Chapter 15 Nicotine and Tobacco

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Chapter 15. Nicotine and Tobacco

NICOTINE AND TOBACCO: INTRODUCTION

Although rates of tobacco use and dependence have been reduced substantially since the 1960s,

one in five Americans continues to smoke. The prevalence of smoking appears to be substantially

higher in persons with psychiatric and substance use disorders, and these individuals also have less

success when they attempt smoking cessation. In this chapter we review the epidemiology of

tobacco use and dependence and the pharmacological effects of nicotine and tobacco and discuss

the clinical assessment of tobacco users. We then review behavioral and pharmacological

treatments, including the U.S. Food and Drug Administration (FDA)–approved pharmacotherapies:

nicotine replacement therapies (NRTs), sustained-release bupropion, and varenicline. Finally, we

discuss the integration of tobacco dependence treatment into mental health settings with the view

that tobacco dependence is a chronic medical disorder and that more effective treatment of this

comorbidity in psychiatric disorders may require targeted treatments based on a better

understanding of the pathophysiology of individual psychiatric disorders.

EPIDEMIOLOGY OF TOBACCO USE

Cigarette smoking is the single largest preventable cause of morbidity and mortality in Western

countries. In the United States, approximately 22% of the population are tobacco users, compared

with a rate of 47% in 1965. Since the release of the Surgeon General’s report in 1965, smoking

prevalence has been substantially reduced, but this reduction appears to have slowed in recent

years. Cigarette smoking is the most common (>90%) method of tobacco use (Centers for Disease

Control and Prevention 2002; Giovino 2002), although other forms of tobacco are also commonly

used, including pipe tobacco, cigars, and smokeless tobacco. Approximately 440,000 people in the

United States die each year as a result of smoking-attributable medical illnesses such as lung

cancer, chronic obstructive pulmonary disease, cardiovascular disease, and stroke. Economic and

health care costs of tobacco use exceed $400 billion annually (Giovino 2002). Worldwide, it is

estimated that approximately 1.1 billion people use tobacco on a regular basis, including

approximately 65 million in the United States (Centers for Disease Control and Prevention 2002).

Smoking is now increasing rapidly throughout the developing world, and it is estimated that current

cigarette smoking will cause about 450 million deaths worldwide in the next 50 years. Reducing

current smoking by 50% would prevent 20–30 million premature deaths in the first quarter of this

century and 150 million in the second quarter (Centers for Disease Control and Prevention 2002).

For most smokers, quitting is the single most important thing that can be done to improve health.

The results of a recent epidemiological study in Norway suggest that even with sustained

reductions in smoking consumption (>50%), there is little if any reduction in cardiovascular

disease or lung or other smoking-related cancer risk (Tverdal and Bjartveit 2006), further

substantiating the merits of quitting rather than reducing smoking.

MOLECULAR BIOLOGY AND PHARMACOLOGY OF NICOTINIC RECEPTORS

Nicotine is the primary reinforcer in tobacco smoke, with contributions from over 4,000

components to the sensory (nonnicotinic) aspects of cigarette smoking. In tobacco dependence, the

primary site of action of nicotine is the 4 2 nicotinic acetylcholine receptor (nAChR), and the

endogenous transmitter acting on nAChRs is acetylcholine. nAChRs in the central nervous system

(CNS) are pentameric ion channel complexes (Leonard and Bertrand 2001), which are composed of

two and three subunits, with the seven subunits designated 2– 9 and the three subunits

designated 2– 4. This produces considerable diversity in subunit combinations, which may explain

some of the region-specific and functional selectivity of nicotinic effects in the CNS. Activation of

nAChRs leads to Na+/Ca2+ ion channel fluxes and neuronal firing. nAChRs are locatedPrint: Chapter 15. Nicotine and Tobacco http://www.psychiatryonline.com/popup.aspx?aID=347934&print=yes…

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presynaptically on several neurotransmitter-secreting neuron types in the CNS, including

mesolimbic dopamine (DA) neurons that project from the ventral tegmental area to the nucleus

accumbens (McGehee et al. 2006). In addition, nAChR activation on mesolimbic DA neurons leads

to DA secretion in the nucleus accumbens. The regulation of mesolimbic DA neurons is depicted in

Figure 15–1.

FIGURE 15–1. Mesolimbic dopamine neurons and their regulation by nicotinic, cholinergic,

GABAergic, and glutamatergic inputs.

