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P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58 88 Tobacco Use and Dependence 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 United States, responsible for one in every five deaths. Smoking harms nearly every organ of the body, causing many diseases (including, but not limited to, cardiovascular disease, pulmonary disease, and cancers) and reducing the health of 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. Case 88-2 (Questions 1, 4), Case 88-3 (Question 1), Case 88-5 (Question 1), Case 88-6 (Question 1) 2 Tobacco products are effective delivery systems for the drug nicotine. Nicotine is a highly addictive drug that activates the dopamine reward pathway in the brain that reinforces continued tobacco use. Nicotine withdrawal symptoms (e.g., irritability, anxiety, difficulty concentrating, restlessness, depressed mood, insomnia, impaired performance, increased appetite or weight gain, cravings) generally occur when nicotine is discontinued. Case 88-1 (Questions 2, 4), Case 88-3 (Question 1), Case 88-6 (Questions 1, 2) 3 Constituents in tobacco smoke are associated with a number of clinically significant drug interactions. Case 88-4 (Questions 1, 3), Case 88-6 (Question 3) 4 Tobacco dependence, a chronic disease that often requires repeated intervention and multiple attempts to quit, is characterized by physiological dependence (addiction to nicotine) and behavioral habit of using tobacco. Case 88-1 (Question 5), Case 88-2 (Question 3), Case 88-3 (Question 1) 5 Numerous effective medications, as delineated in the Clinical Practice Guideline, are available for treating tobacco use and dependence. Most patients should be encouraged to use one or more first-line agents, which include the nicotine patch, nicotine gum, nicotine lozenge, nicotine nasal spray, nicotine oral inhaler, sustained-release bupropion, and varenicline. All first-line agents approximately 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. Case 88-1 (Questions 1–3), Case 88-2 (Questions 3, 4), Case 88-3 (Question 1), Case 88-4 (Question 2), Case 88-6 (Questions 1, 4) 6 Comprehensive counseling, as defined by the Clinical Practice Guideline, includes asking about tobacco use, advising patients to quit, assessing readiness to quit, assisting patients with quitting, and arranging follow-up. This approach is referred to as “The 5 A’s.” Counseling and support can be provided a variety of ways, such 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. Case 88-1 (Questions 2, 5), Case 88-3 (Question 1), Case 88-5 (Question 1), Case 88-6 (Questions 1, 2, 4) continued 2055

Transcript of APPLIED THERAPEUTICS CHAPTER 85.pdf - Rxforchange

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88Tobacco Use and DependenceRobin L. Corelli and Karen Suchanek Hudmon

C O R E P R I N C I P L E S

C H A P T E R C A S E S

1 Cigarette smoking is the single most preventable cause of premature death in theUnited States, responsible for one in every five deaths. Smoking harms nearly everyorgan of the body, causing many diseases (including, but not limited to,cardiovascular disease, pulmonary disease, and cancers) and reducing the health ofsmokers in general. Quitting smoking has immediate as well as long-term benefits,reducing risks for diseases caused by smoking and improving health in general.

Case 88-2 (Questions 1, 4),Case 88-3 (Question 1),Case 88-5 (Question 1),Case 88-6 (Question 1)

2 Tobacco products are effective delivery systems for the drug nicotine. Nicotine is ahighly addictive drug that activates the dopamine reward pathway in the brain thatreinforces continued tobacco use. Nicotine withdrawal symptoms (e.g., irritability,anxiety, difficulty concentrating, restlessness, depressed mood, insomnia, impairedperformance, increased appetite or weight gain, cravings) generally occur whennicotine is discontinued.

Case 88-1 (Questions 2, 4),Case 88-3 (Question 1),Case 88-6 (Questions 1, 2)

3 Constituents in tobacco smoke are associated with a number of clinically significantdrug interactions.

Case 88-4 (Questions 1, 3),Case 88-6 (Question 3)

4 Tobacco dependence, a chronic disease that often requires repeated interventionand multiple attempts to quit, is characterized by physiological dependence(addiction to nicotine) and behavioral habit of using tobacco.

Case 88-1 (Question 5),Case 88-2 (Question 3),Case 88-3 (Question 1)

5 Numerous effective medications, as delineated in the Clinical Practice Guideline,are available for treating tobacco use and dependence. Most patients should beencouraged to use one or more first-line agents, which include the nicotine patch,nicotine gum, nicotine lozenge, nicotine nasal spray, nicotine oral inhaler,sustained-release bupropion, and varenicline. All first-line agents approximatelydouble quit rates, and therefore the choice of therapy is based largely oncontraindications, precautions, patient preference, and tolerability of the availabledosage forms. In some cases, medications can be combined or used for extendeddurations. Although complementary therapies are available, these are notrecommended because of insufficient evidence of efficacy.

Case 88-1 (Questions 1–3),Case 88-2 (Questions 3, 4),Case 88-3 (Question 1),Case 88-4 (Question 2),Case 88-6 (Questions 1, 4)

6 Comprehensive counseling, as defined by the Clinical Practice Guideline, includesasking about tobacco use, advising patients to quit, assessing readiness to quit,assisting patients with quitting, and arranging follow-up. This approach is referredto as “The 5 A’s.” Counseling and support can be provided a variety of ways, suchas through individual counseling, group programs, telephone, or the Internet. Twocomponents of counseling are especially effective and should be applied whenassisting patients with quitting: practical counseling (problem solving or skillstraining) and social support delivered as part of treatment. Relapse is common, andclinicians should work with patients throughout the quit attempt to increase thechances for long-term abstinence.

Case 88-1 (Questions 2, 5),Case 88-3 (Question 1),Case 88-5 (Question 1),Case 88-6 (Questions 1, 2, 4)

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C H A P T E R C A S E S

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

Case 88-5 (Question 1)

8 Patients with psychiatric disorders exhibit a higher prevalence of tobacco use and adisproportionately high level of tobacco-related morbidity and mortality.

Case 88-6 (Question 1)

9 Cigarettes are the most common form of tobacco used in the United States;however, other forms of tobacco exist (spit tobacco, pipes, cigars, bidis, hookah).All forms of tobacco are harmful.

Case 88-2 (Question 2),Narrated PowerPointslides on Forms of Tobacco

Long before Christopher Columbus traveled to the New World,tobacco use was widespread in the Americas—tobacco prepara-tions were part of religious ceremonies for the Native Ameri-cans, and tobacco was also used medicinally. At that time, andfor several subsequent centuries, little was known or suspectedabout the dangers of tobacco use. In retrospect, it is not sur-prising that these dangers were not recognized initially becausethe more pressing health issues at that time were related to life-threatening, acute diseases as opposed to chronic diseases suchas those imposed by tobacco. However, it is now well establishedthat tobacco is a detrimental substance, and its use dramaticallyincreases a person’s odds of dependence, disease, disability, anddeath.

Cigarettes are the only marketed consumable product thatwhen used as intended will contribute to the death of half ormore of its users.1 Tobacco products are carefully engineeredformulations that optimize the delivery of nicotine, a chemicalthat meets the criteria for an addictive substance: (a) nicotineinduces psychoactive effects, (b) it is used in a highly controlledor compulsive manner, and (c) behavioral patterns of tobaccouse are reinforced by the pharmacologic effects of nicotine.2 Asa major risk factor for a wide range of diseases, including cardio-vascular conditions, cancers, and pulmonary disorders, tobaccois the primary known preventable cause of premature death inour society.3 During the 20th century, 100 million deaths werecaused by tobacco, and currently, an estimated 5.4 million deathsoccur annually.3 Unless tobacco control efforts are able to reversethis trend, the number of annual deaths is likely to exceed 8million by the year 2030.4 According to Dr. Margaret Chan,Director-General of the World Health Organization, “Reversingthis entirely preventable epidemic must now rank as a top priorityfor public health and for political leaders in every country of theworld.”4

In the United States, smoking is responsible for approximately443,000 premature deaths each year.5 In addition to the harmimposed on users of tobacco, exposure to secondhand smokeresults in an estimated 50,000 deaths each year.5,6 According tothe Office of the US Surgeon General, there is no risk-free level ofexposure to tobacco smoke.7 Because of the health and societalburdens that it imposes, tobacco use and dependence shouldbe addressed during each clinical encounter with all tobaccousers.8

EPIDEMIOLOGY OF TOBACCO USEAND DEPENDENCE

In the United States, cigarettes are the most common formof tobacco that is consumed, but other forms are also preva-

lent: smokeless tobacco (chewing tobacco, oral snuff ), pipes,cigars, clove cigarettes, bidis, hookah, and electronic cigarettes(“e-cigarettes”). Among adults, smoking prevalence varies bysociodemographic factors, including sex, race or ethnicity, edu-cation level, age, and poverty level. The Centers for Disease Con-trol and Prevention (CDC) reported that in 2009, the percent-age of current smokers (defined as having smoked 100 or morecigarettes during their lifetime and currently smoking every dayor some days) was 20.6% (23.5% of men and 17.9% of women).9

Table 88-1 summarizes the smoking prevalence estimates forvarious population subgroups, stratified by sex.9 An estimated44.3% of cigarettes smoked in the United States are among per-sons with mental illness,10 with the prevalence of smoking being2 to 4 times higher among patients with psychiatric and substanceuse disorders.11

For a narrated PowerPoint presentation onforms of tobacco, go to http://thepoint.lww.com/AT10e.

Experimentation with cigarettes and the development of reg-ular smoking typically occur during adolescence; in 2007, 59.7%of new smokers were younger than the age of 18 when theysmoked their first cigarette.12 Because most teens who smokeat least monthly continue to smoke in adulthood,13 tobacco usetrends among youth are a key indicator of the overall healthtrends for the nation.14 According to the CDC, the prevalence ofcurrent smoking (defined as having smoked at least one cigarettein the preceding 30 days) among high school students increasedthroughout the early and mid-1990s,15 identifying an urgentneed for tobacco prevention and cessation programs focused onyounger age groups. Subsequent decreases occurred, but overallthe rate of decline has slowed substantially in recent years.15 In2009, an estimated 25.2% of 12th graders had smoked one ormore cigarettes in the past 30 days; combining grades 9 through12, the prevalence of current smoking was higher among males(19.4%) than among females (16.7%).12

Despite tobacco control efforts at the state and national levels,only a few subgroups have met the Healthy People 2010 target goalof ≤12% smoking prevalence.14 In 2009, the highest statewidemedian prevalence of current smoking was evident in WestVirginia and Kentucky (25.6%), and the lowest prevalence wasevident in Utah (9.8%).16 Although much of tobacco control iscoordinated through the states, the extent to which tobacco con-trol is addressed in states’ cancer control plans is highly variable,and there is significant room for improvement in compliancewith the CDC’s tobacco-related recommendations.17

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T A B L E 8 8 - 1Percentage of Current Smokersa Ages 18 Years and Older, by Sex and Selected Characteristics—National Health InterviewSurvey, 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 22.1Black, non-Hispanic 23.9 19.2 21.3Hispanic 19.0 9.8 14.5American Indian/Alaska Native, non-Hispanicc 29.7 − 23.2Asian, non-Hispanicd 16.9 7.5 12.0Multiple race, non-Hispanic 33.7 24.8 29.5

Educatione 0–12 years (no diploma) 30.5 22.2 26.4GED 53.2 44.7 49.1High school graduate 29.0 21.5 25.1Some college (no degree) 26.1 21.0 23.3Associate degree 20.6 19.1 19.7Undergraduate degree 12.4 9.9 11.1Graduate degree 4.9 6.3 5.6

Age group (years) 18–24 28.0 15.6 21.825–44 26.5 21.5 24.045–64 24.5 19.5 21.965 and older 9.5 9.5 9.5

Poverty status f At or above poverty level 22.2 16.7 19.4Below poverty level 34.2 28.7 31.1Unknown 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 128respondents 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 MortalWkly Rep. 2010;59(35):1135.

Factors Contributing to Tobacco UseTobacco addiction is maintained by nicotine dependence.18,19

Nicotine induces a variety of pharmacologic effects, describedas follows, that lead to dependence.19 However, tobacco depen-dence is not simply a matter of nicotine pharmacology—it is aresult of the interplay of complex processes, including the desirefor the direct pharmacologic actions of nicotine, the relief ofwithdrawal, learned associations, and environmental cues (e.g.,advertising, the smell of a cigarette, or observing others whoare smoking).19 Physiological factors, such as pre-existing med-ical conditions (e.g., psychiatric comorbidities10,11,19) and one’sgenetic profile, also can predispose individuals to tobacco use.20,21

Notably, it has been estimated in twin studies that 40% to 60%of smoking is heritable.20,21

The rapidity with which nicotine, the addictive componentof tobacco, is absorbed and passes through the blood-brainbarrier contributes to its addictive nature. After inhalation,nicotine reaches the brain within seconds.18 As such, smok-ers experience nearly immediate onset of the positive effects ofnicotine, including pleasure, relief of anxiety, improved task per-formance, improved memory, mood modulation, and skeletalmuscle relaxation.18 These effects, mediated by alterations inneurotransmitter levels, reinforce continued use of nicotine-containing products.18,19

Nicotine PharmacologyNicotine (Nicotiana tabacum), which is composed of a pyridinering and a pyrrolidine ring, is one of the few natural alkaloidsthat exist in the liquid state. Nicotine is a clear, weak base with

a pKa of 8.0.22 In acidic media, nicotine is ionized and poorlyabsorbed; conversely, in alkaline media, nicotine is nonionizedand well absorbed. Under physiological conditions (pH = 7.4), alarge proportion of nicotine is nonionized and readily crosses cellmembranes.22 Given the relation between pH and absorption,the tobacco industry and pharmaceutical companies are able totitrate the pH of their tobacco products and nicotine replacementtherapy (NRT) products to maximize the absorption potentialof nicotine.22–24

Once absorbed, nicotine induces a variety of central nervoussystem, cardiovascular, and metabolic effects. Nicotine stimu-lates the release of several neurotransmitters, inducing a rangeof pharmacologic effects such as pleasure (dopamine), arousal(acetylcholine, norepinephrine), cognitive enhancement (acetyl-choline), appetite suppression (dopamine, norepinephrine, sero-tonin), learning (glutamate), memory enhancement (glutamate),mood modulation (serotonin), and reduction of anxiety andtension (β-endorphin and γ -aminobutyric acid [GABA]).25 Thedopamine reward pathway, a network of nervous tissue that elic-its feelings of pleasure in response to certain stimuli, is centralto drug-induced reward. Key structures of the reward pathwayinclude the ventral tegmental area, nucleus accumbens, and pre-frontal cortex (the area of the brain that is responsible for thinkingand judgment). The neurons of the ventral tegmental area con-tain the neurotransmitter dopamine, which is released in thenucleus accumbens and in the prefrontal cortex. Immediatelyafter inhalation, a bolus of nicotine enters the brain, stimulatingthe release of dopamine, which induces nearly immediate feel-ings of pleasure, along with relief of the symptoms of nicotinewithdrawal. This rapid dose response reinforces repeated admin-istration of the drug and perpetuates the smoking behavior.19,25

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08 AM 6 PM 4 AM

Hour

Pleasure/Arousal

NeutralZone

AbstinencesymptomsP

lasm

a N

icotine C

oncentr

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ng/m

L)

FIGURE 88-1 Nicotine addiction cycle throughout the day.� The sawtooth line represents venous plasma concentrations of nicotine as a cigaretteis smoked every 40 minutes between 8 AM and 9 PM.� The upper solid line indicates the threshold concentration for nicotine to producepleasure or arousal.� The lower solid line indicates the concentrations at which symptoms of abstinence(i.e., withdrawal symptoms) from nicotine occur.� The shaded area represents the zone of nicotine concentrations (neutral zone) in whichthe smoker is comfortable without experiencing either pleasure and arousal orabstinence 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 resultin an increased number of nicotine receptors in specific regionsof the brain,26,27 which is believed to represent upregulation inresponse to nicotine-mediated desensitization of the receptorsand may play a role in nicotine tolerance and dependence.25,27

Chronic administration also leads to tolerance of the behavioraland cardiovascular effects of nicotine during the course of the day;however, tobacco users regain sensitivity to the effects of nico-tine after overnight abstinence from nicotine,18,19 as shown inFigure 88-1.28 After smoking the first cigarette of the day, thesmoker experiences marked pharmacologic effects, particularlyarousal. No other cigarette throughout the day produces thesame degree of pleasure or arousal. For this reason, many smok-ers describe the first cigarette as the most important one of theday. Shortly after the initial cigarette, tolerance begins to develop.Accordingly, the threshold levels for both pleasure or arousal andabstinence rise progressively throughout the day as the smokerbecomes tolerant to the effects of nicotine. With continued smok-ing, nicotine accumulates, leading to an even greater degree oftolerance. Late in the day, each individual cigarette produces onlylimited pleasure or arousal; instead, smoking primarily alleviatesnicotine withdrawal symptoms. Lack of exposure to nicotineovernight results in resensitization of drug responses (i.e., lossof tolerance). Most dependent smokers tend to smoke a certainnumber of cigarettes per day and tend to consume sufficient nico-tine per day to achieve the desired effects of cigarette smoking andminimize the symptoms of nicotine withdrawal.19,28 Withdrawalsymptoms, which include anger, anxiety, depression, difficultyconcentrating, impatience, insomnia, and restlessness, typicallymanifest within a few days after quitting, peak within a week,and subside within 2 to 4 weeks.29 Tobacco users become adeptat titrating their nicotine levels throughout the day to avoid with-drawal symptoms, maintain pleasure and arousal, and modulatemood.

