Rx for CHANGE Clinician-Assisted Tobacco Cessation

Rx for CHANGE Clinician-Assisted Tobacco Cessation
♪ Note to instructor(s): Please update this slide by inserting instructor name(s).

TRAINING OVERVIEW Epidemiology of Tobacco Use
Nicotine Pharmacology & Principles of Addiction Drug Interactions with Smoking Assisting Patients with Quitting Medications for Cessation Tobacco Trigger Tapes Role Playing with Case Scenarios and Video Counseling Sessions ♪ Note to instructor(s): The following modules are considered core components (i.e., essential to the training): Epidemiology of Tobacco Use Nicotine Pharmacology & Principles of Addiction Drug Interactions with Smoking Assisting Patients with Quitting – available in two versions: (1) The Clinical Practice Guideline version, which categorizes smokers as not ready to quit, ready to quit (in the next 30 days), a recent quitter, or a former smoker, and (2) the Transtheoretical Model of Change version, which categorizes smokers as being in the precontemplation, contemplation, preparation, action, or maintenance stage of change for quitting Medications for Cessation The Forms of Tobacco module (which includes e-cigarettes) is an optional but highly recommended module. The following activities supplement the slide modules and can be used to create an interactive teaching and learning experience. Tobacco Trigger Tapes – A trigger tape is a brief video segment—usually one or two phrases from an actor who plays the role of a patient—that is used as a stimulus to elicit, or “trigger,” responses from the audience. Play the brief video segment, then query the audience for appropriate methods of responding to the patient. A total of 40 trigger tape files are available for download from the website, and an accompanying Trigger Tape Synopsis file is provided to guide instructors through the process (by providing appropriate responses). Role Playing with Case Scenarios and Video Counseling Sessions – the Rx for Change program provides dozens of case scenarios and video segments demonstrating appropriate counseling sessions for a wide range of patients and clinical settings. Virtual Patients – The goal of our tobacco cessation virtual patients is to simulate real-life encounters and allow students to practice their decision-making in a virtual setting, before counseling real patients. This tool can be used as a stand-alone exercise AND/OR can be used to prepare students for their standardized patient/OSCE encounters (Objective Structured Clinical Examinations). Standardized Patients/OSCEs – These tools can be used as formative exercises (e.g., with a primary goal of learning) or as a formal OSCE (e.g., with a primary goal of testing). One or more of these individual cases can also be integrated into a comprehensive OSCE covering a range of other clinical content areas. ♪ Note to instructor(s): Please update this slide to reflect the modules that you will be teaching.

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

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; USDHHS 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 (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. WHO Report on the Global Tobacco Epidemic, (2008). The MPOWER package. Geneva, World Health Organization. C. Everett Koop, M.D., former U.S. Surgeon General All forms of tobacco are harmful.

WORLDWIDE PREVALENCE of ADULT TOBACCO USE (Men/Women)
Canada 13/9 USA 16/12 Brazil 15/9 Greece 34/22 Russian Federation 51/15 China 45/2 UK 20/18 France 32/22 South Africa 27/6 Japan 27/9 India 17/4 Iran 19/1 Australia 16/13 Mexico 12/4 The prevalence of tobacco use varies worldwide, and in many countries it varies greatly between men and women (CDC, 2019; American Cancer Society, 2018). Centers for Disease Control and Prevention (CDC). (2019). Tobacco product use and cessation indicators among adults—United States, MMWR 68;1013–1019. American Cancer Society. The Tobacco Atlas, Sixth Edition. (2018). Available at Accessed November 17, 2019. World Lung Foundation. The Tobacco Atlas, Sixth Edition, 2018. U.S. data from: Centers for Disease Control and Prevention (CDC). (2018). MMWR 67:1225–1232.

TRENDS in ADULT SMOKING, by SEX—U.S., 1955–2018
Trends in cigarette current smoking among persons aged 18 or older 13.7% of adults are current smokers Males Percent This graph demonstrates trends in cigarette smoking among adults in the U.S. between 1955 and 2018 (CDC, 1999; CDC, 2019). In 2018, results of the National Health Interview Survey (NHIS) indicated that approximately 49.1 million adults (19.7% of the U.S. adult population) currently used any tobacco product, including cigarettes (13.7%), cigars (3.9%), electronic cigarettes (3.2%), smokeless tobacco (2.4%), and pipes (1.0%). Daily use was reported by 74.6% of cigarette smokers, 59.1% of smokeless tobacco users, 42.6% of e-cigarette users, and 15.8% of cigar smokers. More men (15.6%) than women (12.0%) were current1 cigarette smokers (CDC, 2019). An estimated 68% of all smokers want to quit completely (CDC, 2017). In 2018, 55.1% of adult smokers reported making a quit attempt in the past 12 months (increased from 52.8% in 2009), and successful smoking cessation increased from 6.3% in 2009 to 7.5% in 2018 (CDC, 2019). 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). (2017). Current cigarette smoking among adults—United States, 2000–2015. MMWR 65;1457–1464. Centers for Disease Control and Prevention (CDC). (2019). Tobacco product use and cessation indicators among adults—United States, MMWR 68;1013–1019. Females 15.6% 12.0% Year 68% want to quit 55% tried to quit in the past year Graph provided by the Centers for Disease Control and Prevention Current Population Survey; 1965–2018 NHIS. Estimates since 1992 include some-day smoking.

STATE-SPECIFIC PREVALENCE of SMOKING among ADULTS, 2014–2015
The prevalence of current smoking among adults varies by state, in ranging from 8.0% in California and Utah to 21.7% in West Virginia (CDC, 2018). Cigarette excise taxes, which vary by state, impact the overall price of cigarettes for consumers and thereby impact per capita consumption and associated rates of tobacco-related morbidity and mortality. Most of the states with the highest smoking prevalence have the lowest state taxes on cigarettes. The state-local cigarette excise tax varies widely by state and city, with the highest being $6.16 per pack in Chicago, IL and $5.85 in New York City. On March 31, 2009, President Obama raised the federal cigarette tax from 39 cents per pack to $1.01 per 20-cigarette pack. State cigarette excise tax rates and rankings as of June 28, 2019, for several states (rank shown on left, out of 50 states and Washington, DC) (Campaign for Tobacco-Free Kids, 2019): 1 DC – $4.50 2 New York – $4.35 2 Connecticut – $4.35 4 Rhode Island – $4.25 5 Massachusetts – $3.51 6 Hawaii – $3.20 7 Vermont – $3.08 47 North Carolina – $0.45 48 North Dakota – $0.44 49 Georgia – $0.37 50 Virginia – $0.30 51 Missouri – $0.17 ♪ Note to instructor(s): Excise taxes for each state are available on the Campaign for Tobacco-Free Kids fact sheet, which is updated regularly to reflect changes in legislation. Nationally, the weighted average price for a pack of cigarettes is approximately $6.30 (including statewide sales taxes but not local cigarette or sales taxes, other than New York City’s $1.50 per pack cigarette tax). Campaign for Tobacco-Free Kids. (2019). “State Cigarette Excise Tax Rates & Rankings.” Retrieved November 17, 2019, from Centers for Disease Control and Prevention (CDC). (2018). State-specific prevalence of tobacco product use among adults—United States, MMWR 67:97–102. Prevalence of current* cigarette smoking ` ≥ 18.0% 15.0 – 17.9% 12.0 – 14.9% 8.0 – 11.9% Centers for Disease Control and Prevention (CDC). (2018). MMWR 67:97–102. * Has smoked ≥ 100 cigarettes during lifetime and currently smokes either every day or some days.

PREVALENCE of ADULT SMOKING, by RACE/ETHNICITY—U.S., 2018
American Indian/Alaska Native 22.6% Multiple races 19.1% In 2018, the prevalence of smoking in the U.S. was highest among persons identifying as American Indian/Alaska Native background (22.6%) and next highest among persons of multiple races (19.2%), followed by non-Hispanic White (15.0%), Black (14.6%), Hispanic (9.8%), and non-Hispanic Asian (7.1%) (CDC, 2019). Centers for Disease Control and Prevention (CDC). (2019). Tobacco product use and cessation indicators among adults—United States, MMWR 68;1013–1019. White 15.0% Black 14.6% Hispanic 9.8% Asian 7.1% Percent Centers for Disease Control and Prevention (CDC). (2019). MMWR 68:1013–1019.

PREVALENCE of ADULT SMOKING, by EDUCATION—U.S., 2018
No high school diploma 21.8% GED diploma 36.0% High school graduate 19.7% In 2018, the prevalence of current smoking1 in the U.S. was highest among adults (aged 25 years or older) who had received a General Educational Development (GED) diploma (36.0%). Persons with a graduate degree (masters, professional, or doctorate) had the lowest prevalence (3.7%) (CDC, 2019). Also notable is the fact that the prevalence of adult smoking is inversely associated with annual income. The persons who smoke the most tend to be the ones who can least afford to smoke. The cigarette smoking prevalence is 7.8% for persons aged 18–24; 16.5% for persons aged 25–44; 16.3% for persons aged 45–64; and 8.4% for persons at least 65 years of age (CDC, 2019). Persons with a self-reported sexual orientation of lesbian/gay/bisexual exhibit a smoking prevalence of 20.6%, compared to 13.5% among heterosexual persons (CDC, 2019). 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 interview. Centers for Disease Control and Prevention (CDC). (2019). Tobacco product use and cessation indicators among adults—United States, MMWR 68;1013–1019. . Some college 18.3% Undergraduate degree 7.1% Graduate degree 3.7% Percent Centers for Disease Control and Prevention (CDC). (2019). MMWR 68:1013–1019.

TRENDS in TEEN SMOKING, by ETHNICITY—U.S., 1977–2017
Trends in cigarette smoking among 12th graders: 30-day prevalence of use White Cigarette smoking among adolescents is a public health concern of utmost importance. In the U.S., experimentation with cigarettes and the development of regular smoking typically occur during adolescence. It is estimated that 5,753 persons became new smokers each day in 2013, with 50.5% of these persons being under the age of 18 years (the legal age for smoking) when they smoked their first cigarette (SAMSA, 2014). The average age at first cigarette use is 17.8 years (SAMSA, 2014). Because most youth who smoke at least monthly continue to smoke in adulthood, tobacco use trends among youth are a key indicator of the overall health trends for the U.S. During 1991–1997, the smoking prevalence (defined as one or more cigarettes in the 30 days before survey completion) among high school seniors increased to 36.5%. At that time, the prevalence was highest among whites (40.7%) and lowest among blacks (14.3%). This worrisome increasing trend highlighted a need for tobacco prevention and cessation programs focused on this age group. In 2017, an estimated 9.7% of 12th graders (10.6% of males and 8.3% of females) had smoked one or more cigarettes in the past 30 days (Miech et al., 2018). As can be seen in the graph, smoking among adolescents varies substantially by racial/ethnic groups. ♪ Note to instructor(s): Monitoring the Future data, publications, and press releases are available at Miech RA, Johnston LD, O’Malley PM, Bachman JG, Schulenberg JE, Patrick ME. (2018). Monitoring the Future national survey results on drug use, 1975–2017: Volume I, Secondary school students. Ann Arbor: Institute for Social Research, The University of Michigan. Retrieved November 17, 2019, at: Substance Abuse and Mental Health Services Administration (SAMSA). (2014). Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings NSDUH Series H-48, HHS Publication No. (SMA) Rockville, MD: Substance Abuse and Mental Health Services Administration Retrieved January 25, 2018 from Hispanic Percent Black Institute for Social Research, University of Michigan, Monitoring the Future Project

PUBLIC HEALTH versus “BIG TOBACCO”
The biggest opponent to tobacco control efforts is the tobacco industry itself. Historically, public health efforts to reduce tobacco-related morbidity and mortality have faced strong opposition. The biggest opponent to tobacco control efforts is the tobacco industry itself. Most states fail to spend even the minimum amount recommended by the CDC for expenditures on tobacco control, yet over the past decade the tobacco industry has dramatically increased its promotional. For every $1 spent by the states on tobacco control initiatives, it is estimated that the tobacco industry spends an estimated $12.4 to market its products (Campaign for Tobacco-Free Kids, 2017). Campaign for Tobacco-Free Kids. (2017). “Spending vs. Tobacco Company Marketing.” Retrieved November 17, 2019, from Nationally, the tobacco industry is outspending our state tobacco control funding. For every $1 spent by the states, the tobacco industry spends $12.4 to market its products.

TOBACCO INDUSTRY MARKETING
$8.6 billion spent in the U.S. in 2017 $23.7 million a day New marketing restrictions A report from the National Cancer Institute (NCI, 2008) delineates a causal association between tobacco advertising and promotion and increased tobacco use. Each year, the tobacco industry spends billions of dollars in promoting its products in the U.S. and abroad. This graph shows the most current data on advertising expenditures in the U.S., along with data for 1970, the first year for which these data are available in the FTC annual reports, to give a basis for comparison (FTC, 2019). Highlights of the report for 2017 (published in 2019) are as follows: Annual spending (in the U.S. only) for advertising and promotional expenditures was $8.637 billion (decreased from $8.706 billion in 2016). The total number of cigarettes sold by the five major manufacturers to wholesalers and retailers in the U.S. was billion in 2017 (decreased by 11.4 billion units in 2016). Significant increases in marketing were witnessed when the Master Settlement Agreement, which introduced new marketing restrictions, went into effect in 1998. Federal Trade Commission (FTC). (2019). Cigarette Report for Retrieved November 17, 2019, from National Cancer Institute (NCI). (2008). The Role of the Media in Promoting and Reducing Tobacco Use. Tobacco Control Monograph No. 19. Bethesda, MD: U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. NIH Pub. No Billions of dollars spent Year Federal Trade Commission (FTC). (2018). Cigarette Report for 2016.

The TOBACCO INDUSTRY For decades, the tobacco industry publicly denied the addictive nature of nicotine and the negative health effects of tobacco. April 14, 1994: Seven top executives of major tobacco companies state, under oath, that they believe nicotine is not addictive: Tobacco industry documents indicate otherwise Documents available at The cigarette is a heavily engineered product. Designed and marketed to maximize bioavailability of nicotine and addictive potential Profits over people For decades, the tobacco industry has publicly denied the addictive nature of nicotine and the negative health effects of tobacco. On April 14, 1994, the top executives of all the major tobacco companies stated, under oath, that they believe nicotine is not addictive. Yet tobacco industry documents, which are now available publicly on the Internet ( suggest otherwise. The cigarette is a heavily-engineered product that was designed and marketed to maximize the bioavailability of nicotine and hence maximize its addictive potential. ♪ Note to instructor(s): Consider proceeding to the link, and play this brief (1 minute), historic video segment for your audience. The tobacco industry is financially vested in selling its product and has taken affirmative steps to maximize profits and minimize anti-tobacco public health efforts. At times the industry has actively sought to disrupt particular public health programs and legislation, and other times it is simply trying to promote its own interests above the interests of the public health. An example of this is the development and marketing of “light” cigarettes.

An EFFECTIVE MARKETING STRATEGY: “LIGHT” CIGARETTES
The difference between Marlboro and Marlboro Lights… As smokers became more concerned about the negative health consequences of smoking, the tobacco industry created “mild,” “light,” and “ultra-light” cigarettes. These products incorporate ventilation holes on the cigarette filters in order to “reduce” the nicotine and tar yields as measured by the FTC machine-test method. During inhalation, room air is drawn through the ventilation holes into the smoke stream, diluting the amount of smoke in each puff. When “light” or “ultra-light” cigarettes are tested using a smoking machine, the yields of tar, nicotine, and carbon monoxide are significantly reduced. However, smokers do not smoke cigarettes in the same manner that the machine does. Smokers easily obstruct the ventilation holes with their lips or fingers, thereby inhaling higher amounts of tar and nicotine than might be expected based on the reported product-yield rating (machine-test yields). The actual yield of tar and nicotine for the smoker, however, might be similar or greater—depending on the smoking technique. The tobacco industry knows this but continues to market the products as if they are safer alternatives. These products often appeal to smokers who are health conscious or are thinking about quitting. However, data suggest smokers tend to compensate for reduced nicotine delivery by smoking more cigarettes per day or by smoking ‘light’ cigarettes more intensely. As a result, these products do not significantly reduce exposure to nicotine or toxins in tobacco smoke including carbon monoxide and carcinogens (Benowitz et al., 2005). The 2004 Surgeon General Report on the Health Consequences of Smoking concluded that “smoking cigarettes with lower machine-measured yields of tar and nicotine provides no clear benefit to health” (USDHHS, 2004). Under the 2009 Family Smoking Prevention and Tobacco Control Act, a tobacco company cannot use the words “light,” “low,” or “mild” on cigarette products without filing an application for a modified risk tobacco product and obtaining an order to market as such (FDA, 2018). This image, courtesy of Dr. Richard D. Hurt, director of the Mayo Clinic Nicotine Dependence Center - Research Program, illustrates the difference between Marlboro and Marlboro Lights. As can be appreciated from the photo, the products have cosmetic differences (white vs. brown filter-tip paper color) and an extra row of ventilation holes is found in the light version. When tested by the smoking machine, the tar and nicotine yields for Marlboro are 15 mg and 1.1 mg per cigarette, respectively. The corresponding tar and nicotine yields for Marlboro Lights are 10 mg and 0.8 mg per cigarette, respectively (FTC, 2000). Benowitz NL, Jacob P 3rd, Bernert JT, Wilson M, Wang L, Allen F, Dempsey D. (2005). Carcinogen exposure during short-term switching from regular to “light" cigarettes. Cancer Epidemiol Biomarkers Prev 14:1376–1383. Federal Trade Commission (FTC). (2000). “Tar,” Nicotine and Carbon Monoxide of the Smoke of 1294 Varieties of Domestic Cigarettes for the Year Retrieved January 9, 2019, from U.S. Food and Drug Administration (FDA). (2018). “Family smoking prevention and tobacco control act – An overview. Retrieved January 9, 2019 from U.S. Department of Health and Human Services (USDHHS). (2004). The Health Consequences of Smoking: A Report of the Surgeon General. 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. an extra row of ventilation holes Image courtesy of Mayo Clinic Nicotine Dependence Center - Research Program / Dr. Richard D. Hurt The Marlboro and Marlboro Lights logos are registered trademarks of Philip Morris USA.

This image depicts the marketing strategy of the tobacco industry for an ultra-light cigarette targeted toward women, a population with a lower smoking prevalence and concerns about the effect of cessation on weight gain.

1932 As part of massive marketing campaigns, the tobacco industry promoted its products through trusted health professionals, including nurses.

Physicians also were central to tobacco advertising in the early to mid-1900s. It wasn’t until the 1950s that the link between smoking and cancer became public knowledge. 1936

Analysis of tobacco-industry marketing campaigns has revealed that tobacco company advertising efforts intentionally targeted the youth market (Cummings et al., 2002; Ling & Glantz, 2002). As depicted in this slide, the widely popular R. J. Reynolds “Joe Camel” ad campaign, which ran between 1988 and 1997, was specifically developed to appeal to children and adolescents. During the first three years of the Joe Camel campaign, Camel's share of the under-18 cigarette market jumped from 0.5% to 32.8%, representing a $470 million increase in annual sales for RJR Nabisco (DiFranza et al., 1991). In a study of young children, more than 90% of 6-year-olds were able to correctly matched Joe Camel with a picture of a cigarette, making him as well-known as Mickey Mouse; in comparison, only 67% of adults recognized Joe Camel (Fischer et al., 1991). A Cochrane Database Systematic Review concluded that exposure to tobacco advertising and promotion is associated with an increased likelihood that adolescents will initiate smoking. This conclusion was based on the strength of this association, the consistency of findings across observational studies, temporality of the exposure versus smoking behavior, and a theoretical plausibility for the impact of advertising on smoking behavior (Lovato et al., 2011). Cummings KM, Morley CP, Horan JK, Steger C, Leavell NR. (2002). Marketing to America's youth: Evidence from corporate documents. Tob Control 11(Suppl 1):I5–I17. DiFranza JR, Richards JW, Paulman PM, Wolf-Gillespie N, Fletcher C, Jaffe RD, Murray D. (1991). RJR Nabisco's cartoon camel promotes Camel cigarettes to children. JAMA 266:3149–3153. Fischer PM, Schwartz MP, Richards JW Jr., Goldstein AO, Rojas TH. (1991). Brand logo recognition by children aged 3 to 6 years. Mickey Mouse and Old Joe the Camel. JAMA 266:3145–3148. Ling PM, Glantz SA. (2002). Using tobacco-industry marketing research to design more effective tobacco-control campaigns. JAMA 287:2983–2999. Lovato C, Watts A, Stead L. (2011). Impact of tobacco advertising and promotion on increasing adolescent smoking behaviours. Cochrane Database Syst Rev (10):CD 1990

70% of adults support assigning an “R” rating to movies with smoking.
SMOKING in MOVIES Cigarette smoking is pervasive in movies Evident in at least ¾ of box-office hits Average, 10.9 smoking incidents per hour Charlesworth and Glantz. (2005). Pediatrics 116:1516–1528. Smoking has been pervasive in contemporary movies for decades, and the tobacco industry has paid millions to movie stars over the years (including Clark Gable, Joan Crawford, Spencer Tracy, Bob Hope, and Henry Fonda) as a means of promoting its products (Lum et al., 2008). In recent years, cigarette smoking is evident in at least ¾ of box-office hits, with an average (in 2002) of 10.9 smoking incidents per hour (Charlesworth et al., 2005). A report by the National Cancer Institute concludes that there is sufficient scientific evidence to support a causal relationship between exposure to depictions of smoking and youth smoking initiation (NCI, 2008). This conclusion draws from cross-sectional, longitudinal, and experimental studies. It is well known that the tobacco industry also has collaborated with Hollywood through paid product placement agreements. As an example, in a letter dated October 18, 1979, Phillip Morris and Pinewood Studios reached an agreement to include exposure to the Marlboro brand name. This letter delineated the precise details of the exposure – the billboard (see photo insert; from was to be “approximately 20 feet by 10 feet and will be illuminated” and the price to be paid for product placement (£20,000). This letter is part of the UCSF online tobacco industry document library and can be viewed at State Attorneys General (AG) have, on numerous occasions over the fast several years, submitted letters to the Motion Picture Association of America (MPAA) and major film studios to request that new movies depicting smoking be rated “R” unless the tobacco use clearly reflects the negative consequences of tobacco use or is necessary to represent the smoking of a real historical figure. In May 2007, a letter submitted by 31 AGs stated: “Each time a member of the industry releases another movie that depicts smoking, it does so with the full knowledge of the harm it will bring to children who watch it...” “Eliminate the depiction of tobacco smoking from films accessible to children and youth. There is simply no justification for further delay.” It is estimated that smoking in movies is responsible for about half of all youth initiation (390,000 per year), and that implementing an R rating for smoking in films would immediately remove smoking from all youth-rated films and would prevent about 200,000 children a year from starting to smoke. Between 2005 and 2009, the number of smoking incidents in movies declined steadily (CDC, 2010), but a recent increase (7% for R-rated movies; 34% for G, PG, or PG-13 movies) was observed between 2010 and 2011 (Glantz et al., 2012). ♪ Note to instructor(s): For more about smoking in movies, go to Centers for Disease Control and Prevention (CDC). (2010). Smoking in top-grossing movies—United States, 1991–2009. MMWR 59:1014–1017. Charlesworth A, Glantz SA. (2005). Smoking in the movies increases adolescent smoking: A review. Pediatrics 116:1516–1528. Lum KL, Polansky JR, Jackler RK, Glantz SA. (2008). Signed, sealed and delivered: “bit tobacco” in Hollywood, 1927– Tob Control 17:313–323. Glantz SA, Iaccopucci A, Titus K, Polansky JR. (2012). Smoking in Top-Grossing US Movies, Prev Chronic Dis 9: National Cancer Institute (NCI). (2008). The Role of the Media in Promoting and Reducing Tobacco Use. Tobacco Control Monograph N. 19. Bethesda, MD: U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. NIH Pub. No There is a dose-response, causal relationship between exposure to smoking in movies and youth smoking initiation Superman II (1980) National Cancer Institute. (2008). The Role of the Media in Promoting and Reducing Tobacco Use. 70% of adults support assigning an “R” rating to movies with smoking. For more information on smoking in movies, go to

FDA REGULATION of TOBACCO PRODUCTS
The 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, 2018): 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, 2017). ♪ 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). (2017). Electronic Cigarettes (e-Cigarettes). Retrieved January 9, 2019 from U.S. Food and Drug Administration (FDA). (2018). Family Smoking Prevention and Tobacco Control Act. Retrieved January 9, 2019 from *Not a tobacco product.

COMPOUNDS in TOBACCO SMOKE
An 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.

TOTAL: >480,000 deaths annually
ANNUAL 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 U.S., 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 200, 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, Taylor B, Rehm J, Murray CJL, Ezzati M. (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.

CORONARY HEART DISEASE and STROKE with LOW CIGARETTE CONSUMPTION
Additional risk associated with smoking 1 cigarette per day (compared to never smokers) Smoking cigarette/day: 40-50% of the additional risk associated with smoking cigarettes/day In a meta-analysis of 55 publications representing 141 cohort studies, Hackshaw and colleagues characterized the additional risk for coronary heart disease and stroke for individuals with low levels of cigarette consumption (e.g., 1 or 5 cigarettes per day). Studies were published between 1946 and Data shown on this slide indicate the additional risk (displayed as percentages) for heart disease and stroke, stratified by sex. Compared to never smokers, men who smoke approximately one cigarette/day exhibit 48% higher risk of heart disease and a 25% higher risk of stroke (74% and 30%, respectively, when not adjusting for confounders). These estimates are higher among women, with a 57% increased risk for heart disease and 31% increased risk for stroke (119% and 46%, respectively, when not adjusting for confounders. Individuals who smoke approximately one cigarette/day exhibit an estimated 40-50% of the additional risk associated with smoking 20 cigarettes/day (coronary heart disease and stroke). Although reduced smoking can yield some benefits for cardiovascular health, the risk is not linear -- even low levels of smoking are significantly more harmful than one might expect (e.g., as much as half the risk of smoking 20 per day). We There is no safe level of smoking when it comes to cardiovascular disease. Patients who smoke should be encouraged to quit completely. Hackshaw A, Morris JK, Boniface S, Tang J, Milenkovic D. (2018). Low cigarette consumption and risk of coronary heart disease and stroke: meta-analysis of 141 cohort studies in 55 study reports. BMJ 360:j2984. Percent of additional risk Smokers should aim to quit completely. Hackshaw et al. (2018). BMJ 360:j2984. [Meta-analysis of 55 publications representing 141 cohort studies]

ANNUAL SMOKING-ATTRIBUTABLE ECONOMIC COSTS
Health-care expenditures $132.5 billion Lost productivity costs due to premature mortality $156.4 billion The economic costs to society associated with smoking are enormous. Grand total annual smoking-attributable economic costs in the United States is approximately $288.9 billion, of which an estimated $132.5 billion are due to health care expenditures and $156.4 billion are associated with lost productivity costs due to premature mortality. This latter number includes premature deaths due to second-hand smoke exposure but does not include lost productivity costs due to smoking morbidity; as such, this estimate significantly understates the full impact of lost productivity. Smoking-related health care expenditures account for approximately 8% (USDHHS, 2014) of total annual spending on health care in the U.S. For each pack of cigarettes sold, the societal costs due to smoking-related health care costs and lost productivity are estimated at $19.16 per pack, around 3 times the cost of the cigarettes ($6.26/pack; Campaign for Tobacco-Free Kids, 2018). Strong tobacco control programs can reduce the prevalence of smoking, save lives, and also substantially impact health-care expenditures. In California, the tobacco control program was associated with an estimated $86 billion reduction in total health costs between 1989 and 2004—a strong return on investment (Lightwood et al., 2008). Campaign for Tobacco-Free Kids. (2018). “State Cigarette Excise Tax Rates & Rankings.” Retrieved January 9, 2019, from Lightwood JM, Dinno A, Glantz SA. (2008). Effect of the California Tobacco Control Program on personal health care expenditures. PLoS Med 5(8)e178:1214–1222. 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. Total economic burden of smoking, per year $288.9 billion Billions of US dollars Societal costs: $19.16 per pack of cigarettes smoked 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.

2014 REPORT of the SURGEON GENERAL: HEALTH CONSEQUENCES OF SMOKING
MAJOR 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 secondhand 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: 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 secondhand 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.

HEALTH CONSEQUENCES of SMOKING
Cancers 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. 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.

