco lozengesSouth AmericaChimo, tobacco with NaHCO3, brown sugar, vanillaSwedenSnus (finely ground moist tobacco)BritainGutka (betal quid with tobacco, betel nut and slaked lime), snuffCentral AsiaGul (tobacco powder and molasses), nass or naswar, niswar, pan masala or betel quid, zardaEast/SE AsiaGutka, pan masala or betel quidSouth AsiaSnuff (creamy), gul, gutka, khaini, mawa, mishri, misheri, qiwam or kima, red tooth powder, snus, snuffMiddle EastNass or naswar, niswar, shammah, zardSudanToombak (fermented ground powdered tobacco with NaHCO3
32Chemical Composition of ST Products Similar to cigarettes, nicotine is the principal alkaloidAmount of total and free nicotine varies substantially - generally, concentration similar in oral snuff and cigarette tobacco, somewhat lower in chewing tobaccoMinor alkaloids: nornicotine, anatabine, anabasineCarcinogens: Combustion-derived Benzo[a]pyrene and other polycyclics lower than in cigarette smokingCarcinogens: Nitrosamines - highest known nonoccupational exposureNitrite, nitrate, formate, chloride, sulfate, phosphate
33Impact of Smokeless Tobacco Products on Cardiovascular Disease: Implications for Policy, Prevention and Treatment: A Policy Statement From The American Heart Association2010Long-term use of smokeless tobacco products increases the odds of fatal heart attack or fatal stroke (according to analysis of several studies).The AHA advises against smokeless tobacco products for smoking cessation - they are not a “safe” alternative to smoking, and carry the risk of addiction and return to smoking.
34Second-Hand Smoke (Environmental Tobacco Smoke “ETS” – Passive Smoking) Secondhand smoke is a mixture of the smoke given off by the burning end of a cigarette, pipe or cigar and the smoke exhaled from the lungs of smokers.It is involuntarily inhaled by nonsmokers, lingers in the air hours after cigarettes have been extinguished and can cause or exacerbate a wide range of adverse health effects, including Cardiovascular cancer, respiratory infections, and asthma.California Environmental Protection Agency.Identification of Environmental Tobacco Smoke as a Toxic Air Contaminant. Executive Summary. June 2005.
35The Effects of Second-Hand Smoke Short-term effects of second-hand smoke:CoughingHeadacheEye irritationSore throatSneezing and runny noseFeeling sickBreathing problems (and possibly an asthma attack)Irregular heartbeat (a particular problem for people with heart disease)Long-term effects of second-hand smoke:Worsening of chest problems and allergies like asthma, hay fever,bronchitis and emphysemaIncreased risk of heart diseaseIncreased risk of lung cancerPregnant women exposed to second hand smoke can pass on the harmful gases and chemicals onto their babies.
36Coronary heart disease The health consequences of smoking and second hand smoke evolve over a lifetime.PregnancyInfant healthChild HealthandSmokingPhysical GrowthBehavior and cognitivedevelopmentRespiratory infectionsMore hospitalizationFetal growthBirth weightAbortionsPremature BirthFetal DeathSIDSAdulthoodAdolescenceChronic bronchitisEmphysemaLung cancer by 20%–30%Coronary heart diseaseStrokeCOPDSmall airwaydysfunctionCoughWheezingPhlegm productionother respiratorysymptomsNews release, June 27, 2006; US Department of Health & Human Services. Available at:Mackay J, et al. The Tobacco Atlas. World Health Organization, 2006.Teo KK, et al. Lancet. 2006;368:Fagerström K. Drugs. 2002;62:1-9.Blizzard L, et al. Arch Pediatr Adolesc Med. 2004;158:Leung GM, et al. Arch Pediatr Adolesc Med. 2004;158:
37Passive Smoking and CV Disability Have a clear relationship to CV disability & mortality~ 37,000 to 40,000 people die from cardiovascular disease caused by other people’s smoke every year. Of these, 35,000 non-smokers die from coronary heart disease.Non-smoking adults exposed to secondhand or environmental tobacco smoke (ETS) have an increased risk of lung cancer and heart disease.Young children are especially vulnerable to health hazards of ETS. They are at an increased risk of respiratory illnesses as asthma, bronchitis, pneumonia, as well as sudden infant death syndrome (SIDS).Passive (= Secondhand = Environmental Smoke) has a clear relationship to CV disability & mortality.~ 37,000 to 40,000 people die from cardiovascular disease caused by other people’s smoke every year. Of these, 35,000 non-smokers die from CHD.Secondhand smoke contains >4000 chemical compounds, >60 of which are known or suspected to be human carcinogens.American Heart Association 2007
38Importance of Not Smoking During Pregnancy Rate of Infants with Low-Birth Weight* in Taiwanese Infants by Smoking Status of the Mother (N=9499)OR 1.7 (95% CI: 1.0–2.8)†18.104.22.1686810Rate of Infants With Low Birth Weight (%)NeverSmokedQuitting Smoking‡Continued SmokingOR 1.1 (95% CI: 0.9–1.4)Key PointsData were analysed from the Pregnancy Risk Assessment Monitoring System in TaiwanRates of low birth weight infants by mothers’ smoking status were assessedThe “Continued Smoking” population had a significantly higher (OR 1.7) rate of low birth weight infants than the “Never Smoked” populationHowever, the “Quitting Smoking” population (defined as quitting before or by the time of the 1st prenatal visit in the 1st trimester) did not have significantly different birth weight offspring than “Never Smoked” mothers (OR 1.1).Quitting smoking before or during the first trimester may help to decrease the odds of low birth weight infantsBackgroundUsing data from the Pregnancy Risk Assessment Monitoring System in Taipei City, Taiwan, Wen and colleagues studied the effects of smoking in 9499 women on the health of their newborns. Two-thirds of the women who smoked quit during the first trimester of pregnancy, and only 2.2% of mothers smoked throughout pregnancy. Smoking throughout pregnancy resulted in significantly reduced mean birth weight and a significant increase in the rate of infants with low-birth weight (P<0.05). However, for mothers who quit smoking early in the first trimester, mean birth weights were normal and the rate of infants with low-birth weight was reduced—although it remained significantly greater compared with the rate in mothers who never smoked.Reference1. Wen CP, Cheng TY, Lin CL, et al. The health benefits of smoking cessation for adult smokers and for pregnant women in Taiwan. Tob Control. 2005;14(Suppl 1):i56–i61.* Low birth weight defined as <2500 g† ORs of having low birth weight infants, adjusted for mothers’ age, education level, parity, and alcohol consumption level, as well as the sex of the infants‡ Before or during first trimester.Abbreviations: CI, confidence interval; OR, odds ratioWen CP, et al. Tob Control. 2005;14(Suppl 1):i56-i61.
40Smoking and coronary artery disease HistoryEpidemiologyCV EffectsImportance of Cessation
41Why Quit? Potential Health Benefits of Quitting Smoking CHD risk is similar to never smokers15 yearsLung cancer risk is 30%–50% that of continuing smokers10 yearsStroke risk returns to the level of people who have never smoked at 5–15 years post-cessation5 yearsCardiovascular Heart Disease (CHD): excess risk is reduced by 50% among ex-smokers1 year3 monthsLung function may start to improve with decreased cough, sinus congestion, fatigue, and shortness of breathKey PointsThe US Surgeon General Report and the American Cancer Society indicate that the health benefits of quitting smoking can start as early as 2 weeks and are sustainedAfter quitting smokingWithin 2 weeks to 3 months, lung function can improve and over time, can reach the levels of never smokersAfter 1 year, risk of cardiovascular heart disease (CHD) can decrease by 50% and continues to decline thereafterBetween 5-15 years, risk of stroke can become comparable to never smokersAfter 10 years, lung cancer risk is reduced to 30%-50% of continuing smokersMoreover, the risk can be reduced for cancers of the larynx, oral cavity, esophagus, pancreas, urinary bladder, and of developing ulcers of the stomach or