Tobacco Use and Dependence 88 Robin L

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Tobacco Use and Dependence 88 Robin L. Corelli and Karen Suchanek Hudmon

CORE PRINCIPLES

CHAPTER CASES

1 Cigarette smoking is the single most preventable cause of premature death in the Case 88-2 (Questions 1, 4), United States, responsible for one in every ﬁve deaths. Smoking harms nearly every Case 88-3 (Question 1), organ of the body, causing many diseases (including, but not limited to, Case 88-5 (Question 1), cardiovascular disease, pulmonary disease, and cancers) and reducing the health of Case 88-6 (Question 1) smokers in general. Quitting smoking has immediate as well as long-term beneﬁts, reducing risks for diseases caused by smoking and improving health in general.

2 Tobacco products are effective delivery systems for the drug nicotine. Nicotine is a Case 88-1 (Questions 2, 4), highly addictive drug that activates the dopamine reward pathway in the brain that Case 88-3 (Question 1), reinforces continued tobacco use. Nicotine withdrawal symptoms (e.g., irritability, Case 88-6 (Questions 1, 2) anxiety, difﬁculty concentrating, restlessness, depressed mood, insomnia, impaired performance, increased appetite or weight gain, cravings) generally occur when nicotine is discontinued.

3 Constituents in tobacco smoke are associated with a number of clinically signiﬁcant Case 88-4 (Questions 1, 3), drug interactions. Case 88-6 (Question 3)

4 Tobacco dependence, a chronic disease that often requires repeated intervention Case 88-1 (Question 5), and multiple attempts to quit, is characterized by physiological dependence Case 88-2 (Question 3), (addiction to nicotine) and behavioral habit of using tobacco. Case 88-3 (Question 1)

5 Numerous effective medications, as delineated in the Clinical Practice Guideline, Case 88-1 (Questions 1–3), are available for treating tobacco use and dependence. Most patients should be Case 88-2 (Questions 3, 4), encouraged to use one or more first-line agents, which include the nicotine patch, Case 88-3 (Question 1), nicotine gum, nicotine lozenge, nicotine nasal spray, nicotine oral inhaler, Case 88-4 (Question 2), sustained-release bupropion, and varenicline. All first-line agents approximately Case 88-6 (Questions 1, 4) double quit rates, and therefore the choice of therapy is based largely on contraindications, precautions, patient preference, and tolerability of the available dosage forms. In some cases, medications can be combined or used for extended durations. Although complementary therapies are available, these are not recommended because of insufficient evidence of efficacy.

6 Comprehensive counseling, as deﬁned by the Clinical Practice Guideline, includes Case 88-1 (Questions 2, 5), asking about tobacco use, advising patients to quit, assessing readiness to quit, Case 88-3 (Question 1), assisting patients with quitting, and arranging follow-up. This approach is referred Case 88-5 (Question 1), to as “The 5 A’s.” Counseling and support can be provided a variety of ways, such Case 88-6 (Questions 1, 2, 4) as through individual counseling, group programs, telephone, or the Internet. Two components of counseling are especially effective and should be applied when assisting patients with quitting: practical counseling (problem solving or skills training) and social support delivered as part of treatment. Relapse is common, and clinicians should work with patients throughout the quit attempt to increase the chances for long-term abstinence.

continued

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2056 CHAPTER CASES

7 Brief tobacco-dependence treatment (<3 minutes) is effective. In the absence of Case 88-5 (Question 1) time or expertise, ask about tobacco use, advise patients to quit, and refer patients to other resources (e.g., telephone quitlines, web-based support, local programs) for additional assistance. This approach is referred to as “Ask-Advise-Refer.”

8 Patients with psychiatric disorders exhibit a higher prevalence of tobacco use and a Case 88-6 (Question 1) disproportionately high level of tobacco-related morbidity and mortality.

9 Cigarettes are the most common form of tobacco used in the United States; Case 88-2 (Question 2), however, other forms of tobacco exist (spit tobacco, pipes, cigars, bidis, hookah). Narrated PowerPoint All forms of tobacco are harmful. slides on Forms of Tobacco

Long before Christopher Columbus traveled to the New World, lent: smokeless tobacco (chewing tobacco, oral snuff), pipes, tobacco use was widespread in the Americas—tobacco prepara- cigars, clove cigarettes, bidis, hookah, and electronic cigarettes tions were part of religious ceremonies for the Native Ameri- (“e-cigarettes”). Among adults, smoking prevalence varies by cans, and tobacco was also used medicinally. At that time, and sociodemographic factors, including sex, race or ethnicity, edu- for several subsequent centuries, little was known or suspected cation level, age, and poverty level. The Centers for Disease Con- about the dangers of tobacco use. In retrospect, it is not sur- trol and Prevention (CDC) reported that in 2009, the percent- prising that these dangers were not recognized initially because age of current smokers (defined as having smoked 100 or more the more pressing health issues at that time were related to life- cigarettes during their lifetime and currently smoking every day threatening, acute diseases as opposed to chronic diseases such or some days) was 20.6% (23.5% of men and 17.9% of women).9 as those imposed by tobacco. However, it is now well established Table 88-1 summarizes the smoking prevalence estimates for that tobacco is a detrimental substance, and its use dramatically various population subgroups, stratified by sex.9 An estimated increases a person’s odds of dependence, disease, disability, and 44.3% of cigarettes smoked in the United States are among per- death. sons with mental illness,10 with the prevalence of smoking being Cigarettes are the only marketed consumable product that 2 to 4 times higher among patients with psychiatric and substance when used as intended will contribute to the death of half or use disorders.11 more of its users.1 Tobacco products are carefully engineered formulations that optimize the delivery of nicotine, a chemical eto 16 Section that meets the criteria for an addictive substance: (a) nicotine For a narrated PowerPoint presentation on induces psychoactive effects, (b) it is used in a highly controlled forms of tobacco, go to http://thepoint.lww. or compulsive manner, and (c) behavioral patterns of tobacco com/AT10e. use are reinforced by the pharmacologic effects of nicotine.2 As a major risk factor for a wide range of diseases, including cardiovascular conditions, cancers, and pulmonary disorders, tobacco Experimentation with cigarettes and the development of reg- usac Abuse Substance is the primary known preventable cause of premature death in 3 ular smoking typically occur during adolescence; in 2007, 59.7% our society. During the 20th century, 100 million deaths were of new smokers were younger than the age of 18 when they caused by tobacco, and currently,an estimated 5.4 million deaths 12 3 smoked their first cigarette. Because most teens who smoke occur annually. Unless tobacco control efforts are able to reverse at least monthly continue to smoke in adulthood,13 tobacco use this trend, the number of annual deaths is likely to exceed 8 4 trends among youth are a key indicator of the overall health million by the year 2030. According to Dr. Margaret Chan, trends for the nation.14 According to the CDC, the prevalence of Director-General of the World Health Organization, “Reversing current smoking (defined as having smoked at least one cigarette this entirely preventable epidemic must now rank as a top priority in the preceding 30 days) among high school students increased for public health and for political leaders in every country of the 15 4 throughout the early and mid-1990s, identifying an urgent world.” need for tobacco prevention and cessation programs focused on In the United States, smoking is responsible for approximately 5 younger age groups. Subsequent decreases occurred, but overall 443,000 premature deaths each year. In addition to the harm the rate of decline has slowed substantially in recent years.15 In imposed on users of tobacco, exposure to secondhand smoke 5,6 2009, an estimated 25.2% of 12th graders had smoked one or results in an estimated 50,000 deaths each year. According to more cigarettes in the past 30 days; combining grades 9 through the Office of the US Surgeon General, there is no risk-free level of 7 12, the prevalence of current smoking was higher among males exposure to tobacco smoke. Because of the health and societal (19.4%) than among females (16.7%).12 burdens that it imposes, tobacco use and dependence should Despite tobacco control efforts at the state and national levels, be addressed during each clinical encounter with all tobacco 8 only a few subgroups have met the Healthy People 2010 target goal users. of ≤12% smoking prevalence.14 In 2009, the highest statewide median prevalence of current smoking was evident in West Virginia and Kentucky (25.6%), and the lowest prevalence was EPIDEMIOLOGY OF TOBACCO USE evident in Utah (9.8%).16 Although much of tobacco control is AND DEPENDENCE coordinated through the states, the extent to which tobacco control is addressed in states’ cancer control plans is highly variable, In the United States, cigarettes are the most common form and there is significant room for improvement in compliance of tobacco that is consumed, but other forms are also preva- with the CDC’s tobacco-related recommendations.17 P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

2057 TABLE 88-1 Percentage of Current Smokersa Ages 18 Years and Older, by Sex and Selected Characteristics—National Health Interview Survey, United States, 2009

Characteristic Category Men (n = 12,193) Women (n = 15,410) Total (n = 27,603)

Race/ethnicityb White, non-Hispanic 24.5 19.8 22.1 Black, non-Hispanic 23.9 19.2 21.3 Hispanic 19.0 9.8 14.5 American Indian/Alaska Native, non-Hispanicc 29.7 − 23.2 Asian, non-Hispanicd 16.9 7.5 12.0 Multiple race, non-Hispanic 33.7 24.8 29.5 Educatione 0–12 years (no diploma) 30.5 22.2 26.4 GED 53.2 44.7 49.1 High school graduate 29.0 21.5 25.1 Some college (no degree) 26.1 21.0 23.3 Associate degree 20.6 19.1 19.7 Undergraduate degree 12.4 9.9 11.1 Graduate degree 4.9 6.3 5.6 Age group (years) 18–24 28.0 15.6 21.8 25–44 26.5 21.5 24.0 45–64 24.5 19.5 21.9 65 and older 9.5 9.5 9.5 Poverty status f At or above poverty level 22.2 16.7 19.4 Below poverty level 34.2 28.7 31.1 Unknown 22.3 13.2 17.3 Total 23.5 17.9 20.6

aPersons who reported having smoked ≥100 cigarettes during their lifetimes and who, at the time of interview, reported smoking every day or some days. Excludes 128 respondents whose smoking status was unknown. bExcludes 53 respondents of unknown race. cData for women not reported because of unstable percentages; relative standard error ≥30%. dDoes not include Native Hawaiians and Other Paciﬁc Islanders. ePersons ages 25 years and older, excluding 137 persons whose educational level was unknown. f Based on family income reported by respondents and 2008 poverty thresholds published by the US Census Bureau. GED, general educational development certiﬁcate. Adapted from Centers for Disease Control and Prevention. Vital signs: current cigarette smoking among adults aged ≥18 years—United States, 2009. MMWR Morb Mortal Wkly Rep. 2010;59(35):1135.

22 Factors Contributing to Tobacco Use apKa of 8.0. In acidic media, nicotine is ionized and poorly absorbed; conversely, in alkaline media, nicotine is nonionized 18,19 Tobacco addiction is maintained by nicotine dependence. and well absorbed. Under physiological conditions (pH = 7.4), a

Nicotine induces a variety of pharmacologic effects, described large proportion of nicotine is nonionized and readily crosses cell Chapter 88 19 as follows, that lead to dependence. However, tobacco depen- membranes.22 Given the relation between pH and absorption, dence is not simply a matter of nicotine pharmacology—it is a the tobacco industry and pharmaceutical companies are able to result of the interplay of complex processes, including the desire titrate the pH of their tobacco products and nicotine replacement for the direct pharmacologic actions of nicotine, the relief of therapy (NRT) products to maximize the absorption potential withdrawal, learned associations, and environmental cues (e.g., of nicotine.22–24 advertising, the smell of a cigarette, or observing others who Once absorbed, nicotine induces a variety of central nervous 19 are smoking). Physiological factors, such as pre-existing med- system, cardiovascular, and metabolic effects. Nicotine stimu- 10,11,19 ical conditions (e.g., psychiatric comorbidities ) and one’s lates the release of several neurotransmitters, inducing a range 20,21 geneticproﬁle,alsocanpredisposeindividualstotobaccouse. of pharmacologic effects such as pleasure (dopamine), arousal Notably, it has been estimated in twin studies that 40% to 60% (acetylcholine, norepinephrine), cognitive enhancement (acetyl- 20,21 of smoking is heritable. choline), appetite suppression (dopamine, norepinephrine, sero- Tobacco Use and Dependence The rapidity with which nicotine, the addictive component tonin),learning(glutamate),memoryenhancement(glutamate), of tobacco, is absorbed and passes through the blood-brain mood modulation (serotonin), and reduction of anxiety and barrier contributes to its addictive nature. After inhalation, tension (β-endorphin and γ -aminobutyric acid [GABA]).25 The 18 nicotine reaches the brain within seconds. As such, smok- dopamine reward pathway,a network of nervous tissue that elic- ers experience nearly immediate onset of the positive effects of its feelings of pleasure in response to certain stimuli, is central nicotine, including pleasure, relief of anxiety, improved task per- to drug-induced reward. Key structures of the reward pathway formance, improved memory, mood modulation, and skeletal include the ventral tegmental area, nucleus accumbens, and pre- 18 muscle relaxation. These effects, mediated by alterations in frontalcortex(theareaofthebrainthatisresponsibleforthinking neurotransmitter levels, reinforce continued use of nicotine- and judgment). The neurons of the ventral tegmental area con- 18,19 containing products. tain the neurotransmitter dopamine, which is released in the nucleus accumbens and in the prefrontal cortex. Immediately after inhalation, a bolus of nicotine enters the brain, stimulating Nicotine Pharmacology the release of dopamine, which induces nearly immediate feel- Nicotine (Nicotiana tabacum), which is composed of a pyridine ings of pleasure, along with relief of the symptoms of nicotine ring and a pyrrolidine ring, is one of the few natural alkaloids withdrawal. This rapid dose response reinforces repeated admin- , that exist in the liquid state. Nicotine is a clear, weak base with istration of the drug and perpetuates the smoking behavior.19 25 P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

2058 30

Pleasure/ Arousal

Neutral Zone Abstinence Plasma Nicotine Concentration (ng/mL) symptoms 0 8 AM 6 PM 4 AM Hour FIGURE 88-1 Nicotine addiction cycle throughout the day. s The sawtooth line represents venous plasma concentrations of nicotine as a cigarette is smoked every 40 minutes between 8 AM and 9 PM. s The upper solid line indicates the threshold concentration for nicotine to produce pleasure or arousal. s The lower solid line indicates the concentrations at which symptoms of abstinence (i.e., withdrawal symptoms) from nicotine occur. s The shaded area represents the zone of nicotine concentrations (neutral zone) in which the smoker is comfortable without experiencing either pleasure and arousal or abstinence symptoms. (Reprinted with permission from Benowitz NL. Cigarette smoking and nicotine addiction. Med Clin North Am. 1992;76(2):415.) Chronic administration of nicotine has been shown to result administration. The half-life of cotinine, however, is much longer in an increased number of nicotine receptors in speciﬁc regions (t1/2 = 18–20 hours), and for this reason, cotinine is commonly of the brain,26,27 which is believed to represent upregulation in usedasamarkeroftobaccouseaswellasamarkerforexposureto response to nicotine-mediated desensitization of the receptors secondhandsmoke.22 Measurementofcotininecannot,however, and may play a role in nicotine tolerance and dependence.25,27 differentiate between the nicotine from tobacco products and the

eto 16 Section Chronic administration also leads to tolerance of the behavioral nicotine from NRT products. Nicotine and other metabolites andcardiovasculareffectsofnicotineduringthecourseoftheday; are excreted in the urine. Urinary excretion is pH dependent; the however, tobacco users regain sensitivity to the effects of nico- excretion rate is increased in acidic urine.22 Nicotine crosses the tine after overnight abstinence from nicotine,18,19 as shown in placenta and accumulates in breast milk.22 Figure 88-1.28 After smoking the ﬁrst cigarette of the day, the smoker experiences marked pharmacologic effects, particularly Drug Interactions With Smoking

usac Abuse Substance arousal. No other cigarette throughout the day produces the same degree of pleasure or arousal. For this reason, many smok- It is widely recognized that polycyclic aromatic hydrocarbons ers describe the first cigarette as the most important one of the (PAHs), present in appreciably large quantities in tobacco smoke, day.Shortly after the initial cigarette, tolerance begins to develop. are responsible for most drug interactions with smoking.30,31 Accordingly,the threshold levels for both pleasure or arousal and PAHs, which are the products of incomplete combustion of abstinence rise progressively throughout the day as the smoker tobacco, are potent inducers of several hepatic cytochrome-P450 becomestoleranttotheeffectsofnicotine.Withcontinuedsmok- microsomal enzymes (CYP1A1, CYP1A2, and possibly CYP2E1). ing, nicotine accumulates, leading to an even greater degree of Although other substances in tobacco smoke, including acetone, tolerance. Late in the day,each individual cigarette produces only pyridines, benzene, nicotine, carbon monoxide, and heavy met- limited pleasure or arousal; instead, smoking primarily alleviates als (e.g., cadmium), might also interact with hepatic enzymes, nicotine withdrawal symptoms. Lack of exposure to nicotine their effects appear to be less significant. Most drug interactions overnight results in resensitization of drug responses (i.e., loss with tobacco smoke are pharmacokinetic, resulting from the of tolerance). Most dependent smokers tend to smoke a certain induction of drug-metabolizing enzymes (especially CYP1A2) number of cigarettes per day and tend to consume sufficient nico- by compounds in tobacco smoke. Table 88-2 summarizes key tineperdaytoachievethedesiredeffectsofcigarettesmokingand interactions with smoking.30–32 Patients who begin smoking, minimize the symptoms of nicotine withdrawal.19,28 Withdrawal quit smoking, or dramatically alter their level of smoking might symptoms, which include anger, anxiety, depression, difficulty require dosage adjustments for some medications. concentrating, impatience, insomnia, and restlessness, typically manifest within a few days after quitting, peak within a week, and subside within 2 to 4 weeks.29 Tobacco users become adept Health Consequences of Tobacco Use at titrating their nicotine levels throughout the day to avoid with- All forms of tobacco are harmful, and there is no safe level of drawal symptoms, maintain pleasure and arousal, and modulate exposure to tobacco products.7 Smoking has a causal or con- mood. tributory role in the development of a variety of medical condi- Nicotine is extensively metabolized in the liver and, to a lesser tions (Table 88-3).3,7 In the United States, tobacco use accounts extent, in the kidney and lung. Approximately 70% to 80% of for an estimated 443,595 deaths each year,5 and millions suffer nicotine is metabolized to cotinine, an inactive metabolite.22 The from chronic conditions attributable to smoking. Among current rapid metabolism of nicotine (half-life [t1/2] = 2 hours) to inactive smokers, emphysema is the most common condition (49.1%), compounds underlies tobacco users’ needs for frequent, repeated followed by chronic bronchitis (41.1%).33 Overall, an estimated P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