HEALTH CONSEQUENCES of SMOKELESS TOBACCO USE
Periodontal effects Gingival recession Bone attachment loss Dental caries Oral leukoplakia Cancer Oral cancer Pharyngeal cancer ♪ Note to instructor(s): Please delete this slide if you are also teaching the Forms of Tobacco module. In addition to cosmetic concerns (e.g., halitosis, staining of teeth), the use of smokeless tobacco is associated with numerous adverse health effects (Ebbert et al., 2004) including the following: Periodontal Effects Regular users of smokeless tobacco are at significant risk for the development of gingival recession (complete or partial loss of the tissue covering the root of the tooth), caries, and tooth abrasion. The loss of gingival tissue, observed in up to 27% of smokeless tobacco users, generally occurs at sites constantly exposed to tobacco (Taybos, 2003). The high sugar content found in many smokeless tobacco products in contact with exposed tooth root tissue might account for the increased incidence of dental caries in smokeless tobacco users (Hatsukami & Severson, 1999; Taybos, 2003; Ebbert et al., 2004). Soft Tissue Alterations/Leukoplakia Smokeless tobacco users commonly develop an oral soft tissue condition called leukoplakia or "snuff dipper's lesion." These white-colored patches or plaques, which are observed in approximately 15% of chewing tobacco users and 60% of snuff users, generally develop at mucosal sites in contact with the tobacco (Ebbert et al., 2004; Taybos, 2003). Of concern is the fact that a small percentage of these lesions may transform into squamous cell carcinomas (Hatsukami & Severson, 1999; Napier & Speight, 2008). Following cessation, the oral leukoplakia appears to regress or completely disappear in the majority of cases (Napier & Speight, 2008; Martin et al., 1999). Cancer The most serious consequence of smokeless tobacco use is an increased risk for developing oral and pharyngeal cancers; the risk appears to be dose related with heavy, long-time users being more likely to develop oral cancer compared with nonusers (Ebbert et al., 2004). The risk of developing oral and lung cancer among smokeless tobacco users appears to be lower than that of smokers, but higher than that of non-tobacco users (Boffetta et al., 2008). Boffetta P, Hecht S, Gray N, Gupta P, Straif K. (2008). Smokeless tobacco and cancer. Lancet Oncol 9:667–675. Ebbert JO, Carr AB, Dale LC. (2004). Smokeless tobacco: An emerging addiction. Med Clin N Am 88:1593–1605. Hatsukami DK, Severson HH. (1999). Oral spit tobacco: addiction, prevention and treatment. Nicotine Tob Res 1:21–44. Martin GC, Brown JP, Eifler CW, Houston GD. (1999). Oral leukoplakia status six weeks after cessation of smokeless tobacco use. J Am Dent Assoc 130:945–954. Napier SS, Speight PM. (2008). Natural history of potentially malignant oral lesions and conditions: an overview of the literature. J Oral Pathol Med 37:1–10. Taybos G. (2003). Oral changes associated with tobacco use. Am J Med Sci 326:179–182. Oral Leukoplakia Image courtesy of Dr. Sol Silverman - University of California San Francisco

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.

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: 1. Second-hand smoke causes premature death and disease in children and in adults who do not smoke. 2. 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. 3. Exposure of adults to second-hand smoke has immediate adverse effects on the cardiovascular system and causes coronary heart disease and lung cancer. 4. The scientific evidence indicates that there is no risk-free level of exposure to second-hand smoke. 5. 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. 6. 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 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 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.

QUITTING: HEALTH BENEFITS
Time 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 The 1990 Surgeon General’s Report on the health benefits of smoking cessation outlines the numerous and substantial health benefits incurred when patients quit smoking (USDHHS, 1990): 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, 15 years after quitting, 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. The next two slides depict some advantages of quitting earlier in life, as opposed to later. 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 ). U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention and Health Promotion, Office on Smoking and Health. Excess risk of CHD decreases to half that of a continuing smoker 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

BENEFICIAL EFFECTS of QUITTING: PULMONARY EFFECTS
AT ANY AGE, there are benefits of quitting. Never smoked or not susceptible to smoke 100 This graph (Fletcher & Peto, 1977) shows measurable improvements in lung function as a result of quitting. 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. 75 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.

Reduction in cumulative risk of death from lung cancer in men
Age in years Reduction in cumulative risk of death from lung cancer in men Despite the detrimental effects of tobacco on pulmonary health, smoking cessation can lead to a significant reduction in the cumulative risk of death from lung cancer. This graph demonstrates the risk of lung cancer mortality incurred by men at age 75; the risk estimates are 15.9% for those who do not quit smoking cigarettes and 9.9%, 6.0%, 3.0%, and 1.7% for men who stopped at ages 60, 50, 40, and 30, respectively (Peto et al., 2000). Similar trends are seen for women. These aggregate data suggest that quitting, at any age, reduces the risk of death from lung cancer. Peto R, Darby S, Deo H, Silcocks P, Whitley E, Doll R. (2000). Smoking, smoking cessation, and lung cancer in the UK since 1950: Combination of national statistics with two case-control studies. BMJ 321(7257):323–329. Reprinted with permission. Peto et al. (2000). BMJ 321(7257):323–329.

SMOKING CESSATION: REDUCED RISK of DEATH
Prospective study of 34,439 male British doctors Mortality was monitored for 50 years (1951–2001) On average, cigarette smokers die approximately 10 years younger than do nonsmokers. Perhaps one of the greatest tobacco studies of all times is a prospective cohort of British male doctors (Doll et al., 2004). This study was conducted by Oxford University Professor Richard Doll, a leading cancer epidemiologist, who more than 50 years ago first reported that smoking causes lung cancer. Recent findings show a clear picture of the risks associated with smoking. Doll and colleagues compared the hazards of cigarette smoking in men who formed their smoking habits at different periods, and the extent of the reduction in risk when cigarette smoking was stopped at different ages. Quitting at ages 30, 40, 50, and 60 resulted in 10, 9, 6, and 3 years of life gained, respectively. On average, cigarette smokers die approximately 10 years younger than do nonsmokers, and of those who continue smoking, at least half will eventually die due to a tobacco-related disease. Persons who quit before age 35 add 10 years of life and have a life expectancy similar to men who had never smoked. In addition to losing years of life due to smoking, a 26-year prospective study of smoking in mid-life showed a dose-dependent reduction in the health-related quality of life in old age among men. Never smokers live longer than heavy smokers, and their extra years are of higher quality (Strandberg et al., 2008). ♪ Note to instructor(s): The number of years of life saved by quitting varies across studies. For example, in a CDC report (2002), it was shown that the average number of years of life lost because of smoking was 13.2 years for male smokers and 14.5 years for female smokers. ♪ Note to instructor(s): Sir Richard Doll passed away on Sunday July 24, He was the foremost epidemiologist of the twentieth century and is best known for his research establishing the correlation between smoking and lung cancer. It is a rare occasion when a researcher can, within the course of his or her own lifetime, both open and close the book on a research question of such profound public health importance as the link between smoking and cancer. Sir Richard Doll's pioneering research has, perhaps more so than any other epidemiologist of his time, altered the landscape of disease prevention and consequently saved millions of lives worldwide. Centers for Disease Control and Prevention (CDC). (2002). Annual smoking-attributable mortality, years of potential life lost, and economic costs—United States, 1995–1999. MMWR 51:300–303. Doll R, Peto R, Boreham J, Sutherland I. (2004). Mortality in relation to smoking: 50 years’ observations on male British doctors. BMJ 328(7455):1519–1527. Strandberg AY, Strandberg TE, Pitkala J, Salomaa VV, Tilvis RS, Miettinen TA. (2008). The effect of smoking in midlife on health-related quality of life in old age. Arch Intern Med 168:1968–1974. Years of life gained Among those who continue smoking, at least half will die due to a tobacco-related disease. Age at cessation (years) Doll et al. (2004). BMJ 328(7455):1519–1527.

FINANCIAL IMPACT of SMOKING
Buying cigarettes every day for 50 years at $6.30 per pack* (does not include interest) $755,177 2.0 $229,950 Packs per day In addition to the many health benefits of quitting, there are financial benefits associated with quitting. The financial costs of tobacco use can be substantial to a smoker, particularly when costs are accrued over a lifetime. This figure depicts what three levels of smokers who buy cigarettes every day for 50 years at $6.30 pack (average national cost; Campaign for Tobacco-Free Kids, 2019) will have if they instead save their cigarette money. In 2019, the annual cost of smoking is $2,300 for a pack-a-day smoker. 1 These values are not adjusted for interest rates, which vary over time. To compute values with associated interest, a savings calculator tool available is at Campaign for Tobacco-Free Kids. (2019). “State Cigarette Excise Tax Rates & Rankings.” Retrieved November 17, 2019, from Annual cost of smoking pack per day: $2,300 1.5 $503,451 $172,463 1.0 $114,975 $251,725 Dollars lost, in thousands * Average national cost, as of November Campaign for Tobacco-Free Kids, 2019.

EPIDEMIOLOGY of TOBACCO USE: SUMMARY
Fewer 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 $2,300 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 $2,300 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.

FORMS of TOBACCO This module reviews forms of tobacco that are commonly available in the U.S.

FORMS of TOBACCO Cigarettes
Smokeless tobacco (chewing tobacco, oral snuff) Pipes Cigars Clove cigarettes Bidis Hookah (waterpipe smoking) Electronic cigarettes (“e-cigarettes”)* Many forms of tobacco are available in the U.S.: Cigarettes Smokeless tobacco (also called “spit tobacco”; includes chewing tobacco and oral snuff) Pipes Cigars Clove cigarettes Bidis Hookah (waterpipe smoking), also called shisha, narghile, goza, hubble bubble Electronic cigarettes (“e-cigarettes”) – these are devices that deliver nicotine and are not a form of tobacco. Also referred to as “electronic nicotine delivery systems, or ENDS. Several of these forms, such as hookah and e-cigarettes, have attained increased popularity in recent years. *e-cigarettes are devices that deliver nicotine and are not a form of tobacco. Image courtesy of the Centers for Disease Control and Prevention / Rick Ward

AMERICAN CIGARETTES Most common form of tobacco used in U.S.
Sold in packs (20 cigarettes/pack) Total nicotine content, per cigarette: - Average 13.5 mg (range, 11.9 to 14.5 mg) Machine-measured nicotine yield: Smoker’s nicotine yield, per cigarette: - Approximately 1 to 2 mg In the U.S., cigarettes are generally sold in packs containing 20 cigarettes, and a carton of cigarettes generally contains 10 packs. In a study analyzing cigarettes sold by the major American manufacturers (Philip Morris; RJ Reynolds; Brown & Williamson; Lorillard Tobacco) from 1997 to 2005 (~200 brands/year), the total nicotine content per cigarette averaged 13.5 mg (range, 11.9 to 14.5 mg/cig) (Connolly, et al., 2007). Notably, this study found a significant increase in the nicotine yield (0.03 mg/cigarette/year, which represents a 1.6% mg/cigarette increase per year) during 1998 to Modifications in cigarette design, including (a) higher concentrations of nicotine per cigarette and (b) alterations to reduce the “burn rate,” which increase the number of puffs/cigarette, are believed to increase the nicotine yield (Connolly, et al., 2007). Cigarette ratings for tar and nicotine are determined by a standardized U.S. Federal Trade Commission machine testing procedure that involves inhalation of 35 mL of smoke over 2 seconds every 60 seconds (NCI, 2001). Under these conditions, in 1998 and 2004 the average machine yield of nicotine among the top-selling brands of American cigarettes (n=116) was 0.9 mg (MDPH, 2006). Full-flavor (regular) brands had higher machine nicotine yields (1.1 mg/cigarette) compared to light (0.8 mg/cigarette) or ultra-light brands (0.4 mg/cigarette). (MDPH, 2006). In contrast, studies with smokers have consistently demonstrated higher nicotine yields (1–2 mg/cigarette) suggesting the FTC machine method underestimates the true nicotine exposure under actual smoking conditions (Benowitz & Jacob, 1984; Jarvis et al., 2001; NCI, 2001). ♪ Note to instructor(s): Researchers from the Massachusetts Department of Public Health have developed a testing method hypothesized to more closely approximate the smoking behavior of a typical smoker (e.g., 45 mL puff volume over 2 seconds every 30 seconds with 50% blockage of filter ventilation holes). Using this approach, the measured nicotine yield was 2-fold higher with the Massachusetts method when compared to the standard FTC method (MDPH, 2006). Benowitz NL, Jacob P. (1984). Daily intake of nicotine during cigarette smoking. Clin Pharmacol Ther 35:499–504. Connolly GN, Alpert HR, Wayne GF, Koh H. (2007). Trends in nicotine yield in smoke and its relationship with design characteristics among popular US cigarette brands, Tob Control 16:e5. Jarvis MJ, Boreham R, Primatesta P, Feyerabend C, Bryant A. (2001). Nicotine yield from machine-smoked cigarettes and nicotine intakes in smokers: evidence from a representative population survey. J Natl Cancer Inst 17:134–138. Massachusetts Department of Public Health (MDPH). (2006). Change in Nicotine Yields National Cancer Institute. (2001). Risks Associated with Smoking Cigarettes with Low Machine Yields of Tar and Nicotine. Smoking and Tobacco Control Monograph No. 13. Bethesda, MD: U.S. Department of Health and Human Services, National Institutes of Health, NIH Pub. No Type of cigarette Yield per cigarette Full-flavor (regular) 1.1 mg Light 0.8 mg Ultra-light 0.4 mg Average (all brands) 0.9 mg Marlboro and Marlboro Light are registered trademarks of Philip Morris, Inc.

SMOKELESS TOBACCO Chewing tobacco Snuff Looseleaf Plug Twist Moist Dry
Smokeless tobacco is classified as either chewing tobacco or snuff (Hatsukami et al, 2007; USDHHS, 1986). Chewing tobacco is chewed or held in the cheek or lower lip. The following types of chewing tobacco are marketed in the U.S.: Looseleaf: consists of stripped and processed tobacco leaves that are stemmed, cut, and loosely packed to form small strips of shredded tobacco (depicted in slide). Most brands are sweetened and flavored with licorice. Generally available in a 3-ounce pouch. Users tuck a piece of tobacco ¾ to 1 inch in diameter in the back of the mouth between the gum and jaw and chew intermittently. Plug: made from tobacco leaves or fragments wrapped in fine tobacco and pressed into bricks (depicted in slide). Most plug tobacco is sweetened and flavored with licorice. Generally available in compressed bricks or blocks. Users chew or hold a piece inside cheek or lower lip. Twist: handmade from leaf tobacco treated with a tar-like tobacco leaf extract and twisted into strands (depicted in slide) that are dried. Usually contains no sweeteners or flavoring agents. Generally sold by the piece. Used in a manner similar to plug tobacco. Snuff has a much finer consistency than chewing tobacco and is held in place in the mouth without chewing. The following types of snuff are marketed in the U.S.: Moist snuff: consists of tobacco stems and leaves that are processed into fine particles, strips, or mini-sachets resembling tea bags (depicted in slide). Some products are flavored. Has moisture content of up to 50%. Available in cans and plastic containers. Users place a small amount (a “pinch”) between the lip or cheek and gum (also known as dipping) and suck on the moist mass of tobacco for 30 minutes or longer. Because of increased surface area, finer cuts of tobacco result in more rapid absorption of nicotine. Dry snuff: consists of tobacco that is fermented and processed into a dry powdered form. Generally has a moisture content of less than 10%. Available in cans and glass containers. Used in a manner similar to moist snuff but also may be sniffed. Hatsukami DK, Ebbert JO, Feuer RM, Stepanov I, Hecht SS. (2007). Changing smokeless tobacco products new tobacco-delivery systems. Am J Prev Med 33(6 Suppl):S368-S378. U.S. Department of Health and Human Services (USDHHS). (1986). The Health Consequences of Using Smokeless Tobacco. A Report of the Advisory Committee to the Surgeon General (NIH Publication No ). The Copenhagen and Skoal logos are registered trademarks of U.S. Smokeless Tobacco Company, and Red Man is a registered trademark of Swedish Match.

SMOKELESS FORMS of TOBACCO
Estimated 8.8 million users in the U.S. in 2013 (3.4%) Adult males (6.5%) more likely than adult females (0.4%) to be current users Prevalence highest among Young adults aged years Residents of the Midwest and Southern U.S. Residents of nonmetropolitan areas Significant health risks Numerous carcinogens Nicotine exposure comparable to that of smokers, leading to Physical dependence Withdrawal symptoms after abstinence According to the U.S. Department of Health and Human Services (2014), in 2013 an estimated 9.0 million Americans aged 12 years or older (3.5%) had used smokeless tobacco in the past month. Males (6.7%) were more likely than females (0.3%) to be current users. The prevalence of smokeless tobacco use is highest among individuals aged 18–25 years, residents of the Midwest and Southern U.S. and nonmetropolitan areas. Users of smokeless tobacco products often believe this is a safe alternative to smoking cigarettes, because it is not inhaled. This is not true. Smokeless tobacco has high concentrations of numerous carcinogens, including nitrosamines, polycyclic aromatic hydrocarbons, and radioactive polonium-210, which are in direct contact with mucosal tissues for prolonged periods (Boffetta et al., 2008; USDHHS, 1986). Furthermore, regular smokeless tobacco users experience comparable exposure to nicotine and are as likely to develop physical dependence as are regular smokers (Ebbert, 2004). Boffetta P, Hecht S, Gray N, Gupta P, Straif K. (2008). Smokeless tobacco and cancer. Lancet Oncol 9:667–675. Ebbert JO, Carr AB, Dale LC. (2004). Smokeless tobacco: An emerging addiction. Med Clin N Am 88:1593–1605. U.S. Department of Health and Human Services (USDHHS). (1986). The Health Consequences of Using Smokeless Tobacco. A Report of the Advisory Committee to the Surgeon General (NIH Publication No ). U.S. Department of Health and Human Services (USDHHS), Substance Abuse and Mental Health Services Administration. (2013). Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-48, HHS Publication No. (SMA) Retrieved December 30, 2014, from

NICOTINE CONTENT in SMOKELESS TOBACCO PRODUCTS
Dose Product pH Total free nicotine (mg/g) Low Hawken Wintergreen 5.2 – 5.7 0.01 – 0.02 Skoal Bandits Wintergreen 6.9 – 7.1 0.5 – 1.0 Medium Skoal Long Cut Straight 7.5 – 7.6 2.4 – 3.7 High Kodiak Wintergreen 8.2 – 8.4 5.8 – 6.5 Copenhagen 7.6 – 8.6 3.1 – 9.4 This slide presents the nicotine content of some commonly used smokeless tobacco products (Hatsukami et al., 2007). Absorption of nicotine from chewing tobacco and snuff is pH dependent. With increasing pH, the fraction of free (un-ionized) nicotine increases, leading to increased absorption of nicotine across the buccal mucosa. Spit tobacco manufacturers manipulate the nicotine content and pH of their products by adding alkaline buffering agents and changing the tobacco processing methods to control the delivery of nicotine (Alpert et al., 2008). For example, a “starter” formulation, such as Hawken Wintergreen or Skoal Bandits, is more acidic (pH = 5.2–7.1) and has a lower amount of free nicotine, thereby increasing tolerability. Once dependence has been established, users generally advance to more alkaline, higher free nicotine content products such as Skoal Long Cut (pH = 7.5–7.6) and Copenhagen (pH =7.6–8.6), which are capable of delivering higher levels of nicotine. Under standardized laboratory conditions, the observed peak plasma levels of nicotine were 4.6 times higher with Copenhagen than with Skoal Bandits (Fant et al., 1999). Alpert HA, Koh H, Connollly GN. (2008). Free nicotine content and strategic marketing of moist snuff tobacco products in the United States: Tob Control 17: Fant RV, Henningfield JE, Nelson RA, Pickworth WB. (1999). Pharmacokinetics and pharmacodynamics of moist snuff in humans. Tob Control 8:387–392. Hatsukami DK, Ebbert JO, Feuer RM, Stepanov I, Hecht SS. (2007). Changing smokeless tobacco products new tobacco-delivery systems. Am J Prev Med 33(6 Suppl):S Data from Hatsukami et al. (2007). Am J Prev Med 33(6S):S368–78.

HEALTH CONSEQUENCES of SMOKELESS TOBACCO USE
Periodontal effects Gingival recession Bone attachment loss Dental caries Oral leukoplakia Cancer Oral cancer Pharyngeal cancer ♪ Note to instructor(s): Please delete this slide if you are also teaching the Epidemiology of Tobacco Use module. In addition to the cosmetic concerns (e.g., halitosis, staining of teeth), the use of smokeless tobacco is associated with numerous adverse health effects (Ebbert, 2004) including the following: Periodontal Effects Regular users of smokeless tobacco are at significant risk for the development of gingival recession (complete or partial loss of the tissue covering the root of the tooth), caries, and tooth abrasion. The loss of gingival tissue, observed in up to 27% of smokeless tobacco users, generally occurs at sites constantly exposed to tobacco (Taybos, 2003). The high sugar content found in many smokeless tobacco products in contact with exposed tooth root tissue might account for the increased incidence of dental caries in smokeless tobacco users (Hatsukami & Severson, 1999; Taybos, 2003; Ebbert et al., 2004). Soft Tissue Alterations/Leukoplakia Smokeless tobacco users commonly develop an oral soft tissue condition called leukoplakia or "snuff dipper's lesion." These white-colored patches or plaques, which are observed in approximately 15% of chewing tobacco users and 60% of snuff users, generally develop at mucosal sites in contact with the tobacco (Ebbert et al., 2004; Taybos, 2003). Of concern is the fact that a small percentage of these lesions may transform into squamous cell carcinomas (Hatsukami & Severson, 1999; Napier & Speight, 2008). Following cessation, the oral leukoplakia appears to regress or completely disappear in the majority of cases (Napier & Speight, 2008; Martin et al., 1999). Cancer The most serious consequence of smokeless tobacco use is an increased risk for developing oral and pharyngeal cancers; the risk appears to be dose related with heavy, long-time users being more likely to develop oral cancer compared with nonusers (Ebbert et al., 2004). The risk of developing oral and lung cancer among smokeless tobacco users appears to be lower than that of smokers, but higher than that of non-tobacco users (Boffetta et al., 2008). Buffett P, Hecht S, Gray N, Gupta P, Straif K. (2008). Smokeless tobacco and cancer. Lancet Oncol 9:667–675. Ebbert JO, Carr AB, Dale LC. (2004). Smokeless tobacco: An emerging addiction. Med Clin N Am 88:1593–1605. Hatsukami DK, Severson HH. (1999). Oral spit tobacco: addiction, prevention and treatment. Nicotine Tob Res 1:21–44. Martin GC, Brown JP, Eifler CW, Houston GD. (1999). Oral leukoplakia status six weeks after cessation of smokeless tobacco use. J Am Dent Assoc 130:945–954. Napier SS, Speight PM. (2008). Natural history of potentially malignant oral lesions and conditions: an overview of the literature. J Oral Pathol Med 37:1–10. Taybos G. (2003). Oral changes associated with tobacco use. Am J Med Sci 326:179–182. Oral Leukoplakia Image courtesy of Dr. Sol Silverman - University of California San Francisco

PIPE TOBACCO Prevalence of pipe smoking in the U.S. is less than 1%
Pipe smokers have an increased risk of death due to: Cancer (lung, oral cavity, esophagus, larynx) Chronic obstructive pulmonary disease Risk of smoking tobacco-related death: cigarettes > pipes ≈ cigars In 2013, 0.9% of Americans aged 12 or older were current (past month) pipe smokers (USDHHS, 2014). Compared to never-smokers, pipe smokers have an increased risk of death from lung, oral, esophageal, and laryngeal cancer and chronic obstructive pulmonary disease (Henley et al., 2004). The risk of tobacco-related mortality among pipe smokers is lower than that observed in cigarette smokers and comparable to that found among cigar smokers (Henley et al., 2004). These differences might result from the tendency of pipe and cigar smokers to smoke less and generally to inhale less deeply than do cigarette smokers. Henley SJ, Thun MJ, Chao A, Calle EE. (2004). Association between exclusive pipe smoking and mortality from cancer and other diseases. J Natl Cancer Inst 96:853–861. U.S. Department of Health and Human Services (USDHHS), Substance Abuse and Mental Health Services Administration. (2013). Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-48, HHS Publication No. (SMA) Retrieved December 30, 2014, from

CIGARS Estimated 12.4 million cigar smokers in the U.S. in 2013
Tobacco content of cigars varies greatly One cigar can deliver enough nicotine to establish and maintain dependence Cigar smoking is not a safe alternative to cigarette smoking Cigars are conventionally defined as “any roll of tobacco wrapped in leaf tobacco or in any substance containing tobacco” (Baker et al., 2000). Cigar tobacco is generally air cured and produces smoke with a more alkaline pH, which allows for buccal absorption of nicotine (Henningfield et al., 1999). According to the U.S. Department of Health and Human Services (2014), in 2013 an estimated 12.4 (4.7%) of Americans aged 12 or older were current (past month) cigar smokers. The prevalence of cigar use was highest among individuals aged years (10.0%); males (7.7%) were more likely than females (2.0%) to be current cigar smokers (USDHHS, 2014). Exactly how much nicotine an individual might obtain from a single cigar is difficult to determine or generalize, because cigar weight and nicotine content vary widely from brand to brand and from cigar to cigar. Most cigars range in weight from about 1 to 22 g; a typical cigarette weighs less than 1 g. The nicotine content in 10 commercially available cigars studied in 1996 ranged from 10 to 444 mg (Henningfield et al., 1999). In comparison, standard U.S. cigarettes have a relatively narrow total nicotine content, ranging between 11.9 and 14.5 mg of nicotine per cigarette (Connolly et al., 2007). Relating these data, Henningfield and colleagues concluded that it is possible for one large cigar to contain as much tobacco as an entire pack of cigarettes and deliver enough nicotine to establish and maintain dependence (Henningfield et al., 1999). Cigar smoking is not a safe alternative to cigarette smoking. The adverse health effects of cigar smoking have been well described and include an increased risk of cancer of the lung, oral cavity, larynx, esophagus, and pancreas. In addition, cigar smokers who inhale deeply are at increased risk for developing cardiovascular disease and chronic obstructive pulmonary disease (Baker et. al., 2000; NCI, 1998). On average, cigarette smokers who switch to smoking only cigars will decrease their risk of developing lung cancer, but their risk remains markedly higher than if they were to quit smoking altogether (NCI, 1998). Baker F, Ainsworth SR, Dye JT, Crammer C, Thun MJ, et al. (2000). Health risks associated with cigar smoking. JAMA 284:735–740. Centers for Disease Control and Prevention. (2006). Tobacco use among adults—United States, MMWR 55:1145–1147. Connolly GN, Alpert HR, Wayne GF, Koh H. (2007). Trends in nicotine yield in smoke and its relationship with design characteristics among popular US cigarette brands, Tob Control 16:e5. Eaton DK, Kann L, Kinchen S, Shanklin S, Ross J, et al. (2008). Youth risk behavior surveillance--United States, MMWR Surveill Summ 57:1–131. Henningfield JE, Fant RV, Radzius A, Frost S. (1999). Nicotine concentration, smoke pH, and whole tobacco aqueous pH of some cigar brands and types popular in the U.S. Nicotine Tob Res 1:163–168. National Cancer Institute (NCI). (1998). Cigars: Health Effects and Trends (Smoking and Tobacco Control Monograph No. 9; NIH Publication No ). Bethesda, MD: U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute, p. 67. U.S. Department of Health and Human Services (USDHHS), Substance Abuse and Mental Health Services Administration. (2013). Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-48, HHS Publication No. (SMA) Retrieved December 30, 2014, from