duodenumAfter 15 years, CHD risk can return to level of never smokersBackgroundWhen gauging the health benefits from smoking cessation one is encouraged to assess both the short-term and long-term improvements. Within 2 weeks to 3 months lung function may begin to improve and there may be notable decreases in coughing, sinus congestion, fatigue, and shortness of breath.Around the year mark, coronary heart disease risk, the leading cause of death in the United States, improves with smoking cessation to a point where excess risk is reduced by 50% and continues to decline thereafter. Within the 5–15 year range, the risk of stroke for smoking cessators returns to the level of a person who has never smoked.Other potential long-term benefits include: the risk of lung cancer—the most common cause of cancer death in the United States—declines steadily after smoking cessation; and by 10 years after cessation, the risk of lung cancer is 30%-50% that of continuing smokers. And beyond this, smoking cessation may also reduce the risk of cancers of the larynx, oral cavity, esophagus, pancreas, urinary bladder, and of developing ulcers of the stomach or duodenum. Other long-term benefits include the rate of decline in lung function among former smokers returns to that of never smokers, reducing the risk of COPD. And the risk of coronary heart disease, after 15 years of abstinence, becomes similar to that of a person who has never smoked. Clearly, a patient has health benefits to gain if they successfully quit and remain quit.ReferencesUS Department of Health & Human Services. The Health Benefits of Smoking Cessation: A Report of the Surgeon General. Centers for Disease Control and Prevention (CDC), Office on Smoking and Health Available at: Accessed July 2006.American Cancer Society. Guide to Quitting Smoking. Available at:CessationUSDHHS. The Health Benefits of Smoking Cessation: A Report of the Surgeon General, Available at:American Cancer Society. Guide to Quitting Smoking. Available at:
42Quitting at Any Age May Increase Life Expectancy Age Stopped Smoking: 45–54 Years Old Results From a Study of Male Physician Smokers in the UKNonsmokersAge Stopped: 45–54Cigarette SmokersPercentage Survival from Age 50Key PointsThis prospective study investigated the impact of smoking and of quitting smoking on the overall mortality of 34,439 male doctors in the United Kingdom from 1951 to 2001Survival curves from age 45 years revealed that, compared to lifelong smokers:Nonsmokers have about a 10 year longer life expectancySmokers who stop by age 50, have a 6 year longer life expectancyThe sooner smokers quit, the more likely their life expectancy would return to that of non-smokersAlthough even quitting smoking later in life can provide benefits in life expectancyBackgroundThis prospective study by Doll and colleagues, used periodically mailed questionnaires to investigate the impact of smoking and of quitting smoking, on the overall mortality of 34,439 male doctors in the United Kingdom from 1951 to Survival curves for percentage survival from age 35 years for male physicians born in 1900–1930 revealed a 10-year shift in overall survival for those who continued smoking cigarettes vs lifelong nonsmokers. This means that, on average, participants who never smoked lived 10 years longer than those who were current smokers. By age 70 years, 81% of lifelong nonsmokers were alive vs 59% of continuing cigarette smokers. A mortality rate of approximately 75% was reached at age 80 years for smokers, but was not reached until age 90 years for nonsmokers.Reference1. Doll R, Peto R, Boreham J, Sutherland I. Mortality in relation to smoking: 50 years’ observations on male British doctors. BMJ. 2004;328:1519–1527.Age (Years)Even quitting smoking later in life can lead to longer life expectancyDoll R, et al. BMJ. 2004;328:
44Smoking bans in public places and workplaces are significantly associated with a reduction in AMI incidence, particularly if enforced over several years.