Nicotine is extensively metabolized in the liver and, to a lesserextent, in the kidney and lung. Approximately 70% to 80% ofnicotine is metabolized to cotinine, an inactive metabolite.22 Therapid metabolism of nicotine (half-life [t1/2] = 2 hours) to inactivecompounds underlies tobacco users’ needs for frequent, repeated

administration. The half-life of cotinine, however, is much longer(t1/2 = 18–20 hours), and for this reason, cotinine is commonlyused as a marker of tobacco use as well as a marker for exposure tosecondhand smoke.22 Measurement of cotinine cannot, however,differentiate between the nicotine from tobacco products and thenicotine from NRT products. Nicotine and other metabolitesare excreted in the urine. Urinary excretion is pH dependent; theexcretion rate is increased in acidic urine.22 Nicotine crosses theplacenta and accumulates in breast milk.22

Drug Interactions With SmokingIt is widely recognized that polycyclic aromatic hydrocarbons(PAHs), present in appreciably large quantities in tobacco smoke,are responsible for most drug interactions with smoking.30,31

PAHs, which are the products of incomplete combustion oftobacco, are potent inducers of several hepatic cytochrome-P450microsomal enzymes (CYP1A1, CYP1A2, and possibly CYP2E1).Although other substances in tobacco smoke, including acetone,pyridines, benzene, nicotine, carbon monoxide, and heavy met-als (e.g., cadmium), might also interact with hepatic enzymes,their effects appear to be less significant. Most drug interactionswith tobacco smoke are pharmacokinetic, resulting from theinduction of drug-metabolizing enzymes (especially CYP1A2)by compounds in tobacco smoke. Table 88-2 summarizes keyinteractions with smoking.30–32 Patients who begin smoking,quit smoking, or dramatically alter their level of smoking mightrequire dosage adjustments for some medications.

Health Consequences of Tobacco UseAll forms of tobacco are harmful, and there is no safe level ofexposure to tobacco products.7 Smoking has a causal or con-tributory role in the development of a variety of medical condi-tions (Table 88-3).3,7 In the United States, tobacco use accountsfor an estimated 443,595 deaths each year,5 and millions sufferfrom chronic conditions attributable to smoking. Among currentsmokers, emphysema is the most common condition (49.1%),followed by chronic bronchitis (41.1%).33 Overall, an estimated

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T A B L E 8 8 - 2Drug Interactions With Smoking

a

Drug/Class Mechanism of Interaction and Effects

Pharmacokinetic InteractionsAlprazolam (Xanax) � Conflicting data on significance of a PK interaction, but possible ↓ plasma concentrations (up to 50%); ↓ half-life

(35%).Bendamustine (Treanda) � Metabolized by CYP1A2. Manufacturer recommends using with caution in smokers because of likely

↓ bendamustine concentrations, with ↑ concentrations of its two active metabolites.Caffeine � ↑ Metabolism (induction of CYP1A2); ↑ clearance (56%).� Likely ↑ caffeine levels after cessation.Chlorpromazine (Thorazine) � ↓ AUC (36%) and serum concentrations (24%).� ↓ Sedation and hypotension possible in smokers; smokers may need ↑ dosages.Clopidogrel (Plavix) � ↑ Metabolism (induction of CYP1A2) of clopidogrel to its active metabolite.� 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) � ↑ Metabolism (induction of CYP1A2); ↓ plasma concentrations (18%).� ↑ Levels on cessation may occur; closely monitor drug levels and reduce dose as required to avoid toxicity.Erlotinib (Tarceva) � ↑ Clearance (24%); ↓ trough serum concentrations (twofold).Flecainide (Tambocor) � ↑ Clearance (61%); ↓ trough serum concentrations (25%).� Smokers may need ↑ dosages.Fluvoxamine (Luvox) � ↑ Metabolism (induction of CYP1A2); ↑ clearance (24%); ↓ AUC (31%); ↓ plasma concentrations (32%).� Dosage modifications not routinely recommended but smokers may need ↑ dosages.Haloperidol (Haldol) � ↑ Clearance (44%); ↓ serum concentrations (70%).Heparin � Mechanism unknown but ↑ clearance and ↓ half-life are observed. Smoking has prothrombotic effects.� Smokers may need ↑ dosages because of PK and PD interactions.Insulin, subcutaneous � Possible ↓ insulin absorption secondary to peripheral vasoconstriction; smoking may cause release of endogenous

substances that cause insulin resistance.� PK and PD interactions likely not clinically significant; smokers may need ↑ dosages.Irinotecan (Camptosar) � ↑ Clearance (18%); ↓ serum concentrations of active metabolite SN-38 (∼40%; via induction of glucuronidation);↓ systemic exposure resulting in lower hematologic toxicity and may reduce efficacy.� Smokers may need ↑ dosages.

Mexiletine (Mexitil) � ↑ Clearance (25%; via oxidation and glucuronidation); ↓ half-life (36%).Olanzapine (Zyprexa) � ↑ Metabolism (induction of CYP1A2): ↑ clearance (98%); ↓ serum concentrations (12%).� Dosage modifications not routinely recommended but smokers may require ↑ dosages.Propranolol (Inderal) � ↑ Clearance (77%; via side-chain oxidation and glucuronidation).Ropinirole (Requip) � ↓ Cmax (30%) and AUC (38%) in study with patients with restless legs syndrome.� Smokers may need ↑ dosages.Tacrine (Cognex) � ↑ Metabolism (induction of CYP1A2); ↓ half-life (50%); serum concentrations threefold lower.� Smokers may need ↑ dosages.Theophylline (Theo-Dur,

etc.)

� ↑ Metabolism (induction of CYP1A2); ↑ clearance (58–100%); ↓ half-life (63%).� Levels should be monitored if smoking is initiated, discontinued, or changed.� ↑ Clearance with second-hand smoke exposure.� Maintenance doses are considerably higher in smokers.Tricyclic antidepressants

(e.g., imipramine,nortriptyline)

� Possible interaction with tricyclic antidepressants in the direction of ↓ blood levels, but the clinical significance isnot established.

Tizanidine (Zanaflex) � ↓ AUC (30–40%) and ↓ half-life (10%) observed in male smokers.Warfarin � ↑ 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 InteractionsBenzodiazepines (diazepam,

chlordiazepoxide)

� ↓ Sedation and drowsiness, possibly caused by nicotine stimulation of central nervous system.

β-Blockers � Less effective antihypertensive and heart rate control effects; might be caused by nicotine-mediated sympatheticactivation.� Smokers may need ↑ dosages.

Corticosteroids, inhaled � Smokers with asthma may have less of a response to inhaled corticosteroids.Hormonal contraceptives � ↑ 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 venousthromboembolism compared with oral contraceptive users, likely as a result of ↑ estrogen exposure (60% higherlevels).� ↑ Risk with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women age 35 andolder.

Opioids (propoxyphene,pentazocine)

� ↓ Analgesic effect; smoking may ↑ the metabolism of propoxyphene (15–20%) and pentazocine (40%).Mechanism unknown.� 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.

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T A B L E 8 8 - 3Health Consequences of Smoking

Cancer Acute myeloid leukemiaBladderCervicalEsophagealGastricKidneyLaryngealLungOral cavity and pharyngealPancreatic

Cardiovascular Abdominal aortic aneurysmdisease Coronary heart disease (angina pectoris, ischemic

heart disease, myocardial infarction)Cerebrovascular disease (transient ischemic attacks,

stroke)Peripheral arterial disease

Pulmonary Acute respiratory illnessesdisease Upper respiratory tract (rhinitis, sinusitis,

laryngitis, pharyngitis)Lower respiratory tract (bronchitis, pneumonia)

Chronic respiratory illnessesChronic obstructive pulmonary diseaseRespiratory symptomsPoor asthma controlReduced lung function

Reproductive Reduced fertility in womeneffects Pregnancy and pregnancy outcomes

Preterm, premature rupture of membranesPlacenta previaPlacental abruptionPreterm deliveryLow infant birth weight

Infant mortalitySudden infant death syndrome

Other effects CataractOsteoporosis (reduced bone density in

postmenopausal women, increased risk of hipfracture)

PeriodontitisPeptic ulcer disease (in patients who are infected

with Helicobacter pylori)Surgical outcomes

Poor wound healing

Reprinted from National Center for Chronic Disease Prevention and HealthPromotion, Office on Smoking and Health. The Health Consequences of Smoking: AReport of the Surgeon General. Washington, DC: Office on Smoking and Health,National Center for Chronic Disease Prevention and Health Promotion, Centersfor Disease Control and Prevention, US Dept of Health and Human Services;2004.

36.9% of current smokers and 26.0% of former smokers live witha smoking-related chronic disease.33 In the United States, lungcancer is the leading cause of cancer-related mortality for menand women and is a disease for which the 5-year survival rate isapproximately 16%.34

SECONDHAND SMOKE EXPOSUREExposure to secondhand smoke, which includes the smoke ema-nating from burning tobacco and that exhaled by the smoker,affects an estimated 88 million nonsmokers older than the age of3 in the United States,35 resulting in an estimated 50,000 deathsannually, in addition to contributing to numerous diseases amongnonsmoking children and adults.6 Major conclusions of the 2006Surgeon General’s Health Effects of Involuntary Exposure toTobacco Smoke6 report are: (a) many millions of Americans,both children and adults, are still exposed to secondhand smokein their homes and workplaces despite substantial progress in

tobacco control; (b) secondhand smoke exposure causes diseaseand premature death in children and adults who do not smoke;(c) children exposed to secondhand smoke are at an increasedrisk for sudden infant death syndrome, acute respiratory infec-tions, ear problems, and more severe asthma. Smoking by parentscauses respiratory symptoms and slows lung growth in their chil-dren; (d) exposure of adults to secondhand smoke has immediateadverse events on the cardiovascular system and causes coronaryheart disease and lung cancer; (e) the scientific evidence indi-cates that there is no risk-free level of exposure to secondhandsmoke; and (f ) eliminating smoking in indoor spaces fully pro-tects nonsmokers from exposure to secondhand smoke. Separat-ing smokers from nonsmokers, cleaning the air, and ventilatingbuildings cannot eliminate exposures of nonsmokers to second-hand smoke. In 2006, the California Environmental ProtectionAgency designated secondhand smoke as a “toxic air contami-nant” and, in addition to the list of diseases described in the Sur-geon General’s report, specified that exposure is associated withbreast cancer in younger, primarily premenopausal women.36

Benefits of QuittingThe 1990 Surgeon General’s Report on the health benefits ofsmoking cessation describes numerous and substantial healthbenefits associated with quitting.37 Benefits incurred soon afterquitting (e.g., within 2 weeks to 3 months) include improvementsin pulmonary function, circulation, and ambulation. Smokingcessation results in measurable improvements in lung function38

(see Chapter 24, Chronic Obstructive Pulmonary Disease). Oneyear after cessation, the excess risk of coronary heart disease isreduced to half that of continuing smokers. After 5 to 15 years,the risk of stroke is reduced to a rate similar to that of people whoare lifetime nonsmokers, and 10 years after quitting, the chanceof dying of lung cancer is approximately half that of continu-ing smokers. In addition, the risk of developing mouth, throat,esophagus, bladder, kidney, or pancreatic cancer is decreased.Finally, 15 years after quitting, the risk of coronary heart diseaseis reduced to a rate that is similar to that of people who have neversmoked.37 Similarly, more recent data suggest that smokers whoquit for good over a sustained period have an overall mortal-ity rate and death rate associated with cardiovascular disease,ischemic heart disease, and stroke that is similar to individualswho have never smoked. In contrast, individuals who had suc-cessfully quit, but later resumed smoking, had mortality risksthat were significantly higher than lifetime nonsmokers.39

Quitting at ages 30, 40, 50, and 60 results in 10, 9, 6, and3 years of life gained, respectively.1 On average, cigarette smokersdie approximately 10 years younger than do nonsmokers, and ofthose who continue smoking, at least half will eventually die asa result of a tobacco-related disease.1 Persons who quit beforeage 35 add 10 years of life and have a life expectancy similar tomen who had never smoked.1 In addition to losing years of lifebecause of smoking, a 26-year prospective study of smoking inmidlife showed a dose-dependent reduction in the health-relatedquality of life in old age among men. Never smokers live longerthan heavy smokers, and their extra years are of higher quality.40

A reduction in smoking does not equate to a reduction in harm41;even low levels of smoking (e.g., 1–4 cigarettes per day) havedocumented risks,42,43 and therefore, decreasing the number ofcigarettes smoked per day should be viewed as a positive steptoward quitting, but should not be recommended as a targetedend point. For any patient who uses tobacco, the target goalis complete, long-term abstinence from all nicotine-containingproducts. In summary, there is no safe level of tobacco use, andalthough it is never too late to incur benefits of quitting, there aresubstantial benefits associated with quitting at a younger age.