CLOVE CIGARETTES (also known as KRETEKS)
Mixture of tobacco and cloves Imported from Indonesia In 2012, an estimated 3.0% of 12th graders in the U.S. reported smoking kreteks in the past year Two times the tar and nicotine content of standard cigarettes Clove cigarettes or “kreteks” are cigarettes imported from Indonesia containing a mixture of approximately 60% to 70% tobacco and 30% to 40% minced cloves (Deckers et al., 2006). While usage data in adults are not available, in 2012, an estimated 3.0% of 12th graders had smoked kreteks in the past year (Johnston et al., 2013). In smoking machine tests, clove cigarettes deliver nearly twice as much nicotine and carbon monoxide and nearly three times as much tar as conventional filtered U.S. cigarettes (Malson et al., 2003). ♪ Note to instructor(s): Clove cigarettes are tobacco products, and smoking them carries all the hazards associated with smoking all-tobacco cigarettes. In addition, the smoking of clove cigarettes has been associated with rare but serious cases of hemorrhagic pulmonary edema, pneumonia, bronchitis, and hemoptysis (AMA, 1988; CDC, 1985; Guidotti et al., 1989). It has been speculated that eugenol, a compound possessing local anesthetic properties and present in large quantities in clove cigarette smoke, might be toxic to pulmonary tissue. The anesthetic effects of eugenol also might increase the risk of pulmonary aspiration resulting from an impaired gag reflex (Guidotti et al., 1989). American Medical Association (AMA) Council on Scientific Affairs. (1988). Council report: Evaluation of the health hazard of clove cigarettes. JAMA 260:3641–3644. Centers for Disease Control and Prevention (CDC). (1985). Epidemiologic notes and reports illnesses possibly associated with smoking clove cigarettes. MMWR 34:297–299. Deckers SK, Farley J, Heath J. (2006). Tobacco and its trendy alternatives: implications for pediatric nurses. Crit Care Nurs Clin North Am 18:95–104. Guidotti TL, Laing L, Prakash U. (1989). Clove cigarettes: The basis for concern regarding health effects. West J Med 151:220–228. Johnston LD, O'Malley PM, Bachman JG, Schulenberg, JE. (2013). Monitoring the Future national survey results on drug use, 1975–2012: Volume I, Secondary school students. Ann Arbor: Institute for Social Research, The University of Michigan. Retrieved December 30, 2014, from Malson JL, Lee EM, Murty R, Moolchan ET, Pickworth WB. (2003). Clove cigarette smoking: Biochemical, physiological, and subjective effects. Pharmacol Biochem Behav 74:739–745

BIDIS Imported from India Resemble marijuana joints
Available in candy flavors In 2010, an estimated 1.4% of 12th graders in the U.S. reported smoking bidis in the past year Deliver 3-fold higher levels of carbon monoxide and nicotine and 5-fold higher levels of tar when compared to standard cigarettes Bidis are small, hand-rolled cigarettes imported to the U.S. primarily from India and other Southeast Asian countries. They consist of finely ground tobacco wrapped in a brown tendu or temburni leaf. Bidis, which are similar in appearance to marijuana cigarettes, are readily available in tobacco shops and ethnic stores and via internet retailers in a variety of flavors (e.g., chocolate, vanilla, strawberry, cherry, mango) (Deckers et al., 2006). While there was initial concern in the late 1990’s that bidi use would become prevalent among adolescents and young adults, this does not appear to be a significant public health concern compared to other forms of tobacco. In 2010, an estimated 1.4% of 12th graders reported smoking bidis in the past year (Johnston et al., 2013). Note: data were not collected beyond 2010. Although bidis contain less tobacco than standard cigarettes, studies have shown they produce substantial amounts of tar, nicotine, and carbon monoxide (Malson et al., 2001; Watson et al., 2003). A study using standardized smoking machine testing methods found that bidis deliver three times the amount of carbon monoxide and nicotine and nearly five times the amount of tar found in standard cigarettes (Malson et al., 2001). Because of the low combustibility of the leaf wrapper, bidis must be puffed constantly to keep them lit. As a result, bidi smokers inhale more frequently and more deeply, thereby markedly increasing the delivery of tar and other toxins (CDC, 1999). Most bidis do not have a traditional filter tip, which further increases exposure to toxic constituents present in smoke. Studies in India have shown that bidi smokers have a comparable or greater risk of developing tobacco-related respiratory, cardiovascular, and neoplastic disease than cigarette smokers. Even low levels of bidi smoking (1 to 7 bidis/day) is associated with an elevated risk of death (risk ratio estimate, 1.3) compared to nonsmokers. Higher levels of bidi smoking (≥ 8 bidis/day) incur an even higher risk of death (risk ratio estimate, 2.2) (Jha et al., 2008). Centers for Disease Control and Prevention (CDC). (1999). Bidi use among urban youth—Massachusetts, March–April MMWR 48:796–799. Deckers SK, Farley J, Heath J. (2006). Tobacco and its trendy alternatives: implications for pediatric nurses. Crit Care Nurs Clin North Am 18:95–104. Jha P, Jacob B, Gajalakshmi V, Gupta PC, Dhingra N, et al. (2008). A nationally representative case-control study of smoking and death in India. N Engl J Med 358:1137–1147. Malson JL, Sims K, Murty R, Pickworth WB. (2001). Comparison of the nicotine content of tobacco used in bidis and conventional cigarettes. Tob Control 10:181–183. Johnston LD, O'Malley PM, Bachman JG, Schulenberg, JE. (2013). Monitoring the Future national survey results on drug use, 1975–2012: Volume I, Secondary school students. Ann Arbor: Institute for Social Research, The University of Michigan. Retrieved December 30, 2014, from Watson CH, Polzin GM, Calafat AM, Ashley DL. (2003). Determination of tar, nicotine, and carbon monoxide yields in the smoke of bidi cigarettes. Nicotine Tob Res 5:747–753. Image courtesy of the Centers for Disease Control and Prevention / Dr. Clifford H. Watson

HOOKAH (WATERPIPE SMOKING)
Also known as Shisha, Narghile, Goza, Hubble bubble Tobacco flavored with fruit pulp, honey, and molasses Increasingly popular among young adults in coffee houses, bars, and lounges In 2012, 18.3% of 12th graders and 25.7% of U.S. college students had smoked hookah in the past year Nicotine, tar and carbon monoxide levels comparable to or higher than those in cigarette smoke Hookah, which is smoked through a waterpipe, is an ancient method of tobacco use whereby users inhale smoke that is passed through water. Nomenclature for this form of smoked tobacco is region-specific and includes names such as “hookah” (Africa and Indian subcontinent), “narghile” [nar-gee-leh], “nargile” (Israel, Jordan, Lebanon, Syria), “shisha”, “boory” or “goza” (Egypt, Saudi Arabia) and “hubble bubble” (many regions) (Maziak et al., 2004; Maziak, 2011). A waterpipe is a multi-component apparatus consisting of a mouthpiece, hose, water bowl, body and head. Maassel (a mixture of tobacco, dried fruit pulp, honey, and molasses in a variety of flavors) is placed in the head and then covered with perforated aluminum foil. Small pieces of burning charcoal are placed on top of the foil. Following inhalation, heat emanating from the burning charcoal is drawn through the tobacco mixture generating smoke. A vacuum created in the water bowl causes the smoke to “bubble” through the water and collect in the airspace above the water. The cooled smoke is then transported to the user through the hose and mouthpiece during inhalation (Maziak et al., 2004). Hookah bars and cafes, many of which are in close proximity to college campuses, have been emerging throughout the U.S. and data suggest this form of tobacco use is becoming increasingly popular among young adults (Eissenberg et al., 2008; Maziak, 2011). Surveys of U.S. college students have found that an estimated 30-40% of students have ever tried waterpipe smoking (Primack et al., 2008; Primack et al., 2010), and the prevalence of past-year use has been estimated at 25.7% (Johnston et al., 2013). In 2012, an estimated 18.3% of 12th graders reported hookah smoking in the past year (Johnston et al., 2013). Although many waterpipe users assume that the water will filter out toxins and believe this form of smoking is less harmful than cigarette smoking (Eissenberg et al., 2008; Smith-Simone et al., 2008; Primack et al., 2008) data are lacking to substantiate this belief. Indeed, studies have found that waterpipe smokers who inhale are exposed to nicotine, tar, and carbon monoxide in levels that are comparable to, or exceed those found in cigarette smoke (Sepetdjian et al., 2008; Shihadeh & Saleh, 2005; Neergaard et al., 2007) suggesting that waterpipe smoking is not "safe." Preliminary data suggest that waterpipe smokers are at risk for developing dependence and other adverse health-related conditions associated with smoking (Maziak et al., 2011). Eissenberg T, Ward KD, Smith-Simone S, Maziak W. (2008). Waterpipe tobacco smoking on a U.S. College campus: prevalence and correlates. J Adolesc Health 42:526–529. Johnston LD, O'Malley PM, Bachman JG, Schulenberg, JE. (2013). Monitoring the Future national survey results on drug use, 1975–2012: Volume I, Secondary school students. Ann Arbor: Institute for Social Research, The University of Michigan. Retrieved December 30, 2014, from Maziak W, Ward KD, Afifi Soweid RA, Eissenberg T. (2004). Tobacco smoking using a waterpipe: A re-emerging strain in a global epidemic. Tob Control 13:327–333. Maziak, W. (2011). The global epidemic of waterpipe smoking. Addictive Behaviors 36:1-5. Neergaard J, Singh P, Job J, Montgomery S. (2007). Waterpipe smoking and nicotine exposure: a review of the current evidence. Nicotine Tob Res 9:987–994. Primack BA, Sidani J, Agarwal AA, et al. (2008). Prevalence of and associations with waterpipe tobacco smoking among U.S. university students. Ann Behav Med 36:81-86. Primack BA, Fertman CI, Rice KR, et al. (2010). Waterpipe and cigarette smoking among college athletes in the United States. J Adolesc Health 2010 46:45-51. Shihadeh A, Saleh R. (2005). Polycyclic aromatic hydrocarbons, carbon monoxide, "tar", and nicotine in the mainstream smoke aerosol of the narghile water pipe. Food Chem Toxicol 43:655–661. Sepetdjian E, Shihadeh A, Saliba NA. (2008). Measurement of 16 polycyclic aromatic hydrocarbons in narghile waterpipe tobacco smoke. Food Chem Toxicol 46:1582–1590. Smith-Simone S, Maziak W, Ward KD, Eissenberg T. (2008). Waterpipe tobacco smoking: knowledge, attitudes, beliefs, and behavior in two U.S. samples. Nicotine Tob Res 10:393–398. Image courtesy of Mr. Sami Romman /

ELECTRONIC CIGARETTES
Generally similar in appearance to cigarettes, cigars, pipes, or pens Battery-operated devices that create a vapor for inhalation Simulates smoking but does not involve combustion of tobacco Also known as E-cigarette E-hookah, Hookah pen Vapes, Vape pen, Vape pipe Electronic nicotine delivery system (ENDS) “e-cigarettes” are battery-operated devices that generally contain cartridges filled with nicotine, flavor, and other chemicals. The electronic cigarette turns nicotine and other chemicals into a vapor that is 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 may appeal to youth. Public health experts are concerned that electronic cigarettes could increase nicotine addiction and tobacco use in young people (US FDA, 2009a). FDA laboratory analysis (US 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 non-existent. On September 9, 2010, the FDA announced that it had taken enforcement action against five electronic cigarette companies for violations of the Federal Food, Drug, and Cosmetic Act, including unsubstantiated claims and poor manufacturing practices (US FDA, 2010). However, on April 25, 2011, 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, 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 (US FDA, 2011). FDA is aware that certain products made or derived from tobacco, such as electronic 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 FDA urging the FDA to regulate e-cigarettes, especially the advertising of the products to youth. In the letter, attorneys general argued that FDA has the authority to regulate electronic 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, 627 F.3d 891 (D.C. Cir. 2010) 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 FDA urging the agency to ensure all tobacco products are tested and regulated to ensure that companies do not continue to advertise to youth. U.S. Food and Drug Administration. FDA and Public Health Experts Warn About Electronic Cigarettes. Released July 22, 2009a. Available at: Retrieved December 30, 2014. U.S. Food and Drug Administration. Summary of results: Laboratory analysis of electronic cigarettes conducted by FDA. Released July 22, 2009b. Available at: Retrieved December 30, 2014. U.S. Food and Drug Administration. FDA acts against 5 electronic cigarette distributors. Released September 9, Available at: Retrieved December 30, 2014. U.S. Food and Drug Administration. Regulation of e-cigarettes and other tobacco products. Released April 25, Available at: Retrieved December 30, 2014. National Association of Attorneys General. Letter to Honorable Margaret Hamburg, Commissioner, US FDA. September 24, 2013.

An e-cigarette user inhales in the same manner as one would inhale from a conventional cigarette. Following exhalation, a cloud of smoke-like vapor is visible in the users exhaled breath.

ELECTRONIC CIGARETTES: Components
Power source Rechargeable or disposable battery Cartridge containing liquid solution Propylene glycol Glycerin Flavorings (tobacco, fruit, chocolate, mint, cola, candy, etc.) Nicotine (0-36 mg/mL) Electronic atomizer/vaporizer Heating element vaporizes liquid at temperatures °C This slide lists the components of a standard electronic cigarette. The cartridge solutions generally contain propylene glycol, glycerin, flavorings, and nicotine. The heating element of the device vaporizes this liquid at temperatures of degrees Celsius.

Electronic cigarettes are not proven to be safe.
ELECTRONIC CIGARETTES: Potential health risks Propylene glycol may cause respiratory irritation and increase the risk for asthma Glycerin may cause lipoid pneumonia on inhalation Nicotine is highly addictive and can be harmful Refill cartridges with high concentrations of nicotine are a poisoning risk, especially in children 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, electronic cigarettes have not been proven to be safe. This slide lists various sources of concern. Electronic cigarettes are not proven to be safe.

ELECTRONIC CIGARETTES: Indoor Air Pollution
E-cigarettes are not emission-free During vaping sessions, compounds and particles emitted into the indoor air include Propylene glycol Glycerin Heavy metals Levels of most substances lower than conventional cigarettes Long-term safety of second-hand exposure to e- cigarette aerosols is unknown Nicotine Flavoring agents Polycyclic aromatic hydrocarbons 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, 2013. Schober W, Szendrei K, Matzen W, Osiander-Fuchs H, Heitmann D, Schettgen T, Jörres RA, Fromme H. (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. German Cancer Research Center (Ed). Electronic Cigarettes—An Overview. Heidelberg, 2013. Schober et al., Int J Hyg Environ Health 2014; 217:

ELECTRONIC CIGARETTES: Current Trends and Evidence
Predominantly used by smokers and smokers who are considering quitting Used as an alternative to cigarette smoking and as an aid for cessation Perceived as less harmful than conventional cigarettes Use is increasing among adolescents and young adults Currently, e-cigarettes are used by smokers as well as smokers who are considering quitting. For some, it is an alternative to cigarette smoking and/or as an aid for cessation. E-cigarettes are often perceived as less harmful than smoking conventional cigarettes. It is of particular concern, among the public health community, that its use is increasing among adolescents and young adults.

ELECTRONIC CIGARETTES: Current Trends and Evidence, cont’d
Can 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- cigarettes Have not been proven effective as an aid for sustained smoking cessation 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. There is insufficient evidence, however, to ensure long-term safety or to demonstrate efficacy of e-cigarette use as an aid for cessation. Long-term safety and efficacy data are lacking.

FORMS of TOBACCO: SUMMARY
Cigarettes are, by far, the most common form of tobacco used in the U.S. Other forms of tobacco and nicotine delivery devices exist, and some are increasing in popularity. All forms of tobacco are harmful. The safety/efficacy of e-cigarettes is not established. Attention to all forms of tobacco is needed. To summarize, although cigarettes are by far the most commonly used form of tobacco in the U.S., other forms of tobacco and nicotine delivery devices exist. Many of these have increased in popularity in recent years, in part because of their social appeal and because of intensive marketing efforts by tobacco companies. However, all forms of tobacco carry significant health risks. The safety/efficacy of e-cigarettes has not yet been established. As a result, it is important for clinicians to become familiar with these products and to routinely assess their use among patients.

NICOTINE PHARMACOLOGY and PRINCIPLES of ADDICTION
This module focuses on the pharmacology of nicotine and principles of addiction.

NICOTINE ADDICTION U.S. Surgeon General’s Report
Cigarettes and other forms of tobacco are addicting. Nicotine is the drug in tobacco that causes addiction. The pharmacologic and behavioral processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine. In 1988 the U.S. Surgeon General released a report entitled The Health Consequences of Smoking: Nicotine Addiction. This landmark document summarized the scientific evidence supporting the concept that tobacco products are effective nicotine-delivery systems capable of inducing and sustaining chemical dependence. The major findings of the report (USDHHS, 1988) were as follows: Cigarettes and other forms of tobacco are addicting. Nicotine is the drug in tobacco that causes addiction. The pharmacologic and behavioral processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine. The last point is significant in that we, as health care providers, must treat tobacco use and dependence as a serious medical condition. Tobacco dependence should be considered as a chronic disease, not just a “bad habit” (Fiore et al., 2008). By acknowledging the chronic nature of tobacco dependence, clinicians can appreciate the need for ongoing care (which includes patient education, behavioral counseling, and pharmacotherapy) rather than episodic care (e.g., a single treatment course or periodic/occasional interventions). Nicotine addiction is a complex disorder that requires treatment directed at both the biological and the behavioral aspects of the disease. 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. (1988). The Health Consequences of Smoking: Nicotine Addiction. A Report of the Surgeon General (DHHS Publication No. PHS ). Washington, DC: U.S. Government Printing Office. Retrieved January 9, 2019, from U.S. Department of Health and Human Services. (1988). The Health Consequences of Smoking: Nicotine Addiction. A Report of the Surgeon General.

CHEMISTRY of NICOTINE N Nicotiana tabacum Natural liquid alkaloid
Pyridine ring Pyrrolidine ring As discussed in the Epidemiology of Tobacco Use module, tobacco and tobacco smoke have numerous constituents. From a pharmacologic perspective, the most important constituent is nicotine. Nicotine (Nicotiana tabacum), which is composed of a pyridine ring and a pyrrolidine ring, is one of the few natural alkaloids that exist in the liquid state. Nicotine is a clear, weak base with a pKa of 8.0 (Benowitz et al., 2009). Nicotine mimics the effects of acetylcholine at the acetylcholine receptor site. Benowitz N, Hukkanen J, Jacob P III. (2009). Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol. 192:29–60. Nicotiana tabacum Natural liquid alkaloid Colorless, volatile base pKa = 8.0

PHARMACOLOGY Pharmacokinetics Effects of the body on the drug
Absorption Distribution Metabolism Excretion Effects of the drug on the body Pharmacokinetics Pharmacology is divided into two areas: pharmacokinetics and pharmacodynamics. Pharmacokinetics is defined as the effects that the body has on a drug—specifically, the drug’s absorption, distribution, metabolism, and excretion. Each of these factors significantly influences how a drug affects a given individual. Pharmacodynamics is defined as the effects of a drug on the body. The effects can be either positive (therapeutic effects) or negative (adverse reactions or side effects). The next several slides cover nicotine pharmacokinetics and pharmacodynamics. Then we’ll discuss nicotine addiction as a form of chronic brain disease requiring a multifaceted therapeutic approach. ♪ Note to instructor(s): For a comprehensive review of the metabolism and disposition kinetics of nicotine, refer to Benowitz, Hukkanen, & Jacob (2009). Benowitz N, Hukkanen J, Jacob P III. (2009). Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol. 192:29–60. Pharmacodynamics

nicotine is readily absorbed.
NICOTINE ABSORPTION Absorption is pH dependent In acidic media Ionized  poorly absorbed across membranes In alkaline media Nonionized  well absorbed across membranes At physiologic pH (7.4), ~31% of nicotine is nonionized To understand nicotine pharmacology, it’s important to know that absorption of nicotine is pH dependent. Because nicotine is a weak base: In acidic media… nicotine is ionized and poorly absorbed across membranes. In alkaline media… nicotine is nonionized and well absorbed across membranes. In acidic media, nicotine is ionized and poorly absorbed; conversely, in alkaline media, nicotine is nonionized and well absorbed. Under physiological conditions (pH = 7.4), a large proportion of nicotine (approximately 31%) is nonionized and readily crosses cell membranes (Benowitz et al., 2009). Benowitz N, Hukkanen J, Jacob P III. (2009). Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol. 192:29–60. At physiologic pH, nicotine is readily absorbed.

NICOTINE ABSORPTION: BUCCAL (ORAL) MUCOSA
The pH inside the mouth is 7.0. Acidic media (limited absorption) Cigarettes Alkaline media (significant absorption) Pipes, cigars, spit tobacco, oral nicotine products Most American cigarette smoke is acidic. As a result, limited nicotine is absorbed across the buccal (oral) mucosa. In contrast, air-cured tobacco (found in pipe tobacco and cigars) produces smoke with an alkaline pH, which allows for buccal absorption of nicotine (Benowitz et al., 2009). Even pipe or cigar smokers who don’t inhale experience considerable nicotine absorption through the buccal mucosa (Benowitz, 1992). Smokeless tobacco products (snuff and chew) and nicotine gum and lozenge are more alkaline and this facilitates buccal absorption of nicotine (Benowitz et al, 2009). If the pH of the mouth is lowered by drinking acidic beverages (e.g., coffee, juice, or cola), absorption of nicotine from nicotine gum is reduced substantially (Henningfield et al., 1990). This fact is important when counseling patients on the proper use of nicotine gum, lozenge, and oral inhaler. Notably, the tobacco industry documents reveal that the industry alters the ammonia and acid aldehyde chemistry to manipulate the pH of its products, rendering them more addictive (Stevenson & Proctor, 2008). Benowitz NL. (1992). Cigarette smoking and nicotine addiction. Med Clin N Am 76:415–437. Benowitz N, Hukkanen J, Jacob P III. (2009). Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol. 192:29–60. 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. Stevenson T, Proctor R. (2008). The secret and soul of Marlboro: Phillip Morris and the origins, spread, and denial of nicotine freebasing. Am J Public Health. 98(7):1184–1194. Beverages can alter pH, affect absorption.

NICOTINE ABSORPTION: SKIN and GASTROINTESTINAL TRACT
Nicotine is readily absorbed through intact skin. Nicotine is well absorbed in the small intestine but has low bioavailability (20-45%) due to first-pass hepatic metabolism. Nicotine is readily absorbed across intact skin. This allows for transdermal administration of nicotine as a therapeutic adjunct to tobacco cessation (Benowitz et al., 2009). Conversely, the bioavailability of nicotine in the gastrointestinal tract is limited. Absorption across the gastric mucosa is poor as a result of low gastric pH. In the small intestine, nicotine is well absorbed due to the large surface area for absorption and increased pH; however, the systemic bioavailability is low (20-45%) because it undergoes significant first-pass hepatic metabolism (Benowitz et al., 2009). Nicotine formulations that are absorbed primarily across the buccal mucosa (e.g., gum, lozenges, oral inhaler, and sublingual tablets) are not subject to first-pass hepatic metabolism. Benowitz N, Hukkanen J, Jacob P III. (2009). Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol. 192:29–60. .

NICOTINE ABSORPTION: LUNG
Nicotine is “distilled” from burning tobacco and carried in tar droplets. Nicotine is rapidly absorbed across respiratory epithelium. Lung pH = 7.4 Large alveolar surface area Extensive capillary system in lung Approximately 1 mg of nicotine is absorbed from each cigarette. Nicotine is “distilled” from burning tobacco and carried in droplets to the small airways of the lung. The droplets are composed of water, tar, and alkaloids, including nicotine (Hukkanen et al., 2005). When tobacco smoke reaches the alveoli, nicotine is rapidly absorbed across respiratory epithelial cells due to the following factors (Benowitz et al., 2009): The pH of the lung is 7.4 (a larger fraction of nicotine is nonionized). The alveolar surface area of the lung is large. The capillary system in the lung is extensive. A smoker absorbs, on average, approximately 1 mg (range 0.4–1.6 mg) of nicotine per cigarette (Benowitz & Jacob, 1984). Benowitz NL, Jacob P III. (1984). Daily intake of nicotine during cigarette smoking. Clin Pharmacol Ther 35:499–504. Benowitz N, Hukkanen J, Jacob P III. (2009). Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol. 192:29–60.

NICOTINE DISTRIBUTION
Arterial Inhalation of tobacco smoke is an effective means of delivering nicotine to the central nervous system. After inhalation, nicotine is rapidly absorbed 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, thereby 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.

NICOTINE METABOLISM N H CH3 N 70–80% cotinine ~ 10% other metabolites
10–20% excreted unchanged in urine N CH3 N Nicotine is metabolized extensively in the liver and to a lesser extent in the kidney and lung. Approximately 70–80% of nicotine is metabolized to cotinine, an inactive metabolite, and about 4–7% is metabolized to nicotine N′-oxide (Benowitz et al., 1994; Benowitz et al., 2009). The metabolism of nicotine to cotinine is a two-step process likely involving CYP2A6 and aldehyde oxidase. Cotinine is further metabolized to 3′-hydroxycotinine, which undergoes renal elimination. However, nicotine, cotinine, and 3′-hydroxycotinine also undergo glucuronidation. A small fraction (10–15%) of an administered dose of nicotine is excreted as unchanged drug in the urine (Benowitz et al., 1994; Benowitz et al., 2009). ♪ Note to instructor(s): For a comprehensive review of nicotine metabolism, refer to Benowitz et al., 2009. Benowitz N, Hukkanen J, Jacob P III. (2009). Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol. 192:29–60. Benowitz NL, Jacob P, Fong I, Gupta S. (1994). Nicotine metabolic profile in man: Comparison of cigarette smoking and transdermal nicotine. J Pharmacol Exp Ther 268:296–303. 70–80% cotinine ~ 10% other metabolites Metabolized and excreted in urine Adapted and reprinted with permission. Benowitz et al. (1994). J Pharmacol Exp Ther 268:296–303.

NICOTINE EXCRETION Half-life Nicotine t½ = 2 hr Cotinine t½ = 16 hr
Occurs through kidneys (pH dependent; h with acidic pH) Through breast milk The half-life of nicotine in the body is approximately 2 hours. This rapid metabolism of nicotine to inactive compounds underlies tobacco users’ need for frequent, repeated administration of nicotine. With regular tobacco use, significant nicotine levels accumulate during waking hours (Benowitz et al., 2009). The half-life of cotinine (major metabolite of nicotine) is much longer ~16 hours (range, 13–19 hours). For this reason, cotinine can be used as a more reliable marker of tobacco use and exposure to second-hand smoke (Benowitz et al., 2009). Nicotine and other metabolites are excreted in the urine. Urinary excretion is pH dependent; the excretion rate is increased in acidic urine. Nicotine accumulates in breast milk and can be detected in the blood and urine of infants of nursing smokers (Benowitz et al., 2009). Benowitz N, Hukkanen J, Jacob P III. (2009). Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol. 192:29–60.

NICOTINE PHARMACODYNAMICS
Nicotine binds to receptors in the brain and other sites in the body. Central nervous system Cardiovascular system Exocrine glands Nicotine pharmacodynamics refers to the effects that nicotine has on the body. Nicotine is a potent agent that affects numerous organ systems, including the cardiovascular, endocrine, musculoskeletal, and neurologic systems, as shown in this diagram. Following absorption, nicotine binds to receptors in the brain and other sites in the body, inducing a variety of predominantly stimulatory and, to a lesser extent, inhibitory effects (Benowitz, 2008; Benowitz, 2010). Benowitz N. (2008) Neurobiology of nicotine addiction: implications for smoking cessation treatment. Am J Med. 121(4 Suppl 1):S3–S10. Benowitz N. Nicotine addiction. (2010). N Engl J Med. 362(24):2295–2303. Gastrointestinal system Adrenal medulla Other: Neuromuscular junction Sensory receptors Other organs Peripheral nervous system Nicotine has predominantly stimulatory effects.

NICOTINE PHARMACODYNAMICS (cont’d)
Central nervous system Pleasure Arousal, enhanced vigilance Improved task performance Anxiety relief Other Appetite suppression Increased metabolic rate Skeletal muscle relaxation Cardiovascular system  Heart rate  Cardiac output  Blood pressure Coronary vasoconstriction Cutaneous vasoconstriction Pharmacodynamic effects of nicotine on the central nervous system (Benowitz, 1992): Pleasure: Tobacco users commonly report they find tobacco use pleasurable. Arousal, enhanced vigilance: Tobacco use may help with thinking, concentration, and mood elevation. Improved task performance: Nicotine has been shown to increase vigilance and performance for some types of tasks (e.g., repetitive/monotonous tasks). Relief of anxiety: Many tobacco users report reduced anger, tension, and stress after administration. It is not known whether the improvements in mood or task performance are due to relief of nicotine withdrawal symptoms or a direct effect of nicotine on the brain. Pharmacodynamic effects of nicotine on the cardiovascular system: Nicotine’s effects on the cardiovascular system include increased heart rate, cardiac output, and blood pressure as well as cutaneous and coronary vasoconstriction (Benowitz, 2003). After a cigarette is smoked, the smoker’s blood pressure rises by 5–10 mmHg for 15–30 minutes, and the heart rate increases an average of 10–20 beats/min for up to 60 minutes (Benowitz et al., 1988). Studies suggest there is a flat dose-response to the cardiovascular effects of nicotine. This so-called ceiling effect might be due to a rapid but partial development of tolerance to the cardiovascular effects of nicotine (Benowitz, 1997). Other pharmacodynamic effects of nicotine: Nicotine is an effective appetite suppressant and causes modest acute increases in the metabolic rate (Benowitz, 1992). Most people who quit using tobacco will gain weight, although the average person will gain less than 10 pounds (Fiore et al., 2008). Weight gain after tobacco cessation is a major concern for many patients, especially females. Nicotine also causes relaxation of some skeletal muscle (Benowitz, 1992). Benowitz NL. (1992). Cigarette smoking and nicotine addiction. Med Clin N Am 76:415–437. Benowitz NL. (2003). Cigarette smoking and cardiovascular disease: pathophysiology and implications for treatment. Prog Cardiovasc Dis 46: Benowitz NL. (1997). The role of nicotine in smoking-related cardiovascular disease. Prev Med 26:412–417. Benowitz NL, Porchet H, Sheiner L, Jacob P III. (1988). Nicotine absorption and cardiovascular effects with smokeless tobacco use: Comparison with cigarettes and nicotine gum. Clin Pharmacol Ther 44:23–28. 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.