ACh = acetylcholine; DA = dopamine; GABA = γ-aminobutyric acid; Glu = glutamate; NAc = nucleus

accumbens; nAChR = nicotinic acetylcholine receptor; VTA = ventral tegmental area.

At low concentrations of nicotine, 4 2 nAChR stimulation of afferent -aminobutyric acid

(GABA)-ergic projections onto mesoaccumbal DA neurons predominates, leading to reduced

mesolimbic DA neuron firing and DA release. At higher nicotine concentrations, 4 2 nAChRs

desensitize, and activation of 7 nAChRs on glutamatergic projections predominates, leading to

increased mesolimbic DA neuron firing and DA secretion. Subsequently, within several milliseconds

of activation by nicotine, nAChRs desensitize. After overnight abstinence, nAChRs resensitize,

which presumably explains why most smokers report that the first cigarette in the morning is the

most satisfying. Interestingly, recent positron emission tomography (PET) neuroimaging studies

have shown that smoking two to three puffs from a cigarette produces saturation of nAChRs in the

brain reward system (Brody et al. 2006), suggesting that although binding to central nAChRs is an

important first step in the effects of nicotine, it is not a complete explanation for continued

smoking behavior.

CLINICAL EFFECTS OF NICOTINE AND TOBACCO

More than 90% of tobacco users are cigarette smokers and, although there is a subset of cigarette

smokers who do not smoke every day, most cigarette smokers are daily users and have some

degree of physiological dependence on nicotine (Rigotti 2002). degree of physiological dependence

on nicotine (Rigotti 2002). Smokers typically describe a “rush” and feelings of alertness and

relaxation when smoking, and it is well known that nicotine has both stimulating and anxiolytic

effects, depending on basal level of arousal (Parrott 1998). Airway stimulation is an important

aspect of smoking behavior and additives such as menthol enhance the experience by increasing

the taste and reducing the harshness of smoked tobacco. Determination of nicotine dependence is

typically accomplished clinically by historical documentation of daily smoking (typically, 10–40

cigarettes/day) for several weeks, evidence of tolerance (e.g., lack of aversive effects of nicotine,

such as nausea), and the presence of symptoms of nicotine withdrawal upon smoking cessation.

These withdrawal symptoms, which peak within 24 hours of cessation, include dysphoria, anxiety,

irritability, decreased heart rate, insomnia (waking in the middle of the night), increased appetite,Print: Chapter 15. Nicotine and Tobacco http://www.psychiatryonline.com/popup.aspx?aID=347934&print=yes…

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and craving for cigarettes. In addition, most dependent smokers state that they smoke their first

cigarette of the day within 5 minutes of awakening. Timeline follow-back procedures (Sobell et al.

1988) and smoking diaries have been used successfully to monitor smoking consumption over time.

Scales such as the Fagerström Test for Nicotine Dependence (Heatherton et al. 1991) allow

assessment of the level of nicotine dependence, with scores of 4 or higher on a scale of 0–10

consistent with physiological dependence to nicotine. Nicotine craving and withdrawal can be

reliably monitored using validated scales such as the Tiffany Questionnaire for Smoking Urges

(Tiffany and Drobes 1991) and the Minnesota Nicotine Withdrawal Scale (Hughes and Hatsukami

1986). These scales also appear to have reasonable test-retest reliability and internal consistency

among people with schizophrenia, compared with nonpsychiatric control smokers (Weinberger et

1. 2007).

Interestingly, the positive effects of cigarette smoking (e.g., taste, satisfaction) appear to be

mediated by non-nicotine components of tobacco, such as tar (Dallery et al. 2003). In addition to

positive reinforcement, withdrawal, and craving, there are several secondary effects of nicotine and

tobacco use that may contribute to both maintenance of smoking and smoking relapse, such as

mood modulation (e.g., reduction of negative affect), stress reduction, and weight control. In

addition, conditioned cues can elicit the urge to smoke even after prolonged periods of abstinence.

Specific effects might be most relevant to individuals focused on dietary restraint (weight

reduction), or those with psychiatric disorders (mood modulation, cognitive enhancement, stress

reduction). These secondary effects may present additional targets for pharmacological

intervention in certain subgroups of smokers (e.g., schizophrenic, depressed, or overweight

smokers).

