1 Rx for CHANGE Tobacco Cessation in Respiratory Care♪ Note to instructor(s): Please update this slide by inserting instructor name(s).

2 TRAINING OVERVIEW Epidemiology of Tobacco UseImpact of Tobacco Use on Respiratory Health Nicotine Pharmacology & Addiction Assisting Patients with Quitting Medications for Smoking Cessation ♪ Note to instructor(s): The following modules are considered core components (i.e., essential to the training): Epidemiology of Tobacco Use Impact of Tobacco Use on Respiratory Health Nicotine Pharmacology & Addiction Assisting Patients with Quitting, focusing on brief (Ask-Advise-Refer) interventions Medications for Smoking Cessation ♪ Note to instructor(s): Please update this slide to reflect the modules that you will be teaching.

3 EPIDEMIOLOGY of TOBACCO USEThis module focuses on the epidemiology of tobacco use and provides an overview of adverse health consequences associated with tobacco use.

4 All forms of tobacco are harmful.“CIGARETTE SMOKING… is the chief, single, avoidable cause of death in our society and the most important public health issue of our time.” As the former U.S. Surgeon General C. Everett Koop noted in 1982, “Cigarette smoking is the chief, single, avoidable cause of death in our society and the most important public health issue of our time” (USDHHS, 1982). The first Surgeon General’s report on smoking was published in 1964—since this time, dozens of Surgeon General’s reports have summarized the conclusive evidence from biologic, epidemiologic, behavioral, and pharmacologic studies that tobacco use is detrimental to health (USDHHS, 2010). It is well established that smoking harms nearly every organ in the body, causing a wide range of diseases and reducing quality of life and life expectancy (USDHHS, 2004, 2010). Approximately 100 million persons died due to tobacco use in the 20th century—which is just a fraction of the number that we anticipate losing during the 21st century. Currently, 5.4 million deaths occur annually worldwide due to tobacco (WHO, 2008). If urgent action is not taken, by 2030 we will witness more than 8 million deaths annually and more than 80% of those deaths will be in developing countries (WHO, 2008). If current trends continue, one billion persons worldwide will die during the 21st century as a result of tobacco use (WHO, 2008). While users of non-cigarette forms of tobacco (e.g., cigars, smokeless tobacco, pipes) often believe these products are safe (or safer), it’s important for clinicians to convey to their patients that all forms of tobacco are harmful. As the death toll continues to rise, public health advocates continue to work toward identifying effective ways to (1) prevent the onset of tobacco use and (2) help patients to cease use of all tobacco products. Health care professionals can have an important public health impact by helping to counter tobacco use. However, research studies consistently demonstrate that students in the health professions receive insufficient training for providing comprehensive tobacco cessation counseling. U.S. Department of Health and Human Services (USDHHS). (1982). The Health Consequences of Smoking: Cancer. A Report of the Surgeon General (DHHS Publication No. PHS ). Rockville, MD: Public Health Service, Office on Smoking and Health. U.S. Department of Health and Human Services (USDHHS). (2004). The Health Consequences of Smoking: A Report of the Surgeon General. Atlanta, GA: U.S. 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. U.S. Department of Health and Human Services (USDHHS). (2010). How Tobacco Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General. Atlanta, GA: U.S. 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. World Health Organization (WHO). (2008). WHO Report on the Global Tobacco Epidemic, The MPOWER package. Geneva, Switzerland: World Health Organization. C. Everett Koop, M.D., former U.S. Surgeon General All forms of tobacco are harmful.

5 TRENDS in ADULT SMOKING, by SEX—U.S., 1955–2015Trends in cigarette current smoking among persons aged 18 or older 15.1% of adults are current smokers Males Percent This graph demonstrates trends in smoking among adults in the U.S. between 1955 and 2015 (CDC, 1999; CDC, 2016). In 2015, results of the National Health Interview Survey (NHIS) indicated that approximately 36.5 million adults (15.1% of the U.S. adult population) were current smokers1 (CDC, 2016); of these, 75.7% smoked every day and 24.3% smoked some days (CDC, 2016). More men (16.7%) than women (13.6%) were current smokers (CDC, 2016). An estimated 69% of all smokers want to quit completely (CDC, 2011), and in 2012, 53% of current cigarette smokers reported having made a quit attempt for > 1 day in the past year (CDC, 2014). 1Current smokers: persons who reported having smoked 100 or more cigarettes during their lifetime and who smoked every day or some days at the time of the assessment. 2Former smokers: persons who reported having smoked 100 or more cigarettes during their lifetime but currently did not smoke. Centers for Disease Control and Prevention (CDC). (1999). Achievements in public health, 1900–1999: Tobacco use—United States, 1900–1999. MMWR 48:986–993. Centers for Disease Control and Prevention (CDC). (2011). Quitting smoking among adults—United States, 2001–2010. MMWR 60:1513–1519. Centers for Disease Control and Prevention (CDC). (2016). Current cigarette smoking among adults—United States, 2005–2015. MMWR 65;1205–1211. Centers for Disease Control and Prevention (CDC). (2014). Current cigarette smoking among adults—United States, 2005–2012. MMWR 63;29–34. Females 16.7% 13.6% Year 69% want to quit 53% tried to quit in the past year Graph provided by the Centers for Disease Control and Prevention Current Population Survey; 1965–2015 NHIS. Estimates since 1992 include some-day smoking.

6 TOTAL: >480,000 deaths annuallyANNUAL U.S. DEATHS ATTRIBUTABLE to SMOKING, 2005–2009 Percent of all smoking-attributable deaths Cardiovascular & metabolic diseases 160,600 Lung cancer 130,659 Pulmonary diseases 113,100 Second-hand smoke 41,280 Cancers other than lung 36,000 Other 1,633 33% 27% Cigarette smoking is the primary known preventable cause of premature death in the United States, with nearly one of every five deaths being smoking related (Danaei et al., 2009). This number surpasses the combined death toll due to alcohol, car accidents, suicides, homicides, HIV disease, and illicit drug use. Between 2005 and 2009, more than 480,000 deaths annually were attributable to smoking. This slide delineates the percentage of smoking-attributable deaths, by disease (USDHHS, 2014). Danaei G, Ding EL, Mozarrarian D, et al. (2009). The preventable causes of death in the United States: comparative risk assessment of dietary, lifestyle, and metabolic risk factors. PLoS Med 6(4): e U.S. Department of Health and Human Services (USDHHS). (2014). The Health Consequences of Smoking – 50 Years of Progress. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Coordinating Center for Health Promotion, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. 23% 9% 7% <1% TOTAL: >480,000 deaths annually U.S. Department of Health and Human Services (USDHHS). (2014). The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General.

7 2014 REPORT of the SURGEON GENERAL: HEALTH CONSEQUENCES OF SMOKINGMAJOR DISEASE-RELATED CONCLUSIONS: Cigarette smoking is causally linked to diseases of nearly all organs of the body, diminished health status, and harm to the fetus. Additionally, smoking has many adverse effects on the body, such as causing inflammation and impairing immune function. Exposure to second-hand smoke is causally linked to cancer, respiratory, and cardiovascular diseases, and to adverse effects on the health of infants and children. Disease risks from smoking by women have risen over the last 50 years and for many tobacco-related diseases are now equal to those for men. In 2014, the Surgeon General published a comprehensive report detailing the health consequences of smoking and the progress since 1964, when the first Surgeon General’s report on smoking was published. Major disease-related conclusions are as follows: Cigarette smoking is causally linked to diseases of nearly all organs of the body, diminished health status, and harm to the fetus. Additionally, smoking has many adverse effects on the body, such as causing inflammation and impairing immune function. Exposure to second-hand smoke is causally linked to cancer, respiratory, and cardiovascular diseases, and to adverse effects on the health of infants and children. Disease risks from smoking by women have risen over the last 50 years and for many tobacco-related diseases (lung cancer, chronic obstructive pulmonary disease, and cardiovascular diseases) are now equal to those for men. Smoking remains the leading cause of preventable death and has negative impacts on people at all stages of life. It harms unborn babies, infants, children, adolescents, adults, and seniors. U.S. Department of Health and Human Services (USDHHS). (2014). The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta, GA: U.S. 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. U.S. Department of Health and Human Services (USDHHS). (2014). The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General.

8 HEALTH CONSEQUENCES of SMOKINGCancers Bladder/kidney/ureter Blood (acute myeloid leukemia) Cervix Colon/rectum Esophagus/stomach Liver Lung Oropharynx/larynx Pancreatic Pulmonary diseases Asthma COPD Pneumonia/tuberculosis Chronic respiratory symptoms Cardiovascular diseases Aortic aneurysm Coronary heart disease Cerebrovascular disease Peripheral vascular disease Reproductive effects Reduced fertility in women Poor pregnancy outcomes (e.g., congenital defects, low birth weight, preterm delivery) Infant mortality Other: cataract, diabetes (type 2), erectile dysfunction, impaired immune function, osteoporosis, periodontitis, postoperative complications, rheumatoid arthritis The 2014 Surgeon General’s Report on the health consequences of smoking describes a long list of diseases with sufficient evidence to infer a causal relationship with smoking. These are summarized on this slide – it is clear that tobacco use negatively impacts virtually every organ system of the body. Many of these health consequences are associated with compromised respiratory health. U.S. Department of Health and Human Services (USDHHS). (2014). The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta, GA: U.S. 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. U.S. Department of Health and Human Services (USDHHS). (2014). The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General.

9 COMPOUNDS in TOBACCO SMOKEAn estimated 4,800 compounds in tobacco smoke, including 16 proven human carcinogens Gases Particles Carbon monoxide Hydrogen cyanide Ammonia Benzene Formaldehyde Nicotine Nitrosamines Lead Cadmium Polonium-210 Tobacco smoke, which is inhaled either directly or as second-hand smoke, contains an estimated 4,800 compounds. The majority of the compounds are present in the particulate phase, suspended in tobacco smoke. Based on a classification system by the International Agency for Research on Cancer, cigarette smoke contains 72 proven or suspected human carcinogens, including 16 Group 1 (proven), 9 Group 2A (probable), and 47 Group 2B (possible) (Hecht, 2012). Examples of detrimental compounds (some of which are carcinogens) in tobacco smoke include the following: Carbon monoxide: automobile exhaust; binds to hemoglobin, inhibits respiration Hydrogen cyanide: gas chamber poison; highly ciliotoxic, inhibits lung clearance Ammonia: floor/toilet cleaning agent; irritation of respiratory tract Nicotine : addictive substance; toxic alkaloid Benzene: solvent, banned substance in organic chemistry labs; Group 1 carcinogen Nitrosamines: carcinogenic in animals and probably in humans; Group 2A and 2B carcinogens Lead: heavy metal, toxic to central nervous system; Group 2A carcinogen Cadmium: heavy metal found in rechargeable batteries; Group 1 carcinogen Hexavalent chromium: highlighted in the movie Erin Brockovich; Group I carcinogen Arsenic: pesticide; Group 1 carcinogen Polonium-210: radioactive agent; Group 1 carcinogen Formaldehyde: embalming fluid; Group 1 carcinogen ♪ Note to instructor(s): It is important to emphasize that although nicotine is the addictive component of tobacco products, it does not cause the ill health effects of tobacco use. Hecht SS. (2012). Research opportunities related to establishing standards for tobacco products under the Family Smoking Prevention and Tobacco Control Act. Nicotine Tobacco Research 14(1):18–28. National Cancer Institute (NCI). (2001). Risks Associated with Low Machine-Measured Yields of Tar and Nicotine (NIH Publication No ). Smoking and Tobacco Control Monograph No. 13. Bethesda, MD: U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Nicotine is the addictive component of tobacco products, but it does NOT cause the ill health effects of tobacco use.

10 FDA REGULATION of TOBACCO PRODUCTSThe FDA Center for Tobacco Control Products is responsible for regulation of: Cigarettes Cigarette tobacco Roll-your-own tobacco Smokeless tobacco E-cigarettes* The Family Smoking Prevention and Tobacco Control Act, also referred to as the Tobacco Control Act, gives the U.S. Food and Drug Administration (FDA) authority to regulate the manufacture, distribution, and marketing of tobacco products to protect public health. This Act, which was signed into law on June 22, 2009, aims to curb the trend of new users becoming addicted to tobacco before they are old enough to understand the associated risks. Specifically, the Tobacco Control Act (FDA, 2017a): Recognizes that virtually all new users of tobacco products are under 18 – the minimum legal age to purchase these products. Many new users will become addicted before they are old enough to understand the risks and ultimately will die too young of tobacco-related diseases. The Tobacco Control Act seeks to, among other things, prevent and reduce tobacco use by these young people. Recognizes that tobacco products are legal products available for adult use, prohibits false or misleading labeling and advertising for tobacco products and provides the tobacco industry with several mechanisms to submit an application to FDA for new products or tobacco products with modified risk claims. Gives FDA enforcement authority as well as a broad set of sanctions for violations of the law, and directs FDA to contract with states to assist FDA with retailer inspections. The list of products regulated by the FDA Center for Tobacco Products is shown on this slide. E-cigarettes (and other electronic nicotine delivery devices), which technically are not tobacco products, are now also regulated by the FDA Center for Tobacco Control Products (FDA, 2017b). ♪ Note to instructor(s): For more details regarding what the act does, and does not do, go to ♪ Note to instructor(s): To learn more about current FDA regulatory activities surrounding electronic cigarettes (e-cigarettes), go to U.S. Food and Drug Administration (FDA). (2017a). Family Smoking Prevention and Tobacco Control Act. Available at: Retrieved January 21, 2017. U.S. Food and Drug Administration (FDA). (2017b). Electronic Cigarettes (e-Cigarettes). Available at: Retrieved January 21, 2017. *Not a tobacco product.

11 ELECTRONIC CIGARETTES (“e-cigarettes”)Battery-operated devices Known to contain nicotine (0–36 mg/ml), flavoring (e.g., tobacco, fruit, chocolate, mint, cola), propylene glycol, and glycerin Battery warms cartridge; user inhales nicotine vapor or “smoke” Heating element vaporizes liquid at temperatures of 65–120°C Not labeled with health warnings Electronic cigarettes (“e-cigarettes”) are battery-operated devices that generally contain cartridges filled with nicotine (0–36 mg/ml), flavor, and other chemicals including propylene glycol and glycerin. The e-cigarette warms the cartridge, turning the nicotine and other chemicals into a vapor that is then inhaled by the user. These products, which are readily available online and in shopping malls, do not contain health warnings that are comparable to conventional cigarettes or FDA-approved nicotine replacement therapy products. They are also available in different flavors, such as chocolate and mint, which might appeal to youth. Public health experts are concerned that e-cigarettes could increase nicotine addiction and tobacco use in young people (FDA, 2009a). FDA laboratory analysis (FDA, 2009b) has identified toxic chemicals such as diethylene glycol (used in antifreeze) and carcinogens (including nitrosamines). Cartridges labeled as containing “no nicotine” had low levels of nicotine in all cartridges tested, except one. Manufacturing quality-control measures are virtually nonexistent. On September 9, 2010, the FDA announced that it had taken enforcement action against five e-cigarette companies for violations of the Federal Food, Drug, and Cosmetic (FD&C) Act, including unsubstantiated claims and poor manufacturing practices (FDA, 2010). However, on April 25, 2011, the FDA announced in a letter to stakeholders that it will not appeal the recent decision by the U.S. Court of Appeals for the D.C. Circuit in Sottera, Inc. v. Food & Drug Administration, 627 F.3d 891 (D.C. Cir. 2010) , stating that e-cigarettes and other products are not drugs/devices unless they are marketed for therapeutic purposes, but that products “made or derived from tobacco” can be regulated as “tobacco products” under the FD&C Act (FDA, 2011). The FDA is aware that certain products made or derived from tobacco, such as e-cigarettes, are not currently subject to pre-market review requirements of the Family Smoking Prevention and Tobacco Control Act.  On September 24, 2013, a letter from the National Association of Attorneys General was addressed to the commissioner of the FDA urging the FDA to regulate e-cigarettes, especially the advertising of the products to youth. In the letter, attorneys general argued that the FDA has the authority to regulate e-cigarettes as “tobacco products” under the Tobacco Control Act , since they are products “made or derived from tobacco” that are not a “drug,” “device,” or combination product. Writers of the letter cited Sottera, Inc. v. Food & Drug Administration as support to further the contention that e-cigarettes are “made or derived from tobacco” and can be regulated as “tobacco products” under the Tobacco Control Act. The letter concluded with a message to the FDA urging the agency to ensure that all tobacco products are tested and regulated to ensure that companies do not continue to advertise to youth. ♪ Note to instructor(s): The literature is moving very rapidly on this topic. Please consult current references for more up-to-date information. U.S. Food and Drug Administration (FDA). (2009a, July 22). FDA and public health experts warn about electronic cigarettes. Retrieved from U.S. Food and Drug Administration (FDA). (2009b, July 22). Summary of results: laboratory analysis of electronic cigarettes conducted by FDA. Retrieved from U.S. Food and Drug Administration (FDA). (2010, September 9). FDA acts against 5 electronic cigarette distributors. Retrieved from U.S. Food and Drug Administration (FDA). (2011, April 25). Regulation of e-cigarettes and other tobacco products. Retrieved from National Association of Attorneys General. Letter to Honorable Margaret Hamburg, Commissioner, U.S. FDA. September 24, 2013.

12 ELECTRONIC CIGARETTES: Potential Health RisksNicotine is highly addictive and can be harmful. Refill cartridges with high concentrations of nicotine are a poisoning risk, especially in children. Propylene glycol may cause respiratory irritation and increase the risk for asthma. Glycerin may cause lipoid pneumonia on inhalation. Carcinogenic substances are found in some aerosols. Use of e-cigarettes leads to emission of propylene glycol, particles, nicotine, and carcinogens into indoor air. Long-term safety of second-hand exposure to e-cigarette aerosols is unknown. Currently, e-cigarettes have not been proven to be safe. This slide lists various sources of concern. Note that propylene glycol is the main chemical ingredient in antifreeze, and the effects of inhaling it have not yet been adequately studied. In many localities, smoking bans have been expanded to include smoke emitted from electronic nicotine delivery devices. The long-term safety of second-hand exposure to e-cigarette aerosols is not known (German Cancer Research Center, 2013; Schober et al., 2014). German Cancer Research Center (Ed.). (2013). Electronic Cigarettes—An Overview. Heidelberg: Author, 2013. Schober W, Szendrei K, Matzen W, et al. (2014). Use of electronic cigarettes (e-cigarettes) impairs indoor air quality and increases FeNO levels of e-cigarette consumers. Int J Hyg Environ Health 217:628–637.

13 ELECTRONIC CIGARETTES: Current Trends and EvidenceCan reduce the desire (craving) to smoke cigarettes and alleviate nicotine withdrawal symptoms Some smokers reduce the number of cigarettes smoked or quit smoking as a result of using e- e-cigarettes Have not been proven effective as an aid for sustained smoking cessation Concern about “gateway” to tobacco use in adolescents E-cigarettes can reduce the desire (craving) to smoke cigarettes and alleviate nicotine withdrawal symptoms, and some smokers are able to reduce the number of cigarettes smoked or quit smoking as a result of using e-cigarettes. E-cigarettes are often perceived as less harmful than smoking conventional cigarettes. Of particular concern, among the public health community, is that the use of e-cigarettes is increasing among adolescents and young adults. At this time, there is insufficient evidence to ensure long-term safety or to demonstrate efficacy of e-cigarette use as an aid for cessation. Long-term safety and cessation efficacy data are lacking.

14 HERMAN ® is reprinted with permission from Although the decision to use tobacco lies in the hands of each person, regulations help to determine the extent to which nonsmokers are exposed to the harms of tobacco smoke. HERMAN ® is reprinted with permission from LaughingStock Licensing Inc., Ottawa, Canada All rights reserved.

15 There is no safe level of second-hand smoke.2006 REPORT of the SURGEON GENERAL: INVOLUNTARY EXPOSURE to TOBACCO SMOKE Second-hand smoke causes premature death and disease in nonsmokers (children and adults). Children: Increased risk for sudden infant death syndrome (SIDS), acute respiratory infections, ear problems, and more severe asthma There is no safe level of second-hand smoke. As noted previously, approximately 50,000 persons die annually in the United States due to second-hand smoke exposure (USDHHS, 2006). Despite the tobacco industry’s efforts to cast doubt on the link between second-hand smoke and health risks (USDHHS, 2006), few scientists and clinicians would deny that second-hand smoke is harmful. Major conclusions of the 2006 Surgeon General’s Report The Health Consequences of Involuntary Exposure to Tobacco Smoke (USDHHS, 2006) are as follows: Second-hand smoke causes premature death and disease in children and in adults who do not smoke. Children exposed to second-hand smoke are at an increased risk for sudden infant death syndrome (SIDS), acute respiratory infections, ear problems, and more severe asthma. Smoking by parents causes respiratory symptoms and slows lung growth in their children. Exposure of adults to second-hand smoke has immediate adverse effects on the cardiovascular system and causes coronary heart disease and lung cancer. The scientific evidence indicates that there is no risk-free level of exposure to second-hand smoke. Many millions of Americans, both children and adults, are still exposed to second-hand smoke in their homes and workplaces despite substantial progress in tobacco control. Eliminating smoking in indoor spaces fully protects nonsmokers from exposure to second-hand smoke. Separating smokers from nonsmokers, cleaning the air, and ventilating buildings cannot eliminate exposures of nonsmokers to second-hand smoke. In the 2014 Surgeon General’s Report on the health consequences of smoking, one of the major conclusions was stated as: “Exposure to secondhand tobacco smoke has been causally linked to cancer, respiratory, and cardiovascular diseases, and to adverse effects on the health of infants and children” (USDHHS, 2014). A comprehensive literature review concluded that the cardiovascular effects of second-hand smoke are substantial and rapid (Barnoya & Glantz, 2005). The effects of even brief exposure (minutes to hours) to second-hand smoke are often nearly as large (averaging 80–90%) as those related to chronic active smoking. Barnoya J, Glantz SA. (2005). Cardiovascular effects of secondhand smoke: nearly as large as smoking. Circulation 24;111:2684–2698. U.S. Department of Health and Human Services (USDHHS). (2006). The Health Consequences of Involuntary Exposure to Tobacco Smoke: A Report of the Surgeon General. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Coordinating Center for Health Promotion, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. U.S. Department of Health and Human Services (USDHHS). (2014). The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta, GA: U.S. 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. Respiratory symptoms and slowed lung growth if parents smoke Adults: Immediate adverse effects on cardiovascular system Increased risk for coronary heart disease and lung cancer Millions of Americans are exposed to smoke in their homes/workplaces. Indoor spaces: eliminating smoking fully protects nonsmokers; separating smoking areas, cleaning the air, and ventilation are ineffective. U.S. Department of Health and Human Services (USDHHS). (2006). The Health Consequences of Involuntary Exposure to Tobacco Smoke: Report of the Surgeon General.

16 EPIDEMIOLOGY of TOBACCO USE: SUMMARYFewer than one in five adults are current smokers; smoking prevalence varies by sociodemographic characteristics. Nearly half a million U.S. deaths are attributable to smoking annually. Smoking costs the U.S. an estimated $288.9 billion annually. For the individual, a smoking a pack-a-day costs $2,256 annually, plus associated health-care costs. At any age, there are benefits to quitting smoking. The biggest opponent to tobacco control efforts is the tobacco industry. To summarize: Fewer than one in five U.S. adults smoke. Nearly half a million U.S. deaths are attributable to smoking annually. Smoking costs the U.S. an estimated $288.9 billion annually. For the individual, smoking a pack-a-day costs $2,248 annually, plus associated health-care costs. There are benefits to quitting smoking at any age, but there are clear advantages to quitting earlier. The biggest opponent to tobacco control efforts is the tobacco industry, which has lied and deceived the public for decades and continues to put profits over people. Thus, it is clear that tobacco use is a significant public health problem. The morbidity and mortality associated with tobacco use can be curbed through effective tobacco prevention and cessation efforts.