NEUROCHEMICAL and RELATED EFFECTS of NICOTINE
Dopamine Norepinephrine Acetylcholine Glutamate Serotonin -Endorphin GABA Pleasure, appetite suppression Arousal, appetite suppression Arousal, cognitive enhancement Learning, memory enhancement Mood modulation, appetite suppression Reduction of anxiety and tension On a neurochemical level, nicotine induces a variety of central nervous system, cardiovascular, and metabolic effects. Nicotine stimulates the release of many neurotransmitters, which have been associated with the following effects (Benowitz, 2008): Neurotransmitter Effects Dopamine Pleasure, appetite suppression Norepinephrine Arousal, appetite suppression Acetylcholine Arousal, cognitive enhancement Glutamate Learning, memory enhancement Serotonin Mood modulation, appetite suppression -Endorphin Reduction of anxiety and tension GABA Reduction of anxiety and tension Nicotine induces a constellation of effects that reinforce tobacco use behavior. Benowitz NL. (2008). Clinical pharmacology of nicotine: implications for understanding, preventing, and treating tobacco addiction. Clin Pharmacol Ther 83:531–41. Benowitz. (2008). Clin Pharmacol Ther 83:531–541.

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, simply defines drug addiction as “compulsive use, without medical purpose, in the face of negative consequences” (Leshner, 1997). 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. 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.

DOPAMINE REWARD PATHWAY Ventral tegmental area
Prefrontal 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

CHRONIC ADMINISTRATION of NICOTINE: EFFECTS on the BRAIN
Nonsmoker Smoker Human smokers have increased nicotine receptors in the prefrontal cortex. High Low Image courtesy of George Washington University / Dr. David C. Perry Chronic administration of nicotine results in an increased number of CNS nicotine receptors in smokers compared to non-smokers (Breese et al., 1997; Govind et al., 2009; Perry et al., 1999). This upregulation of nicotine receptors leads to the development of tolerance, by which repeated doses of a drug produce less of an effect than did the initial exposure. Post-mortem data suggest these smoking-induced changes are reversible following smoking cessation (Breese et al., 1997). Breese CR, Marks MJ, Logel J, et al. (1997). Effect of smoking history on [3H]nicotine binding in human postmortem brain. J Pharmacol Exp Ther 282:7–13. Govind A, Vezina P, Green W. (2009). Nicotine-induced upregulation of nicotinic receptors: underlying mechanisms and relevance to nicotine addiction. Biochem Pharmacol 78(7):756–765. Perry DC, Davila-Garcia MI, Stockmeier CA, Kellar KJ. (1999). Increased nicotinic receptors in brains from smokers: Membrane binding and autoradiography studies. J Pharmacol Exp Ther 289:1545–1552. Perry et al. (1999). J Pharmacol Exp Ther 289:1545–1552.

NICOTINE WITHDRAWAL SYMPTOMS: Time Course*
Irritability / Frustration / Anger Anxiety Difficulty concentrating Restlessness / Impatience Depressed mood / Depression Insomnia Impaired task 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. Nicotine replacement therapy, bupropion, and varenicline are used as aids for cessation in the management of the physiologic aspect of tobacco dependence. These agents work by alleviating the symptoms of nicotine withdrawal, which include (Hughes, 2007): Irritability/frustration/anger Anxiety Difficulty concentrating Restlessness/impatience Depressed mood/depression Insomnia Impaired task performance Increased appetite Weight gain Cravings for tobacco ♪ Note to instructor(s): Other symptoms of quitting have been described in the literature. Please refer to Hughes, 2007 for further details. This slide depicts the general time course for common nicotine withdrawal symptoms that is observed following the cessation tobacco use. Most withdrawal symptoms manifest within the first 1–2 days, peak in intensity within the first week, and gradually subside within 2 to 4 weeks after cessation (Hughes, 2007). In some individuals, prolonged appetite effects (e.g., hunger, weight gain) may occur continuously for 6 months or more (Hughes, 2007), and strong cravings for tobacco can 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 9:315–27. 6 months Can persist for months to years after quitting 1 week 4 weeks 12 weeks Quit date Recent quitter Former tobacco user Data from Hughes. (2007). Nicotine Tob Res 9:315–327. *Timeline aspect of the figure is not according to scale.

NICOTINE ADDICTION CYCLE
To alleviate the symptoms of withdrawal, smokers re-dose themselves throughout the day. This figure depicts the typical nicotine addiction cycle a cigarette smoker experiences on a daily basis. ♪ Note to instructor(s): Orient the students to the following elements on this figure: The jagged line represents venous plasma concentrations of nicotine as a cigarette is smoked every 40 minutes from 8 am to 9 pm. The upper solid line indicates the threshold concentration for nicotine to produce pleasure or arousal. The lower solid line indicates the concentrations at which symptoms of abstinence (i.e., withdrawal symptoms) from nicotine occur. The shaded area represents the zone of nicotine concentrations (neutral zone) in which the smoker is comfortable without experiencing either pleasure/arousal or abstinence symptoms. After smoking the first cigarette of the day, the smoker experiences marked pharmacologic effects, particularly arousal. No other cigarette throughout the day produces the same degree of pleasure/arousal. For this reason, many smokers describe the first cigarette as the most important one of the day. Shortly after the initial cigarette, tolerance begins to develop. Accordingly, the threshold levels for both pleasure/arousal and abstinence rise progressively throughout the day as the smoker becomes tolerant to the effects of nicotine. With continued smoking, nicotine accumulates, leading to an even greater degree of tolerance. As a result, the smoker experiences greater withdrawal symptoms between successive cigarettes. Late in the day, each individual cigarette produces only limited pleasure/arousal; instead, smoking primarily alleviates nicotine withdrawal symptoms. Cessation of smoking overnight allows resensitization of drug responses (i.e., loss of tolerance). Most dependent smokers tend to smoke a certain number of cigarettes per day (usually more than 10) and tend to consume 10–40 mg of nicotine per day to achieve the desired effects of cigarette smoking and minimize the symptoms of nicotine withdrawal (Benowitz, 1992; Benowitz, 2008). Benowitz NL. (1992). Cigarette smoking and nicotine addiction. Med Clin N Am 76:415–437. Benowitz NL. (2008). Clinical pharmacology of nicotine: implications for understanding, preventing, and treating tobacco addiction. Clin Pharmacol Ther 83:531–41. Reprinted with permission. Benowitz. (1992). Med Clin N Am 2:415–437.

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 As shown in the previous slide, 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 (Benowtiz, 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 83:531–41. 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.

ASSESSING NICOTINE DEPENDENCE
Fagerström Test for Nicotine Dependence (FTND) Developed in 1978 (8 items); revised in 1991 (6 items) Most common research measure of nicotine dependence; sometimes used in clinical practice Responses coded such that higher scores indicate higher levels of dependence Scores range from 0 to 10; score of greater than 5 indicates substantial dependence In research, and sometimes in clinical practice, it is useful to be able to measure a patient’s level of nicotine dependence. A commonly used scale for assessing nicotine dependence is the Fagerström Test for Nicotine Dependence (FTND). The FTND, which originally was an 8-item scale called the Fagerström Tolerance Questionnaire, consists of the following 6 items (Heatherton et al., 1991): How soon after you wake up do you smoke your first cigarette? Within 5 minutes, 6–30 minutes, 31–60 minutes, after 60 minutes Do you find it difficult to refrain from smoking in places where it is forbidden? Yes, No Which cigarette would you hate most to give up? The first one in the morning, Any other How many cigarettes per day do you smoke? 10 or less, 11–20, 21–30, 31 or more Do you smoke more frequently during the first hours after waking than during the rest of the day? Do you smoke if you are so ill that you are in bed most of the day? ♪ Note to instructor(s): Refer students to the FTND handout, which lists the items, describes the scoring, and presents cutoffs for categories of dependence. As shown on the scoring sheet, the responses are coded such that higher scores indicate higher levels of nicotine dependence. The total scores, after summing the items, range from 0 to 10. Although there are no established cutoffs for score interpretations, many researchers and clinicians generally consider scores of greater than 5 indicative of substantial dependence. Modified versions of the scale have been developed and tested for use with spit tobacco users (Severson & Hatsukami, 1999) and adolescents (Prokhorov et al., 1998). Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO. (1991). The Fagerström Test for Nicotine Dependence: A revision of the Fagerström Tolerance Questionnaire. British Journal of Addiction 86:1119–1127. Prokhorov AV, Koehly LM, Pallonen UE, Hudmon KS. (1998). Adolescent nicotine dependence measured by the modified Fagerström Tolerance Questionnaire at two time points. J Child Adol Subst Use 7:35–47. Severson HH, Hatsukami DK. (1999). Smokeless tobacco cessation. Prim Care 26:529–551. Heatherton et al. (1991). British Journal of Addiction 86:1119–1127.

CLOSE TO HOME © 2000 John McPherson.
Patients often describe tobacco cessation as the most difficult achievement of their life. 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.

FACTORS CONTRIBUTING to TOBACCO USE
Individual 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

TOBACCO DEPENDENCE: A 2-PART PROBLEM
Physiological 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-prong approach for maximal treatment effectiveness (Fiore et al., 2008). Prolonged tobacco 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 Medications 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 the behavioral aspects of dependence.

NICOTINE PHARMACOLOGY and ADDICTION: SUMMARY
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. 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.

DRUG INTERACTIONS with SMOKING
Many interactions between tobacco smoking and medications have been identified (Kroon 2007; Schein, 1995; Zevin & Benowitz, 1999). Clinically significant interactions result not from nicotine but from the combustion products of tobacco smoke. As discussed previously, tobacco smoke is a complex mixture of gaseous and particulate matter. It is widely recognized that the polycyclic aromatic hydrocarbons (PAHs) are largely responsible for the majority of drug interactions with smoking. PAHs, which are the products of incomplete combustion of tobacco, are found in appreciably large quantities in tobacco smoke and are potent inducers of hepatic microsomal (cytochrome P450) enzymes. Although other substances in tobacco smoke, including acetone, pyridines, benzene, nicotine, carbon monoxide, and heavy metals (e.g., cadmium), may also interact with hepatic enzymes, their effects appear to be less significant. ♪ Note to instructor(s): It is important to emphasize that the drug interactions described in this module refer to interactions between medications and constituents in tobacco smoke, and NOT between medications and nicotine. ♪ Note to instructor(s): This module reviews the clinically significant drug interactions reported with tobacco smoking and nicotine. Other interactions are described in the Drug Interactions with Smoking handout. The references noted below provide overviews of drug interactions with smoking. Kroon LA. (2007). Drug interactions with smoking. Am J Health Syst Pharm 64:1917–1921. Schein JR. (1995). Cigarette smoking and clinically significant drug interactions. Ann Pharmacother 29:1139–1148. Zevin S, Benowitz NL. (1999). Drug interactions with tobacco smoking. Clin Pharmacokinet 36:425–438.

PHARMACOKINETIC DRUG INTERACTIONS with SMOKING
Drugs that may have a decreased effect due to induction of CYP1A2: Bendamustine Haloperidol Tasimelteon Caffeine Olanzapine Theophylline Clozapine Riociguat Erlotinib Ropinirole Fluvoxamine Tacrine Irinotecan (clearance increased and systemic exposure decreased, due to increased glucuronidation of its active metabolite) Tobacco smoke interacts with medications through pharmacokinetic and pharmacodynamic mechanisms. Pharmacokinetic interactions affect the absorption, distribution, metabolism, or elimination of other drugs, potentially causing an altered response. Polycyclic aromatic hydrocarbons (PAHs) in tobacco are responsible for induction of cytochrome P450 enzymes (CYP1A1, CYP1A2, and possibly CYP2E1 and CYP3A). The majority of drug interactions with tobacco smoke are pharmacokinetic, resulting from the induction of drug-metabolizing enzymes (especially CPY1A2) by compounds in tobacco smoke. All of these drugs are metabolized via CYP1A2. Induction of CYP1A2 by PAHs in tobacco smoke will increase metabolism, resulting in potentially clinically significant decreased pharmacologic effects of the following drugs. Following smoking cessation, a patient titrated on these medications may experience enhanced pharmacologic effects or toxicity: Bendamustine (Treanda): Bendamustine is metabolized by CYP1A2. Manufacturer recommends caution in using this drug in smokers as lower bendamustine concentrations might occur, with increased concentrations of its 2 active minor metabolites (Cephalon, Inc., 2013). Caffeine: Clearance is increased by 56%. It is reasonable to advise patients to decrease their intake of caffeinated beverages when quitting smoking, because nicotine withdrawal effects might be enhanced by increased caffeine levels. Clozapine (Clozaril): Studies have shown mixed results on the clinically significant changes in clozapine levels in smokers. However, upon cessation, a mean increase of 57.4% in clozapine levels has been demonstrated. Doses should be closely monitored upon smoking cessation to avoid high levels and increased toxicity (Meyer, 2001). Erlotinib (Tarceva): Clearance of this injectable antineoplastic agent used for pancreatic and non-small cell lung cancer is increased 24% with ~2-fold lower trough concentrations compared to nonsmokers; AUC in smokers is ~one third that of never/former smokers (Lu, 2006; OSI Pharmaceuticals, Inc., 2014). Fluvoxamine (Luvox): Clearance of this antidepressant is increased by 24%; plasma concentrations are decreased by 32%. Yoshimura et al. (2002) determined that plasma fluvoxamine concentrations were significantly lower in smokers (by 39%) compared with nonsmokers. Dosage modifications are not routinely recommended, but smokers might require higher dosages. Olanzapine (Zyprexa): Clearance of this atypical antipsychotic is increased by 40–98%. Gex-Fabry et al. (2003) showed that smokers had significantly lower concentrations (by 12%) compared with nonsmokers. Dosage modifications are not routinely recommended, but smokers might require higher dosages to achieve clinical response (Carrillo et al. 2003). Riociguat (Adempas): Plasma concentrations are reduced by 50–60% in smokers compared to nonsmokers. A smoker may require dosages higher than 2.5 mg three times a day if tolerated. Dose decrease may be required in patients who stop smoking (Bayer HealthCare Pharmaceuticals, Inc., 2014). Ropinirole (Requip): Plasma concentrations may be reduced in smokers and dose increase may be required. In a study of patients with restless leg syndrome, Cmax and AUC were reduced by 30% and 38% respectively in smokers compared to nonsmokers (GlaxoSmithKline, 2014). Tacrine (Cognex): Clearance is substantially increased in smokers. The manufacturer states that mean plasma tacrine concentrations in smokers are threefold lower than those achieved in nonsmokers. The half-life of tacrine is decreased by 50%. Smokers might require higher dosages. Tasimelteon (Hetlioz): Decreased exposure by ~40% in smokers compared to nonsmokers (Vanda Pharmaceuticals Inc., 2014). Theophylline: Clearance is increased by 58–100%; half-life is decreased by 63%. Closely monitor theophylline levels if smoking is initiated, discontinued, or changed. Maintenance doses are considerably higher in smokers. Within 7 days of smoking cessation, theophylline clearance might decrease by 35%. Note: A similar interaction occurs with aminophylline. PAHs also induce the enzymes involved in glucuronic acid conjugation. Propranolol, mexiletine, and codeine have been reported to have increased rates of glucuronidation in patients who smoker. Irinotecan (Camptosar): Clearance of this antineoplastic agent for colorectal cancer is increased by 18%; lower levels of irinotecan (a pro-drug) and its active metabolite, SN-38 (~40% lower) occur mainly due to induction of the UGT1A1, which conjugates SN-38, and possibly CYP3A. Reduced systemic exposure of SN-38 results in lower toxicity (e.g., hematologic) and likely reduced efficacy; dose increases may be required (van der Bol 2007; Benowitz 2007). Benowitz NL. (2007). Cigarette smoking and the personalization of irinotecan therapy. J Clin Oncol 25:2646–2647. Bayer HealthCare Pharmaceuticals, Inc. (2014). Adempas Package Insert. Whippany, NJ. Carrillo JA, Herraiz AG, Ramos SI, Gervasini G, Vizcaino S, Benitez J. (2003). Role of the smoking-induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine. J Clin Psychopharmacol 23:119–127. Cephalon, Inc. (2013). Treanda Package Insert. North Wales, PA. Gex-Fabry M, Balant-Gorgia AE, Balant LP. (2003). Therapeutic drug monitoring of olanzapine: The combined effect of age, gender, smoking and comedication. Ther Drug Monit 25:46–53. GlaxoSmithKline. (2014). Requip Package Insert. Research Triangle Park, NC. Lu JF. (2006). Clinical pharmacokinetics of erlotinib in patients with solid tumors and exposure-safety relationship in patients with non-small cell lung cancer. Clin Pharmacol Ther 80:136–145. Meyer JM. (2001). Individual changes in clozapine levels after smoking cessation: results and a predictive model. J of Clin Psychopharmacol 21:569–574. OSI Pharmaceuticals, Inc. and Genentech, Inc. (2014). Tarceva Package Insert. Melville, NY. van der Bol JM. (2007). Cigarette smoking and irinotecan treatment: pharmacokinetic interaction and effects on neutropenia. J Clin Oncol 25:2719–2726. Vanda Pharmaceuticals, Inc. (2014). Hetlioz Package Insert. Washington, DC. Yoshimura R, Ueda N, Nakamura J, Eto S, Matsushita M. (2002). Interaction between fluvoxamine and cotinine or caffeine. Neuropsychobiology 45:32–35. Smoking cessation will reverse these effects.

DRUG INTERACTION: TOBACCO SMOKE and CAFFEINE
Constituents in tobacco smoke induce CYP1A2 enzymes, which metabolize caffeine Caffeine levels increase ~56% upon quitting Nicotine withdrawal effects might be enhanced by increased caffeine levels Decrease caffeine intake by 50% when quitting; no caffeine after 1PM for individuals with a typical bedtime Constituents in tobacco smoke induce the CYP1A2 enzymes, which metabolize caffeine. As such, caffeine levels have been documented to increase an estimated 56% upon quitting smoking. Because the effects of caffeine excess somewhat mimic nicotine withdrawal symptoms (e.g., jitteriness, insomnia), patients should be advised to reduce their caffeine intake when quitting smoking. As a general guide, they should decrease by 50% and not have any caffeine after 1PM for individuals with a typical bedtime. This will help to ensure that they are not experiencing nicotine withdrawal, caffeine excess, and insomnia simultaneously.

PHARMACODYNAMIC DRUG INTERACTIONS with SMOKING
Smokers who use combined hormonal contraceptives have an increased risk of serious cardiovascular adverse effects: Stroke Myocardial infarction Thromboembolism This interaction does not decrease the efficacy of hormonal contraceptives. Pharmacodynamic interactions alter the expected response or actions of other drugs. In general, these are less common than pharmacokinetic interactions, but the potential interaction of combined hormonal contraceptives (those containing both estrogen and progestin) with smoking is important. The use of combined hormonal contraceptives (e.g., pill, patch, ring) should be strongly discouraged in women who are regular smokers. The cardiovascular effects of combined hormonal contraceptives include venous thromboembolism (deep leg vein thrombosis and pulmonary embolism) and myocardial infarction and ischemic or hemorrhagic stroke (arterial events). Considerable epidemiologic evidence indicates that cigarette smoking substantially increases the risk of adverse cardiovascular events (mainly stroke and myocardial infarction [MI]) in women using oral contraceptive (OC) agents (Burkman et al., 2004; Seibert et al., 2003). This risk also applies to other delivery forms (e.g., patch, ring). This risk is age-related: The overall risk of death from cardiovascular disease in low-dose OC users who smoke is 3.3 per 100,000 women aged 15–34 years versus 29.4 per 100,000 women aged 35–44 years. The corresponding risk of death from cardiovascular disease in nonsmoking women who use OC is lower: 0.65 per 100,000 women aged 15–34 years and 6.21 per 100,000 women aged 35–44 years (Schwingl et al., 1999). A case-control study of 627 women younger than age 45 with a nonfatal first MI and 2,947 control subjects assessed whether use of low-dose OC increased the risk of MI. The odds ratio for current OC use was 2.5 among heavy smokers (25 cigarettes/day) and 1.3 among nonsmokers and light smokers. Current OC use together with heavy smoking increased the risk of MI ~30 times that of nonsmokers who did not use OC (Rosenberg et al., 2001). In a large Dutch population-based case-control study, the risk of venous thrombosis was assessed in smokers from 1999–2004. Women who were current smokers and used OCs had an 8.8-fold higher risk than nonsmoking women who did not use OC (women who used OC but did not smoke had 3.9-fold increased risk for VTE and women who smoked but did not use OC had OR 2.03) (Pomp, 2007). In January 2008, the FDA revised the label of the Ortho-Evra patch, indicating that 2 of 3 epidemiologic studies have demonstrated a 2-fold greater risk of venous thromboembolism with the patch compared to OC users (30-35 mcg). OrthoEvra patch results in 60% higher steady state concentrations of estrogen compared to OC with 35 mcg estrogen (Janssen Pharmaceuticals, Inc., 2014). Accordingly, experts generally recommend that combined hormonal contraceptive use is contraindicated (i.e., method should not be used) in women who are 35 years of age or older AND heavy (at least 15 cigarettes/day) smokers (Schiff et al., 1999; World Health Organization, 2010). For women age 35 and older, who smoke <15 cigarettes/day, the WHO categorizes the use of combined hormonal contraceptives as “not usually recommended unless other more appropriate methods are not available or not acceptable.” Smoking is not a contraindication for use of emergency contraception or progestin-only contraceptives. The American College of Obstetricians and Gynecologists (ACOG) recommendations are consistent with the WHO (ACOG, 2006). There are ample opportunities for health care providers to intervene with women who use tobacco. At the very minimum, women should be advised to consult with their physician/provider about alternative birth control methods (i.e., non-hormonal method, such as IUD, or progestin-only contraceptive). However it is far preferable for women to quit smoking. It is important to note, however, that this interaction does not decrease the efficacy of hormonal contraceptives. ACOG practice bulletin. (2006). No. 73: use of hormonal contraception in women with coexisting medical conditions. Obstet Gynecol 107;1453–1472. Burkman R, Schlesselman JJ, Zieman M. (2004). Safety concerns and health benefits associated with oral contraception. Am J Obstet Gynecol 190:S5–S22. Grimes DA, Raymond EG. (2002). Emergency contraception. Ann Intern Med 137: Janssen Pharmaceuticals, Inc. (September 2014). Ortho Evra Transdermal System Package Insert. Raritan, NJ. Pomp ER, Rosendaal FR, Doggen CJM. (2007). Smoking increases the risk of venous thrombosis and acts synergistically with oral contraceptive use. Am J Hemotol 83: Rosenberg L, Palmer JR, Rao S, Shapiro S. (2001). Low-dose oral contraceptive use and the risk of myocardial infarction. Arch Intern Med 161:1065–70. Schiff I, Bell WR, Davis V, Kessler CM, Meyers C, Nakajima S, Sexton BJ. (1999). Oral contraceptives and smoking, current considerations: Recommendations of a consensus panel. Am J Obstet Gynecol 180:S383–S384. Schwingl PJ, Ory HW, Visness CM. (1999). Estimates of the risk of cardiovascular death attributable to low-dose oral contraceptives in the United States. Am J Obstet Gynecol 180:241–249. Seibert C, Barbouche E, Fagan J, Myint E, Wetterneck T, Wittemyer M. (2003). Prescribing oral contraceptives for women older than 35 years of age. Ann Intern Med 138:54–64. World Heath Organization. (2010). Medical Eligibility Criteria for Contraceptive Use, 4th ed. Geneva, Switzerland: World Health Organization, pp. 1–121. Retrieved January 9, 2019, from Women who are 35 years of age or older AND smoke at least 15 cigarettes per day are at significantly elevated risk.

For more detail about each drug interaction with smoking, refer your audience to the “Drug Interactions with Tobacco Smoke” ancillary handout within Rx for Change. The shaded rows in the table indicate clinically significant drug interactions.

DRUG INTERACTIONS with SMOKING: SUMMARY
Clinicians should be aware of their patients’ smoking status: Clinically significant interactions result the combustion products of tobacco smoke, not from nicotine. Constituents in tobacco smoke (e.g., polycyclic aromatic hydrocarbons; PAHs) may enhance the metabolism of other drugs, resulting in an altered pharmacologic response. Changes in smoking status might alter the clinical response to the treatment of a wide variety of conditions. Drug interactions with smoking should be considered when patients start smoking, quit smoking, or markedly alter their levels of smoking. To summarize: Clinicians should be aware of their patients’ smoking status for the following reasons: Smoking has the potential for pharmacokinetic and pharmacodynamic interactions. Clinically significant interactions result not from nicotine but from the combustion products of tobacco smoke. Constituents in tobacco smoke (e.g., polycyclic aromatic hydrocarbons; PAHs) may enhance the metabolism of other drugs, resulting in an altered pharmacologic response. Changes in smoking status might alter the clinical response to the treatment of a wide variety of conditions. Drug interactions with smoking should be considered when patients start smoking, quit smoking, or markedly alter their levels of smoking.

ASSISTING PATIENTS with QUITTING
This module focuses on behavioral techniques for helping patients to quit using tobacco. Tobacco use is a highly significant health threat (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). ♪ Note to instructor(s): Rx for Change also provides a parallel (optional) module that applies the Transtheoretical Model of Change as a framework for assisting patients with 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. 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.

CLINICAL PRACTICE GUIDELINE for TREATING TOBACCO USE and DEPENDENCE
Update released May 2008 Sponsored by the U.S. Department of Health and Human Services, Public Heath Service with: Agency for Healthcare Research and Quality National Heart, Lung, & Blood Institute National Institute on Drug Abuse Centers for Disease Control and Prevention National Cancer Institute In May 2008, the U.S. Public Health Service published an updated Clinical Practice Guideline for treating tobacco use and dependence (Fiore et al., 2008). This guideline, which represents a distillation of more than 8,700 articles from the literature, reaches a consensus on strategies and recommendations designed to assist health care providers in delivering state-of-the-art interventions for tobacco cessation. The slides that follow describe feasible, practical, and effective behavioral strategies that clinicians can apply when assisting patients with quitting. These strategies derive from recommendations set forth in the Clinical Practice Guideline. The recommended strategies might not be appropriate in all circumstances, and health care providers should exercise clinical judgment based on individual patient characteristics, available resources, and any new information that becomes available such as that provided by the Food and Drug Administration (FDA) (Fiore et al., 2008). The complete guideline is available at ♪ Note to instructor(s): The first Clinical Practice Guideline on the topic of tobacco cessation was published in 1996 (based on approximately 3,000 articles); a second Guideline was published in 2000 (based on more than 6,000 articles). The most recent Guideline (May 2008; based on more than 8,700 articles) is an update of the 2006 version, in that new information and recommendations were added, but not all meta-analyses from the 2006 version were re-examined. It is our understanding that there currently are no plans for an updated version of the Guideline, despite this last version having been published in As such, we supplement the 2008 Guideline recommendations with current literature, and in particular with meta-analyses published in various Cochrane Reviews. These authoritative references are cited throughout Rx for Change. 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.

Physiological Behavioral Recall that tobacco dependence is a chronic condition that requires a two-prong approach for maximal treatment effectiveness (Fiore et al., 2008). There are two parts to smoking, so there are two parts to quitting. In this module, we will be focusing on addressing the behavioral aspects of quitting, with an emphasis on cognitive and behavioral strategies for behavior change. ♪ Note to instructor(s): Specific methods for treating the physiological aspects of tobacco use and dependence are covered in detail in the Medications for Cessation module. 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 The addiction to nicotine Medications for cessation The habit of using tobacco Behavior change program Treatment should address the physiological and the behavioral aspects of dependence.