PSYCHOSOCIAL TREATMENTS

Behavioral therapies are based on the theory that learning processes operate in the development,

maintenance, and cessation of smoking. Behavioral treatments for smoking can facilitate

motivation to quit, provide an emphasis on the social and contextual aspects of smoking, and

enhance overall success at smoking cessation (Patten and Brockman 2006). In most reviews and

meta-analyses, 6-month quit rates with behavior therapies are 20%–25%, and behavior therapy

typically increases quit rates up to twofold over control groups (see Lancaster and Stead 2006 for

review). The primary goals of behavioral therapies in treatment of tobacco dependence include 1)

providing necessary skills to smokers to aid them in quitting smoking; and 2) teaching skills to

avoid smoking in high-risk situations. See Table 15–1 for a summary of behavioral treatments for

tobacco dependence.

Brief Interventions and Self-Help Materials

Brief advice has been found to increase the rate of smoking cessation (Fiore et al. 2000); therefore,

it is recommended that doctors use the five As with all patients: ask patients if they smoke, advise

patients to quit, assess patients’ motivation level for quitting, assist with quit attempts, and

arrange follow-up contacts. Providing self-help material is a form of brief intervention used to

increase motivation to quit and impart smoking cessation skills. Several recent studies have

documented that minimal behavioral interventions such as community support groups (Bakkevig et

1. 2000), telephone counseling (Stead et al. 2006), and computer-generated, tailored self-help

materials (Etter and Perneger 2001) can augment smoking cessation rates in controlled settings.

Motivational Interventions

The goal of motivational interviewing (MI) interventions is to elicit change by addressing

ambivalence, increasing intrinsic motivation for change, and creating an atmosphere of acceptance

in which patients take responsibility for making changes happen. Brief MI interventions have been

developed for smoking cessation (Rollnick et al. 1997), and there is some evidence for increased

smoking cessation using MI techniques (Carpenter et al. 2004). Rollnick et al. (1997) reported that

clinicians found MI interventions to be feasible and acceptable due to the brief nature of the

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relationship.

Cognitive-Behavioral Therapies

In cognitive-behavioral therapies, patients learn to anticipate situations in which they are likely to

smoke and then enact a plan to cope with these situations using behavioral (e.g., substitution of

behavior) and cognitive (e.g., challenging thoughts) techniques. Some degree of efficacy of

cognitive-behavioral therapies in smokers with and without psychiatric and substance use

disorders has been observed for both individual (Lancaster and Stead 2006) and group (Stead and

Lancaster 2005) counseling formats.

Relapse Prevention

A large number of smokers relapse within 6 months of quitting. Focusing on relapse prevention

skills, including recognizing high-risk situations and coping with lapses can be included in initial

smoking cessation treatment or following a quit attempt. Recent studies (Lancaster et al. 2006)

have not found an overall benefit for including relapse prevention with smokers after a quit attempt

and indicate that more work is needed in this area of treatment research.

TABLE 15–1. Pharmacological and behavioral treatments for tobacco dependence

Treatment Mechanism of action

Rating

Nicotine replacement

therapiesa

Gum (OTC) Slow nicotine absorption gradually reduces nicotine craving and

withdrawal

1

Transdermal nicotine

patch (OTC)

Slow nicotine absorption gradually reduces nicotine craving and

withdrawal

1

Lozenge (OTC) Slow nicotine absorption gradually reduces nicotine craving and

withdrawal

1

Vapor inhaler

(prescription)

Fast nicotine absorption leads to stimulation of nAChR, which rapidly

reduces nicotine craving and withdrawal

1

Nasal spray

(prescription)

Fast nicotine absorption leads to stimulation of nAChR, which reduces

craving and withdrawal

1

Non-nicotine

pharmacotherapies

Bupropion SRa

Blocks reuptake of dopamine and norepinephrine; high affinity,

noncompetitive nAChR antagonism reduces nicotine reinforcement,

withdrawal, and craving

1

Vareniclinea

Acts as a partial agonist of 4 2 nAChRs

1

Nortriptyline Blocks reuptake of norepinephrine and serotonin; probably reduces

withdrawal symptoms and comorbid depressive symptoms; side effects

limit utility

1–2

Clonidine

2-Adrenoreceptor agonist reduces nicotine withdrawal symptoms 2

Mecamylamine Noncompetitive, high-affinity nAChR antagonist combined with TNP

reduces nicotine reinforcement, craving, and withdrawal

2

Naltrexone Endogenous opioid peptide receptor antagonist reduces nicotine

craving and withdrawal in combination with TNP; may reduce alcohol use

and obviate cessation-induced weight gain

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Treatment Mechanism of action