2059 TABLE 88-2 Drug Interactions With Smokinga

Drug/Class Mechanism of Interaction and Effects

Pharmacokinetic Interactions Alprazolam (Xanax) s Conflicting data on significance of a PK interaction, but possible ↓ plasma concentrations (up to 50%); ↓ half-life (35%). Bendamustine (Treanda) s Metabolized by CYP1A2. Manufacturer recommends using with caution in smokers because of likely ↓ bendamustine concentrations, with ↑ concentrations of its two active metabolites. Caffeine s ↑ Metabolism (induction of CYP1A2); ↑ clearance (56%). s Likely ↑ caffeine levels after cessation. Chlorpromazine (Thorazine) s ↓ AUC (36%) and serum concentrations (24%). s ↓ Sedation and hypotension possible in smokers; smokers may need ↑ dosages. Clopidogrel (Plavix) s ↑ Metabolism (induction of CYP1A2) of clopidogrel to its active metabolite. s Clopidogrel’s effects are enhanced in smokers (≥10 cigarettes/day): significant ↑ platelet inhibition, ↓ platelet aggregation; although improved clinical outcomes have been shown, may also ↑ risk of bleeding. Clozapine (Clozaril) s ↑ Metabolism (induction of CYP1A2); ↓ plasma concentrations (18%). s ↑ Levels on cessation may occur; closely monitor drug levels and reduce dose as required to avoid toxicity. Erlotinib (Tarceva) s ↑ Clearance (24%); ↓ trough serum concentrations (twofold). Flecainide (Tambocor) s ↑ Clearance (61%); ↓ trough serum concentrations (25%). s Smokers may need ↑ dosages. Fluvoxamine (Luvox) s ↑ Metabolism (induction of CYP1A2); ↑ clearance (24%); ↓ AUC (31%); ↓ plasma concentrations (32%). s Dosage modifications not routinely recommended but smokers may need ↑ dosages. Haloperidol (Haldol) s ↑ Clearance (44%); ↓ serum concentrations (70%). Heparin s Mechanism unknown but ↑ clearance and ↓ half-life are observed. Smoking has prothrombotic effects. s Smokers may need ↑ dosages because of PK and PD interactions. Insulin, subcutaneous s Possible ↓ insulin absorption secondary to peripheral vasoconstriction; smoking may cause release of endogenous substances that cause insulin resistance. Irinotecan (Camptosar) s PK↑ Clearance and PD interactions (18%); ↓ serum likely concentrations not clinically significant; of active metabolite smokers may SN-38 need (∼40%;↑ dosages. via induction of glucuronidation); ↓ systemic exposure resulting in lower hematologic toxicity and may reduce efficacy. s Smokers may need ↑ dosages. Mexiletine (Mexitil) s ↑ Clearance (25%; via oxidation and glucuronidation); ↓ half-life (36%). Olanzapine (Zyprexa) s ↑ Metabolism (induction of CYP1A2): ↑ clearance (98%); ↓ serum concentrations (12%). s Dosage modifications not routinely recommended but smokers may require ↑ dosages. Propranolol (Inderal) s ↑ Clearance (77%; via side-chain oxidation and glucuronidation). s Ropinirole (Requip) ↓ Cmax (30%) and AUC (38%) in study with patients with restless legs syndrome. s Smokers may need ↑ dosages. Tacrine (Cognex) s ↑ Metabolism (induction of CYP1A2); ↓ half-life (50%); serum concentrations threefold lower. s Smokers may need ↑ dosages. Theophylline (Theo-Dur, s ↑ Metabolism (induction of CYP1A2); ↑ clearance (58–100%); ↓ half-life (63%). etc.) s Levels should be monitored if smoking is initiated, discontinued, or changed. s ↑ Clearance with second-hand smoke exposure. Chapter 88 s Maintenance doses are considerably higher in smokers. Tricyclic antidepressants s Possible interaction with tricyclic antidepressants in the direction of ↓ blood levels, but the clinical significance is (e.g., imipramine, not established. nortriptyline) Tizanidine (Zanaflex) s ↓ AUC (30–40%) and ↓ half-life (10%) observed in male smokers. Warfarin s ↑ Metabolism (induction of CYP1A2) of R-enantiomer; however, S-enantiomer is more potent and effect on INR is inconclusive. Consider monitoring INR on smoking cessation. Pharmacodynamic Interactions Benzodiazepines (diazepam, s ↓ Sedation and drowsiness, possibly caused by nicotine stimulation of central nervous system. chlordiazepoxide) β-Blockers s Less effective antihypertensive and heart rate control effects; might be caused by nicotine-mediated sympathetic activation. Tobacco Use and Dependence s Smokers may need ↑ dosages. Corticosteroids, inhaled s Smokers with asthma may have less of a response to inhaled corticosteroids. Hormonal contraceptives s ↑ Risk of cardiovascular adverse effects (e.g., stroke, myocardial infarction, thromboembolism) in women who smoke and use oral contraceptives. Ortho Evra patch users shown to have twofold ↑ risk of venous thromboembolism compared with oral contraceptive users, likely as a result of ↑ estrogen exposure (60% higher levels). s ↑ Risk with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women age 35 and older. Opioids (propoxyphene, s ↓ Analgesic effect; smoking may ↑ the metabolism of propoxyphene (15–20%) and pentazocine (40%). pentazocine) Mechanism unknown. s Smokers may need ↑ opioid dosages for pain relief.

aShaded rows indicate the most clinically signiﬁcant interactions. AUC, area under the curve; Cmax, maximal concentration; INR, international normalized ratio; PD, pharmacodynamic; PK, pharmacokinetic. Reprinted with permission from Rx for Change: Clinician-Assisted Tobacco Cessation. Copyright c 1999–2012. The Regents of the University of California. All rights reserved. P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

2060 TABLE 88-3 tobacco control; (b) secondhand smoke exposure causes disease Health Consequences of Smoking and premature death in children and adults who do not smoke; (c) children exposed to secondhand smoke are at an increased Cancer Acute myeloid leukemia risk for sudden infant death syndrome, acute respiratory infec- Bladder tions,earproblems,andmoresevereasthma.Smokingbyparents Cervical causes respiratory symptoms and slows lung growth in their chil- Esophageal dren; (d) exposure of adults to secondhand smoke has immediate Gastric adverse events on the cardiovascular system and causes coronary Kidney Laryngeal heart disease and lung cancer; (e) the scientific evidence indi- Lung cates that there is no risk-free level of exposure to secondhand Oral cavity and pharyngeal smoke; and (f) eliminating smoking in indoor spaces fully pro- Pancreatic tects nonsmokers from exposure to secondhand smoke. Separat- Cardiovascular Abdominal aortic aneurysm ing smokers from nonsmokers, cleaning the air, and ventilating disease Coronary heart disease (angina pectoris, ischemic buildings cannot eliminate exposures of nonsmokers to second- heart disease, myocardial infarction) hand smoke. In 2006, the California Environmental Protection Cerebrovascular disease (transient ischemic attacks, Agency designated secondhand smoke as a “toxic air contami- stroke) nant” and, in addition to the list of diseases described in the Sur- Peripheral arterial disease geon General’s report, specified that exposure is associated with Pulmonary Acute respiratory illnesses 36 disease Upper respiratory tract (rhinitis, sinusitis, breast cancer in younger, primarily premenopausal women. laryngitis, pharyngitis) Lower respiratory tract (bronchitis, pneumonia) Chronic respiratory illnesses Benefits of Quitting Chronic obstructive pulmonary disease Respiratory symptoms The 1990 Surgeon General’s Report on the health benefits of Poor asthma control smoking cessation describes numerous and substantial health Reduced lung function benefits associated with quitting.37 Benefits incurred soon after Reproductive Reduced fertility in women quitting (e.g., within 2 weeks to 3 months) include improvements effects Pregnancy and pregnancy outcomes in pulmonary function, circulation, and ambulation. Smoking Preterm, premature rupture of membranes 38 Placenta previa cessation results in measurable improvements in lung function Placental abruption (see Chapter 24, Chronic Obstructive Pulmonary Disease). One Preterm delivery year after cessation, the excess risk of coronary heart disease is Low infant birth weight reduced to half that of continuing smokers. After 5 to 15 years, Infant mortality the risk of stroke is reduced to a rate similar to that of people who Sudden infant death syndrome are lifetime nonsmokers, and 10 years after quitting, the chance eto 16 Section Other effects Cataract of dying of lung cancer is approximately half that of continu- Osteoporosis (reduced bone density in ing smokers. In addition, the risk of developing mouth, throat, postmenopausal women, increased risk of hip esophagus, bladder, kidney, or pancreatic cancer is decreased. fracture) Finally, 15 years after quitting, the risk of coronary heart disease Periodontitis Peptic ulcer disease (in patients who are infected is reduced to a rate that is similar to that of people who have never smoked.37 Similarly,more recent data suggest that smokers who usac Abuse Substance with Helicobacter pylori) Surgical outcomes quit for good over a sustained period have an overall mortal- Poor wound healing ity rate and death rate associated with cardiovascular disease, ischemic heart disease, and stroke that is similar to individuals Reprinted from National Center for Chronic Disease Prevention and Health who have never smoked. In contrast, individuals who had suc- Promotion, Office on Smoking and Health. The Health Consequences of Smoking: A cessfully quit, but later resumed smoking, had mortality risks Report of the Surgeon General. Washington, DC: Office on Smoking and Health, that were significantly higher than lifetime nonsmokers.39 National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, US Dept of Health and Human Services; Quitting at ages 30, 40, 50, and 60 results in 10, 9, 6, and 1 2004. 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 as 36.9% of current smokers and 26.0% of former smokers live with a result of a tobacco-related disease.1 Persons who quit before a smoking-related chronic disease.33 In the United States, lung age 35 add 10 years of life and have a life expectancy similar to cancer is the leading cause of cancer-related mortality for men men who had never smoked.1 In addition to losing years of life and women and is a disease for which the 5-year survival rate is because of smoking, a 26-year prospective study of smoking in approximately 16%.34 midlife showed a dose-dependent reduction in the health-related quality of life in old age among men. Never smokers live longer SECONDHAND SMOKE EXPOSURE than heavy smokers, and their extra years are of higher quality.40 Exposure to secondhand smoke, which includes the smoke ema- A reduction in smoking does not equate to a reduction in harm41; nating from burning tobacco and that exhaled by the smoker, even low levels of smoking (e.g., 1–4 cigarettes per day) have affects an estimated 88 million nonsmokers older than the age of documented risks,42,43 and therefore, decreasing the number of 3 in the United States,35 resulting in an estimated 50,000 deaths cigarettes smoked per day should be viewed as a positive step annually,inadditiontocontributingtonumerousdiseasesamong toward quitting, but should not be recommended as a targeted nonsmoking children and adults.6 Major conclusions of the 2006 end point. For any patient who uses tobacco, the target goal Surgeon General’s Health Effects of Involuntary Exposure to is complete, long-term abstinence from all nicotine-containing Tobacco Smoke6 report are: (a) many millions of Americans, products. In summary, there is no safe level of tobacco use, and both children and adults, are still exposed to secondhand smoke although it is never too late to incur benefits of quitting, there are in their homes and workplaces despite substantial progress in substantial benefits associated with quitting at a younger age. P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

Tobacco Use and Dependence: more months after cessation). Although even brief advice from 2061 a clinician has been shown to lead to increased odds of quitting,8 Treatment Approaches more intensive counseling yields more dramatic increases in quit Most tobacco users attempt to quit without assistance, despite rates.8 Other effective methods for delivery of counseling include , the fact that persons who receive assistance are more likely group programs8 45 and telephone counseling.46 Internet-based to be successful in quitting.8,44 Given the complexity of the interventions have become more prevalent in recent years, but a tobacco-dependence syndrome and the constellation of factors recent meta-analysis of 20 trials revealed inconsistent results.47 that contribute to tobacco use, treatment requires a multifaceted Numerous effective medications are available for tobacco approach. To assist clinicians and other specialists in providing dependence, and clinicians should encourage their use by all cessation treatment to patients who use tobacco, the US Pub- patients attempting to quit smoking—except when medically lic Health Service published the Clinical Practice Guideline for contraindicated or with specific populations for which there Treating Tobacco Use and Dependence. This document, which is insufficient evidence of effectiveness (i.e., pregnant women, represents a distillation of more than 8,700 published articles,8 smokeless tobacco users, light smokers, adolescents).8 Although specifies that clinicians can have an important impact on their both pharmacotherapy and behavioral counseling are effec- patients’ ability to quit. A meta-analysis of 29 studies8 estimated tive independently, patients’ odds of quitting are substantially that compared with patients who do not receive an intervention increased when the two approaches are used simultaneously.The from a clinician, patients who receive a tobacco-cessation inter- estimated efficacies of various treatment strategies are shown in vention from a physician clinician or a nonphysician clinician Table 88-4. Clinicians can have a significant impact on a patient’s are 2.2 and 1.7 times, respectively, more likely to quit (at 5 or likelihood of success by recommending pharmacotherapy agents

TABLE 88-4 Efﬁcacy of Treatment Methods for Tobacco Use and Dependence8

Treatment Method Estimated Odds Ratioa (95% CI) Estimated Abstinenceb Rate (95% CI)

Behavioral Interventions

Advice to quit No advice to quit 1.0 7.9 Physician advice to quit 1.3 (1.1–1.6) 10.2 (8.5–12.0) Clinician intervention No counseling by a clinician 1.0 10.2 Counseling by a nonphysician clinician 1.7 (1.3–2.1) 15.8 (12.8–18.8) Counseling by a physician 2.2 (1.5–3.2) 19.9 (13.7–26.2) Format of smoking cessation counseling No format 1.0 10.8 Self-help 1.2 (1.0–1.3) 12.3 (10.9–13.6) Proactive telephone counselingc 1.2 (1.1–1.4) 13.1 (11.4–14.8)

Group counseling 1.3 (1.1–1.6) 13.9 (11.6–16.1) Chapter 88 Individual counseling 1.7 (1.4–2.0) 16.8 (14.7–19.1) Pharmacotherapy Interventions

Placebo 1.0 13.8 First-line agents Bupropion SRd 2.0 (1.8–2.2) 24.2 (22.2–26.4) Nicotine gum (6–14 weeks) 1.5 (1.2–1.7) 19.0 (16.5–21.9) Nicotine inhaler 2.1 (1.5–2.9) 24.8 (19.1–31.6) Nicotine lozenge (2 mg) 2.0 (1.4–2.8) 24.2e Nicotine patch (6–14 weeks) 1.9 (1.7–2.2) 23.4 (21.3–25.8) Nicotine nasal spray 2.3 (1.7–3.0) 26.7 (21.5–32.7)

Varenicline (2 mg/day) 3.1 (2.5–3.8) 33.2 (28.9–37.8) Tobacco Use and Dependence Second-line agents f Clonidine 2.1 (1.2–3.7) 25.0 (15.7–37.3) Nortriptyline 1.8 (1.3–2.6) 22.5 (16.8–29.4) Combination therapy Nicotine patch (>14 weeks) + ad lib NRT (gum or nasal spray) 3.6 (2.5–5.2) 36.5 (28.6–45.3) Nicotine patch + bupropion SRd 2.5 (1.9–3.4) 28.9 (23.5–35.1) Nicotine patch + nortriptyline 2.3 (1.3–4.2) 27.3 (17.2–40.4) Nicotine patch + nicotine inhaler 2.2 (1.3–3.6) 25.8 (17.4–36.5)

aEstimated relative to referent group. bAbstinence percentages for speciﬁed treatment method. cA quitline that responds to incoming calls and makes outbound follow-up calls. Following an initial request by the smoker or via a fax-to-quit program, the clinician initiates telephone contact to counsel the patient. dSustained-release bupropion. eOne qualifying randomized trial; 95% CI not reported in 2008 Clinical Practice Guideline. f Not approved by the US Food and Drug Administration as a smoking cessation aid; recommended by the US Public Health Service Guideline as a second-line agent for treating tobacco use and dependence. CI, conﬁdence interval; NRT, nicotine replacement therapy. Reprinted with permission from Rx for Change: Clinician-Assisted Tobacco Cessation. Copyright c 1999–2012. The Regents of the University of California. All rights reserved. P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