METHODS for QUITTING Pharmacologic Nonpharmacologic
FDA-approved medications Nonpharmacologic Counseling and other non-drug approaches Consistent with the two-pronged approach to quitting, there are two key elements to be addressed in this training: Pharmacologic (FDA-approved medications), to be addressed in the next module (Medications for Cessation) Nonpharmacologic (counseling and other non-drug approaches), to be addressed in this module Nonpharmacologic methods primarily involve counseling and behavioral therapies. This includes the provision of social support systems within the context of treatment, and problem solving and skills training. As discussed in the Assisting Patients with Quitting module, these methods should be used with all patients attempting to quit using tobacco. Pharmacologic methods approved by the U.S. Food and Drug Administration (FDA) for tobacco cessation include nicotine replacement therapy (NRT), sustained-release bupropion (Zyban) and varenicline (Chantix). Other pharmacologic methods for cessation that are not FDA approved for smoking cessation are also discussed in this module, as are complementary and alternative therapies. Most tobacco users quit without assistance, and overall, around 95% of unaided quit attempts end in relapse (Fiore et al., 2008; p. 15). In general, combination therapy consisting of behavioral counseling with pharmacotherapy is more effective (40–70% improvement) than either method used alone (Fiore et al., 2008; pp ). This combined approach is similar to that used in the treatment of other chronic conditions. For example, a diabetic patient may administer insulin in combination with a prescribed diet and exercise regimen. A patient with asthma might use a corticosteroid inhaler in combination with various environmental control measures to prevent asthma exacerbations. Similarly, effective treatment of tobacco use and dependence involves a management plan consisting of behavioral counseling, support, and appropriate pharmacotherapy. It is important to emphasize that interventions combining both pharmacotherapy and behavioral assistance are associated with increased cessation success compared to a minimal intervention or usual care (Stead et al., 2016). As such, state-of-the-art, evidence-based interventions should focus on behavioral support in combination with one or more FDA-approved medications for cessation, as appropriate. 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, Koilillai P, Fanshawe TR, Lancaster T. (2016). Combined pharmacotherapy and behavioral interventions for smoking cessation. Cochrane Database Syst Rev. 3:CD Counseling and medications are both effective, but the combination of counseling and medication is more effective than either alone. Fiore et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: USDHHS, PHS, May 2008.

NONPHARMACOLOGIC METHODS
Cold turkey: Just do it! Unassisted tapering (fading) Reduced frequency of use Lower nicotine cigarettes Special filters or holders Assisted tapering QuitKey (PICS, Inc.) Computer developed taper based on patient’s smoking level Includes telephone counseling support Nonpharmacologic methods include the following: Cold turkey: The “simplest” nonpharmacologic method, but the least successful (approximately 5% success; Fiore et al., 2008), is cold turkey—the smoker just quits abruptly, without the assistance of any clinical intervention or medication and without tapering off of nicotine. Unassisted tapering: Tobacco users can taper off of tobacco products in a variety of ways. For example, they can self-regulate and reduce the number of cigarettes that they smoke, they can switch to cigarettes with a progressively lower nicotine content (“light” or “ultra-light” cigarettes), or they can purchase special filters or holders that decrease the nicotine inhalation concentration over time. However, many people who use this method smoke fewer cigarettes but still get the same amount of nicotine because they compensate for the low nicotine content by altering the way they smoke. For example, they may inhale more deeply, smoke each cigarette longer, or obstruct the vents on the filters. This method may be a reasonable approach for some smokers to “get ready to quit,” because it disrupts the behavior or habit. However, in general, tapering is not a very effective method of quitting. Assisted tapering: Products such as the QuitKey (developed and marketed by PICS, Inc.) help patients to quit using tobacco gradually through a computer-assisted behavior modification program. The hand-held QuitKey computer assists the smoker in decreasing the frequency of cigarette use over time. Based on data that patients enter during a 1-week baseline period when they smoke “normally,” the computer develops a patient-specific tapering curve appropriate to the patient’s level of smoking. The scheduled gradual reduction concept for smoking cessation has been tested in research studies (Cinciripini et al., 1997). The QuitKey program, which was developed with funding from the National Institutes of Health, has been tested and proven to be effective in clinical trials (Jerome et al., 1992, 2000; Riley et al., 2002). The program results in a 19–24% abstinence rate 1 year after quitting. ♪ Note to instructor(s): For more information on the QuitKey, please consult the PICS, Inc. website, Cinciripini PM, Wetter DW, McClure JB. (1997). Scheduled reduced smoking: Effects on smoking abstinence and potential mechanisms of action. Addict Behav 22:759–767. 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. Jerome A, Fiero PL, Behar A. (2000). Computerized scheduled gradual reduction for smokeless tobacco cessation: Development and preliminary evaluation of a self-help program. Computers in Human Behavior 16:493–505. Jerome A, Perrone R, Kalfus G. (1992). Computer-assisted smoking treatment: A controlled evaluation and long-term follow-up. Journal of Advancement in Medicine 5:29–41. Riley W, Jerome A, Behar A, Zack S. (2002). Feasibility of computerized scheduled gradual reduction for adolescent smoking cessation. Substance Use & Misuse 37:277–285.

NONPHARMACOLOGIC METHODS (cont’d)
Formal cessation programs Self-help programs Individual counseling Group programs Telephone counseling 1-800-QUITNOW Web-based counseling Acupuncture therapy Hypnotherapy Massage therapy Formal cessation programs: An abundance of formal smoking cessation programs are available. These range from self-help manuals to individual and group counseling programs. The National Quitline, launched in 2004 (1-800-QUITNOW), provides all Americans with toll-free telephone-based counseling. For individuals with Internet access, many Web-based programs offer private and convenient (“24/7/365” availability) cessation support. The effectiveness of these types of behavioral programs is enhanced further when pharmacologic agents also are used for cessation. Alternative and complementary therapies: A variety of alternative and complementary therapies for cessation are also available (Villano & White, 2004; Sood et al., 2006): Acupuncture therapy (and related techniques including acupressure, laser therapy and electrostimulation) are believed to modulate neurotransmitter release thereby attenuating symptoms of nicotine withdrawal (Villano & White, 2004; White et al., 2006). A recent meta-analysis (White et al., 2014) concluded that there is no consistent evidence that acupuncture, acupressure, laser therapy, or electrostimulation are effective and the Clinical Practice Guideline (Fiore et al., 2008) does not recommend these approaches for smoking cessation. Hypnotherapy also has been used for smoking cessation. Hypnotherapists implant subconscious suggestions to deter smoking. Evidence on its efficacy is conflicting, and currently the evidence is insufficient to support hypnosis as a treatment for smoking cessation (Barnes et al., 2010; Fiore et al., 2008). Massage therapy is thought to reduce anxiety, decrease stress hormones, and improve mood. In one study, patients used either hand or ear self-massage during tobacco cravings for a period of 1 month. Patients reported improved moods and decreased anxiety, withdrawal symptoms, and number of cigarettes smoked per day (Hernandez-Reif et al., 1999). Massage therapy might be useful as an adjunct therapy to alleviate cravings and anxiety. Abbot NC, Stead LF, White AR, et al. (2000). Hypnotherapy for smoking cessation. Cochrane Database Syst Rev 2:CD Barnes J, Dong CY, McRobbie H, et al. (2010). Hypnotherapy for smoking cessation. Cochrane Database of Syst Rev 2;CD 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. Hernandez-Reif M, Field T, Hart S. (1999). Smoking cravings are reduced by self-massage. Prev Med 28:28–31. Sood A, Ebbert JO, Sood R, Stevens SR. (2006). Complementary treatments for tobacco cessation: a survey. Nicotine Tob Res 8:767–771. White AR, Rampes H, Liu JP, Stead LF, Campbell J. (2014). Acupuncture and related interventions for smoking cessation. Cochrane Database Syst Rev 1:CD Villano LM, White AR. (2004). Alternative therapies for tobacco dependence. Med Clin N Am 88:1607–1621.

EFFECTS of CLINICIAN INTERVENTIONS
With help from a clinician, the odds of quitting approximately doubles. 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 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, May 2008.

The NUMBER of CLINICIAN TYPES CAN MAKE a DIFFERENCE, too
Compared 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). 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, May 2008.

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. A clinician who does not address tobacco use during a clinical encounter 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.

The 5 A’s ASK ADVISE ASSESS ASSIST ARRANGE
The Clinical Practice Guideline (Fiore et al., 2008) delineates five key components for tobacco cessation interventions. These components, referred to as the 5 A’s, offer a practical method for implementing tobacco counseling in clinical practice. The 5 A’s are: Ask – systematically identify all tobacco users at every visit Advise – strongly urge all tobacco users to quit Assess – determine willingness to make a quit attempt Assist – aid the patient in quitting (provide counseling and medication) Arrange – ensure follow-up care ♪ Note to instructor(s): The 5 A’s presented in the guideline are a modified form of the National Cancer Institute’s original 5 A’s (Anticipate [tobacco use], Ask, Advise, Assist, and Arrange; Frankowski & Secker-Walker, 1994; Glynn & Manley, 1990). ♪ Note to instructor(s): Throughout this module, ask audience to refer to their Tobacco Cessation Counseling Guidesheet (ancillary handout A1 GUIDE.pdf). The slides in this module are designed to parallel the guidesheet. 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. Frankowski BL, Secker-Walker RH. (1994). Pediatricians’ Role in Smoking Prevention and Cessation (Smoking and Tobacco Control Monograph No. 5; NIH Publication No ). Bethesda, MD: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Cancer Institute. Glynn TJ, Manley MW. (1990). How to Help Your Patients Stop Smoking: A National Cancer Institute Manual for Physicians (NIH Publication No ). Bethesda, MD: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Cancer Institute. ASSESS ASSIST ARRANGE Fiore et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: USDHHS, PHS, May 2008.

The 5 A’s (cont’d) about tobacco use; with a tone that conveys sensitivity, concern and is non-judgmental: “Do you smoke or use other types of tobacco or nicotine, such as e-cigarettes?” “It’s important for us to have this information so we can check for potential interactions between tobacco smoke and your other medicines.” “We ask all of our patients, because tobacco smoke can affect how well some medicines work.” “We care about your health, and we have resources to help our patients quit smoking.” “Has there been any change in your smoking status?” ASK Ask. Tobacco use can induce early onset of disease and exacerbate existing medical conditions, and tobacco smoke has the potential to interact with many medications, altering both drug levels and efficacy. It is appropriate, if not essential, for 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). Appropriate language for assessing tobacco use status could be: “Do you ever smoke or use other types 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. The query also can be linked to the clinician’s knowledge of a patient’s disease status or medication profile. For example: “Condition X often is caused or worsened by smoking. Do you, or does someone in your household smoke?” or “Medication X often is used for conditions linked with or caused by smoking. Do you, or does someone in your household smoke?” When clinicians ask about tobacco use, it is important that they take a genuine and sensitive approach, conveying concern for their patients’ well-being. A judgmental tone likely will not result in accurate disclosure of tobacco use. In an effort to promote autonomy with a patient, consider establishing autonomy by asking for permission to ask questions: “May I ask you a few questions?,” before launching a series of inquiries. It could also be helpful to tell patients: “We like to have this information so we can check for potential interactions between tobacco smoke and your other medicines.” “We ask all of our patients, because tobacco smoke can affect how well some medicines work.” “We care about your health, and we have resources to help our patients quit smoking.”

The 5 A’s (cont’d) tobacco users to quit (clear, strong, personalized)
“It’s important for your health that you quit smoking, and I can help you.” “Quitting smoking is the most important thing you can do to...[control your asthma, reduce your chance for another heart attack, better manage your diabetes, etc.]” “Quitting smoking is the single most important thing you can do to protect your health now and in the future.” “I can help you select medications that can increase your chances for quitting successfully.” “I can provide additional resources to help you quit.” 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 (Fiore et al., 2008). 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: “It’s important for your health that you quit smoking, and I can help you.” “Quitting smoking is the most important think you can do to…[control your asthma, reduce your change for another heart attack, better manage your diabetes, etc.]” “Quitting smoking is the single most important thing you can do to protect your health now and in the future.” “I can help you select medications that can increase your chances for quitting successfully.” “I can provide additional resources to help you quit.” 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: “May I tell you what concerns me?” … [If patient says “yes”]: If you continue to smoke, your [insert health condition] will worsen/fail to improve, and that will significantly impact your quality of life. I’d hate to see that happen.” 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.

The 5 A’s (cont’d) readiness to make a quit attempt ASSESS
with the quit attempt Not ready to quit: enhance motivation (the 5 R’s) Ready to quit: design a treatment plan Recently quit: relapse prevention ASSIST Assess. After the clinician advises the patient to quit, the next step is to assess the patient’s readiness, or willingness, to try to quit. Is the patient considering quitting in the next month? Or did he or she quit recently? Assist. The patient’s readiness to try to quit will define the next course of action, which is delivering an intervention tailored to his or her needs. By being a good listener and gathering appropriate information, the clinician can tailor the interventions effectively. A patient who is not ready to quit will receive a very different type of intervention than will one who is ready to quit in the upcoming weeks. For the patient who is not ready to quit, clinicians should apply the 5 R’s (to be discussed later). If the patient is ready to quit (i.e., in the next 30 days), a treatment plan should be designed. Ideally, this should include including counseling and pharmacotherapy (if appropriate). The clinician could suggest that the patient enroll in a structured tobacco cessation program to increase the likelihood of quitting—this is particularly important for persons who are at high risk of relapse or for patients who are highly dependent, refractory smokers (i.e., having made multiple serious quit attempts). Other patient populations that might be particularly well suited for structured programs include adolescent smokers, pregnant smokers, and patients with coexisting psychiatric conditions. A patient who recently quit (i.e., in the past 6 months) will need continued support and encouragement, and reminders regarding the need to abstain from all tobacco use—even a puff. A patient who has been off of tobacco for more than 6 months typically is relatively stable but often needs to be reminded to remain vigilant for potential triggers for relapse.

Provide assistance throughout the quit attempt.
The 5 A’s (cont’d) follow-up care ARRANGE Number of sessions Estimated quit rate* 0 to 1 12.4% 2 to 3 16.3% 4 to 8 20.9% More than 8 24.7% Arrange. The clinician should make certain to arrange for follow-up care and patient monitoring. With each contact, it is important to document the counseling session. These records can provide a starting point for subsequent discussions. Follow-up visits can be arranged in several ways. For example, the clinician can do the following: “Check in” with the patient when he or she next returns. Schedule specific follow-up visits to discuss tobacco cessation. Invite the patient to enroll in a tobacco cessation group with which the clinician is affiliated, or provide a referral to the tobacco quitline (1-800-QUIT NOW). With prior approval, call the patient at home to see how he or she is progressing. (If a message is left, the clinician should not indicate that he or she is calling regarding a quit attempt—this might be private information that the patient does not want others to hear. Be sure to comply with HIPAA regulations.) Document key dates (e.g., quit dates, tobacco-free anniversaries); acknowledge important milestones. The best approach for spacing the counseling sessions (i.e., the number of days or weeks over which treatment is spread) is not known (Fiore et al., 2008), but in general follow-up contact should be scheduled within the first week after the quit date. The next follow-up is recommended within the first month. Further follow-up contact should be scheduled as needed or indicated. During the follow-up contacts, the patient should be congratulated for success. If tobacco use has occurred, the circumstances should be reviewed and a commitment sought to return to total abstinence. The patient should be reminded that lapses (slips) occur as part of the normal learning process and should be viewed as such. Pharmacotherapy use should be assessed, including adherence with the regimen and side effects experienced. When appropriate, referral to more intensive treatment should be considered. According to the Clinical Practice Guideline, multiple patient contacts are associated with higher quit rates (Fiore et al., 2008; p. 86). The estimated abstinence rates, based on number of treatment sessions (i.e., counseling contact sessions) are presented in this slide. Even brief interventions (1–3 minutes) can increase patients’ odds of quitting (odds ratio, 1.4; 95% CI, 1.1–1.8), increasing abstinence rates from 11.0% with no counseling to 14.4% with counseling. More intensive interventions (greater length of session, greater total amount of contact time, and greater number of sessions), however, are clearly associated with a higher odds of quitting (Fiore et al., 2008; pp. 83–86). Yet in the absence of time or expertise, clinicians should, at a minimum ask patients about tobacco use, advise them to quit, and provide information about other resources for quitting, such as the tobacco quitline (1-800-QUIT NOW) or local programs. 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. * 5 months (or more) postcessation Provide assistance throughout the quit attempt. Fiore et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: USDHHS, PHS, May 2008.

READINESS to make a quit attempt
The 5 A’s: REVIEW ASK about tobacco USE ADVISE tobacco users to QUIT As a final review, 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

The (DIFFICULT) DECISION to QUIT
Faced with change, most people are not ready to act. Change is a process, not a single step. Typically, it takes multiple attempts. Historically, clinicians have been trained to provide action-oriented, “just do it” counseling interventions. It’s important to recognize that not all patients have the same level of commitment, or readiness, to take action. When faced with change, most people (about 70%) are not ready to act (Prochaska et al., 1992). Patients at different stages of readiness to quit require different kinds of interventions. Counseling should be tailored to patients’ readiness to quit (often referred to as their “stage of change”). This is particularly important when counseling through various steps of tobacco cessation. Consider the following: Some patients are determined smokers…they might never quit! Some might know that they need to quit but have tried and failed so many times that they have no confidence in their ability to quit. Some are considering quitting but might not have gathered the courage or information necessary to make a serious quit attempt. Some will be ready to set a quit date. Others might have stopped recently but remain highly vulnerable to relapse. And some will have been smoke-free for at least 6 months yet remain at risk for relapse. In most cases, behavior change is a process, not a single step. The process ranges from not thinking about making a change to successful implementation of a behavioral change over a sustained period of time. Typically, it takes multiple attempts before success is achieved. Prochaska JO, DiClemente CC, Norcross JC. (1992). In search of how people change: Applications to addictive behaviors. Am Psychol 47:1102–1114. HOW CAN I LIVE WITHOUT TOBACCO?

HELPING PATIENTS QUIT IS a CLINICIAN’S RESPONSIBILITY
TOBACCO 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 tobacco users forward in their decision to quit. However, the decision to quit ultimately lies in the hands of the patient. THE DECISION TO QUIT LIES IN THE HANDS OF EACH PATIENT.

ASSESSING READINESS to QUIT
Patients differ in their readiness to quit. STAGE 1: Not ready to quit in the next month STAGE 2: Ready to quit in the next month Prior to providing assistance with tobacco cessation, it is helpful to assess each patient’s readiness to quit (Fiore et al., 2008). Patients can be categorized into four discrete categories: Stage 1: Not ready to quit in the next month Stage 2: Ready to quit in the next month Stage 3: Recent quitter, quit with the past 6 months Stage 4: Former tobacco user, quit more than 6 months ago Assessing a patient’s readiness to quit enables clinicians to deliver relevant, appropriate counseling messages. 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. STAGE 3: Recent quitter, quit within past 6 months STAGE 4: Former tobacco user, quit > 6 months ago Assessing a patient’s readiness to quit enables clinicians to deliver relevant, appropriate counseling messages.

ASSESSING READINESS to QUIT (cont’d)
For most patients, quitting is a cyclical process, and their readiness to quit (or stay quit) will change over time. Not thinking about it Former tobacco user Not ready to quit This diagram emphasizes that behavior change is a process. Over time, patients often cycle into and out of the different stages. They might quit for a while, then return to tobacco use before they quit again for good. This movement between the stages is normal and is to be expected, particularly for an addictive behavior that patients know they need to stop but might not have the time, energy, or will to stop at the present time. For this reason, it is important to determine the patient’s readiness to commit to quitting at each contact. Do not assume that patients who inquire about quitting are ready to quit. Commonly, they are just thinking about it and gathering information. Similarly, do not assume that a patient who asks for a prescription for bupropion, varenicline, or nicotine replacement therapy or who presents at a pharmacy to purchase these medications is ready to quit. Learning about the different stages of readiness to quit will help clinicians gain a better understanding of why it is important to think of behavior change as a process, not an event. For most people, the process of quitting is characterized by a series of quit attempts and subsequent relapses. Relapse Thinking about it, not ready Recent quitter Assess readiness to quit (or to stay quit) at each patient contact. Ready to quit

STAGE 1: Not ready to quit Not thinking about quitting in the next month Some patients are aware of the need to quit. Patients struggle with ambivalence about change. Patients are not ready to change, yet. Pros of continued tobacco use outweigh the cons. Most patients who use tobacco will not be ready to quit in the immediate future. These patients generally fall into one of two categories: Those who are not aware of any need to change—the problem is not yet on their “radar screen.” Those who are unwilling or unable to change—commonly because they are defensive about their negative health behavior or because they are too discouraged to change (perhaps because of prior failed attempts). Health care providers commonly label patients in this stage as difficult or unmotivated. Many of these patients simply are not ready. They struggle with ambivalence and see the pros (positive effects) of tobacco use as being more important than the cons (negative effects). The goal of interventions at this stage is to encourage patients to start thinking about quitting. GOAL: Start thinking about quitting.

STAGE 1: NOT READY to QUIT Counseling Strategies
DO Strongly advise to quit Provide information Ask noninvasive questions; identify reasons for tobacco use Raise awareness of health consequences/concerns Demonstrate empathy, foster communication Leave decision up to patient DON’T Persuade “Cheerlead” Tell patient how bad tobacco is, in a judgmental manner Provide a treatment plan When counseling a patient who is not ready to quit, it is important to demonstrate understanding and empathy, to foster ongoing communication, and to ask questions noninvasively. Instead of pressuring the patient for an immediate behavioral shift, request the patient’s permission to ask questions and discuss the issue of tobacco use prior to imparting advice. For example, a clinician might say, “May I tell you why your smoking concerns me?” Messages that either emphasize the cons of tobacco use or deemphasize the pros of tobacco use help move the patient forward in the process of change. It is useful to tailor messages based on the patient’s health history, such as highlighting how tobacco use can induce early onset of particular diseases for which the patient may be at risk, or how it can exacerbate existing conditions. An approach that might be effective with parents is discussing how smoking can negatively affect their children’s health and increase the likelihood that their children will grow up to be smokers. Clinicians should encourage patients to quit while emphasizing that the decision to quit, or not to quit, is theirs. ♪ Note to instructor(s): One technique to gauge a patient’s level of resistance to quitting is to ask, “If I were to give you an envelope, what would the message inside need to say for you to consider quitting?” If the patient says, “There is nothing that you could write that would make me consider quitting,” then there is little that you can do at this point, except to (1) stress the importance of quitting for the patient’s health, (2) ask that the patient not rule out the possibility of quitting, and (3) offer to assist the patient with quitting, should the patient change his or her mind. Aggressive efforts to persuade the patient into making a change are not advisable during this stage. Likewise, high-spirited “cheerleading” may only heighten the patient’s resistance. It is not yet time to provide a treatment plan, although it might be useful to inform patients of the various options available. Offer assistance. Make it clear that it is an ongoing, standing offer, which the patient can accept whenever he or she is ready.

STAGE 1: NOT READY to QUIT Counseling Strategies (cont’d)
Consider 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, quitting generally becomes more difficult. Most patients will agree that there is never an ideal time to quit, and procrastinating 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.

STAGE 1: NOT READY to QUIT Counseling Strategies (cont’d)
The 5 R’s—Methods for enhancing motivation: Relevance Risks Rewards Roadblocks Repetition Tailored, motivational messages For patients who are not ready to quit, clinicians can deliver tailored, motivational messages by applying the 5 R’s: Relevance: Encourage the patient to indicate why quitting is personally relevant. Be as specific as possible. Motivational information has the most impact if it is relevant to the patient’s disease status or risk, family or social situation (e.g., having children in the home), health concerns, age, sex, and other important patient characteristics (e.g., prior quitting experience, personal barriers to cessation). Risks: Ask the patient to identify consequences of tobacco use. Suggest and highlight those that seem most relevant to the patient and emphasize that other forms of tobacco (such as smokeless, or light cigarettes) will not eliminate the risks. Risks of tobacco use are discussed in the Epidemiology of Tobacco Use and Pathophysiology of Tobacco-Related Disease modules. Rewards: Ask the patient to identify benefits of quitting. Highlight those that seem relevant to the patient. Examples of benefits of cessation are discussed in the Epidemiology of Tobacco Use module. Roadblocks: Ask the patient to identify barriers to quitting and potential methods for circumventing each barrier. Suggest and highlight those that seem most relevant to the patient. Common barriers include withdrawal symptoms, fear of failure, weight gain, lack of support, depression, and enjoyment of tobacco. Repetition: Repeat the motivational intervention whenever possible. Tobacco users who have failed in previous quit attempts should be reminded that most people make repeated quit attempts before they are successful. 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. Fiore et al. (2008). Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: USDHHS, PHS, May 2008.

STAGE 1: NOT READY to QUIT A Demonstration
CASE SCENARIO: Ms. Lilly Vitale ♪ Note to instructor(s): This video is a pharmacy-based counseling session, but similar strategies should be used, regardless of clinician type or setting. To access the video file, go to Under the “5 A’s Curriculum,” click “Video Segments” and locate video V6a in the table. Other videos, for patients who are not ready to quit, are available for download from this webpage and might be more appropriate for your audience. Edit this slide as needed to incorporate other videos. After showing the video, debrief with your audience. The clinician has provided an appropriate intervention for a patient who is not ready to quit at this time. The goal was to try to plant a seed to get the patient thinking about quitting, to move the patient forward in the process of change. And, in doing so, the clinician has fostered communication and a relationship with one of her patients. Note that this brief intervention required very little time (2 minutes). You are a clinician providing care to Ms. Vitale, a young woman with early-stage emphysema. VIDEO # V6a

GOAL: Achieve cessation.
ASSESSING READINESS to QUIT (cont’d) STAGE 2: Ready to quit Ready to quit in the next month Patients are aware of the need to, and the benefits of, making the behavioral change. Patients are getting ready to take action. At the second stage in the continuum of change, patients are ready to quit in the very near future (likely in the next month). These patients recognize the need to change and the benefits to be had by quitting. They are getting ready to quit. Often, they might have made a quit attempt in the past year. The goal is to assist these patients in achieving cessation. GOAL: Achieve cessation.

STAGE 2: READY to QUIT Three Key Elements of Counseling
Assess tobacco use history Discuss key issues Facilitate quitting process Practical counseling (problem solving/skills training) Social support delivered as part of treatment Three key elements of tobacco cessation counseling: Assess tobacco use history Discuss key issues Facilitate the quitting process, including practical counseling (problem solving/skills training) and social support delivered as part of treatment (Fiore et al., 2008) Assessing tobacco use history and discussing key issues are important information-gathering steps of counseling. Clinicians must develop an understanding of their patients’ unique history and perspective on tobacco use before facilitating the quitting process. ♪ Note to instructor(s): These three elements parallel those presented on the Tobacco Cessation Counseling Guidesheet (ancillary handout A1 GUIDE.pdf). 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.

STAGE 2: READY to QUIT Assess Tobacco Use History
Praise the patient’s readiness Assess tobacco use history Current use: type(s) of tobacco, amount Past use: duration, recent changes Past quit attempts: Number, date, length Methods/medications used, adherence, duration Reasons for relapse This stage represents a window of opportunity for helping a patient make a quit attempt. Clinicians should do the following prior to making treatment recommendations: Praise the patient’s readiness to quit. Assess tobacco use history, including current use, past use, and history of quit attempts: Current use of tobacco: What types of tobacco are used? How much? Past use of tobacco: How long has the patient been using tobacco? Has the patient changed his or her level of tobacco use recently? Past quit attempts: How many quit attempts has the patient made, how long was he or she off of tobacco, and when was the last quit attempt? What methods were used? What worked? What didn’t work? If medications were used, how were they used? What factors contributed to relapse (e.g., medication nonadherence, situational factors)? Identifying reasons for relapse can provide important information for an upcoming quit attempt.