17 IMPACT of TOBACCO USE on RESPIRATORY HEALTHThis module focuses on the impact of tobacco use on respiratory health, highlighting the unique and important role of respiratory therapists for smoking cessation.

18 SMOKING and RESPIRATORY DISEASEAcute respiratory diseases: increased risk, duration, severity Upper respiratory tract Rhinitis, laryngitis, pharyngitis, sinusitis Lower respiratory tract Bronchitis, pneumonia Chronic respiratory diseases Asthma Chronic obstructive pulmonary disease (COPD) Tuberculosis Lung cancer Smoking has significant adverse health effects on the upper and lower respiratory tract system (USDHHS, 2010; USDHHS, 2014). These effects can be broadly divided into two categories: acute (predominantly caused by infections) and chronic (disorders of the conducting airways and alveoli). Acute Respiratory Diseases Exposure to tobacco smoke induces a variety of acute respiratory diseases affecting both the upper and lower respiratory tracts. Toxins (particularly carbon monoxide) present in tobacco smoke paralyze cilia on columnar respiratory epithelium and compromise protective mucociliary transport host defenses. Additionally, tars in smoke concentrate in pulmonary alveolar macrophages and inhibit the phagocytic activity of these cells. The net effect is reduced host defenses against infections caused by respiratory pathogens (Kamholz, 2004). Clinically, smokers have a higher incidence of acute respiratory tract infections of the upper airways (rhinitis, laryngitis, pharyngitis, and sinusitis) and lower airways (bronchitis and pneumonia), compared to nonsmokers (USDHHS, 2010; USDHHS, 2014). Chronic Respiratory Diseases Infants exposed to maternal smoking in utero are more likely to have measurable evidence of impaired lung function, although the mechanism for this impairment is not known (USDHHS, 2014). Likewise, children, adolescents, and adults exposed to tobacco smoke are more likely to experience chronic respiratory symptoms (cough, increased phlegm production, wheezing, and dyspnea) (USDHHS, 2014). Individuals with asthma who smoke are more likely to have poor asthma control, compared to nonsmoking asthmatics. Irritants and oxidant gases present in tobacco smoke are believed to worsen airway inflammation and exacerbate bronchial hyperresponsiveness (USDHHS, 2014). Some data suggest that asthmatic smokers have a reduced therapeutic response to inhaled corticosteroids, compared to nonsmokers (Tomlinson et al., 2005). Finally, smoking is the single most important cause of chronic obstructive pulmonary disease. This topic is addressed in greater detail in subsequent slides. Kamholz SL. (2004). Pulmonary and cardiovascular consequences of smoking. Med Clin North Am 88:1415–1430. Tomlinson JE, McMahon AD, Chaudhuri R, et al. (2005). Efficacy of low and high dose inhaled corticosteroid in smokers versus non-smokers with mild asthma. Thorax 60:282–287. U.S. Department of Health and Human Services (USDHHS). (2010). How Tobacco Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General. Atlanta, GA: Author, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. U.S. Department of Health and Human Services (USDHHS). (2014). The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta, GA: Author, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

19 PNEUMONIA Smokers exhibit increased risk for pneumoniaBiologic mechanisms: Damages cilia Increases permeability of airway epithelium Enables infection to more easily enter lungs Reduces overall immune response Risk increases as number of cigarettes smoked increases Risk returns to baseline after ten years of not smoking Several studies have shown that smokers are also at a increased risk of contacting pneumonia. This is due to several biologic mechanisms; damage to the cilia, increased permeability of the epithelium and an overall decrease in immune response. Interestingly, risk increases as the number of cigarettes smoked increases. Risk returns to baseline after ten years of not smoking. Baik I, Curhan GC, Rimm EB, Bendich A, Willett WC, Fawzi WW. (2000). A prospective study of age and lifestyle factors in relation to community-acquired pneumonia in US men and women. Arch Intern Med 160(20):3082–3088. U.S. Department of Health and Human Services (USDHHS). (2014). The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta, GA: U.S. 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.

20 Patients with asthma should not smoke.An estimated 21% of patients with asthma are current smokers Smoking increases the risk of asthma exacerbations in adults Reduced response to treatment with inhaled and systemic corticosteroids Tobacco smoke is an important trigger for exacerbation of asthma, yet the estimated prevalence of smoking among U.S. adults with asthma was 21%, exceeding that in the general population (17%) (CDC, 2010). According to the U.S. Surgeon General, smoking is associated with exacerbation of asthma and poor disease control among adults (USDHHS, 2014). Furthermore, patients who smoke and have asthma have a reduced response to treatment with inhaled and systemic corticosteroids (Chalmers et al., 2002; Chaudhuri et al., 2003; Lazarus et al 2007). All patients with asthma should be strongly advised not to smoke. Centers for Disease Control and Prevention (CDC). (2010). AsthmaStats Factsheet: Percentage of People with Asthma who Smoke. Retrieved from Chalmers GW, Macleod KJ, Little SA, Thomson LJ, McSharry CP, Thomson NC. (2002). Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma. Thorax 57(3):226–230. Chaudhuri R, Livingston E, McMahon AD, Thomson L, Borland W, Thomson NC. (2003). Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am J Respir Crit Care Med 168(11):1308–1311. Lazarus SC, Chinchilli VM, Rollings NJ, et al. (2007). Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Am J Respir Crit Care Med 175(8):783–790. U.S. Department of Health and Human Services (USDHHS). (2014). The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta, GA: Author, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. Patients with asthma should not smoke.

21 ASTHMA: IN UTERO EXPOSUREMaternal smoking results in infant/child: 1.8 times increased likelihood of developing asthma as well as lifetime history of wheezing 3.6 times increased likelihood of severe asthma Deficits in lung function up to age 6 Reduction in forced expiratory flow and suppression of child’s: formation of the alveoli functional residual capacity tidal flow volume The 2004 Surgeon General’s Report on Smoking states that “The evidence is sufficient to infer a causal relationship between maternal smoking during pregnancy and a reduction of lung function in infants.” The studies cited below support this finding. Smoking mothers should be made aware of this relationship in a clear, matter of fact way, because knowing this might provide motivation to quit. Gilliland FD, Berhane K, McConnell R, et al. (2000). Maternal smoking during pregnancy, environmental tobacco smoke exposure and childhood lung function. Thorax 55:271–276. Gilliland FD, Berhane K, Li YF, et al. (2003). Effects of early onset asthma and in utero exposure to maternal smoking on childhood lung function. Am J Respir Crit Care Med 167:917–24. Li YF, Langholz B, Salam MT, et al. (2005). Maternal and grandmaternal smoking patterns are associated with early childhood asthma. Chest 127(4):1232–1241. Pattenden S, Antova T, Neuberger M, et al. (2006). Parental smoking and children’s respiratory health: independent effects of prenatal and postnatal exposure. Tob Control 15:294–301.

22 CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)Characterized by airflow limitation (not fully reversible) Progressive airflow limitation associated with abnormal inflammatory lung response to noxious particles or gases Characteristic symptoms: cough, sputum production, dyspnea COPD mortality has increased dramatically in the past 50 years; currently, more women than men die due to COPD 3rd leading cause of death in the United States Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases (NHLBI/WHO, 2005). The characteristic symptoms of COPD are chronic cough, sputum production, and dyspnea on exertion. Cough and sputum production can manifest years before the development of measurable airflow limitation (NHLBI/WHO, 2005). COPD is currently the third leading cause of death in the United States (CDC, 2013). If global tobacco use patterns remain unchanged, the World Health Organization (WHO) predicts that by 2020, COPD will be the fifth most common cause of death worldwide (NHLBI/WHO, 2005). Currently, more women than men die due to COPD. Cigarette smoking is, by far, the single most important risk factor for the development of COPD (USDHHS, 2014). Although the vast majority of patients with COPD are current or former tobacco smokers, only a fraction of smokers (15–20%) develop clinically significant COPD. This finding suggests an underlying genetic predisposition for the disease (NHLBI/WHO, 2005). The WHO cautions that the percentage of smokers who develop COPD is likely an underestimate because COPD is often underdiagnosed (NHLBI/WHO, 2005). Centers for Disease Control and Prevention (CDC). (2013). National Center for Health Statistics. National Vital Statistics Report. Deaths: Final data for Retrieved from National Heart, Lung, & Blood Institute/World Health Organization (NHLBI/WHO). (2005). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Workshop Report, Global Initiative for Chronic Obstructive Lung Disease (GOLD). Retrieved from U.S. Department of Health and Human Services (USDHHS). (2014). The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta, GA: Author, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. The primary risk factor for COPD is tobacco smoking. U.S. Department of Health and Human Services (USDHHS). (2014). The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General, p. 385.

23 COPD: BIOLOGIC MECHANISMSTobacco smoke induces inflammation and damage to pulmonary tissue through Release of inflammatory cells and mediators Imbalance between proteases and antiproteases Oxidative stress Constituents in tobacco smoke are believed to induce lung inflammation and impair normal host defense mechanisms, leading to damage of pulmonary tissues. Pathologic changes in the lung include airway narrowing and fibrosis, parenchymal destruction (emphysema), and thickening of the pulmonary vasculature. Several mechanisms are postulated to explain the pathology associated with COPD (NHLBI/WHO, 2005; USDHHS, 2014). Tobacco smoke is thought to induce inflammation and cause direct damage to pulmonary tissue through the following mechanisms: Release of inflammatory cells and mediators: Tobacco smoke appears to activate a variety of inflammatory cells including macrophages, T lymphocytes, and neutrophils. Following activation, macrophages and neutrophils release proteases that break down lung tissue. Macrophages also release mediators, including leukotriene B4 and interleukin-8, which further recruit neutrophils from the blood into the airways. The interplay of these inflammatory cells and mediators leads to the hypersecretion of mucus and destruction of lung tissue. Imbalance between proteases and antiproteases: Proteases are enzymes released from neutrophils and macrophages that cleave elastin in lung parenchymal tissue, leading to emphysema. Normally these proteases are held in check by antiproteases present in the lung, the most important of which is 1-antitrypsin. In the majority of smokers, increased levels of proteases are effectively neutralized by antiproteases, preventing lung damage. However, in a small minority of susceptible smokers, the production of antiproteases may be insufficient and COPD develops. Oxidative stress: Increasing evidence suggests that oxidative stress might play a role in the pathogenesis of COPD. Reactive oxygen species such as superoxide anion, hydrogen peroxide, hydroxyl radical, and peroxynitrate from tobacco smoke or inflammatory cells can promote inflammation and proteolysis in pulmonary tissue. National Heart, Lung, & Blood Institute/World Health Organization (NHLBI/WHO). (2005). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Workshop Report, Global Initiative for Chronic Obstructive Lung Disease (GOLD). Retrieved from U.S. Department of Health and Human Services (USDHHS). (2014). The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta, GA: Author, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. The best treatment for COPD is to quit smoking. Medications simply manage the symptoms.

24 TUBERCULOSIS Smoking is a causal risk factor for contracting TB2.0–2.6 increased risk compared to nonsmokers Risk increases with Number of cigarettes smoked Duration of smoking Exposure to second-hand smoke increases risk for TB in children Smoking is causally associated with recurrent TB and TB-related mortality As early as the 1950s, smoking was identified as a risk factor for tuberculosis (TB)-related mortality, but only recently have studies demonstrated that high rates of TB-related mortality are attributable to smoking (Jha et al., 2008). As delineated in the 2014 Surgeon General’s report (USDHHS, 2014), and in several systematic reviews cited therein, cigarette smoking is associated with an estimated doubling of the risks for TB infection, for having clinical evidence of TB, and for TB-related mortality. An analysis from WHO (2010) of the role of risk factors and social determinants in driving the global TB epidemic concluded that in the 22 countries experiencing 80% of the global TB burden, 23% of the cases can be attributed to smoking. Jha P, Jacob B, Gajalakshmi V, et al. (2008). A nationally representative case-control study of smoking and death in India. N Engl J Med 358(11):1137–1147. U.S. Department of Health and Human Services (USDHHS). (2014). The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta, GA: Author, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. World Health Organization. (2010). Global Tuberculosis Control: WHO Report Geneva (Switzerland)..

25 SMOKING and LUNG CANCERLung cancer accounts for an estimated 27% of smoking-attributable deaths Smoking cessation yields meaningful improvements in all forms of cancer treatment (surgery, chemotherapy, radiation) Early-stage non-small-cell lung cancer: 5-year survival rates are up to 70% in those who quit, versus 33% in those who do not Patients who continue to smoke are nearly 2X as likely to have a recurrence and more than 4X as likely to develop a second primary tumor It is well established that tobacco smoke is the primary risk factor for lung cancer, and lung cancer is responsible for more deaths than any other cancer in both men and women. Overall, it accounts an estimated 27% of all causes of smoking-attributable deaths in the United States (USDHHS, 2014). Smoking cessation can result in meaningful improvements in success rates for all forms of cancer treatment: surgery, chemotherapy, and radiation. Data on this slide demonstrate substantial improvement in survival rates for treatment; additionally, patients who do not quit are at a significantly higher risk for recurrence and/or development of a second primary tumor (Parsons et al., 2010). Parsons A, Dailey A, Begh R, Aveyard P. (2010). Influence of smoking cessation after diagnosis of early stage lung cancer on prognosis: systematic review of observational studies with meta-analysis. BMJ 340:b5569. U.S. Department of Health and Human Services (USDHHS). (2014). The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta, GA: Author, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

26 SMOKING and LUNG CANCER (cont’d)Despite the benefits of quitting, lung cancer patients have a high prevalence of smoking and relapse to tobacco use About 50% of lung cancer patients who quit resume smoking 39% of lung cancer physicians actively provide cessation assistance to their patients Despite the benefits of quitting, particularly in patients with early-stage lung cancer (Parsons et al., 2010), these patients exhibit a high prevalence of smoking and incidence of relapse (Walker et al., 2006). An estimated 50% resume smoking. Among oncology physicians who treat lung cancer, 81% advise patients to quit, 40% discuss medication options, 39% actively provide cessation assistance, and fewer address tobacco at follow-up visits. Only 33% report that they are adequately trained to provide cessation interventions (Warren et al., 2013), Parsons A, Dailey A, Begh R, Aveyard P. (2010). Influence of smoking cessation after diagnosis of early stage lung cancer on prognosis: systematic review of observational studies with meta-analysis. BMJ 340:b5569. Walker MS, Vidrine DJ, Gritz ER. (2006). Smoking relapse during the first year after treatment for early-stage non-small-cell lung cancer. Cancer Epidemiol Biomarkers Prev 15:2370–2377. Warren GW, Marshall JR, Cummings KM, et al. (2013). Practice patterns and perceptions of thoracic oncology providers on tobacco use and cessation in cancer patients. J Thorac Oncol 8(5):543–548.

27 EFFECT of SECOND-HAND SMOKE on CYSTIC FIBROSIS PATIENTSFor every 10 cigarettes/day smoked in household: FEV1 decreased by 4% FVC decreased by 3% Increase in coughing and severity of respiratory illnesses Fivefold increase in pulmonary-related hospitalizations Exposure to second-hand smoke has profound effects on patients with cystic fibrosis, with an increase in exposure associated with a progressive decrease in both FEV1 and FVC (Collaco et al., 2008; Kopp et al., 2015). These patients should be strongly advised to avoid all exposure to all forms of smoke. Collaco JM, Vanscoy L, Bremer L, et al. (2008). Interactions between secondhand smoke and genes that affect cystic fibrosis lung disease. JAMA 299(4):417–424. Kopp BT, Sarzynski L, Khalfoun S, et al. (2015). Detrimental effects of secondhand smoke exposure on infants with cystic fibrosis. Pediatr Pulmonol 50(1):25–34.

28 THIRD-HAND SMOKE The residual chemicals from smoking that deposit on clothing, hair, skin, and other surfaces Contains more than 250 harmful chemicals; can last for days or weeks Can cause respiratory irritation and is particularly dangerous to infants While most adults know that second-hand smoke is harmful, few know about third-hand smoke Third-hand smoke is the chemical residue from smoking that is left on clothing, hair, skin, and other surfaces after a cigarette is extinguished. This can be a source of long-term exposure to pollutants, thereby impacting health (Sleiman et al., 2014), including respiratory irritation, particularly in children (Winickoff et al., 2009). Few smokers perceive this exposure to be harmful (Winickoff et al., 2009). Individuals who are fathers and heavier smokers tend to be less likely to believe that third-hand smoke is harmful (Drehmer et al., 2012). ♪ Note to instructor(s): Counseling suggestions for discussing the dangers of third-hand smoke, and how to avoid them, are included in the Assisting Patients with Quitting module. Drehmer JE, Ossip DJ, Rigotti NA, et al. (2012). Pediatrician interventions and thirdhand smoke beliefs of parents. Am J Prev Med 43(5):533–536. Sleiman M, Logue JM, Luo W, Pankow JF, Gundel LA, Destaillats H. (2014). Inhalable constituents of thirdhand tobacco smoke: chemical characterization and health impact considerations. Environ Sci Technol 18;48(22):13093–13101. Winickoff JP, Friebely J, Tanski SE, et al. (2009). Beliefs about the health effects of “thirdhand” smoke and home smoking bans. Pediatrics 2009;123;e74–e79.

29 SMOKING and POSTOPERATIVE COMPLICATIONSRespiratory complications Pneumonia Respiratory failure Surgical wound complications Delayed healing Wound dehiscence Infection Scarring A meta-analysis (Grønkjær et al., 2014) and data from a U.S. Surgeon General report (USDHHS, 2014) suggest that smokers experience a greater incidence of postoperative complications (wound and respiratory complications), compared to nonsmokers. Surgical wound complications include delayed healing, wound dehiscence, infections, and scarring. Constituents in tobacco smoke (e.g., carbon monoxide, hydrogen cyanide, acrolein, nicotine) are believed to contribute to poor wound healing through impaired wound epithelialization; thrombosis; decreased oxygen delivery; direct microvascular injury; and dysfunction of leukocytes, macrophages, fibroblasts, and platelets (Krueger & Rohrich, 2001). Respiratory complications (pneumonia, respiratory failure, and death due to pulmonary disease) are believed to be more common among smokers, because toxins in tobacco smoke are known to impair respiratory immune function. Furthermore, many smokers have preexisting compromised respiratory function secondary to underlying COPD; this further increases the risk for respiratory complications (USDHHS, 2014). Grønkjær M, Eliasen M, Skov-Ettrup LS, et al. (2014). Preoperative smoking status and postoperative complications: a systematic review and meta-analysis. Ann Surg 259(1):52–71. Krueger JK, Rohrich RJ. (2001). Clearing the smoke: the scientific rationale for tobacco abstention with plastic surgery. Plast Reconstr Surg 108:1063–1073. U.S. Department of Health and Human Services (USDHHS). (2014). The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta, GA: Author, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

30 CARBON MONOXIDE (CO): PULSE OXIMETRYThe CO from tobacco smoke binds to hemoglobin, taking the place of oxygen Oximeters cannot differentiate between hemoglobin molecules that are saturated in oxygen versus those carrying CO Readings will be higher Effects last for up to 4 hours after smoking a cigarette Arterial blood gas assessment is more accurate for determining oxygen saturation in patients who smoke Tobacco contains carbon monoxide (CO), and this CO binds to hemoglobin (Hgb), taking the place of oxygen. Among smokers, the reading on an oximeter is typically higher than the actual oxygen saturation. This is because smoking increases carbon monoxide levels in the blood, and the oximeter cannot differentiate between Hgb molecules that are saturated in oxygen versus those carrying carbon monoxide. As such, false high readings almost always occur in smokers, and readings are affected for up to 4 hours after smoking a cigarette (Dobson, 1993). Therefore, when oxygen saturation must be determined accurately in patients who smoke, it is recommended that arterial blood gases be assessed. Dobson F. (1993). Shedding light on pulse oximetry. Nursing Standard 7: 46, 4–11.

31 QUITTING: HEALTH BENEFITSTime Since Quit Date Circulation improves Walking becomes easier Lung function increases Lung cilia regain normal function Ability to clear lungs of mucus increases Coughing, fatigue, shortness of breath decrease 2 weeks to 3 months 1 to 9 months Excess risk of CHD decreases to half that of a continuing smoker ♪ Note to Respiratory Care instructor(s): Please highlight the respiratory-related benefits of quitting. The 1990 Surgeon General’s Report on the health benefits of smoking cessation outlined the numerous and substantial health benefits incurred when patients quit smoking (USDHHS, 1990). As can be seen on this slide, there are many benefits to respiratory health. Health benefits realized 2 weeks to 3 months after quitting include the following: circulation improves, walking becomes easier, and lung function increases. One to nine months later, lung ciliary function is restored. This improved mucociliary clearance greatly decreases the chance of infection because the lung environment is no longer as conducive to bacterial growth. Consequently, coughing, sinus congestion, fatigue, and shortness of breath decrease. In some patients, coughing might actually increase shortly after quitting. This is because the cilia in pulmonary epithelial cells are functioning “normally” and are more effectively clearing the residual tars and other accumulated components of tobacco smoke. One year later, excess risk of coronary heart disease (CHD) is decreased to half that of a smoker. After 5 to 15 years, stroke risk is reduced to a rate similar to that of people who have never smoked. Ten years after quitting, an individual’s chance of dying of lung cancer is approximately half that of continuing smokers. Additionally, the chance of getting mouth, throat, esophagus, bladder, kidney, or pancreatic cancer is decreased. Finally, after 15 years, an individual’s risk of CHD is reduced to a rate similar to that of people who have never smoked. Thus, the benefits of quitting are significant. It is never too late to quit to incur many of the benefits of quitting. U.S. Department of Health and Human Services (USDHHS). (1990). The Health Benefits of Smoking Cessation. A Report of the Surgeon General (DHHS Publication No. CDC ). Washington, DC: Author, Public Health Service, Centers for Disease Control and Prevention and Health Promotion, Office on Smoking and Health. 1 year Risk of stroke is reduced to that of people who have never smoked Lung cancer death rate drops to half that of a continuing smoker Risk of cancer of mouth, throat, esophagus, bladder, kidney, pancreas decrease 5 years 10 years Risk of CHD is similar to that of people who have never smoked after 15 years

32 BENEFICIAL EFFECTS of QUITTING: PULMONARY EFFECTSAT ANY AGE, there are pulmonary benefits of quitting. Never smoked or not susceptible to smoke 100 75 This graph shows measurable improvements in lung function as a result of quitting (Fletcher & Peto, 1977) . Forced expiratory volume (FEV1) falls gradually with age; for the majority of nonsmokers and many smokers, clinically significant FEV1 reduction does not occur. However, in susceptible individuals, smoking causes irreversible obstructive damage to the respiratory system. If a susceptible smoker quits smoking at age 45 years, he or she likely will regain a substantial proportion of potentially lost FEV1. Less substantial, but still visible, benefits of quitting can be seen among persons who quit even at a much older age (65 years). Fletcher C, Peto R. (1977). The natural history of chronic airflow obstruction. Br Med J 1(6077):1645–1648. Stopped smoking at 45 (mild COPD) Smoked regularly and susceptible to effects of smoke FEV1 (% of value at age 25) 50 Disability 25 Stopped smoking at 65 (severe COPD) Death 25 50 75 Age (years) COPD = chronic obstructive pulmonary disease Reprinted with permission. Fletcher & Peto. (1977). BMJ 1(6077):1645–1648.