2062 and by supplementing medication use with behavioral counsel- you are on two different inhalers for your emphysema. Quitting ing as described later in this chapter. smoking is the single most important treatment to improve your breathing. I strongly encourage you to quit. Would you be interested in having me help you with this?” Assisting Patients With Quitting s Assess: Key to the provision of appropriate counseling inter- BEHAVIORAL COUNSELING STRATEGIES ventions is the assessment of a patient’s readiness to quit. According to the Clinical Practice Guideline,8 five key compo- Patients should be categorized as being (a) not ready to quit nents constitute comprehensive counseling for tobacco cessa- in the next month; (b) ready to quit in the next month; (c) a recent quitter, having quit in the past 6 months; or tion: (a) asking patients whether they use tobacco, (b) advising , tobacco users to quit, (c) assessing patients’ readiness to quit, (d) a former user, having quit more than 6 months ago.8 48 (d) assisting patients with quitting, and (e) arranging follow-up This classification defines the clinician’s next step, which is care. These steps are referred to as the “5 A’s” and are described, to provide counseling that is tailored to the patient’s level in brief, as follows. Figure 88-2 can be used as a guide for struc- of readiness to quit. As an example for a current smoker: turing counseling interactions. “Mr. Malkin, what are your thoughts about quitting, and would s you consider quitting sometime in the next month?” The coun- Ask: Screening for tobacco use is essential and should be a seling interventions for patients who are ready to quit will routine component of clinical care. The following question be different from those for patients who are not considering can be used to identify tobacco users: “Do you ever smoke or quitting. use any type of tobacco?” At a minimum, tobacco use status s Assist: When counseling tobacco users, it is important that (current, former, never user) and level of use (e.g., num- clinicians view quitting as a process that might take months ber of cigarettes smoked per day) should be assessed and or even years to achieve, rather than a “now or never” event. documented in the medical record. Also, patients should be The goal is to promote forward progress in the process of asked about exposure to secondhand smoke. Before impart- change,withthetargetendpointbeingsustainedabstinence ing advice, consider asking the patient for permission to do from all nicotine-containing products. so: “Ms. Crosby, may I tell you why this concerns me?” s Advise: Tobacco users should be advised to consider quit- Whencounselingpatientswhoarenotreadytoquit,animpor- ting; the advice should be clear and compelling, yet deliv- tant first step is to foster motivation. Some patients who are not ered with sensitivity and a tone of voice that communi- ready to quit truly might not believe that they need to quit; cates concern and a willingness to assist with quitting. however, most will recognize the need to quit but are simply Whenpossible,messagesshouldbepersonalizedbyrelating not ready to make the commitment to do so. Often, patients advice to factors such as a patient’s health status, medication have tried to quit multiple times and failed, and thus are too regimen, personal reasons for wanting to quit, or the impact discouraged to try again. Strategies for working with patients oftobaccouseonothers.Forexample,“I’mconcernedbecause who are not ready to quit involve enhancing motivation to quit, eto 16 Section

STEP One: ASK about Tobacco Use STEP Four: ASSIST with Quitting Suggested Dialogue Assess Tobacco Use History • Current use: type(s) of tobacco used, brand, amount – “Do you ever smoke or use any type of tobacco?” • Past use: – “I take time to talk with all of my patients about tobacco use—because it’s important.” – Duration of tobacco use – “Medication X often is used for conditions linked with or caused by smoking. Do you, – Changes in levels of use recently or does someone in your household smoke?” • Past quit attempts: usac Abuse Substance – “Condition X often is caused or worsened by exposure to tobacco smoke. Do you, or – Number of attempts, date of most recent attempt, duration does someone in your household smoke?” – Methods used previously—What did or didn’t work? Why or why not? – Prior medication administration, dose, compliance, duration of treatment STEP Two: Strongly ADVISE to Quit –Reasonsforrelapse Suggested Dialogue Discuss Key Issues (for the upcoming or current quit attempt) • Reasons/motivation for wanting to quit (or avoid relapse) – Quitting is the most important thing you can do to protect your health now and in the • Confidence in ability to quit (or avoid relapse) future. I have training to help my patients quit, and when you are ready I would be • Triggers for tobacco use more than happy to work with you to design a treatment plan. • Routines and situations associated with tobacco use – What are your thoughts about quitting? Might you consider quitting sometime in the •Stress-relatedtobaccouse next month? • Social support for quitting Prior to imparting advice, consider asking the patient for permission to do so – e.g., •Concernsaboutweightgain “May I tell you why this concerns me?” {then elaborate on patient-specific concerns). •Concernsaboutwithdrawalsymptoms Facilitate Quitting Process STEP Three: ASSESS Readiness to Quit • Discuss methods for quitting: pros and cons of the different methods • Set a quit date: ideally, less than 2 weeks away Does the patient now use tobacco? • Recommend completion of a Tobacco Use Log YES NO • Discuss coping strategies (cognitive, behavioral) for key issues • Discuss withdrawal symptoms • Discuss concept of “ slip” versus relapse Did the patient use • Provide medication counseling: compliance, proper use, with demonstration Is the patient now • Offer to assist throughout the quit attempt tobacco previously? willing to quit? Evaluate the Quit Attempt (at follow-up) YES NO YES NO • Status of attempt • Inquire about “slips” and relapse • Medication compliance and plans for discontinuation Foster Provide Prevent Encourage motivation treatment relapse* continued STEP Five: ARRANGE Follow-up Counseling abstinence The 5 R’s The 5 A’s or referral Monitor patients’ progress throughout the quit attempt. Follow-up contact should occur during the first week after quitting. A second follow-up contact is recommended in the first month. Additional contacts should be scheduled as needed. Counseling contacts can occur face-to-face, by telephone, or by e-mail. Keep patient progress notes. * Relapse prevention interventions not necessary in the case of the adult who has not used tobacco for many years. Address temptations and triggers; discuss strategies to prevent relapse. Fiore MC, Jaen CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Congratulate patients for continued success. Guideline. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service. May 2008.

FIGURE 88-2 Tobacco-cessation counseling guide sheet. (Reprinted with permission from Rx for Change: Clinician-Assisted Tobacco Cessation. Copyright c 1999–2012. The Regents of the University of California. All rights reserved.) P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

2063 TABLE 88-5 Enhancing Motivation to Quit: The “5 R’s” for Tobacco Cessation Counseling

s Relevance—Encourage patients to think about the reasons why quitting is important. Counseling should be framed such that it relates to the patient’s risk for disease or exacerbation of disease, family or social situations (e.g., having children with asthma), health concerns, age, or other patient factors, such as prior experience with quitting. s Risks—Ask patients to identify potential negative health consequences of smoking, such as acute risks (shortness of breath, asthma exacerbations, harm to pregnancy, infertility), long-term risks (cancer, cardiac, and pulmonary disease), and environmental risks (promoting smoking among children by being a negative role model; effects of secondhand smoke on others, including children and pets). s Rewards—Ask patients to identify potential beneﬁts that they anticipate from quitting, such as improved health, enhanced physical performance, enhanced taste and smell, reduced expenditures for tobacco, less time wasted or work missed, reduced health risks to others (fetus, children, housemates), and reduced aging of the skin. s Roadblocks—Help patients identify barriers to quitting and assist in developing coping strategies (Table 88-6) for addressing each barrier. Common barriers include nicotine withdrawal symptoms, fear of failure, a need for social support while quitting, depression, weight gain, and a sense of deprivation or loss. s Repetition—Continue to work with patients who are successful in their quit attempt. Discuss circumstances in which smoking occurred to identify the trigger(s) for relapse; this is part of the learning process and will be useful information for the next quit attempt. Repeat interventions when possible.

Reprinted from Fiore MC et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: Public Health Service, US Dept of Health and Human Services; 2008.

and this can be accomplished by applying the “5 R’s”8 (Table Additional strategies for coping with quitting are shown in Table 88-5) and by offering to work closely with the patient in design- 88-6.32 Patients should be counseled about withdrawal symp- ing a treatment plan. Although it might be useful to educate toms,medicationuse,andtheimportanceofreceivingbehavioral patients about the pharmacotherapy options, it is inappropriate counseling throughout the quit attempt. Finally, patients should to prescribe a treatment regimen for patients who are not ready be commended for taking important steps toward improving to quit. For patients who are not ready to quit in the next 30 their health. days, encourage them to seriously consider quitting and ask the s Arrange: Because patients’ ability to quit increases when following questions: multiple counseling interactions are provided, arrang- 1. Do you ever plan to quit? ing follow-up counseling is an important, yet typically If the patient responds “no,” the clinician should ask, “What neglected, element of treatment for tobacco dependence. would have to change for you to decide to quit?” If the patient Follow-up contact should occur soon after the quit date, responds “nothing,” then offer to assist, if or when the patient preferably during the first week. A second follow-up changes his or her mind. If the patient responds “yes,” the contact is recommended within the first month after clinician should continue with question 2. quitting.8 Periodically,additional follow-up contacts should 2. What might be some benefits of quitting now, instead of later? occur to monitor patient progress, assess compliance Thelongerapatientsmokes,quittinggenerallybecomesmore with pharmacotherapy regimens, and provide additional difficult. Most patients will agree that there is never an ideal support. time to quit, and procrastinating a quit date has more negative Chapter 88 Relapse prevention counseling should be part of every follow- effects than positive. up contact with patients who have recently quit smoking. When 3. What would have to change for you to decide to quit sooner? counseling recent quitters, it is important to address challenges This question probes patients’ perceptions of quitting, which in countering withdrawal symptoms and cravings or temptations reveals some of the barriers to quitting that can then be dis- to use tobacco. A list of strategies for key triggers or temptations cussed. for tobacco use is provided in Table 88-6.32 Importantly, because For patients who are ready to quit (i.e., in the next month), tobacco use is a habitual behavior, patients should be advised to the goal is to work with the patient in designing an individual- alter their daily routines; this helps disassociate specific behaviors ized treatment plan, addressing the key issues listed under the from the use of tobacco. Patients who slip and smoke a cigarette “Assist” component of Figure 88-2.32 The first steps are to dis- (or use any form of tobacco) or experience a full relapse back

cuss the patient’s tobacco use history, inquiring about levels of to habitual tobacco use should be encouraged to think through Tobacco Use and Dependence smoking, number of years smoked, methods used previously for the scenario in which tobacco use first occurred and identify the quitting (what worked, what did not work and why), and rea- trigger(s) for relapse. This process provides valuable information son(s) for previous failed quit attempts. Clinicians should elicit for future quit attempts. patients’ opinions about the different medications for quitting and should work with patients in selecting the quitting methods PHARMACOTHERAPY OPTIONS (e.g., medications, behavioral counseling programs). Although it All smokers who are trying to quit should be encouraged to is important to recognize that pharmaceutical agents might not use one or more US Food and Drug Administration (FDA)- be appropriate, desirable, or affordable for all patients, clinicians approved pharmacologic aids for cessation; potential exceptions should educate patients that medications, when taken correctly, that require special consideration include medical contraindica- can substantially increase the likelihood of success. tions or use in specific populations for which there is insuffi- Patients should be advised to select a quit date. Ideally, this cient evidence of effectiveness (i.e., pregnant women, smokeless date will be within the next 2 weeks to allow sufficient time tobacco users, light smokers, adolescents).8 Currently, the FDA- to prepare for the quit attempt, including mental preparation, approved first-line agents that have been shown to be effective as well as preparation of the environment, such as by remov- in promoting smoking cessation include five NRT dosage forms, ing all tobacco products and ashtrays from the home, car, and sustained-release bupropion, and varenicline.8 Dosing informa- workspace and informing their family, friends, and coworkers tion, precautions, and adverse effects for the first-line agents about their upcoming quit attempt and requesting their support. are shown in Table 88-7. Pharmacologic agents that have not P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

2064 TABLE 88-6 Cognitive and Behavioral Strategies for Tobacco Cessation

Cognitive Strategies

Focus on retraining the way a patient thinks. Often, patients deliberate on the fact that they are thinking about a cigarette, and this leads to relapse. Patients must recognize that thinking about a cigarette does not mean they need to have one. Review commitment to quit, Reminding oneself that cravings and temptations are temporary and will pass. Announce, either silently or aloud, focus on downside of tobacco “I want to be a nonsmoker, and the temptation will pass.” Distractive thinking Deliberate, immediate refocusing of thinking when cued by thoughts about tobacco use. Positive self-talks, “pep talks” Saying “I can do this” and reminding oneself of previous difﬁcult situations in which tobacco use was avoided with success. Relaxation through imagery Centering of mind toward positive, relaxing thoughts. Mental rehearsal, visualization Preparing for situations that might arise by envisioning how best to handle them. For example, envision what would happen if offered a cigarette by a friend—mentally craft and rehearse a response, and perhaps even practice it by saying it aloud. Behavioral Strategies

Involve specific actions to reduce risk for relapse. For maximal effectiveness, these should be considered before quitting, after determining patient-specific triggers for tobacco use. Here, we list some behavioral strategies for several common cues or triggers for relapse. Stress Anticipate upcoming challenges at work, at school, or in personal life. Develop a substitute plan for tobacco use during times of stress (e.g., breathe deeply several times, take a break or leave the situation, call a supportive friend or family member, perform self-massage, or use nicotine replacement therapy to manage situational cravings). Alcohol Drinking alcohol can lead to relapse. Consider limiting or abstaining from alcohol during the early stages of quitting. Other tobacco users Quitting is more difficult when around other tobacco users. This is especially difficult if there is another tobacco user in the household. When possible during the early stages of quitting, limit prolonged contact with individuals who are using tobacco. Ask coworkers, friends, and housemates not to smoke or use tobacco in your presence. Oral gratification needs Have nontobacco oral substitutes (e.g., gum, sugarless candy, straws, toothpicks, lip balm, toothbrush, nicotine replacement therapy, bottled water) readily available. Automatic smoking routines Anticipate routines that are associated with tobacco use and develop an alternative plan.

eto 16 Section Examples: Morning coffee with cigarettes: change morning routine, drink tea instead of coffee, take shower before drinking coffee, take a brisk walk shortly after awakening. Smoking while driving: remove all tobacco from car, have car interior detailed, listen to an audio book or talk radio, use oral substitute. Smoking while on the phone: stand while talking, limit call duration, change phone location, keep hands occupied by

usac Abuse Substance doodling or sketching. Smoking after meals: get up and immediately do dishes or take a brisk walk after eating, call supportive friend. Postcessation weight gain The majority of tobacco users gain weight after quitting. Most quitters will gain <10 pounds, but there is a broad range of weight gain reported, with up to 10% of quitters gaining as much as 30 pounds. Do not attempt to modify multiple behaviors at one time. If weight gain is a barrier to quitting, engage in regular physical activity and adhere to a healthful diet (as opposed to strict dieting). Carefully plan and prepare meals, increase fruit and water intake to create a feeling of fullness, and chew sugarless gum or eat sugarless candies. Consider use of pharmacotherapy shown to delay weight gain (e.g., nicotine gum, lozenge, or sustained-release bupropion). Cravings for tobacco Cravings for tobacco are temporary and usually pass within 5–10 minutes. Handle cravings through distractive thinking, take a break, change activities or tasks, take deep breaths, perform self-massage, or use nicotine replacement therapy.