STAGE 2: READY to QUIT Discuss Key Issues
Reasons/motivation to quit Confidence in ability to quit Triggers for tobacco use What situations lead to temptations to use tobacco? What led to relapse in the past? Routines/situations associated with tobacco use Key issues to address include the following: Discuss reasons and motivations for wanting to quit. Ask the patient to think about why it is important, to him or her, to adopt a tobacco-free lifestyle. What are the patient’s motivations for wanting to quit? Discuss whether the patient has concerns about the effects of second-hand smoke on others. How confident is the patient in his or her ability to quit? Ideally, the patient will be highly confident, but many will lack confidence because of previously failed attempts. By providing additional support and working with the patient in designing the treatment plan, a clinician can infuse confidence into the patient. It will be “different,” this time, because the patient will be more prepared. Discuss specific triggers for tobacco use. Triggers might include negative affect, being around other smokers, meal times, alcohol or coffee consumption, cravings for tobacco, time pressures, or other situations such as celebrating with others. Triggers should be identified prior to quitting, while the patient is still smoking “normally.” Encourage patients to think about the times and places where they smoke or use tobacco, each time they do so. This provides important insight into a person’s tobacco use behavior, including the circumstances that underlie the need or desire for tobacco. Having a clear understanding of the behavior will help a person to be more effective when attempting to change it. Determine whether there are certain routines or situations that the patient associates with tobacco use (e.g., when drinking coffee, while driving in the car, while bored or stressed, while watching television, while at a bar with friends, after meals or after sex, during breaks at work, while on the telephone, or while with specific friends or family members who smoke). When drinking coffee While driving in the car When bored or stressed While watching television While at a bar with friends After meals or after sex During breaks at work While on the telephone While with specific friends or family members who use tobacco

STAGE 2: READY to QUIT Discuss Key Issues (cont’d)
Stress-Related Tobacco Use THE MYTHS THE FACTS “Smoking gets rid of all my stress.” “I can’t relax without a cigarette.” There will always be stress in one’s life. There are many ways to relax without a cigarette. Stress is often cited as the primary reason for smoking. What types of triggers or situations invoke stress-related tobacco use? This slide presents the myths versus the facts. Smokers often confuse the relief of their nicotine withdrawal with the feeling of relaxation. The goal is to help patients to realize that tobacco is the problem, not the solution. ♪ Note to instructor(s): Video V25b depicts a discussion between a clinician and a patient about stress-related smoking. Smokers confuse the relief of withdrawal with the feeling of relaxation. STRESS MANAGEMENT SUGGESTIONS: Deep breathing, shifting focus, taking a break.

On average, quitters gain 9 to 11 pounds, but there is a wide range.
HERMAN ® is reprinted with permission from LaughingStock Licensing Inc., Ottawa, Canada All rights reserved. On average, quitters gain 9 to 11 pounds, but there is a wide range. Postcessation weight gain is an important consequence of tobacco cessation that often is also a barrier to quitting. Most tobacco users will gain weight after quitting, and clinicians should neither deny the likelihood of weight gain nor minimize its significance (Fiore et al., 2008). For nearly all patients, the health risks associated with post-cessation weight gain are negligible compared to the risks of continued smoking. A meta-analysis of 62 studies concluded that quitters gain, on average 9 to 11 pounds, but a broad range of weight changes occur: 16% of quitters lose weight, and 13% gain more than 22 pounds (Aubin et al., 2012). For men and women, subgroups that are more likely to gain significant weight after quitting are African Americans, younger tobacco users (<55 years of age), and heavier tobacco users (those smoking more than 25 cigarettes per day) (Fiore et al., 2008). The weight-suppressing effects of tobacco are well known. However, the mechanisms to explain why most successful quitters gain weight are not completely understood. Smokers have been found to have an approximately 10% higher metabolic rate compared with nonsmokers (Perkins, 1992). Higher caloric intakes have been documented after cessation (Hatsukami et al., 1993), and it has been speculated that the increased caloric intake might be caused either by an increase in appetite or by quitters eating more because the taste buds have become more receptive after cessation and foods taste better (Hamilton et al., 1992). Aubin HJ, Farley A, Lycett D, Lahmek P, Aveyard P. (2012). Weight gain in smokers after quitting cigarettes: meta-analysis. BMJ 345:e4439. 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. Hamilton E, Whitney E, Sizer F. (1992). Nutrition: Concepts and Controversies, 6th ed. St. Paul: West Publishing. Hatsukami D, LaBounty L, Hughes J, Laine D. (1993). Effects of tobacco abstinence on food intake among cigarette smokers. Health Psychol 12:499–502. Perkins KA. (1992). Metabolic effects of cigarette smoking. J Appl Physiol 72:401–409.

Weight Gain Discourage strict dieting while quitting Encourage healthful diet and meal planning Suggest increasing water intake or chewing sugarless gum Recommend selection of nonfood rewards When fear of weight gain is a barrier to quitting Consider pharmacotherapy with evidence of delaying weight gain (bupropion SR or 4-mg nicotine gum or lozenge) Assist patient with weight maintenance or refer patient to specialist or program Many patients will be concerned about weight gain after quitting; these patients should be discouraged from strict dieting while quitting (Fiore et al., 2008). Patients should carefully plan and prepare meals to avoid binge eating, increase fruit and water intake to create a feeling of fullness, and chew sugarless gum or eat sugarless candies. Advise patients to select nonfood rewards. For patients who are greatly concerned about weight gain, it may be most appropriate to recommend bupropion SR or nicotine gum or lozenge (4-mg strength), as these have been shown to delay weight gain after quitting (Fiore et al., 2008). Once the medications are terminated, however, the average patient will gain approximately the same amount of weight as those patients who did not use these medications. Patients also can be referred to a dietary specialist or weight maintenance program. In general, exercise programs have not been shown to reduce weight gain among quitters (Parsons et al., 2009) in the long term, but not in the short term (Farley et al., 2012). Currently, there is insufficient evidence to support clinical recommendations for any specific type of program to prevent weight gain after cessation (Farley et al., 2012). ♪ Note to instructor(s): Research studies have shown that patients who attempt to modify their diet at the same time as quitting smoking are less likely to succeed in smoking cessation than are patients who just try to quit smoking. We recommend that clinicians advise most of their patients to quit smoking first, then address weight gain. The average gain of 9 to 11 pounds is less detrimental to one’s health than is smoking, but it is not prudent for clinicians to overlook patients’ concerns about weight gain. If concern about weight gain is a key barrier to quitting, it should be addressed simultaneously with quitting. Farley AC, Hajek P, Lycett D, Aveyard P. (2012). Interventions for preventing weight gain after smoking cessation. Cochrane Database Syst Rev 1:CD 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. Parsons A, Shraim M, Inglis J, Aveyard P, Hajek P. (2009) Interventions for preventing weight gain after smoking cessation. Cochrane Database Syst Rev, CD

Withdrawal Symptoms Most pass within 2–4 weeks after quitting Cravings can last longer, up to several months or years Often can be ameliorated with cognitive or behavioral coping strategies Refer to Withdrawal Symptoms Information Sheet Symptom, cause, duration, relief Most symptoms manifest within the first 1–2 days, peak within the first week, and subside within 2–4 weeks. As described in the Pharmacology of Nicotine and Principles of Addiction module, cessation is associated with a wide range of withdrawal symptoms. In general, withdrawal symptoms manifest within the first 1–2 days, peak within the first week, and gradually subside over the next 2–4 weeks (Hughes, 2007). Strong cravings for tobacco may persist for months to years after cessation (Benowitz, 1992). These cravings typically are psychologically motivated, not physiologic, and can be ameliorated using cognitive or behavioral coping strategies. Sometimes a simple change of surroundings can help alleviate cravings, such as leaving the office to step outside for a breath of fresh air, or taking a quick walk up a flight or two of stairs to get some exercise. When counseling a patient who is quitting, it is important to address concerns about withdrawal symptoms. The extent of withdrawal symptoms that a smoker experiences when abstinent from tobacco will be a function of his or her level of dependence. ♪ Note to instructor(s): At this time, direct students to pull out their one-page Withdrawal Symptoms Information Sheet (ancillary handout A2 WDR SX.pdf). This handout describes each symptom, when it occurs after cessation, and potential coping methods. The Withdrawal Symptoms Information Sheet can be used as a resource for distribution to patients. 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.

Living with Another Smoker Discuss importance and negotiate where and when he/she will smoke, but do not make demands “Please keep your cigarettes where I won’t find them.” Give the smoker one ashtray: “Please keep this clean and hidden from me.” Surprise the smoker with a gift at the end of your first month of quitting as a thank you Many patients will express concern about living with another smoker. While this is never easy, there are a few strategies that will be helpful. First, discuss the importance of your quitting and why their cooperation is needed in order for you to be successful. Also, negotiate where and when he/she will smoke, but doing so without making demands. Additionally, it is advisable to ask the smoker to “Please keep your cigarettes where I won’t find them.” Provide them with one ashtray, which should be kept clean and hidden. Finally, consider surprising the smoker with a gift at the end of the first month of quitting, as a thank you for their cooperation.

Alcohol and Socializing Explore alternative ways to socialize Avoid going to a bar If they do go, advise patients: Don’t drink alcohol, or limit drinks to one or two Have a plan and practice it Visualize yourself saying “No thank you, I don’t smoke” several times before going out Another potentially stressful situation, particularly for recent quitters, is drinking alcohol and socializing. Some individuals will say “When I have a drink in one hand, I want a cigarette in the other.” Also, drinking alcohol lowers individuals’ ability to resist temptations. Quitters should be advised to: Explore alternative ways to socialize Avoid going to a bar, particularly in the first few months of quitting If they do go, advise them to consider not drinking alcohol or limiting drinks to one or two, having a plan and practicing it, and visualizing saying “No thank you, I don’t smoke” several times before going out

Smoking After Meals Immediately get up from the table Brush teeth While doing so, look in the mirror and confirm commitment to quitting—”I can do this!” Take a short walk Call a supportive friend Most patients will describe “after meals” as one of their primary challenges. Lighting a cigarette immediately after eating is often one’s way to “finish a meal.” As such, it is essential that patients establish new routines that distract them from wanting to smoke. A few ideas are listed on this slide. As your patient what they think will work best for them, and encourage them to make this their new post-meal routine.

Boredom Advise patients to: Always carry a book/newspaper/crossword puzzle Plan ahead, avoiding long periods of inactivity Learn to enjoy doing nothing from time to time; rethink the belief that it’s necessary to always be doing something Restart an old hobby or start to exercise Boredom is another challenge for many patients. When the mind slows, it has time to wander and often that means it wanders toward wanting a cigarette. It is “normal” for recent quitters to think about smoking, and patients should be advised to proactively attempt to divert their thoughts elsewhere. A few examples of ways to occupy one’s time are listed on this slide. As your patient what they think will work best for them, and encourage them to be proactive in their approaches to handling boredom.

STAGE 2: READY to QUIT Facilitate Quitting Process
Discuss methods for quitting Discuss pros and cons of available methods Pharmacotherapy: a treatment, not a crutch! Importance of behavioral counseling Set a quit date Recommend Tobacco Use Log Helps patients to understand when and why they use tobacco Identifies activities or situations that trigger tobacco use Can be used to develop coping strategies to overcome the temptation to use tobacco In facilitating the quitting process, clinicians should Discuss the pros and cons of different methods for quitting. It is important to elicit the patient’s point of view—each patient will have his or her own perceptions of the different methods. Encourage use of pharmacotherapy in addition to behavioral counseling. Many patients will feel that pharmacotherapy is a “crutch”—these patients should be advised that tobacco use is a chronic condition that alters brain chemistry and that, when feasible and not contraindicated, pharmacotherapy should be used because it increases the chances of quitting. It should be viewed as a treatment, not a crutch. Help the patient set a quit date. Ideally, this will be within the next two weeks (Fiore et al., 2008). Recommend the Tobacco Use Log, if appropriate. This tool helps patients to identify moods, activities, or situations that trigger the desire to smoke or use other forms of tobacco. Triggers for tobacco use might include negative affect, being around other smokers, meal times, alcohol or coffee consumption, cravings for tobacco, stress, time pressures, or other situations such as celebrating with others. Triggers should be identified prior to quitting, while the patient is still smoking “normally.” Information gathered in the log can be used to develop coping strategies to overcome the temptation to use tobacco. ♪ Note to instructor(s): Have audience refer to the Tobacco Use Log handout. The Tobacco Use Log (ancillary handout A5 TOB USE LOG.pdf) is most appropriate for patients who are ready to quit, but it can be used with any patient who wants to learn more about his or her tobacco use behavior. This exercise provides important insight into the circumstances that underlie the need or desire for tobacco. Having a clear understanding of the behavior will help a person to be more effective when attempting to change it. 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. Tobacco Use Log adapted from The Wrap Sheet and the Daily Cigarette Count (Wrap Sheet). In: The Washington State Pharmacists Association. (1997). “Smoking Cessation Training: Pharmacists Becoming Smoking Cessation Counselors,” pp. 3, 25.

STAGE 2: READY to QUIT Facilitate Quitting Process (cont’d)
Tobacco Use Log: Instructions for use Continue regular tobacco use for 3 or more days Each time any form of tobacco is used, log the following information: Time of day Activity or situation during use “Importance” rating (scale of 1–3) Instructions for use: The Tobacco Use Log is a documentation tool that is kept with the patient’s tobacco product(s). For example, the Tobacco Use Log could be folded and wrapped around the cigarette pack or can of snuff with a rubber band. The log should be readily available at the times when the patient uses the tobacco. Through careful documentation of tobacco use over a period of several days, patient-specific tobacco usage patterns become evident. Instruct the patient to continue his or her regular tobacco use for a period of at least 3 days (including one non–work day). It is preferable to complete the Tobacco Use Log for 7 consecutive days, because usage patterns may fluctuate as a function of the day of the week (e.g., weekends vs. work days). The patient should not attempt to reduce tobacco use during this time. The intent is to document current tobacco use habits and patterns. The following information should be noted in the Tobacco Use Log each time any form of tobacco is used: Time of day Brief description of the activity or situation while using the tobacco; other persons present at that time. Encourage the patient to think about the times and places where he or she uses tobacco, each time it is used. It is important for the patient to understand these cues so that effective coping strategies can be developed to overcome the temptation to use tobacco. Rating of the patient’s perceived importance of using the tobacco, at that time, using the following scale: 1 = Very important (would have missed it a great deal) 2 = Moderately important 3 = Not very important (would not have missed it) Log sheets should be reviewed prior to the quit attempt, to identify situations that trigger tobacco use and to develop coping strategies to prevent relapse. Cognitive and behavioral coping strategies are described in the slides that follow. Review log to identify situational triggers for tobacco use; develop patient-specific coping strategies

Discuss coping strategies Cognitive coping strategies Focus on retraining the way a patient thinks Occur prior to the situation or “in the moment” Behavioral coping strategies Involve specific actions to reduce risk for relapse The clinician and patient should discuss and develop effective cognitive and behavioral coping strategies for handling specific situations in which a person will be tempted to use tobacco. Research shows that using both cognitive and behavioral strategies increases a patient’s likelihood of quitting (Prochaska & DiClemente, 1992). These strategies are described in the next few slides. ♪ Note to instructor(s): Have audience refer to Coping with Quitting: Cognitive and Behavioral Strategies (ancillary handout A6 COPING.pdf). This handout provides specific examples of coping strategies for various situations. Prochaska JO, DiClemente CC. (1992). Stages of change in the modification of problem behaviors. In: Progress in Behavior Modification, edited by Hersen M, Eisler RM, Miller PM. Sycamore, IL: Sycamore, pp. 184–218. HANDOUT

TEACH and ENCOURAGE COPING
Think in terms of “alternatives” There is always some other way to think or something else to do in every situation (to avoid smoking) Use a variety of techniques Foster creativity A role of the tobacco cessation counseling is to teach and encourage coping strategies. When discussing strategies with a patient, it is important to ask them for their ideas first, before offering your own. You are attempting to think in terms of “alternatives” -- there is always some other way to think, or something else to do, in every situation to avoid smoking. You will want to use a variety of techniques and foster creativity.

TEACH and ENCOURAGE COPING: STEP #1
Ask: “What could you do differently in this situation so you won’t be prompted to want a cigarette?” “How could you think differently in this situation, so that you aren’t triggered to want to smoke?” As a first step, ask patients, “What could you do differently in this situation so you won’t be prompted to want a cigarette?” or “How could you think differently in this situation so that you are not triggered to want to smoke?”

TEACH and ENCOURAGE COPING: STEP #2
If they provide a reasonable alternative, be supportive If they say “I don’t know” or “I can’t think of anything” Suggest a coping technique (or two) Make suggestions appropriate to their lifestyle As a second step, you will respond to your patient. If they provide a reasonable alternative, be supportive of that suggestion. However, if they say “I don’t know” or “I can’t think of anything,” then you will offer your own suggestions. Perhaps saying, “Would you like to hear a few ideas that I’ve learned from other patients who struggled with this same type of situation?” And then suggest a coping technique (or two). Be sure to make suggestions appropriate to their lifestyle.

Cognitive Coping Strategies Review commitment to quit Distractive thinking Positive self-talk Relaxation through imagery Mental rehearsal and visualization Cognitive strategies focus on retraining the way a patient thinks. Many quitters panic because they are thinking about tobacco after they quit, and this leads to relapse. Thinking about cigarettes (or other forms of tobacco) is normal. The trick is not to dwell on the thought. As tobacco users move toward sustained abstinence, they learn to recognize that thinking about a cigarette doesn’t mean they need to have one. Some examples of cognitive strategies include the following: Review of one’s commitment to quitting can help, including reminding oneself that cravings and temptations are temporary and will pass. Sometimes it helps a patient to announce, either silently or out loud, “I want to be a nonsmoker, and the temptation will pass.” Or each morning, to look in the mirror and say, “I am proud that I made it through another day without tobacco!” Deliberate, distractive thinking can help the patient move current thought processes to issues other than craving or temptation to use tobacco. Positive self-talks, or “pep-talks,” involve saying things such as, “I can do this,” or reminding oneself of previous difficult situations in which tobacco use was avoided successfully. Relaxation through imagery helps the patient to center the mind on positive, relaxing thoughts. This can help to ease the anxiety, stress, and negative moods that may trigger tobacco use. Mental rehearsal and visualization involves envisioning situations that might arise and how best to handle them. This method is commonly used by athletes prior to a game. For example, a goalie might envision (or enact, during pregame warmups) how to block different types of shots or plays from opposing players. In the case of smoking, a person might envision what would happen if he or she were offered a cigarette by a friend—he or she would mentally craft and rehearse a response and perhaps even practice it by saying it out loud. Remind yourself that urges are brief.

Cognitive Coping Strategies: Examples Thinking about cigarettes doesn’t mean you have to smoke one: “Just because you think about something doesn’t mean you have to do it!” Tell yourself, “It’s just a thought,” or “I am in control.” As soon as you get up in the morning, look in the mirror and say to yourself: “I am proud that I made it through another day without tobacco.” Reframe how you think about yourself: Begin thinking of yourself as a non-smoker, instead of as a struggling quitter This slide presents several examples of cognitive statements that can be used while quitting.

Behavioral Coping Strategies Control your environment Tobacco-free home and workplace Remove cues to tobacco use; actively avoid trigger situations Modify behaviors that you associate with tobacco: when, what, where, how, with whom Substitutes for smoking Water, sugar-free chewing gum or hard candies (oral substitutes) Minimize stress where possible, obtain social support, take a break, and alleviate withdrawal symptoms Behavioral strategies involved specific actions for coping with the effects of quitting and reducing risk for relapse. The effectiveness of these strategies may be patient specific, meaning that one technique will work better for some patients than for others. To determine which strategies work best for a specific patient, a clinician must understand the patient’s reasons for tobacco use and routines or situations with which tobacco use is associated. General approaches include enhanced control of the environment. Tobacco-free environments (e.g., home and workplace) can increase chances of success (e.g., Bauer et al., 2005; Eriksen & Cerak, 2008)—nationally, the effects of transitioning all workplaces to smoke-free environments would yield an estimated 4.5% decrease in the overall prevalence of smoking (Fichtenberg & Glantz, 2002). Patients should be advised to remove cues for tobacco use, modify behaviors associated with tobacco use, and actively avoid specific situations in which tobacco use is likely to occur. Oral substitutes for tobacco use include drinking water, chewing sugar-free gum, or sucking on sugar-free candies. Taking walks helps to change the tobacco user’s environment and also increases circulation and oxygenation while burning calories. Minimize stress where possible, obtain social support, and take frequent breaks. Withdrawal symptoms are inevitable, especially with patients who are heavy users of tobacco products. It is important that clinicians educate their patients so that they know what to expect, how to alleviate specific symptoms, and how long to expect the symptoms to last. ♪ Note to instructor(s): Specific behavioral strategies for common cues or causes of relapse (stress, alcohol, other tobacco users, oral gratification needs, automatic smoking routines, postcessation weight gain, cravings for tobacco) are presented in the Coping with Quitting: Cognitive and Behavioral Strategies handout. Bauer JE, Hyland A, Li Q, Steger C, Cummings KM. (2005). A longitudinal assessment of the impact of smoke-free worksite policies on tobacco use. Am J Public Health 95:1024–1029. Ericksen MP, Cerak RL. (2008). The diffusion and impact of clean indoor air laws. Annu Rev Public Health 29:171–185. Fichtenberg CM, Glantz SA. (2002). Effect of smoke-free workplaces on smoking behavior: systematic review. BMJ 325:188–191.

Provide medication counseling Promote adherence Discuss proper use, with demonstration Discuss concept of “slip” versus relapse “Let a slip slide.” Offer to assist throughout quit attempt Follow-up contact #1: first week after quitting Follow-up contact #2: in the first month Additional follow-up contacts as needed Congratulate the patient! It is imperative that clinicians counsel patients on their pharmacotherapy regimens (proper use, with demonstration as needed) and encourage patients to adhere to the prescribed regimen. Patients should be advised to take cessation medications as prescribed, not as needed. If a patient waits until he or she is in dire need of nicotine, it is too late. Nicotine replacement therapy products do not have the same rapid onset of action as tobacco formulations. Prior to embarking on a quit attempt, the patient should be strongly advised not to smoke an occasional cigarette, or to have “just one drag” off of a friend’s cigarette. These are precursors for a full relapse. But, the patient should know the difference between a slip and a full relapse. A slip is a situation in which a person smokes one or just a few cigarettes. Although this can lead to a full relapse, it is not a complete failure, and it should be considered part of the learning process. If this occurs, encourage the patient to think through the scenario and determine the trigger(s) for smoking. Suggest coping strategies that will enable the patient to avoid smoking in similar situations. The last of the 5 A’s is to arrange follow-up. At this point, the clinician should summarize and discuss the acceptability of the treatment plan and offer to assist throughout the quit attempt. The most effective timing for follow-up contacts is not well understood (Fiore et al., 2008), and likely will vary by patient. In general, contact should occur the first week after quitting and a few weeks later (within the first month), with additional follow-up contacts as needed until the patient is stable in his or her new role as a nonuser of tobacco. At follow-up contact, it is important to reassess the patient’s commitment to quitting and his or her confidence in quitting. The patient’s response will, in part, be a reflection of his or her confidence in the treatment plan. As needed, offer resources and referrals (e.g., to other health care providers, tobacco quitlines). Finally, congratulate the patient for making the important decision 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.

STAGE 2: READY to QUIT A Demonstration
CASE SCENARIO: Ms. Staal ♪ Note to instructor(s): This video takes place in an emergency room setting, but similar strategies should be used, regardless of clinician type or setting. To access the video file, go to Under the “5 A’s Curriculum,” click “Video Segments” and locate video V17a in the table. Other videos are available for download from this webpage and might be more appropriate for your audience. Edit this slide as needed to incorporate other videos. After showing the video, debrief with your audience. You are a clinician providing care to Ms. Staal, a 44-year old woman in the emergency room with pulmonary distress. VIDEO # V17a

GOAL: Remain tobacco-free for at least 6 months.
ASSESSING READINESS to QUIT (cont’d) STAGE 3: Recent quitter Actively trying to quit for good Patients have quit using tobacco sometime in the past 6 months and are taking steps to increase their success. Withdrawal symptoms occur. Patients are at risk for relapse. Patients who quit (in the past 6 months) are considered recent quitters. These patients are taking steps to enhance the likelihood that they can successfully quit by using medications such as nicotine replacement therapy. They dispose of unused cigarettes and remove lighters and other smoking apparatus from their homes and cars. They alter their routines to avoid habituated smoking patterns. These patients likely are experiencing withdrawal symptoms—some pleasant (such as revived taste buds) and some not so pleasant (such as cravings, irritability, and weight gain). Recent quitters are at high risk for relapse. The goal is to help them remain tobacco-free. GOAL: Remain tobacco-free for at least 6 months.

STAGE 3: RECENT QUITTERS Evaluate the Quit Attempt
Tailor interventions to match each patient’s needs Status of attempt Ask about social support Identify ongoing temptations and triggers for relapse (negative affect, smokers, eating, alcohol, cravings, stress) Encourage healthy behaviors to replace tobacco use Slips and relapse Has the patient used tobacco/inhaled nicotine at all—even a puff? Medication adherence, plans for termination Is the regimen being followed? Are withdrawal symptoms being alleviated? How and when should pharmacotherapy be terminated? Recent quitters face many challenges in adopting their new behavior (not smoking). During the quit attempt, clinicians should carefully tailor interventions to match each patient’s needs. It is an opportunity to problem solve, or intervene, most creatively. Here are the basic strategies for evaluating a patient’s quit attempt: Inquire about available social support. Identify temptations and triggers relapse. Key triggers are negative affect, being around other tobacco users, eating, drinking alcohol, cravings for tobacco, and stress. Suggest coping strategies as needed, to remove or modify cues in the environment that make a person want to use tobacco, such as removing ashtrays, not entering an office where smokers are congregating, and not drinking alcohol if it will increase the likelihood of tobacco use. Encourage healthful behaviors to replace smoking (e.g., drinking water, exercise). Determine whether the patient has had any slips or has relapsed. Evaluate the treatment regimen. Is adherence with medications adequate? Are withdrawal symptoms being alleviated? How and when should pharmacotherapy be terminated?

STAGE 3: RECENT QUITTERS Facilitate Quitting Process
Relapse Prevention Congratulate success! Encourage continued abstinence Discuss benefits of quitting, problems encountered, successes achieved, and potential barriers to continued abstinence Ask about strong or prolonged withdrawal symptoms (change dose, combine or extend use of medications) Promote smoke-free environments Schedule additional follow-up as needed Relapse prevention is an important component of tobacco cessation interventions and should be part of every encounter with patients who recently quit using tobacco. At a minimum, the quitter should be congratulated for his or her successes and should be strongly encouraged to remain tobacco-free. Relapse prevention interventions should include a discussion of the patient’s perceived benefits of quitting, challenges during the process, successes achieved (specific situations in which the patient was tempted to use tobacco but resisted), and potential barriers to continued abstinence (e.g., depression, alcohol use, weight gain, stress, and other tobacco users who are not supportive of cessation). For patients who are feeling a sense of loss after quitting (some individuals feel as though they have lost a best friend), acknowledge their feelings and reassure them that the feelings will subside over time. Identify and recommend other activities that the particular patient views as rewarding. For patients who are complying with their pharmacotherapy regimens but continue to have strong or prolonged withdrawal symptoms, consider adding, combining, or extending use of medications. For a recent quitter, it is important to attempt to reduce relapse risk by promoting tobacco-free environments (e.g., in the home and workplace). Social support, delivered as part of treatment, is recommended and the clinician should schedule follow-up visits or calls as needed to prevent relapse. If necessary, refer the patient to a tobacco cessation support group in the community. ♪ Note to instructor(s): The 2008 update of the Clinical Practice Guideline does not recommend extra-treatment social support, because the literature does not show a strong effect of helping patients identify and utilize support outside of the treatment relationship (Fiore et al., 2008; p. 97). 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.

STAGE 3: RECENT QUITTER A Demonstration
CASE SCENARIO: Mr. Angelo Fleury ♪ Note to instructor(s): This video takes place in a patient examination room, but similar strategies should be used, regardless of clinician type or setting. To access the video file, go to Under the “5 A’s Curriculum,” click “Video Segments” and locate video V25b in the table. Other videos are available for download from this webpage and might be more appropriate for your audience. Edit this slide as needed to incorporate other videos. After showing the video, debrief with your audience. Note that this intervention provided a substantial amount of counseling, addressing key issues, in only 4 minutes. You are a clinician providing follow-up care to Mr. Angelo Fleury, who recently quit and is experiencing difficulty sleeping and coping with job-related stress. VIDEO # V25b

STAGE 4: Former tobacco user Tobacco-free for 6 months Patients remain vulnerable to relapse. Ongoing relapse prevention is needed. Patients who have been tobacco-free for 6 or more months can be classified as former tobacco users. Nevertheless, many remain vulnerable to relapse. The strategies to be applied for former tobacco users are similar to, but less intensive than, those used for recent quitters. The goal for these patients is to remain tobacco-free for life. GOAL: Remain tobacco-free for life.

Quitting is difficult for most patients, and tobacco users typically make multiple serious quit attempts before they are able to quit for good. For this reason, clinicians should routinely screen for periodic tobacco use among former users and continue to demonstrate support and encouragement for the patient’s continued success. HERMAN ® is reprinted with permission from LaughingStock Licensing Inc., Ottawa, Canada All rights reserved.