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Tobacco Use and Dependence:Treatment ApproachesMost tobacco users attempt to quit without assistance, despitethe fact that persons who receive assistance are more likelyto be successful in quitting.8,44 Given the complexity of thetobacco-dependence syndrome and the constellation of factorsthat contribute to tobacco use, treatment requires a multifacetedapproach. To assist clinicians and other specialists in providingcessation treatment to patients who use tobacco, the US Pub-lic Health Service published the Clinical Practice Guideline forTreating Tobacco Use and Dependence. This document, whichrepresents a distillation of more than 8,700 published articles,8

specifies that clinicians can have an important impact on theirpatients’ ability to quit. A meta-analysis of 29 studies8 estimatedthat compared with patients who do not receive an interventionfrom a clinician, patients who receive a tobacco-cessation inter-vention from a physician clinician or a nonphysician clinicianare 2.2 and 1.7 times, respectively, more likely to quit (at 5 or

more months after cessation). Although even brief advice froma clinician has been shown to lead to increased odds of quitting,8

more intensive counseling yields more dramatic increases in quitrates.8 Other effective methods for delivery of counseling includegroup programs8,45 and telephone counseling.46 Internet-basedinterventions have become more prevalent in recent years, but arecent meta-analysis of 20 trials revealed inconsistent results.47

Numerous effective medications are available for tobaccodependence, and clinicians should encourage their use by allpatients attempting to quit smoking—except when medicallycontraindicated or with specific populations for which thereis insufficient evidence of effectiveness (i.e., pregnant women,smokeless tobacco users, light smokers, adolescents).8 Althoughboth pharmacotherapy and behavioral counseling are effec-tive independently, patients’ odds of quitting are substantiallyincreased when the two approaches are used simultaneously. Theestimated efficacies of various treatment strategies are shown inTable 88-4. Clinicians can have a significant impact on a patient’slikelihood of success by recommending pharmacotherapy agents

T A B L E 8 8 - 4Efficacy of Treatment Methods for Tobacco Use and Dependence8

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

Behavioral Interventions

Advice to quitNo advice to quit 1.0 7.9Physician advice to quit 1.3 (1.1–1.6) 10.2 (8.5–12.0)

Clinician interventionNo counseling by a clinician 1.0 10.2Counseling 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 counselingNo format 1.0 10.8Self-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)Individual counseling 1.7 (1.4–2.0) 16.8 (14.7–19.1)

Pharmacotherapy Interventions

Placebo 1.0 13.8First-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)

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 therapyNicotine 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 clinicianinitiates 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 fortreating 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.

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and by supplementing medication use with behavioral counsel-ing as described later in this chapter.

Assisting Patients With QuittingBEHAVIORAL COUNSELING STRATEGIESAccording to the Clinical Practice Guideline,8 five key compo-nents constitute comprehensive counseling for tobacco cessa-tion: (a) asking patients whether they use tobacco, (b) advisingtobacco users to quit, (c) assessing patients’ readiness to quit,(d) assisting patients with quitting, and (e) arranging follow-upcare. These steps are referred to as the “5 A’s” and are described,in brief, as follows. Figure 88-2 can be used as a guide for struc-turing counseling interactions.� Ask: Screening for tobacco use is essential and should be a

routine component of clinical care. The following questioncan be used to identify tobacco users: “Do you ever smoke oruse any type of tobacco?” At a minimum, tobacco use status(current, former, never user) and level of use (e.g., num-ber of cigarettes smoked per day) should be assessed anddocumented in the medical record. Also, patients should beasked about exposure to secondhand smoke. Before impart-ing advice, consider asking the patient for permission to doso: “Ms. Crosby, may I tell you why this concerns me?”� Advise: Tobacco users should be advised to consider quit-ting; the advice should be clear and compelling, yet deliv-ered with sensitivity and a tone of voice that communi-cates concern and a willingness to assist with quitting.When possible, messages should be personalized by relatingadvice to factors such as a patient’s health status, medicationregimen, personal reasons for wanting to quit, or the impactof tobacco use on others. For example, “I’m concerned because

you are on two different inhalers for your emphysema. Quittingsmoking is the single most important treatment to improve yourbreathing. I strongly encourage you to quit. Would you be inter-ested in having me help you with this?”� Assess: Key to the provision of appropriate counseling inter-ventions is the assessment of a patient’s readiness to quit.Patients should be categorized as being (a) not ready to quitin the next month; (b) ready to quit in the next month;(c) a recent quitter, having quit in the past 6 months; or(d) a former user, having quit more than 6 months ago.8,48

This classification defines the clinician’s next step, which isto provide counseling that is tailored to the patient’s levelof readiness to quit. As an example for a current smoker:“Mr. Malkin, what are your thoughts about quitting, and wouldyou consider quitting sometime in the next month?” The coun-seling interventions for patients who are ready to quit willbe different from those for patients who are not consideringquitting.� Assist: When counseling tobacco users, it is important thatclinicians view quitting as a process that might take monthsor even years to achieve, rather than a “now or never” event.The goal is to promote forward progress in the process ofchange, with the target end point being sustained abstinencefrom all nicotine-containing products.

When counseling patients who are not ready to quit, an impor-tant first step is to foster motivation. Some patients who are notready to quit truly might not believe that they need to quit;however, most will recognize the need to quit but are simplynot ready to make the commitment to do so. Often, patientshave tried to quit multiple times and failed, and thus are toodiscouraged to try again. Strategies for working with patientswho are not ready to quit involve enhancing motivation to quit,

STEP Five: ARRANGE Follow-up CounselingMonitor patients’ progress throughout the quit attempt. Follow-up contact should occurduring the first week after quitting. A second follow-up contact is recommended in thefirst month. Additional contacts should be scheduled as needed. Counseling contacts canoccur face-to-face, by telephone, or by e-mail. Keep patient progress notes.

Address temptations and triggers; discuss strategies to prevent relapse.

Congratulate patients for continued success.

STEP Three: ASSESS Readiness to Quit

* Relapse prevention interventions not necessary in the case of the adult who has not used tobacco for many

years.

Fiore MC, Jaen CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice

Guideline. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service. May 2008.

Fostermotivation

Providetreatment

The 5 R’s The 5 A’s or referral

Preventrelapse*

Encouragecontinuedabstinence

YES

YES

NO NO

NO

YES

STEP Four: ASSIST with QuittingAssess Tobacco Use History• Current use: type(s) of tobacco used, brand, amount

• Past use:

– Duration of tobacco use

– Changes in levels of use recently

• Past quit attempts:

– Number of attempts, date of most recent attempt, duration

– Methods used previously—What did or didn’t work? Why or why not?

– Prior medication administration, dose, compliance, duration of treatment

– Reasons for relapse

Discuss Key Issues (for the upcoming or current quit attempt)

• Reasons/motivation for wanting to quit (or avoid relapse)

• Confidence in ability to quit (or avoid relapse)

• Triggers for tobacco use

• Routines and situations associated with tobacco use

• Stress-related tobacco use

• Social support for quitting

• Concerns about weight gain

• Concerns about withdrawal symptoms

Facilitate Quitting Process• Discuss methods for quitting: pros and cons of the different methods

• Set a quit date: ideally, less than 2 weeks away

• Recommend completion of a Tobacco Use Log

• Discuss coping strategies (cognitive, behavioral) for key issues

• Discuss withdrawal symptoms

• Discuss concept of “slip” versus relapse

• Provide medication counseling: compliance, proper use, with demonstration

• Offer to assist throughout the quit attempt

Evaluate the Quit Attempt (at follow-up)

• Status of attempt

• Inquire about “slips” and relapse

• Medication compliance and plans for discontinuation

Is the patient now

willing to quit?

Does the patient now use tobacco?

Did the patient use

tobacco previously?

STEP One: ASK about Tobacco UseSuggested Dialogue

– “Do you ever smoke or use any type of tobacco?”

– “I take time to talk with all of my patients about tobacco use—because it’s important.”

– “Medication X often is used for conditions linked with or caused by smoking. Do you,

or does someone in your household smoke?”

– “Condition X often is caused or worsened by exposure to tobacco smoke. Do you, ordoes someone in your household smoke?”

STEP Two: Strongly ADVISE to QuitSuggested Dialogue

– Quitting is the most important thing you can do to protect your health now and in thefuture. I have training to help my patients quit, and when you are ready I would bemore than happy to work with you to design a treatment plan.

– What are your thoughts about quitting? Might you consider quitting sometime in thenext month?

Prior to imparting advice, consider asking the patient for permission to do so – e.g.,“May I tell you why this concerns me?” {then elaborate on patient-specific concerns).

FIGURE 88-2 Tobacco-cessation counseling guide sheet. (Reprinted with permission from Rx for Change: Clinician-AssistedTobacco Cessation. Copyright c© 1999–2012. The Regents of the University of California. All rights reserved.)

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T A B L E 8 8 - 5Enhancing Motivation to Quit: The “5 R’s” for Tobacco Cessation Counseling

� Relevance—Encourage patients to think about the reasons why quitting is important. Counseling should be framed such that it relates to thepatient’s risk for disease or exacerbation of disease, family or social situations (e.g., having children with asthma), health concerns, age, or otherpatient factors, such as prior experience with quitting.� 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 amongchildren by being a negative role model; effects of secondhand smoke on others, including children and pets).� 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.� Roadblocks—Help patients identify barriers to quitting and assist in developing coping strategies (Table 88-6) for addressing each barrier. Commonbarriers include nicotine withdrawal symptoms, fear of failure, a need for social support while quitting, depression, weight gain, and a sense ofdeprivation or loss.� Repetition—Continue to work with patients who are successful in their quit attempt. Discuss circumstances in which smoking occurred toidentify the trigger(s) for relapse; this is part of the learning process and will be useful information for the next quit attempt. Repeat interventionswhen 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 andHuman Services; 2008.

and this can be accomplished by applying the “5 R’s”8 (Table88-5) and by offering to work closely with the patient in design-ing a treatment plan. Although it might be useful to educatepatients about the pharmacotherapy options, it is inappropriateto prescribe a treatment regimen for patients who are not readyto quit. For patients who are not ready to quit in the next 30days, encourage them to seriously consider quitting and ask thefollowing questions:

1. Do you ever plan to quit?If the patient responds “no,” the clinician should ask, “Whatwould have to change for you to decide to quit?” If the patientresponds “nothing,” then offer to assist, if or when the patientchanges his or her mind. If the patient responds “yes,” theclinician should continue with question 2.

2. What might be some benefits of quitting now, instead of later?The longer a patient smokes, quitting generally becomes moredifficult. Most patients will agree that there is never an idealtime to quit, and procrastinating a quit date has more negativeeffects than positive.

3. What would have to change for you to decide to quit sooner?This question probes patients’ perceptions of quitting, whichreveals some of the barriers to quitting that can then be dis-cussed.

For patients who are ready to quit (i.e., in the next month),the goal is to work with the patient in designing an individual-ized treatment plan, addressing the key issues listed under the“Assist” component of Figure 88-2.32 The first steps are to dis-cuss the patient’s tobacco use history, inquiring about levels ofsmoking, number of years smoked, methods used previously forquitting (what worked, what did not work and why), and rea-son(s) for previous failed quit attempts. Clinicians should elicitpatients’ opinions about the different medications for quittingand should work with patients in selecting the quitting methods(e.g., medications, behavioral counseling programs). Although itis important to recognize that pharmaceutical agents might notbe appropriate, desirable, or affordable for all patients, cliniciansshould educate patients that medications, when taken correctly,can substantially increase the likelihood of success.

Patients should be advised to select a quit date. Ideally, thisdate will be within the next 2 weeks to allow sufficient timeto prepare for the quit attempt, including mental preparation,as well as preparation of the environment, such as by remov-ing all tobacco products and ashtrays from the home, car, andworkspace and informing their family, friends, and coworkersabout their upcoming quit attempt and requesting their support.

Additional strategies for coping with quitting are shown in Table88-6.32 Patients should be counseled about withdrawal symp-toms, medication use, and the importance of receiving behavioralcounseling throughout the quit attempt. Finally, patients shouldbe commended for taking important steps toward improvingtheir health.� Arrange: Because patients’ ability to quit increases when

multiple counseling interactions are provided, arrang-ing follow-up counseling is an important, yet typicallyneglected, element of treatment for tobacco dependence.Follow-up contact should occur soon after the quit date,preferably during the first week. A second follow-upcontact is recommended within the first month afterquitting.8 Periodically, additional follow-up contacts shouldoccur to monitor patient progress, assess compliancewith pharmacotherapy regimens, and provide additionalsupport.

Relapse prevention counseling should be part of every follow-up contact with patients who have recently quit smoking. Whencounseling recent quitters, it is important to address challengesin countering withdrawal symptoms and cravings or temptationsto use tobacco. A list of strategies for key triggers or temptationsfor tobacco use is provided in Table 88-6.32 Importantly, becausetobacco use is a habitual behavior, patients should be advised toalter their daily routines; this helps disassociate specific behaviorsfrom the use of tobacco. Patients who slip and smoke a cigarette(or use any form of tobacco) or experience a full relapse backto habitual tobacco use should be encouraged to think throughthe scenario in which tobacco use first occurred and identify thetrigger(s) for relapse. This process provides valuable informationfor future quit attempts.

PHARMACOTHERAPY OPTIONSAll smokers who are trying to quit should be encouraged touse one or more US Food and Drug Administration (FDA)-approved pharmacologic aids for cessation; potential exceptionsthat require special consideration include medical contraindica-tions or use in specific populations for which there is insuffi-cient evidence of effectiveness (i.e., pregnant women, smokelesstobacco users, light smokers, adolescents).8 Currently, the FDA-approved first-line agents that have been shown to be effectivein promoting smoking cessation include five NRT dosage forms,sustained-release bupropion, and varenicline.8 Dosing informa-tion, precautions, and adverse effects for the first-line agentsare shown in Table 88-7. Pharmacologic agents that have not

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T A B L E 8 8 - 6Cognitive 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,focus on downside of tobacco

Reminding oneself that cravings and temptations are temporary and will pass. Announce, either silently or aloud,“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 withsuccess.

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 whatwould happen if offered a cigarette by a friend—mentally craft and rehearse a response, and perhaps evenpractice 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-specifictriggers 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 useduring times of stress (e.g., breathe deeply several times, take a break or leave the situation, call a supportivefriend or family member, perform self-massage, or use nicotine replacement therapy to manage situationalcravings).

Alcohol Drinking alcohol can lead to relapse. Consider limiting or abstaining from alcohol during the early stages ofquitting.

Other tobacco users Quitting is more difficult when around other tobacco users. This is especially difficult if there is another tobaccouser in the household. When possible during the early stages of quitting, limit prolonged contact withindividuals who are using tobacco. Ask coworkers, friends, and housemates not to smoke or use tobacco inyour presence.

Oral gratification needs Have nontobacco oral substitutes (e.g., gum, sugarless candy, straws, toothpicks, lip balm, toothbrush, nicotinereplacement therapy, bottled water) readily available.

Automatic smoking routines Anticipate routines that are associated with tobacco use and develop an alternative plan.

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 bydoodling 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 broadrange of weight gain reported, with up to 10% of quitters gaining as much as 30 pounds. Do not attempt tomodify multiple behaviors at one time. If weight gain is a barrier to quitting, engage in regular physical activityand adhere to a healthful diet (as opposed to strict dieting). Carefully plan and prepare meals, increase fruit andwater intake to create a feeling of fullness, and chew sugarless gum or eat sugarless candies. Consider use ofpharmacotherapy 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 distractivethinking, take a break, change activities or tasks, take deep breaths, perform self-massage, or use nicotinereplacement 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.

received an approval from the FDA for smoking cessation but arerecommended as second-line agents8 include clonidine andnortriptyline.

FIRST-LINE AGENTS

NICOTINE REPLACEMENT THERAPYNRT improves cessation rates by reducing the physical with-drawal symptoms associated with tobacco cessation while thepatient focuses on modifying his or her behavior and copingwith the psychological aspects of quitting. In addition, becausethe onset of action for NRT is not as rapid as that of nicotineobtained through smoking, patients become less accustomed

to the nearly immediate, reinforcing effects of inhaled nico-tine. A meta-analysis of 111 controlled trials, enrolling morethan 43,000 participants, found that all NRT formulations (gum,inhaler, lozenge, patch, and nasal spray) result in statistically sig-nificant improvements in abstinence rates when compared withplacebo. Patients using NRT are 1.6 times as likely to quit smok-ing than are those receiving placebo.49 Figure 88-332 depicts theconcentration–time curves for the various NRT formulations,compared with a cigarette and moist snuff (a smokeless formof tobacco).50–52 It can be seen that of the five NRT dosageforms, the nicotine nasal spray reaches its peak concentrationmost rapidly. The nicotine gum, lozenge, and oral inhaler havesimilar concentration curves, and the nicotine transdermal patch

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2065

P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in

LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

TA

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yrig

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1999

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2066

P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in

LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

2067

Toba

cco

Use

and

Dep

ende

nce

Cha

pte

r88

Cigarette Moist snuff Nasal spray Inhaler Lozenge (2 mg)

Time (minutes)

Gum (2 mg) Patch

25

20

15

10

5

00 10 20 30 40 50 60

Pla

sm

a N

icotine (

μχg

/L)

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 nicotineconcentration 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 pharmacokineticsand comparison with other nicotine treatments. Clin Pharmacokinet. 2001;40(9):661; and Fant RV etal. Pharmacokinetics and pharmacodynamics of moist snuff in humans. Tob Control. 1999;8(4):387.)

has the slowest onset, but offers more consistent blood levels ofnicotine for a sustained period.