45Countries Banning Smoking in Public Places NigeriaNorway 2004ParaguayPeruPhilippines (partial)Poland (partial)Portugal 2007Puerto RicoSingaporeSerbiaSloveniaSouth Africa 2001SpainSweden (partial)Syria 2009Thailand and more!Albania 2007Andorra (partial)Argentina-Buenos Aires 2006Armenia (partial)AustraliaAustria (partial)Bahrain 2008Bosnia-Herzegv.2007Brazil 2009Bulgaria (partial)CanadaChile (partial)China (partial)Colombia 2009CroatiaCyprus 2009Czech Rep.(partial)Denmark 2007Estonia (partial)Finland 2007France 2008Germany (contested)Greece 1010GuatemalaHong Kong 2007Hungary (partial)IcelandIndia (partial)Indonesia (partial)Ireland 2004IsraelKazakhstanKenya 2007Latvia 2010Lithuania (partial)Luxemburg (partial)Macedonia 2010MaltaMalaysiaMexico 2008Monaco (partial)MontenegroMoroccoMozambique 2007Namibia 2010NetherlandsNew Zealand 2004Source: Wikipedia
46Beneficial Effects of Smoking Ban for Employees 10203040Before banAfter BanSymptoms among 67 barmen beforeand after bandyspneamorning coughcoughsputumeye irritationnose irritationthroat irritationNumber of barmen with symptomsSource:Eisner M et coll., JAMA 1998, 280,
47Smoking and coronary artery disease HistoryEpidemiologyCV EffectsImportance of CessationNicotine addiction
49WHAT IS ADDICTION?”Compulsive drug use, without medical purpose, in the face of negative consequences”Alan I. Leshner, Ph.D.Former Director, National Institute on Drug AbuseNational Institutes of HealthMany people believe that addiction is a result of weakness in character and an inability to change one’s behavior. But is it really that simple? Research contradicts this position. Nicotine addiction is a form of chronic brain disease resulting from an alteration in brain chemistry (Leshner, 1997, 1999). Dr. Alan Leshner, the former director of the National Institute on Drug Abuse, simply defines drug addiction as “compulsive use, without medical purpose, in the face of negative consequences” (Leshner, 1997).But how does human behavior fit into this equation?Leshner Al. (1997, April). Drug abuse and addiction are biomedical problems. Hosp Pract (special report):2–4.Leshner AI. (1999). Science-based views of drug addiction and its treatment. JAMA 282:1314–1316.
51NICOTINE PHARMACODYNAMICS Nicotine binds to receptors in the brain and othersites in the body.Central nervous systemCardiovascular systemExocrine glandsNicotine pharmacodynamics refers to the effects that nicotine has on the body.Nicotine is a potent agent that affects numerous organ systems, including the cardiovascular, endocrine, musculoskeletal, and neurologic systems, as shown in this diagram. Following absorption, nicotine binds to receptors in the brain and other sites in the body, inducing a variety of predominantly stimulant and, to a lesser extent, sedative effects (Taylor, 2006).Taylor P. (2006). Agents acting at the neuromuscular junction and autonomic ganglia. In Brunton LL, Lazo JS, Parker KL (eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 11th ed. New York: McGraw-Hill.Gastrointestinal systemAdrenal medullaOther:Neuromuscular junctionSensory receptorsOther organsPeripheral nervous systemNicotine has predominantly stimulant effects.
52Mechanism of Action of Nicotine in the Central Nervous System b24b2nicotinic acetylcholine receptor (nAChR)Key PointsNicotine stimulates dopamine release in areas of the brain (eg, α4β2 nicotinic acetylcholine receptors in ventral tegmental area)This stimulation is believed to cause dopamine release in the nucleus accumbensActivation of nucleus accumbens neurons may be related to the reward and satisfaction effect associated with smokingBackgroundAfter inhalation, nicotine preferentially binds to nicotinic acetylcholine receptors (nAChRs) located in the mesolimbic-dopamine system of the brain within a matter of seconds. Nicotine specifically activates 4β2 nicotinic receptors in the Ventral Tegmental Area (VTA) causing an immediate dopamine release at the Nucleus Accumbens (nAcc).1 The dopamine release is believed to be a key component of the reward circuitry associated with cigarette smoking.1Reference1. Picciotto MR, Zoli M, Changeux J. Use of knock-out mice to determine the molecular basis for the actions of nicotine. Nicotine Tob Res. 1999; Suppl 2:SNicotine binds preferentially to nAChRs in the central nervous system; one key area is the α4β2 nicotinic receptor in the VTAAfter nicotine binds to the α4β2 nAChR in the VTA, dopamine is released in the nAcc which is believed to be linked to reward