Rating

Monoamine oxidase

inhibitors

Increases monoamine levels; can reduce nicotine reinforcement,

withdrawal, and craving; might be helpful for smokers with co-morbid

mood disorders

2

Rimonabant Endocannabinoid receptor (CB1) antagonist that has shown efficacy in

smoking cessation trials; may be particularly useful in weight-concerned

smokers

2

Nicotine vaccine Limited evidence of efficacy for smoking cessation in early human trials,

may also have utility in relapse prevention

2

Behavioral treatments

Self-help materials Increase motivation to quit and impart cessation skills (e.g., community

support, telephone counseling)

2

Cognitive-behavioral

therapy

Behavioral strategies are developed to manage triggers; cognitive coping

strategies target maladaptive thoughts to prevent relapse

1

Motivational

enhancement therapy

Therapist promotes patient’s self-motivational statements, and, in turn,

patient gains greater awareness of the problems associated with

smoking; increases intention for smoking cessation

2

Note. nAChR = nicotinic acetylcholine receptor; OTC = over the counter; TNP = transdermal nicotine patch.

Effectiveness rating: 1 = strong evidence to support efficacy; 2 = moderate evidence to support efficacy; 3 =

little evidence to support efficacy.

a Treatment has been approved by the U.S. Food and Drug Administration.

PHARMACOLOGICAL TREATMENTS

There are three FDA-approved classes of smoking cessation pharmacotherapies—nicotine

replacement therapies (NRTs), sustained-release bupropion, and varenicline. Several other

off-label and novel medications are also discussed in this section. See Table 15–1 for a summary of

pharmacological treatments for tobacco dependence.

Nicotine Replacement Therapies

The goal of NRT is to relieve tobacco withdrawal, which allows smokers to focus on habit and

conditioning factors when attempting cessation. After the acute withdrawal period, NRT is

gradually reduced so that patients experience fewer withdrawal symptoms. NRTs rely on systemic

venous absorption and therefore do not produce the rapid, high levels of arterial nicotine achieved

when cigarette smoke is inhaled. Thus, individuals are unlikely to become addicted to NRTs. NRTs

should be discontinued if the individual resumes smoking, although safety concerns regarding

smoking while using a patch appear to be less serious than previously thought. All commercially

available forms of NRT are effective and increase quit rates by approximately 1.5- to 2.5-fold

compared with placebo (Silagy et al. 2004). The transdermal patch, gum, and lozenge are available

over the counter (OTC), whereas the nasal spray and inhaler are only available by prescription.

Nicotine gum

Nicotine ingested orally is extensively metabolized on first pass through the liver. Nicotine

polacrilex gum avoids this problem via buccal absorption. Nicotine gum was approved as an OTC

medication in the United States in 1996, and contains 2 mg or 4 mg of nicotine that can be released

from a resin by chewing. Nicotine gum should be administered by scheduled dosing (e.g., one piece

of 2-mg gum/hour). The original recommended duration of treatment was 3 months, although

many experts believe longer treatment is more effective. Nicotine absorption from the gum peaks

30 minutes after start of gum chewing . Venous nicotine levels from 2-mg and 4-mg gum are about

one-third and two-thirds, respectively, of the steady-state (i.e., between cigarettes) levels of

nicotine achieved with cigarette smoking. Nicotine via cigarettes is absorbed directly into thePrint: Chapter 15. Nicotine and Tobacco http://www.psychiatryonline.com/popup.aspx?aID=347934&print=yes…

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arterial circulation; thus, arterial levels from smoking are 5–10 times higher than those from the

2-mg and 4-mg gums. Absorption of nicotine in the buccal mucosa is decreased by an acidic

environment, and patients should not use beverages (e.g., coffee, soda, juice) immediately before,

during, or after nicotine gum use.

Several placebo-controlled trials established the safety and efficacy of nicotine gum for smoking

cessation (reviewed in Silagy et al. 2004). There appears to be some evidence to support using

higher doses of nicotine gum (4-mg pieces) in more highly dependent cigarette smokers (25

cigarettes/day), which supports the idea of matching nicotine gum dose to dependence level of the

smoker.