received an approval from the FDA for smoking cessation but are to the nearly immediate, reinforcing effects of inhaled nico- recommended as second-line agents8 include clonidine and tine. A meta-analysis of 111 controlled trials, enrolling more nortriptyline. than 43,000 participants, found that all NRT formulations (gum, inhaler, lozenge, patch, and nasal spray) result in statistically significant improvements in abstinence rates when compared with FIRST-LINE AGENTS placebo. Patients using NRT are 1.6 times as likely to quit smok- 49 32 NICOTINE REPLACEMENT THERAPY ing than are those receiving placebo. Figure 88-3 depicts the NRT improves cessation rates by reducing the physical with- concentration–time curves for the various NRT formulations, drawal symptoms associated with tobacco cessation while the compared with a cigarette and moist snuff (a smokeless form 50–52 patient focuses on modifying his or her behavior and coping of tobacco). It can be seen that of the five NRT dosage with the psychological aspects of quitting. In addition, because forms, the nicotine nasal spray reaches its peak concentration the onset of action for NRT is not as rapid as that of nicotine most rapidly. The nicotine gum, lozenge, and oral inhaler have obtained through smoking, patients become less accustomed similar concentration curves, and the nicotine transdermal patch P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58 for 18 years) (continued) < (category C) d e c Severe renal impairment (dosage adjustment is necessary) Pregnancy Adolescents ( Black-boxed warning neuropsychiatric symptoms Safety and efficacy have not been established in patients with serious psychiatric illness Cardiovascular adverse events in patients with existing cardiovascular disease and breast-feeding s s s s s s Warnings: 0.5-mg, 1-mg tablet e for 18 years) < (category C) d Generic Chantix a tablet Concomitant therapy with medications or medical conditions known to lower seizure threshold Severe hepatic cirrhosis Pregnancy Adolescents ( Black-boxed warning neuropsychiatric symptoms Seizure disorder Concomitant bupropion (e.g., Wellbutrin) therapy Current or prior diagnosis of bulimia or anorexia nervosa Simultaneous abrupt discontinuation of alcohol or sedatives (including benzodiazepines) Monoamine oxidase inhibitor therapy in previous 14 days and breast-feeding s s s s s s s s s s Warning: Contraindications: Zyban, 18 years) c < (category D) d 2 weeks) ≤ nicotine vapor Recent ( myocardial infarction Serious underlying arrhythmias Bronchospastic disease Pregnancy Adolescents ( and breast-feeding s s s s s Delivers 4 mg of inhaled Nicotrol Inhaler L μ 18 years) < (category D) and d c 2 weeks) ≤ aqueous nicotine solution breast-feeding Recent ( myocardial infarction Serious underlying arrhythmias Serious or worsening angina pectoris Underlying chronic nasal disorders (rhinitis, nasal polyps, sinusitis) Severe reactive airway disease Pregnancy Adolescents ( s s s s s s s 0.5 mg of nicotine in 50- Nicotrol NS b Generic 18 years) a < (Rx d 2 weeks) ≤ NRT Formulations release) Recent ( myocardial infarction Serious underlying arrhythmias Serious or worsening angina pectoris Pregnancy Adolescents ( formulations, category D) and breast-feeding s s s s s NicoDerm CQ, 18 years) < and d 2 weeks) Generic ≤ a mini), Recent ( myocardial infarction Serious underlying arrhythmias Serious or worsening angina pectoris Pregnancy Adolescents ( breast-feeding s s s s s Cherry, mint 7 mg, 14 mg, 21 mg (24-hour 18 years) < and d 2 weeks) Generic Nicorette (standard and a ≤ mint, orange Recent ( myocardial infarction Serious underlying arrhythmias Serious or worsening angina pectoris Temporomandibular joint disease Pregnancy Adolescents ( breast-feeding s s s s s s GumProduct Nicorette, OTC2 mg, 4 mgOriginal, cinnamon, fruit, LozengePrecautions, Warnings, and Contraindications 2 mg, 4 OTC mg Transdermal Patch Nasal Spray Rx (generic) OTC (NicoDerm CQ, generic) Rx Oral Inhaler Metered spray Bupropion SR Rx 10-mg cartridge Varenicline 150-mg sustained-release Rx Rx TABLE 88-7 Pharmacotherapy Options: Products; Precautions, Warnings, and Contraindications; Dosing; and Adverse Effects

2065 P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58 ) quit date. morning 0.5 mg PO BID 1mgPOBID 0.5 mg PO every Begin therapy 1 week before Alternatively, the patient can begin therapy and then quit smoking between days 8 and 35 of treatment. Take dose after eating and with a full glass of water Dose tapering is not necessary Dosing adjustment is recommended for patients with severe renal impairment Duration: 12 weeks; an additional 12-week course may be used in selected patients Nausea Sleep disturbances (insomnia, abnormal or vivid dreams) Constipation Flatulence Vomiting Neuropsychiatric symptoms (rare; see Precautions s s s s s s s s s s s Days 1–3: Days 4–7: Weeks 2–12: 0.1%) ∼ ) quit date 3 days, then increase × to 150 mg PO BID Do not exceed 300 mg/day Begin therapy 1–2 weeks before Allow at least 8 hours between doses Avoid bedtime dosing to minimize insomnia Dose tapering is not necessary Can be used safely with NRT Duration: 7–12 weeks, with maintenance up to 6 months in selected patients Insomnia Dry mouth Nervousness or difficulty concentrating Rash Constipation Seizures (risk is Neuropsychiatric symptoms (rare; see Precautions s s s s s s s s s s s s s s 150 mg PO every morning ) Continued 1 cartridge every 1–2 hours ectiveness and theoretical concerns with safety. Pregnant smokers should be offered Best effects with continuous puffing for 20 minutes Initially use at least 6 cartridges/day Nicotine in cartridge is depleted after 20 minutes of active puffing Inhale into back of throat or puff in short breaths Do NOT inhale into the lungs (like a cigarette) but “puff” as if lighting a pipe Open cartridge retains potency for 24 hours No food or beverages 15 minutes before or during use Duration: 3–6 months Mouth or throat irritation Cough Headache Rhinitis Dyspepsia Hiccups s s s s s s s s s s s s s s 6–16 cartridges/day Individualize dosing; initially use ng highlighting the risk of serious neuropsychiatric symptoms, including changes in behavior, ment is stopped because of neuropsychiatric symptoms, patients should be monitored until the enicline or bupropion SR and contact a health care provider immediately if they experience agitation, 2 sprays (one = nostril); each each in spray delivers 0.5 mg of nicotine to the nasal mucosa Maximum –5 or doses/hour –40 doses/day For best results, initially use at least 8 doses/day Do not sniff, swallow, or inhale through the nose as the spray is being administered Duration: 3–6 months Nasal or throat irritation (hot, peppery, or burning sensation) Rhinitis Tearing Sneezing Cough Headache s s s s s s s s s s 1–2 doses/hour (8–40 doses/day) One dose 2 weeks 6 weeks 1999–2012. The Regents of the University of California. All rights reserved. 2 weeks 2 weeks c × × × × 4 weeks (generic) 6 weeks (NicoDerm CQ) × × May wear patch for 16 hours if patient experiences sleep disturbances (remove at bedtime) Duration: 8–10 weeks Local skin reactions (erythema, pruritus, burning) Headache Sleep disturbances (insomnia, abnormal or vivid dreams); associated with nocturnal nicotine absorption 10 cigarettes/day: 10 cigarettes/day: s s s s s > 21 mg/day 14 mg/day 7 mg/day ≤ 14 mg/day 7 mg/day Copyright NRT Formulations 30 minutes after 30 minutes after ≤ > 4mg 2mg waking: waking: 1 lozenge every 1–2 hours 1 lozenge every 2–4 hours 1 lozenge every 4–8 hours Maximum, 20 lozenges/day Allow to dissolve slowly (20–30 minutes for standard; 10 minutes for mini) Nicotine release may cause a warm, tingling sensation Do not chew or swallow Occasionally rotate to different areas of the mouth No food or beverages 15 minutes before or during use Duration: up to 12 weeks Nausea Hiccups Cough Heartburn Headache Flatulence Insomnia s s s s s s s s s s s s s s First cigarette First cigarette Weeks 1–6: Weeks 7–9: Weeks 10–12: Rx for Change: Clinician-Assisted Tobacco Cessation. 30 minutes after 30 minutes after 15–30 chews) ≤ > ∼ 4mg 2mg f waking: waking: 1 piece every 1–2 hours 1 piece every 2–4 hours 1 piece every 4–8 hours Maximum, 24 pieces/day Chew each piece slowly Park between cheek and gum when peppery or tingling sensation appears ( Resume chewing when tingle fades Repeat chew and park steps until most of nicotine is gone (tingle does not return; generally 30 minutes) Park in different areas of mouth No food or beverages 15 minutes before or during use Duration: up to 12 weeks Mouth or jaw soreness Hiccups Dyspepsia Hypersalivation Effects associated with incorrect chewing technique: –Lightheadedness –Nausea or vomiting –Throat and mouth irritation The US Clinical Practice Guideline states that pregnant smokers should be encouraged to quit without medication based on insufficient evidence of eff Marketed by GlaxoSmithKline. Transdermal patch formulation previously marketed as Habitrol. Marketed by Pfizer. In July 2009, the FDA mandated that the prescribing information for all bupropion- and varenicline-containing products include a black-boxed warni s s s s s s s s s s s s s b c d e hostility, agitation, depressed mood, suicidal thoughtsdepressed and mood, behavior, and and attempted any suicide. changes Clinicians insymptoms should behavior resolve. that advise patients are to not stop typical taking ofFor complete nicotine var prescribing withdrawal, information, or if refer to theyNRT, nicotine experience the replacement suicidal manufacturers’ therapy; thoughts package OTC, or inserts. over-the-counter behavior. (nonprescription); IfReprinted Rx, treat with prescription; permission SR, from sustained-release. behavioral counseling interventions that exceed minimal advice to quit. a GumDosing First cigarette First cigarette Weeks 1–6: Weeks 7–9: Weeks 10–12: Lozenge Transdermal Patch Nasal Spray Oral InhalerAdverse Effects Bupropion SR Varenicline TABLE 88-7 Pharmacotherapy Options: Products; Precautions, Warnings, and Contraindications; Dosing; and Adverse Effects (

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25 2067

20 g/L) μχ 15

10 Plasma Nicotine (

0 0102030405060 Time (minutes)

Cigarette Moist snuff Nasal spray Inhaler Lozenge (2 mg) Gum (2 mg) Patch

FIGURE 88-3 Plasma nicotine concentrations for various nicotine-containing products. (Reprinted with permission from Rx for Change: Clinician-Assisted Tobacco Cessation. Copyright c 1999–2012. The Regents of the University of California. All rights reserved. Plasma nicotine concentration curves derived from Choi JH et al. Pharmacokinetics of a nicotine polacrilex lozenge. Nicotine Tob Res. 2003;5(5):635; Schneider NG et al. The nicotine inhaler: clinical pharmacokinetics and comparison with other nicotine treatments. Clin Pharmacokinet. 2001;40(9):661; and Fant RV et al. Pharmacokinetics and pharmacodynamics of moist snuff in humans. Tob Control. 1999;8(4):387.)

has the slowest onset, but offers more consistent blood levels of PHARMACOTHERAPY FOR TREATING nicotine for a sustained period. TOBACCO USE AND DEPENDENCE

SUSTAINED-RELEASE BUPROPION Sustained-release bupropion is an atypical antidepressant med- Transdermal Nicotine Patch ication hypothesized to promote smoking cessation by block- CASE 88-1 ing the reuptake of dopamine and norepinephrine in the central QUESTION 1: T.B. is a 32-year-old woman who is enrolled in nervous system8 and possibly by acting as a nicotine receptor a worksite smoking-cessation program. During the previous antagonist.53 These neurochemical effects are believed to mod- group session, the cessation counselor discussed the vari- ulate the dopamine reward pathway and reduce cravings for ous medications for cessation. T.B. has set her quit date for Chapter 88 nicotine and symptoms of withdrawal.8 Use of sustained-release 1 week from today, and she is interested in starting the nico- bupropion approximately doubles the long-term abstinence rate tine transdermal patch. She is currently smoking 1.5 packs when compared with placebo.8,54 per day (PPD), which is a reduction from the 2 PPD she had been smoking for the past 10 years. T.B. reports she smokes VARENICLINE several cigarettes in succession immediately after waking in Varenicline, a cytisine analog, is a partial agonist that binds with the morning. She takes no medications and has no medical α β high afﬁnity and selectivity at 4 2 neuronal nicotinic acetyl- problems. Which nicotine transdermal product should T.B. 55 choline receptors. The efﬁcacy of varenicline in smoking ces- select, and how should it be used? sation is believed to be the result of sustained, low-level agonist activity at the receptor site combined with competitive inhibition Transdermalnicotinedeliverysystems,availablewithorwith-

of nicotine binding. The partial agonist activity induces modest out a prescription, consist of an impermeable surface layer, a Tobacco Use and Dependence receptorstimulation,leadingtoincreaseddopaminelevels,which nicotine reservoir, an adhesive layer, and a removable protec- attenuates the symptoms of nicotine withdrawal. In addition, by tive liner. Although the transdermal delivery technology varies α β blocking the ability of nicotine to activate 4 2 nicotinic acetyl- by manufacturer, nicotine is well absorbed, with 68% to 82% choline receptors, varenicline inhibits the surges of dopamine of the dose released from 24-hour patch formulations systemi- release that are believed to be responsible for the reinforcement cally bioavailable across the skin. Plasma nicotine concentrations 55,56 andrewardassociatedwithsmoking. Useofvareniclinemore from the patch rise slowly during 1 to 4 hours and peak within than doubles the long-term abstinence rate when compared in 3 to 12 hours after application.22 Levels of nicotine achieved 8,57 clinical trials with placebo. with the transdermal patch are lower and fluctuate less than do thoseachievedwithtobaccoproductsorotherNRTformulations SECOND-LINE AGENTS (Fig. 88-3). Although not FDA-approved specifically for smoking cessation, The transdermal nicotine patch exhibits significantly the prescription medications clonidine and nortriptyline are rec- improved abstinence rates relative to placebo (Table 88-4).8,49 ommended as second-line agents.8 Lack of an FDA-approved A meta-analysis of 25 randomized, controlled trials found treat- indication for smoking cessation and less desirable side-effect ment with the nicotine patch (6–14 weeks) approximately dou- profiles currently prohibit these agents from achieving first-line bled the likelihood of long-term abstinence compared with classification.8 placebo.8 P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

2068 DOSING bedtime and apply a new patch as soon as possible after waking The manufacturers’ recommended dosages are listed in Table the following morning.8 88-7. In general, higher levels of smoking necessitate the use of The clinician should also provide behavioral counseling sup- higher-strength formulations and a longer duration of therapy. port by asking T.B. about the current quit attempt. Appropriate Ultimately,the starting dose, rate of tapering, and total duration issues to address include her confidence in remaining tobacco of therapy must be individualized to the patient’s baseline smok- free, situations in which she has been tempted to smoke and ing levels, development of side effects (e.g., nausea, dyspepsia, potential triggers for relapse, nicotine withdrawal symptoms, nervousness, dizziness, sweating), and the presence or absence her social support system for quitting, and any other questions of withdrawal symptoms. T.B. currently smokes 30 cigarettes per or concerns she might have. It is reasonable to review poten- day,and thus she should initiate the regimen using the 21-mg/day tial coping strategies (behavioral and cognitive; Table 88-6) and patch. schedule a future follow-up call. The clinician should commend T.B. for her decision to quit, congratulate her for remaining free PATIENT EDUCATION of cigarettes for 48 hours, and reassure her that skin irritation Regardless of the product selected, T.B. should be instructed to is a common, yet generally manageable, complication with the apply the patch to a clean, dry, hairless area of skin on the upper nicotine patch. body or the upper outer part of her arm at approximately the same time each day. To minimize the potential for local skin PRODUCT SELECTION CONSIDERATIONS reactions, the patch application site should be rotated daily, and The primary advantage of the transdermal nicotine patch com- the same area should not be used again for at least 1 week. After pared with other NRT formulations is that the patch is easy to patch application, T.B. should ensure that the patch adheres well use and conceal, releases a continuous dose of nicotine through- to the skin, especially around the edges. The clinician should out the day, and requires administration only once daily. Disad- reassure T.B. that water will not reduce the effectiveness of the vantages of the patch include a high incidence of skin irritation nicotine patch if it is applied correctly,and she may bathe, shower, associated with the patch adhesives and the inability to acutely swim, or exercise while wearing the patch. Finally, T.B. should adjust the dose of nicotine to alleviate symptoms of withdrawal. be advised to discontinue use of the nicotine patch and contact a Finally, patients with underlying dermatologic conditions (e.g., health care provider if skin redness caused by the patch does not psoriasis, eczema, atopic dermatitis) should not use the patch resolveafter4days;iftheskinswellsorarashdevelops;ifirregular because they are more likely to experience skin irritation.8 heartbeatorpalpitationsoccur;orifsheexperiencessymptomsof nicotine overdose such as nausea, vomiting, dizziness, diarrhea, CASE 88-1, QUESTION 3: T.B. would like to discontinue the sweating, weakness, or rapid heartbeat. nicotine transdermal patch. She would like to purchase a nonprescription smoking-cessation medication and wants to ADVERSE REACTIONS know whether the gum or lozenge is an effective alternative. CASE 88-1, QUESTION 2: Ten days later, T.B. calls to com- eto 16 Section plain of an itchy rash that she believes is caused by the nicotine patch. She noticed the rash yesterday when she Nicotine Gum removed the first patch from her left upper arm. This morning, after removing the second patch from her right upper Nicotine polacrilex gum is a resin complex of nicotine and arm, she noticed a similar rash. T.B. describes the skin on polacrilin in a chewing gum base that provides slow release her right arm as slightly red but not swollen; the rash on and absorption of nicotine across the oral mucosa. The prod- usac Abuse Substance her left arm has only a faint trace of pink discoloration. Her uct is available in 2- and 4-mg strengths, and in multiple flavors last cigarette was 2 days ago. How should T.B. be managed (regular, cinnamon, fruit, mint, and orange). The gum has a at this time? distinct, tobaccolike, slightly peppery, minty, or fruity taste and contains buffering agents (sodium carbonate and sodium bicar- The most common side effects associated with the nicotine bonate) to increase the salivary pH, which enhances the buccal patch are local reactions (erythema, burning, and pruritus) at absorption of nicotine. The amount of nicotine absorbed from the skin application site. These reactions are generally caused by each piece is variable, but when used properly, approximately skin occlusion or sensitivity to the patch adhesives. Rotating the 1.6 mg and 2.2 mg of nicotine is absorbed from each 2-mg and patch application sites on a daily basis minimizes skin irritation; 4-mg piece of gum, respectively.22 Peak plasma concentrations nonetheless, skin reactions to the patch adhesives occur in up of nicotine are achieved approximately 30 minutes after chew- to 50% of patch users. Fewer than 5% of patients discontinue ing a single piece of gum and then slowly decline thereafter therapy because of a skin reaction.8 (Fig. 88-3). Patients using short-term (6–14 weeks) or long-term T.B.appearstobeexperiencingamildskinreactionandshould (>14 weeks) treatment with nicotine gum are significantly more be reassured that it is common for the skin to appear erythema- likely to remain abstinent compared with those receiving placebo tous for up to 24 to 48 hours after the patch is removed. T.B. (Table 88-4).8 can apply topical hydrocortisone cream (0.5% or 1%) or triam- cinolone cream (0.5%), or she can take an oral antihistamine for DOSING symptomatic treatment.8 Because the rash on her left arm has Table 88-7 outlines the manufacturers’ recommended dosing nearly resolved, it is reasonable for T.B. to continue using the schedule for the nicotine gum. The recommended dosage of nicotine transdermal patch provided that the erythema is not the nicotine gum is based on the “time to first cigarette” (TTFC) too bothersome. of the day. Having a strong desire or need to smoke soon after Other less common side effects associated with the transder- waking is viewed as a key indicator of nicotine dependence.58 mal nicotine patch include vivid or abnormal dreams, insomnia, Therefore, patients who smoke their first cigarette of the day and headache. Sleep disturbances likely result from nocturnal within 30 minutes of waking are likely to be more highly depen- nicotine absorption. Patients experiencing troublesome sleep dent on nicotine and require higher dosages than those who delay disturbances should be instructed to remove the patch before smoking for more than 30 minutes after waking (Table 88-7). P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