53The Cycle of Nicotine Addiction Nicotine binding causes an increase in release of dopamine1,2Dopamine gives feelings of pleasure and calmness1competitive binding of nicotine to nicotinic acetylcholine receptorscauses prolonged activation, desensitization, and upregulation2DopamineNicotineKey PointsFor most people, smoking is a nicotine addictionNicotine addiction is a cycle, as described in the slideIt begins with nicotine binding to receptors in the brainThis causes a release of dopamine, which in turn results in feelings of pleasure and calmnessA lack of nicotine (eg, during smoking abstinence) leads to dopamine decreaseCraving is increased to replenish dopamine levelsBackgroundThe binding of nicotine to its relevant receptors results in the release of multiple neurotransmitters, most critically dopamine. The release of dopamine in the nucleus accumbens neurons is thought to play a critical role in the addictive nature of nicotine. This release of dopamine requires binding of nicotine to 42 receptors.1,2Absorption of cigarette smoke from the lungs is rapid and complete, producing with each inhalation a high concentration of arterial nicotine that reaches the brain within 10 to 16 seconds. Nicotine has a terminal half-life in blood of 2 hours. Smokers therefore experience a pattern of repetitive and transient high blood nicotine concentrations from each cigarette. Nicotine’s activation of acetylcholinergic receptors induces the release of dopamine in the nucleus accumbens. This is similar to the effect produced by other drugs of misuse, such as amphetamines and cocaine. The symptoms of nicotine withdrawal are a major barrier to smoking cessation for most people. Smokers start to experience impairment of mood and performance within hours of their last cigarette. These effects are completely alleviated by smoking a cigarette. Withdrawal symptoms include irritability, restlessness, feeling miserable, impaired concentration, and increased appetite, as well as craving for cigarettes. Cravings, sometimes intense, can persist for many months.ReferencesJarvis MJ. Why people smoke. BMJ. 2004;328:Picciotto MR, Zoli M, Changeux J. Use of knock-out mice to determine the molecular basis for the actions of nicotine. Nicotine Tob Res. 1999; Suppl 2:S121-S125.Jarvis MJ. BMJ. 2004; 328:Picciotto MR, et al. Nicotine and Tob Res. 1999:Suppl 2:S121-S125.
54The Cycle of Nicotine Addiction ( continued) As nicotine levels decrease, receptorsrevert to an open state causing hyperexcitability leading to cravings1,2The dopamine decrease betweencigarettes leads to withdrawalsymptoms of irritability and stress1The smoker craves nicotine to release more dopamine to restore pleasure and calmness1DopamineNicotineKey PointsFor most people, smoking is a nicotine addictionNicotine addiction is a cycle, as described in the slideIt begins with nicotine binding to receptors in the brainThis causes a release of dopamine, which in turn results in feelings of pleasure and calmnessA lack of nicotine (eg, during smoking abstinence) leads to dopamine decreaseCraving is increased to replenish dopamine levelsBackgroundThe binding of nicotine to its relevant receptors results in the release of multiple neurotransmitters, most critically dopamine. The release of dopamine in the nucleus accumbens neurons is thought to play a critical role in the addictive nature of nicotine. This release of dopamine requires binding of nicotine to 42 receptors.1,2Absorption of cigarette smoke from the lungs is rapid and complete, producing with each inhalation a high concentration of arterial nicotine that reaches the brain within 10 to 16 seconds. Nicotine has a terminal half-life in blood of 2 hours. Smokers therefore experience a pattern of repetitive and transient high blood nicotine concentrations from each cigarette. Nicotine’s activation of acetylcholinergic receptors induces the release of dopamine in the nucleus accumbens. This is similar to the effect produced by other drugs of misuse, such as amphetamines and cocaine. The symptoms of nicotine withdrawal are a major barrier to smoking cessation for most people. Smokers start to experience impairment of mood and performance within hours of their last cigarette. These effects are completely alleviated by smoking a cigarette. Withdrawal symptoms include irritability, restlessness, feeling miserable, impaired concentration, and increased appetite, as well as craving for cigarettes. Cravings, sometimes intense, can persist for many months.ReferencesJarvis MJ. Why people smoke. BMJ. 2004;328:Picciotto MR, Zoli M, Changeux J. Use of knock-out mice to determine the molecular basis for the actions of nicotine. Nicotine Tob Res. 1999; Suppl 2:S121-S125.Jarvis MJ. BMJ. 2004; 328:Picciotto MR, et al. Nicotine and Tob Res. 1999:Suppl 2:S121-S125.