33 IMPACT of TOBACCO USE: SUMMARYExposure to tobacco smoke significantly compromises pulmonary health Acute and chronic disease rates are elevated in persons of all ages who are exposed to tobacco smoke There is no safe level of exposure to second-hand smoke, and third-hand smoke can be harmful to patients with respiratory disorders Quitting smoking can improve, reverse, or halt the progression of many tobacco-related respiratory diseases and improve surgical outcomes To summarize: Exposure to tobacco smoke significantly compromises pulmonary health. Acute and chronic disease rates are elevated in persons of all ages who are exposed to tobacco smoke. There is no safe level of exposure to second-hand smoke, and third-hand smoke can be harmful to patients with respiratory disorders. Quitting smoking can improve, reverse, or halt the progression of many tobacco-related respiratory diseases and improve surgical outcomes. As such, cessation counseling should be integrated into all patient encounters, and respiratory therapists can be key providers of these services.

34 NICOTINE PHARMACOLOGY and PRINCIPLES of ADDICTIONThis module focuses on the pharmacology of nicotine and principles of addiction.

35 Nicotine addiction is a chronic condition with a biological basis.WHAT 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 Abuse National Institutes of Health Many 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, defines drug addiction simply as “compulsive use, without medical purpose, in the face of negative consequences” (Leshner, 1997). Benowitz NL. (1992). Cigarette smoking and nicotine addiction. Med Clin N Am 76:415–437. Benowitz NL. (2010). Nicotine addiction. N Engl J Med 362:2295–2303. 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. Nicotine addiction is a chronic condition with a biological basis.

36 TOBACCO DEPENDENCE: A 2-PART PROBLEMPhysiological Behavioral Treatment The addiction to nicotine Medications for cessation The habit of using tobacco Behavior change program Tobacco dependence is a chronic condition that requires a two-pronged approach for maximal treatment effectiveness (Fiore et al., 2008). Prolonged use of tobacco results in tobacco dependence, which is characterized as a physiological dependence (addiction to nicotine) and behavioral habit of using tobacco. Addiction can be treated with FDA-approved medications for smoking cessation, and the behavioral habit can be treated through behavior change programs, such as individualized counseling and group or online cessation programs. The Clinical Practice Guideline for treating tobacco use and dependence (Fiore et al., 2008), which summarizes more than 8,700 published articles, advocates the combination of behavioral counseling with pharmacotherapy in treating patients who smoke. ♪ Note to instructor(s): Specific methods for treating tobacco use and dependence are covered in detail in the Assisting Patients with Quitting and Aids for Cessation modules. Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. Treatment should address the physiological and behavioral aspects of dependence.

37 NICOTINE DISTRIBUTIONArterial Inhalation of tobacco smoke is an effective means of delivering nicotine to the central nervous system. After inhalation, nicotine is absorbed rapidly across pulmonary epithelium into the arterial circulation, traveling via the carotid arteries to the central nervous system. Nicotine readily penetrates the blood-brain barrier, resulting in transient exposure of the brain to high levels of nicotine. Nicotine has been estimated to reach the brain within 10–20 seconds of inhalation. Following systemic distribution, brain nicotine levels decline rapidly (Benowitz et al., 2009). This graph depicts the arterial and venous concentrations of nicotine achieved during cigarette smoking. Within 1 minute after smoking a cigarette, arterial levels of nicotine are nearly seven times the corresponding venous levels (Henningfield et al., 1993). These rapid, high levels of nicotine in the central nervous system produce an almost immediate effect, reinforcing the behavioral act of smoking, which further stimulates repeated administration. Benowitz N, Hukkanen J, Jacob P III. (2009). Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol. 192:29–60. Henningfield JE, Stapleton JM, Benowitz NL, Grayson RF, London ED. (1993). Higher levels of nicotine in arterial than in venous blood after cigarette smoking. Drug Alcohol Depend 33:23–29. Venous Nicotine reaches the brain within 10–20 seconds. Henningfield et al. (1993). Drug Alcohol Depend 33:23–29.

38 DOPAMINE REWARD PATHWAY Ventral tegmental areaPrefrontal cortex Dopamine release Drugs such as cocaine, heroin, amphetamine, and nicotine exert profound effects on the brain. These agents have in common the ability to stimulate the release of the neurotransmitter dopamine in the midbrain. Dopamine induces feelings of euphoria and pleasure and is responsible for activating the dopamine reward pathway (Leshner, 1997). The dopamine reward pathway, as depicted in this simplified diagram, is a network of nervous tissue in the middle of the brain that elicits feelings of pleasure in response to certain stimuli. The important interconnected structures of the reward pathway include the ventral tegmental area (VTA), the nucleus accumbens, and the prefrontal cortex (area of the brain responsible for thinking and judgment). The neurons of the VTA contain the neurotransmitter dopamine, which is released in the nucleus accumbens and in the prefrontal cortex. Behaviors that naturally stimulate the reward pathway include eating to relieve hunger, drinking to alleviate thirst, or engaging in sexual activity. On a primitive, neurochemical level, stimulation of the reward pathway reinforces the behavior so that it will be repeated. Obviously these behaviors are necessary for continued survival of the organism. The reward pathway can also be stimulated by drugs of abuse such as cocaine, opiates, amphetamine, and nicotine. When these unnatural stimuli trigger the reward pathway, the same pleasurable feelings are elicited. Researchers believe that, with chronic drug use, the brain becomes chemically altered—transforming a drug user into a drug addict (Leshner, 1997). Consider cigarette smoking as an example. Immediately following inhalation, a bolus of nicotine enters the brain, stimulating the release of dopamine, which induces nearly immediate feelings of pleasure and relief of symptoms of nicotine withdrawal. This rapid dose-response reinforces and perpetuates the smoking behavior. This slide was made available to the public through the National Institute on Drug Abuse and was adapted with permission by Dr. Rochelle D. Schwartz-Bloom, Duke University. Leshner Al. (1997, April). Drug abuse and addiction are biomedical problems. Hosp Pract (special report):2–4. Stimulation of nicotine receptors Nucleus accumbens Ventral tegmental area Nicotine enters brain

39 NICOTINE PHARMACODYNAMICS: WITHDRAWAL EFFECTSIrritability/frustration/anger Anxiety Difficulty concentrating Restlessness/impatience Depressed mood/depression Insomnia Impaired performance Increased appetite/weight gain Cravings Most symptoms manifest within the first 1–2 days, peak within the first week, and subside within 2–4 weeks. ♪ Note to instructor(s): Refer students to the Withdrawal Symptoms Information Sheet handout. This handout describes several symptoms, when they occur postcessation, and how to cope with withdrawal. In addition to being an educational aid for students, it can be copied and distributed to patients who are quitting. When nicotine is discontinued abruptly, the following withdrawal symptoms develop (Hughes, 2007): Irritability/frustration/anger Anxiety Difficulty concentrating Restlessness/impatience Depressed mood/depression Insomnia Impaired performance Increased appetite/weight gain Cravings ♪ Note to instructor(s): Other symptoms of quitting have been described in the literature. Please refer to Hughes (2007) for further details. Tobacco users usually experience a strong desire or craving for tobacco. In general, withdrawal symptoms manifest within the first 1–2 days, peak within the first week, and gradually dissipate over the next 2–4 weeks (Hughes, 2007). Strong cravings for tobacco may persist for months to years after cessation (Benowitz, 1992). Benowitz NL. (1992). Cigarette smoking and nicotine addiction. Med Clin N Am 76:415–437. Hughes JR. (2007). Effects of abstinence from tobacco: valid symptoms and time course. Nicotine Tob Res 9:315–327. Hughes. (2007). Nicotine Tob Res 9:315–327.

40 BIOLOGY of NICOTINE ADDICTION: ROLE of DOPAMINEstimulates dopamine release is not just a bad habit. Pleasurable feelings Discontinuation leads to withdrawal symptoms. Many smokers believe that smoking/dipping/chewing is simply a bad habit. Research has shown that nicotine addiction is a chronic condition, one with a biological basis. Nicotine stimulates the release of brain neurotransmitters, including dopamine, which activates the dopamine reward pathway. This induces feelings of pleasure, which reinforce repeat administration of the drug. With chronic administration, tolerance to the behavioral and cardiovascular effects of nicotine develops over the course of the day. Tobacco users regain sensitivity to the effects of nicotine after overnight abstinence from smoking. When tobacco users abruptly discontinue nicotine, they experience symptoms of withdrawal. These withdrawal symptoms serve as a powerful stimulus to repeat nicotine administration (Benowitz, 1992; Benowitz, 2010). Benowitz NL. (1992). Cigarette smoking and nicotine addiction. Med Clin N Am 76:415–437. Benowitz NL. (2010). Nicotine addiction. N Engl J Med 362:2295–2303. Repeat administration Tolerance develops Benowitz. (2008). Clin Pharmacol Ther 83:531–541.

41 NICOTINE ADDICTION Tobacco users maintain a minimum serum nicotine concentration in order to Prevent withdrawal symptoms Maintain pleasure/arousal Modulate mood Users self-titrate nicotine intake by Smoking/dipping more frequently Smoking more intensely Obstructing vents on low-nicotine brand cigarettes Tobacco users tend to carefully titrate, or regulate, their tobacco intake to maintain a relatively constant level of nicotine in the body, in order to (Benowitz, 1999; Benowitz, 2008): Prevent withdrawal symptoms Maintain pleasure/arousal Modulate mood (e.g., to handle stress or anxiety) Although many tobacco users might not think about it consciously, they are able to alter nicotine delivery in a number of ways, including (Benowitz, 1999): By smoking or dipping more frequently By smoking more intensely (e.g., inhaling deeper or longer, smoking cigarette down to the filter) By obstructing the vents (with fingers or lips) on “light” cigarettes, thereby increasing the amount of nicotine delivered to the lung Excess nicotine concentrations will result in symptoms of nicotine toxicity. These include headache, nausea and vomiting, abdominal pain, diarrhea, salivation, dizziness, blurred vision, weakness, cold sweat, mental confusion, weakness, and in severe overdose, hypotension, seizures, and respiratory depression (Taylor, 2006). Benowitz NL. (1999). Nicotine addiction. Prim Care 26:611–631. Benowitz NL. (2008). Clinical pharmacology of nicotine: implications for understanding, preventing, and treating tobacco addiction. Clin Pharmacol Ther 83:531–541. 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. Benowitz. (2008). Clin Pharmacol Ther 83:531–541.

42 CLOSE TO HOME © 2000 John McPherson.Patients often describe tobacco cessation as the most difficult achievement of their lives. Tobacco users can be very creative in the methods they choose for quitting, as is illustrated in this cartoon. CLOSE TO HOME © 2000 John McPherson. Reprinted with permission of UNIVERSAL PRESS SYNDICATE. All rights reserved.

43 FACTORS CONTRIBUTING to TOBACCO USEIndividual Sociodemographics Genetic predisposition Coexisting medical conditions Pharmacology Alleviation of withdrawal symptoms Weight control Pleasure, mood modulation Tobacco Use Nicotine is a powerful drug capable of inducing a variety of pharmacologic effects, including an alteration in brain chemistry. However, tobacco addiction is more than just a brain disease. It is a complex process involving the interplay of many factors (pharmacologic, environmental, and physiologic) that influence an individual’s decision to use tobacco (Benowitz, 2010). As such, treatment of addiction requires a multifaceted approach (Lerman et al., 2005; Leshner, 1999). This slide depicts several important factors that influence tobacco use behavior. Individual factors: Tobacco prevalence differs by various sociodemographic factors (e.g., age, sex), and these factors are also associated with susceptibility to tobacco use (initiation, maintenance). Some individuals exhibit a genetic predisposition for nicotine addiction, and the impact of some coexisting medical conditions (in particular, mental illness) increases an individual’s likelihood of using and becoming dependent on tobacco. Pharmacologic factors: As discussed previously, there is a pharmacologic basis for a nicotine-dependent individual’s decision to use tobacco. Environmental factors: Tobacco industry advertising: For years, the tobacco industry has engineered major marketing plans to design more addictive cigarettes and to defy the public regarding the hazards of smoking. Their multibillion-dollar marketing effort is an important contributor to tobacco use. Conditioned stimuli: All drug-taking behavior is learned, a result of conditioning. Drug-taking behavior is reinforced by the consequences of the pharmacologic actions of the drug. At the same time, smokers begin to associate specific moods, situations, or environmental factors with nicotine’s reward effects. The association between such cues and anticipated drug effects and the resulting urge to smoke is another type of conditioning. For example, people often smoke cigarettes in specific situations, such as after a meal or with coffee or alcoholic beverages. The association between smoking and these other events, repeated many times, causes the environmental situations to become powerful cues for the urge to smoke. A nondrug example of this type of conditioning is the desire to eat popcorn at the movies or hot dogs at baseball games Other aspects of smoking (e.g., manipulation of smoking materials; taste, smell, feel of smoke in the throat) become associated with the pleasurable effects of smoking. Even unpleasant moods can become conditioned cues for smoking. For example, a smoker may learn that not having a cigarette provokes irritability, a common nicotine withdrawal symptom. Smoking a cigarette relieves withdrawal symptoms. After repeated similar experiences, a smoker may come to regard irritability from any source, such as stress or frustration, as a cue for smoking. Conditioning is a major factor that leads to relapse. As such, it must be addressed as a component of behavioral therapy for nicotine addiction. Social interactions: Having family or peer-group members who smoke increases the likelihood of tobacco use and, therefore, addiction. Among adolescents, peer pressure is often a reason for initiating tobacco use. Benowitz NL. (1992). Cigarette smoking and nicotine addiction. Med Clin N Am 76:415–437. Benowitz NL. (2008). Neurobiology of nicotine addiction: implications for smoking cessation treatment. Am J Med 121(4A):S3–10. Lerman C, Patterson F, Berrettini W. (2005). Treating tobacco dependence: state of the science and new directions. J Clin Oncol 23:311–323. Leshner AI. (1999). Science-based views of drug addiction and its treatment. JAMA 282:1314–1316. Environment Tobacco advertising Conditioned stimuli Social interactions

44 NICOTINE PHARMACOLOGY and ADDICTION: SUMMARYTobacco products are effective delivery systems for the drug nicotine. Nicotine is a highly addictive drug that induces a constellation of pharmacologic effects, including activation of the dopamine reward pathway in the brain. Tobacco use is complex, involving the interplay of a wide range of factors. Treatment of tobacco use and dependence requires a multifaceted treatment approach. To summarize: Tobacco products are effective delivery systems for the drug nicotine. Nicotine is a highly addictive drug that induces a constellation of pharmacologic effects, including activation of the dopamine reward pathway in the brain (which reinforces continued tobacco use). Tobacco users who are dependent on nicotine self-regulate their tobacco intake to maintain pleasurable effects and prevent withdrawal. Tobacco use is complex, involving the interplay of a wide range of contributing factors. Treatment of tobacco use and dependence requires a multifaceted approach. This topic is covered in the remainder of the program.

45 ASSISTING PATIENTS with QUITTINGThis module focuses on behavioral techniques for helping patients to quit using tobacco. A key barrier to patients’ success with quitting is the general lack of preparation and planning. As noted previously, tobacco use is a significant risk factor for a wide range of diseases (USDHHS, 2010) for which clinicians fail to intervene consistently, despite the availability of effective interventions (Fiore et al., 2008). Tobacco use is a complex, addictive behavior, and to maximize patients’ chances of successfully quitting, clinicians should advocate behavioral interventions in combination with one or more FDA-approved medications for cessation. Research shows that both counseling and medication are effective independently, but the combination is more effective than either alone (Fiore et al., 2008). Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. U.S. Department of Health and Human Services. (2010). How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease. A Report of the Surgeon General. Atlanta, GA: U.S. 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.

46 is an important component of PATIENT CARE.WHY BOTHER? Single-most effective strategy to lengthen and improve patients’ lives. Quitting tobacco has immediate and long-term benefits for all patients. It is inconsistent to provide health care and, at the same time, remain silent (or inactive) about a major health risk. So, why should a health care professional discuss tobacco cessation with a patient? Tobacco use is the leading cause of preventable death and disability in the U.S., and it negatively impacts all users. By contrast, for virtually all patients who smoke, quitting is the single most important thing that they can do to enhance their health. It is inconsistent to provide health care and, at the same time, remain silent (or inactive) about this major health risk. TOBACCO CESSATION is an important component of PATIENT CARE.

47 WHY SHOULD CLINICIANS ADDRESS TOBACCO?Tobacco users expect to be encouraged to quit by health professionals. Screening for tobacco use and providing tobacco cessation counseling are positively associated with patient satisfaction (Barzilai et al., 2001; Conroy et al., 2005). Tobacco users expect to be encouraged to quit by health professionals. In a study examining whether health habit counseling affects patient satisfaction, Barzilai et al. (2001) determined that of 12 health habits examined (exercise, diet, alcohol history, alcohol counseling, tobacco history, tobacco counseling, passive tobacco exposure, contraception and condom use, substance use history, substance use counseling, STD prevention, and counseling about HIV testing or prevention), only tobacco history and tobacco counseling were significantly associated with full satisfaction with the clinician visit. Similarly, in a study conducted by Conroy and colleagues (2005), patients’ reports of smoking cessation interventions, delivered during visits at primary care practices, were linked with higher levels of patient satisfaction with their health care, even among smokers who were not ready to quit smoking. It was concluded that health care providers can address tobacco use and provide cessation interventions without fear of alienating patients who are not yet ready to quit. Tobacco use should be addressed at each patient encounter. A clinician who chooses not to address tobacco use tacitly implies that quitting is not important. Barzilai DA, Goodwin MA, Zyzanski SJ, Stange KC. (2001). Does health habit counseling affect patient satisfaction? Prev Med 33:595–599. Conroy MB, Majchrzak NE, Regan S, Silverman CB, Schneider LI, Rigotti NA. (2005). The association between patient-reported receipt of tobacco intervention at a primary care visit and smokers’ satisfaction with their health care. Nicotine Tob Res 7 Suppl 1:S29–S34. Failure to address tobacco use tacitly implies that quitting is not important. Barzilai et al. (2001). Prev Med 33:595–599; Conroy et al. (2005). Nicotine Tob Res 7 Suppl 1:S29–S34.

48 TOBACCO DEPENDENCE: A 2-PART PROBLEMPhysiological Behavioral Treatment The addiction to nicotine Medications for cessation The habit of using tobacco Behavior change program As we mentioned in an earlier module, tobacco dependence is a chronic condition that requires a two-pronged approach for maximal treatment effectiveness. In this module, we explore methods for changing smoking-related behavior. Treatment should address the physiological and the behavioral aspects of dependence.

49 EFFECTS of CLINICIAN INTERVENTIONSWith help from a clinician, the odds of quitting approximately double. Compared to patients who receive no assistance from a clinician, patients who receive assistance are 1.7–2.2 times as likely to quit successfully for 5 or more months. n = 29 studies Furthermore, decades of research tell us that clinicians can have an important impact on their patients’ likelihood of achieving cessation. A meta-analysis of 29 studies determined that patients who received a tobacco cessation intervention from a nonphysician clinician or a physician clinician were 1.7 and 2.2 times as likely to quit (at 5 or more months postcessation), respectively, compared with patients who did not receive such an intervention (Fiore et al., 2008, p. 88). Self-help materials were only slightly better than no clinician. Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. 2.2 1.7 1.0 1.1 Intervention Estimated odds ratio (95% CI) Estimated abstinence rate (95% CI) No clinician 1.0 10.2 Self-help material 1.1 (0.9–1.3) 10.9% (9.1–12.7) Nonphysician clinician 1.7 (1.3–2.1) 15.8% (12.8–18.8) Physician clinician 2.2 (1.5–3.2) 19.9% (13.7–26.2) Fiore et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: USDHHS, PHS.

50 The NUMBER of CLINICIAN TYPES CAN MAKE a DIFFERENCE, TOOCompared to smokers who receive assistance from no clinicians, smokers who receive assistance from two or more clinician types are 2.4–2.5 times as likely to quit successfully for 5 or more months. n = 37 studies Similarly, the number of clinician types who assist with quitting is related to success rates. An analysis of 37 studies determined that patients who received a tobacco cessation intervention from two or more types of clinicians were more than twice as likely to quit (for 5 or more months) than were patients who received no assistance from a clinician (Fiore et al., 2008, pp. 87–88). Respiratory therapists can work, in tandem with other types of clinicians, to create an even greater impact on their patients’ likelihood of quitting. Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. 2.5 2.4 Estimated abstinence rate at 5+ months 1.8 1.0 Fiore et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: USDHHS, PHS.

51 WHY RESPIRATORY THERAPISTS?Long-term relationships with many patients Engender a sense of trust Patients listen to what you have to say Patients look to you for expert advice on issues concerning the lungs Cessation can be discussed during the course of breathing treatments, etc. Why should respiratory therapists get involved in cessation? From the perspective of adult patients, smoking causes the majority of the illnesses you treat as well as exacerbates symptoms of many others. With children, exposure to second-hand smoke can exacerbate symptoms of asthma, cystic fibrosis, and many other respiratory conditions, so living in a smoke-free environment is paramount. Quitting smoking can have profound positive effects on respiratory health. Because many of these illnesses are chronic and treatment can last for months, you see patients over a long period of time, which allows you to create a relationship with these patients. This relationship engenders a sense of trust, so much so that patients will listen to advice you may give on various behavior changes, especially when it comes to lung health. Treatment sessions can be a bit longer than a doctor’s visit or an interaction with a pharmacist, so, in many cases, you may have more time than other health professionals to interact with patients. The bottom line is this: Because of your special relationship with a particular patient, you just might be the one person to whom they will pay attention. So, it is important to make cessation counseling an integral part of your practice with every patient who smokes so that you don’t miss an opportunity to interact with just such a patient. You might be the ONE person who a patient listens to about smoking.

52 TOBACCO CESSATION REQUIRES BEHAVIOR CHANGEFewer than 5% of people who quit without assistance are successful in quitting for more than a year Few patients adequately PREPARE and PLAN for their quit attempt Many patients do not understand the need to change behavior Patients think they can just “make themselves quit” Fewer than 5% of smokers are able to quit successfully without assistance (Fiore et al., 2008). The subsequent failures that the other 95% of smokers encounter reinforce the already-held belief by these individuals that they cannot quit or that quitting is impossible. Likewise, most patients who smoke underestimate how strong the habit of smoking can be and the need to make changes in patterns and routines. They mistakenly view smoking as only an addiction and often think that all they have to do to quit is wear a patch or use the gum. A more successful approach is to view quitting as a learning process. Every smoker had to teach himself or herself how to smoke. Quitting is then a case of learning how not to smoke. In order to learn anything successfully, one must prepare properly and have a plan. However, most quitters not only do not make changes in their smoking-related behaviors, they often do not understand the need to do so. Many patients believe that they can simply “make” themselves quit by somehow “willing” it to happen. Consequently, many somewhat haphazardly just decide to “try” to quit one day and see what happens. Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. Behavioral counseling is a key component of treatment for tobacco use and dependence.

53 BEHAVIOR CHANGE (cont’d)Often, patients automatically smoke in the following situations: Behavioral counseling helps patients learn to cope with these difficult situations without having a cigarette. When drinking coffee While driving in the car When bored While stressed While at a bar with friends After meals During breaks at work While on the telephone While with specific friends or family members who use tobacco The average smoker takes about 10 puffs on a cigarette and smokes about 20–30 cigarettes a day. Therefore, they puff on a cigarette, on average, 200–300 times a day. For most patients who smoke, smoking is the most common thing that they do in any given day. Smoking becomes unconsciously linked to certain behaviors, situations, and moods (e.g., those listed on this slide). For routine smokers, these behaviors, situations, and moods can automatically prompt the smoker to want a cigarette, regardless of how little or how much nicotine is in the body. Examples of these unconscious triggers for smoking include the following: A smoker finishes a meal and grabs a cigarette without thinking. Another gets stressed and automatically starts smoking. Still another goes out with friends, has a few drinks, and begins smoking one cigarette after another. In each of these situations, the smoker is prompted to smoke because of habitual links with the other behavior they are engaged in, not because they are in withdrawal or have a craving for nicotine. Therefore, using a smoking cessation medication will not help to deal with this aspect of smoking. Rather, in order to quit smoking successfully, these links have to be broken. Behavioral counseling helps patients learn to (a) identify and deal with these situations without a cigarette and (b) change patterns and routines to break the automaticity of smoking. Behavioral programs teach quitters something else they can do or think that is not linked to smoking, enabling them to deal with the situation without having a cigarette. For example, an individual might get up after a meal and brush his teeth. In stressful situations, another individual might do some deep breathing and visualize being on a beach. When out with friends, the quitter could refrain from drinking or go to a location where smoking is not permitted. In all cases, the new behaviors are not connected to smoking, so the quitter is not triggered to want a cigarette.