Specifically, if the TTFC is 30 minutes or less, therapy should be Nicotine Lozenge 2069 initiated with the 4 mg gum. If the TTFC is more than 30 minutes, therapy should be initiated with the 2 mg gum. During the initial The nicotine polacrilex lozenge is a resin complex of nicotine and 6 weeks of therapy,patients should use 1 piece of gum every 1 to polacrilin in a sugarfree, light mint, or cherry-flavored lozenge. 2hourswhileawake.Ingeneral,thisamountstoatleast9piecesof Theproductisavailablein2-and4-mgstrengths,whicharemeant gumdaily.The“chewandpark”methoddescribedhereallowsfor to be consumed like hard candy or other medicinal lozenges the slow, consistent release of nicotine from the polacrilin resin. (e.g., sucked and moved from side to side in the mouth until Patients can use additional pieces of gum (to the daily maximum fully dissolved). Because the nicotine lozenge dissolves com- of 24 pieces per day) if cravings occur between scheduled doses. pletely, it delivers approximately 25% more nicotine than does 50 In general, patients who smoke a greater number of cigarettes an equivalent dose of nicotine gum. Like the nicotine gum, the per day will require more nicotine gum to alleviate their crav- lozenge also contains buffering agents (sodium carbonate and ings than will patients who smoke fewer cigarettes per day. It is potassium bicarbonate) to increase salivary pH, thereby enhanc- preferable to use the gum on a fixed schedule of administration, ing buccal absorption of the nicotine. Peak nicotine concentra- tapering during 1 to 3 months rather than using it as needed to tions of nicotine with the lozenge are achieved after 30 to 60 control cravings.8 minutes of use and then slowly decline thereafter (Fig. 88-3). In a trial evaluating the formulation currently available in the United States, the nicotine lozenge approximately doubled the 6-month PATIENT EDUCATION abstinence rates compared with placebo (23.9% vs. 12.3%).60 A Proper chewing technique is crucial when using the nicotine meta-analysis of five studies using either the nicotine lozenge gum. Patients should be instructed to chew the gum slowly until (nicotine polacrilin) or sublingual tablet (not available in the a peppery,minty,or fruity taste or a slight tingling sensation in the United States) concluded that the odds of abstinence at 6 or more mouth is detected; this varies but generally occurs after about 15 monthswas2.0withthetabletorlozengerelativetoplacebo(95% chews. When the taste or tingling sensation is noted, the patient CI, 1.6–2.5).49 should “park” the gum between the cheek and gum to allow absorption of nicotine across the buccal mucosa. When the taste DOSING or tingling dissipates (generally after 1–2 minutes), the patient Table 88-7 outlines the manufacturers’ recommended dosing should resume chewing slowly.When the taste or tingle returns, schedule for the nicotine lozenge. Like the nicotine gum, the the patient should stop chewing and park the gum in a different lozenge is dosed based on the TTFC. Patients who smoke their area in the mouth. Rotating the gum placement site within the first cigarette of the day within 30 minutes of waking should mouth helps decrease the incidence of oral irritation. The chew use the 4-mg strength lozenge, and patients who smoke their and park steps should be repeated until most of the nicotine is first cigarette of the day more than 30 minutes after waking extracted; this generally occurs after 30 minutes and becomes should use the 2-mg strength lozenge. Patients are more likely obvious when chewing no longer elicits the characteristic taste to succeed if they use the lozenge on a fixed schedule rather or tingling sensation. than as needed. During the initial 6 weeks of therapy, patients Patients should be warned that the absorption and therefore should use 1 lozenge every 1 to 2 hours while awake. In gen- the effectiveness of nicotine gum might be reduced by acidic bev- eral, this amounts to at least 9 lozenges daily. Patients can use erages (e.g., coffee, juices, wine, soft drinks),59 which transiently additional lozenges (up to 5 lozenges in 6 hours or a maximum reduce the salivary pH. To prevent this interaction, patients of 20 lozenges per day) if cravings occur between scheduled shouldbeadvisednottoeatordrink(exceptwater)for15minutes doses. Chapter 88 before or while using the nicotine gum.

PATIENT EDUCATION ADVERSE REACTIONS Similar to the gum, the nicotine lozenge is a specially formulated The most common side effects associated with use of the nicotine nicotine delivery system that must be used properly for optimal gum include unpleasant taste, mouth irritation, jaw muscle sore- results. The lozenge should be allowed to dissolve slowly in the ness or fatigue, hypersalivation, hiccups, and dyspepsia. Many of mouth; when nicotine is released from the polacrilin resin, a these side effects can be minimized or prevented by using proper warm,tinglingsensationmaybeexperienced.Thepatientshould 8 chewing technique. Patients should be warned that chewing the occasionally rotate the lozenge to different areas of the mouth gum too rapidly may result in excessive release of nicotine, lead- to reduce the potential for mucosal irritation. When used cor- ing to lightheadedness, nausea, vomiting, irritation of the throat rectly,the lozenge should completely dissolve within 30 minutes. Tobacco Use and Dependence and mouth, hiccups, and indigestion. Patients should be counseled not to chew or swallow the lozenge because this increases the incidence of gastrointestinal-related PRODUCT SELECTION CONSIDERATIONS side effects. Advantages of nicotine gum include the fact that this formula- Because the nicotine in the lozenge is dissolved in saliva and tion may be used to satisfy oral cravings and the 4-mg strength absorbed through the buccal mucosa, patients should be cau- might delay weight gain.8 For these reasons, the gum may be par- tioned that the effectiveness of the nicotine lozenge may be ticularly beneficial for patients who have weight-gain concerns reduced by acidic beverages such as coffee, juices, wine, or soft or for patients who report boredom as a trigger for smoking. drinks. As recommended for the nicotine gum, patients should The gum might also be advantageous for patients who desire be advised not to eat or drink (except water) for 15 minutes before flexibility in dosing and prefer the ability to self-regulate nicotine or while using the nicotine lozenge. levels to manage withdrawal symptoms. Some patients may find that the viscous consistency of the gum makes it difficult to use ADVERSE REACTIONS because it sticks to dental work. Others may find it difficult or In general, the nicotine lozenge is well tolerated. The most socially unacceptable to chew the gum so frequently. Nicotine common side effects include nausea, hiccups, cough, dyspep- gum should not be used by patients with temporomandibular sia, headache, and flatulence. Patients who use more than one joint (TMJ) conditions. lozenge at a time, continuously use one lozenge after another, P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

2070 or chew or swallow the lozenge are more likely to experience should be counseled that the average weight gain of fewer than dyspepsia or hiccups. 10 pounds is less detrimental to her overall health than is continued smoking. Although exercise interventions have not been 63 PRODUCT SELECTION CONSIDERATIONS shown to reduce weight gain among quitters, it should not be The nicotine lozenge is similar to the nicotine gum formula- ruled out as a recommendation for T.B. because she expresses tion in that it may be used to satisfy oral cravings, the 4-mg significant concern about weight gain, and this might be a bar- strength might delay weight gain,8,59 and patients can self-titrate rier to her quitting. As such, it is reasonable for the clinician to therapy to acutely manage withdrawal symptoms. Because the recommend that T.B. engage in some form of physical activity, lozenge does not require chewing, many patients find this to be such as walking 30 minutes daily. Even small changes, such as a more discrete nicotine delivery system. The disadvantages of taking the stairs instead of the elevator, or parking toward the the lozenge are the fact that it requires frequent dosing, and the end of a parking lot instead of in the closest spot, can make a dif- gastrointestinal side effects (nausea, hiccups, and heartburn) may ference. Furthermore, T.B. should be advised to plan her meals be bothersome. in advance to avoid binge eating, increase her water intake to cre- T.B. has expressed interest in either the nicotine gum or ate a feeling of fullness, chew sugarless gum, and limit alcohol lozenge formulation for her quit attempt. Both agents are effec- consumption. T.B. may consider pharmacotherapy options that tive, and the choice of therapy is dependent on the patient’s have been shown to delay weight gain—according to the Clinical perceptions and expectations regarding treatment, including the Practice Guideline, this would include the 4-mg nicotine gum or 8 ability to comply with the regimen, previous experience with lozenge or sustained-release bupropion. It is important to note, cessation medications, and other concerns (e.g., adverse effects, however, that once the medication is terminated, most quitters weight gain, cost of medications). T.B. would be a candidate for gain, on average, an amount of weight that is comparable to that 8 either agent provided she is able to comply with the frequent dos- which would have been gained in the absence of medication. ing schedule (one lozenge or piece of gum every 1–2 hours while she is awake). T.B. smokes her first cigarette of the day immediately after waking in the morning and she smokes approximately Relapse Back to Smoking 30 cigarettes/day; this smoking pattern suggests a higher degree of nicotine dependence, and therefore T.B. would benefit from a CASE 88-1, QUESTION 5: During a follow-up contact, the higher dose of NRT.T.B. should initiate treatment with the 4-mg clinician learns that T.B. smoked half a pack of cigarettes at strength of either the nicotine lozenge or nicotine gum dosed a party over the weekend and has relapsed to her previous every 1 to 2 hours while she is awake and tapered according to smoking levels after not having smoked for more than a the schedule outlined in Table 88-7. month. How should the clinician respond? The clinician should thank T.B. for being honest about her Postcessation Weight Gain smoking and ask whether she is comfortable discussing the circumstances during which the smoking occurred. At the time of eto 16 Section CASE 88-1, QUESTION 4: T.B. is very concerned about gain- her smoking, where was she, who was she with, how did she ing weight after she quits smoking. Is weight gain common get access to cigarettes, and how was she feeling at the time? after quitting, and if so, how can this be prevented? What, specifically,were the triggers for her relapse (e.g., alcohol, depression, friends who were smoking around her)? It is impor- Most tobacco users gain weight after quitting, and clinicians tant that the clinician help the patient to use this information as should neither deny the likelihood of weight gain nor minimize part of the learning process, but it also is important to focus on usac Abuse Substance its significance.8 For nearly all patients, the health risks associated the “positive,” such as T.B.’s ability to have remained tobacco free with postcessation weight gain are negligible compared with the for more than 1 month. Four weeks after quitting, most physi- risks of continued smoking. cal effects of nicotine withdrawal have completely resolved, and Studies suggest that most quitters gain fewer than 10 pounds, thus, the relapse trigger for T.B. likely was psychological or situa- but there is a broad range of weight gain reported, with up tional and could be abated through application of effective coping to 10% of quitters gaining as much as 30 pounds.8 In general, techniques. After an informative discussion about the situation women tend to gain more weight than men. In a study of nearly in which the smoking occurred, it is important that the clini- 6,000 smokers who were followed for 5 years after quitting, the cian work with the patient in identifying strategies for avoiding average weight gain during the follow-up period was 19.2 and relapse in the future (Table 88-6). 16.7 pounds among women and men, respectively.61 For men and women, subgroups that are more likely to gain weight after Smoking and Cardiovascular Disease quitting are African Americans, younger tobacco users (younger than 55 years), and heavier tobacco users (those smoking more CASE 88-2 than 25 cigarettes per day). QUESTION 1: P.J. is a 62-year-old man admitted for an The weight-suppressing effects of tobacco are well known. elective coronary artery bypass graft (CABG) procedure. However, the mechanisms to explain why most successful quit- His medical history is significant for angina, hypertension, ters gain weight are not completely understood. Smokers have dyslipidemia, peripheral vascular disease (PVD), and aller- been found to have an approximately 10% higher metabolic rate gic rhinitis. He underwent a bilateral carotid endarterec- 62 compared with nonsmokers. Increased postcessation caloric tomy procedure 2 years ago and had iliac artery angio- intake might result from an increase in appetite, improved sense plasty with stent placement 5 years ago for PVD. P.J.’s of taste, or a change in the hand-to-mouth ritual through the social history is significant for tobacco use (2 PPD) and substitution of tobacco with food. alcohol (3–4 drinks/day). He is approximately 10 pounds In general, a patient is less likely to be successful if he or overweight. His preoperative laboratory results are signifi- she attempts to change multiple behaviors at once. For most cant for a total cholesterol of 270 mg/dL (desirable, <200), patients, strict dieting to prevent weight gain, especially during low-density lipoprotein cholesterol (LDL-C) of 163 mg/dL the early stages of quitting, is generally not recommended.8 T.B. P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

2071 (optimal, <70), high-density lipoprotein cholesterol (HDL-C) Noncigarette Forms of Tobacco of 35 mg/dL (low, <40), and triglycerides of 350 mg/dL (normal, <150). His medications before admission include CASE 88-2, QUESTION 2: The cardiothoracic surgeon has atenolol 50 mg daily, aspirin 81 mg daily, isosorbide dini- strongly advised P.J. to quit smoking. P.J. would like to trate 20 mg TID, atorvastatin 20 mg daily, fluticasone nasal know whether cutting down to one to two cigars a day is spray (50 mcg/spray) 1 spray/nostril daily, and nitroglycerin an acceptable alternative to his current one to two packs of 0.4 mg sublingually as needed. Which of P.J.’s chronic medi- cigarettes per day. cal conditions may be caused or exacerbated by his tobacco use? 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 A wealth of evidence suggests that cigarette smoking is a smokers who inhale deeply are at increased risk for developing major cause of cardiovascular disease and is responsible for cardiovascular disease and chronic obstructive pulmonary dis- approximately 128,000 premature cardiovascular-related deaths 70,71 5 ease (COPD). Cigarette smokers who switch to smoking each year. Smoking is known to accelerate the process of only cigars decrease their risk of developing lung cancer, but atherosclerosis, leading to chronic cardiovascular disorders, their risk is markedly higher than if they were to quit smoking including coronary heart disease, cerebrovascular disease, PVD, 71 3 altogether. aorticaneurysm,andcongestiveheartfailure. Inaddition,smok- Cigar weight and nicotine content vary widely from brand to ing substantially elevates the risk for acute cardiovascular events, brand and from cigar to cigar. Most cigars range in weight from including sudden death, myocardial infarction (MI), stroke, and about 1 to 22 g, and a typical cigarette weighs less than 1 g. The reocclusion of coronary or peripheral vessels after graft surgery 3,64 nicotine content of ten commercially available cigars studied in or angioplasty. 1996 ranged from 10 to 444 mg. In comparison, US cigarettes There are numerous plausible pathophysiological mecha- have a relatively narrow total nicotine content range (mean, nisms by which tobacco smoking contributes to the development ± 72 7 13.5 0.1 mg) per cigarette. Relating these data, Henningfield of cardiovascular disease. Oxidant gases and other compounds and colleagues concluded that it is possible for one large cigar in tobacco smoke are believed to induce a hypercoagulable state to contain as much tobacco as an entire pack of cigarettes and characterized by increased platelet aggregation and thrombo- deliver enough nicotine to establish and maintain dependence.73 sis, which substantially increases the risk of MI and sudden 64,65 P.J.shouldbecounseledthatswitchingfromcigarettesmoking death. The carbon monoxide in smoke reduces the amount to low-level daily cigar smoking is not acceptable given his signif- of oxygen available to tissues and organs, including myocardial 64 icant underlying cardiovascular disease. The amount of nicotine tissue, and may reduce the ventricular fibrillation threshold. delivered by one to two cigars per day is capable of sustaining his Smoking may accelerate atherosclerosis through effects on dependence on nicotine. Furthermore, former cigarette smok- serum lipids; smokers tend to have higher levels of total ers are more likely to inhale deeply, which further increases the cholesterol, LDL-C, and triglycerides and lower HDL-C than 3 risk of cancer and cardiovascular and pulmonary disease. The nonsmokers. Smoking increases the levels of inflammatory clinician should strongly advise P.J. to quit smoking cigarettes mediators (C-reactive protein, leukocytes, and fibrinogen), and that switching to cigars is not a safe alternative. which might contribute to the development and progression of atherosclerosis.66 Finally, smoking stimulates the release of neu- CASE 88-2, QUESTION 3: P.J. is willing to quit completely, rotransmitters (e.g., epinephrine, norepinephrine) that increase Chapter 88 myocardial workload and induce coronary vasoconstriction, but he is worried because he has tried to quit smoking “hun- leading to ischemia, arrhythmias, and sudden death.3,64 dreds of times” and has never been able to quit for longer P.J.’s hospital admission for a CABG procedure for coronary than 1 week. He expresses a desire for a medication to assist heart disease and angina, as well as previous procedures for him during this quit attempt. He has tried the nicotine gum peripheral vascular disease (angioplasty with stent placement) and transdermal patch during three previous quit attempts. and cerebrovascular disease (bilateral carotid endarterectomy), He did not like the gum because it made his jaw sore. He are all conditions associated with chronic tobacco use. His ele- had temporary success with the nicotine patch but found vated total cholesterol, LDL-C, and triglycerides, and reduced it to be less flexible than the gum. For example, when he HDL-C levels are consistent with smoking-induced dyslip- needed extra nicotine during stressful situations, he could idemia. Cigarette smoking in combination with P.J.’s other estab- not apply a second patch. What treatment alternatives are reasonable for P.J.? lished cardiovascular risk factors (hypertension, dyslipidemia) Tobacco Use and Dependence have synergistically increased his risk for serious cardiovascular disease.3,64 Fortunately, the effects of smoking on lipids, coagu- P.J. has inadequately responded to treatment with the trans- lation, myocardial workload, and coronary blood flow appear to dermal patch and experienced intolerable jaw soreness with the be reversible, and P.J.’s risk of developing further cardiovascular- nicotine gum. Newer formulations of the nicotine gum are less related complications will markedly decrease if he is able to viscous, and therefore easier to chew, than earlier formulations quit smoking.37,67 A meta-analysis of 20 studies determined that of the gum; however, other options are available. First-line treat- smoking cessation is associated with a 36% reduction in the risk ment options that he has not tried include the nicotine lozenge of death among patients with established coronary heart disease. (see Case 88-1, Question 3), nicotine nasal spray,nicotine inhaler, The reduced mortality risk associated with quitting smoking is sustained-release bupropion, varenicline, or an effective combi- comparable to that observed with other established secondary nation of first-line agents (see Case 88-3, Question 1). preventative approaches such as therapies for hyperlipidemia and hypertension.68 The clinician should approach this hospi- talization as an opportunity to assist P.J. with quitting smoking.8 Nicotine Nasal Spray Furthermore, published data suggest that initiation of intensive The nicotine nasal spray is an aqueous solution of nicotine cessation counseling interventions for hospitalized patients is available in a metered-spray pump for administration to the effective in achieving long-term abstinence.69 nasal mucosa. Each actuation delivers a metered 50-μL spray P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