55Withdrawal Syndrome: A Combination of Physical and Psychological Conditions, Making Smoking Hard to TreatDecreased heart rateIrritability, frustration,or angerInsomnia/sleep disturbanceAnxiety(may increase or decreasewith quitting)Increased appetite or weight gainKey PointsAccording to the Diagnostic and Statistical Manual of Mental Disorders, IV-TR, during periods of abstinence, smokers can undergo nicotine withdrawal syndromeNicotine withdrawal syndrome:Can occur rapidly after a smoker attempts to quitIs characterised by a combination of physical and psychological conditionsThe typical duration of most of these symptoms is <4 weeksIncreased appetite is an exception, often lasting >10 weeksBackgroundRecognizing that nicotine withdrawal results in clinically significant impairment in a person’s ability to function, the American Psychiatric Association’s Diagnostic and Statistical Manual (DSM) classifies these symptoms as a distinct condition: nicotine withdrawal syndrome. The symptoms of nicotine withdrawal syndrome can develop rapidly after a smoker tries to quit, and characteristics include the psychological symptoms of dysphoric or depressed mood; anxiety; irritability, frustration, or anger; and restlessness or impatience and the physical symptoms of insomnia, increased appetite/weight gain, and difficulty concentrating. Although present in those who use other nicotine-containing products, the manifestations of nicotine withdrawal syndrome are more intense in individuals who smoke compared with those who use other forms of tobacco. The rapidity of onset and intensity of withdrawal syndrome in smokers may suggest a greater dependence on tobacco.1The typical duration of most of these symptoms is <4 weeks. Increased appetite is an exception, often lasting for >10 weeks. Although anxiety is listed as a classic symptom of nicotine withdrawal in the DSM, additional information is available about the relationship between anxiety and smoking. Some evidence suggests that while smokers increase their smoking when stressed, smoking does not help relieve the stress. As smokers stop smoking, levels of stress and anxiety actually decrease.2References1. Diagnostic and Statistical Manual of Mental Disorders, IV-TR. Washington, DC: APA; 2006: Available at Accessed November 7, 2006.2. West R, Shiffman S. Fast Facts: Smoking Cessation. 1st ed. Oxford, United Kingdom. Health Press LimitedRestlessness or impatienceDysphoric or depressed moodDifficulty concentratingDSM-IV-TR. APA; 2006: Available at:
5650% are likely to relapse in the first month The greatest risk of relapse is during the first three months after quitting.37% have their first lapse between 8:00pm and midnight50% are likely to relapse in the first month67% are likely to relapse in the first three monthsDSM-IV-TR. APA; 2006: Available at:
57“Nine out of ten ex-smokers who have a cigarette after quitting later return to smoking” (Brandon, 1990)
58Many Health Organizations Emphasise the Important Role Physicians Can Play in Helping Their Patients Quit SmokingWorld Health Organization1Health Professionals Against Smoking2The American Academy of Family Physicians3American Medical Association2National Institute for Health and Clinical Excellence4Key PointsLeading health organizations from around the world emphasise the physician’s role in helping their patients to quit smokingBackground:WHO: “Health workers function as exemplars and educators for their patients, and consequently should set an example by abstaining from tobacco.”Health Professional Against Smoking: “The detrimental effects of smoking constitute one of the most urgent health problems in Europe. Individual doctors have a clear duty and responsibility toward their patients in this respect. Campaigns to inform the public of the damage to health caused by smoking will not be convincing if doctors—as individuals and as a profession—are seen as smokers.”AAFP: “The American Academy of Family Physicians strongly encourages all of its members and staff to personally avoid tobacco use. The AAFP urges its members to:save lives by working toward elimination of all tobacco use;document use of tobacco products in patient charts;work cooperatively with other health professionals to provide cessation counselling and other treatments;discourage tobacco use in all public and workplace settings; and,list tobacco as a cause on death certificates when appropriate.”AMA: “Tobacco dependence is a chronic illness, much like diabetes