STAGE 4: FORMER TOBACCO USERS
Assess status of quit attempt Congratulate continued success Inquire about and address slips and relapse Plans for termination of pharmacotherapy Review tips for relapse prevention As with recent quitters, clinicians must evaluate the status of the quit attempt. Has the patient had any strong temptations to use tobacco, or any occasional use of tobacco products (even a puff)? Patients might be particularly vulnerable to relapse during times of extreme stress. Also, it is important to ensure that patients are appropriately terminating or tapering off of pharmacotherapy products. Relapse prevention strategies should be discussed as needed, and healthy behaviors should be encouraged—ones that the patient does not associate with tobacco use—such as exercise, hobbies (particularly ones that involve use of the hands), and going to movies with friends. To reduce weight gain, it is important for patients to maintain a healthy diet. Finally, patients who have been off of tobacco for 6 or more months should be congratulated for their enormous success. Staying tobacco-free is a continuous process of learning how to cope with the change. Clinicians should acknowledge, reward, and reinforce the patient’s triumphs in the face of this challenge. Continue to assist throughout the quit attempt. Remember: Behavioral change is a process, not a single step. It’s common for patients to experience at least one episode of relapse. This should not be regarded as a failure on the part of the patient or the provider, but rather one of the many possible steps within the process of establishing long-term change. Continue to assist throughout the quit attempt.

READINESS to QUIT: A REVIEW
Quit date - 30 days + 6 months This diagram reviews the relationship between the different stages of readiness to quit as a function of time. Not ready to quit Recent quitter Former tobacco user Enhance motivation The 5 R’s Behavioral counseling Pharmacotherapy Relapse prevention Behavioral counseling Relapse prevention Ready to quit Behavioral counseling Pharmacotherapy The 5 A’s

COMPREHENSIVE COUNSELING: SUMMARY
Routinely identify tobacco users (ASK) Strongly ADVISE patients to quit ASSESS readiness to quit at each contact Tailor intervention messages (ASSIST) Be a good listener Minimal intervention in absence of time for more intensive intervention ARRANGE follow-up Use the referral process, if needed To summarize the 5 A’s approach (Fiore et al., 2008), clinicians should routinely identify tobacco users, advise patients to quit, and assess stage of readiness to quit at each contact. Patients who are not ready to quit should receive brief motivational interventions (the 5 R’s). In counseling patients, it is imperative that the clinician be a good listener and work with patients in designing treatment plans. When time is limited, a minimal intervention (ask, advise, and refer to other resources for additional assistance; see next slide) should be administered. Follow-up is a key component of successful quit attempts. Refer patients to other health care providers, to tobacco cessation group programs or to a tobacco quitline if needed. 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.

BRIEF COUNSELING: ASK, ADVISE, REFER
about 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

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 5 A’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.

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) 28.1% success rate for patients who use the quitline and a medication for cessation 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 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. An estimated 28.1% success rate is seen for patients who use the quitline and medication for cessation (versus 12.7% for quitline alone) (Fiore et al., 2008). 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,et al. (2000). A self-help cessation program for smokeless tobacco users: Comparison of two interventions. Nicotine Tob Res 2:363–370. 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. A systematic review of interventions for smokers who contact quitlines. Tob Control. 2007;16(Suppl 1):i3–8. Stead LF, Hartmann-Boyce J, Perera R, Lancaster T. (2013). Telephone counselling for smoking cessation. Cochrane Database Syst Rev 8:CD Zhu SH, 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.

WHEN a PATIENT CALLS the QUITLINE
Caller 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 hrs 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 conducted, 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 (this is dependent on 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.

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 five 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.

WHAT IF… a patient asks you about your use of tobacco?
If a patient asks you whether you use tobacco or have used tobacco in the past, be honest. If you have never been a tobacco user, you really can’t understand how difficult it is to quit. But, being a health care provider, you understand the physiologic and psychosocial nature of addiction—which helps to provide insight. Clinicians counsel patients for all types of diseases without having the diseases themselves. It is appropriate to admit that, while you have not personally experienced quitting yourself, you have worked with plenty of patients who have. Acknowledge that it is a very difficult process. If you have been a tobacco user (or are a current user), then you probably have greater insight into the meaning of tobacco dependence. If you’ve tried to quit before (whether successfully or not), don’t assume that your patients’ experience with quitting will be similar to yours. It may be useful to provide some “this is what happened to me” insight, but don’t express an “I did it, so can you” attitude—this is not a sensitive approach to dealing with patients. Often, some of the best tobacco cessation counselors are individuals who used to use tobacco regularly. Current tobacco users are strongly encouraged to quit.

There is no place for tobacco in any health-care setting.
Sales of tobacco in pharmacies is an important issue that many believe casts a negative light on the pharmacy profession (Hudmon et al., 2006; Katz, 2008; Brennan & Schroeder, 2014). The reasons that pharmacies cite for selling tobacco have been described as “weak and unconvincing” (Hussar, 2004). Evidence suggests that there is little public or professional support for tobacco sales in pharmacies. For example, in California, only 1.6% of licensed pharmacists (of 1,168 surveyed) and 2.0% of pharmacy students (of 1,518 surveyed) are in favor of tobacco sales in pharmacies. Furthermore, of 988 adult consumers interviewed, 72.3% disagreed with the statement “I am in favor of tobacco products being sold in drugstores,” and 83% stated that if the drugstore where they most commonly shopped were to stop selling tobacco products, they would shop there just as often, 14% would shop there more often, and 3% would shop there less often (Hudmon et al., 2006). In 2014, CVS Caremark, Inc. chose to remove all tobacco products and electronic cigarettes from all of its stores. Although it followed in the steps of Target and Wegmans, it was the first major pharmacy chain to do so, citing the paradox between (a) the distribution of medications to promote health and (b) the sale of tobacco products, the leading cause of preventable death (Brennan & Schroeder, 2014). ♪ Note to instructor(s): Please encourage audience members to sign our online petition at ♪ Note to pharmacy instructor(s): Please engage your pharmacists/pharmacy students in a discussion/debate about whether they believe it is appropriate for pharmacies to sell tobacco. Hudmon KS, Fenlon CM, Corelli RL, Prokhorov AV, Schroeder SA. (2006). Tobacco sales in pharmacies: Time to quit. Tobacco Control 15(1)35–38. Hussar D. (2004, December 13). Let's get tobacco out of pharmacies! Drug Topics. [No longer accessible via the Web]. Katz MH. (2008). Banning tobacco sales in pharmacies: the right prescription. JAMA 300(12):1451–1453. Brennan TA, Schroeder SA. (2014). Ending sales of tobacco products in pharmacies. JAMA 311(11):1105–11106. Courtesy of Mell Lazarus and Creators Syndicate. Copyright 2000, Mell Lazarus. There is no place for tobacco in any health-care setting.

The RESPONSIBILITY of HEALTH PROFESSIONALS
It is inconsistent to provide health care and —at the same time— remain silent (or inactive) about a major health risk. As a final note, it is important to emphasize that it is inconsistent, and perhaps unethical, to provide health care and—at the same time—remain silent (or inactive) about a major health risk. Addressing tobacco use is an essential component of clinical care. Promoting tobacco cessation is, in itself, an important component of therapy—it has immediate payoff in terms of both health improvements and cost savings (Lightwood & Glantz, 1997). The primary goal of the Rx for Change: Clinician-Assisted Tobacco Cessation program is to provide current and future health professionals with the knowledge and skills necessary to make an impact on the incidence of tobacco-related disease in the U.S. and abroad. Clinicians can make a difference (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. Lightwood JM, Glantz SA. (1997). Short-term economic and health benefits of smoking cessation: Myocardial infarction and stroke. Circulation 96:1089–1096. TOBACCO CESSATION is an important component of THERAPY.

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.

MEDICATIONS for CESSATION
This module focuses on patient education and the proper use of the medications 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. Most tobacco users quit without assistance, and overall, around 95% of unaided quit attempts end in relapse (Fiore et al., 2008). In general, combination therapy consisting of behavioral counseling with pharmacotherapy is more effective (40–70% improvement) than either method used alone (Fiore et al., 2008; pp ). Furthermore, interventions combining both pharmacotherapy and behavioral assistance are associated with increased cessation success compared to a minimal intervention or usual care (Stead et al., 2016). As such, state-of-the-art, evidence-based interventions should focus on behavioral support in combination with one or more FDA-approved medications for cessation, as appropriate. ♪ 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 breast-feeding 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. 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, Koilillai P, Fanshawe TR, Lancaster T. (2016). Combined pharmacotherapy and behavioral interventions for smoking cessation. Cochrane Database Syst Rev. 3:CD

Physiological Behavioral Tobacco dependence is a chronic condition that requires a two-prong approach for maximal treatment effectiveness (Fiore et al., 2008). Prolonged tobacco use of tobacco results in tobacco dependence, which is characterized as a physiological dependence (addiction to nicotine) and behavioral habit of using tobacco. This module addresses the use of FDA-approved medications to treat tobacco dependence. 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 the behavioral aspects of tobacco use and dependence such as individualized counseling and group or online cessation programs are covered in detail in the Assisting Patients with Quitting module. 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 The addiction to nicotine Medications for cessation The habit of using tobacco Behavior change program Treatment should address the physiological and the behavioral aspects of dependence.

NICOTINE WITHDRAWAL SYMPTOMS: Time Course* and Management
Irritability / Frustration / Anger Anxiety Difficulty concentrating Restlessness / Impatience Depressed mood / Depression Insomnia Impaired task 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. Nicotine replacement therapy, bupropion, and varenicline are used as aids for cessation in the management of the physiologic aspect of tobacco dependence. These agents work by alleviating the symptoms of nicotine withdrawal, which include (Hughes, 2007): Irritability/frustration/anger Anxiety Difficulty concentrating Restlessness/impatience Depressed mood/depression Insomnia Impaired task performance Increased appetite Weight gain Cravings for tobacco ♪ Note to instructor(s): Other symptoms of quitting have been described in the literature. Please refer to Hughes, 2007 for further details. This slide depicts the general time course for common nicotine withdrawal symptoms that is observed following the cessation tobacco use. Most withdrawal symptoms manifest within the first 1–2 days, peak in intensity within the first week, and gradually subside within 2 to 4 weeks after cessation (Hughes, 2007). In some individuals, prolonged appetite effects (e.g., hunger, weight gain) may occur continuously for 6 months or more (Hughes, 2007), and strong cravings for tobacco can persist for months to years after cessation (Benowitz, 1992). For this reason, the typical recommended duration of therapy for pharmacotherapy is 6–12 weeks; this helps to alleviate the symptoms of nicotine withdrawal during the early stages of quitting. When patients are more comfortable, it’s easier to address the habits and routines associated with tobacco use through use of cognitive and behavioral coping strategies. For additional information please refer to the Assisting Patients with Quitting module. 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 9:315–27. 6 months Can persist for months to years after quitting 1 week 4 weeks 12 weeks Quit date Recent quitter Former tobacco user Cognitive & behavioral coping strategies Medications for cessation Data from Hughes. (2007). Nicotine Tob Res 9:315–327. *Timeline aspect of the figure is not according to scale.

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 breast-feeding 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, May 2008.

PHARMACOTHERAPY: Use in SPECIAL POPULATIONS
Pharmacotherapy is not recommended for: Pregnant smokers Insufficient evidence of effectiveness Smokeless tobacco users No FDA indication for smokeless tobacco cessation Individuals smoking fewer than 10 cigarettes per day Adolescents Nonprescription sales of nicotine replacement therapy (NRT) products (i.e., patch, gum, lozenge) are restricted to adults ≥18 years of age NRT use in minors requires a prescription For each of these special populations, the recommended treatment is behavioral counseling (Fiore et al., 2008). According to multiple national practice guidelines pregnant smokers should be encouraged to quit without medication based on insufficient evidence of effectiveness and hypothetical concerns with safety. For this reason, the recommended first-line treatment approach for pregnant women who use tobacco is behavioral interventions that exceed minimal advice to quit (Fiore et al., 2008; Siu et al, 2015; ACOG Committee Opinion, 2017). The manufacturers of varenicline, bupropion and prescription formulations of nicotine replacement therapy recommend medication use during pregnancy only if the potential benefit justifies the potential risk to the fetus (Pfizer, 2016; Pfizer, 2016; GlaxoSmithKline, 2017; Pfizer, 2018). Although medications 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). The American College of Obstetrics and Gynecology states “the use of nicotine replacement therapy should be undertaken with close supervision and after careful consideration and discussion with the patient of the now risks of continued smoking and the possible risks of nicotine replacement therapy. There is insufficient evidence to evaluate the safety and efficacy of varenicline and bupropion” (ACOG, 2017). ♪ Note to instructor(s): The manufacturer of Zyban (GlaxoSmithKline; removed from market July 2019) 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). 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, and therefore limited data are available. Non-prescription NRT sales (nicotine patch, gum, lozenge) are restricted to adults ≥18 years of age, and use in minors requires a prescription. ♪ Note to instructor(s): Limited data suggest that varenicline and the nicotine lozenge might help smokeless tobacco users to quit (Ebbert et al., 2015). The adolescent population is particularly challenging and there is limited evidence demonstrating long-term cessation with either behavioral counseling or pharmacotherapy (Fanshawe et al, 2017). American College of Obstetricians and Gynecologists. (2017). Smoking cessation during pregnancy. Committee Opinion 721. Available at: Benowitz NL, Dempsey DA. (2004). Pharmacotherapy for smoking cessation during pregnancy. Nicotine Tob Res 6(Suppl. 2):S189–S202. Ebbert JO, Elrashidi MY, Stead LF. (2015). Interventions for smokeless tobacco use cessation. Cochrane Database Syst Rev 10:CD Fanshawe TR, Halliwell W, Lindson N, et al. (2017).Tobacco cessation interventions for young people. Cochrane Database Syst Rev 11: CD 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. (2017, May). Zyban Package Insert. Research Triangle Park, NC. GlaxoSmithKline. (2008, August). The bupropion pregnancy registry. Final report 1 September 1997 through 31 March Wilmington, NC. For Information on obtaining the report, see Pfizer, Inc. (2018, June). Chantix Package Insert. New York, NY. Pfizer Inc.a (2016, July). Nicotrol NS Package Insert. New York, NY. Pfizer Inc.b (2016, July). Nicotrol Inhaler Package Insert. New York, NY. Siu AL, for the U.S. Preventive Services Task Force (2015). Behavioral and pharmacotherapy interventions for tobacco smoking cessation in adults, including pregnant women: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 163:622–634. Recommended treatment is behavioral counseling.

FDA-APPROVED MEDICATIONS for CESSATION
Nicotine polacrilex gum* Nicorette (OTC) Generic nicotine gum (OTC) Nicotine lozenge* Generic nicotine lozenge (OTC) Nicotine transdermal patch* NicoDerm CQ (OTC) Generic nicotine patches (OTC) Nicotine inhaler * Nicotrol (Rx) Nicotine nasal spray * Nicotrol NS (Rx) Bupropion SR Generic (Rx) Varenicline Chantix (Rx) There are three general classes of FDA-approved drugs for cessation: Nicotine replacement therapy (NRT) includes the nicotine gum, patch, lozenge, inhaler and nasal spray. A nicotine sublingual tablet currently is available in Europe. The only psychotropic agent currently approved by the FDA for smoking cessation is bupropion SR. Varenicline, a partial nicotinic receptor agonist, was approved by the FDA in 2006 for smoking cessation. Medications that are available in the U.S. 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. According to the U.S. Public Health Service Clinical Practice Guideline for treating tobacco use and dependence (Fiore et al., 2008), first-line pharmacotherapies for smoking cessation include NRT, sustained-release bupropion and varenicline. Currently, no medications have an FDA indication for the cessation of smokeless tobacco or electronic nicotine delivery system use. ♪ Note to instructor(s): The following pharmacotherapies have been studied but are not recommended by the U.S. Public Health Service Clinical Practice Guideline for treating tobacco use and dependence based on a lack of benefit relative to placebo therapy (David et al., 2013; Fiore et al., 2008; Hughes et al., 2014): Anxiolytic agents (buspirone, diazepam) Beta-blockers (propranolol) Mecamylamine Opioid antagonists (buprenorphine, naloxone, naltrexone) Selective serotonin reuptake inhibitors (citalopram, fluoxetine, paroxetine, sertraline) Silver acetate David S, Lancaster T, Stead LF, Evins AE, Prochaska JJ. (2013). Opioid antagonists for smoking cessation. Cochrane Database Syst Rev 4:CD 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. Hughes JR, Stead LF, Hartmann-Boyce J, Cahill K, Lancaster T. (2014). Antidepressants for smoking cessation. Cochrane Database Syst Rev 1:CD * Nicotine replacement therapy (NRT) products.

NICOTINE REPLACEMENT THERAPY (NRT) RATIONALE for USE
Reduces 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 Currently available formulations of NRT include gum, lozenge, transdermal patch, nasal spray, and inhaler. 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 their addictive properties are negligible compared to tobacco products, some patients might have difficulty terminating NRT use. NRT use significantly improves the success rates of smoking cessation. Meta-analyses of controlled trials of NRT have found that all products (gum, patch, lozenge, inhaler, and nasal spray) significantly improve abstinence rates when compared to placebo. Use of NRT almost doubles long-term quit rates relative to placebo (Fiore et al., 2008; Stead et al., 2012; Hartmann-Boyce et al., 2018). Because these medications are intended for use to prevent withdrawal, it is essential that patients adhere to a fixed dosing schedule. When the medications are used to treat withdrawal after it occurs, they are less effective because they do not work as rapidly as nicotine inhaled from a cigarette. 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. Hartmann-Boyce J, Chepkin SC, Ye W, Bullen C, Lancaster T. (2018). Nicotine replacement therapy versus control for smoking cessation. Cochrane Database of Syst Rev 5:CD Stead LF, Perera R, Bullen C, et al. (2012). Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 1:CD NRT products approximately doubles quit rates.

PLASMA NICOTINE CONCENTRATIONS for NICOTINE-CONTAINING PRODUCTS
Cigarette 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)

NRT: PRECAUTIONS Patients with underlying cardiovascular disease
Recent myocardial infarction (within past 2 weeks) Serious arrhythmias Serious or worsening angina Some general precautions to consider when recommending the use of NRT as a cessation aid: Nicotine activates the sympathetic nervous system leading to an increase in heart rate, blood pressure, and myocardial contractility. Nicotine may also cause coronary artery vasoconstriction (Benowitz, 2003). These known hemodynamic effects of nicotine have led to concerns about the safety of NRT use in patients with established cardiovascular disease, particularly those with serious arrhythmias, serious or worsening angina, or those patients in the immediate post-myocardial infarction period (within past 2 weeks) (Fiore et al., 2008). Soon after the nicotine patch was approved, anecdotal case reports appeared in the lay press linking NRT use (patch and gum) with adverse cardiovascular events (i.e., arrhythmias, myocardial infarction, stroke). Since then, several randomized, controlled trials have evaluated the safety of NRT in patients with cardiovascular disease including angiographically documented coronary artery stenosis, myocardial infarction, stable angina, and previous coronary artery bypass surgery or angioplasty (Joseph et al., 1996; Tzivoni et al., 1998; Working Group for the Study of Transdermal Nicotine in Patients with Coronary Artery Disease, 1994). These trials found no significant increase in the incidence of cardiovascular events or mortality among patients receiving NRT when compared to placebo. However, because the trials specifically excluded patients with unstable angina, serious arrhythmias, and recent myocardial infarction, the Clinical Practice Guideline recommends that NRT be used with caution among patients in the immediate (within 2 weeks) post-myocardial infarction period, those with serious arrhythmias, and those with serious or worsening angina, owing to a lack of safety data in these high-risk populations (Fiore et al., 2008). In summary, NRT use in patients with cardiovascular disease has been the subject of numerous reviews, and it is widely believed by experts in the field that the risks of NRT in this patient population are small in relation to the risks of continued tobacco use (Benowitz, 2003; Joseph & Fu, 2003; McRobbie & Hajek, 2001; Stead et al., 2012; Mills et al., 2014). The 2008 updated Clinical Practice Guideline concludes that there is no evidence of increased cardiovascular risk with these medications (Fiore et al., 2008). ♪ Note to instructor(s): It is important to emphasize that in patients with NRT precautions, OTC/self-care is not appropriate. Benowitz NL. (2003). Cigarette smoking and cardiovascular disease: Pathophysiology and implications for treatment. Prog Cardiovasc Dis 46:91–111. 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. Joseph AM, Fu SS. (2003). Safety issues in pharmacotherapy for smoking in patients with cardiovascular disease. Prog Cardiovasc Dis 45:429–441. Joseph AM, Norman SM, Ferry LH, et al. (1996). The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease. N Engl J Med 335:1792–1798. McRobbie H, Hajek P. (2001). Nicotine replacement therapy in patients with cardiovascular disease: guidelines for health professionals. Addiction 96:1547–1551. Mills EJ, Thorlund K, Eapen S, Wu P, Prochaska JJ. (2014) Cardiovascular events associated with smoking cessation pharmacotherapies: a network meta- analysis. Circulation 129:28–41. 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 Tzivoni D, Keren A, Meyler S, et al. (1998). Cardiovascular safety of transdermal nicotine patches in patients with coronary artery disease who try to quit smoking. Cardiovasc Drugs Ther 12:239–244. Working Group for the Study of Transdermal Nicotine in Patients with Coronary Artery Disease. (1994). Nicotine replacement therapy for patients with coronary artery disease. Arch Intern Med 154:989–995. NRT products may be appropriate for these patients if they are under medical supervision.

NICOTINE GUM Nicorette; generics
Resin 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. To increase palatability, newer, softer-to-chew formulations have been released over the years in a variety of flavors. All gum formulations contain buffering agents (sodium carbonate and sodium bicarbonate) to increase salivary pH, thereby enhancing buccal absorption of nicotine.

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. Choi JH, Dresler CM, Norton MR, Strahs KR. (2003). Pharmacokinetics of a nicotine polacrilex lozenge. Nicotine Tob Res 5:635–644.

NICOTINE GUM & LOZENGE: DOSING
Dose based on the “time to first cigarette” (TTFC) as an indicator of nicotine dependence Use the 2 mg gum/lozenge: If first cigarette of the day is smoked more than 30 minutes after waking The recommended dosage of the nicotine gum and 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. 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). Pharmacokinetic studies with the nicotine lozenge have found that 1.0 mg and 3.2 mg of nicotine is systemically available from the 2 mg and 4 mg lozenge, respectively. Peak nicotine plasma levels of 10.8 mcg/L and 4.4 mcg/L were attained at ~60 minutes with the 2 mg and 4 mg lozenge, respectively (Choi et al., 2003). 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. Choi JH, Dresler CM, Norton MR, Strahs KR. (2003). Pharmacokinetics of a nicotine polacrilex lozenge. Nicotine Tob Res 5:635–644. 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):S555–70. Use the 4 mg gum/lozenge: If first cigarette of the day is smoked within 30 minutes of waking 164

NICOTINE GUM & LOZENGE: DOSING (cont’d)
Recommended Usage Schedule 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 Patients using nicotine gum and lozenge are more likely to quit successfully if they use the product 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 use one piece of gum every 1–2 hours while awake. In general, this amounts to at least nine lozenges or pieces of gum daily. Patients can use additional pieces (up to the daily maximum of 24 pieces of gum or 20 lozenges per day) if cravings occur between the scheduled doses. Persons who smoke heavily generally need more pieces to alleviate withdrawal. 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. Do not use more than 24 pieces of GUM or 20 LOZENGES per day.

NICOTINE GUM: DIRECTIONS FOR USE
Chew slowly 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 when 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. “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, but this varies between individuals. Anecdotally, many of the generic formulations of the gum are more viscous and often require more chews to achieve the tingling sensation. Stop chewing at first sign of peppery taste or tingling sensation Chew again when peppery taste or tingle fades Park between cheek & gum

NICOTINE LOZENGE: DIRECTIONS for USE
Place in mouth and allow to dissolve slowly (nicotine release may cause warm, tingling sensation) Do not chew or swallow 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. Individuals who are unable to allow a piece of hard candy to dissolve slowly in their mouth (without chewing it) are more likely to experience a higher incidence of adverse effects with the nicotine lozenge. Nicotine lozenge: Directions for use 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.

NICOTINE GUM/LOZENGE: ADDITIONAL PATIENT EDUCATION
To improve chances of quitting, use at least nine pieces daily during the first 6 weeks The gum/lozenge will not provide the same rapid satisfaction that smoking provides The effectiveness of the nicotine gum/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 or pieces of gum daily (one every 1–2 hours) during the first 6 weeks of treatment. Persons who smoke heavily generally need more pieces to reduce their cravings. It is important to emphasize that patients often do not use enough of the gum to derive benefit. They commonly use 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). Use of nicotine gum and lozenges will not provide the same rapid satisfaction that smoking provides. Recall that buccal absorption of nicotine is far less rapid from oral NRT formulations (peak nicotine concentrations are achieved within 30–60 minutes), compared to nicotine absorption from cigarette smoking (peak concentrations <10 minutes). ♪ Note to instructor(s): The Nicorette Mini lozenge dissolves more rapidly, but marketing materials suggest that situational cravings can be alleviated within 5 minutes and this is comparable to the standard lozenges. The effectiveness of the nicotine gum and lozenge may be reduced by some foods and beverages, such as coffee, juices, wine, or soft drinks (Henningfield et al., 1990). Patients should be instructed not to eat or drink for 15 minutes anything other than water before or while using oral formulations of NRT. 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. 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 the nicotine gum or lozenge.

NICOTINE GUM/LOZENGE: ADD’L PATIENT EDUCATION (cont’d)
Chewing the lozenge or using incorrect gum chewing technique can cause excessive and rapid release of nicotine, resulting in: Lightheadedness/dizziness Nausea and vomiting Hiccups Irritation of throat and mouth Patients should be warned that chewing the lozenge or using incorrect gum chewing technique can cause excessive and rapid 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/dizziness Nausea and vomiting Hiccups Irritation of the throat and mouth

NICOTINE GUM/LOZENGE: ADD’L PATIENT EDUCATION (cont’d)
Adverse effects of nicotine gum and lozenge: Mouth and throat irritation Hiccups Gastrointestinal complaints (dyspepsia, nausea) Adverse effects associated with nicotine gum: Jaw muscle ache May stick to dental work The most common adverse effects associated with nicotine gum and lozenge include the following (Mills et al, 2010; Hartmann-Boyce et al, 2018): Mouth and throat irritation Hiccups Gastrointestinal complaints (dyspepsia, nausea) These side effects are more common during the first few days of therapy. Additional adverse effects associated with the nicotine gum are related to the consistency of the polacrilin resin (increased viscosity compared to ordinary chewing gum) which may lead to: Jaw muscle ache Increased adherence to dental work and therefore not 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. Mills EJ, Wu P, Lockhart I, Wilson K, Ebbert JO. (2010). Adverse events associated with nicotine replacement therapy (NRT) for smoking cessation. A systematic review and meta-analysis of one hundred and twenty studies involving 177,390 individuals. Tob Induc Dis. 13;8:8. Hartmann-Boyce J, Chepkin SC, Ye W, Bullen C, Lancaster T. (2018) Nicotine replacement therapy versus control for smoking cessation. Cochrane Database Syst Rev. 2018;5:CD

NICOTINE GUM/LOZENGE: SUMMARY
ADVANTAGES Might 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 Relatively inexpensive DISADVANTAGES Need for frequent dosing can compromise adherence Gastrointestinal adverse effects (nausea, hiccups, and dyspepsia) may be bothersome Specific to nicotine gum: Might be problematic for patients with significant dental work Proper chewing technique is necessary for effectiveness and to minimize adverse effects Chewing might not be acceptable or desirable for some patients Advantages of nicotine gum and lozenge include the following: Might serve as an oral substitute for tobacco (e.g., satisfy oral cravings for tobacco). 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. Relatively inexpensive (generally less than the cost of a pack of cigarettes) Disadvantages of the gum and lozenge include the following: Need for frequent dosing can compromise adherence. Gastrointestinal adverse effects (nausea, hiccups, and dyspepsia) might be bothersome. Disadvantages specific to the nicotine gum formulation: 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

TRANSDERMAL NICOTINE PATCH NicoDerm CQ; generic
Continuous (24-hour) nicotine delivery system Nicotine is well absorbed across the skin Transdermal 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 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 patchOTC Manufacturers: Novartis Consumer Health and others (Novartis product first 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, 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. 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 transdermal nicotine delivery varies by manufacturer. NicoDerm CQ (GlaxoSmithKline) uses a rate-controlling membrane. The generic patches typically 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, with 68–82% of the dose released from the patch reaching 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. Benowitz NL, Hukkanen J, Jacob P. (2009) Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol: 29–60. Gore AV, Chien YW. (1998). The nicotine transdermal system. Clin Dermatol 16:599–615.

TRANSDERMAL NICOTINE PATCH: DOSING
Product 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 be 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.