Side effects from nicotine gum are rare and include those of mechanical origin (e.g., difficulty

chewing, sore jaw) or local pharmacological origin (e.g., burning in mouth, throat irritation).

Tolerance develops to most side effects over the first week, and education about proper use of the

gum (e.g., do not chew too vigorously) decreases side effects.

Nicotine polacrilex lozenges

Nicotine lozenges that deliver nicotine (2-mg and 4-mg preparations) by buccal absorption were

approved for OTC use in the United States in 2002. Lozenges offer further flexibility for nicotine

replacement options for smokers and are known to allow greater absorption of nicotine compared

with nicotine gum. Mild throat and mouth irritation have been reported in preliminary trials

(Shiffman et al. 2002). A 6-week, double-blind, placebo-controlled, randomized, controlled trial of

2-mg and 4-mg nicotine lozenges has shown their superiority to placebo lozenges (Shiffman et al.

2002), with significant reduction in nicotine craving and withdrawal. Furthermore, high doses of

lozenges may be more efficacious in more highly dependent smokers, suggesting that lozenge dose

can be matched with dependence level.

Nicotine transdermal patch

The four available transdermal formulations take advantage of ready absorption of nicotine across

the skin. Three of the patches are for 24-hour use and one is for 16-hour use. Starting doses are

21- to 22-mg/24-hour patch and 15-mg/16-hour patch. Patches are applied every morning.

Nicotine via patches is slowly absorbed, such that on the first day venous nicotine levels peak 6–10

hours after administration. Thereafter, nicotine levels remain fairly steady, with a decline from

peak to trough of 25%–40% with 24-hour patches. Nicotine levels obtained with the use of patches

are typically half of those obtained by smoking. After 4–6 weeks on a high-dose patch (21 mg or 22

mg/24 hour, and 15 mg/16 hour), smokers are tapered to a middle dose (e.g., 14 mg/24 hours or

10 mg/16 hours), and then to the lowest dose after 2–4 more weeks (7 mg/24 hours or 5 mg/16

hours). Results of most studies indicate that abrupt cessation of the use of patches often causes no

significant withdrawal; thus, tapering does not appear to be necessary (Silagy et al. 2004). The

recommended total duration of treatment is usually 6–12 weeks.

The overall efficacy of the nicotine transdermal patch (NTP) for smoking cessation has been well

documented (Silagy et al. 2004). A meta-analysis of 17 randomized controlled trials in 1994 (Fiore

et al. 2000) reported end-of-treatment abstinence rates for NTP of 27% versus 13% for placebo

patch (odds ratio [OR] = 2.6) and 22% versus 9% at 6-month follow-up (OR = 3.0). The effects of

active NTP were independent of patch type, treatment duration, tapering procedures, and

behavioral therapy format or intensity, although it should be noted that behavioral treatment with

patch enhanced outcomes, compared with patch alone.

Significant adverse events with nicotine patches have not been found; the most common minor side

effects have been skin reactions (50%), insomnia and increased or vivid dreams (15% with

24-hour patches), and nausea (5%–10%). Tolerance to these side effects usually develops within a

week. Rotation of patch sites decreases skin irritation. Insomnia reported in the first week

postcessation appears to be mostly due to nicotine withdrawal rather than the nicotine patch itself.

A 24-hour patch can be removed before bedtime to determine if the insomnia is due to the nicotine

patch. Without treatment, insomnia usually abates after 4–7 days. There appears to be littlePrint: Chapter 15. Nicotine and Tobacco http://www.psychiatryonline.com/popup.aspx?aID=347934&print=yes…

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dependence liability associated with patch use, given that only 2% of patch users continue to use

this product for an extended period after a cessation trial (West et al. 2001).

Nicotine nasal spray

Nicotine nasal spray is a nicotine solution in a nasal spray bottle similar to those used with saline

sprays. This NRT was approved for treatment of nicotine dependence in the United States in 1996.

Nasal spray delivers droplets that average about 1 mg of nicotine per administration, and the

patient administers the spray (10 mg/mL) to each nostril every 4–6 hours. This formulation

produces a more rapid rise in nicotine levels than does nicotine gum, and the rise in nicotine levels

produced by nicotine spray falls between the levels produced by nicotine gum and cigarettes. Peak

nicotine levels occur within 10 minutes, and venous nicotine levels are about two-thirds those of

between-cigarette levels. Smokers may use the nasal spray ad lib up to 30 times/day for 12 weeks,

including a tapering period.