or high blood pressure, and it requires that doctors take the same long-term treatment approach to help patients succeed.”NICE: “A body of level 1+ evidence directly applicable to UK health care settings supports the efficacy of physician advice as a brief intervention for smoking cessation.”References1. World Health Organization. Mayo report on addressing the worldwide tobacco epidemic through effective, evidence-based treatment. Report of an expert meeting, March 1999, Rochester (Minnesota) USA. Available at: Accessed July 2006.2. The American Academy of Family Physicians. Tobacco use, prevention and cessation. Available at: Accessed July 2006.3. American Cancer Society. Tobacco control strategy planning, companion guide #2: Engaging doctors in tobacco control. Available at: Accessed July 2006.4. National Institute for Health and Clinical Excellence. Brief interventions and referral for smoking cessation in primary care. Available at: Accessed August 2006.World Health Organization. Mayo report on addressing the worldwide tobacco epidemic through effective, evidence-based treatment. Report of an expert meeting, March 1999, Rochester (Minnesota) USA. Available at: Accessed July 2006.American Cancer Society. Tobacco control strategy planning, companion guide #2: Engaging doctors in tobacco control. Available at:The American Academy of Family Physicians. Tobacco use, prevention and cessation. Available at:National Institute for Health and Clinical Excellence. Brief interventions and referral for smoking cessation in primary care and other settings. Available at:
59READINESS to make a quit attempt US PHS Guideline – Treating Tobacco Use and Dependence: 2008 Update Tobacco Dependence Support – The “5 A’s”ASKabout tobacco USEADVISEtobacco users to QUITAs a final review, the 5 A’s are as follows:Ask about tobacco use.Advise tobacco users to quit.Assess readiness to make a quit attempt.Assist with the quit attempt.Arrange follow-up care.Each of these is a key component of comprehensive tobacco cessation counseling interventions.ASSESSREADINESS to make a quit attemptASSISTwith the QUIT ATTEMPTARRANGEFOLLOW-UP care
60ReferenceRigotti NA. Treatment of tobacco use and dependence. N Engl J Med. 2002;346:
61All decrease cravings, withdrawal US PHS Guideline – Treating Tobacco Use and Dependence: 2008 Update First-line Pharmacotherapies for Tobacco Dependence1Nicotine replacement therapy (NRT)PatchGumInhalerNasal spraySublingual tablets/lozengesBupropion SRChampix (Varenicline)Key PointsBased upon systematic review and meta-analyses, these are the first-line therapies recommended by the US PHS Guideline – Treating Tobacco Use and Dependence: 2008 UpdateNicotine replacement therapy comes in 5 forms1 slow-acting sustained form (patch)4 faster-acting acute forms (gum, inhaler, nasal spray, sublingual tablet/lozenge)Bupropion SR (sustained-release) is an antidepressant with an indication for smoking cessationVarenicline is an α4β2 nicotinic receptor partial agonist that was specifically designed for smoking cessationReferences1. Fiore MC, et al. Clinical Practice Guideline. Treating Tobacco Use and Dependence: 2008 Update. US Department of Health and Human Services. Public Health Service. Rockville, MDAll decrease cravings, withdrawal20-25% quit rates at 1 yearFiore MC, et al. Clinical Practice Guideline. Treating Tobacco Use and Dependence: 2008 Update. USDHHS. PHS. Rockville, MD
6221ReferencesBenowitz NL, Porchet H, Sheiner L, et al. Nicotine absorption and cardiovascular effects with smokeless tobacco use: comparison with cigarettes and nicotine gum. Clin Pharmacol Ther. 1988; 44:23-28.Schneider NG, Lunell E, Olmstead RE, et al. Clinical pharmacokinetics of nasal nicotine delivery. A review and comparison to other nicotine systems. Clin Pharmacokinet. 1996; 31:Benowitz NL. Nicotine replacement therapy: what has been accomplished – can we do better? Drugs. 1993;45:
63(varenicline) A Selective 42 Nicotinic Acetylcholine Receptor Partial Agonist