54 READINESS to make a quit attemptThe 5 A’s ASK about tobacco USE ADVISE tobacco users to QUIT As described in the Clinical Practice Guideline for Treating Tobacco Use and Dependence, the 5 A’s are as follows (Fiore et al., 2008): Ask about tobacco use; systematically identify all tobacco users at every visit Advise tobacco users to quit Assess readiness, or willingness to make a quit attempt Assist with the quit attempt (provide counseling and medication) Arrange follow-up care Each of these is a key component of comprehensive tobacco cessation counseling interventions. Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. ASSESS READINESS to make a quit attempt ASSIST with the QUIT ATTEMPT ARRANGE FOLLOW-UP care

55 BRIEF COUNSELING: ASK, ADVISE, REFERabout tobacco USE ADVISE tobacco users to QUIT An alternative to the 5 A’s approach is the Ask-Advise-Refer strategy, which shares the counseling responsibility between providers. Any clinician can initiate the quitting process by asking about tobacco use, advising patients to quit, and then referring patients to other resources who then provide additional assistance and arrange follow-up counseling. This approach has been deemed effective and is a recommended approach in the Clinical Practice Guideline (Fiore et al., 2008). Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. REFER to other resources ASSIST Patient receives assistance from other resources, with follow-up counseling arranged ARRANGE

56 STEP 1: ASK ASK about tobacco use“If it’s OK with you, it would be helpful if we could talk about your tobacco use.” “Do you, or does anyone in your household, ever smoke or use other types of tobacco or nicotine, such as e- cigarettes?” “We ask our patients about tobacco use, because it contributes to many medical conditions.” “I take time to ask all of my patients about tobacco use— because it’s important.” ASK Ask. Tobacco smoke has the potential to interact with many medications, altering both drug levels and efficacy. Tobacco use also can induce early onset of disease and exacerbate existing medical conditions. It is appropriate, if not essential, for all clinicians to assess and document each patient’s tobacco use status, preferably at each visit. Asking about tobacco use should be considered to be as important as evaluating vital signs during a routine medical screening, and when obtaining a medication history, clinicians should ask about tobacco in the same way that they would ask about any other drug. Clinicians also should consider including a query about tobacco use on the new patient profile form. At a minimum, the form should assess tobacco use status (i.e., current, former, never). Always begin your interactions by asking permission to discuss a person’s tobacco use. This puts the patient in control of the conversation, which allows him or her to feel more open and forthright about discussing the subject. Appropriate language for assessing tobacco use status would be: “Do you, or does anyone in your household, ever smoke or use any type of tobacco or nicotine, such as e-cigarettes?” This question will capture not only cigarette smoking but all forms of tobacco and inhaled nicotine use. This question can be followed with one of the following statements: “We ask our patients about tobacco use, because it contributes to many medical conditions.” “I take time to ask all of my patients about tobacco use—because it’s important.” When asking about tobacco use, it is important to take a genuine and sensitive approach, conveying concern for the patient’s well-being. A judgmental tone likely will not result in accurate disclosure of tobacco use.

57 STEP 2: ADVISE tobacco users to quit (clear, strong, personalized)“It’s important that you quit as soon as possible, and I can help you.” “Cutting down while you are ill is not enough.” “Occasional or light smoking is still harmful.” “I realize that quitting is difficult. It is the most important thing you can do to protect your health now and in the future. I have training to help my patients quit, and when you are ready, I will work with you to design a specialized treatment plan.” ADVISE Advise. It is the clinician’s responsibility to assist patients in improving their health. Patients who use tobacco should be strongly advised to quit. At the very least, these patients should be advised to consider quitting. The message should be clear and strong, yet personalized and sensitive. The message must be delivered without judgment—or the clinician will likely waste that “teachable moment” and potentially alienate his or her patient. Tone and manner should convey a concern for the patient’s well-being as well as a commitment to help him or her quit—when the patient is ready. Consider the following statements (Fiore et al., 2008): “It’s important that you quit as soon as possible, and I can help you.” “Cutting down while you are ill is not enough.” “Occasional or light smoking is still harmful.” “I realize that quitting is difficult. It is the most important thing you can do to protect your health now and in the future. I have training to help my patients quit, and when you are ready, I will work with you to design a specialized treatment plan.” The clinician can personalize the message by tying tobacco use to current health or illness; its social and economic costs; the patient’s motivation level and readiness to quit; or the impact of tobacco use on children, others in the household and in their environment, and pets. For example: “If you continue to smoke, your [disease] will worsen/fail to improve.” Using a genuine and sensitive approach that acknowledges the difficulty of what is being requested, the clinician is more likely to move the patient forward in the process of preparing to quit. Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service.

58 NOT READY TO QUIT: COUNSELING STRATEGIESConsider asking: “Do you ever plan to quit?” “What might be some of the benefits of quitting now, instead of later?” “What would have to change for you to decide to quit sooner?” Advise patients to quit, and offer to assist (if or when they change their mind). If NO If YES For patients who are not ready to quit, encourage them to seriously consider quitting by asking the following series of three questions: 1. Do you ever plan to quit? Most patients will respond “yes,” in which case the clinician should continue with question #2. If they respond “no,” the clinician should strongly advise the patient to quit and offer to assist, should the patient change his mind. 2. What might be some of the benefits of quitting now, instead of later? The longer a patient smokes, the more difficult quitting generally becomes. Most patients will agree that there is never an ideal time to quit, and procrastinating over a quit date has more negative effects than positive. 3. What would have to change for you to decide to quit sooner? This question probes patients’ perceptions of quitting, which reveals some of the barriers to quitting that can then be discussed.  Most patients will agree: There is no “good” time to quit, and there are benefits to quitting sooner as opposed to later. Responses will reveal some of the barriers to quitting.

59 ADVISING PARENTS/CAREGIVERS“Smoking outside, in the doorway, or in a separate room is not enough. The smoke clings to your hair, clothes, and skin, and can irritate your child’s lungs and impair breathing.” “Quitting is the best thing you can do for the your long-term health and that of your child.” Anecdotally, many respiratory therapists who work in pediatric settings report a reluctance to advise parents to quit as they are not sure what to say. Here we find some sample language to start the conversation. Note that students should not repeat these statements verbatim. Rather, they should use them as a basis for creating their own messages in their personal style.

60 COUNSELING PARENTS WHO SMOKEExplain connection between smoking and child’s illness in clear, matter-of-fact manner Refer interested parents to the quitline or other cessation programs For those not interested in quitting, offer suggestions to protect the child Discuss progress at follow-up visits It is best to avoid an “I’m the expert and you better do what I tell you” attitude with parents or come across as scolding in any way. Doing so will most likely cause the parent to resist any suggestions you make. Rather, present the case to the parents in a very matter-of-fact manner, being sure to explain clearly how their smoking contributes to the child's particular problem. Avoid jargon, making sure to tailor your explanation to the parent(s) educational level. Strongly suggest that the parent(s) quit altogether, but respect an individual’s decision not to do so. For parents who choose not to quit, discuss how to reduce and minimize exposure as a first step. And make sure the parent knows that you will be following up with his or her progress at each visit.

61 COUNSELING PARENTS (cont’d)Explain the connection: “Your child has impaired lung function due to___. Exposing him/her to second- or third-hand smoke causes additional problems.” “Smoking outside or by the doorway is not sufficient, because the smoke clings to clothes/hair.” “For your child, the only safe amount of exposure to smoke is none.” On this slide, we provide examples of language that can be used when talking with parents, explaining the connection between their smoking and their child's condition.

62 COUNSELING PARENTS WHO ARE NOT INTERESTED IN QUITTINGDo not smoke in the car or in front of your child Children who see parents smoke are more likely to smoke Wear a “smoking jacket” and remove it when entering the home Only removing exposed clothing and washing exposed skin/hair reduces risk When handling infants: Remove all clothing worn while smoking Wash hands/hair first For parents who do not want to quit, strongly encourage them to do the following: Do not smoke in front of your child. Not only will this reduce actual exposure to smoke but it will help in reducing the chance that the child will smoke as an adult. Set aside certain clothes to wear when smoking and remove them when interacting with the child. This is particularly important with infants, who can absorb many harmful chemicals found in smoke directly through their thin, delicate skin when in contact with skin, hair, or clothes of a person who has smoked. Therefore, also wash hands and hair before handling the infant.

63 ADDITIONAL RECOMMENDATIONSExplaining the link between smoking and symptoms is important, because most parents underestimate The amount of exposure The harm of exposure Determine and modify exposure by other caregivers Refer to cessation programs Most parents are willing to modify exposure to some extent In studies where exposure to smoke was verified by biochemical markers, many parents underestimated their child’s level of second-hand smoke exposure. They also rarely included or considered exposure by family caregivers; as such, it is also very important to discuss this subject with parents who smoke (Farber et al., 2008). Although a Cochrane review of existing cessation programs for parents shows weak evidence for the success of brief interventions, it does appear that clearly explaining the link between smoking and increased asthma symptoms/attacks does motivate significant numbers of parents to modify exposure to second-hand smoke by quitting smoking themselves, smoking outside the home, or reducing the child’s exposure to places where smoking occurs (Baxi et al., 2014). Baxi R, Sharma M, Roseby R, et al. (2014). Family and carer smoking control programmes for reducing children's exposure to environmental tobacco smoke. Cochrane Database Syst Rev 3:CD Farber JH, Knowles SB, Brown NL, et al. (2008). Secondhand tobacco smoke in children with asthma: Sources of and parental perceptions about exposure in children and parental readiness to change. Chest 133(6):1367–1374.

64 FOLLOW-UP For those patients seen multiple times:Inform parents that you will be asking about their smoking behavior at each visit Offer support and encouragement Praise any change Strategize solutions to challenges, as appropriate Follow-up is an essential component of counseling (Fiore et al., 2008). Expecting to be asked about their smoking status at each visit increases the importance of this issue in patients’ eyes and might lead to their taking the proposition of quitting more seriously. When you follow up, be sure to praise any success, even small ones, that the individual exhibits and avoid using words like “failure,” “defeat,” etc. Refer to problem situations as “challenges.” This puts the process into a more positive light and enables the two of you to strategize effective solutions. Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service.

65 STEP 3: REFER REFER tobacco users to other resources Referral options:A doctor, a nurse, a pharmacist, or another clinician, for additional counseling A hospital-based group program Web-based programs The support program provided (at no cost) with each smoking cessation medication The toll-free telephone quitline: QUIT-NOW REFER Most quitters do not know the extent of the behavior change options open to them. Simply informing patients of their choices can be a powerful intervention and can be done is less than a minute. As such, consider compiling a list of all smoking cessation programs in your area. Options can include but are not limited to the following: The health care professional with whom you work. Many hospitals systems now routinely provide cessation groups and individual counseling. Local group programs offered by the American Cancer Society, the American Lung Association, or community hospitals. All seven smoking cessation medications offer free behavioral support programming as part of their treatment package. This programming generally consists of a toll-free help line, written materials, and/or a web site with tailored quitting materials. Even if patients use other behavior change options, it is helpful to have them enroll in the program that comes with their chosen smoking cessation medication. The federal government supports a toll-free national telephone quitline number, QUIT-NOW. This number automatically routes callers to their state quitlines and takes calls for those states that do not currently have a quitline.

66 BRIEF COUNSELING: ASK, ADVISE, REFER (cont’d)Brief interventions have been shown to be effective In the absence of time or expertise: Ask, advise, and refer to other resources, such as local group programs or the toll-free quitline QUIT-NOW Brief interventions have been shown to be effective (Fiore et al., 2008). When time or logistics do not permit comprehensive tobacco cessation counseling during a patient visit, clinicians are encouraged to apply a truncated 5A’s model, whereby they Ask about tobacco use, Advise tobacco users to quit, and Refer patients who are willing to quit to a telephone quitline or other community-based resource for tobacco cessation. Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. This brief intervention can be achieved in less than 1 minute.

67 WHAT ARE “TOBACCO QUITLINES”?Tobacco cessation counseling, provided at no cost via telephone to all Americans Staffed by highly trained specialists Up to 4–6 personalized sessions (varies by state) Some state quitlines offer pharmacotherapy at no cost (or reduced cost) Up to 30% success rate for patients who complete sessions What is a tobacco quitline? Tobacco quitlines are telephone services that provide tobacco cessation counseling at no cost to the caller. Quitlines have proliferated over the past decade, providing comprehensive interventions that can reach patients who might otherwise have limited access to medical treatment because of geographic location or lack of insurance or financial resources. In clinical trials, telephone counseling services for which at least some of the contacts are initiated by the quitline counselor have been shown to be effective in promoting abstinence (Fiore et al., 2008; Stead et al., 2007; Stead et al., 2013), and these positive results have been shown to translate into real-world effectiveness (Zhu et al., 2000). The addition of medication to quitline counseling significantly improves abstinence rates compared to medication alone (Fiore et al., 2008; Stead & Lancaster, 2012). In addition, preliminary evidence suggests that quitlines also are effective for smokeless tobacco cessation (Severson et al., 2000). The telephone number for the toll-free tobacco quitline is QUIT-NOW. In some states, clinicians can submit a fax-referral form, on behalf of a patient, to the quitline. This form initiates a process whereby a quitline counselor then contacts the patient directly. Success rates of up to 30% have been found for patients who complete all follow-up sessions. However, most physicians, and most smokers, know almost nothing about them, so they are not being utilized by most smokers who want to quit. Even the busiest of clinicians can serve an important role by simply identifying tobacco users and referring them to a quitline for more comprehensive counseling. Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. Severson HH, Andrews JA, Lichtenstein E, et al. (2000). A self-help cessation program for smokeless tobacco users: Comparison of two interventions. Nicotine Tob Res 2:363–370. Stead LF, Hartmann-Boyce J, Perera R, Lancaster T. (2013). Telephone counselling for smoking cessation. Cochrane Database Syst Rev 8:CD Stead LF, Lancaster T. (2012). Behavioral interventions as adjuncts to pharmacotherapy for smoking cessation. Cochrane Database Syst Rev 12:CD Stead LF, Perera R, Lancaster T. (2007). A systematic review of interventions for smokers who contact quitlines. Tob Control 16(Suppl 1):i3–i8. Zhu SH, Anderson CM, Tedeschi GJ, et al. (2002). Evidence of real-world effectiveness of a telephone quitline for smokers. N Engl J Med 347:1087–1093. Most health care providers, and most patients, are not familiar with tobacco quitlines.

68 WHEN a PATIENT CALLS the QUITLINECaller is routed to language-appropriate staff Brief questionnaire Contact and demographic information Smoking behavior Choice of services Individualized telephone counseling Quitting literature mailed within 24 hr Referral to local programs, as appropriate When a patient calls the quitline, a counselor or intake specialist answers. In most states, counseling is available in more than one language and the caller is routed to an appropriate staff member. A brief questionnaire is administered, to assess contact and demographic information, smoking behavior, and type of service requested. In most states, the quitline can refer callers to local programs, provide quitting literature by mail, and/or provide individualized telephone counseling. Some states are able to provide multiple counseling sessions (depending on the level of funding provided at the state level). Quitlines have a broad reach and, as noted previously, are recommended as an effective strategy in the 2008 Clinical Practice Guideline (Fiore et al., 2008). Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. Quitlines have broad reach and are recommended as an effective strategy in the 2008 Clinical Practice Guideline.

69 WEB-BASED PROGRAMS www.becomeanex.org www.quitnet.com This slide lists additional resources (other than the quitline) to which you can refer your patients. Explore options for local group programs. Three web-based programs are listed: BecomeAnEx is a website that is geared more for younger tobacco users. Quit Net is a private organization that has extensive information about quitting and features chat rooms for all types of individuals who feel more comfortable getting support from like-minded individuals. Smokefree.gov is operated by the Department of Health and Human Services and provides smokers with extensive information on quitting as well as healthy lifestyle information. ♪ Note to instructors: Consider suggesting to students that they explore each of these web sites on their own.

70 MAKE a COMMITMENT… Address tobacco use with all patients. At a minimum, make a commitment to incorporate brief tobacco interventions as part of routine patient care. Ask, Advise, and Refer. In summary, then, it is recommended that all clinicians, at a minimum, make a commitment to incorporate brief tobacco interventions as part of their routine care with all patients. You can successfully intervene in 5 minutes in the context of a regular interaction with a patient. Should even that prove to be impractical, clinicians should ask patients about tobacco use, advise patients to quit, and refer patients to other resources for additional assistance.

71 HELPING PATIENTS QUIT IS a CLINICIAN’S RESPONSIBILITYTOBACCO USERS DON’T PLAN TO FAIL. MOST FAIL TO PLAN. Clinicians have a professional obligation to address tobacco use and can have an important role in helping patients plan for their quit attempts. Tobacco users don’t plan to fail in their quit attempts. But most fail to plan. Health care providers have a professional obligation to help patients improve their health. This includes addressing tobacco use and helping patients to quit. Clinicians serve as facilitators in the process, calling attention to the need to quit, advising patients to quit, assisting with the quit attempt, and monitoring patient progress over time. For current tobacco users, the goal is to move them forward in their decision to quit. However, the decision to quit ultimately lies in the patient’s hands. THE DECISION TO QUIT LIES IN THE PATIENT’S HANDS.

72 IF YOU DON’T SAY ANYTHING…You inadvertently give patients… a reason to smoke, and therefore a reason not to quit. “How bad could my smoking be, if my respiratory therapist never said anything to me?” Think of this from the patient’s perspective: You are an expert on respiratory problems and are treating the patient for a illness that is either caused or exacerbated by smoking. If you don’t advise the patient to quit, naturally he or she is going to assume that smoking is no big deal and there is no real need to quit. Not saying anything inadvertently gives the patient permission to continue to smoke. Remember, just because you advise a patient to quit does not mean you have to conduct an entire cessation program with that patient. There are plenty of excellent intensive programs to which you can refer patients, especially the national toll-free quitline: QUIT-NOW. This is why this training program emphasizes the following protocol: ASK, ADVISE, REFER. ♪ Note to instructor(s): Remind students that you will be reviewing several referral sources later in the presentation. It is not necessary to conduct the entire cessation program, just get it started.

73 DR. GRO HARLEM BRUNTLAND, FORMER DIRECTOR-GENERAL of the WHO:“If we do not act decisively, a hundred years from now our grandchildren and their children will look back and seriously question how people claiming to be committed to public health and social justice allowed the tobacco epidemic to unfold unchecked.” This quote, from Dr. Gro Harlem Bruntland, former director-general of the World Health Organization, is the closing remark in the 2001 Surgeon General’s report on women and smoking (USDHHS, 2001). It appropriately emphasizes the urgency of the need for clinicians and other health professionals to take a more active role in countering tobacco use. According to Dr. Margaret Chan, director-general of the World Health Organization, “Reversing this entirely preventable epidemic must now rank as a top priority for public health and for political leaders in every country of the world” (WHO, 2008). U.S. Department of Health and Human Services (USDHHS). (2001). Women and Smoking: A Report of the Surgeon General. Washington, DC: Public Health Service. World Health Organization (WHO). (2008). Report on the Global Tobacco Epidemic, The MPOWER package. Geneva: World Health Organization. USDHHS. (2001). Women and Smoking: A Report of the Surgeon General. Washington, DC: PHS.

74 MEDICATIONS for SMOKING CESSATIONThis module focuses on patient education and the proper use of the various aids for tobacco cessation. The information provided in this module derives primarily from the product package inserts. The audience should be referred to the Pharmacologic Product Guide during this component of the training. ♪ Note to instructor(s): The following manufacturers’ product-specific web sites are a source of additional important information: ♪ Note to instructor(s): If using pharmacologic aids for cessation for in-class demonstration or workshops, please emphasize to students that the hands-on experience with the products is optional. Each instructor should decide whether it is appropriate for the audience to participate in these exercises. Former tobacco users and women who are pregnant or breastfeeding should NOT participate in exercises with active drug formulations, because it might be harmful (for current women who are pregnant or breastfeeding) or might lead to relapse (in former tobacco users). Risks associated with these exercises should be clearly indicated, and those who participate in the hands-on experience must remove any active dosage formulations as soon as the manipulation is completed, to avoid exposure to nicotine.

75 TOBACCO DEPENDENCE: A 2-PART PROBLEMPhysiological Behavioral Treatment The addiction to nicotine Medications for cessation The habit of using tobacco Behavior change program As we mentioned in an earlier module, tobacco dependence is a chronic condition that requires a two-pronged approach for maximal treatment effectiveness. In this module, we explore medications for cessation. Treatment should address the physiological and the behavioral aspects of dependence.

76 FDA-APPROVED MEDICATIONS for CESSATIONNicotine polacrilex gum Nicorette (OTC) Generic nicotine gum (OTC) Nicotine lozenge Nicorette Lozenge (OTC) Nicorette Mini Lozenge (OTC) Generic nicotine lozenge (OTC) Nicotine transdermal patch NicoDerm CQ (OTC) Generic nicotine patches (OTC, Rx) Nicotine nasal spray Nicotrol NS (Rx) Nicotine inhaler Nicotrol (Rx) Bupropion SR (Zyban, generic) Varenicline (Chantix) Currently five formulations of nicotine replacement therapy and two nonnicotine agents have FDA approval as aids for smoking cessation (Fiore et al., 2008). Medications that are available without a prescription include the nicotine gum, nicotine lozenge, and nicotine transdermal patch. Medications available only with a prescription are the nicotine nasal spray, nicotine inhaler, sustained-release bupropion, and varenicline. One formation of the generic transdermal patch also is available with a prescription. Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. These are the only medications that are approved by the FDA for smoking cessation.

77 Medications significantly improve success rates.PHARMACOTHERAPY “Clinicians should encourage all patients attempting to quit to use effective medications for tobacco dependence treatment, except where contraindicated or for specific populations* for which there is insufficient evidence of effectiveness.” The U.S. Public Health Service Clinical Practice Guideline for treating tobacco use and dependence states that “clinicians should encourage all patients attempting to quit to use effective medications for tobacco dependence treatment, except where contraindicated or for specific populations for which there is insufficient evidence of effectiveness” (Fiore et al., 2008, p. 106). Use of pharmacotherapy requires special consideration in the following patient populations (Fiore et al., 2008): Pregnant or breastfeeding women Smokeless tobacco users Patients smoking fewer than 10 cigarettes per day (light smokers) Adolescents Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. * Includes pregnant women, smokeless tobacco users, light smokers, and adolescents. Medications significantly improve success rates. Fiore et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: USDHHS, PHS.