Randomized, double-blind, placebo-controlled trials of nasal spray compared with placebo spray

(Silagy et al. 2004) have established the safety and efficacy of the nasal spray for smoking

cessation. Both trials employed treatment for 3–6 months, and active nasal spray led to a doubling

of quit rates during active use. Differences were reduced or absent with extended follow-up,

suggesting the need for maintenance use of this agent. However, to date, such long-term studies

have not been published.

The major side effects from nicotine nasal spray are nasal and throat irritation, rhinitis, sneezing,

coughing, and watering eyes. Nicotine nasal spray may have some dependence liability. In a

controlled study by West et al. (2001), this prolonged use of nasal spray was determined to be

nicotine dependence among 10% of smokers using the nasal spray; therefore, follow-up of smokers

using nasal spray is recommended.

Nicotine vapor inhalers

Nicotine vapor inhalers are cartridges (plugs) of nicotine (containing about 1 mg of nicotine each)

placed inside hollow cigarette-like plastic rods. The cartridges produce a nicotine vapor when warm

air is passed through them. Absorption from the nicotine inhaler is primarily buccal rather than

respiratory. More recent versions of inhalers produce a rise in venous nicotine levels more rapidly

than with nicotine gum but less rapidly than with nicotine nasal spray, with nicotine blood levels of

about one-third that of between-cigarette levels. Smokers are instructed to puff continuously on

the inhaler (0.013 mg/puff) during the day, and recommended dosing is 6–16 cartridges daily. The

inhaler is to be used ad lib for about 12 weeks.

No serious medical side effects have been reported with nicotine inhalers; 50% of subjects report

throat irritation or coughing. Double-blind, placebo-controlled, randomized, controlled trials have

demonstrated the superiority of nicotine vapor inhaler to placebo inhalers for smoking cessation

(Silagy et al. 2004). Results revealed a two- to threefold increase in quit rates (17%–26%) at trial

endpoint compared with placebo inhalers, but smaller differences at follow-up periods of 1 year or

longer. These data support the short-term efficacy of nicotine vapor inhalers in cigarette smokers,

but longer-term trials with the inhaler are needed. There is some modest concern about abuse

liability based on long-term use of the product in fewer than 10% of smokers (West et al. 2001).

Sustained-release bupropion

The phenylaminoketone, atypical antidepressant agent bupropion in the sustained-release (SR)

formulation (Zyban) is a non-nicotine, first-line pharmacological treatment for nicotine-dependent

smokers who want to quit smoking. The exact mechanism of action of this antidepressant agent in

the treatment of nicotine dependence is unclear, but it is likely to involve dopamine and

norepinephrine reuptake blockade (Ascher et al. 1995), as well as antagonism of high-affinity

nAChRs (Slemmer et al. 2000). The goals of bupropion therapy are 1) smoking cessation, 2)

reduction of nicotine craving and withdrawal symptoms, and 3) prevention of cessation-induced

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The target dose of this agent in nicotine dependence is 300 mg/day (150 mg, two times a day). It

is typically started 7 days prior to the target quit date at 150 mg/day, and then increased to 150

mg two times a day after 3–4 days. Unlike the NRTs, there is no absolute requirement that smokers

completely cease smoking by the target quit date, though many smokers report a significant

reduction in urges to smoke and craving, which facilitates cessation at the time of the target quit

date when drug levels reach steady-state plasma levels. Some smokers gradually reduce their

cigarette smoking over several weeks prior to quitting. There presently is little data about the

subgroups of smokers for whom bupropion may have the most utility.

A pivotal multicenter study by Hurt et al. (1997) established the efficacy and safety of bupropion

SR for treatment of nicotine dependence, which led to its FDA approval in the United States in

1998. In a 7-week double-blind, placebo-controlled, multicenter trial, three doses of bupropion SR

(100, 150, and 300 mg/day in two divided doses) in combination with weekly, individual cessation

counseling were given to 615 cigarette smokers using at least 15 cigarettes per day. The

end-of–trial, 7-day, point-prevalence cessation rates were 19.0%, 28.8%, 38.6%, and 44.2%,

respectively, for placebo and 100 mg/day, 150 mg/day, and 300 mg/day bupropion dosages,

respectively. At 1-year follow-up, cessation rates were 12.4%, 19.6%, 22.9%, and 23.1%,

respectively. Bupropion treatment dose-dependently reduced weight gain associated with smoking

cessation and significantly reduced nicotine withdrawal symptoms at the 150 mg/day and 300

mg/day dosages.