2072 containing 0.5 mg of nicotine. Nicotine in the nasal spray is accompany smoking. The nicotine inhaler was designed to pro- more rapidly absorbed than other NRT formulations (Fig. 88-3), vide nicotine replacement in a manner similar to smoking while with peak venous nicotine concentrations achieved within 11 to addressing the sensory and ritualistic factors that are important 18 minutes after administration.22 Use of the nicotine nasal spray to many patients who smoke.51 more than doubles long-term abstinence rates when compared As a patient inhales through the mouthpiece, nicotine vapor with placebo (Table 88-4).8,49 is released from the cartridge and is distributed throughout the oral cavity. When the inhaler is used correctly, approximately DOSING 4 mg of nicotine vapor is released from the cartridge, and Table 88-7 outlines the manufacturers’ recommended dosing 2 mg is absorbed across the buccal mucosa.76 Peak plasma nico- schedule for the nicotine nasal spray. A dose of nicotine (1 mg) tine concentrations with the inhaler are achieved after approx- is administered as two sprays, one (0.5-mg spray) in each nostril. imal 30 minutes of use22 and then slowly decline thereafter The recommended initial regimen is one to two doses every hour (Fig. 88-3). Use of the nicotine inhaler approximately dou- while awake for 6 to 8 weeks. This may be increased, as needed, bles long-term abstinence rates when compared with placebo to a maximum recommended dosage of five doses per hour or (Table 88-4).8,49 40 mg/day. For best results, patients should be encouraged to use at least eight doses per day during the initial 6 to 8 weeks of DOSING therapy because less frequent administration may be less effec- Table 88-7 outlines the manufacturers’ recommended dosing tive. After 6 to 8 weeks, the dose should be gradually decreased schedule for the nicotine inhaler. During the initial 3 to 6 weeks during an additional 4 to 6 weeks. of treatment, the patient should use 1 cartridge every 1 to 2 hours while awake. This should be increased, as needed, to a maximum PATIENT EDUCATION of 16 cartridges per day.In clinical trials, most successful quitters Before using the nasal spray for the first time, the nicotine nasal used an average of 6 to 16 cartridges per day. The manufacturer spray pump must be primed. This is done by actuating the device recommends that each cartridge be depleted of nicotine by fre- into a tissue until a fine spray is visible (about six to eight times). quent continuous puffing for 20 minutes. The recommended When administering a dose, the patient should tilt the head back duration of treatment is 3 months, after which patients may be slightly and insert the tip of the bottle into the nostril as far as is weaned from the inhaler by gradual reduction of the daily dose comfortable. After actuation of the pump, the patient should not during the following 6 to 12 weeks. sniff, swallow, or inhale through the nose because this increases the irritant effects of the spray. The spray increases the likelihood of tearing, coughing, and sneezing, so patients should wait PATIENT EDUCATION 5 minutes before driving or operating heavy machinery. Tominimize the likelihood of throat irritation, patients should be instructed to inhale shallowly (as if puffing a pipe). When used ADVERSE REACTIONS correctly, 100 shallow puffs from the inhaler mouthpiece dur- Side effects commonly reported with the nicotine nasal spray ing 20 minutes approximate 10 puffs from one cigarette during eto 16 Section include nasal and throat irritation (hot peppery sensation), sneez- 5 minutes.51 The release of nicotine from the inhaler is tem- ing, coughing, watery eyes, and rhinorrhea. In clinical trials, 94% perature dependent and significantly reduced at temperatures of patients report moderate-severe nasal irritation during the first less than 40◦F. 8,51 In cold conditions, patients should store the 2 days of therapy; 81% of patients still reported mild to moderate inhaler and cartridges in a warm place (e.g., inside pocket).8 Con- nasal irritation after 3 weeks of therapy.8 Nasal congestion and versely, under warmer conditions, more nicotine is released per 8

usac Abuse Substance transient changes in taste and smell have also been reported. puff. However, nicotine plasma concentrations achieved using Despite the high incidence of local adverse effects, most patients the inhaler in hot climates at maximal doses will not exceed become tolerant to the irritant effects of the spray during the first levels normally achieved with smoking.51 week.74 As with all forms of NRT that are absorbed across the buccal mucosa, the effectiveness of the nicotine inhaler is reduced by PRODUCT SELECTION CONSIDERATIONS acidic foods and beverages, such as coffee, juices, wine, or soft The primary advantage in using the nicotine nasal spray is the drinks. Therefore, patients should be instructed not to eat or ability to rapidly titrate therapy to manage withdrawal symp- drink anything (except water) for 15 minutes before or while toms. However, because nicotine from the spray more rapidly using the inhaler. penetrates the central nervous system, there may be a higher likelihood of developing dependence during treatment. The nicotine ADVERSE REACTIONS nasal spray has a dependence potential intermediate between The most common side effects associated with the nicotine tobacco products and other NRT products. Individuals with inhaler include mouth or throat irritation (40%) and cough chronic nasal disorders (e.g., rhinitis, polyps, sinusitis) or severe (32%).8 Most patients rated cough and mouth and throat irri- reactive airway disease should not use the nicotine nasal spray tation symptoms as mild, decreasing with continued use. Other because of its irritant effects. Exacerbation of asthma has been less common side effects are rhinitis, dyspepsia, hiccups, and reported after use of the nicotine nasal spray.75 headache. Adverse reactions necessitating discontinuation of treatment occurred in less than 5% of patients using the inhaler. Nicotine Inhaler The nicotine oral inhaler consists of a plastic mouthpiece and a PRODUCT SELECTION CONSIDERATIONS disposable cartridge containing a porous plug containing 10 mg Patients who express a preference for therapy that can be easily of nicotine and 1 mg of menthol. Menthol is added to reduce the titrated to manage withdrawal symptoms or one that mimics the irritant effect of nicotine. hand-to-mouth ritual of smoking may find the nicotine inhaler to Given that the usual pack-a-day smoker repeats the hand-to- be an appealing option. Patients with underlying bronchospastic mouth motion up to 200 times per day or 73,000 times each year, conditions should use the nicotine inhaler with caution, because it is not surprising that many smokers find they miss the phys- the nicotine vapor can be irritating and might induce bron- ical manipulation of the cigarette and associated behaviors that chospasm. P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

Sustained-Release Bupropion In clinical trials for smoking cessation, the frequency of seizures 2073 with sustained-release bupropion was less than 0.1% (seven Sustained-release bupropion was the ﬁrst nonnicotine medica- seizures among 8,000 bupropion-treated patients),54 which is tion to receive FDA approval for smoking cessation. Clinical comparable to the reported incidence of seizures (0.1%) with trials involving more than 11,000 patients have conﬁrmed its the sustained-release formulation (Wellbutrin) when used for the 54 effectiveness as an aid for smoking cessation, and meta-analyses treatment of depression.78 For this reason, bupropion should be estimate that sustained-release bupropion treatment approxi- used with extreme caution in patients with a history of seizures or mately doubles long-term abstinence rates relative to placebo cranial trauma, in individuals taking medications that may lower 8,54 (Table 88-4). the seizure threshold, and in patients with underlying severe hepatic cirrhosis. Animal studies suggest that seizures may be PHARMACOKINETICS related to the peak plasma concentration of bupropion,79 and as a Animal data suggest the absolute bioavailability of bupro- precautionary measure, the manufacturer recommends that pion ranges from 5% to 20%. It undergoes extensive hepatic patients space the doses at least 8 hours apart and limit the metabolism to three active metabolites; one of the metabolites, total daily dose to no more than 300 mg. In July 2009, the FDA hydroxybupropion, is formed by the cytochrome-P450 isoen- mandated that the prescribing information for all bupropion- zyme CYP2B6. Bupropion and its metabolites are eliminated in containing products include a black-boxed warning highlight- urine (87%) and feces (10%), with less than 1% being excreted ing the risk of serious neuropsychiatric symptoms, including unchanged in the urine. The half-life for bupropion is 21 hours, changes in behavior, hostility,agitation, depressed mood, suicidal and its metabolites have a half-life range of 20 to 27 hours; steady- thoughtsandbehavior,andattemptedsuicide.77 Theseadditional state plasma concentrations are reached within 5 and 8 days, warnings were based on postmarketing adverse-event surveil- respectively.77 lance reports received by the FDA.

DOSING PRODUCT SELECTION CONSIDERATIONS Treatment with sustained-release bupropion (Table 88-7) should Sustained-release bupropion may be the drug of choice for be initiated while the patient is still smoking, because approxi- patients who prefer to take oral medications (an alternative oral mately 1 week of treatment is necessary to achieve steady-state optionisvarenicline,describedbelow).Becausesustained-release blood levels. Patients should set a target quit date that falls within bupropion tablets are easy to dose (twice daily oral dosing), this the first 2 weeks of treatment, generally in the second week. The agent may be preferable for patients with regimen compliance starting dose of sustained-release bupropion is one 150-mg tablet concerns (e.g., those unable to consistently use short-acting NRT each morning for the first 3 days. If the initial dose is tolerated, formulations that require multiple daily doses). Sustained-release the dosage should be increased on the fourth day to the recom- bupropion might be beneficial for use in patients with coexisting mended maximal dosage of 300 mg/day (150 mg BID). Therapy depression or in individuals with a history of depressive symp- should be continued for 7 to 12 weeks after the quit date. toms during a previous quit attempt. Finally, sustained-release bupropion has been found to reduce postcessation weight gain PATIENT EDUCATION during treatment,8,63 and this might be of short-term benefit Patients should be instructed to follow the dosing regimen in selected patients with concerns about weight gain after quit- described previously. Advise patients experiencing insomnia to ting.Disadvantagesofsustained-releasebupropionincludeahigh avoid taking the second dose close to bedtime. Inform patients prevalence of insomnia and several contraindications and precau-

that bupropion might cause dizziness, drowsiness, or reduced tions that preclude use in some patients. Chapter 88 alertness, and caution should be exercised when driving or operating machinery. Because alcohol use might increase the likelihood of seizures, patients should avoid or drink alcohol only Varenicline in moderation while taking bupropion. Patients who consume Varenicline is the most recent agent approved by the FDA for alcohol regularly should be advised to talk with a health care smoking cessation. Clinical trials involving nearly 5,000 patients provider about their alcohol use before initiating bupropion ther- treated with varenicline have conﬁrmed its effectiveness as an apy because abrupt cessation of alcohol use while taking bupro- aid for smoking cessation. Data from meta-analyses indicate that pion might increase the risk of seizure. Patients should also be varenicline signiﬁcantly increases long-term abstinence rates rel- advised not to take Zyban and Wellbutrin or generic bupropion ative to placebo,8,57 NRT,57 and sustained-release bupropion.8,57 formulations concomitantly to avoid dose-related adverse effects, The pooled risk ratio for long-term abstinence (≥6 months) for

including seizures. varenicline compared with placebo was 2.3 (95% CI, 1.9-2.9). The Tobacco Use and Dependence pooled risk ratio for varenicline versus sustained-release bupro- ADVERSE REACTIONS pion and the nicotine patch at 1-year follow-up was 1.5 (95% CI, The most common adverse effects associated with bupropion 1.2-1.9) and 1.3 (95% CI, 1.0-1.7), respectively.57 therapy include insomnia (35%–40%) and dry mouth (10%)8; these usually lessen with continued use. Taking the second PHARMACOKINETICS daily dose in the early evening, but no sooner than 8 hours Varenicline absorption is virtually complete after oral admin- after the ﬁrst dose, might reduce insomnia. Less common side istration, and oral bioavailability is unaffected by food. Once effects include headache, nausea, tremors, and rash. Seizures are absorbed, varenicline undergoes minimal metabolism, with 92% a dose-related toxicity associated with bupropion therapy. For excreted unchanged in the urine. Renal elimination is pri- this reason, bupropion is contraindicated in patients with under- marily through glomerular ﬁltration, along with active tubu- lying seizure disorders and those receiving concurrent therapy lar secretion.80 The half-life is approximately 24 hours,80 and with other forms of bupropion (Wellbutrin, Wellbutrin SR, and following administration of multiple oral doses, steady-state con- Wellbutrin XL). Bupropion also is contraindicated in patients ditions are reached within 4 days.81 withanorexiaorbulimianervosa,patientsundergoingabruptdis- continuation of alcohol or sedatives (including benzodiazepines), DOSING and patients currently taking monoamine oxidase inhibitors Treatment with varenicline (Table 88-7) should be initiated owing to the increased potential for seizures in these populations. 1 week before the patient stops smoking. This dosing regimen P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