78 PHARMACOTHERAPY: USE in PREGNANCYThe Clinical Practice Guideline makes no recommendation regarding use of medications in pregnant smokers Insufficient evidence of effectiveness Category C: varenicline, bupropion SR Category D: prescription formulations of NRT The Clinical Practice Guideline states that pregnant smokers should be encouraged to quit without medication, based on insufficient evidence of effectiveness and hypothetical concerns with safety. Pregnant smokers should be offered person-to-person psychosocial interventions that exceed minimal advice to quit (Fiore et al., 2008). The FDA has classified both bupropion and varenicline as a pregnancy category C agent based on a lack of controlled studies in pregnant women and animal studies that have demonstrated fetal harm (varenicline—decreased fetal weights, decreased fertility in offspring; bupropion—fetal malformations and skeletal variations) in dosages exceeding the maximum recommended human dosage (on a mg/m2 basis). The manufacturers of bupropion and varenicline both recommend use during pregnancy only if the potential benefit justifies the potential risk to the fetus (GlaxoSmithKine, 2014; Pfizer, 2014). ♪ Note to instructor(s): The manufacturer of Zyban (GlaxoSmithKline) maintained a bupropion pregnancy registry from September 1, 1997, through March 31, 2008, and published interim reports every 6 months. After more than a decade of surveillance, the registry was closed based on evidence that excluded a major teratogenic effect in pregnancies with exposure to any formulation of bupropion (GlaxoSmithKline, 2008). The FDA has classified prescription formulations of nicotine as a pregnancy category D drug, meaning there is evidence of risk to the human fetus. Accordingly, none of the NRT formulations have been FDA approved for use in pregnancy. Although NRT may pose a risk to the developing fetus, some researchers have argued this risk is considerably less than the risks of continued smoking (Benowitz & Dempsey, 2004). However, because it is assumed that NRT can cause fetal harm, the Clinical Practice Guideline does not recommend its use during pregnancy (Fiore et al., 2008). The American College of Obstetrics and Gynecology (ACOG) endorses counseling, including referral to tobacco quitlines and recommends the use of NRT only for women who can be closely monitored and demonstrate a clear commitment to quitting smoking (ACOG, 2010). American College of Obstetrics and Gynecology. (2010). Committee opinion no. 471: Smoking cessation during pregnancy. Obstet Gynecol 116:1241–1244. Benowitz NL, Dempsey DA. (2004). Pharmacotherapy for smoking cessation during pregnancy. Nicotine Tob Res 6(Suppl. 2):S189–S202. Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. GlaxoSmithKline. (2008, August). The bupropion pregnancy registry. Final report 1 September 1997 through 31 March Wilmington, NC. For information on obtaining the report, see GlaxoSmithKline. (2014, August). Zyban Package Insert. Research Triangle Park, NC. Pfizer. (2014, October). Chantix Package Insert. New York, NY. “Because of the serious risks of smoking to the pregnant smoker and the fetus, whenever possible pregnant smokers should be offered person-to-person psychosocial interventions that exceed minimal advice to quit.” Fiore et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: USDHHS, PHS.

79 PHARMACOTHERAPY: OTHER SPECIAL POPULATIONSPharmacotherapy is not recommended for: Smokeless tobacco users No FDA indication for smokeless tobacco cessation Individuals smoking fewer than 10 cigarettes per day Adolescents Nonprescription sales (patch, gum, lozenge) are restricted to adults ≥18 years of age NRT use in minors requires a prescription Pharmacotherapy is not recommended for use in smokeless tobacco users, individuals smoking fewer than 10 cigarettes per day (light smokers), or adolescents because of insufficient evidence of effectiveness (Fiore et al., 2008). These populations tend to be excluded in randomized controlled trials; therefore, limited data are available. Nonprescription NRT sales (nicotine patch, gum, lozenge) are restricted to adults ≥18 years of age, and use of NRT use in minors requires a prescription. For each of these special populations, the recommended treatment is behavioral counseling (Fiore et al., 2008). Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. Recommended treatment is behavioral counseling. Fiore et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: USDHHS, PHS.

80 NICOTINE REPLACEMENT THERAPY: RATIONALE for USEReduces physical withdrawal from nicotine Eliminates the immediate, reinforcing effects of nicotine that is rapidly absorbed via tobacco smoke Allows patient to focus on behavioral and psychological aspects of tobacco cessation The rationale for using NRT in tobacco cessation include the following: NRT reduces physical withdrawal symptoms associated with nicotine cessation. NRT increases success by alleviating physical nicotine withdrawal symptoms, which are usually experienced following tobacco cessation. This makes patients more comfortable while they are quitting. NRT eliminates the immediate, reinforcing effects of nicotine that is rapidly absorbed via tobacco smoke. NRT allows the patient to focus on behavioral and psychological aspects of tobacco cessation. While NRT products are helping to alleviate withdrawal symptoms, the patient is able to focus on the behavioral and psychological changes necessary for successful tobacco cessation. NRT itself can be addicting, and although the addictive properties of NRT are negligible compared to those of tobacco products, some patients might have difficulty terminating NRT use. NRT use significantly improves smoking cessation success rates. Meta-analyses of controlled trials of NRT have found that all products (gum, lozenge, patch, inhaler, and nasal spray) significantly improve abstinence rates when compared to placebo. Use of NRT approximately doubles long-term quit rates relative to placebo (Fiore et al., 2008; Stead et al., 2012). Advantages of NRT include the following: Patients are not exposed to the carcinogens and other toxic components found in tobacco and tobacco smoke. NRT provides lower, slower, and less variable plasma nicotine concentrations than do cigarettes, which reduces the behaviorally reinforcing effect of smoking. Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. Stead LF, Perera R, Bullen C, Mant D, Hartmann-Boyce J, Cahill K, Lancaster T. (2012). Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 1:CD The use of NRT products approximately doubles quit rates.

81 PLASMA NICOTINE CONCENTRATIONS for NICOTINE-CONTAINING PRODUCTSCigarette Moist snuff This graph depicts the plasma venous nicotine concentrations achieved with the various nicotine delivery systems. Peak plasma concentrations are higher and are achieved more rapidly when nicotine is delivered via cigarette smoke compared to the available NRT formulations. Among the NRT formulations, the nasal spray has the most rapid absorption, followed by the gum, lozenge, and inhaler; absorption is slowest with the transdermal formulations. The concentration time curves in this slide depict levels achieved after administration of a single dose of nicotine following a period of overnight abstinence. The administration of nicotine varied across the studies as follows: the cigarette was smoked over 5 minutes, the moist snuff (2 grams Copenhagen) was placed between the check and gum for 30 minutes, the inhaler was used over 20 minutes (80 puffs), the gum was chewed over 30 minutes, the lozenge was held in the mouth for approximately 30 minutes, and the patch was applied to the skin for 1 hour. The data presented in the graph derive from multiple studies and are meant to illustrate the differences between nicotine absorption from tobacco and NRT (Choi et al., 2003; Fant et al., 1999; Schneider et al., 2001). Because NRT formulations deliver nicotine more slowly and at lower levels (e.g., 30–75% of those achieved by smoking), these agents are far less likely to be associated with dependence when compared to tobacco products. Choi JH, Dresler CM, Norton MR, Strahs KR. (2003). Pharmacokinetics of a nicotine polacrilex lozenge. Nicotine Tob Res 5:635–644. Fant RV, Henningfield JE, Nelson RA, Pickworth WB. (1999). Pharmacokinetics and pharmacodynamics of moist snuff in humans. Tob Control 8:387–392. Schneider NG, Olmstead RE, Franzon MA, Lunell E. (2001). The nicotine inhaler. Clinical pharmacokinetics and comparison with other nicotine treatments. Clin Pharmacokinet 40:661–684. Time (minutes)

82 NICOTINE GUM Nicorette; genericsResin complex Nicotine Polacrilin Sugar-free chewing gum base Contains buffering agents to enhance buccal absorption of nicotine Available: 2 mg, 4 mg; original, cinnamon, fruit and mint (various) flavors FDA approved: 1984 Switched to OTC status: 1996 Available strengths: 2 mg, 4 mg Available flavors: Nicorette (GlaxoSmithKline) gum: original; mint (released 1998); FreshMint (coated formulation, released 2005); Fruit Chill (coated formulation, released 2006); Cinnamon Surge (coated formulation, released 2007); White Ice Mint (coated formulation, released 2008); Nicorette Orange (no longer available—discontinued by GlaxoSmithKline 12/2005) Generic gum: original; mint; coated-mint Description of Product Nicotine polacrilex (polé-ah-kril-ex) is a resin complex of nicotine and polacrilin in a sugar-free chewing gum base. The original flavor gum has a distinct, tobacco-like, slightly peppery taste. Newer, softer to chew formulations, in a variety of flavors, have been released over the years to increase palatability. All gum formulations contain buffering agents (sodium carbonate and sodium bicarbonate) to increase salivary pH, thereby enhancing buccal absorption of nicotine. Clinical Efficacy (Fiore et al., 2008) In a meta-analysis of 13 trials, nicotine gum was found to significantly improve quit rates compared to placebo. The effectiveness and abstinence rates at 6-months post-quit date are shown in the table below. The 4-mg gum is more efficacious than the 2-mg gum as a cessation aid in highly dependent smokers (Fiore et al., 2008). Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. Treatment Estimated odds ratio (95% CI) Estimated abstinence rate (95% CI) Placebo 1.0 13.8% Nicotine gum (6–14 weeks) 1.5 (1.2–1.7) 19.0% (16.5–21.9) Nicotine gum, long-term (>14 weeks) 2.2 (1.5–3.2) 26.1% (19.7–33.6)

83 NICOTINE GUM: DOSING Dosage is based on the “time to first cigarette” (TTFC) as an indicator of nicotine dependence Use the 2 mg gum: If you smoke your first cigarette more than 30 minutes after waking The recommended dosage of the nicotine gum is based on the "time to first cigarette" (TTFC) of the day. Having a strong desire or need to smoke soon after waking is viewed as a key indicator of nicotine dependence (TTURC, 2007). Therefore, patients who smoke their first cigarette of the day within 30 minutes of waking are likely to be more highly dependent on nicotine and require higher dosages than are those who delay smoking for more than 30 minutes after waking. Specifically: Patients who smoke their first cigarette of the day within 30 minutes of waking should use the 4-mg strength. Patients who smoke their first cigarette of the day more than 30 minutes after waking should use the 2-mg strength. When the 2-mg gum is used properly, ~0.9 mg of nicotine is absorbed from each piece (Benowitz et al., 1987). In comparison, approximately 1 mg of nicotine is absorbed from each cigarette (Benowitz & Jacob, 1984). Nicotine plasma levels are lower (~8 mcg/L) and peak approximately 30 minutes after chewing a 2-mg piece of nicotine gum compared to smoking a single cigarette with peak nicotine levels of ~26 mcg/L, which are achieved within 10 minutes (Schneider et al., 1996). Benowitz NL, Jacob P III. (1984). Daily intake of nicotine during cigarette smoking. Clin Pharmacol Ther 35:499–504. Benowitz NL, Jacob P, Savanapridi C. (1987). Determinants of nicotine intake while chewing nicotine polacrilex gum. Clin Pharmacol Ther 41:467–473. Schneider NG, Lunell E, Olmstead RE, Fagerström KO. (1996). Clinical pharmacokinetics of nasal nicotine delivery. A review and comparison to other nicotine systems. Clin Pharmacokinet 31:65–80. Transdisciplinary Tobacco Use Research Center (TTURC) Tobacco Dependence Phenotype Workgroup. (2007). Time to first cigarette in the morning as an index of ability to quit smoking: implications for nicotine dependence. Nicotine Tob Res 9 (Suppl 4):S555–S570. Use the 4 mg gum: If you smoke your first cigarette of the day within 30 minutes of waking

84 NICOTINE GUM: DOSING (cont’d)Recommended Usage Schedule for Nicotine Gum Weeks 1–6 Weeks 7–9 Weeks 10–12 1 piece q 1–2 h 1 piece q 2–4 h 1 piece q 4–8 h DO NOT USE MORE THAN 24 PIECES PER DAY. Patients using nicotine gum are more likely to quit successfully if they chew the gum on a fixed schedule rather than as needed (Fiore et al., 2008). This slide shows the manufacturers’ recommended dosing schedule. During the initial 6 weeks of therapy, patients should chew one piece of gum every 1–2 hours while awake. In general, this amounts to at least nine pieces of gum daily. Patients can use additional pieces (up to the daily maximum of 24 pieces per day) if cravings occur between the scheduled doses. Persons who smoke heavily generally need more pieces to reduce their cravings. Patients will gradually increase the interval between doses using the following schedule: Weeks 7–9: 1 piece every 2–4 hours Weeks 10–12: 1 piece every 4–8 hours ♪ Note to instructor(s): Participants might ask about the use of long-term nicotine gum therapy (e.g., >12 weeks of treatment). Data from the Lung Health Study found that ~40% and 15% of subjects were still using nicotine gum 1 and 5 years after quitting, respectively, with no serious adverse effects (Murray et al, 1996). The Clinical Practice Guideline encourages eventual discontinuation of all cessation pharmacotherapy but does state that continued use of medications is “clearly preferable to a return to smoking with respect to health consequences” (Fiore, et al., 2008). Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. Murray RP, Bailey WC, Daniels K, et al. (1996). Safety of nicotine polacrilex gum used by 3,094 participants in the Lung Health Study. Chest 109:438–445.

85 NICOTINE GUM: DIRECTIONS for USEChew each piece very slowly several times Stop chewing at first sign of peppery taste or slight tingling in mouth (~15 chews, but varies) “Park” gum between cheek and gum (to allow absorption of nicotine across buccal mucosa) Resume slow chewing when taste or tingle fades When taste or tingle returns, stop and park gum in different place in mouth Repeat chew/park steps until most of the nicotine is gone (taste or tingle does not return; generally 30 minutes) Nicotine gum is not like ordinary chewing gum. It is a specially formulated nicotine delivery system that must be chewed properly for optimal results. When chewed like ordinary gum, nicotine will be released rapidly from the polacrilin resin, possibly leading to adverse effects including hiccups, heartburn, or gastric upset. ♪ Note to instructor(s): Instruct participants to open the nicotine gum sample and follow along with the directions for use. This is an optional exercise. Former tobacco users, and women who are pregnant or breast-feeding should not participate in exercises with active drug formulations. Consult with your university or organization to gain approval for the hands-on component of the training. Although the nicotine exposure from a few chews of the gum is negligible with very brief exposure, always use placebo products when possible. Alternatively, distribute pieces of sugarless chewing gum for participants to use in practicing the chew-park method. Nicotine gum: Directions for use Chew each piece of gum very slowly several times. Stop chewing at the first sign of peppery taste or slight tingling sensation in the mouth. (This usually happens after about 15 chews, but it varies.) “Park” the gum between the cheek and gum to allow absorption of nicotine across the buccal mucosa (mouth lining). When the taste or tingling dissipates (generally about 1–2 minutes), slowly resume chewing. When the taste or tingling returns, stop chewing and park the gum in a different place in the mouth. Parking the gum in different areas of the mouth will decrease the incidence of mucosal irritation. The chew/park steps should be repeated until most of the nicotine is gone. At this point, the taste or tingling does not return. On average, each piece of gum lasts 30 minutes. ♪ Note to instructor(s): The number of chews necessary for the taste or tingling sensation generally ranges from 15 to 30 chews.

86 NICOTINE GUM: CHEWING TECHNIQUE SUMMARYChew slowly Stop chewing at first sign of peppery taste or tingling sensation The following is a review of proper chewing technique for nicotine gum: Chew slowly. Stop chewing at the first sign of a peppery taste or a slight tingling sensation. Park the gum between the cheek and gum. Chew again when the peppery taste or tingling sensation fades. Repeat steps 1–4 until most of the nicotine is gone (taste or tingle won’t return; generally about 30 minutes). The importance of proper gum chewing technique should be stressed to increase the likelihood of success with this form of NRT. Chew again when peppery taste or tingle fades Park between cheek & gum

87 NICOTINE GUM: ADDITIONAL PATIENT EDUCATIONTo improve chances of quitting, use at least nine pieces of gum daily The effectiveness of nicotine gum may be reduced by some foods and beverages:  Coffee  Juices  Wine  Soft drinks To improve the chances of quitting, patients should use at least nine pieces of nicotine gum daily (one piece every 1–2 hours). Persons who smoke heavily generally need more pieces to reduce their cravings. Emphasize that patients often do not use enough of the gum to derive benefit: They commonly chew too few pieces per day and/or shorten the length of treatment. For this reason, it may be preferable to recommend a fixed schedule of administration, tapering over 1–3 months (Fiore et al., 2008). The effectiveness of nicotine gum may be reduced by some foods and drinks, such as coffee, juices, wine or soft drinks (Henningfield et al., 1990). Patients should be instructed not to eat or drink anything other than water for 15 minutes before or while using the nicotine gum. To enhance buccal absorption, nicotine polacrilex is buffered to pH 8.5. Acidic beverages might transiently reduce the pH of the saliva below that which is necessary for optimal buccal absorption of nicotine. Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. Henningfield JE, Radzius A, Cooper TM, Clayton RR. (1990). Drinking coffee and carbonated beverages blocks absorption of nicotine from nicotine polacrilex gum. JAMA 264:1560–1564. Do NOT eat or drink for 15 minutes BEFORE or while using nicotine gum.

88 NICOTINE GUM: ADD’L PATIENT EDUCATION (cont’d)Chewing gum will not provide same rapid satisfaction that smoking provides Chewing gum too rapidly can cause excessive release of nicotine, resulting in Lightheadedness Nausea and vomiting Irritation of throat and mouth Hiccups Indigestion Chewing the gum will not provide the same rapid satisfaction that smoking provides. Recall that buccal absorption of nicotine is far less rapid (peak nicotine concentrations are achieved within 30 minutes), compared to nicotine absorption from cigarette smoking (peak concentrations <10 minutes). Patients should be warned that chewing the gum too rapidly can cause excessive release of nicotine and effects similar to those associated with smoking a cigarette too rapidly or those experienced by nonsmokers when they inhale from a cigarette for the first time: Lightheadedness Nausea and vomiting Irritation of the throat and mouth Hiccups Indigestion

89 NICOTINE GUM: ADD’L PATIENT EDUCATION (cont’d)Side effects of nicotine gum include Mouth soreness Hiccups Dyspepsia Jaw muscle ache Nicotine gum may stick to dental work Discontinue use if excessive sticking or damage to dental work occurs Side effects associated with nicotine gum include the following: Mouth soreness Hiccups Dyspepsia Jaw muscle ache These side effects are more common during the first few days of therapy. The consistency of nicotine gum (increased viscosity compared to ordinary chewing gum) may lead to increased adherence to dental work and may not be suitable for patients with the following: Extensive restorations (fillings) Bridges Dentures Caps or crowns Braces If excessive sticking or damage to dental work occurs, patients should discontinue use.

90 NICOTINE GUM: SUMMARY ADVANTAGES DISADVANTAGESMight serve as an oral substitute for tobacco Might delay weight gain Can be titrated to manage withdrawal symptoms Can be used in combination with other agents to manage situational urges DISADVANTAGES Need for frequent dosing can compromise adherence Might be problematic for patients with significant dental work Proper chewing technique is necessary for effectiveness and to minimize adverse effects Gum chewing might not be acceptable or desirable for some patients Advantages of nicotine gum include the following: Might serve as an oral substitute for tobacco (e.g., satisfy oral cravings for tobacco). Gum use might delay weight gain (Farley et al., 2012; Fiore et al., 2008). Can be titrated to manage withdrawal symptoms. Can be used in combination with other agents to manage situational urges/cravings for tobacco. Disadvantages of the gum include the following: Need for frequent dosing can compromise adherence. Might be problematic for patients with significant dental work (e.g., gum might stick to dentures, braces, fillings, etc.). Proper chewing technique is necessary for effectiveness and to minimize adverse effects. Gum chewing might not be acceptable or desirable for some patients. Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. Farley AC, Hajek P, Lycett D, Aveyard P. (2012). Interventions for preventing weight gain after smoking cessation. Cochrane Database Syst Rev 1:CD

91 Continuous 6-month abstinence rate (active / placebo)NICOTINE LOZENGE Nicorette Lozenge and Nicorette Mini Lozenge; generics Nicotine polacrilex formulation Delivers ~25% more nicotine than equivalent gum dose Sugar-free mint, cherry flavors Contains buffering agents to enhance buccal absorption of nicotine Available: 2 mg, 4 mg FDA approved for use without a prescription: 2002 Available strengths: 2 mg, 4 mg Generic lozenge available: 2006; Nicorette Mini available: 2010 Available flavors: Nicorette (GlaxoSmithKline) lozenge: mint; cherry. The “Commit” name is no longer used by GlaxoSmithKline (it was replaced with the Nicorette Lozenge), and the cappuccino flavor is no longer available. Nicorette Mini lozenge: mint Generic lozenge: original; mint Description of Product Nicotine polacrilex (polé-ah-kril-ex) is a resin complex of nicotine and polacrilin in a sugar-free (contains aspartame) mint (various), or cherry flavored lozenge. The lozenge is meant to be consumed like hard candy or other medicinal lozenges (e.g., sucked and moved from side to side in the mouth until it dissolves). Because the nicotine lozenge dissolves completely, it delivers approximately 25% more nicotine than does an equivalent dose of nicotine gum (Choi et al., 2003). Like the nicotine gum, the lozenge also contains buffering agents (sodium carbonate and potassium bicarbonate) to increase salivary pH, thereby enhancing buccal absorption of the nicotine. Clinical Efficacy (Fiore et al., 2008) Data from a large randomized clinical trial suggest the nicotine lozenge improves quit rates significantly compared to placebo. The effectiveness at 6-months post-quit date are as follows: Choi JH, Dresler CM, Norton MR, Strahs KR. (2003). Pharmacokinetics of a nicotine polacrilex lozenge. Nicotine Tob Res 5:635–644. Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. Treatment Odds ratio (95% CI) Continuous 6-month abstinence rate (active / placebo) Nicotine lozenge (2 mg) 2.0 (1.4–2.8) 24.2% / 14.4% Nicotine lozenge (4 mg) 2.8 (1.9–4.0) 23.6% / 10.2%

92 NICOTINE LOZENGE: DOSINGDosage is based on the “time to first cigarette” (TTFC) as an indicator of nicotine dependence Use the 2 mg lozenge: If you smoke your first cigarette more than 30 minutes after waking Like the nicotine gum, the recommended dosage of the nicotine lozenge is based on the "time to first cigarette" (TTFC) of the day. Having a strong desire or need to smoke soon after waking is viewed as a key indicator of nicotine dependence (TTURC, 2007). Therefore, patients who smoke their first cigarette of the day within 30 minutes of waking are likely to be more highly dependent on nicotine and require higher dosages than are those who delay smoking for more than 30 minutes after waking. Specifically: Patients who smoke their first cigarette of the day within 30 minutes of waking should use the 4-mg strength. Patients who smoke their first cigarette of the day more than 30 minutes after waking should use the 2-mg strength. Transdisciplinary Tobacco Use Research Center (TTURC) Tobacco Dependence Phenotype Workgroup. (2007). Time to first cigarette in the morning as an index of ability to quit smoking: implications for nicotine dependence. Nicotine Tob Res 9 (Suppl 4):S555–S570. Use the 4 mg lozenge: If you smoke your first cigarette of the day within 30 minutes of waking

93 NICOTINE LOZENGE: DOSING (cont’d)Recommended Usage Schedule for the Nicotine Lozenge Weeks 1–6 Weeks 7–9 Weeks 10–12 1 lozenge q 1–2 h q 2–4 h q 4–8 h DO NOT USE MORE THAN 20 LOZENGES PER DAY. Patients using the nicotine lozenge are more likely to quit successfully if they use the lozenge on a fixed schedule rather than as needed. This slide shows the manufacturer’s recommended dosing schedule. During the initial 6 weeks of therapy, patients should suck on one lozenge every 1–2 hours (while awake). In general, this amounts to at least nine lozenges daily. Patients can use additional lozenges (up to 5 lozenges in 6 hours or a maximum of 20 lozenges per day) if cravings occur between the scheduled doses. Patients should gradually increase the interval between doses using the following schedule: Weeks 7–9: 1 lozenge every 2–4 hours Weeks 10–12: 1 lozenge every 4–8 hours

94 NICOTINE LOZENGE: DIRECTIONS for USEUse according to recommended dosing schedule Place in mouth and allow to dissolve slowly (nicotine release may cause warm, tingling sensation) Do not chew or swallow lozenge Occasionally rotate to different areas of the mouth Lozenges will dissolve completely in about 2030 minutes The nicotine lozenge is a specially formulated nicotine delivery system that must be used properly for optimal results. Although the nicotine lozenge is used like hard candy or other medicinal lozenges, if patients chew or swallow the lozenge or consume too many in a short period of time, they increase their likelihood experiencing adverse effects. Nicotine lozenge: Directions for use The lozenge should be used on a regular basis to reduce nicotine cravings and other withdrawal symptoms. Allow the lozenge to dissolve slowly. When nicotine is released from the polacrilin resin, the patient may experience a warm, tingling sensation. To reduce the risk of gastrointestinal side effects, the lozenge should not be chewed or swallowed. The patient should occasionally rotate the lozenge to different areas of the mouth to minimize the potential for mucosal irritation. Lozenges will dissolve completely in about 20–30 minutes.