64Champix (varenicline): A Highly Selective 42 Receptor Partial Agonist NicotineVareniclineBinding of nicotine at the 42 nicotinic receptor in the Ventral Tegmental Area (VTA) is believed to cause large amounts of dopamine to be released at the Nucleus Accumbens (nAcc)Ref1/Coe/ 1/1/2/5-8Ref2/Picciotto/ S123/2/3/1-16The initial view of the mesolimbic system identifies the Ventral Tegmental Area (VT) where the 42 receptors predominate, as well as the Nucleus Accumbens (nAcc). The release of dopamine at the nAcc from the axons of the dopamine cells of the VTA is believed to produce a reward response. When nicotine binds at the 42 nicotinic receptor in the Ventral Tegmental Area (VTA), it is believed to cause release of dopamine at the Nucleus Accumbens (nAcc). Chantix was deliberately designed for the 42 receptor, as an 42 nicotinic receptor partial agonist (with dual agonist and antagonist properties) and physically prevents nicotine from binding and releases intrinsically less dopamine at the nAcc.Binding of nicotine at the 42 nicotinic receptor in the Ventral Tegmental Area (VTA) is believed to cause release of dopamine at the Nucleus Accumbens (nAcc)Varenicline is an 42 nicotinic receptor partial agonist, a compound with dual agonist and antagonist activities. This is believed to result in both a lesser amount of dopamine release from the VTA at the nAcc as well as the prevention of nicotine binding at the 42 receptors1. Coe JW et al. Presented at the 11th Annual Meeting and 7th European Conference of the Society for Research on Nicotine and Tobacco Prague, Czech Republic. 2. Picciotto MR et al. Nicotine Tob Res. 1999; Suppl 2:SReferencesCoe JW, Brooks PR, Wirtz MC, et al. Varenicline (CP-526, 555): A novel, potent, and selective nicotinic receptor partial agonist for the treatment of smoking cessation: Rationale, discovery, and mode of action. Presented at the 11th Annual Meeting and 7th European Conference of the Society for Research on Nicotine and Tobacco, March 20–23, 2005, Prague, Czech Republic.Picciotto MR, Zoli M, Changeux J. Use of knock-out mice to determine the molecular basis for the actions of nicotine. Nicotine Tob Res. 1999; Suppl 2:S
65Continuous Abstinence Champix (varenicline) Efficacy Measurements: CO-Confirmed 4-Wk Continuous Abstinence Rates Wks 9–12Ref1/Gonzalez/ 51/1/2/1-10Ref1/Gonzalez/ 51/Fig 210044.043.929.829.517.617.7204060n=352n=329n=344n=342n=341P < 0.001P < 0.001Ref2/Jorenby/ 59/1/2/10-16Ref2/Jorenby/ 60/Fig 2P < 0.001P < 0.001Continuous AbstinenceRate (%)P < 0.001P = 0.001Analyses of smoking cessation rates for the All Subjects population showed that varenicline was significantly more efficacious than placebo in all measures of abstinence, both at the end of the 12-week treatment period and during the non-pharmacologic treatment follow-up through Week 24 and Week 52. The 9-12 week Continuous Abstinence Rate is defined as the percentage of randomized subjects who abstained from smoking (not even a puff) from Week 9 through 12 of the study as confirmed by both subject self-report and by end-expiratory CO measurement of ≤10 parts per million at each clinic visit.The primary endpoint, which was abstinence from even a single puff of a cigarette (patient reported and CO-confirmed at study visits) during weeks 9, 10, 11, and 12, was nearly identical in the two studies. This Continuous Abstinence Rate was 44% in the varenicline groups. Each of the comparisons were statistically significant. Varenicline also showed significantly greater response rates vs.bupropion SR in these analyses.The studies above correspond to Study 4 and Study 5 in the Chantix full prescribing information.The most frequently reported adverse events (>10%) with Chantix were nausea, headache, insomnia, and abnormal dreams.Nausea was reported by approximately 30% of patients treated with Chantix 1 mg bid, with approximately a 3% discontinuation rate during 12 weeks of treatment. Nausea was generally described as mild or moderate and often transient. For some subjects, it was persistent over several months.Gonzales et al.Jorenby et al.VareniclineBupropion SRPlaceboThe 9-12 week Continuous Abstinence Rate is defined as the percentage of subjects who abstained from smoking (not even a puff) from Week 9 through 12 of the study as confirmed by both subject self-report and by end-expiratory carbon monoxide (CO) measurementChantix PI/ 13/1/¶1Chantix PI/ 9/1/¶51. Gonzalez D et al. JAMA. 2006;296: Jorenby DE et al. JAMA. 2006;296:56-63.ReferencesGonzalez D, Rennard SI, Billing CB, et al. Varenicline, an 42 Nicotinic Acetylcholine Receptor Partial Agonist, vs Sustained-Release Bupropion and Placebo for Smoking Cessation. JAMA. 2006;296:47-55.Jorenby DE, Hays JT, Rigotti MD, et al. Efficacy of Varenicline, an 42 Nicotinic Acetylcholine Receptor Partial Agonist, vs Placebo or Sustained-Release Bupropion for Smoking Cessation. JAMA. 2006;296:56-63.Chantix Prescribing Information. Pfizer Inc, New York, NY. (May 2006)