2074 allows for gradual titration of the dose to minimize treatment- medications, varenicline should be combined with behavioral related nausea and insomnia. The recommended dosage titra- counseling to maximize chances for a successful, long-term quit tion for varenicline is as follows: 0.5 mg daily days 1 to 3, attempt. Given its potential for inducing negative neuropsychi- 0.5 mg twice daily days 4 to 7, and 1 mg twice daily weeks 2 to atric effects, varenicline should be used with extreme caution in 12. For patients who have successfully quit smoking at the end patients with a current or past history of psychiatric illness. of 12 weeks, an additional course of 12 weeks may be considered P.J. has tried the nicotine gum and transdermal patch during to increase the likelihood of long-term abstinence. Varenicline previous quit attempts. Because he was intolerant to the nico- should be used with caution in patients with impaired renal func- tine gum (it stuck to his dental work), this form of NRT is not tion. For patients with severe renal dysfunction (estimated cre- appropriate. P.J.’s experience with the transdermal patch sug- atinine clearance <30 mL/minute) the recommended maximal gests he may benefit from a short-acting NRT formulation that dose of varenicline is 0.5 mg twice daily. In patients with end- enables active administration and titration of drug as needed to stage renal disease undergoing hemodialysis, a maximal dose of alleviate symptoms of withdrawal and situational cravings. Other 0.5 mg daily is recommended.80 first-line therapies include the nicotine nasal spray, inhaler, and lozenge; sustained-release bupropion; or varenicline. P.J. should PATIENT EDUCATION not use the nicotine nasal spray because he has allergic rhinitis The tablets are to be taken after eating and with 8 ounces of and may be more susceptible to the irritant effects of the spray. water. Nausea and insomnia are side effects that are usually tem- In addition, some data suggest that the bioavailability of nicotine porary.Patients should be advised to discontinue varenicline and is reduced in patients with rhinitis.82 Furthermore, the safety contact their health care provider immediately if they experi- and efficacy of the nasal spray in patients with chronic nasal ence agitation, hostility,depressed mood, or changes in behavior disorders have not been adequately studied. Reasonable choices or thinking that are not typical for them (see adverse reactions for P.J. therefore include sustained-release bupropion, nicotine below). lozenge, nicotine inhaler, or varenicline. Any of these options are reasonable, and the choice of therapy should be dictated ADVERSE REACTIONS by P.J.’s individual preference. If varenicline is chosen, given P.J. Varenicline is generally well tolerated. Common side effects has underlying cardiovascular disease, he should be instructed to (≥5% and twice the rate observed in placebo-treated patients) notify a health care provider for new or worsening cardiovascular include nausea (30%), sleep disturbance (insomnia 18%; abnor- symptoms and to seek immediate medical attention if he expe- mal dreams 13%), constipation (8%), flatulence (6%), and vomit- riences signs and symptoms of myocardial infarction. Finally, it ing (5%). Per the manufacturer’s prescribing information, nausea is reasonable to consider combination therapy (see Case 88-3, was the most common adverse event associated with varenicline Question 1). treatment. Nausea was dose dependent and generally described as mild or moderate and often transient; however, for some Safety of Nicotine Replacement Therapy patients, it was persistent for several months. Initial dose titration was beneficial in reducing the occurrence of nausea. Approxi- Among Patients With Cardiovascular eto 16 Section mately 3% of subjects receiving varenicline 1 mg BID discontin- Disease ued treatment prematurely because of nausea. For patients with intolerable nausea, dose reduction should be considered.80 CASE 88-2, QUESTION 4: P.J. would like to try the nicotine In July 2009, the FDA mandated that the prescribing infor- inhaler. Is NRT safe for use in patients with cardiovascular mation for varenicline include a black-boxed warning high- disease? lighting the risk of serious neuropsychiatric symptoms includ- usac Abuse Substance ing changes in behavior, hostility, agitation, depressed mood, Nicotine activates the sympathetic nervous system, leading to and suicidal-related events including ideation, behavior, and an increase in heart rate, blood pressure, and myocardial contrac- attempted suicide.80 These additional warnings were based tility.Nicotinealsomaycausecoronaryarteryvasoconstriction.83 on continued postmarketing adverse-event surveillance reports Theseknownhemodynamiceffectsofnicotinehaveledtodoubts received by the FDA. As such, the warnings and precautions about the safety of using NRT in patients with established car- sections of the medication’s prescribing information have been diovascular disease, particularly those with serious arrhythmias, updated, and the FDA recommends that (a) patients tell their unstable angina, or recent MI. health care providers about any history of psychiatric illness Soon after the nicotine patch was approved, anecdotal case before starting varenicline, and (b) clinicians and patients mon- reports in the lay press linked NRT (patch and gum) with adverse itor for changes in mood and behavior during treatment with cardiovascular events (i.e., arrhythmias, MI, stroke). Since then, varenicline.80 Because patients with serious psychiatric illness several randomized, controlled trials have evaluated the safety of such as schizophrenia, bipolar disorder, and major depressive NRT in patients with cardiovascular disease, including angio- disorder did not participate in the premarketing studies of vareni- graphically documented coronary artery stenosis, MI, stable cline, the safety and efficacy of varenicline has not been estab- angina, and previous CABG surgery or angioplasty.84–86 The lished in these populations.80 Recently the prescribing infor- results of these trials suggest no significant increase in the inci- mation for varenicline was revised to include warning for a dence of cardiovascular events or mortality among patients possible increased risk of cardiovascular events (MI, ischemic receiving the nicotine patch when compared with placebo. How- and hemorrhagic stroke) in patients with stable cardiovascular ever,becausethesetrialsspecificallyexcludedpatientswithunsta- disease.80 ble angina, serious arrhythmias, and recent MI, the manufacturers of NRT products recommend that these agents be used PRODUCT SELECTION CONSIDERATIONS with caution among patients in the immediate (within 2 weeks) Varenicline is a first-line agent for the treatment of tobacco use post-MI period, those with serious arrhythmias, and those with anddependence.8 Itoffersaconvenientoraldosingregimenanda unstable angina.8 It is notable, however, that NRT products new mechanism of action that might be particularly appealing for (patch, nasal spray) have been shown to have fewer effects on patients who have failed quit attempts with other first-line agents biomarkers of cardiovascular risk than does smoking,87 and (e.g., NRT or sustained-release bupropion). As with any of these smoking cessation has been shown to improve cardiovascular P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

parameters with no negation of these improvements with use of nosed with COPD are current or former smokers.93 Medica- 2075 NRT.88 tions (e.g., bronchodilators, anti-inflammatory agents) used to Although two small, retrospective studies have raised ques- treat the symptoms of COPD have not been shown to alter the tions regarding the safety of NRT use in intensive care disease progression.93 J.B.’s pulmonary function tests indicate he settings,89,90 NRT use in patients with cardiovascular disease has has stage II (moderate) COPD.93 Given his escalating pulmonary been the subject of numerous reviews, and it is widely believed symptoms, it is imperative that he stop smoking as soon as possi- by experts in the field that the risks of NRT in this patient pop- ble. J.B. should be advised that medications for COPD offer only ulation are small in relation to the risks of continued tobacco limited symptomatic relief, and the most important component use.7,49,64,83,91,92 The 2008 Clinical Practice Guideline con- of his treatment is smoking cessation.93,94 The clinician should cludes that there is no evidence of increased cardiovascular risk commend J.B. for his interest in quitting and help him devise a with these medications.8 Although the use of NRT may pose patient-specific treatment plan. some theoretical risk in a patient like P.J., cigarette smoking is Although the use of first- and second-line medications approx- far more hazardous to his health. Cigarettes, unlike NRT,deliver imately double the likelihood that a patient will successfully quit numerous toxins that induce a hypercoagulable state, reduce the smoking, data from clinical trials suggest that only 15% to 25% oxygen-carrying capacity of hemoglobin, and adversely affect of patients remain abstinent for more than 6 months.49,54,57,95 serum lipids. The amount of nicotine that P.J. would receive using Given these modest success rates, clinicians and researchers have the recommended dose of any NRT product will not exceed the explored modified approaches to standard therapies, including amount he previously obtained from his 2 PPD smoking habit. the use of combination therapy. The clinician should strongly encourage pharmacotherapy dur- Plasma levels of nicotine achieved with standard doses of ing P.J.’s current quit attempt. P.J. is 10 pounds overweight; the NRT are generally much lower than those attained with reg- additional risk imposed by a modest weight gain after smoking ular smoking.74,96,97 As such, conventionally dosed NRT may cessation likely will not be of clinical significance compared with deliver subtherapeutic nicotine levels for some individuals, and that of continued smoking. in particular, for moderate-to-heavy smokers. Indeed, based on data from eight clinical trials, the 2008 Clinical Practice Guide- line has identified selected combinations of medications that Combination Therapy for Tobacco can be considered in the initial treatment of tobacco depend- Dependence ence.8 CombinationNRTregimens,whichtypicallyconsistofalong- CASE 88-3 acting agent (nicotine patch) in combination with a short-acting QUESTION 1: J.B. is a 60-year-old man referred to the formulation (i.e., gum, lozenge, inhaler, or nasal spray), are being pulmonary clinic for further evaluation and management increasingly used as initial therapy.The long-acting formulation, of his chronic obstructive pulmonary disease (COPD). He which delivers nicotine at a relatively constant level, is used to complains of decreased exercise tolerance and has noted prevent the onset of severe withdrawal symptoms, and the short- increasing shortness of breath (SOB) with minimal exertion actingformulation,whichdeliversnicotineatamorerapidrate,is (e.g., while golfing or climbing stairs). He currently uses an used as needed to control withdrawal symptoms that may occur albuterol inhaler (90 mcg/puff), 2 puffs every 4 hours regu- during potential relapse situations (e.g., after meals, during times larly for SOB. His medical history is otherwise unremarkable of stress, when around other smokers). except for osteoarthritis controlled with acetaminophen Controlled trials suggest that the nicotine patch in combi-

1 g TID. He has smoked approximately 1.5 to 2 PPD for nation with short-acting NRT formulations (i.e., gum, lozenge, Chapter 88 more than 40 years. J.B. indicates he has made several quit nasal spray, or inhaler) significantly increase quit rates relative , , attempts during the past year. On the first attempt (quitting to placebo.8 49 98 Similar results have been observed in trials “cold turkey”), J.B. relapsed within 2 days. J.B. successfully using combination therapy with sustained-release bupropion quit for nearly 2 weeks on his second attempt (using the 4- and the nicotine patch. More recent data suggest that aggres- mg nicotine lozenge), but he found it difficult to adhere to sive combination regimens including triple-agent NRT (e.g., the frequent dosing schedule and relapsed shortly after dis- patch, inhaler, and nasal spray) with or without sustained-release continuing the lozenge. His most recent quit attempt was bupropion99 and triple-combination therapy (e.g., patch, inhaler, 6 months ago using varenicline. After 1 month of absti- and sustained-release bupropion)100 are a safe and effective treat- nence, J.B. self-terminated varenicline (“I thought I didn’t ment approach. need it anymore”) and relapsed within 1 week. On further Clinicians should be aware that although the combination

questioning, J.B. states that he did not enroll in a behavioral of the nicotine patch and sustained-release bupropion has been Tobacco Use and Dependence counseling program or seek additional assistance (other approved by the FDA, the concurrent use of multiple NRT prod- than pharmacotherapy) during any of his quit attempts. He uctsisnotFDA-approvedfortobaccocessation.Furthermore,the expresses an interest in smoking cessation but is discour- optimal agents, dosages, and durations of therapy for NRT com- aged by his prior lack of success. On physical examination, bination therapy are currently unknown. Although the safety coarse breath sounds that clear after coughing are noted. A and efficacy of varenicline-based combination regimens have chest radiograph obtained in the office shows no infiltrates. not been established, preliminary uncontrolled data suggest that Spirometry reveals a forced expiratory volume in 1 second varenicline in combination with sustained-release bupropion101 (FEV1) of 2.8 L (72% of predicted) and a forced vital capac- or NRT (patch in combination with gum, lozenge, inhaler or 102 ity (FVC) of 4.1 L (81% of predicted). His FEV1/FVC ratio is nasal spray) might be a viable treatment approach. However, 68%. He weighs 76 kg and is 72 inches tall. J.B. is concerned data from randomized, controlled trials are needed before vareni- about his worsening pulmonary function and is committed cline combination therapy can be recommended as a therapeutic to making another effort to quit. What treatment options approach for smoking cessation. are appropriate for J.B.? Given the severity of J.B.’s condition and his willingness to quit now, the clinician should initiate treatment as soon as possible. Tobacco smoking is the single most important risk factor His treatment should consist of pharmacotherapy in conjunction for the development of COPD7, and nearly all patients diag- with behavioral counseling and appropriate follow-up. P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

2076 PHARMACOTHERAPY 10 mg as needed for allergies, and ibuprofen 400 mg as The clinician should work with J.B. to select the most appropri- needed for dysmenorrhea. She has no significant medical ate pharmacotherapy. As noted previously, appropriate options history. Her father has hypertension and suffered an MI would include the various NRT formulations, sustained-release last year. Her mother has type 2 diabetes and dyslipidemia. bupropion, varenicline, or an effective combination of first-line Her social history is significant for tobacco use (1 PPD for agents. The choice of therapy is dictated by considerations such 15 years), alcohol (1 glass of wine per night), and caffeine as patient preference for a given agent, previous experience with (3–4 cups of coffee daily). Are there any potential drug inter- cessation medications, current medical conditions, previous lev- actions with M.K.’s new prescription? els of smoking, medication adherence issues, and the patient’s out-of-pocket costs. For patients reporting a positive experience with a given medication, retreatment with the same agent or a combination of agents might be appropriate, with consideration SMOKING AND COMBINED HORMONAL given to increasing the dose, frequency, or duration of therapy. CONTRACEPTIVES For patients reporting a negative experience with pharmacother- One of the most important, but often unrecognized, precautions apy (e.g., poor adherence, side effects, palatability issues, cost), toconsiderwithoralcontraceptiveuseisthepotentialinteraction an alternative agent should be considered. Given J.B.’s previ- between tobacco smoke and estrogens in combination hormonal ous adherence issues with the nicotine lozenge as monotherapy, contraceptives (see Chapter 47, Contraception). Estrogens are it might be preferable to use a long-acting cessation medica- known to promote coagulation by altering clotting factor levels tion such as the nicotine patch, sustained-release bupropion, or and increasing platelet aggregation. As described in Case 88-2, varenicline. Combination therapy with the nicotine patch and Question 1, substances present in tobacco smoke, including oxi- sustained-release bupropion or a short-acting NRT formulation dant gases and other products of combustion, induce a hyperco- (e.g., nicotine gum, lozenge, or inhaler used as needed) would agulable state, increasing the risk of acute cardiovascular events. also be appropriate. Exposure to both factors (smoking and high levels of estrogen) greatly increases the risk of thromboembolic and thrombotic disorders. Considerable epidemiologic evidence indicates that BEHAVIORAL COUNSELING cigarette smoking substantially increases the risk of adverse car- Although medications are effective alone in helping patients quit diovascular events, including stroke, MI, and thromboembolism smoking, maximizing patients’ chances for a long-term, suc- in women who use oral combination hormonal contraceptive cessful quit attempt requires the use of one or more medica- agents.104,105 This risk is age-related, in that the absolute risk of tions in combination with behavioral counseling. J.B.’s previous death as a result of cardiovascular disease in oral contraceptive 1-month-long quit attempt highlights the successful impact users who smoke is 3.3 per 100,000 women ages 15 to 34 years of varenicline in this patient; however, J.B.’s relapse likely is compared with 29.4 per 100,000 women ages 35 to 44 years. attributable to a shortened course of therapy and the absence To put this in perspective, the corresponding risk of death as a of a behavioral change program. J.B. should be advised that result of cardiovascular disease in nonsmoking women who use eto 16 Section the medications are designed to make patients more comfort- oral contraceptives is much lower, with a death rate of 0.65 per able while quitting and that behavioral counseling is needed to 100,000 women ages 15 to 34 years and 6.21 per 100,000 women address the “habit” of smoking by helping him cope with diffi- ages 35 to 44 years.106 Because of the increased risk of adverse cult situations and triggers for relapse. J.B. should be advised to cardiovascular events, current guidelines from the American Col- (a) call the toll-free tobacco quitline at 1-800-QUIT NOW (see lege of Obstetricians and Gynecologists (ACOG) and the World Case 88-5, Question 1), (b) call the toll-free number that accom- Health Organization (WHO) state that combination estrogen- usac Abuse Substance panies the selected medication (most medications include a free progestin contraceptives should not be used in women who are counseling program), (c) enroll in a local group program, (d) join older than 35 years of age and smoke, and progestin-only con- an online quitting program such as Quitnet.com, or (e) request traceptives (oral and injectable formulations) and intrauterine individualized counseling from a health professional with exper- devices are recommended for use in this population.107,108 M.K. tise in tobacco cessation. In addition, J.B. should be reminded is 32 years of age, and despite smoking 20 cigarettes per day,oral that adherence with the medication regimen—daily adherence, contraceptive use is not contraindicated, per drug manufacturer as well as duration of therapy—will increase his chances of quit- recommendations, at this time. However, the clinician should ting for good. Clinician-delivered counseling might also include a strongly advise M.K. to quit smoking and assess her readiness to personalized message to further enhance his motivation to quit. do so. M.K. should be informed that if she continues to smoke For example, the clinician could perform pulmonary function while using oral combined hormonal contraceptives, her risk of testing and translate J.B.’s spirometry results into an effective developing a blood clot, stroke, or heart attack will continue to “lung age” (e.g., the age of the average healthy individual with increase with time. Risk factors associated with her family his- similar spirometry values). Given J.B.’s height (72 inches) and tory (hypertension, MI, diabetes, and hyperlipidemia) suggest a 103 FEV1 (2.8 L), his estimated lung age is almost 80 years. This genetic predisposition to cardiovascular disease, and thus efforts educational approach has been found to significantly increase to minimize preventable risk factors should be encouraged. long-term (12-month) quit rates in a recent controlled trial.103 COMPLEMENTARY THERAPIES Drug Interactions With Smoking CASE 88-4, QUESTION 2: M.K. asks whether any of the CASE 88-4 natural herbal products for cessation that she “hears about QUESTION 1: M.K. is a new patient requesting Ortho Tri- on the radio” are effective. Cyclen (norgestimate/ethinyl estradiol). The new patient history form completed by M.K. reveals that she is 32 years Although many herbal and homeopathic products are avail- old, weighs 65 kg, and is 70 inches tall. She takes no able to help people quit smoking, data that support their safety prescription medications but occasionally uses loratadine and efficacy are lacking. Most herbal preparations for smoking cessation contain lobeline, an herbal alkaloid with partial P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