SUSTAINED-RELEASE BUPROPIONSustained-release bupropion is an atypical antidepressant med-ication hypothesized to promote smoking cessation by block-ing the reuptake of dopamine and norepinephrine in the centralnervous system8 and possibly by acting as a nicotine receptorantagonist.53 These neurochemical effects are believed to mod-ulate the dopamine reward pathway and reduce cravings fornicotine and symptoms of withdrawal.8 Use of sustained-releasebupropion approximately doubles the long-term abstinence ratewhen compared with placebo.8,54

VARENICLINEVarenicline, a cytisine analog, is a partial agonist that binds withhigh affinity and selectivity at α4β2 neuronal nicotinic acetyl-choline receptors.55 The efficacy of varenicline in smoking ces-sation is believed to be the result of sustained, low-level agonistactivity at the receptor site combined with competitive inhibitionof nicotine binding. The partial agonist activity induces modestreceptor stimulation, leading to increased dopamine levels, whichattenuates the symptoms of nicotine withdrawal. In addition, byblocking the ability of nicotine to activate α4β2 nicotinic acetyl-choline receptors, varenicline inhibits the surges of dopaminerelease that are believed to be responsible for the reinforcementand reward associated with smoking.55,56 Use of varenicline morethan doubles the long-term abstinence rate when compared inclinical trials with placebo.8,57

SECOND-LINE AGENTSAlthough not FDA-approved specifically for smoking cessation,the prescription medications clonidine and nortriptyline are rec-ommended as second-line agents.8 Lack of an FDA-approvedindication for smoking cessation and less desirable side-effectprofiles currently prohibit these agents from achieving first-lineclassification.8

PHARMACOTHERAPY FOR TREATINGTOBACCO USE AND DEPENDENCE

Transdermal Nicotine PatchCASE 88-1

QUESTION 1: T.B. is a 32-year-old woman who is enrolled ina worksite smoking-cessation program. During the previousgroup session, the cessation counselor discussed the vari-ous medications for cessation. T.B. has set her quit date for1 week from today, and she is interested in starting the nico-tine transdermal patch. She is currently smoking 1.5 packsper day (PPD), which is a reduction from the 2 PPD she hadbeen smoking for the past 10 years. T.B. reports she smokesseveral cigarettes in succession immediately after waking inthe morning. She takes no medications and has no medicalproblems. Which nicotine transdermal product should T.B.select, and how should it be used?

Transdermal nicotine delivery systems, available with or with-out a prescription, consist of an impermeable surface layer, anicotine reservoir, an adhesive layer, and a removable protec-tive liner. Although the transdermal delivery technology variesby manufacturer, nicotine is well absorbed, with 68% to 82%of the dose released from 24-hour patch formulations systemi-cally bioavailable across the skin. Plasma nicotine concentrationsfrom the patch rise slowly during 1 to 4 hours and peak within3 to 12 hours after application.22 Levels of nicotine achievedwith the transdermal patch are lower and fluctuate less than dothose achieved with tobacco products or other NRT formulations(Fig. 88-3).

The transdermal nicotine patch exhibits significantlyimproved abstinence rates relative to placebo (Table 88-4).8,49

A meta-analysis of 25 randomized, controlled trials found treat-ment with the nicotine patch (6–14 weeks) approximately dou-bled the likelihood of long-term abstinence compared withplacebo.8

P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in

LWBK915-88 LWW-KodaKimble-educational November 17, 2011 13:58

2068

Section

16Substance

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DOSINGThe manufacturers’ recommended dosages are listed in Table88-7. In general, higher levels of smoking necessitate the use ofhigher-strength formulations and a longer duration of therapy.Ultimately, the starting dose, rate of tapering, and total durationof therapy must be individualized to the patient’s baseline smok-ing levels, development of side effects (e.g., nausea, dyspepsia,nervousness, dizziness, sweating), and the presence or absenceof withdrawal symptoms. T.B. currently smokes 30 cigarettes perday, and thus she should initiate the regimen using the 21-mg/daypatch.

PATIENT EDUCATIONRegardless of the product selected, T.B. should be instructed toapply the patch to a clean, dry, hairless area of skin on the upperbody or the upper outer part of her arm at approximately thesame time each day. To minimize the potential for local skinreactions, the patch application site should be rotated daily, andthe same area should not be used again for at least 1 week. Afterpatch application, T.B. should ensure that the patch adheres wellto the skin, especially around the edges. The clinician shouldreassure T.B. that water will not reduce the effectiveness of thenicotine patch if it is applied correctly, and she may bathe, shower,swim, or exercise while wearing the patch. Finally, T.B. shouldbe advised to discontinue use of the nicotine patch and contact ahealth care provider if skin redness caused by the patch does notresolve after 4 days; if the skin swells or a rash develops; if irregularheartbeat or palpitations occur; or if she experiences symptoms ofnicotine overdose such as nausea, vomiting, dizziness, diarrhea,sweating, weakness, or rapid heartbeat.

ADVERSE REACTIONS

CASE 88-1, QUESTION 2: Ten days later, T.B. calls to com-plain of an itchy rash that she believes is caused by thenicotine patch. She noticed the rash yesterday when sheremoved the first patch from her left upper arm. This morn-ing, after removing the second patch from her right upperarm, she noticed a similar rash. T.B. describes the skin onher right arm as slightly red but not swollen; the rash onher left arm has only a faint trace of pink discoloration. Herlast cigarette was 2 days ago. How should T.B. be managedat this time?

The most common side effects associated with the nicotinepatch are local reactions (erythema, burning, and pruritus) atthe skin application site. These reactions are generally caused byskin occlusion or sensitivity to the patch adhesives. Rotating thepatch application sites on a daily basis minimizes skin irritation;nonetheless, skin reactions to the patch adhesives occur in upto 50% of patch users. Fewer than 5% of patients discontinuetherapy because of a skin reaction.8

T.B. appears to be experiencing a mild skin reaction and shouldbe reassured that it is common for the skin to appear erythema-tous for up to 24 to 48 hours after the patch is removed. T.B.can apply topical hydrocortisone cream (0.5% or 1%) or triam-cinolone cream (0.5%), or she can take an oral antihistamine forsymptomatic treatment.8 Because the rash on her left arm hasnearly resolved, it is reasonable for T.B. to continue using thenicotine transdermal patch provided that the erythema is nottoo bothersome.

Other less common side effects associated with the transder-mal nicotine patch include vivid or abnormal dreams, insomnia,and headache. Sleep disturbances likely result from nocturnalnicotine absorption. Patients experiencing troublesome sleepdisturbances should be instructed to remove the patch before

bedtime and apply a new patch as soon as possible after wakingthe following morning.8

The clinician should also provide behavioral counseling sup-port by asking T.B. about the current quit attempt. Appropriateissues to address include her confidence in remaining tobaccofree, situations in which she has been tempted to smoke andpotential triggers for relapse, nicotine withdrawal symptoms,her social support system for quitting, and any other questionsor concerns she might have. It is reasonable to review poten-tial coping strategies (behavioral and cognitive; Table 88-6) andschedule a future follow-up call. The clinician should commendT.B. for her decision to quit, congratulate her for remaining freeof cigarettes for 48 hours, and reassure her that skin irritationis a common, yet generally manageable, complication with thenicotine patch.

PRODUCT SELECTION CONSIDERATIONSThe primary advantage of the transdermal nicotine patch com-pared with other NRT formulations is that the patch is easy touse and conceal, releases a continuous dose of nicotine through-out the day, and requires administration only once daily. Disad-vantages of the patch include a high incidence of skin irritationassociated with the patch adhesives and the inability to acutelyadjust the dose of nicotine to alleviate symptoms of withdrawal.Finally, patients with underlying dermatologic conditions (e.g.,psoriasis, eczema, atopic dermatitis) should not use the patchbecause they are more likely to experience skin irritation.8

CASE 88-1, QUESTION 3: T.B. would like to discontinue thenicotine transdermal patch. She would like to purchase anonprescription smoking-cessation medication and wants toknow whether the gum or lozenge is an effective alterna-tive.

Nicotine GumNicotine polacrilex gum is a resin complex of nicotine andpolacrilin in a chewing gum base that provides slow releaseand absorption of nicotine across the oral mucosa. The prod-uct is available in 2- and 4-mg strengths, and in multiple flavors(regular, cinnamon, fruit, mint, and orange). The gum has adistinct, tobaccolike, slightly peppery, minty, or fruity taste andcontains buffering agents (sodium carbonate and sodium bicar-bonate) to increase the salivary pH, which enhances the buccalabsorption of nicotine. The amount of nicotine absorbed fromeach piece is variable, but when used properly, approximately1.6 mg and 2.2 mg of nicotine is absorbed from each 2-mg and4-mg piece of gum, respectively.22 Peak plasma concentrationsof nicotine are achieved approximately 30 minutes after chew-ing a single piece of gum and then slowly decline thereafter(Fig. 88-3). Patients using short-term (6–14 weeks) or long-term(>14 weeks) treatment with nicotine gum are significantly morelikely to remain abstinent compared with those receiving placebo(Table 88-4).8

DOSINGTable 88-7 outlines the manufacturers’ recommended dosingschedule for the nicotine gum. The recommended dosage ofthe nicotine gum is based on the “time to first cigarette” (TTFC)of the day. Having a strong desire or need to smoke soon afterwaking is viewed as a key indicator of nicotine dependence.58

Therefore, patients who smoke their first cigarette of the daywithin 30 minutes of waking are likely to be more highly depen-dent on nicotine and require higher dosages than those who delaysmoking for more than 30 minutes after waking (Table 88-7).

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Specifically, if the TTFC is 30 minutes or less, therapy should beinitiated with the 4 mg gum. If the TTFC is more than 30 minutes,therapy should be initiated with the 2 mg gum. During the initial6 weeks of therapy, patients should use 1 piece of gum every 1 to2 hours while awake. In general, this amounts to at least 9 pieces ofgum daily. The “chew and park” method described here allows forthe slow, consistent release of nicotine from the polacrilin resin.Patients can use additional pieces of gum (to the daily maximumof 24 pieces per day) if cravings occur between scheduled doses.In general, patients who smoke a greater number of cigarettesper day will require more nicotine gum to alleviate their crav-ings than will patients who smoke fewer cigarettes per day. It ispreferable to use the gum on a fixed schedule of administration,tapering during 1 to 3 months rather than using it as needed tocontrol cravings.8

PATIENT EDUCATIONProper chewing technique is crucial when using the nicotinegum. Patients should be instructed to chew the gum slowly untila peppery, minty, or fruity taste or a slight tingling sensation in themouth is detected; this varies but generally occurs after about 15chews. When the taste or tingling sensation is noted, the patientshould “park” the gum between the cheek and gum to allowabsorption of nicotine across the buccal mucosa. When the tasteor tingling dissipates (generally after 1–2 minutes), the patientshould resume chewing slowly. When the taste or tingle returns,the patient should stop chewing and park the gum in a differentarea in the mouth. Rotating the gum placement site within themouth helps decrease the incidence of oral irritation. The chewand park steps should be repeated until most of the nicotine isextracted; this generally occurs after 30 minutes and becomesobvious when chewing no longer elicits the characteristic tasteor tingling sensation.

Patients should be warned that the absorption and thereforethe effectiveness of nicotine gum might be reduced by acidic bev-erages (e.g., coffee, juices, wine, soft drinks),59 which transientlyreduce the salivary pH. To prevent this interaction, patientsshould be advised not to eat or drink (except water) for 15 minutesbefore or while using the nicotine gum.

ADVERSE REACTIONSThe most common side effects associated with use of the nicotinegum include unpleasant taste, mouth irritation, jaw muscle sore-ness or fatigue, hypersalivation, hiccups, and dyspepsia. Many ofthese side effects can be minimized or prevented by using properchewing technique.8 Patients should be warned that chewing thegum too rapidly may result in excessive release of nicotine, lead-ing to lightheadedness, nausea, vomiting, irritation of the throatand mouth, hiccups, and indigestion.

PRODUCT SELECTION CONSIDERATIONSAdvantages of nicotine gum include the fact that this formula-tion may be used to satisfy oral cravings and the 4-mg strengthmight delay weight gain.8 For these reasons, the gum may be par-ticularly beneficial for patients who have weight-gain concernsor for patients who report boredom as a trigger for smoking.The gum might also be advantageous for patients who desireflexibility in dosing and prefer the ability to self-regulate nicotinelevels to manage withdrawal symptoms. Some patients may findthat the viscous consistency of the gum makes it difficult to usebecause it sticks to dental work. Others may find it difficult orsocially unacceptable to chew the gum so frequently. Nicotinegum should not be used by patients with temporomandibularjoint (TMJ) conditions.

Nicotine LozengeThe nicotine polacrilex lozenge is a resin complex of nicotine andpolacrilin in a sugarfree, light mint, or cherry-flavored lozenge.The product is available in 2- and 4-mg strengths, which are meantto be consumed like hard candy or other medicinal lozenges(e.g., sucked and moved from side to side in the mouth untilfully dissolved). Because the nicotine lozenge dissolves com-pletely, it delivers approximately 25% more nicotine than doesan equivalent dose of nicotine gum.50 Like the nicotine gum, thelozenge also contains buffering agents (sodium carbonate andpotassium bicarbonate) to increase salivary pH, thereby enhanc-ing buccal absorption of the nicotine. Peak nicotine concentra-tions of nicotine with the lozenge are achieved after 30 to 60minutes of use and then slowly decline thereafter (Fig. 88-3). In atrial evaluating the formulation currently available in the UnitedStates, the nicotine lozenge approximately doubled the 6-monthabstinence rates compared with placebo (23.9% vs. 12.3%).60 Ameta-analysis of five studies using either the nicotine lozenge(nicotine polacrilin) or sublingual tablet (not available in theUnited States) concluded that the odds of abstinence at 6 or moremonths was 2.0 with the tablet or lozenge relative to placebo (95%CI, 1.6–2.5).49

DOSINGTable 88-7 outlines the manufacturers’ recommended dosingschedule for the nicotine lozenge. Like the nicotine gum, thelozenge is dosed based on the TTFC. Patients who smoke theirfirst cigarette of the day within 30 minutes of waking shoulduse the 4-mg strength lozenge, and patients who smoke theirfirst cigarette of the day more than 30 minutes after wakingshould use the 2-mg strength lozenge. Patients are more likelyto succeed if they use the lozenge on a fixed schedule ratherthan as needed. During the initial 6 weeks of therapy, patientsshould use 1 lozenge every 1 to 2 hours while awake. In gen-eral, this amounts to at least 9 lozenges daily. Patients can useadditional lozenges (up to 5 lozenges in 6 hours or a maximumof 20 lozenges per day) if cravings occur between scheduleddoses.