95 NICOTINE LOZENGE: ADDITIONAL PATIENT EDUCATIONTo improve chances of quitting, use at least nine lozenges daily during the first 6 weeks The lozenge will not provide the same rapid satisfaction that smoking provides The effectiveness of the nicotine lozenge may be reduced by some foods and beverages:  Coffee  Juices  Wine  Soft drinks To improve the chances of quitting, patients should use at least nine nicotine lozenges daily (one every 1–2 hours) during the first 6 weeks of treatment. The nicotine lozenge will not provide the same rapid satisfaction that smoking provides. Peak nicotine concentrations achieved for the standard lozenge range from 30 to 60 minutes (Choi et al., 2003) and are significantly prolonged compared to cigarette smoking (peak concentrations <10 minutes). The effectiveness of the nicotine lozenge may be reduced by some foods and beverages, such as coffee, juices, wine, or soft drinks. Patients should be instructed not to eat or drink for 15 minutes anything other than water before or while using the nicotine lozenge. To enhance buccal absorption, nicotine polacrilex is buffered to an alkaline pH. Acidic beverages might transiently reduce the pH of the saliva below that which is necessary for optimal buccal absorption of nicotine. Choi JH, Dresler CM, Norton MR, Strahs KR. (2003). Pharmacokinetics of a nicotine polacrilex lozenge. Nicotine Tob Res 5:635–644. Do NOT eat or drink for 15 minutes BEFORE or while using the nicotine lozenge.

96 NICOTINE LOZENGE: ADD’L PATIENT EDUCATION (cont’d)Side effects of the nicotine lozenge include Nausea Hiccups Cough Heartburn Headache Flatulence Insomnia Side effects associated with the nicotine lozenge include the following: Nausea Hiccups Cough Heartburn Headache Flatulence Insomnia Patients who use more than one lozenge at a time, continuously use one lozenge after another, or chew or swallow the lozenge are more likely to experience heartburn or indigestion.

97 NICOTINE LOZENGE: SUMMARYDISADVANTAGES Need for frequent dosing can compromise adherence Gastrointestinal side effects (nausea, hiccups, heartburn) might be bothersome ADVANTAGES Might serve as an oral substitute for tobacco Use might delay weight gain Can be titrated to manage withdrawal symptoms Can be used in combination with other agents to manage situational urges Advantages of nicotine lozenge include the following: Might serve as an oral substitute for tobacco (e.g., satisfy oral cravings for tobacco). Use might delay weight gain (Farley et al., 2012; Fiore et al., 2008). Can be titrated to manage withdrawal symptoms. Can be used in combination with other agents to manage situational urges/cravings for tobacco. Disadvantages of the lozenge include the following: Need for frequent dosing can compromise adherence. Gastrointestinal side effects (nausea, hiccups, and heartburn) may be bothersome. Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. Farley AC, Hajek P, Lycett D, Aveyard P. (2012). Interventions for preventing weight gain after smoking cessation. Cochrane Database Syst Rev 1:CD

98 TRANSDERMAL NICOTINE PATCH NicoDerm CQ; genericNicotine is well absorbed across the skin Delivery to systemic circulation avoids hepatic first-pass metabolism Plasma nicotine levels are lower and fluctuate less than with smoking FDA approved: 1991 Available OTC: 1996 Description of Product Transdermal nicotine delivery systems consist of an impermeable surface layer, a nicotine reservoir, an adhesive layer, and a removable protective liner. The technology for delivery of nicotine across the skin varies by manufacturer. NicoDerm CQ (GlaxoSmithKline) uses a rate-controlling membrane. The generic patches (previously marketed as Habitrol) use drug-dispersion-type systems whereby release of nicotine is controlled by diffusion of the drug across an adhesive layer (Gore & Chien, 1998). Nicotine is well absorbed across the skin; 68–82% of the dose released from the patch reaches the systemic circulation. Plasma nicotine concentrations from the patch rise slowly over 1–4 hours and peak within 3–12 hours following application [Benowitz et al., 2009]. Blood levels of nicotine achieved with the transdermal patch are lower and fluctuate less than do those achieved with tobacco products or other NRT formulations. Clinical Efficacy (Fiore et al., 2008) In a meta-analysis of 25 trials, the transdermal nicotine patch was found to significantly improve quit rates compared to placebo. The effectiveness and abstinence rates at 6-months post-quit date are as follows: Benowitz NL, Hukkanen J, Jacob P. (2009) Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol: Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. Gore AV, Chien YW. (1998). The nicotine transdermal system. Clin Dermatol 16:599–615. Treatment Estimated odds ratio (95% CI) Estimated abstinence rate (95% CI) Placebo 1.0 13.8% Nicotine patch (6–14 weeks) 1.9 (1.7–2.2) 23.4% (21.3–25.8) Nicotine patch, (>14 weeks) 1.9 (1.7–2.3) 23.7% (21.0–26.6)

99 TRANSDERMAL NICOTINE PATCH: PREPARATION COMPARISONProduct NicoDerm CQ Generic Nicotine delivery 24 hours Availability OTC Rx/OTC Patch strengths 7 mg 14 mg 21 mg Products Available NicoDerm CQ PatchOTC (GlaxoSmithKline) Switched to OTC status: August 1996 Availability: 7 mg, 14 mg, 21 mg (24-hour nicotine delivery system); also available in a clear formulation Generic nicotine patchRx,OTC Manufacturers: OTC product (Novartis Consumer Health) Rx product (Watson Pharmaceuticals) Available OTC: November 1999 Availability: 7 mg, 14 mg, 21 mg (24-hour nicotine delivery system) ♪ Note to instructor(s): Novartis manufactures the OTC product but has sold the rights to a private- label company that is responsible for marketing and distributing the product for various retail pharmacies (e.g., Albertsons, CVS, Duane Reade, Kroger, Longs, Medicine Shoppe, Rite-Aid, Safeway, Walgreens, Wal-Mart). The product is labeled as Nicotine Transdermal System Step 1, Step 2, and Step 3. ♪ Note to instructor(s): Previously, Pfizer marketed the Nicotrol transdermal patch (5 mg, 10 mg, 15 mg; 16-hour nicotine delivery systems). This patch formulation was discontinued in 2005 and is no longer commercially available. Additionally, a fourth nicotine transdermal patch (11 mg, 22 mg; 24-hour nicotine delivery systems) utilizing a non-tapering 6-week regimen was available. The prescription product was originally marketed as Prostep (Lederle). In December 1998 the product was switched to OTC status and distributed to drug stores, grocery stores, and discount stores under a private label. This patch formulation was discontinued in 2003 and is no longer commercially available.

100 TRANSDERMAL NICOTINE PATCH: DOSINGProduct Light Smoker Heavy Smoker NicoDerm CQ 10 cigarettes/day Step 2 (14 mg x 6 weeks) Step 3 (7 mg x 2 weeks) >10 cigarettes/day Step 1 (21 mg x 6 weeks) Step 2 (14 mg x 2 weeks) Generic Step 1 (21 mg x 4 weeks) The dosing schedules for the nicotine patches vary. In general, persons who smoke heavily require higher doses of nicotine. Although each of the currently-marketed formulations uses a tapering course of therapy, no evidence indicates that gradual weaning is more effective than abrupt discontinuation (Stead et al., 2012). Furthermore, 8 weeks of treatment appears to be as efficacious as longer durations (Stead et al., 2012). When patches applied for 16 hours (e.g., the previously-available Nicotrol patch) were compared to patches applied for 24 hours, no significant differences were found in quit rates (Stead et al., 2012). However, one study found that patients with strong morning cravings for cigarettes might hy more success with a patch applied for 24 hours (Shiffman et al., 2000). ♪ Note to instructor(s): Some participants might ask about use of higher than recommended doses of transdermal nicotine for persons who smoke heavily. High-dose transdermal nicotine (44–63 mg/day) appears to be safe (Benowitz et al., 1998; Dale et al., 1995; Fredrickson et al., 1995; Hurt et al., 2003; Bars et al., 2006). However, trials evaluating higher dosages of the nicotine patch (Dale et al., 1995; Tonnesen et al.,1999; Hughes et al., 1999; Jorenby et al., 1995; Killen et al., 1999; Paoletti et al., 1996; Kalman et al., 2006; Rose et al., 2010) have yielded conflicting results. When the results of eight studies were pooled, the odds ratio for abstinence was 1.1 for high-dose NRT compared to conventional NRT (95% CI, 1.01–1.29), suggesting only marginal benefit from higher dosages (Stead et al., 2012). This approach should be reserved for patients not able to quit using conventional doses of transdermal NRT. ♪ Note to instructor(s): The Clinical Practice Guideline does not recommend use of pharmacotherapy in patients smoking fewer than 10 cigarettes per day (light smokers), because of insufficient evidence of effectiveness (Fiore et al., 2008), yet nicotine patches have FDA-approved labeling that includes dosing recommendations for patients smoking <10 cigarettes/day. Bars MP, Banauch GI, Appel D, Andreachi M, Mouren P et al. (2006). "Tobacco Free With FDNY": the New York City Fire Department World Trade Center tobacco cessation study. Chest 129: Benowitz NL, Zevin S, Jacob P, 3rd. (1998). Suppression of nicotine intake during ad libitum cigarette smoking by high-dose transdermal nicotine. J Pharmacol Exp Ther 287:958–962. Dale LC, Hurt RD, Offord KP, Lawson GM. (1995). High-dose nicotine patch therapy; percentage of replacement and smoking cessation. JAMA 274:1353–1358. Fredrickson PA, Hurt RD, Lee GM, et al. (1995). Safety and tolerability of high dose transdermal nicotine therapy for heavy smokers. Psychopharmacology 122:215– 222. Hughes JR, Lesmes GR, Hatsukami DK, et al. (1999). Are higher doses of nicotine replacement more effective for smoking cessation? Nicotine Tob Res 1:169–174. Hurt RD, Krook JE, Croghan IT, et al. (2003). Nicotine patch therapy based on smoking rate followed by bupropion for prevention of relapse to smoking. J Clin Oncol 21:914–920. Jorenby D, Smith SS, Fiore MC, et al. (1995). Varying nicotine patch dose and type of smoking cessation counseling. JAMA 274:1347–1352. Kalman D, Kahler CW, Garvey AJ, Monti PM. (2006). High-dose nicotine patch therapy for smokers with a history of alcohol dependence: 36-week outcomes. J Subst Abuse Treat 30:213–217. Killen JD, Fortmann SP, Davis L, Strausberg L, Varady A. (1999). Do heavy smokers benefit from higher dose nicotine patch therapy? Exp Clin Psychopharmacol 7:226–233. Paoletti P, Fornai E, Maggiorelli F, Puntoni R, Viegi G, et al. (1996). Importance of baseline cotinine plasma values in smoking cessation: Results from a double-blind study with nicotine patch. Eur Respir J 9:643–651. Rose JE, Behm FM, Drgon T, Johnson C, Uhl GR. (2010). Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular Medicine 16:247–53. Shiffman S, Elash CA, Paton SM, et al. (2000). Comparative efficacy of 24-hour and 16-hour transdermal nicotine patches for relief of morning craving. Addiction 95:1185–1195. Stead LF, Perera R, Bullen C, Mant D, Hartmann-Boyce J, Cahill K, Lancaster T. (2012). Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 1:CD Tonnesen P, Paoletti P, Gustavsson G, et al. (1999). Higher dosage nicotine patches increase one-year smoking cessation rates: Results from the European CEASE trial. Collaborative European Anti-Smoking Evaluation. European Respiratory Society. Eur Respir J 13:238–246.

101 TRANSDERMAL NICOTINE PATCH: DIRECTIONS for USEChoose an area of skin on the upper body or upper outer part of the arm Make sure skin is clean, dry, hairless, and not irritated Apply patch to different area each day Do not use same area again for at least 1 week Transdermal nicotine patch: Directions for use Choose an area of skin on the upper body or the upper outer part of the arm. To ensure that the patch will adhere well, make sure the skin is nonhairy, clean (not oily), dry, and free of creams, lotions, oils, or powder. Do not apply the patch to skin that is inflamed, burned, broken out, or irritated in any way. These conditions may alter the amount of drug absorbed. The patch should be applied to a different area each day. To minimize the potential for local skin reactions, the same area should not be used again for at least 1 week.

102 TRANSDERMAL NICOTINE PATCH: DIRECTIONS for USE (cont’d)Remove patch from protective pouch Peel off half of the backing from patch Transdermal nicotine patch: Directions for use (cont’d) Remove the patch from the protective pouch (save pouch for later disposal of used patch). Remove half of the protective liner from the patch. Try not to touch the exposed adhesive (i.e., the sticky side) because nicotine on hands can get into the eyes or nose and cause stinging or redness.

103 TRANSDERMAL NICOTINE PATCH: DIRECTIONS for USE (cont’d)Apply adhesive side of patch to skin Peel off remaining protective covering Press firmly with palm of hand for 10 seconds Make sure patch sticks well to skin, especially around edges Transdermal nicotine patch: Directions for use (cont’d) Immediately apply the sticky side of the patch to the skin. Peel off the remaining half of the protective covering. Press the patch firmly on the skin with the palm of the hand for 10 seconds. Make sure the patch sticks well to the skin, especially around the edges. This is necessary to ensure a good seal.

104 TRANSDERMAL NICOTINE PATCH: DIRECTIONS for USE (cont’d)Wash hands: Nicotine on hands can get into eyes or nose and cause stinging or redness Do not leave patch on skin for more than 24 hours— doing so may lead to skin irritation Adhesive remaining on skin may be removed with rubbing alcohol or acetone Dispose of used patch by folding it onto itself, completely covering adhesive area Transdermal nicotine patch: Directions for use (cont’d) Wash hands after patch application, because nicotine on hands could get into the eyes or nose and cause stinging or redness. After 24 hours, remove the old patch; the patch should not be left on the skin for more than 24 hours, because this may lead to skin irritation. Any adhesive remaining on the skin may be removed with rubbing alcohol or acetone. Dispose of a used patch by folding it onto itself, completely covering the adhesive area.

105 TRANSDERMAL NICOTINE PATCH: ADDITIONAL PATIENT EDUCATIONWater will not harm the nicotine patch if it is applied correctly; patients may bathe, swim, shower, or exercise while wearing the patch Do not cut patches to adjust dose Nicotine may evaporate from cut edges Patch may be less effective Keep new and used patches out of the reach of children and pets Remove patch before MRI procedures Water will not harm the nicotine patch if it is applied correctly. Patients may bathe, swim, shower, or exercise while wearing the patch. Some patients might ask about cutting patches in half during the dose tapering phase to save money. It is important to tell patients that they should not cut patches to adjust the dose. Nicotine in the patch may evaporate from the cut edges and the patch may be less effective. Keep new and used patches out of the reach of children and pets. Burns from nicotine patches worn during an MRI have been reported, and are likely caused by the metallic component in the backing of some patches. For this reason, the Institute for Same Medical Practices recommends that nicotine patches be removed prior to MRI procedures (Institute for Safe Medical Practices, 2004). Institute for Safe Medical Practices. (2004, April 8). Burns in MRI patients wearing transdermal patches. Medication Safety Alert! 9(7). Retrieved December 30, 2014, from https://www.ismp.org/newsletters/acutecare/articles/ asp

106 TRANSDERMAL NICOTINE PATCH: ADD’L PATIENT EDUCATION (cont’d)Side effects to expect in first hour: Mild itching Burning Tingling Additional possible side effects: Vivid dreams or sleep disturbances Headache Shortly after applying the nicotine patch, patients may experience the following side effects: Mild itching Burning Tingling These effects are normal and should resolve within an hour. Additional possible side effects include the following: Vivid dreams or sleep disturbances. Patients should be advised to remove the patch at bedtime if this side effect becomes troublesome. Headache

107 TRANSDERMAL NICOTINE PATCH: ADD’L PATIENT EDUCATION (cont’d)After patch removal, skin may appear red for 24 hours If skin stays red more than 4 days or if it swells or a rash appears, contact health care provider—do not apply new patch Local skin reactions (redness, burning, itching) Usually caused by adhesive Up to 50% of patients experience this reaction Fewer than 5% of patients discontinue therapy Avoid use in patients with dermatologic conditions (e.g., psoriasis, eczema, atopic dermatitis) After removal, the skin under the patch may appear red for the next 24 hours. If a skin rash develops after the use of a nicotine patch, or if the skin under the patch becomes swollen or very red, the patient should contact a health care professional. The patient should not apply a new patch. Local skin reactions (redness, burning, itching) These reactions are usually caused by irritation resulting from skin occlusion or from a reaction to the adhesives. Up to 50% of patients experience local skin reactions. Fewer than 5% of patients discontinue therapy: Make certain patient is rotating patch application sites. Consider different brand of patch. Each manufacturer uses different adhesives. Consider treating skin reactions with OTC hydrocortisone cream (1%) or oral antihistamines. Patients with dermatologic conditions (e.g., psoriasis, eczema, atopic dermatitis) are more likely to experience skin irritation and should not use the nicotine patch.

108 TRANSDERMAL NICOTINE PATCH: SUMMARYADVANTAGES Once daily dosing associated with fewer adherence problems Of all NRT products, its use is least obvious to others Can be used in combination with other agents; delivers consistent nicotine levels over 24 hrs DISADVANTAGES When used as monotherapy, cannot be titrated to acutely manage withdrawal symptoms Not recommended for use by patients with dermatologic conditions (e.g., psoriasis, eczema, atopic dermatitis) Advantages of the nicotine patch include the following: Once daily dosing associated with fewer adherence problems Of all NRT products, its use is least obvious to others Can be used in combination with other agents; delivers consistent nicotine levels over 24 hours Disadvantages of the patch include the following: When used as monotherapy, cannot be titrated to to acutely manage withdrawal symptoms. Not recommended for us by patients with dermatologic conditions (e.g., psoriasis, eczema, atopic dermatitis) because they are more likely to experience skin irritation.

109 NICOTINE NASAL SPRAY Nicotrol NSAqueous solution of nicotine in a 10-ml spray bottle Each metered dose actuation delivers 50 mcL spray 0.5 mg nicotine ~100 doses/bottle Rapid absorption across nasal mucosa  FDA approved: March 1996 (prescription only) Description of Product Nicotrol NS (Pfizer) is an aqueous solution of nicotine available in a metered-spray pump for administration to the nasal mucosa. Each actuation delivers a metered 50-µL spray containing 0.5 mg of nicotine. Each bottle contains approximately 100 doses (200 sprays) or about a 1-week supply (Pfizer, 2010). Nicotine is absorbed rapidly, and plasma nicotine concentrations attained via the nasal spray are comparable to (but lower than) those achieved by smoking. The nasal spray has a faster onset of action (tmax 11–13 minutes) compared to the gum, patch, or inhaler (Schneider et al., 1996). ♪ Note to instructor(s): The nicotine nasal spray has a higher dependence potential relative to other NRT formulations but a lower dependence potential relative to tobacco products. About 13–20% of patients continue to use the nicotine nasal spray for longer periods than recommended (6–12 months) (Fiore et al., 2008; Hajek et al., 2007), and 5% use the spray at higher doses than recommended (Fiore et al., 2008). Clinical Efficacy (Fiore, et al., 2008) In a meta-analysis of four trials, the nicotine nasal spray was found to significantly improve quit rates compared to placebo. The effectiveness and abstinence rates at 6-months post-quit date are as follows Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. Hajek P, McRobbie H, Gillison F. (2007). Dependence potential of nicotine replacement treatments: effects of product type, patient characteristics, and cost to user. Prev Med 44:230–234. Pfizer Inc. (2010, January). Nicotrol NS Package Insert. New York, NY. Schneider NG, Lunell E, Olmstead RE, Fagerström KO. (1996). Clinical pharmacokinetics of nasal nicotine delivery. A review and comparison to other nicotine systems. Clin Pharmacokinet 31:65–80. Treatment Estimated odds ratio (95% CI) Estimated abstinence rate (95% CI) Placebo 1.0 13.8% Nicotine nasal spray 2.3 (1.7–3.0) 26.7% (21.5–32.7)

110 NICOTINE NASAL SPRAY: DOSING & ADMINISTRATIONOne dose = 1 mg nicotine (2 sprays, one 0.5 mg spray in each nostril) Start with 1–2 doses per hour Increase prn to maximum dosage of 5 doses per hour or 40 mg (80 sprays; ~½ bottle) daily For best results, patients should use at least 8 doses daily for the first 6–8 weeks Termination: Gradual tapering over an additional 4–6 weeks One dose is 1 mg of nicotine—two sprays, one (0.5 mg spray) in each nostril. The manufacturer’s recommended starting regimen is one or two doses per hour for 6–8 weeks. This may be increased up to a maximum recommended dose of 40 mg/day (80 sprays, about half a bottle). For best results, patients should be encouraged to use at least the recommended minimum of 8 doses per day during the first 6–8 weeks of therapy. Less frequent administration may be less effective. After 6–8 weeks, the dose should be decreased gradually over an additional 4–6 weeks.

111 NICOTINE NASAL SPRAY: DIRECTIONS for USEPress in circles on sides of bottle and pull to remove cap Nicotine nasal spray: Directions for use Remove the cap. Using your thumb and index finger, press in on the circles on the sides of the bottle. Pull off the cap. Note: This child-resistant cap can be very difficult to remove. It is important to press firmly on the circles on the side of the bottle to unlock the cap. ♪ Note to instructor(s): If a placebo unit is available, demonstrate for participants. Pass around sample for class to see and handle.

112 NICOTINE NASAL SPRAY: DIRECTIONS for USE (cont’d)Prime the pump (before first use) Re-prime (1-2 sprays) if spray not used for 24 hours Blow nose (if not clear) Tilt head back slightly and insert tip of bottle into nostril as far as comfortable Breathe through mouth, and spray once in each nostril Do not sniff or inhale while spraying Nicotine nasal spray: Directions for use (cont’d) Before using the nasal spray for the first time, the pump must be primed. This is done by actuating the device into a tissue: Hold the bottle and press firmly on the glass bottom of the unit with thumb. Pump into the tissue until a fine spray is visible (about 6–8 times). The tissue should be discarded after use. If the pump is not used for 24 hours, it should be primed into a tissue 1–2 times. To minimize drug wastage, avoid excessive priming. Before using the spray, blow nose if it is not clear. Tilt head back slightly and insert the tip of the bottle into the nostril as far as is comfortable. Breathe through the mouth, and spray once in each nostril. Do not sniff, swallow, or inhale through the nose while administering the medication because this increases the irritating effects of the spray.

113 NICOTINE NASAL SPRAY: DIRECTIONS for USE (cont’d)If nose runs, gently sniff to keep nasal spray in nose Wait 2–3 minutes before blowing nose Avoid contact with skin, eyes, and mouth If contact occurs, rinse with water immediately Nicotine is absorbed through skin and mucous membranes Nicotine nasal spray: Directions for use (cont’d) If nose runs, gently sniff to keep nasal spray in the nose. Wait 2–3 minutes before blowing nose to allow the nicotine to be absorbed across the nasal mucosa. Place the cap back on the bottle after use and avoid contact with skin, eyes, and mouth. If contact occurs, rinse immediately with water, because nicotine is readily absorbed across the skin and mucous membranes.