TRANSDERMAL NICOTINE PATCH: DIRECTIONS for USE
Choose 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 non-hairy, 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. Additionally, the patch should not be applied to skin that has been recently shaved. 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.

TRANSDERMAL NICOTINE PATCH: DIRECTIONS for USE (cont’d)
Remove protective liner and 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) 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. 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.

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.

TRANSDERMAL NICOTINE PATCH: ADDITIONAL PATIENT EDUCATION
Water 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 Can unpredictably effect nicotine delivery 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. Cutting nicotine patches is not recommended because the transdermal technology (rate-controlling membrane and drug reservoir) will be altered, which can lead to unpredictable delivery of nicotine across the skin (Ball & Smith, 2008) and reduced effectiveness. To reduce the risk of poisoning, 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, nicotine patches should be removed prior to MRI procedures (Kuehn, 2009). Ball AM, Smith KM. (2008) Optimizing transdermal drug delivery. Am J Health-Syst Pharm. 65:1337—1346. Kuehn, BM. (2009) FDA warning: remove drug patches before MRI to prevent burns to skin. JAMA. 301(13):1328.

TRANSDERMAL NICOTINE PATCH: ADD’L PATIENT EDUCATION (cont’d)
Common adverse effects include: Irritation at the patch application site (generally within the first hour) Mild itching Burning Tingling Sleep disturbances Abnormal or vivid dreams Insomnia Shortly after applying the nicotine patch, patients may experience irritation at the patch application site Mild itching Burning Tingling These effects are common and generally resolve within an hour. Additional possible side effects (associated with stimulating effect of nocturnally delivered nicotine) include the following: Abnormal or vivid dreams Insomnia Patients should be advised to remove the patch at bedtime if these adverse reactions become troublesome Mills EJ, Wu P, Lockhart I, Wilson K, Ebbert JO. (2010). Adverse events associated with nicotine replacement therapy (NRT) for smoking cessation. A systematic review and meta-analysis of one hundred and twenty studies involving 177,390 individuals. Tob Induc Dis. 13;8:8. Hartmann-Boyce J, Chepkin SC, Ye W, Bullen C, Lancaster T. (2018) Nicotine replacement therapy versus control for smoking cessation. Cochrane Database Syst Rev. 2018;5:CD

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 (Fiore et al., 2008). Reactions are generally mild, and fewer than 5% of patients discontinue therapy (Fiore et al., 2008).: 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 generally not use the nicotine patch. 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.

TRANSDERMAL NICOTINE PATCH: SUMMARY
ADVANTAGES 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 Relatively inexpensive 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 is 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 Relatively inexpensive compared to other treatment approaches, and is generally less than the cost of a pack of cigarettes 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.

NICOTINE INHALER Nicotrol Inhaler
Nicotine 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, 2016). 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). Pfizer Inc. (2016, July). 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.

NICOTINE INHALER: SCHEMATIC DIAGRAM
Air/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.

NICOTINE INHALER: DOSING
Initial treatment (up to 12 weeks) Start 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 Gradually reduce daily dosage over the following 6–12 weeks Recommended maximum duration of therapy is 6 months 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, 2016). 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 initial 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. The maximum total recommended duration of therapy is 6 months. Pfizer Inc. (2016, July). Nicotrol Inhaler Package Insert. New York, NY.

NICOTINE INHALER: DIRECTIONS for USE
Align 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. Pfizer Inc. (2016, July). Nicotrol Inhaler Package Insert. New York, NY.

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. Pfizer Inc. (2016, July). Nicotrol Inhaler Package Insert. New York, NY.

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. Pfizer Inc. (2016, July). Nicotrol Inhaler Package Insert. New York, NY. 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

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. Pfizer Inc. (2016, July). Nicotrol Inhaler Package Insert. New York, NY.

NICOTINE INHALER: ADDITIONAL PATIENT EDUCATION
Adverse effects associated with the nicotine inhaler include: Mild irritation of the mouth or throat Cough Hiccups Gastrointestinal complaints (dyspepsia, nausea) Severity generally rated as mild, and frequency of symptoms declined with continued use When initiating treatment, local irritation of the mouth or throat and cough 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, 2016). Other common adverse effects include gastrointestinal complaints (dyspepsia, nausea) and hiccups (Mills et al, 2010; Hartmann-Boyce et al, 2018). 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. Hartmann-Boyce J, Chepkin SC, Ye W, Bullen C, Lancaster T. (2018). Nicotine replacement therapy versus control for smoking cessation. Cochrane Database Syst Rev. 5:CD Mills EJ, Wu P, Lockhart I, Wilson K, Ebbert JO. (2010). Adverse events associated with nicotine replacement therapy (NRT) for smoking cessation. A systematic review and meta-analysis of one hundred and twenty studies involving 177,390 individuals. Tob Induc Dis.13;8:8. Pfizer Inc. (2016, July). Nicotrol Inhaler Package Insert. New York, NY.

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, 2016). 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. (2016, July). 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.

NICOTINE INHALER: SUMMARY
ADVANTAGES 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) Cost of treatment 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). Cost of treatment is usually more than the cost of smoking a pack of cigarettes per day.

NICOTINE NASAL SPRAY Nicotrol NS
Aqueous 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, 2016). 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). 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. (2016, July). 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.

NICOTINE NASAL SPRAY: DOSING & ADMINISTRATION
One dose = 1 mg nicotine (2 sprays, one 0.5 mg spray in each nostril) Start with 1–2 doses per hour Increase as needed to maximum dosage of 5 doses per hour or 40 mg (80 sprays; ~½ bottle) daily At least 8 doses daily for the first 6–8 weeks Termination: Gradual tapering over an additional 4–6 weeks Recommended maximum duration of therapy is 3 months 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. The total recommended maximum duration of therapy is 3 months. Pfizer Inc. (2016, July). Nicotrol NS Package Insert. New York, NY.

NICOTINE NASAL SPRAY: DIRECTIONS for USE
Press 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.

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. Pfizer Inc. (2016, July). Nicotrol NS Package Insert. New York, NY.

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. Pfizer Inc. (2016, July). Nicotrol NS Package Insert. New York, NY.

NICOTINE NASAL SPRAY: ADDITIONAL PATIENT EDUCATION
What to expect (first week): Hot peppery feeling in back of throat or nose Sneezing Coughing Watery eyes Runny nose Adverse 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 adverse effects persist after a week, contact health care provider and consider alternative treatment What to expect during first week (Pfizer, 2016): 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 adverse 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. Hartmann-Boyce J, Chepkin SC, Ye W, Bullen C, Lancaster T. (2018). Nicotine replacement therapy versus control for smoking cessation. Cochrane Database Syst Rev. 2018;5:CD Pfizer Inc. (2016, July). Nicotrol NS Package Insert. New York, NY.

NICOTINE NASAL SPRAY: SUMMARY
ADVANTAGES 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 Cost of treatment 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. Cost of treatment is usually more than the cost of smoking a pack of cigarettes per day.

BUPROPION SR: Generics
Non-nicotine cessation aid Mechanism of action: atypical antidepressant thought to affect levels of various brain neurotransmitters Dopamine Norepinephrine Clinical effects  craving for cigarettes  symptoms of nicotine withdrawal 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, 2017). The same chemical agent is marketed as Wellbutrin for use in treating depression. 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 (Fiore et al., 2008). Bupropion may also function as a nicotinic receptor antagonist (Slemmer et al, 2000). These actions clinically 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. GlaxoSmithKline Inc. (2017, May). Zyban Package Insert. Research Triangle Park, NC. Slemmer JE, Martin BR, Damaj MI. (2000). Bupropion is a nicotinic antagonist. J Pharmacol Exp Ther. 295(1):321–327.

BUPROPION: PHARMACOKINETICS
Absorption Bioavailability: 5–20% Metabolism Undergoes extensive hepatic metabolism (CYP2B6) Elimination Urine (87%) and feces (10%) Half-life Bupropion (21 hours); metabolites (20–37 hours) Absorption: Animal data suggest the absolute bioavailability of bupropion ranges from 5 to 20%. Metabolism: Bupropion undergoes extensive hepatic metabolism to three active metabolites. One of the metabolites, hydroxybupropion, is formed by the cytochrome P450 isoenzyme CYP2B6. Elimination: Bupropion and metabolites are eliminated in urine (87%) and feces (10%). Less than 1% of an oral dose of bupropion is excreted unchanged in urine. Half-life: 21 hours (bupropion); 20–37 hours (metabolites). Steady-state plasma concentrations of bupropion are reached within 8 days. ♪ Note to instructor(s): Drug Interactions (GlaxoSmithKline, 2017) Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between bupropion and drugs that are inhibitors of CYP2B6 (ticlopidine, clopidogrel) or inducers of CYP2B6 (ritonavir, lopinavir, efavirenz, and possibly carbamazepine, phenobarbital, phenytoin) Bupropion and its metabolites are CYP2D6 inhibitors which can affect the metabolism of drugs that are substrates of CYP2D6 including: certain antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone and flecainide). Levodopa and amantadine: CNS toxicity has been reported when bupropion was coadministered with levodopa or amantadine. Adverse reactions have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. Monoamine oxidase (MAO) inhibitors (isocarboxazid [Marplan]), phenelzine [Nardil], tranylcypromine [Parnate]): Bupropion inhibits the reuptake of dopamine and norepinephrine. Concomitant use of MAOIs and bupropion is contraindicated because there is an increased risk of hypertensive reactions if bupropion is used concomitantly with MAO inhibitors. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with bupropion. Conversely, at least 14 days should be allowed after stopping bupropion before starting an MAO inhibitor intended to treat psychiatric disorders. Drugs that lower the seizure threshold: use extreme caution when co-administering bupropion with agents that lower the seizure threshold (e.g., antipsychotics, tricyclic antidepressants, theophylline, systemic corticosteroids). Conditions altering metabolism/elimination (GlaxoSmithKline, 2017) Renal Impairment: The elimination of the major metabolites of bupropion may be reduced by impaired renal function. Use with caution in patients with renal impairment and a reduced frequency and/or dose should be considered. Hepatic Impairment: In patients with moderate to severe hepatic impairment, the maximum dose of bupropion is 150 mg every other day. In patients with mild hepatic impairment, consider reducing the dose and/or frequency of dosing. GlaxoSmithKline Inc. (2017, May). Zyban Package Insert. Research Triangle Park, NC.

BUPROPION: CONTRAINDICATIONS
Patients 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, 2017): In patients with a seizure disorder. In patients with a current or prior diagnosis of eating disorders (e.g., bulimia or anorexia nervosa) as a higher incidence of seizures was observed in patients treated with the immediate-release formulation of bupropion for bulimia (Horne et al., 1988). 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 (Marcucci et al., 2004). GlaxoSmithKline Inc. (2017, May). Zyban Package Insert. Research Triangle Park, NC. Horne RL, Ferguson JM, Pope HG Jr, Hudson JI, Lineberry CG, et al. (1988). Treatment of bulimia with bupropion: a multicenter controlled trial. J Clin Psychiatry. 49(7):262–266. Marcucci C, Sandson NB, Dunlap JA. (2004). Linezolid-bupropion interaction as possible etiology of severe intermittent intraoperative hypertension? Anesthesiology. 101(6):1487–1488.

BUPROPION: WARNINGS and PRECAUTIONS
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, 2017). Bupropion also should be used cautiously in patients with severe hepatic impairment (GlaxoSmithKline, 2017). 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, 2017). 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. (2017, May). Zyban Package Insert. Research Triangle Park, NC. For a comprehensive listing of warnings and precautions, refer to the manufacturer’s prescribing information.

BUPROPION: WARNINGS and PRECAUTIONS (cont’d)
Neuropsychiatric 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). Based on results from an FDA-mandated clinical trial, the box associated with this warning was removed on December 16, 2016. 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, 2017). 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 bupropion SR 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 (formerly marketed as Zyban, Wellbutrin, and generics). Available at: Retrieved December 26, 2018. GlaxoSmithKline Inc. (2017, May). 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.

BUPROPION SR: DOSING Initial treatment Then… 150 mg po q AM for 3 days
To ensure that therapeutic plasma levels of the drug are achieved, patients should begin therapy 1 to 2 weeks PRIOR to their quit date. 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, 2017). 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, 2017). 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. (2017, May). 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. 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

BUPROPION: ADVERSE EFFECTS
Common adverse effects include the following: Insomnia (avoid bedtime dosing) Dry mouth Nausea Less common but reported effects: Anxiety/difficulty concentrating Constipation Tremor Skin rash The most commonly observed adverse reactions include insomnia (30–40%), dry mouth (10%) and nausea (10%). These adverse reactions might be minimized by reducing the dose. Insomnia might be minimized by avoiding bedtime administration (GlaxoSmithKline, 2017). Adverse effects that are less common but sometimes lead to discontinuation of treatment include nervous system disturbances (3–9%; primarily anxiety, difficulty concentrating, nervousness, tremors), constipation (8–9%) and skin disorders (3%; primarily rashes) (GlaxoSmithKline, 2017). ♪ 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, 2017). GlaxoSmithKline Inc. (2017, May). 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

BUPROPION SR: SUMMARY ADVANTAGES DISADVANTAGES
Oral 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 Relatively inexpensive (generic formulations) 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 Relatively inexpensive (generally less than the cost of a pack of cigarettes) 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

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, 2018) Varenicline is a partial agonist selective for the 42 nicotinic acetylcholine receptor indicated for use as an aid to smoking cessation treatment. Pfizer Inc. (2018, June). Chantix Package Insert. New York, NY.

VARENICLINE: MECHANISM of ACTION
Binds 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, 2018). ♪ 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., 2016; Hajek et al, 2013; Walker et al, 2014). Cahill K, Lindson-Hawley N, Thomas KH, Fanshawe TR, Lancaster T. (2016). Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 5: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. (2018, June). 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.

VARENICLINE: PHARMACOKINETICS
Absorption Virtually complete (~90%) after oral administration; not affected by food Metabolism Undergoes minimal metabolism Elimination Primarily renal through glomerular filtration and active tubular secretion; 92% excreted unchanged in urine Half-life 24 hours Absorption: absorption is virtually complete after oral administration (~90%), and oral bioavailability is unaffected by food or time-of-day dosing. Metabolism: Varenicline undergoes minimal metabolism, with 92% excreted unchanged in the urine. Elimination: Renal elimination of varenicline is primarily through glomerular filtration along with active tubular secretion possibly via the organic cation transporter, OCT2. Half-life: ~24 hours; following administration of multiple oral doses of varenicline, steady-state conditions are reached within 4 days. Pfizer Inc. (2018, June). Chantix Package Insert. New York, NY.

VARENICLINE: WARNINGS and PRECAUTIONS
Neuropsychiatric 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). Based on results from an FDA-mandated clinical trial, the box associated with this warning was removed on December 16, 2016. 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, 2018). 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, 2018). 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 (2018, June). Information for healthcare professionals: varenicline (marketed as Chantix) and bupropion (marketed as Zyban, Wellbutrin, and generics). Available at: Retrieved December 29, 2018. Pfizer Inc. (2018, June). Chantix Package Insert. New York, NY. Advise patients to stop taking varenicline 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.

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 Somnambulism Angioedema and hypersensitivity reactions Serious skin reactions In some patients, use of varenicline has been associated with the following (Pfizer, 2018): 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. More recent data, published in 2018, indicate no evidence that cessation medications increase risk for serious cardiovascular disease or cardiovascular adverse events (did not include patients with acute or unstable cardiovascular disease), and in the general population of individuals who smoke, the benefit of improved cardiovascular health from medication-assisted cessation exceeds the risk of medication-induced cardiovascular harm (Benowitz et al., 2018). Somnambulism (sleepwalking): Cases of somnambulism have been reported and included harmful behavior to self, others, or property. 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 varenicline; see adverse effects slide for additional information. Benowitz NL, Pipe A, West R, Hays JT, Tonstad S, McRae T, Lawrence D, St Aubin L, Anthenelli RM. (2018). Cardiovascular safety of varenicline, bupropion, and nicotine patch in smokers: A randomized clinical trial. JAMA Intern Med. 1:178(5):622–631, Pfizer Inc. (2018, June). Chantix Package Insert. New York, NY. These are rare events and most have not been causally linked to varenicline use.

VARENICLINE: STANDARD DOSING
Patients should begin therapy 1 week PRIOR to their quit date. The dose is gradually increased to minimize treatment-related nausea and insomnia. In general, 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 ♪ 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. (2018, June). Chantix Package Insert. New York, NY. 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 Initial dose titration * Up to 12 weeks

VARENICLINE QUIT APPROACHES
FIXED QUIT approach Set quit date for 1 week after starting varenicline Continue treatment for 12 weeks FLEXIBLE QUIT approach Start taking varenicline and pick a quit date between 8 to 35 days from treatment initiation GRADUAL QUIT approach Start taking varenicline and reduce smoking by 50% within the first 4 weeks, an additional % in the next 4 weeks, and continue until complete abstinence by 12 weeks While most patients use the standard dosing of varenicline for smoking cessation (e.g., “fixed quit” approach), there are three dosing regimens described in the product package insert: Fixed Quit Approach As described previously, for this approach patients must set a quit date for 1 week after initiating varenicline, and treatment is continued for 12 weeks. Flexible Quit Approach Begin therapy and then quit smoking between days 8–35 of treatment (Pfizer, 2018). Gradual Quit Approach For patients who are not able to or willing to quit abruptly, consider a gradual approach to quitting smoking. Initiate varenicline and reduce smoking by 50% from baseline within the first four weeks, by an additional 50% in the next four weeks, and continue reducing with the goal of reaching complete abstinence by 12 weeks. Continue treatment for an additional 12 weeks, for a total of 24 weeks (Pfizer, 2018). In general, the flexible and gradual quit approaches should be reserved for individuals who might need more confidence prior to quitting completely completely or those who experienced some success with a prior attempt with varenicline and is a candidate for re-treatment. Regardless of the approach selected, it is advisable that the cessation counselor work with the patient to establish a firm quit date and, for the gradual quit approach, specify dates on which the patient will implement reductions in the number of cigarettes smoked per day. Pfizer Inc. (2018, June). Chantix Package Insert. New York, NY. Images from: 212

VARENICLINE: ADVERSE EFFECTS
Common adverse effects include the following: Nausea Insomnia Abnormal dreams Headache Less common adverse effects: Gastrointestinal (flatulence, constipation) Taste alteration Common side effects, and observed significantly more frequently in varenicline treated patients compared to those receiving placebo (Cahill et al, 2016) include: Nausea (28%) Insomnia (13%) Abnormal (vivid, unusual, or strange) dreams (13%) Headache (12%) Less common, but reported more frequently in varenicline treated patients compared to those receiving placebo (Pfizer, 2018): Gastrointestinal complaints include flatulence (6–9%) and constipation (5–8%) Dysgeusia (taste alteration; 5–8%) ♪ 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. Cahill K, Lindson-Hawley N, Thomas KH, Fanshawe TR, Lancaster T. (2016). Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 5:CD Pfizer Inc. (2018, June). Chantix Package Insert. New York, NY.

VARENICLINE: ADDITIONAL PATIENT EDUCATION
Doses 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. (2018, June). Chantix Package Insert. New York, NY.

VARENICLINE: SUMMARY ADVANTAGES DISADVANTAGES
Oral dosing is simple and associated with fewer adherence problems Offers a different mechanism of action for persons who have failed other agents Most effective agent for cessation when used as monotherapy DISADVANTAGES Cost of treatment Patients should be monitored for potential neuropsychiatric symptoms 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 Most effective agent for smoking cessation with used a monotherapy (Cahill et al., 2013) Disadvantages of varenicline include the following: Cost of treatment is more than with other agents and more than the cost of smoking a pack of cigarettes per day Post-marketing surveillance data indicate potential for neuropsychiatric symptoms and adverse effects not shown to be prevalent in randomized trials Cahill K, Stevens S, Perera R, Lancaster T. (2013). Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev 31;(5):CD

LONG-TERM (6 month) QUIT RATES for AVAILABLE CESSATION MEDICATIONS
28.5 23.9 21.0 19.7 This bar chart summarizes the long-term (≥6-month) quit rates observed with the different NRT products, bupropion SR and varenicline (Hughes et al., 2014; Cahill et al., 2016; Hartmann-Boyce et al., 2018). These data are derived from >200 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 including: 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, Lindson-Hawley N, Thomas KH, Fanshawe TR, Lancaster T. (2016). Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 5:CD Hartmann-Boyce J, Chepkin SC, Ye W, Bullen C, Lancaster T. (2018). Nicotine replacement therapy versus control for smoking cessation. Cochrane Database Syst Rev. 2018;5:CD Hughes JR, Stead LF, Hartmann-Boyce J, Cahill K, Lancaster T. (2014). Antidepressants for smoking cessation. Cochrane Database Syst Rev 1:CD 17.1 16.3 Percent quit 15.7 12.9 11.8 12.4 11.5 10.0 9.4 9.1 Data adapted from Hartmann-Boyce et al. (2018). Cochrane Database Syst Rev; Cahill et al. (2016). Cochrane Database Syst Rev; Hughes et al. (2014). Cochrane Database Syst Rev

COMBINATION PHARMACOTHERAPY
Regimens 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, lozenge, nasal spray) Allows for acute dose titration as needed for nicotine withdrawal symptoms Bupropion SR + Nicotine Patch While the use of first- and second-line medications approximately doubles the likelihood that a patient will successfully quit smoking, data from clinical trials suggest that only 19–33% of patients remain abstinent six 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 2008 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 likely delivers sub-therapeutic nicotine levels for many 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 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 1.3–1.6 times as likely to remain abstinent when compared with patients who use single-agent NRT (Cahill, et al., 2013). Similarly, quit rates with combination therapy that included NRT (gum, patch, lozenge) and bupropion SR were 1.5 times those attained with bupropion SR alone (Cahill et al., 2013). ♪ 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 one-year follow up compared with varenicline alone (Ebbert et al., 2014). While 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. Cahill K, Stevens S, Perera R, Lancaster T. (2013). Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev 31;(5):CD 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, 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 312:155–61. 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.

TREATMENT OPTIONS Multiple Treatment Comparison Meta-Analysis
Odds ratio (95% CI) Nicotine gum vs Placebo 1.7 (1.5–1.9) Bupropion SR vs Placebo 1.9 (1.6–2.1) Nicotine patch vs Placebo 1.9 (1.7–2.1) Other NRT* vs Placebo 2.0 (1.8–2.4) Combination NRT vs Placebo 2.7 (2.1–3.7) Varenicline vs Placebo 2.9 (2.4–3.5) Here we summarize the results of a meta-analyses for monotherapy and combination NRT versus placebo (Cahill et al., 2013). While all of the approaches exhibit odds of quitting that are higher than placebo, there is strong evidence that combination NRT and varenicline are the most effective. Although patient preference is a key factor for regimen selection, these higher odds ratios are clinically significant. As such, the differential efficacy should be considered when providing guidance to patients who are attempting to quit. Cahill K, Stevens S, Perera R, Lancaster T. (2013). Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev 31;(5):CD009329 *Includes nicotine nasal spray, lozenge, and inhaler Strong evidence that combination NRT and varenicline are more effective than bupropion SR or NRT monotherapy Cahill et al. (2013). Cochrane Database Syst Rev 5:CD

COMBINATION NRT: TREATMENT REGIMENS PLUS Nicotine patch
Dose: 21 mg/day x 4–6 wks  14 mg/day x 2 wks  7 mg/day x 2 wks PLUS Nicotine gum or lozenge (2 mg/4 mg; based on TTFC) Dose: Use 1 piece q 1–2 hours as needed (use at least 4-5/day) OR Nicotine inhaler (10 mg cartridge; delivers 4 mg nicotine vapor) Dose: Use 1 cartridge q 1–2 hours as needed Nicotine nasal spray (0.5 mg/spray) Dose: Use 1 spray in each nostril q 1–2 hours as needed Evidence based combination NRT treatment options are presented on this slide. The nicotine patch serves as the ‘backbone’ for combination therapy, because it provides a consistent release of nicotine throughout the day. Short-acting nicotine replacement products such as the gum, lozenge, inhaler, or nasal spray are used as needed for nicotine withdrawal symptoms or when patients experience situational urges or cravings for tobacco. Combination NRT should be reserved for patients smoking more than ½ pack of cigarettes per day, and the starting dose of the patch should be 21 mg/day for the initial 4–6 weeks and tapered over an additional 4 weeks. Short-acting nicotine replacement agents are dosed using the standard doses for the products but rather than being administered on a fixed schedule, they are only used every 1–2 hours if needed for break-through nicotine withdrawal symptoms. Selection of the short-acting NRT agent should be based largely on patient preference. 219

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 licensed prescriber 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 8 or 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.

Medication adherence should be addressed at each encounter.
“Drugs don’t work… …in patients who don’t take them.” As stated by former U.S. Surgeon General, C. Everett Koop, M.D., “Drugs don’t work in patients who don’t take them.” This holds true for cessation medications. Medication counseling should always include a discussion about the patient’s ability to adhere to a given regimen as well as the importance of adherence in increasing their odds of long-term success. C. Everett Koop, M.D., former U.S. Surgeon General Medication adherence should be addressed at each encounter.

ADHERENCE IS KEY to QUITTING
Promote adherence with prescribed regimens Daily use (use according to dosing schedule, NOT as needed) Full duration of treatment regimen Consider telling the patient: “If used properly, the medicines can make you more comfortable while you are quitting.” “Medicines for quitting work best if you take them on a regular schedule, to prevent withdrawal symptoms before they occur. If you wait until you’re already craving a cigarette, it will be too late. The medicines don’t work as quickly as inhaled nicotine from a cigarette.” 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). Some recommended language is provided on this slide. 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, Huynh-Ba M, Fallab Stubi CL, Iorillo D, 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.

ADHERENCE IS KEY to QUITTING (cont’d)
When providing medication counseling, it is important to emphasize three key facets of adherence: Correct strength of medication Taken daily, according to a fixed schedule Taken for the full duration of therapy When providing medication counseling, clinicians should emphasize the importance of adherence to the medical regimens. This includes three key facets: Selecting the correct strength of the medication. For the non-prescription NRT products, the number of cigarettes smoked per day must be assessed for selection of the nicotine patch strength, and the time-to-first cigarette of the day must be assessed for selection of the strength of the nicotine gum and lozenge. Because these medications are intended for use to prevent withdrawal, it is essential that patients adhere to a fixed dosing schedule. When the medications are used to treat withdrawal after it occurs, they are less effective because they do not work as rapidly as nicotine inhaled from a cigarette. For short-acting NRT, which are generally dosed every 1–2 hours while awake, patients can be advised to set an alarm on their watch or smartphone to indicate when it is time for their next dose. All medications have a recommended duration of therapy, and patients should be advised to complete the full regimen to enhance their odds of remaining quit for the long-term. Explaining the rationale for use of a medication, to keep them comfortable while they are quitting while they are learning how to modify their behavior, is a useful approach to helping the patient “make sense” of why several months of medication/treatment is needed. For non-prescription medications, patients should be encouraged to carefully read the product packaging to supplement and re-emphasize what they learn from the clinician. When working prospectively with patients, it is important to assess withdrawal symptoms and adjust treatment as needed. In doing so, be cognizant of differences between the physical withdrawal (and the associated timeline for withdrawal symptoms to occur) versus behavioral challenges, which are best addressed with behavioral coping strategies. At each encounter, assess withdrawal and adjust treatment as needed.

COMPARATIVE DAILY COSTS of PHARMACOTHERAPY
Average $/pack of cigarettes in the US, $6.26 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 NRT (gum, lozenge, nasal spray, or oral inhaler). As a comparison, the cost for one pack of cigarettes (national average, approximately $6.26) is shown (Campaign for Tobacco-Free Kids, 2018). 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 (Redbook, 2018). Campaign for Tobacco-Free Kids. (2018). “State Cigarette Excise Tax Rates & Rankings.” Retrieved January 17, 2019, from Red Book Online. (2019, January). New York, NY: Thomson Reuters. $/day *Wholesale acquisition cost from Red Book Online. Thomson Reuters, January 2019.

SUMMARY To maximize success, interventions should include behavioral counseling and one or more medications 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: Bupropion SR Nicotine replacement therapy (as monotherapy or combination therapy) Varenicline Varenicline and combination NRT approaches demonstrate the highest level of efficacy 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: Bupropion SR Nicotine replacement therapy (gum, lozenge, patch, nasal spray, inhaler) Varenicline Varenicline and combination nicotine replacement therapy approaches demonstrate the highest level of efficacy.

Rx for CHANGE Clinician-Assisted Tobacco Cessation

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Rx for CHANGE Clinician-Assisted Tobacco Cessation

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