PATIENT EDUCATIONSimilar to the gum, the nicotine lozenge is a specially formulatednicotine delivery system that must be used properly for optimalresults. The lozenge should be allowed to dissolve slowly in themouth; when nicotine is released from the polacrilin resin, awarm, tingling sensation may be experienced. The patient shouldoccasionally rotate the lozenge to different areas of the mouthto reduce the potential for mucosal irritation. When used cor-rectly, the lozenge should completely dissolve within 30 minutes.Patients should be counseled not to chew or swallow the lozengebecause this increases the incidence of gastrointestinal-relatedside effects.

Because the nicotine in the lozenge is dissolved in saliva andabsorbed through the buccal mucosa, patients should be cau-tioned that the effectiveness of the nicotine lozenge may bereduced by acidic beverages such as coffee, juices, wine, or softdrinks. As recommended for the nicotine gum, patients shouldbe advised not to eat or drink (except water) for 15 minutes beforeor while using the nicotine lozenge.

ADVERSE REACTIONSIn general, the nicotine lozenge is well tolerated. The mostcommon side effects include nausea, hiccups, cough, dyspep-sia, headache, and flatulence. Patients who use more than onelozenge at a time, continuously use one lozenge after another,

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or chew or swallow the lozenge are more likely to experiencedyspepsia or hiccups.

PRODUCT SELECTION CONSIDERATIONSThe nicotine lozenge is similar to the nicotine gum formula-tion in that it may be used to satisfy oral cravings, the 4-mgstrength might delay weight gain,8,59 and patients can self-titratetherapy to acutely manage withdrawal symptoms. Because thelozenge does not require chewing, many patients find this to bea more discrete nicotine delivery system. The disadvantages ofthe lozenge are the fact that it requires frequent dosing, and thegastrointestinal side effects (nausea, hiccups, and heartburn) maybe bothersome.

T.B. has expressed interest in either the nicotine gum orlozenge formulation for her quit attempt. Both agents are effec-tive, and the choice of therapy is dependent on the patient’sperceptions and expectations regarding treatment, including theability to comply with the regimen, previous experience withcessation medications, and other concerns (e.g., adverse effects,weight gain, cost of medications). T.B. would be a candidate foreither agent provided she is able to comply with the frequent dos-ing schedule (one lozenge or piece of gum every 1–2 hours whileshe is awake). T.B. smokes her first cigarette of the day immedi-ately after waking in the morning and she smokes approximately30 cigarettes/day; this smoking pattern suggests a higher degreeof nicotine dependence, and therefore T.B. would benefit from ahigher dose of NRT. T.B. should initiate treatment with the 4-mgstrength of either the nicotine lozenge or nicotine gum dosedevery 1 to 2 hours while she is awake and tapered according tothe schedule outlined in Table 88-7.

Postcessation Weight Gain

CASE 88-1, QUESTION 4: T.B. is very concerned about gain-ing weight after she quits smoking. Is weight gain commonafter quitting, and if so, how can this be prevented?

Most tobacco users gain weight after quitting, and cliniciansshould neither deny the likelihood of weight gain nor minimizeits significance.8 For nearly all patients, the health risks associatedwith postcessation weight gain are negligible compared with therisks of continued smoking.

Studies suggest that most quitters gain fewer than 10 pounds,but there is a broad range of weight gain reported, with upto 10% of quitters gaining as much as 30 pounds.8 In general,women tend to gain more weight than men. In a study of nearly6,000 smokers who were followed for 5 years after quitting, theaverage weight gain during the follow-up period was 19.2 and16.7 pounds among women and men, respectively.61 For menand women, subgroups that are more likely to gain weight afterquitting are African Americans, younger tobacco users (youngerthan 55 years), and heavier tobacco users (those smoking morethan 25 cigarettes per day).

The weight-suppressing effects of tobacco are well known.However, the mechanisms to explain why most successful quit-ters gain weight are not completely understood. Smokers havebeen found to have an approximately 10% higher metabolic ratecompared with nonsmokers.62 Increased postcessation caloricintake might result from an increase in appetite, improved senseof taste, or a change in the hand-to-mouth ritual through thesubstitution of tobacco with food.

In general, a patient is less likely to be successful if he orshe attempts to change multiple behaviors at once. For mostpatients, strict dieting to prevent weight gain, especially duringthe early stages of quitting, is generally not recommended.8 T.B.

should be counseled that the average weight gain of fewer than10 pounds is less detrimental to her overall health than is con-tinued smoking. Although exercise interventions have not beenshown to reduce weight gain among quitters,63 it should not beruled out as a recommendation for T.B. because she expressessignificant concern about weight gain, and this might be a bar-rier to her quitting. As such, it is reasonable for the clinician torecommend that T.B. engage in some form of physical activity,such as walking 30 minutes daily. Even small changes, such astaking the stairs instead of the elevator, or parking toward theend of a parking lot instead of in the closest spot, can make a dif-ference. Furthermore, T.B. should be advised to plan her mealsin advance to avoid binge eating, increase her water intake to cre-ate a feeling of fullness, chew sugarless gum, and limit alcoholconsumption. T.B. may consider pharmacotherapy options thathave been shown to delay weight gain—according to the ClinicalPractice Guideline, this would include the 4-mg nicotine gum orlozenge or sustained-release bupropion.8 It is important to note,however, that once the medication is terminated, most quittersgain, on average, an amount of weight that is comparable to thatwhich would have been gained in the absence of medication.8

Relapse Back to Smoking

CASE 88-1, QUESTION 5: During a follow-up contact, theclinician learns that T.B. smoked half a pack of cigarettes ata party over the weekend and has relapsed to her previoussmoking levels after not having smoked for more than amonth. How should the clinician respond?

The clinician should thank T.B. for being honest about hersmoking and ask whether she is comfortable discussing the cir-cumstances during which the smoking occurred. At the time ofher smoking, where was she, who was she with, how did sheget access to cigarettes, and how was she feeling at the time?What, specifically, were the triggers for her relapse (e.g., alcohol,depression, friends who were smoking around her)? It is impor-tant that the clinician help the patient to use this information aspart of the learning process, but it also is important to focus onthe “positive,” such as T.B.’s ability to have remained tobacco freefor more than 1 month. Four weeks after quitting, most physi-cal effects of nicotine withdrawal have completely resolved, andthus, the relapse trigger for T.B. likely was psychological or situa-tional and could be abated through application of effective copingtechniques. After an informative discussion about the situationin which the smoking occurred, it is important that the clini-cian work with the patient in identifying strategies for avoidingrelapse in the future (Table 88-6).

Smoking and Cardiovascular DiseaseCASE 88-2

QUESTION 1: P.J. is a 62-year-old man admitted for anelective coronary artery bypass graft (CABG) procedure.His medical history is significant for angina, hypertension,dyslipidemia, peripheral vascular disease (PVD), and aller-gic rhinitis. He underwent a bilateral carotid endarterec-tomy procedure 2 years ago and had iliac artery angio-plasty with stent placement 5 years ago for PVD. P.J.’ssocial history is significant for tobacco use (2 PPD) andalcohol (3–4 drinks/day). He is approximately 10 poundsoverweight. His preoperative laboratory results are signifi-cant for a total cholesterol of 270 mg/dL (desirable, <200),low-density lipoprotein cholesterol (LDL-C) of 163 mg/dL

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(optimal, <70), high-density lipoprotein cholesterol (HDL-C)of 35 mg/dL (low, <40), and triglycerides of 350 mg/dL(normal, <150). His medications before admission includeatenolol 50 mg daily, aspirin 81 mg daily, isosorbide dini-trate 20 mg TID, atorvastatin 20 mg daily, fluticasone nasalspray (50 mcg/spray) 1 spray/nostril daily, and nitroglycerin0.4 mg sublingually as needed. Which of P.J.’s chronic medi-cal conditions may be caused or exacerbated by his tobaccouse?

A wealth of evidence suggests that cigarette smoking is amajor cause of cardiovascular disease and is responsible forapproximately 128,000 premature cardiovascular-related deathseach year.5 Smoking is known to accelerate the process ofatherosclerosis, leading to chronic cardiovascular disorders,including coronary heart disease, cerebrovascular disease, PVD,aortic aneurysm, and congestive heart failure.3 In addition, smok-ing substantially elevates the risk for acute cardiovascular events,including sudden death, myocardial infarction (MI), stroke, andreocclusion of coronary or peripheral vessels after graft surgeryor angioplasty.3,64

There are numerous plausible pathophysiological mecha-nisms by which tobacco smoking contributes to the developmentof cardiovascular disease.7 Oxidant gases and other compoundsin tobacco smoke are believed to induce a hypercoagulable statecharacterized by increased platelet aggregation and thrombo-sis, which substantially increases the risk of MI and suddendeath.64,65 The carbon monoxide in smoke reduces the amountof oxygen available to tissues and organs, including myocardialtissue, and may reduce the ventricular fibrillation threshold.64

Smoking may accelerate atherosclerosis through effects onserum lipids; smokers tend to have higher levels of totalcholesterol, LDL-C, and triglycerides and lower HDL-C thannonsmokers.3 Smoking increases the levels of inflammatorymediators (C-reactive protein, leukocytes, and fibrinogen),which might contribute to the development and progression ofatherosclerosis.66 Finally, smoking stimulates the release of neu-rotransmitters (e.g., epinephrine, norepinephrine) that increasemyocardial workload and induce coronary vasoconstriction,leading to ischemia, arrhythmias, and sudden death.3,64

P.J.’s hospital admission for a CABG procedure for coronaryheart disease and angina, as well as previous procedures forperipheral vascular disease (angioplasty with stent placement)and cerebrovascular disease (bilateral carotid endarterectomy),are all conditions associated with chronic tobacco use. His ele-vated total cholesterol, LDL-C, and triglycerides, and reducedHDL-C levels are consistent with smoking-induced dyslip-idemia. Cigarette smoking in combination with P.J.’s other estab-lished cardiovascular risk factors (hypertension, dyslipidemia)have synergistically increased his risk for serious cardiovasculardisease.3,64 Fortunately, the effects of smoking on lipids, coagu-lation, myocardial workload, and coronary blood flow appear tobe reversible, and P.J.’s risk of developing further cardiovascular-related complications will markedly decrease if he is able toquit smoking.37,67 A meta-analysis of 20 studies determined thatsmoking cessation is associated with a 36% reduction in the riskof death among patients with established coronary heart disease.The reduced mortality risk associated with quitting smoking iscomparable to that observed with other established secondarypreventative approaches such as therapies for hyperlipidemiaand hypertension.68 The clinician should approach this hospi-talization as an opportunity to assist P.J. with quitting smoking.8

Furthermore, published data suggest that initiation of intensivecessation counseling interventions for hospitalized patients iseffective in achieving long-term abstinence.69

Noncigarette Forms of Tobacco

CASE 88-2, QUESTION 2: The cardiothoracic surgeon hasstrongly advised P.J. to quit smoking. P.J. would like toknow whether cutting down to one to two cigars a day isan acceptable alternative to his current one to two packs ofcigarettes per day.

The adverse health effects of cigar smoking have been welldescribed and include an increased risk of cancer of the lung,oral cavity, larynx, esophagus, and pancreas. In addition, cigarsmokers who inhale deeply are at increased risk for developingcardiovascular disease and chronic obstructive pulmonary dis-ease (COPD).70,71 Cigarette smokers who switch to smokingonly cigars decrease their risk of developing lung cancer, buttheir risk is markedly higher than if they were to quit smokingaltogether.71

Cigar weight and nicotine content vary widely from brand tobrand and from cigar to cigar. Most cigars range in weight fromabout 1 to 22 g, and a typical cigarette weighs less than 1 g. Thenicotine content of ten commercially available cigars studied in1996 ranged from 10 to 444 mg. In comparison, US cigaretteshave a relatively narrow total nicotine content range (mean,13.5 ± 0.1 mg) per cigarette.72 Relating these data, Henningfieldand colleagues concluded that it is possible for one large cigarto contain as much tobacco as an entire pack of cigarettes anddeliver enough nicotine to establish and maintain dependence.73

P.J. should be counseled that switching from cigarette smokingto low-level daily cigar smoking is not acceptable given his signif-icant underlying cardiovascular disease. The amount of nicotinedelivered by one to two cigars per day is capable of sustaining hisdependence on nicotine. Furthermore, former cigarette smok-ers are more likely to inhale deeply, which further increases therisk of cancer and cardiovascular and pulmonary disease. Theclinician should strongly advise P.J. to quit smoking cigarettesand that switching to cigars is not a safe alternative.

CASE 88-2, QUESTION 3: P.J. is willing to quit completely,but he is worried because he has tried to quit smoking “hun-dreds of times” and has never been able to quit for longerthan 1 week. He expresses a desire for a medication to assisthim during this quit attempt. He has tried the nicotine gumand transdermal patch during three previous quit attempts.He did not like the gum because it made his jaw sore. Hehad temporary success with the nicotine patch but foundit to be less flexible than the gum. For example, when heneeded extra nicotine during stressful situations, he couldnot apply a second patch. What treatment alternatives arereasonable for P.J.?

P.J. has inadequately responded to treatment with the trans-dermal patch and experienced intolerable jaw soreness with thenicotine gum. Newer formulations of the nicotine gum are lessviscous, and therefore easier to chew, than earlier formulationsof the gum; however, other options are available. First-line treat-ment options that he has not tried include the nicotine lozenge(see Case 88-1, Question 3), nicotine nasal spray, nicotine inhaler,sustained-release bupropion, varenicline, or an effective combi-nation of first-line agents (see Case 88-3, Question 1).

Nicotine Nasal SprayThe nicotine nasal spray is an aqueous solution of nicotineavailable in a metered-spray pump for administration to thenasal mucosa. Each actuation delivers a metered 50-μL spray

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containing 0.5 mg of nicotine. Nicotine in the nasal spray ismore rapidly absorbed than other NRT formulations (Fig. 88-3),with peak venous nicotine concentrations achieved within 11 to18 minutes after administration.22 Use of the nicotine nasal spraymore than doubles long-term abstinence rates when comparedwith placebo (Table 88-4).8,49

DOSINGTable 88-7 outlines the manufacturers’ recommended dosingschedule for the nicotine nasal spray. A dose of nicotine (1 mg)is administered as two sprays, one (0.5-mg spray) in each nostril.The recommended initial regimen is one to two doses every hourwhile awake for 6 to 8 weeks. This may be increased, as needed,to a maximum recommended dosage of five doses per hour or40 mg/day. For best results, patients should be encouraged touse at least eight doses per day during the initial 6 to 8 weeks oftherapy because less frequent administration may be less effec-tive. After 6 to 8 weeks, the dose should be gradually decreasedduring an additional 4 to 6 weeks.

PATIENT EDUCATIONBefore using the nasal spray for the first time, the nicotine nasalspray pump must be primed. This is done by actuating the deviceinto a tissue until a fine spray is visible (about six to eight times).When administering a dose, the patient should tilt the head backslightly and insert the tip of the bottle into the nostril as far as iscomfortable. After actuation of the pump, the patient should notsniff, swallow, or inhale through the nose because this increasesthe irritant effects of the spray. The spray increases the likeli-hood of tearing, coughing, and sneezing, so patients should wait5 minutes before driving or operating heavy machinery.