114 NICOTINE NASAL SPRAY: ADDITIONAL PATIENT EDUCATIONWhat to expect (first week): Hot peppery feeling in back of throat or nose Sneezing Coughing Watery eyes Runny nose Side effects should lessen over a few days Regular use during the first week will help in development of tolerance to the irritant effects of the spray If side effects do not decrease after a week, contact health care provider What to expect during first week (Pfizer, 2010): Hot peppery feeling in the back of the throat or nose Sneezing Coughing Watery eyes Runny nose These adverse effects should lessen over a few days. Regular use during the first week will help the patient adapt to the irritant effects of the spray. Some investigators have found that with regular use during the first week, tolerance to the irritant effects of the spray develops (Benowitz et al., 1997). However, the irritant effects of the spray should not be minimized because nasal or airway reactions are common (Fiore et al., 2008): 94% of patients report moderate-to-severe irritation in the first 2 days of therapy. 81% still report nasal irritation (mild to moderate) after 3 weeks. If side effects do not lessen after a week, patients should be advised to contact their health care provider and consider alternative treatments. . ♪ Note to instructor(s): Because of the potential for tearing, coughing, and sneezing, it is reasonable to advise patients to wait 5 minutes before driving or operating heavy machinery. Benowitz NL, Zevin S, Jacob P. (1997). Sources of variability in nicotine and cotinine levels with use of nicotine nasal spray, transdermal nicotine and cigarette smoking. Br J Clin Pharmacol 43;259–267. Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. Pfizer Inc. (2010, January). Nicotrol NS Package Insert. New York, NY.

115 NICOTINE NASAL SPRAY: SUMMARYADVANTAGES Can be titrated to rapidly manage withdrawal symptoms Can be used in combination with other agents to manage situational urges DISADVANTAGES Need for frequent dosing can compromise adherence Nasal administration might not be acceptable/desirable for some patients; nasal irritation often problematic Not recommended for use by patients with chronic nasal disorders or severe reactive airway disease Advantages of the nicotine nasal spray include the following: Can be titrated to rapidly manage withdrawal symptoms. Can be used in combination with other agents to manage situational urges for tobacco. Disadvantages of the nasal spray include the following: Need for frequent dosing can compromise adherence. Nasal administration might not be acceptable or desirable for some patients; nasal irritation often problematic. Because of the irritant effects of the spray, not recommended for use by patients with chronic nasal disorders (e.g., rhinitis, polyps, sinusitis) or patients with severe reactive airway disease. Asthma exacerbation has been noted in some patients after administration of nicotine nasal spray.

116 NICOTINE INHALER Nicotrol InhalerNicotine inhalation system consists of: Mouthpiece Cartridge with porous plug containing 10 mg nicotine and 1 mg menthol Delivers 4 mg nicotine vapor, absorbed across buccal mucosa FDA approved: May 1997 (prescription only) Description of Product The Nicotrol Inhaler (nicotine inhalation system; Pfizer) consists of a mouthpiece and a plastic cartridge delivering 4 mg of nicotine as an inhaled vapor from a porous plug containing 10 mg of nicotine and 1 mg of menthol (Pfizer, 2008). Menthol is added to decrease the irritant effects of nicotine (Schneider et al., 2001). Given that the usual pack-a-day smoker repeats the hand-to-mouth motion up to 200 times per day or 73,000 times each year, it is not surprising that many smokers find they miss the physical manipulation of the cigarette and associated behaviors that go with smoking. The nicotine inhaler was designed to provide nicotine replacement in a manner similar to smoking while addressing the sensory and ritualistic factors important to many smokers (Schneider et al., 2001). As a patient puffs on the inhaler mouthpiece, buccal nicotine vapor is released and delivers nicotine to the mouth and throat, where it is absorbed through the mucosa. Less than 5% of the nicotine in a dose reaches the lower respiratory tract. With an intensive inhalation regimen (80 puffs over 20 minutes), about 4 mg of nicotine is delivered and, of that, 2 mg is absorbed. Plasma nicotine levels are 50–70% lower than those achieved with cigarette smoking, and peak nicotine concentrations occur after 30 minutes, compared to 5 minutes after cigarette smoking (Schneider et al., 2001). Clinical Efficacy (Fiore et al., 2008) In a meta-analysis of six trials, the nicotine nasal spray was found to significantly improve quit rates compared to placebo. The effectiveness and abstinence rates at 6-months post-quit date are as follows: Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. Pfizer Inc. (2008, December). Nicotrol Inhaler Package Insert. New York, NY. Schneider NG, Olmstead RE, Franzon MA, Lunell E. (2001). The nicotine inhaler. Clinical pharmacokinetics and comparison with other nicotine treatments. Clin Pharmacokinet 40:661–684. Treatment Estimated odds ratio (95% CI) Estimated abstinence rate (95% CI) Placebo 1.0 13.8% Nicotine inhaler 2.1 (1.5–2.9) 24.8% (19.1–31.6)

117 NICOTINE INHALER: DOSINGStart with at least 6 cartridges/day during the first 3-6 weeks of treatment Increase prn to maximum of 16 cartridges/day In general, use 1 cartridge every 1-2 hours Recommended duration of therapy is 3 months Gradually reduce daily dosage over the following 6–12 weeks The initial dose for the inhaler should be individualized. Patients should titrate the dose to the level of nicotine that alleviates withdrawal symptoms. The best effects are achieved by frequent continuous puffing (20 minutes). In clinical trials, the average daily dose was more than 6 cartridges (range 3–18) for patients who successfully quit smoking (Pfizer, 2008). Patients should start with at least 6 cartridges per day during the first 3–6 weeks of treatment and increase as needed to a maximum of 16 cartridges per day. In general, patients should use 1 cartridge every 1–2 hours during the initial 6 weeks of treatment. The recommended duration of treatment is up to 3 months, after which patients may be weaned from the inhaler by gradual reduction of the daily dose over the following 6–12 weeks. Pfizer Inc. (2008, December). Nicotrol Inhaler Package Insert. New York, NY.

118 NICOTINE INHALER: SCHEMATIC DIAGRAMAir/nicotine mixture out Sharp point that breaks the seal Aluminum laminate sealing material This schematic diagram depicts the key components of the nicotine inhalation system. The nicotine inhaler consists of a two-piece plastic unit designed to deliver nicotine contained in individual cartridges. Each foil-sealed cartridge contains a porous plug impregnated with 10 mg of nicotine and 1 mg of menthol. Sharp spikes found on the interior of both mouthpiece components pierce the protective foil covering, allowing the release of nicotine vapor following inhalation. Schneider NG, Olmstead RE, Franzon MA, Lunell E. (2001). The nicotine inhaler. Clinical pharmacokinetics and comparison with other nicotine treatments. Clin Pharmacokinet 40:661–684. Sharp point that breaks the seal Mouthpiece Porous plug impregnated with nicotine Nicotine cartridge Air in Reprinted with permission from Schneider et al. (2001). Clinical Pharmacokinetics 40:661–684. Adis International, Inc.

119 NICOTINE INHALER: DIRECTIONS for USEAlign marks on the mouthpiece ♪ Note to instructor(s): If available, demonstrate the use of inhaler with a placebo nicotine inhaler. Have each participant assemble and use a placebo inhaler unit. Nicotine inhaler: Directions for use Align the marks on the mouthpiece.

120 NICOTINE INHALER: DIRECTIONS for USE (cont’d)Pull and separate mouthpiece into two parts Nicotine inhaler: Directions for use (cont’d) Pull and separate the mouthpiece into two parts.

121 NICOTINE INHALER: DIRECTIONS for USE (cont’d)Press nicotine cartridge firmly into bottom of mouthpiece until it pops down into place Nicotine inhaler: Directions for use (cont’d) Press the nicotine-containing cartridge firmly into the bottom of the mouthpiece until it pops down into place (e.g., the seal breaks). Line up the markings on the mouthpiece again and push the two pieces back together so they fight tightly (e.g., press down firmly to break the top seal on the cartridge) Twist the top piece to misalign the marks and secure the unit. The nicotine inhaler is now ready for use. Line up the markings on the mouthpiece again and push the two pieces back together so they fit tightly Twist top to misalign marks and secure unit

122 NICOTINE INHALER: DIRECTIONS for USE (cont’d)During inhalation, nicotine is vaporized and absorbed across oropharyngeal mucosa Inhale into back of throat or puff in short breaths Nicotine in cartridges is depleted after about 20 minutes of active puffing Cartridge does not have to be used all at once—try different schedules (e.g., 5 minutes at a time) to find what works best Open cartridge retains potency for 24 hours Mouthpiece is reusable; clean regularly with mild detergent Nicotine inhaler: Directions for use (cont’d) When inhaled or puffed through the mouthpiece, nicotine turns into a vapor that is absorbed across the oropharyngeal mucosa. Inhale into the back of throat or puff in short breaths. ♪ Note to instructor(s): Patients should be instructed not to inhale into the lungs (like a cigarette) but to puff as if lighting a pipe. Deep inhalation into the lungs increases the delivery of nicotine and increases the incidence of adverse effects. Nicotine in the cartridges is depleted after about 20 minutes of active puffing: The 20-minute supply is not necessarily meant to be used at one time. Advise patients to try different schedule to help control cravings. Patients can use the inhaler for just a few minutes, put it down, and then pick it up later and use it again for a total of 20 minutes of active puffing per cartridge (~ 80 puffs). Puffing on the inhaler for 5 minutes at a time will provide enough nicotine for 4 uses. Over time, the patient will determine what works bests and will know when the nicotine in a cartridge is depleted. An open cartridge retains potency for 24 hours. Once opened, each cartridge, whether fully used or not, should be replaced after 24 hours. When the cartridge is empty, remove the top of mouthpiece and throw the used cartridge away, out of reach of children and pets. The mouthpiece is reusable and should be cleaned regularly with a mild detergent and water.

123 NICOTINE INHALER: ADDITIONAL PATIENT EDUCATIONSide effects associated with the nicotine inhaler include: Mild irritation of the mouth or throat Cough Headache Rhinitis Dyspepsia Severity generally rated as mild, and frequency of symptoms declined with continued use When initiating treatment, local irritation of the mouth or throat (40%), cough (32%), headache (26%), rhinitis (23%) and dyspepsia (18%) may occur. The majority of patients rated cough and mouth and throat irritation symptoms as mild, decreasing with continued use (Fiore et al., 2008; Pfizer, 2008). Other less common adverse effects include taste disturbances, nausea, diarrhea, and hiccups (Pfizer, 2008). Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. Pfizer Inc. (2008, December). Nicotrol Inhaler Package Insert. New York, NY.

124 NICOTINE INHALER: ADD’L PATIENT EDUCATION (cont’d)Use inhaler at room temperature (>60F); in cold environments, the delivery of nicotine vapor may be compromised Use the inhaler longer and more often at first to help control cravings (best results are achieved with frequent continuous puffing over 20 minutes) Effectiveness of the nicotine inhaler may be reduced by some foods and beverages Release of nicotine from the porous plug is dependent on the vapor pressure of nicotine, which is dependent on the air temperature passing through the plug. Under colder conditions (≤59F), less nicotine is delivered per puff. For this reason, the manufacturer recommends that the inhaler be used at room temperatures (>60F) for optimal use (Pfizer, 2008). Conversely, under warmer conditions more nicotine is released per puff. However, nicotine plasma concentrations achieved using the inhaler in hot climates at maximal doses will not exceed levels normally achieved with smoking (Schneider et al., 2001). Best results are achieved with frequent continuous puffing over 20 minutes. The inhaler should be used longer and more often at first to help control cigarette cravings. Less nicotine per puff is released from the inhaler compared to a cigarette. The effectiveness of the nicotine inhaler may be reduced by some foods and beverages, such as coffee, juices, wine, or soft drinks. Therefore, patients should be instructed not to eat or drink anything other than water for 15 minutes before or while using the inhaler. Acidic beverages may transiently reduce the pH of the saliva below that necessary for optimal buccal absorption of nicotine. Pfizer Inc. (2008, December). Nicotrol Inhaler Package Insert. New York, NY. Schneider NG, Olmstead RE, Franzon MA, Lunell E. (2001). The nicotine inhaler. Clinical pharmacokinetics and comparison with other nicotine treatments. Clin Pharmacokinet 40:661–684. Do NOT eat or drink for 15 minutes BEFORE or while using the nicotine inhaler.

125 NICOTINE INHALER: SUMMARYADVANTAGES Might serve as an oral substitute for tobacco Can be titrated to manage withdrawal symptoms Mimics the hand-to-mouth ritual of smoking Can be used in combination with other agents to manage situational urges DISADVANTAGES Need for frequent dosing can compromise adherence Cartridges might be less effective in cold environments (≤60F) Advantages of the nicotine inhaler include the following: Might serve as an oral substitute for tobacco. Can be titrated to manage withdrawal symptoms. Mimics the hand-to-mouth ritual of smoking (could be perceived as a disadvantage to some). Can be used in combination with other agents to manage situational urges. Disadvantages of the inhaler include the following: Need for frequent dosing can compromise adherence. Cartridges might be less effective in cold environments (≤60F)

126 BUPROPION SR Zyban; genericsNonnicotine cessation aid Sustained-release antidepressant Oral formulation FDA approved for smoking cessation: May 1997 (prescription only), generic approved in 2004 Description of Product Bupropion sustained-release (SR) tablets are an oral antidepressant medication used as a nonnicotine aid to smoking cessation (GlaxoSmithKline, 2014). The same chemical agent is marketed as Wellbutrin for use in treating depression. Clinical Efficacy (Fiore et al., 2008) In a meta-analysis of 24 trials, bupropion was found to significantly improve quit rates compared to placebo. The effectiveness and abstinence rates at 6-months post-quit date are as follows: Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. GlaxoSmithKline Inc. (2016, June). Zyban Package Insert. Research Triangle Park, NC. Treatment Estimated odds ratio (95% CI) Estimated abstinence rate (95% CI) Placebo 1.0 13.8% Bupropion SR 2.0 (1.8–2.2) 24.2% (22.2–26.4)

127 BUPROPION: MECHANISM of ACTIONAtypical antidepressant thought to affect levels of various brain neurotransmitters Dopamine Norepinephrine Clinical effects  craving for cigarettes  symptoms of nicotine withdrawal Bupropion is an atypical antidepressant thought to affect the levels of brain neurotransmitters (e.g., dopamine, norepinephrine). The purported mechanisms of action include blockade of neuronal re-uptake of dopamine and norepinephrine in the central nervous system and through antagonism of nicotinic acetylcholine receptors. The actions result in reduced craving for nicotine and symptoms of withdrawal (Fiore et al., 2008). Recall that the dopaminergic system is thought to play a role in self-reinforcing behavior (reward pathways) and dependence, whereas noradrenergic effects are thought to prevent the symptoms of nicotine withdrawal. Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service.

128 BUPROPION: CONTRAINDICATIONSPatients with a seizure disorder Patients with a current or prior diagnosis of bulimia or anorexia nervosa Patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates and antiepileptic drugs Patients taking MAO inhibitors (within 14 days of initiating or discontinuing therapy) The following are contraindications for the use of bupropion SR (GlaxoSmithKline, 2014): In patients with a seizure disorder. In patients with a current or prior diagnosis of bulimia or anorexia nervosa as a higher incidence of seizures was observed in such patients treated with the immediate-release formulation of bupropion. In patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs. Use of MAO inhibitors (intended to treat psychiatric disorders; isocarboxazid, phenelzine, tranylcypromine) concomitantly with bupropion or within 14 days of discontinuing treatment with bupropion is contraindicated. There is an increased risk of hypertensive reactions when bupropion is used concomitantly with MAO inhibitors. The use of bupropion within 14 days of discontinuing treatment with an MAO inhibitors is also contraindicated. Starting bupropion in a patient treated with reversible MAO inhibitors such as linezolid or intravenous methylene blue is contraindicated. GlaxoSmithKline Inc. (2016, June). Zyban Package Insert. Research Triangle Park, NC.

129 BUPROPION: WARNINGS and PRECAUTIONSNeuropsychiatric symptoms and suicide risk Changes in mood (including depression and mania) Psychosis/hallucinations/paranoia/delusions Homicidal ideation Aggression/hostility/anxiety/panic Suicidal ideation, suicide attempt, completed suicide FDA boxed warning removed Dec 2016 In July 2009, the FDA mandated that the prescribing information for all bupropion-containing products include a black-boxed warning highlighting the risk of serious neuropsychiatric events, including but not limited to depression, suicidal ideation, suicide attempt and completed suicide. These additional warnings were based on post-marketing adverse event surveillance reports received by the FDA (FDA, 2016). The box associated with this warning was removed on December 16, 2016 based on results from a mandated clinical trial. According to the manufacturer’s prescribing information, serious neuropsychiatric symptoms including changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide have been reported (GlaxoSmithKline, 2016). Patients and caregivers should be advised to stop taking the medication and contact a healthcare provider immediately if agitation, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. Clinicians should be aware that patients with serious psychiatric illness (e.g., depression, schizophrenia, bipolar disorder) can also benefit from use of varenicline while quitting smoking without significant increase in neuropsychiatric adverse events associated with bupropion SR use (Anthenelli et al., 2016). Anthenelli RM, Benowitz NL, West R, St Aubin L, McRae T, et al. (2016). Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet 387(10037):2507–2250. Food and Drug Administration (2016, December). Information for healthcare professionals: varenicline (marketed as Chantix) and bupropion (marketed as Zyban, Wellbutrin, and generics). Available at: Retrieved January 5, 2017. GlaxoSmithKline Inc. (2016, June). Zyban Package Insert. Research Triangle Park, NC. Advise patients to stop taking bupropion SR and contact a health care provider immediately if symptoms such as agitation, depressed mood, or changes in behavior or thinking that are not typical are observed or if the patient develops suicidal ideation or suicidal behavior.

130 BUPROPION: WARNINGS and PRECAUTIONS (cont’d)Bupropion should be used with caution in the following populations: Patients with an elevated risk for seizures, including: Severe head injury Concomitant use of medications that lower the seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic antidepressants, theophylline) Severe hepatic impairment Patients with underlying neuropsychiatric conditions Bupropion should be used with caution in patients with an elevated risk for seizures including: severe head injury; arteriovenous malformation; CNS tumor or CNS infection; severe stroke and concomitant use of other medications that lower the seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids) (GlaxoSmithKline, 2014). Bupropion also should be used cautiously in patients with severe hepatic impairment (GlaxoSmithKline, 2014). In these patients a reduced frequency of dosing is required, because peak bupropion levels are substantially increased and drug accumulation is likely to occur to a greater extent. The dose should not exceed 150 mg every other day in these patients. Bupropion should be used with caution in patients with underlying neuropsychiatric conditions. As with most antidepressant agents, bupropion has a black-box warning that specifies that the drug should be used with caution in patients with major depressive disorder (both adult and pediatric) as these patients might experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior. These effects tend to be more prevalent in children, adolescents, and young adults (ages years). Prior to initiating treatment with bupropion, patients with depressive symptoms should be adequately screened to determine whether they are at risk for bipolar disorder (GlaxoSmithKline, 2014). It is advisable to consult with a psychiatrist before initiating bupropion therapy in a patient with depressive or psychiatric disorders. ♪ Note to instructor(s): Because the incidence of seizures is dose related, clinicians should not prescribe doses over 300 mg/day for smoking cessation or use concomitantly with other bupropion formulations (Wellbutrin, Wellbutrin SR, or Wellbutrin XL). GlaxoSmithKline Inc. (2016, June). Zyban Package Insert. Research Triangle Park, NC. For a comprehensive listing of warnings and precautions, refer to the manufacturer’s prescribing information.

131 BUPROPION SR: DOSING Initial treatment Then… 150 mg po q AM for 3 daysTo ensure that therapeutic plasma levels of the drug are achieved, patients should begin therapy 1 to 2 weeks PRIOR to their quit date. Initial treatment 150 mg po q AM for 3 days Then… 150 mg po bid for 7–12 weeks Doses must be administered at least 8 hours apart Tapering not necessary when discontinuing therapy Treatment with bupropion SR should be initiated while the patient is still smoking, because approximately 1 week of treatment is required to achieve steady-state blood levels. Patients should set a “target quit date” that falls within the first 2 weeks of treatment (GlaxoSmithKline, 2014). The starting dose of bupropion SR is one 150-mg tablet each morning for the first 3 days. If the initial dose is tolerated, the dosage should be increased on day 4 to the recommended, maximum dosage of 300 mg/day, given as two 150-mg doses administered at least 8 hours apart. Doses above 300 mg/day should not be used. The recommended duration of therapy is 7–12 weeks; however, some patients may benefit from extended treatment. According to the manufacturer, patients who successfully quit after 12 weeks of treatment but do not feel ready to discontinue treatment should be considered for ongoing therapy and longer treatment should be guided by the relative benefits and risks for individual patients (GlaxoSmithKline, 2014). A meta-analysis of seven trials evaluating extended use of bupropion (25-52 weeks) found a slight benefit for relapse prevention relative to controls (Hughes et al., 2014). ♪ Note to instructor(s): For patients experiencing side effects with the 300 mg/day regimen, data suggest that 150 mg/day is better tolerated and exhibits comparable long-term efficacy (Swan, 2003). Similarly, Hurt and colleagues (1997) found no significant difference in long-term (>6 months) abstinence rates between subjects randomized to 150 mg/day or 300 mg/day. GlaxoSmithKline Inc. (2016, June). Zyban Package Insert. Research Triangle Park, NC. Hughes JR, Stead LF, Hartmann-Boyce J, Cahill K, Lancaster T. (2014). Antidepressants for smoking cessation. Cochrane Database Syst Rev 1:CD Hurt RD, Sachs DP, Glover ED, et al. (1997). A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 337:1195–1202. Swan GE, McAfee T, Curry SJ, et al. (2003). Effectiveness of bupropion sustained release for smoking cessation in a health care setting: a randomized trial. Arch Intern Med 163:2337–2344.