nicotine agonist activity.Although direct-to-consumer advertise- ring formulations. In the absence of published data, only smok- 2077 ments suggest that lobeline-containing preparations are safe and ing cessation can be advocated to definitively reduce the risk of effective, a meta-analysis109 and recent controlled trial110 found stroke, MI, and thromboembolism in women who use combined no evidence to support the role of lobeline as an effective aid for hormonal contraceptives. smoking cessation. Likewise, St. John’s wort (an herbal product with antidepressant properties),111 nicobrevin (an herbal prod- BEHAVIORAL COUNSELING uct not available in the United States that contains quinine, Although M.K. is not considering quitting at this time, it is appro- menthyl valerate, camphor, and eucalyptus oil),112 hypnosis,113 priate for the clinician to apply the 5 R’s (Table 88-5) to promote and acupuncture114 have not been found to be effective treat- motivation to quit. This counseling should be relevant to M.K.’s ments for smoking cessation.8 Furthermore, patients should be situation and should highlight the risks of continued tobacco use, cautioned that herbal cigarettes are not safe alternatives because such as her elevated risk for thromboembolic and thrombotic they result in the inhalation of other toxins present in smoke. disorders (associated with continued use of oral contraceptives). M.K. should be advised that the efficacy of the herbal therapies M.K. should be asked to think about the rewards of quitting and is not well established, and use of these agents cannot be recom- any potential roadblocks to quitting. At subsequent encounters, mended at this time. the clinician should sensitively assess M.K.’s tobacco use status and motivation to quit, and offer assistance with quitting when CASE 88-4, QUESTION 3: M.K. is not considering quitting M.K. is ready. If M.K. decides to quit, it would be important smoking in the next 30 days. She cannot discontinue her to reassess her caffeine intake because caffeine levels have been 30 oral contraceptives because she is sexually active and needs reported to increase by 56% in patients who quit smoking. a reliable form of birth control. She wonders whether the new low-dose birth control pills or other formulations (e.g., Brief Interventions to Promote patch, vaginal ring) are safer for smokers. Tobacco Cessation Combined oral contraceptives available in the United States CASE 88-5 contain estrogen in doses ranging from 20 to 50 mcg of ethinyl QUESTION 1: J.C. is a 52-year-old man with a history estradiol. The results of in vitro studies have shown that oral of asthma requesting a refill of his albuterol inhaler pre- contraceptives containing at least 50 mcg of ethinyl estradiol scription. This is the third request for an albuterol inhaler induce greater procoagulatory effects than do preparations con- (200 doses/inhaler) during the past 2 months. Before this taining either 30 mcg or 35 mcg of ethinyl estradiol; formulations period, his last refill was more than a year ago. J.C. reports containing 20 mcg of ethinyl estradiol appear to have little or no that he has been using albuterol on most days of the week 115,116 adverse effects on coagulation. Early epidemiologic reports for coughing and SOB. He has no other medical conditions linking oral contraceptive use and severe cardiovascular events and takes no other medications. His social history is signif- were largely observed in women using oral contraceptives con- icant for tobacco use (smokes 1.5 PPD; he recently started 117 taining more than 50 mcg of ethinyl estradiol. Since then, smoking again after starting a new job where “everyone manufacturers have reduced the dose of estrogen in oral contra- smokes”). J.C. previously quit smoking 20 years ago using ceptives such that the majority of preparations available in the the “cold turkey” approach (e.g., no medications or coun- 118 United States contain 20 to 35 mcg of ethinyl estradiol. seling), and although he was successful, he was miserable In 2001, the US Surgeon General stated that lower-dose oral for weeks and he expresses reluctance to “go through this

contraceptivesmaybeassociatedwithareducedriskforcoronary again” during a stressful job transition. Chapter 88 heart disease (CHD) compared with higher-dose formulations. The clinician is running behind schedule and does Despite this conclusion, the report cautioned that heavy smokers not have the time to provide comprehensive smoking- who use oral contraceptives still have a greatly elevated risk for cessation counseling during this patient encounter. What 117 CHD. brief smoking-cessation interventions can the clinician pro- Serum estrogen levels obtained with the vaginal ring are sig- vide to J.C. to assist him with quitting? niﬁcantly lower than those achieved with either transdermal or oral combined contraceptive formulations,119 and theoretically, the contraceptive vaginal ring might be a safer formulation for TELEPHONE QUITLINES women who smoke. However, because the contraceptive patch Clinicians should become aware of local, community-based and vaginal ring are relatively new, and their safety has not been resources for tobacco cessation, including telephone quitlines.

established among women who smoke, guidelines issued in 2006 When time or expertise do not afford provision of comprehen- Tobacco Use and Dependence by the ACOG state that the same precautions for the use of oral sive tobacco-cessation counseling during a patient visit, clini- combined contraceptives should apply to these newer formula- cians are encouraged to apply a truncated 5 A’s model, whereby tions as well.107 they ask about tobacco use, advise tobacco users to quit, and M.K.’s prescribed oral contraceptive agent (Ortho Tri-Cyclen) refer patients who are ready to quit to a telephone quitline. is a triphasic formulation containing 35 mcg of ethinyl estradiol in Effective brief interventions can generally be accomplished in combination with weekly increasing doses of norgestimate (0.18, fewer than 3 minutes. Telephone services that provide tobacco- 0.215, and 0.25 mg) throughout each monthly cycle. Although cessation counseling have proliferated since the late 1990s; these some clinicians recommend the use of low-dose (20-mcg) estro- services provide low-cost interventions that can reach patients gen preparations in smokers, the available evidence suggests that who might otherwise have limited access to medical treatment the prescribed regimen poses no additional risk in M.K. However, because of geographic location or lack of insurance or ﬁnan- if M.K. increases her smoking levels to more than 25 cigarettes cial resources. In clinical trials, telephone counseling services for per day,some data suggest that her risk for an MI is increased.120 which at least some of the contacts are initiated by the quit- The clinician should inform M.K. that there are currently no line counselor have been shown to be effective in promoting studies demonstrating a reduced risk of adverse cardiovascular abstinence,8 and these positive results have been shown to trans- events in smokers using oral contraceptives containing low doses late into real world effectiveness.44 The addition of medication (e.g., 20 mcg) of estrogen or the newer transdermal and vaginal to quitline counseling signiﬁcantly improves abstinence rates P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

2078 compared with medication alone.8 In addition, preliminary evi- smoking-cessation intervention is an essential component of the dence suggests that quitlines are also effective for smokeless overall care plan.125 tobacco cessation.121 The telephone number for the toll-free Given that J.D. is currently willing to quit, and her depression tobacco quitline is 1-800-QUIT NOW. In some states, clinicians has been stabilized for more than 4 months in the continuation can submit a fax referral form, on behalf of a patient, to the quit- phase of depression treatment, it is appropriate for the clinician line. This form initiates a process whereby a quitline counselor to discuss a quitting plan with J.D. and initiate therapy.The ther- then contacts the patient directly. apeutic approach should include counseling and pharmacother- J.C.’s asthma is not well controlled (e.g., he has been using a apy, with ongoing monitoring of progress toward quitting and short-acting bronchodilator >2 days/week for SOB and cough- depressive symptoms. ing). The change in J.C.’s asthma control is temporally related to his recent job change and relapse to daily smoking. Exposure TREATMENT SELECTION to tobacco smoke is a potent trigger for asthma exacerbations and an important cause of poor asthma control. Given that the PHARMACOTHERAPY clinician is unable to provide comprehensive smoking-cessation Because no contraindications are present, any of the FDA- counseling at this time, a brief intervention is appropriate. The approved medications for cessation are appropriate. Although clinician should strongly advise J.C. to quit as a key component sustained-release bupropion and varenicline both possess black- of his asthma management plan and refer him to a free telephone boxed warnings highlighting the risk of serious neuropsychiatric symptoms, this does not preclude use of these medications for quitline or to other resources that are available within the com- 77,80 munity (e.g., local individual or group counseling programs). J.D. Recently completed and ongoing studies are examin- Time permitting, the clinician could educate J.C. on the benefits ing the risks in greater detail, and many of these trials include patients with various levels of severity and types of psychiatric of medications in reducing nicotine withdrawal symptoms given 126–129 his previous negative experience with quitting. disorders. In a pooled analysis of patients without psychiatric disorders, only sleep disorders and disturbances exhibited a higher incidence in patients treated with varenicline.130 For a video demonstration of a brief Regardless of whether sustained-release bupropion, vareni- counseling intervention for J.C. delivered cline, or NRT product(s) are selected, the clinician should mon- by a health care provider, go to itor J.D. closely to assess incidence of depressive symptomatol- http://thepoint.lww.com/AT10e. ogy.If sustained-release bupropion or varenicline is selected, J.D. should be advised to stop taking the medication and contact the clinician immediately if she experiences agitation, depressed Smoking Among Individuals With mood,andanychangesinbehaviorthatarenottypicalofnicotine Mental Illness withdrawal, or if she experiences suicidal thoughts or behavior. CASE 88-6 BEHAVIORAL COUNSELING eto 16 Section QUESTION 1: J.D. is a 42-year-old woman presenting to Because J.D. has indicated that she is ready to quit, the clinician clinic for follow-up of her depression management. Nine should commend her for making the important decision that months ago, she was started on venlafaxine XR 75 mg daily. will positively impact her overall health. J.D. should be advised At her 3-month follow-up visit, she was stable on venlafax- that quitting is a process, and it will be important for them to ine XR 150 mg daily, and her depressive symptoms had work closely together to address the physiological as well as improved. She also reported that she was sleeping much psychological aspects of quitting during the upcoming months. usac Abuse Substance better. J.D. has no other significant past medical history, and As outlined in Figure 88-2, the clinician should review with J.D. she takes no other medications. Her social history is positive her primary reasons for wanting to quit, assess her confidence in for current tobacco use (1 PPD for 25 years) and caffeine use her ability to quit, determine key triggers for tobacco use, assess (1–2 Diet Cokes a day). She does not drink alcohol. During and address any concerns related to quitting, and determine a the appointment J.D. indicates that she would like to quit quit date. smoking because she is feeling better about herself, and she knows that her overall health will improve if she quits. CASE 88-6, QUESTION 2: After discussing the various treat- She also states that the last time she attempted to quit (sev- ment options with the clinician, J.D. decides that she would eral years ago, using the nicotine gum), she felt “down and like to add sustained-release bupropion to her regimen had difficulty concentrating and couldn’t sleep.” She now is because the nicotine gum by itself didn’t help her much last fearful that her depression will return if she quits. Is smok- time. She also thinks that the combination of venlafaxine ing cessation appropriate for J.D. at this time, and what are with bupropion might help to “keep her depression more her treatment options? stable” while she is quitting. She confides in the clinician that her biggest fear is the ability to avoid smoking when Althoughpersonswithmentalillnessconstitute22%oftheUS she is stressed because of her job. She is a survey researcher population, they consume an estimated 44% of the cigarettes,10 and must meet client-induced deadlines. How can J.D. cope and incur nearly half of the tobacco-related deaths.122 Tobacco with stressful situations? use and dependence is more common among people with more serious mental illness,10,122,123 with schizophrenia being the high- A variety of coping mechanisms can be applied to alleviate est: 9 of 10 persons with schizophrenia smoke.10 On average, the need to smoke during stressful situations or when exposed patients with mental illness die 25 years earlier than the gen- to other triggers for smoking (Table 88-6). The clinician should eral population,124 and smoking is a key contributor to prema- encourage J.D. to think about strategies that would be effec- ture death. In the past, the mental health community has not tive for her in these situations, such as deep breathing or calling a addressed smoking cessation with their patients, but increas- supportive friend. Additionally,the clinician should consider sug- ing evidence suggests that quitting is possible and should be gesting use of a short-acting NRT product (e.g., nicotine gum, promoted. For patients with mental illness to achieve wellness, lozenge, inhaler, or nasal spray) as needed to alleviate situational P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

cravings to smoke. The clinician should also describe the dosing sion and because she recently encountered a difficult situation 2079 of sustained-release bupropion and the need to begin therapy with her friend’s diagnosis, it is reasonable for the clinician to 1to2weeksbeforethequitdate(Table88-7).Afollow-upappoint- recommend continuation of therapy for an additional 12 weeks ment should be scheduled for approximately 3 months after the and reassess progress at that time. quit date, and the patient should be advised to contact the clinician if she encounters any difficulties before then. KEY REFERENCES AND WEBSITE CASE 88-6, QUESTION 3: Four weeks later, J.D. calls and reports that she has a dry mouth, is having difficulty sleep- A full list of references for this chapter can be found at ing, and feels jittery and anxious. She also is currently using http://thepoint.lww.com/AT10e. Below are the key references nicotine gum (2 mg), approximately four pieces daily. How and websites for this chapter, with the corresponding refer- should J.D. be managed? ence number in this chapter found in parentheses after the reference. As noted above, insomnia and dry mouth are commonly associated with sustained-release bupropion therapy and usually lessen with continued use.77 The nicotine gum dose is low and Key References not likely contributing to this condition. To address insomnia, Benowitz NL. Nicotine addiction. N Engl J Med. 2010;362(24): J.D. can be advised to take the second dose of the day earlier, but 2295. (19) not less than 8 hours after the first dose of the day. Alternatively, the clinician could consider reducing the daily dose to 150 mg in Benowitz NL et al. Nicotine chemistry,metabolism, kinetics and the morning and omitting the evening dose. Although the manu- biomarkers. Handb Exp Pharmacol. 2009;(192):29. (22) facturer recommends 300 mg per day, the 150-mg dose has been Cahill K et al. Nicotine receptor partial agonists for smoking shown to have comparable outcomes with those of the 300-mg cessation. Cochrane Database Syst Rev. 2008;(3):CD006103. (57) dose131,132 and is better tolerated.131 The clinician also should assess J.D.’s caffeine consumption patterns and, if appropriate, Fiore MC et al. Treating Tobacco Use and Dependence: 2008 Update. suggest that she reduce her caffeine intake by 50% and not drink Clinical Practice Guideline. Rockville, MD: Public Health Service, caffeinated beverages after 12 noon so her system is clear of its US Dept of Health and Human Services; 2008. (8) stimulatory properties before sleep.31 Hughes JR et al. Antidepressants for smoking cessation. Cochrane Database Syst Rev. 2007;(1):CD000031. (54) Extended-Use Medications Kroon LA. Drug interactions with smoking. Am J Health Syst for Cessation Pharm. 2007;64(18):1917. (31) National Center for Chronic Disease Prevention and Health Pro- CASE 88-6, QUESTION 4: J.D. returns to the clinician’s motion, Office on Smoking and Health. The Health Consequences office 3 months later, and indicates that she is doing well of Involuntary Exposure to Tobacco Smoke: A Report of the Surgeon but had a few “slips” and smoked four times, most recently General. Atlanta, GA: Office on Smoking and Health, National last week when she learned that her best friend was diag- Center for Chronic Disease Prevention and Health Promotion, nosed with ovarian cancer. Other than feeling down about Centers for Disease Control and Prevention, US Dept of Health

her friend, she has not felt depressed and has been han- and Human Services; 2006. (6) Chapter 88 dling her stress at work through deep-breathing exercises. National Center for Chronic Disease Prevention and Health Pro- Because she is not taking smoke breaks every few hours, motion,OfficeonSmokingandHealth.TheHealthConsequencesof she is able to accomplish more during the day, and meet- Smoking: a Report of the Surgeon General. Washington, DC: Office ing deadlines has not been a problem. She uses the nico- on Smoking and Health, National Center for Chronic Disease tine gum a few times a week, and does not feel ready Prevention and Health Promotion, Centers for Disease Control to discontinue the sustained-release bupropion. She won- and Prevention, US Dept of Health and Human Services; 2004. ders whether it is possible to continue the therapy for a bit (3) longer, until she feels more stable as a nonsmoker. National Center for Chronic Disease Prevention and Health Pro- Extended-duration medication therapy appears to be safe and motion, Office on Smoking and Health. How Tobacco Smoke

effective. Long-term follow-up data from the Lung Health Study Causes Disease: The Biology and Behavioral Basis for Smoking- Tobacco Use and Dependence indicate that approximately 15% of long-term quitters contin- Attributable Disease: A Report of the Surgeon General. Atlanta, GA: ued nicotine gum therapy with no serious side effects.133 The Ofﬁce on Smoking and Health, National Center for Chronic 2008 Clinical Practice Guideline states that extended use of med- Disease Prevention and Health Promotion, Centers for Disease ications might be beneﬁcial in individuals who report persis- Control and Prevention, US Dept of Health and Human Services; tent withdrawal symptoms during treatment, those who have 2010. (7) relapsed shortly after medication discontinuation, or those who 8 Schroeder SA. A 51-year-old woman with bipolar disorder who are interested in long-term therapy. wants to quit smoking. JAMA. 2009;301(5):522. (125) Clinicians should be aware that although many of the medications (sustained-release bupropion, varenicline, nicotine nasal Stead LF et al. Nicotine replacement therapy for smoking cessa- spray, and inhaler) are approved by the FDA for long-term tion. Cochrane Database Syst Rev. 2008;(1):CD000146. (49) (6-month) use, the effectiveness of additional weeks on therapy is not well established. A recent meta-analysis of eight trials found that extended treatment with varenicline might prevent relapse, Key Website extended treatment with bupropion is unlikely to have a clini- Rx for Change: Clinician-Assisted Tobacco Cessation. San Francisco, cally important effect, and studies of extended treatment with CA: The Regents of the University of California; 1999–2012. nicotine replacement are needed.134 Given J.R.’s current depres- http://rxforchange.ucsf.edu/. (32)