ADVERSE REACTIONSSide effects commonly reported with the nicotine nasal sprayinclude nasal and throat irritation (hot peppery sensation), sneez-ing, coughing, watery eyes, and rhinorrhea. In clinical trials, 94%of patients report moderate-severe nasal irritation during the first2 days of therapy; 81% of patients still reported mild to moderatenasal irritation after 3 weeks of therapy.8 Nasal congestion andtransient changes in taste and smell have also been reported.8

Despite the high incidence of local adverse effects, most patientsbecome tolerant to the irritant effects of the spray during the firstweek.74

PRODUCT SELECTION CONSIDERATIONSThe primary advantage in using the nicotine nasal spray is theability to rapidly titrate therapy to manage withdrawal symp-toms. However, because nicotine from the spray more rapidlypenetrates the central nervous system, there may be a higher like-lihood of developing dependence during treatment. The nicotinenasal spray has a dependence potential intermediate betweentobacco products and other NRT products. Individuals withchronic nasal disorders (e.g., rhinitis, polyps, sinusitis) or severereactive airway disease should not use the nicotine nasal spraybecause of its irritant effects. Exacerbation of asthma has beenreported after use of the nicotine nasal spray.75

Nicotine InhalerThe nicotine oral inhaler consists of a plastic mouthpiece and adisposable cartridge containing a porous plug containing 10 mgof nicotine and 1 mg of menthol. Menthol is added to reduce theirritant effect of nicotine.

Given that the usual pack-a-day smoker repeats the hand-to-mouth motion up to 200 times per day or 73,000 times each year,it is not surprising that many smokers find they miss the phys-ical manipulation of the cigarette and associated behaviors that

accompany smoking. The nicotine inhaler was designed to pro-vide nicotine replacement in a manner similar to smoking whileaddressing the sensory and ritualistic factors that are importantto many patients who smoke.51

As a patient inhales through the mouthpiece, nicotine vaporis released from the cartridge and is distributed throughout theoral cavity. When the inhaler is used correctly, approximately4 mg of nicotine vapor is released from the cartridge, and2 mg is absorbed across the buccal mucosa.76 Peak plasma nico-tine concentrations with the inhaler are achieved after approx-imal 30 minutes of use22 and then slowly decline thereafter(Fig. 88-3). Use of the nicotine inhaler approximately dou-bles long-term abstinence rates when compared with placebo(Table 88-4).8,49

DOSINGTable 88-7 outlines the manufacturers’ recommended dosingschedule for the nicotine inhaler. During the initial 3 to 6 weeksof treatment, the patient should use 1 cartridge every 1 to 2 hourswhile awake. This should be increased, as needed, to a maximumof 16 cartridges per day. In clinical trials, most successful quittersused an average of 6 to 16 cartridges per day. The manufacturerrecommends that each cartridge be depleted of nicotine by fre-quent continuous puffing for 20 minutes. The recommendedduration of treatment is 3 months, after which patients may beweaned from the inhaler by gradual reduction of the daily doseduring the following 6 to 12 weeks.

PATIENT EDUCATIONTo minimize the likelihood of throat irritation, patients should beinstructed to inhale shallowly (as if puffing a pipe). When usedcorrectly, 100 shallow puffs from the inhaler mouthpiece dur-ing 20 minutes approximate 10 puffs from one cigarette during5 minutes.51 The release of nicotine from the inhaler is tem-perature dependent and significantly reduced at temperaturesless than 40◦F.8,51 In cold conditions, patients should store theinhaler and cartridges in a warm place (e.g., inside pocket).8 Con-versely, under warmer conditions, more nicotine is released perpuff. However, nicotine plasma concentrations achieved usingthe inhaler in hot climates at maximal doses will not exceedlevels normally achieved with smoking.51

As with all forms of NRT that are absorbed across the buccalmucosa, the effectiveness of the nicotine inhaler is reduced byacidic foods and beverages, such as coffee, juices, wine, or softdrinks. Therefore, patients should be instructed not to eat ordrink anything (except water) for 15 minutes before or whileusing the inhaler.

ADVERSE REACTIONSThe most common side effects associated with the nicotineinhaler include mouth or throat irritation (40%) and cough(32%).8 Most patients rated cough and mouth and throat irri-tation symptoms as mild, decreasing with continued use. Otherless common side effects are rhinitis, dyspepsia, hiccups, andheadache. Adverse reactions necessitating discontinuation oftreatment occurred in less than 5% of patients using the inhaler.

PRODUCT SELECTION CONSIDERATIONSPatients who express a preference for therapy that can be easilytitrated to manage withdrawal symptoms or one that mimics thehand-to-mouth ritual of smoking may find the nicotine inhaler tobe an appealing option. Patients with underlying bronchospasticconditions should use the nicotine inhaler with caution, becausethe nicotine vapor can be irritating and might induce bron-chospasm.

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Sustained-Release BupropionSustained-release bupropion was the first nonnicotine medica-tion to receive FDA approval for smoking cessation. Clinicaltrials involving more than 11,000 patients have confirmed itseffectiveness as an aid for smoking cessation,54 and meta-analysesestimate that sustained-release bupropion treatment approxi-mately doubles long-term abstinence rates relative to placebo(Table 88-4).8,54

PHARMACOKINETICSAnimal data suggest the absolute bioavailability of bupro-pion ranges from 5% to 20%. It undergoes extensive hepaticmetabolism to three active metabolites; one of the metabolites,hydroxybupropion, is formed by the cytochrome-P450 isoen-zyme CYP2B6. Bupropion and its metabolites are eliminated inurine (87%) and feces (10%), with less than 1% being excretedunchanged in the urine. The half-life for bupropion is 21 hours,and its metabolites have a half-life range of 20 to 27 hours; steady-state plasma concentrations are reached within 5 and 8 days,respectively.77

DOSINGTreatment with sustained-release bupropion (Table 88-7) shouldbe initiated while the patient is still smoking, because approxi-mately 1 week of treatment is necessary to achieve steady-stateblood levels. Patients should set a target quit date that falls withinthe first 2 weeks of treatment, generally in the second week. Thestarting dose of sustained-release bupropion is one 150-mg tableteach morning for the first 3 days. If the initial dose is tolerated,the dosage should be increased on the fourth day to the recom-mended maximal dosage of 300 mg/day (150 mg BID). Therapyshould be continued for 7 to 12 weeks after the quit date.

PATIENT EDUCATIONPatients should be instructed to follow the dosing regimendescribed previously. Advise patients experiencing insomnia toavoid taking the second dose close to bedtime. Inform patientsthat bupropion might cause dizziness, drowsiness, or reducedalertness, and caution should be exercised when driving or oper-ating machinery. Because alcohol use might increase the like-lihood of seizures, patients should avoid or drink alcohol onlyin moderation while taking bupropion. Patients who consumealcohol regularly should be advised to talk with a health careprovider about their alcohol use before initiating bupropion ther-apy because abrupt cessation of alcohol use while taking bupro-pion might increase the risk of seizure. Patients should also beadvised not to take Zyban and Wellbutrin or generic bupropionformulations concomitantly to avoid dose-related adverse effects,including seizures.

ADVERSE REACTIONSThe most common adverse effects associated with bupropiontherapy include insomnia (35%–40%) and dry mouth (10%)8;these usually lessen with continued use. Taking the seconddaily dose in the early evening, but no sooner than 8 hoursafter the first dose, might reduce insomnia. Less common sideeffects include headache, nausea, tremors, and rash. Seizures area dose-related toxicity associated with bupropion therapy. Forthis reason, bupropion is contraindicated in patients with under-lying seizure disorders and those receiving concurrent therapywith other forms of bupropion (Wellbutrin, Wellbutrin SR, andWellbutrin XL). Bupropion also is contraindicated in patientswith anorexia or bulimia nervosa, patients undergoing abrupt dis-continuation of alcohol or sedatives (including benzodiazepines),and patients currently taking monoamine oxidase inhibitorsowing to the increased potential for seizures in these populations.

In clinical trials for smoking cessation, the frequency of seizureswith sustained-release bupropion was less than 0.1% (sevenseizures among 8,000 bupropion-treated patients),54 which iscomparable to the reported incidence of seizures (0.1%) withthe sustained-release formulation (Wellbutrin) when used for thetreatment of depression.78 For this reason, bupropion should beused with extreme caution in patients with a history of seizures orcranial trauma, in individuals taking medications that may lowerthe seizure threshold, and in patients with underlying severehepatic cirrhosis. Animal studies suggest that seizures may berelated to the peak plasma concentration of bupropion,79 and as aprecautionary measure, the manufacturer recommends thatpatients space the doses at least 8 hours apart and limit thetotal daily dose to no more than 300 mg. In July 2009, the FDAmandated that the prescribing information for all bupropion-containing products include a black-boxed warning highlight-ing the risk of serious neuropsychiatric symptoms, includingchanges in behavior, hostility, agitation, depressed mood, suicidalthoughts and behavior, and attempted suicide.77 These additionalwarnings were based on postmarketing adverse-event surveil-lance reports received by the FDA.

PRODUCT SELECTION CONSIDERATIONSSustained-release bupropion may be the drug of choice forpatients who prefer to take oral medications (an alternative oraloption is varenicline, described below). Because sustained-releasebupropion tablets are easy to dose (twice daily oral dosing), thisagent may be preferable for patients with regimen complianceconcerns (e.g., those unable to consistently use short-acting NRTformulations that require multiple daily doses). Sustained-releasebupropion might be beneficial for use in patients with coexistingdepression or in individuals with a history of depressive symp-toms during a previous quit attempt. Finally, sustained-releasebupropion has been found to reduce postcessation weight gainduring treatment,8,63 and this might be of short-term benefitin selected patients with concerns about weight gain after quit-ting. Disadvantages of sustained-release bupropion include a highprevalence of insomnia and several contraindications and precau-tions that preclude use in some patients.

VareniclineVarenicline is the most recent agent approved by the FDA forsmoking cessation. Clinical trials involving nearly 5,000 patientstreated with varenicline have confirmed its effectiveness as anaid for smoking cessation. Data from meta-analyses indicate thatvarenicline significantly increases long-term abstinence rates rel-ative to placebo,8,57 NRT,57 and sustained-release bupropion.8,57

The pooled risk ratio for long-term abstinence (≥6 months) forvarenicline compared with placebo was 2.3 (95% CI, 1.9-2.9). Thepooled risk ratio for varenicline versus sustained-release bupro-pion and the nicotine patch at 1-year follow-up was 1.5 (95% CI,1.2-1.9) and 1.3 (95% CI, 1.0-1.7), respectively.57

PHARMACOKINETICSVarenicline absorption is virtually complete after oral admin-istration, and oral bioavailability is unaffected by food. Onceabsorbed, varenicline undergoes minimal metabolism, with 92%excreted unchanged in the urine. Renal elimination is pri-marily through glomerular filtration, along with active tubu-lar secretion.80 The half-life is approximately 24 hours,80 andfollowing administration of multiple oral doses, steady-state con-ditions are reached within 4 days.81

DOSINGTreatment with varenicline (Table 88-7) should be initiated1 week before the patient stops smoking. This dosing regimen

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allows for gradual titration of the dose to minimize treatment-related nausea and insomnia. The recommended dosage titra-tion for varenicline is as follows: 0.5 mg daily days 1 to 3,0.5 mg twice daily days 4 to 7, and 1 mg twice daily weeks 2 to12. For patients who have successfully quit smoking at the endof 12 weeks, an additional course of 12 weeks may be consideredto increase the likelihood of long-term abstinence. Vareniclineshould be used with caution in patients with impaired renal func-tion. For patients with severe renal dysfunction (estimated cre-atinine clearance <30 mL/minute) the recommended maximaldose of varenicline is 0.5 mg twice daily. In patients with end-stage renal disease undergoing hemodialysis, a maximal dose of0.5 mg daily is recommended.80

PATIENT EDUCATIONThe tablets are to be taken after eating and with 8 ounces ofwater. Nausea and insomnia are side effects that are usually tem-porary. Patients should be advised to discontinue varenicline andcontact their health care provider immediately if they experi-ence agitation, hostility, depressed mood, or changes in behavioror thinking that are not typical for them (see adverse reactionsbelow).

ADVERSE REACTIONSVarenicline is generally well tolerated. Common side effects(≥5% and twice the rate observed in placebo-treated patients)include nausea (30%), sleep disturbance (insomnia 18%; abnor-mal dreams 13%), constipation (8%), flatulence (6%), and vomit-ing (5%). Per the manufacturer’s prescribing information, nauseawas the most common adverse event associated with vareniclinetreatment. Nausea was dose dependent and generally describedas mild or moderate and often transient; however, for somepatients, it was persistent for several months. Initial dose titrationwas beneficial in reducing the occurrence of nausea. Approxi-mately 3% of subjects receiving varenicline 1 mg BID discontin-ued treatment prematurely because of nausea. For patients withintolerable nausea, dose reduction should be considered.80

In July 2009, the FDA mandated that the prescribing infor-mation for varenicline include a black-boxed warning high-lighting the risk of serious neuropsychiatric symptoms includ-ing changes in behavior, hostility, agitation, depressed mood,and suicidal-related events including ideation, behavior, andattempted suicide.80 These additional warnings were basedon continued postmarketing adverse-event surveillance reportsreceived by the FDA. As such, the warnings and precautionssections of the medication’s prescribing information have beenupdated, and the FDA recommends that (a) patients tell theirhealth care providers about any history of psychiatric illnessbefore starting varenicline, and (b) clinicians and patients mon-itor for changes in mood and behavior during treatment withvarenicline.80 Because patients with serious psychiatric illnesssuch as schizophrenia, bipolar disorder, and major depressivedisorder did not participate in the premarketing studies of vareni-cline, the safety and efficacy of varenicline has not been estab-lished in these populations.80 Recently the prescribing infor-mation for varenicline was revised to include warning for apossible increased risk of cardiovascular events (MI, ischemicand hemorrhagic stroke) in patients with stable cardiovasculardisease.80

PRODUCT SELECTION CONSIDERATIONSVarenicline is a first-line agent for the treatment of tobacco useand dependence.8 It offers a convenient oral dosing regimen and anew mechanism of action that might be particularly appealing forpatients who have failed quit attempts with other first-line agents(e.g., NRT or sustained-release bupropion). As with any of these

medications, varenicline should be combined with behavioralcounseling to maximize chances for a successful, long-term quitattempt. Given its potential for inducing negative neuropsychi-atric effects, varenicline should be used with extreme caution inpatients with a current or past history of psychiatric illness.

P.J. has tried the nicotine gum and transdermal patch duringprevious quit attempts. Because he was intolerant to the nico-tine gum (it stuck to his dental work), this form of NRT is notappropriate. P.J.’s experience with the transdermal patch sug-gests he may benefit from a short-acting NRT formulation thatenables active administration and titration of drug as needed toalleviate symptoms of withdrawal and situational cravings. Otherfirst-line therapies include the nicotine nasal spray, inhaler, andlozenge; sustained-release bupropion; or varenicline. P.J. shouldnot use the nicotine nasal spray because he has allergic rhinitisand may be more susceptible to the irritant effects of the spray.In addition, some data suggest that the bioavailability of nicotineis reduced in patients with rhinitis.82 Furthermore, the safetyand efficacy of the nasal spray in patients with chronic nasaldisorders have not been adequately studied. Reasonable choicesfor P.J. therefore include sustained-release bupropion, nicotinelozenge, nicotine inhaler, or varenicline. Any of these optionsare reasonable, and the choice of therapy should be dictatedby P.J.’s individual preference. If varenicline is chosen, given P.J.has underlying cardiovascular disease, he should be instructed tonotify a health care provider for new or worsening cardiovascularsymptoms and to seek immediate medical attention if he expe-riences signs and symptoms of myocardial infarction. Finally, itis reasonable to consider combination therapy (see Case 88-3,Question 1).

Safety of Nicotine Replacement TherapyAmong Patients With CardiovascularDisease

CASE 88-2, QUESTION 4: P.J. would like to try the nicotineinhaler. Is NRT safe for use in patients with cardiovasculardisease?

Nicotine activates the sympathetic nervous system, leading toan increase in heart rate, blood pressure, and myocardial contrac-tility. Nicotine also may cause coronary artery vasoconstriction.83

These known hemodynamic effects of nicotine have led to doubtsabout the safety of using NRT in patients with established car-diovascular disease, particularly those with serious arrhythmias,unstable angina, or recent MI.