132 BUPROPION: ADVERSE EFFECTSCommon side effects include the following: Insomnia (avoid bedtime dosing) Dry mouth Less common but reported effects: Tremor Skin rash The most commonly observed adverse reactions include insomnia (31–45%) and dry mouth (10–11%). These adverse reactions might be minimized by reducing the dose. Insomnia might be minimized by avoiding bedtime administration (GlaxoSmithKline, 2014). Adverse effects that are less common but sometimes lead to discontinuation of treatment include nervous system disturbances (3%; primarily tremors) and skin disorders (2%; primarily rashes) (GlaxoSmithKline, 2014). ♪ Note to instructor(s): While seizures are an important potential adverse effect associated with bupropion therapy, clinicians should know that the reported frequency of seizures with bupropion SR in clinical trials for smoking cessation is <0.1% (10 seizures among 13,000 bupropion-treated patients) (Hughes et al, 2014). While seizures are relatively rare, bupropion should not be used in patients with a seizure disorder, current or prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs. The drug should be used with caution in patients with an increased risk of seizure including: severe head injury; arteriovenous malformation; CNS tumor or CNS infection; severe stroke; concomitant use of other medications that lower the seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids), metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia), use of illicit drugs (e.g., cocaine), or abuse or misuse of prescription drugs such as CNS stimulants (GlaxoSmithKline, 2014) GlaxoSmithKline Inc. (2016, June). Zyban Package Insert. Research Triangle Park, NC. Hughes JR, Stead LF, Hartmann-Boyce J, Cahill K, Lancaster T. (2014). Antidepressants for smoking cessation. Cochrane Database Syst Rev 1:CD

133 BUPROPION SR: SUMMARY ADVANTAGES DISADVANTAGESOral dosing is simple and associated with fewer adherence problems Might delay weight gain Bupropion might be beneficial in patients with depression Can be used in combination with NRT agents DISADVANTAGES Seizure risk is increased Several contraindications and precautions preclude use in some patients Patients should be monitored for neuropsychiatric symptoms Advantages of bupropion SR include the following: Oral dosing is simple and associated with fewer adherence problems Might delay weight gain. Bupropion SR might be beneficial for use in patients with coexisting depression. Some data suggest that use of bupropion may increase long-term cessation in smokers with past depression (van der Meer et al., 2013). Can be used in combination with NRT agents Disadvantages of bupropion SR include the following: Seizure risk is increased Several contraindications and precautions preclude use in some patients Patients should be monitored for neuropsychiatric symptoms van der Meer RM, Willemsen MC, Smit F, Cuijpers P. (2013). Smoking cessation interventions for smokers with current or past depression. Cochrane Database Syst Rev 8:CD

134 Estimated abstinence rate (95% CI)VARENICLINE Chantix Nonnicotine cessation aid Partial nicotinic receptor agonist Oral formulation FDA approved for smoking cessation: May 11, 2006 (prescription only) Description of Product (Pfizer, 2016) Varenicline is a partial agonist selective for the 42 nicotinic acetylcholine receptor indicated for use as an aid to smoking cessation treatment. Clinical Efficacy (Fiore et al., 2008) In a meta-analysis of four trials, varenicline was found to significantly improve quit rates compared to placebo. The effectiveness and abstinence rates at 6-months post-quit date are as follows: Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. Pfizer Inc. (2016, December). Chantix Package Insert. New York, NY. Treatment Estimated odds ratio (95% CI) Estimated abstinence rate (95% CI) Placebo 1.0 13.8% Varenicline (1 mg/day) 2.1 (1.5–3.0) 25.4% (19.6–32.2) Varenicline (2 mg/day) 3.1 (2.5–3.8) 33.2% (28.9–37.8)

135 VARENICLINE: MECHANISM of ACTIONBinds with high affinity and selectivity at 42 neuronal nicotinic acetylcholine receptors Stimulates low-level agonist activity Competitively inhibits binding of nicotine Clinical effects  symptoms of nicotine withdrawal Blocks dopaminergic stimulation responsible for reinforcement & reward associated with smoking Varenicline binds with high affinity and selectivity at 42 neuronal nicotinic acetylcholine receptors. The efficacy of varenicline in smoking cessation is believed to be the result of low-level agonist activity at receptor sites while simultaneously preventing nicotine from binding to these receptors. The partial agonist activity induces modest receptor stimulation that attenuates the symptoms of nicotine withdrawal. In addition, by blocking the ability of nicotine to activate 42 nicotinic acetylcholine receptors, varenicline inhibits the surges of dopamine release that are believed to be responsible for the reinforcement and reward associated with smoking (Coe, 2005; Foulds, 2006; Pfizer, 2014). ♪ Note to instructor(s): Cytisine, a plant derived alkaloid (available in Europe under the trade name Tabex) is also believed to act as a partial nicotinic acetylcholine receptor agonist. Meta-analyses comparing cytisine to placebo and a randomized trial comparing cytisine to NRT (patch, gum, lozenge or patch+gum) suggest cytisine might be an effective treatment option, although further studies are needed (Cahill et al., 2012; Hajek et al, 2013; Walker et al, 2014). Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. (2012). Cochrane Database Syst Rev 4:CD Coe JW, Brooks PR, Vetelino MG, et al. (2005). Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation. J Med Chem 48:3474–3477. Foulds J. (2006). The neurobiological basis for partial agonist treatment of nicotine dependence: varenicline. Int J Clin Pract 60:571–576. Hajek P, McRobbie H, Myers K. (2013). Efficacy of cytisine in helping smokers quit: systematic review and meta-analysis. Thorax 68:1037–1042. Pfizer Inc. (2016, December). Chantix Package Insert. New York, NY. Walker N, Howe C, Glover M, et al. (2014). Cytisine versus nicotine for smoking cessation. N Engl J Med 371:2353–2362.

136 VARENICLINE: WARNINGS and PRECAUTIONSNeuropsychiatric symptoms and suicide risk Changes in mood (including depression and mania) Psychosis/hallucinations/paranoia/delusions Homicidal ideation Aggression/hostility/anxiety/panic Suicidal ideation, suicide attempt, completed suicide FDA boxed warning removed Dec 2016 In July 2009, the FDA mandated that the prescribing information for all bupropion-containing products include a black-boxed warning highlighting the risk of serious neuropsychiatric events, including but not limited to depression, suicidal ideation, suicide attempt and completed suicide. These additional warnings were based on post-marketing adverse event surveillance reports received by the FDA (FDA, 2009). The box associated with this warning was removed on December 16, 2016 based on results from a mandated clinical trial. According to the manufacturer’s prescribing information, serious neuropsychiatric symptoms including changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide have been reported (Pfizer, 2016). Patients and caregivers should be advised to stop taking the medication and contact a healthcare provider immediately if agitation, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. Clinicians should be aware that patients with serious psychiatric illness (e.g., depression, schizophrenia, bipolar disorder) can also benefit from use of varenicline while quitting smoking without significant increase in neuropsychiatric adverse events associated with varenicline use (Anthenelli et al., 2016; Pfizer, 2016). Anthenelli RM, Benowitz NL, West R, St Aubin L, McRae T, et al. (2016). Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet 387(10037):2507–2250. Food and Drug Administration (2016, December). Information for healthcare professionals: varenicline (marketed as Chantix) and bupropion (marketed as Zyban, Wellbutrin, and generics). Available at: Retrieved January 5, 2017. Pfizer Inc. (2016, December). Chantix Package Insert. New York, NY. Advise patients to stop taking bupropion SR and contact a health care provider immediately if symptoms such as agitation, depressed mood, or changes in behavior or thinking that are not typical are observed or if the patient develops suicidal ideation or suicidal behavior.

137 VARENICLINE: WARNINGS and PRECAUTIONS (cont’d)In some patients, use of varenicline has been associated with: Seizures Enhanced effects of alcohol Accidental injury Cardiovascular events Angioedema and hypersensitivity reactions Serious skin reactions In some patients, use of varenicline has been associated with the following (Pfizer, 2016): Seizures: New or worsening seizures have been observed in patients taking varenicline; use cautiously in patients with a history of seizures or other factors that can lower the seizure threshold. Interaction with Alcohol: Increased effects of alcohol have been reported. Patients should reduce the amount of alcohol they consume until they know whether varenicline affects them. Accidental injury: Accidental injuries (e.g., traffic accidents) have been reported. Patients should use caution driving or operating machinery until they know how varenicline may affect them. Cardiovascular events: A meta-analysis of 15 clinical trials, including a trial in patients with stable cardiovascular disease, demonstrated that while cardiovascular events were infrequent overall, some were reported more frequently in patients treated with varenicline. These events occurred primarily in patients with known cardiovascular disease. In both the clinical trial and meta-analysis, all-cause and cardiovascular mortality was lower in patients treated with varenicline. Angioedema and hypersensitivity reactions: Such reactions, including angioedema, infrequently life threatening, have been reported. Patients should discontinue varenicline and immediately seek medical care if symptoms occur. Serious skin reactions: Rare, potentially life-threatening skin reactions have been reported. Patients should discontinue varenicline and contact a healthcare provider immediately at first appearance of skin rash with mucosal lesions. ♪ Note to instructor(s): Based on post-marketing reports, the potential for seizures and interaction with alcohol was added to the warnings and precautions section of the prescribing information in September Nausea is also listed in the warnings and precautions section of the prescribing information for varenciline; see adverse effects slide for additional information. Pfizer Inc. (2016, December). Chantix Package Insert. New York, NY. These are rare events and most have not been causally linked to varenicline use.

138 Patients should begin therapy 1 week PRIOR to theirVARENICLINE: DOSING Patients should begin therapy 1 week PRIOR to their quit date. The dose is gradually increased to minimize treatment-related nausea and insomnia. Treatment Day Dose Day 1 to day 3 0.5 mg qd Day 4 to day 7 0.5 mg bid Day 8 to end of treatment* 1 mg bid Treatment with varenicline should be initiated one week BEFORE the patient stops smoking. This dosing regimen allows for gradual titration of the dose to minimize treatment-related nausea and insomnia. The usual recommended dose of varenicline is 1mg bid (taken as one 1mg tablet in the morning and one 1mg tablet in the evening) following a 1-week titration as follows: Treatment Day Dose Days 1– mg once daily Days 4– mg twice daily Weeks 2– mg twice daily Alternatively, the patient can begin therapy and then quit smoking between days 8–35 of treatment (Pfizer, 2016). The manufacturer recommends that the dosage may be lowered temporarily or permanently for patients experiencing intolerable treatment-associated adverse effects. Patients should be treated with varenicline for 12 weeks. For patients who have successfully quit smoking at the end of 12 weeks, an additional course of 12 weeks may be appropriate to increase the likelihood of long-term abstinence (Pfizer, 2016). ♪ Note to instructor(s): Per the manufacturer’s prescribing information, the recommended dosage of varenicline for children, elderly patients, and individuals with impaired renal or hepatic function is as follows: Use in children Safety and effectiveness in pediatric patients have not been established; therefore, varenicline is not recommended for use in patients under 18 years of age. Dosing in elderly patients and patients with impaired hepatic function No dosage adjustment is necessary for patients with hepatic impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Patients with impaired renal function No dosage adjustment is necessary for patients with mild to moderate renal impairment. For patients with severe renal impairment (estimated creatinine clearance <30 mL/min), the recommended starting dose is 0.5 mg once daily. The dose may then be titrated as needed to a maximum of 0.5 mg twice a day. For patients with end-stage renal disease undergoing hemodialysis, a maximum dose of 0.5 mg once daily may be administered if tolerated. Pfizer Inc. (2016, December). Chantix Package Insert. New York, NY. Initial dose titration * Up to 12 weeks

139 VARENICLINE: ADVERSE EFFECTSCommon (≥5% and 2-fold higher than placebo) Nausea Sleep disturbances (insomnia, abnormal dreams) Constipation Flatulence Vomiting Common side effects (≥5% and twice the rate observed in placebo-treated patients) include: Nausea (30%) Sleep disturbances, e.g., insomnia (18%) and abnormal (vivid, unusual, or strange) dreams (13%) Constipation (8%) Flatulence (6%) Vomiting (5%) ♪ Note to instructor(s): Per the manufacturer’s prescribing information, nausea was the most common adverse event associated with varenicline treatment. Nausea was generally described as mild or moderate and often transient; however, for some subjects, it was persistent over several months. The incidence of nausea was dose-dependent. Initial dose titration was beneficial in reducing the occurrence of nausea. Approximately 3% of subjects receiving varenicline 1 mg bid discontinued treatment prematurely because of nausea. For patients with intolerable nausea, dose reduction should be considered. Pfizer Inc. (2016, December). Chantix Package Insert. New York, NY.

140 VARENICLINE: ADDITIONAL PATIENT EDUCATIONDoses should be taken after eating, with a full glass of water Nausea and insomnia are usually temporary side effects If symptoms persist, notify your health care provider May experience vivid, unusual or strange dreams during treatment Use caution driving, drinking alcohol, and operating machinery until effects of quitting smoking with varenicline are known Doses should be taken after eating, with a full glass of water. Nausea and insomnia are side effects that are usually temporary. However, if these symptoms persist, notify your provider so dosage reduction can be considered. Patients should be informed that they may experience vivid, unusual or strange dreams during treatment with varenicline. Patients should be advised to use caution driving, drinking alcohol, or operating machinery until they know how quitting smoking with varenicline may affect them. Pfizer Inc. (2016, December). Chantix Package Insert. New York, NY.

141 VARENICLINE: SUMMARY ADVANTAGES DISADVANTAGESOral dosing is simple and associated with fewer adherence problems Offers a different mechanism of action for persons who have failed other agents DISADVANTAGES Should be taken with food or a full glass of water to reduce the incidence of nausea Patients should be monitored for potential neuropsychiatric symptoms Post-marketing surveillance data indicate potential for neuropsychiatric symptoms and adverse effects not shown to be prevalent in randomized trials Advantages of varenicline include the following: Oral dosing is simple and associated with fewer adherence problems. Offers a different mechanism of action for persons who previously failed using other medications. Disadvantages of varenicline include the following: Should be taken with food or a full glass of water to reduce the incidence of nausea Patients should be monitored for potential neuropsychiatric symptoms Post-marketing surveillance data indicate potential for neuropsychiatric symptoms and adverse effects not shown to be prevalent in randomized trials

142 LONG-TERM (6 month) QUIT RATES for AVAILABLE CESSATION MEDICATIONS28.0 23.9 19.7 18.9 17.1 16.3 15.9 This bar chart summarizes the long-term (≥6-month) quit rates observed with the different NRT products, bupropion SR, and varenicline (Cahill et al., 2012; Hughes et al., 2014; Stead et al., 2012). These data are derived from 161 different randomized-controlled trials; therefore, it is inappropriate to make direct comparisons between the active medications with respect to clinical efficacy. What this chart does illustrate, however, is that the quit rates from each of the methods is approximately twice that of its corresponding placebo control treatment arm. Each of the pharmacotherapy options depicted in the chart is considered effective, and any medication can be recommended, if not contraindicated. However, when assisting patients in choosing a product, clinicians should consider additional factors such as the number of cigarettes smoked per day (or time to first cigarette), advantages and disadvantages of each product, methods used for prior quit attempts, reasons for relapse, and the patient’s own preferences. Behavioral counseling should be used in conjunction with all pharmacologic therapies. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. (2012). Cochrane Database Syst Rev 4:CD Hughes JR, Stead LF, Hartmann-Boyce J, Cahill K, Lancaster T. (2014). Antidepressants for smoking cessation. Cochrane Database Syst Rev 1:CD Stead LF, Perera R, Bullen C, Mant D, Hartmann-Boyce J, Cahill K, Lancaster T. (2012). Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 11:CD Percent quit 11.8 12.0 11.5 10.0 9.8 9.1 8.4 Data adapted from Cahill et al. (2012). Cochrane Database Syst Rev; Hughes et al. (2014). Cochrane Database Syst Rev; and Stead et al. (2012). Cochrane Database Sys Rev.

143 COMBINATION PHARMACOTHERAPYRegimens with enough evidence to be “recommended” first-line Combination NRT Long-acting formulation (patch) Produces relatively constant levels of nicotine PLUS Short-acting formulation (gum, inhaler, nasal spray) Allows for acute dose titration as needed for nicotine withdrawal symptoms Bupropion SR + Nicotine Patch Although the use of first- and second-line medications approximately double the likelihood that a patient will successfully quit smoking, data from clinical trials suggest that only 19–33% of patients remain abstinent 6 months after quitting (Fiore et al, 2008). Given these low success rates, clinicians and researchers have explored modified approaches to standard therapies, including the use of combination therapy. Data from randomized, controlled trials suggest that certain combinations of first-line cessation medications are efficacious in promoting long-term abstinence and the Clinical Practice Guideline recommends that clinicians consider the use of combination therapy as a first-line treatment approach for patients during a quit attempt (Fiore et al., 2008). Plasma levels of nicotine achieved with standard doses of NRT are generally much lower than those attained with regular smoking. As such, conventionally dosed NRT may deliver subtherapeutic nicotine levels for some individuals, and in particular, for moderate-to-heavy smokers. Dual NRT regimens, which typically consist of a long-acting agent (e.g., nicotine patch) in combination with a short-acting formulation (i.e., gum, lozenge, inhaler, or nasal spray) are being increasingly used as initial therapy. The long-acting formulation, which delivers nicotine at a relatively constant level, is used to prevent the onset of severe withdrawal symptoms while the short-acting formulation, which delivers nicotine at a more rapid rate, is used as needed to control withdrawal symptoms that may occur during potential relapse situations (e.g., after meals, during times of stress, when around other smokers). Evidence suggests that patients who use combination NRT are 1.3 times as likely to remain abstinent when compared with patients who use single-agent NRT (Stead et al., 2012). Similarly, quit rates with combination therapy that included NRT (gum, patch, lozenge) and bupropion SR were 1.2 times those attained with bupropion SR alone (Stead et al., 2012). ♪ Note to instructor(s): Experience with other combinations of first-line agents is limited. Randomized trials with varenicline in combination with the nicotine patch have yielded conflicting short-term results (Hajek et al., 2013; Koegelenberg et al., 2014), and a randomized trial of varenicline combined with bupropion SR showed no significant improvement at 1-year follow-up compared with varenicline alone (Ebbert et al., 2014). Although varenicline in combination with bupropion or NRT appears to be reasonably well tolerated, further studies are necessary to establish the long-term safety and efficacy of these combinations. Fiore MC, Jaén CR, Baker TB, et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. Stead LF, Perera R, Bullen C, et al. (2012). Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 1:CD Hajek P, Smith KM, Dhanji AR, et al. (2013). Is a combination of varenicline and nicotine patch more effective in helping smokers quit than varenicline alone? A randomised controlled trial. BMC Med 11:140. Koegelenberg CF, Noor F, Bateman ED, et al. (2014). Efficacy of varenicline combined with nicotine replacement therapy vs varenicline alone for smoking cessation: a randomized clinical trial. JAMA 312:155–161. Ebbert JO, Hatsukami DK, Croghan IT, et al. (2014). Combination varenicline and bupropion SR for tobacco-dependence treatment in cigarette smokers: a randomized trial. JAMA 311:155–63.

144 COMBINATION THERAPIES (cont’d)These combinations have enough evidence to be “recommended” Long-term patch (>14 weeks) + ad lib 2 mg gum Long-term patch (>14 weeks) + ad lib nasal spray Standard-dose patch + oral inhaler Standard-dose patch + bupropion This slide lists combinations that have sufficient evidence to be recommended. Clinicians should be aware that while the combination of the nicotine patch and sustained-release bupropion has been approved by FDA, the concurrent use of multiple NRT products is not FDA-approved for tobacco cessation. Furthermore, the optimal combinations, dosages, and duration of dual NRTs are currently unknown. Data concerning the safety and efficacy of varenicline-based combination regimens are conflicting. Data provided by the manufacturer suggest a higher incidence of adverse effects (nausea headache, vomiting, dizziness) among patients receiving varenicline and the nicotine patch compared to varenicline monotherapy. In contrast, preliminary data from Ebbert and colleagues suggest that varenicline in combination with sustained sustained-release bupropion or NRT is a potentially safe and effective treatment approach (Ebbert et al., 2009). Data from randomized, controlled trials are needed before varenicline combination therapy can be routinely recommended as a therapeutic approach for smoking cessation. Ebbert JO, Croghan IT, Sood A, Schroeder DR, Hays JT, Hurt RD. (2009). Varenicline and bupropion sustained-release combination therapy for smoking cessation. Nicotine Tob Res 11(3):234–239.

145 IDENTIFY KEY ISSUES to STREAMLINE PRODUCT SELECTION*Do you prefer a prescription or nonprescription medication? Would it be a challenge for you to take a medication frequently throughout the day (e.g., a minimum of 9 times)? With the exception of the nicotine patch, all NRT formulations require frequent dosing throughout the day. If patient is unable to adhere to the recommended dosing, these products should be ruled out as monotherapy because they will be ineffective. With seven similarly effective FDA-approved medications for cessation, selecting the “best” product for a patient can be a challenge. On this slide, we list a brief approach to narrowing the options. Consider asking patients whether they prefer a prescription or nonprescription medication. This is particularly relevant for nonprescribing health care providers, such as pharmacists, for whom it would be necessary to contact a physician for the prescription options. A second, very useful question is, “Would it be a challenge for you to take a medication frequently throughout the day, e.g., a minimum of 9 times initially?” With the exception of the nicotine patch, all NRT formulations require frequent dosing throughout the day, and if a patient is unable to adhere to the recommended dosing schedule, these products should be ruled out as monotherapy because they will be ineffective. Once these two questions have been asked, clinicians should continue by asking product-specific questions for the remaining options. Additionally, it is important to ask the patient whether he or she has any personal preferences. Asking these two questions will significantly reduce the time required for product selection. * Product-specific screening—for warnings, precautions, contraindications, and personal preferences—is also essential.

146 ADHERENCE IS KEY to QUITTINGPromote adherence with prescribed regimens Use according to dosing schedule, NOT as needed Consider telling the patient: “When you use a cessation product, it is important to read all the directions thoroughly before using the product. The products work best in alleviating withdrawal symptoms when used correctly, and according to the recommended dosing schedule.” Comprehensive counseling not only provides patients with information and social support for their quit attempts, but it also could improve the poor adherence rates commonly observed with treatment regimens for cessation (Hajek et al., 1999; Pierce & Gilpin, 2002; Schneider et al., 2003; Shiffman et al., 2008). When counseling quitters for pharmacotherapy, particularly with short-acting forms of NRT, it is important to emphasize the need to use the products correctly and to adhere to the recommended dosing schedule. Patients who use more lozenges, for example, have been shown to be more likely to achieve abstinence (Shiffman et al., 2002). Hajek P, West R, Foulds J, Nilsson F, Burrows S, Meadow A. (1999). Randomized comparative trial of nicotine polacrilex, a transdermal patch, nasal spray, and an inhaler. Arch Intern Med 159:2033–2038. Pierce JP, Gilpin EA. (2002). Impact of over-the-counter sales on effectiveness of pharmaceutical aids for smoking cessation. JAMA 288:1260–1264. Schneider MP, van Melle G, Uldry C, et al. (2003). Electronic monitoring of long-term use of the nicotine nasal spray and predictors of success in a smoking cessation program. Nicotine Tob Res 5:719–727. Shiffman S, Dresler CM, Hajek P, Gilburt SJA, Targett DA, Strahs KR. (2002). Efficacy of a nicotine lozenge for smoking cessation. Arch Intern Med 162;1267–1276. Shiffman S, Ferguson SG, Rohay J, Gitchell JG. (2008). Perceived safety and efficacy of nicotine replacement therapies among US smokers and ex-smokers: relationship with use and compliance. Addiction 103:1371–1378.

147 Average cost per pack of cigarettes, $6.00COMPARATIVE DAILY COSTS of PHARMACOTHERAPY Average cost per pack of cigarettes, $6.00 This slide presents the approximate daily costs of treatment for the various pharmacotherapies for cessation. These are estimates based on the recommended initial dosing for each agent.* Costs can vary considerably depending on the patient’s level of smoking, degree of nicotine dependence, product selection (trade versus generic), and need for additional doses of short-acting nicotine replacement therapies (gum, lozenge, nasal spray, or oral inhaler). As a comparison, the cost for one pack of cigarettes (national average, approximately $6.00) is shown (Campaign for Tobacco-Free Kids, 2016). For most cessation medications, the daily cost of therapy is substantially less than the cost of one pack of cigarettes. *Cost calculated using the most expensive wholesale acquisition cost (WAC) for each trade name agent and the least expensive WAC for each generic product (Red Book, 2015). Campaign for Tobacco-Free Kids. (2016). State Excise and Sales Taxes Per Pack of Cigarettes. Retrieved from Red Book Online. (2016, January). New York: Thomson Reuters. $/day

148 SUMMARY To maximize success, interventions should include counseling and one or more medications Clinicians should encourage the use of effective medications by all patients attempting to quit smoking Exceptions include medical contraindications or use in specific populations for which there is insufficient evidence of effectiveness First-line medications that reliably increase long-term smoking cessation rates include the following: Bupropion SR Nicotine replacement therapy (gum, lozenge, patch, nasal spray, inhaler) Varenicline Use of effective combinations of medications should be considered In summary, To maximize success, interventions should include counseling and one or more medications. Clinicians should encourage the use of effective medications by all patients attempting to quit smoking. Exceptions include medical contraindications or specific populations for which there is insufficient evidence of effectiveness. First-line medications that reliably increase long-term smoking cessation rates include the following: Bupropion SR Nicotine replacement therapy (gum, lozenge, patch, nasal spray, inhaler) Varenicline Use of effective combinations of medications should be considered.