Soon after the nicotine patch was approved, anecdotal casereports in the lay press linked NRT (patch and gum) with adversecardiovascular events (i.e., arrhythmias, MI, stroke). Since then,several randomized, controlled trials have evaluated the safety ofNRT in patients with cardiovascular disease, including angio-graphically documented coronary artery stenosis, MI, stableangina, and previous CABG surgery or angioplasty.84–86 Theresults of these trials suggest no significant increase in the inci-dence of cardiovascular events or mortality among patientsreceiving the nicotine patch when compared with placebo. How-ever, because these trials specifically excluded patients with unsta-ble angina, serious arrhythmias, and recent MI, the manufac-turers of NRT products recommend that these agents be usedwith caution among patients in the immediate (within 2 weeks)post-MI period, those with serious arrhythmias, and those withunstable angina.8 It is notable, however, that NRT products(patch, nasal spray) have been shown to have fewer effects onbiomarkers of cardiovascular risk than does smoking,87 andsmoking cessation has been shown to improve cardiovascular

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parameters with no negation of these improvements with use ofNRT.88

Although two small, retrospective studies have raised ques-tions regarding the safety of NRT use in intensive caresettings,89,90 NRT use in patients with cardiovascular disease hasbeen the subject of numerous reviews, and it is widely believedby experts in the field that the risks of NRT in this patient pop-ulation are small in relation to the risks of continued tobaccouse.7,49,64,83,91,92 The 2008 Clinical Practice Guideline con-cludes that there is no evidence of increased cardiovascular riskwith these medications.8 Although the use of NRT may posesome theoretical risk in a patient like P.J., cigarette smoking isfar more hazardous to his health. Cigarettes, unlike NRT, delivernumerous toxins that induce a hypercoagulable state, reduce theoxygen-carrying capacity of hemoglobin, and adversely affectserum lipids. The amount of nicotine that P.J. would receive usingthe recommended dose of any NRT product will not exceed theamount he previously obtained from his 2 PPD smoking habit.The clinician should strongly encourage pharmacotherapy dur-ing P.J.’s current quit attempt. P.J. is 10 pounds overweight; theadditional risk imposed by a modest weight gain after smokingcessation likely will not be of clinical significance compared withthat of continued smoking.

Combination Therapy for TobaccoDependence

CASE 88-3

QUESTION 1: J.B. is a 60-year-old man referred to thepulmonary clinic for further evaluation and managementof his chronic obstructive pulmonary disease (COPD). Hecomplains of decreased exercise tolerance and has notedincreasing shortness of breath (SOB) with minimal exertion(e.g., while golfing or climbing stairs). He currently uses analbuterol inhaler (90 mcg/puff), 2 puffs every 4 hours regu-larly for SOB. His medical history is otherwise unremarkableexcept for osteoarthritis controlled with acetaminophen1 g TID. He has smoked approximately 1.5 to 2 PPD formore than 40 years. J.B. indicates he has made several quitattempts during the past year. On the first attempt (quitting“cold turkey”), J.B. relapsed within 2 days. J.B. successfullyquit for nearly 2 weeks on his second attempt (using the 4-mg nicotine lozenge), but he found it difficult to adhere tothe frequent dosing schedule and relapsed shortly after dis-continuing the lozenge. His most recent quit attempt was6 months ago using varenicline. After 1 month of absti-nence, J.B. self-terminated varenicline (“I thought I didn’tneed it anymore”) and relapsed within 1 week. On furtherquestioning, J.B. states that he did not enroll in a behavioralcounseling program or seek additional assistance (otherthan pharmacotherapy) during any of his quit attempts. Heexpresses an interest in smoking cessation but is discour-aged by his prior lack of success. On physical examination,coarse breath sounds that clear after coughing are noted. Achest radiograph obtained in the office shows no infiltrates.Spirometry reveals a forced expiratory volume in 1 second(FEV1) of 2.8 L (72% of predicted) and a forced vital capac-ity (FVC) of 4.1 L (81% of predicted). His FEV1/FVC ratio is68%. He weighs 76 kg and is 72 inches tall. J.B. is concernedabout his worsening pulmonary function and is committedto making another effort to quit. What treatment optionsare appropriate for J.B.?

Tobacco smoking is the single most important risk factorfor the development of COPD7, and nearly all patients diag-

nosed with COPD are current or former smokers.93 Medica-tions (e.g., bronchodilators, anti-inflammatory agents) used totreat the symptoms of COPD have not been shown to alter thedisease progression.93 J.B.’s pulmonary function tests indicate hehas stage II (moderate) COPD.93 Given his escalating pulmonarysymptoms, it is imperative that he stop smoking as soon as possi-ble. J.B. should be advised that medications for COPD offer onlylimited symptomatic relief, and the most important componentof his treatment is smoking cessation.93,94 The clinician shouldcommend J.B. for his interest in quitting and help him devise apatient-specific treatment plan.

Although the use of first- and second-line medications approx-imately double the likelihood that a patient will successfully quitsmoking, data from clinical trials suggest that only 15% to 25%of patients remain abstinent for more than 6 months.49,54,57,95

Given these modest success rates, clinicians and researchers haveexplored modified approaches to standard therapies, includingthe use of combination therapy.

Plasma levels of nicotine achieved with standard doses ofNRT are generally much lower than those attained with reg-ular smoking.74,96,97 As such, conventionally dosed NRT maydeliver subtherapeutic nicotine levels for some individuals, andin particular, for moderate-to-heavy smokers. Indeed, based ondata from eight clinical trials, the 2008 Clinical Practice Guide-line has identified selected combinations of medications thatcan be considered in the initial treatment of tobacco depend-ence.8

Combination NRT regimens, which typically consist of a long-acting agent (nicotine patch) in combination with a short-actingformulation (i.e., gum, lozenge, inhaler, or nasal spray), are beingincreasingly used as initial therapy. The long-acting formulation,which delivers nicotine at a relatively constant level, is used toprevent the onset of severe withdrawal symptoms, and the short-acting formulation, which delivers nicotine at a more rapid rate, isused as needed to control withdrawal symptoms that may occurduring potential relapse situations (e.g., after meals, during timesof stress, when around other smokers).

Controlled trials suggest that the nicotine patch in combi-nation with short-acting NRT formulations (i.e., gum, lozenge,nasal spray, or inhaler) significantly increase quit rates relativeto placebo.8,49,98 Similar results have been observed in trialsusing combination therapy with sustained-release bupropionand the nicotine patch. More recent data suggest that aggres-sive combination regimens including triple-agent NRT (e.g.,patch, inhaler, and nasal spray) with or without sustained-releasebupropion99 and triple-combination therapy (e.g., patch, inhaler,and sustained-release bupropion)100 are a safe and effective treat-ment approach.

Clinicians should be aware that although the combinationof the nicotine patch and sustained-release bupropion has beenapproved by the FDA, the concurrent use of multiple NRT prod-ucts is not FDA-approved for tobacco cessation. Furthermore, theoptimal agents, dosages, and durations of therapy for NRT com-bination therapy are currently unknown. Although the safetyand efficacy of varenicline-based combination regimens havenot been established, preliminary uncontrolled data suggest thatvarenicline in combination with sustained-release bupropion101

or NRT (patch in combination with gum, lozenge, inhaler ornasal spray)102 might be a viable treatment approach. However,data from randomized, controlled trials are needed before vareni-cline combination therapy can be recommended as a therapeuticapproach for smoking cessation.

Given the severity of J.B.’s condition and his willingness to quitnow, the clinician should initiate treatment as soon as possible.His treatment should consist of pharmacotherapy in conjunctionwith behavioral counseling and appropriate follow-up.

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PHARMACOTHERAPYThe clinician should work with J.B. to select the most appropri-ate pharmacotherapy. As noted previously, appropriate optionswould include the various NRT formulations, sustained-releasebupropion, varenicline, or an effective combination of first-lineagents. The choice of therapy is dictated by considerations suchas patient preference for a given agent, previous experience withcessation medications, current medical conditions, previous lev-els of smoking, medication adherence issues, and the patient’sout-of-pocket costs. For patients reporting a positive experiencewith a given medication, retreatment with the same agent or acombination of agents might be appropriate, with considerationgiven to increasing the dose, frequency, or duration of therapy.For patients reporting a negative experience with pharmacother-apy (e.g., poor adherence, side effects, palatability issues, cost),an alternative agent should be considered. Given J.B.’s previ-ous adherence issues with the nicotine lozenge as monotherapy,it might be preferable to use a long-acting cessation medica-tion such as the nicotine patch, sustained-release bupropion, orvarenicline. Combination therapy with the nicotine patch andsustained-release bupropion or a short-acting NRT formulation(e.g., nicotine gum, lozenge, or inhaler used as needed) wouldalso be appropriate.

BEHAVIORAL COUNSELINGAlthough medications are effective alone in helping patients quitsmoking, maximizing patients’ chances for a long-term, suc-cessful quit attempt requires the use of one or more medica-tions in combination with behavioral counseling. J.B.’s previous1-month-long quit attempt highlights the successful impactof varenicline in this patient; however, J.B.’s relapse likely isattributable to a shortened course of therapy and the absenceof a behavioral change program. J.B. should be advised thatthe medications are designed to make patients more comfort-able while quitting and that behavioral counseling is needed toaddress the “habit” of smoking by helping him cope with diffi-cult situations and triggers for relapse. J.B. should be advised to(a) call the toll-free tobacco quitline at 1-800-QUIT NOW (seeCase 88-5, Question 1), (b) call the toll-free number that accom-panies the selected medication (most medications include a freecounseling program), (c) enroll in a local group program, (d) joinan online quitting program such as Quitnet.com, or (e) requestindividualized counseling from a health professional with exper-tise in tobacco cessation. In addition, J.B. should be remindedthat adherence with the medication regimen—daily adherence,as well as duration of therapy—will increase his chances of quit-ting for good. Clinician-delivered counseling might also include apersonalized message to further enhance his motivation to quit.For example, the clinician could perform pulmonary functiontesting and translate J.B.’s spirometry results into an effective“lung age” (e.g., the age of the average healthy individual withsimilar spirometry values). Given J.B.’s height (72 inches) andFEV1 (2.8 L), his estimated lung age is almost 80 years.103 Thiseducational approach has been found to significantly increaselong-term (12-month) quit rates in a recent controlled trial.103

Drug Interactions With SmokingCASE 88-4

QUESTION 1: M.K. is a new patient requesting Ortho Tri-Cyclen (norgestimate/ethinyl estradiol). The new patienthistory form completed by M.K. reveals that she is 32 yearsold, weighs 65 kg, and is 70 inches tall. She takes noprescription medications but occasionally uses loratadine

10 mg as needed for allergies, and ibuprofen 400 mg asneeded for dysmenorrhea. She has no significant medicalhistory. Her father has hypertension and suffered an MIlast year. Her mother has type 2 diabetes and dyslipidemia.Her social history is significant for tobacco use (1 PPD for15 years), alcohol (1 glass of wine per night), and caffeine(3–4 cups of coffee daily). Are there any potential drug inter-actions with M.K.’s new prescription?

SMOKING AND COMBINED HORMONALCONTRACEPTIVESOne of the most important, but often unrecognized, precautionsto consider with oral contraceptive use is the potential interactionbetween tobacco smoke and estrogens in combination hormonalcontraceptives (see Chapter 47, Contraception). Estrogens areknown to promote coagulation by altering clotting factor levelsand increasing platelet aggregation. As described in Case 88-2,Question 1, substances present in tobacco smoke, including oxi-dant gases and other products of combustion, induce a hyperco-agulable state, increasing the risk of acute cardiovascular events.Exposure to both factors (smoking and high levels of estrogen)greatly increases the risk of thromboembolic and thromboticdisorders. Considerable epidemiologic evidence indicates thatcigarette smoking substantially increases the risk of adverse car-diovascular events, including stroke, MI, and thromboembolismin women who use oral combination hormonal contraceptiveagents.104,105 This risk is age-related, in that the absolute risk ofdeath as a result of cardiovascular disease in oral contraceptiveusers who smoke is 3.3 per 100,000 women ages 15 to 34 yearscompared with 29.4 per 100,000 women ages 35 to 44 years.To put this in perspective, the corresponding risk of death as aresult of cardiovascular disease in nonsmoking women who useoral contraceptives is much lower, with a death rate of 0.65 per100,000 women ages 15 to 34 years and 6.21 per 100,000 womenages 35 to 44 years.106 Because of the increased risk of adversecardiovascular events, current guidelines from the American Col-lege of Obstetricians and Gynecologists (ACOG) and the WorldHealth Organization (WHO) state that combination estrogen-progestin contraceptives should not be used in women who areolder than 35 years of age and smoke, and progestin-only con-traceptives (oral and injectable formulations) and intrauterinedevices are recommended for use in this population.107,108 M.K.is 32 years of age, and despite smoking 20 cigarettes per day, oralcontraceptive use is not contraindicated, per drug manufacturerrecommendations, at this time. However, the clinician shouldstrongly advise M.K. to quit smoking and assess her readiness todo so. M.K. should be informed that if she continues to smokewhile using oral combined hormonal contraceptives, her risk ofdeveloping a blood clot, stroke, or heart attack will continue toincrease with time. Risk factors associated with her family his-tory (hypertension, MI, diabetes, and hyperlipidemia) suggest agenetic predisposition to cardiovascular disease, and thus effortsto minimize preventable risk factors should be encouraged.

COMPLEMENTARY THERAPIES

CASE 88-4, QUESTION 2: M.K. asks whether any of thenatural herbal products for cessation that she “hears abouton the radio” are effective.

Although many herbal and homeopathic products are avail-able to help people quit smoking, data that support their safetyand efficacy are lacking. Most herbal preparations for smok-ing cessation contain lobeline, an herbal alkaloid with partial

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nicotine agonist activity. Although direct-to-consumer advertise-ments suggest that lobeline-containing preparations are safe andeffective, a meta-analysis109 and recent controlled trial110 foundno evidence to support the role of lobeline as an effective aid forsmoking cessation. Likewise, St. John’s wort (an herbal productwith antidepressant properties),111 nicobrevin (an herbal prod-uct not available in the United States that contains quinine,menthyl valerate, camphor, and eucalyptus oil),112 hypnosis,113

and acupuncture114 have not been found to be effective treat-ments for smoking cessation.8 Furthermore, patients should becautioned that herbal cigarettes are not safe alternatives becausethey result in the inhalation of other toxins present in smoke.M.K. should be advised that the efficacy of the herbal therapiesis not well established, and use of these agents cannot be recom-mended at this time.

CASE 88-4, QUESTION 3: M.K. is not considering quittingsmoking in the next 30 days. She cannot discontinue heroral contraceptives because she is sexually active and needsa reliable form of birth control. She wonders whether thenew low-dose birth control pills or other formulations (e.g.,patch, vaginal ring) are safer for smokers.

Combined oral contraceptives available in the United Statescontain estrogen in doses ranging from 20 to 50 mcg of ethinylestradiol. The results of in vitro studies have shown that oralcontraceptives containing at least 50 mcg of ethinyl estradiolinduce greater procoagulatory effects than do preparations con-taining either 30 mcg or 35 mcg of ethinyl estradiol; formulationscontaining 20 mcg of ethinyl estradiol appear to have little or noadverse effects on coagulation.115,116 Early epidemiologic reportslinking oral contraceptive use and severe cardiovascular eventswere largely observed in women using oral contraceptives con-taining more than 50 mcg of ethinyl estradiol.117 Since then,manufacturers have reduced the dose of estrogen in oral contra-ceptives such that the majority of preparations available in theUnited States contain 20 to 35 mcg of ethinyl estradiol.118

In 2001, the US Surgeon General stated that lower-dose oralcontraceptives may be associated with a reduced risk for coronaryheart disease (CHD) compared with higher-dose formulations.Despite this conclusion, the report cautioned that heavy smokerswho use oral contraceptives still have a greatly elevated risk forCHD.117

Serum estrogen levels obtained with the vaginal ring are sig-nificantly lower than those achieved with either transdermal ororal combined contraceptive formulations,119 and theoretically,the contraceptive vaginal ring might be a safer formulation forwomen who smoke. However, because the contraceptive patchand vaginal ring are relatively new, and their safety has not beenestablished among women who smoke, guidelines issued in 2006by the ACOG state that the same precautions for the use of oralcombined contraceptives should apply to these newer formula-tions as well.107

M.K.’s prescribed oral contraceptive agent (Ortho Tri-Cyclen)is a triphasic formulation containing 35 mcg of ethinyl estradiol incombination with weekly increasing doses of norgestimate (0.18,0.215, and 0.25 mg) throughout each monthly cycle. Althoughsome clinicians recommend the use of low-dose (20-mcg) estro-gen preparations in smokers, the available evidence suggests thatthe prescribed regimen poses no additional risk in M.K. However,if M.K. increases her smoking levels to more than 25 cigarettesper day, some data suggest that her risk for an MI is increased.120

The clinician should inform M.K. that there are currently nostudies demonstrating a reduced risk of adverse cardiovascularevents in smokers using oral contraceptives containing low doses(e.g., 20 mcg) of estrogen or the newer transdermal and vaginal

ring formulations. In the absence of published data, only smok-ing cessation can be advocated to definitively reduce the risk ofstroke, MI, and thromboembolism in women who use combinedhormonal contraceptives.

BEHAVIORAL COUNSELINGAlthough M.K. is not considering quitting at this time, it is appro-priate for the clinician to apply the 5 R’s (Table 88-5) to promotemotivation to quit. This counseling should be relevant to M.K.’ssituation and should highlight the risks of continued tobacco use,such as her elevated risk for thromboembolic and thromboticdisorders (associated with continued use of oral contraceptives).M.K. should be asked to think about the rewards of quitting andany potential roadblocks to quitting. At subsequent encounters,the clinician should sensitively assess M.K.’s tobacco use statusand motivation to quit, and offer assistance with quitting whenM.K. is ready. If M.K. decides to quit, it would be importantto reassess her caffeine intake because caffeine levels have beenreported to increase by 56% in patients who quit smoking.30

Brief Interventions to PromoteTobacco Cessation

CASE 88-5

QUESTION 1: J.C. is a 52-year-old man with a historyof asthma requesting a refill of his albuterol inhaler pre-scription. This is the third request for an albuterol inhaler(200 doses/inhaler) during the past 2 months. Before thisperiod, his last refill was more than a year ago. J.C. reportsthat he has been using albuterol on most days of the weekfor coughing and SOB. He has no other medical conditionsand takes no other medications. His social history is signif-icant for tobacco use (smokes 1.5 PPD; he recently startedsmoking again after starting a new job where “everyonesmokes”). J.C. previously quit smoking 20 years ago usingthe “cold turkey” approach (e.g., no medications or coun-seling), and although he was successful, he was miserablefor weeks and he expresses reluctance to “go through thisagain” during a stressful job transition.

The clinician is running behind schedule and doesnot have the time to provide comprehensive smoking-cessation counseling during this patient encounter. Whatbrief smoking-cessation interventions can the clinician pro-vide to J.C. to assist him with quitting?

TELEPHONE QUITLINESClinicians should become aware of local, community-basedresources for tobacco cessation, including telephone quitlines.When time or expertise do not afford provision of comprehen-sive tobacco-cessation counseling during a patient visit, clini-cians are encouraged to apply a truncated 5 A’s model, wherebythey ask about tobacco use, advise tobacco users to quit, andrefer patients who are ready to quit to a telephone quitline.Effective brief interventions can generally be accomplished infewer than 3 minutes. Telephone services that provide tobacco-cessation counseling have proliferated since the late 1990s; theseservices provide low-cost interventions that can reach patientswho might otherwise have limited access to medical treatmentbecause of geographic location or lack of insurance or finan-cial resources. In clinical trials, telephone counseling services forwhich at least some of the contacts are initiated by the quit-line counselor have been shown to be effective in promotingabstinence,8 and these positive results have been shown to trans-late into real world effectiveness.44 The addition of medicationto quitline counseling significantly improves abstinence rates

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compared with medication alone.8 In addition, preliminary evi-dence suggests that quitlines are also effective for smokelesstobacco cessation.121 The telephone number for the toll-freetobacco quitline is 1-800-QUIT NOW. In some states, clinicianscan submit a fax referral form, on behalf of a patient, to the quit-line. This form initiates a process whereby a quitline counselorthen contacts the patient directly.

J.C.’s asthma is not well controlled (e.g., he has been using ashort-acting bronchodilator >2 days/week for SOB and cough-ing). The change in J.C.’s asthma control is temporally relatedto his recent job change and relapse to daily smoking. Exposureto tobacco smoke is a potent trigger for asthma exacerbationsand an important cause of poor asthma control. Given that theclinician is unable to provide comprehensive smoking-cessationcounseling at this time, a brief intervention is appropriate. Theclinician should strongly advise J.C. to quit as a key componentof his asthma management plan and refer him to a free telephonequitline or to other resources that are available within the com-munity (e.g., local individual or group counseling programs).Time permitting, the clinician could educate J.C. on the benefitsof medications in reducing nicotine withdrawal symptoms givenhis previous negative experience with quitting.

For a video demonstration of a briefcounseling intervention for J.C. deliveredby a health care provider, go tohttp://thepoint.lww.com/AT10e.

Smoking Among Individuals WithMental Illness

CASE 88-6

QUESTION 1: J.D. is a 42-year-old woman presenting toclinic for follow-up of her depression management. Ninemonths ago, she was started on venlafaxine XR 75 mg daily.At her 3-month follow-up visit, she was stable on venlafax-ine XR 150 mg daily, and her depressive symptoms hadimproved. She also reported that she was sleeping muchbetter. J.D. has no other significant past medical history, andshe takes no other medications. Her social history is positivefor current tobacco use (1 PPD for 25 years) and caffeine use(1–2 Diet Cokes a day). She does not drink alcohol. Duringthe appointment J.D. indicates that she would like to quitsmoking because she is feeling better about herself, andshe knows that her overall health will improve if she quits.She also states that the last time she attempted to quit (sev-eral years ago, using the nicotine gum), she felt “down andhad difficulty concentrating and couldn’t sleep.” She now isfearful that her depression will return if she quits. Is smok-ing cessation appropriate for J.D. at this time, and what areher treatment options?

Although persons with mental illness constitute 22% of the USpopulation, they consume an estimated 44% of the cigarettes,10

and incur nearly half of the tobacco-related deaths.122 Tobaccouse and dependence is more common among people with moreserious mental illness,10,122,123 with schizophrenia being the high-est: 9 of 10 persons with schizophrenia smoke.10 On average,patients with mental illness die 25 years earlier than the gen-eral population,124 and smoking is a key contributor to prema-ture death. In the past, the mental health community has notaddressed smoking cessation with their patients, but increas-ing evidence suggests that quitting is possible and should bepromoted. For patients with mental illness to achieve wellness,

smoking-cessation intervention is an essential component of theoverall care plan.125

Given that J.D. is currently willing to quit, and her depressionhas been stabilized for more than 4 months in the continuationphase of depression treatment, it is appropriate for the clinicianto discuss a quitting plan with J.D. and initiate therapy. The ther-apeutic approach should include counseling and pharmacother-apy, with ongoing monitoring of progress toward quitting anddepressive symptoms.

TREATMENT SELECTION

PHARMACOTHERAPYBecause no contraindications are present, any of the FDA-approved medications for cessation are appropriate. Althoughsustained-release bupropion and varenicline both possess black-boxed warnings highlighting the risk of serious neuropsychiatricsymptoms, this does not preclude use of these medications forJ.D.77,80 Recently completed and ongoing studies are examin-ing the risks in greater detail, and many of these trials includepatients with various levels of severity and types of psychiatricdisorders.126–129 In a pooled analysis of patients without psychi-atric disorders, only sleep disorders and disturbances exhibited ahigher incidence in patients treated with varenicline.130

Regardless of whether sustained-release bupropion, vareni-cline, or NRT product(s) are selected, the clinician should mon-itor J.D. closely to assess incidence of depressive symptomatol-ogy. If sustained-release bupropion or varenicline is selected, J.D.should be advised to stop taking the medication and contactthe clinician immediately if she experiences agitation, depressedmood, and any changes in behavior that are not typical of nicotinewithdrawal, or if she experiences suicidal thoughts or behavior.

BEHAVIORAL COUNSELINGBecause J.D. has indicated that she is ready to quit, the clinicianshould commend her for making the important decision thatwill positively impact her overall health. J.D. should be advisedthat quitting is a process, and it will be important for them towork closely together to address the physiological as well aspsychological aspects of quitting during the upcoming months.As outlined in Figure 88-2, the clinician should review with J.D.her primary reasons for wanting to quit, assess her confidence inher ability to quit, determine key triggers for tobacco use, assessand address any concerns related to quitting, and determine aquit date.

CASE 88-6, QUESTION 2: After discussing the various treat-ment options with the clinician, J.D. decides that she wouldlike to add sustained-release bupropion to her regimenbecause the nicotine gum by itself didn’t help her much lasttime. She also thinks that the combination of venlafaxinewith bupropion might help to “keep her depression morestable” while she is quitting. She confides in the clinicianthat her biggest fear is the ability to avoid smoking whenshe is stressed because of her job. She is a survey researcherand must meet client-induced deadlines. How can J.D. copewith stressful situations?

A variety of coping mechanisms can be applied to alleviatethe need to smoke during stressful situations or when exposedto other triggers for smoking (Table 88-6). The clinician shouldencourage J.D. to think about strategies that would be effec-tive for her in these situations, such as deep breathing or calling asupportive friend. Additionally, the clinician should consider sug-gesting use of a short-acting NRT product (e.g., nicotine gum,lozenge, inhaler, or nasal spray) as needed to alleviate situational

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cravings to smoke. The clinician should also describe the dosingof sustained-release bupropion and the need to begin therapy1 to 2 weeks before the quit date (Table 88-7). A follow-up appoint-ment should be scheduled for approximately 3 months after thequit date, and the patient should be advised to contact the clini-cian if she encounters any difficulties before then.

CASE 88-6, QUESTION 3: Four weeks later, J.D. calls andreports that she has a dry mouth, is having difficulty sleep-ing, and feels jittery and anxious. She also is currently usingnicotine gum (2 mg), approximately four pieces daily. Howshould J.D. be managed?

As noted above, insomnia and dry mouth are commonlyassociated with sustained-release bupropion therapy and usuallylessen with continued use.77 The nicotine gum dose is low andnot likely contributing to this condition. To address insomnia,J.D. can be advised to take the second dose of the day earlier, butnot less than 8 hours after the first dose of the day. Alternatively,the clinician could consider reducing the daily dose to 150 mg inthe morning and omitting the evening dose. Although the manu-facturer recommends 300 mg per day, the 150-mg dose has beenshown to have comparable outcomes with those of the 300-mgdose131,132 and is better tolerated.131 The clinician also shouldassess J.D.’s caffeine consumption patterns and, if appropriate,suggest that she reduce her caffeine intake by 50% and not drinkcaffeinated beverages after 12 noon so her system is clear of itsstimulatory properties before sleep.31

Extended-Use Medicationsfor Cessation

CASE 88-6, QUESTION 4: J.D. returns to the clinician’soffice 3 months later, and indicates that she is doing wellbut had a few “slips” and smoked four times, most recentlylast week when she learned that her best friend was diag-nosed with ovarian cancer. Other than feeling down abouther friend, she has not felt depressed and has been han-dling her stress at work through deep-breathing exercises.Because she is not taking smoke breaks every few hours,she is able to accomplish more during the day, and meet-ing deadlines has not been a problem. She uses the nico-tine gum a few times a week, and does not feel readyto discontinue the sustained-release bupropion. She won-ders whether it is possible to continue the therapy for a bitlonger, until she feels more stable as a nonsmoker.

Extended-duration medication therapy appears to be safe andeffective. Long-term follow-up data from the Lung Health Studyindicate that approximately 15% of long-term quitters contin-ued nicotine gum therapy with no serious side effects.133 The2008 Clinical Practice Guideline states that extended use of med-ications might be beneficial in individuals who report persis-tent withdrawal symptoms during treatment, those who haverelapsed shortly after medication discontinuation, or those whoare interested in long-term therapy.8

Clinicians should be aware that although many of the medi-cations (sustained-release bupropion, varenicline, nicotine nasalspray, and inhaler) are approved by the FDA for long-term(6-month) use, the effectiveness of additional weeks on therapy isnot well established. A recent meta-analysis of eight trials foundthat extended treatment with varenicline might prevent relapse,extended treatment with bupropion is unlikely to have a clini-cally important effect, and studies of extended treatment withnicotine replacement are needed.134 Given J.R.’s current depres-

sion and because she recently encountered a difficult situationwith her friend’s diagnosis, it is reasonable for the clinician torecommend continuation of therapy for an additional 12 weeksand reassess progress at that time.

KEY REFERENCES AND WEBSITE

A full list of references for this chapter can be found athttp://thepoint.lww.com/AT10e. Below are the key referencesand websites for this chapter, with the corresponding refer-ence number in this chapter found in parentheses after thereference.

Key ReferencesBenowitz NL. Nicotine addiction. N Engl J Med. 2010;362(24):2295. (19)

Benowitz NL et al. Nicotine chemistry, metabolism, kinetics andbiomarkers. Handb Exp Pharmacol. 2009;(192):29. (22)

Cahill K et al. Nicotine receptor partial agonists for smokingcessation. Cochrane Database Syst Rev. 2008;(3):CD006103. (57)

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. (8)

Hughes JR et al. Antidepressants for smoking cessation. CochraneDatabase Syst Rev. 2007;(1):CD000031. (54)

Kroon LA. Drug interactions with smoking. Am J Health SystPharm. 2007;64(18):1917. (31)

National Center for Chronic Disease Prevention and Health Pro-motion, Office on Smoking and Health. The Health Consequencesof Involuntary Exposure to Tobacco Smoke: A Report of the SurgeonGeneral. Atlanta, GA: Office on Smoking and Health, NationalCenter for Chronic Disease Prevention and Health Promotion,Centers for Disease Control and Prevention, US Dept of Healthand Human Services; 2006. (6)

National Center for Chronic Disease Prevention and Health Pro-motion, Office on Smoking and Health. The Health Consequences ofSmoking: a Report of the Surgeon General. Washington, DC: Officeon Smoking and Health, National Center for Chronic DiseasePrevention and Health Promotion, Centers for Disease Controland Prevention, US Dept of Health and Human Services; 2004.(3)

National Center for Chronic Disease Prevention and Health Pro-motion, Office on Smoking and Health. How Tobacco SmokeCauses Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General. Atlanta, GA:Office on Smoking and Health, National Center for ChronicDisease Prevention and Health Promotion, Centers for DiseaseControl and Prevention, US Dept of Health and Human Services;2010. (7)

Schroeder SA. A 51-year-old woman with bipolar disorder whowants to quit smoking. JAMA. 2009;301(5):522. (125)

Stead LF et al. Nicotine replacement therapy for smoking cessa-tion. Cochrane Database Syst Rev. 2008;(1):CD000146. (49)

Key WebsiteRx for Change: Clinician-Assisted Tobacco Cessation. San Francisco,CA: The Regents of the University of California; 1999–2012.http://rxforchange.ucsf.edu/. (32)