The primary side effects reported with bupropion administration in cigarette smokers are

headache, nausea and vomiting, dry mouth, insomnia, and agitation, most of which occur during

the first week of treatment. The main contraindication for the use of bupropion is a past history of

seizures of any etiology. The rates of de novo seizures are low with this agent (<0.5%), at doses of

300 mg/day or less, and have been observed when daily dosing exceeds 450 mg.

The combination of bupropion SR with an NTP was evaluated in a double-blind, double

placebo-controlled, randomized, multicenter trial (Jorenby et al. 1999). A total of 893 cigarette

smokers, using at least 15 cigarettes/day, were randomly selected to one of four experimental

groups: 1) placebo bupropion (0 mg/day) plus placebo patch; 2) bupropion (300 mg/day) plus

placebo patch; 3) placebo bupropion plus nicotine patch (21 mg/day for 4 weeks, with 2 weeks of

14 mg/day and 2 weeks of 7 mg/day); and 4) bupropion plus patch. Bupropion was administered 1

week prior to the target quit date (day 15), at which time patch treatment was initiated for a total

of 8 weeks. All subjects received weekly, individual, smoking-cessation counseling. Cessation rates

at the 1-year follow-up assessment were 15.6% for placebo; 16.4% for active NTP alone; 30.3%

for bupropion alone; and 35.5% for the combination of patch and bupropion. Both

bupropion-plus-patch and bupropion-alone groups fared significantly better than the placebo and

patch-alone conditions, but the group receiving combination did not fare significantly better than

the group receiving bupropion alone. Weight suppression after cessation was most robust in the

combination therapy group. Side effects were consistent with the profiles of patch and bupropion,

and the combination was well tolerated. However, a higher-than-expected rate of

treatment-emergent hypertension (4%–5%) was noted among those in the group receiving the

combination of bupropion and patch (Jorenby et al. 1999).

Hays et al. (2001) examined the effects of bupropion compared with placebo on the prevention of

smoking relapse in 784 cigarette smokers who achieved smoking abstinence after a 7-week,

open-label trial of bupropion (300 mg/day). Abstinent smokers were then randomly assigned to

receive bupropion (300 mg/day) or placebo for a total of 45 weeks. Fifty-nine percent of smokers

enrolled in the open-label phase of the trial quit smoking. Significantly more smokers were

abstinent at the end of the 52-week treatment period in bupropion versus placebo groups (55.1%

42. 42.3%, P <0.01), but not at the 1-year follow-up assessment. In addition, days-to-smoking

relapse was higher in the bupropion group than the placebo group (156 vs. 65 days, P <0.05).

Weight gain was significantly less in the bupropion group at both the end of treatment and at

1-year follow-up. The results of this study indicate the efficacy of bupropion in preventing smoking

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indicate further study is needed.

Varenicline

Varenicline tartarate (Chantix in the United States, Champix in Europe), a 4 2 nAChR partial

agonist, was approved as a first-line smoking cessation agent by the FDA in 2006. The results of

two independent but identical 12-week, Phase III trials comparing varenicline (1 mg, two times a

day) with bupropion SR (150 mg, two times a day) and placebo have recently been published

(Gonzales et al. 2006; Jorenby et al. 2006). The quit rates for both studies were similar for

continuous abstinence over the last 4 weeks (weeks 9–12) of the study: in the Jorenby et al.

(2006) study (study 1), the quit rates were 43.9% for varenicline, 29.8% for bupropion SR, and

17.6% for placebo; in the Gonzales et al. (2006) study (study 2) the quit rates were 44.0% for

varenicline, 29.5% for bupropion SR, and 17.7% for placebo. Quit rates were significantly higher

for participants taking varenicline as compared with those taking bupropion SR (P <0.0001) and

both drugs resulted in significantly higher quit rates than placebo. Continuous abstinence over the

follow-up period (weeks 9–52) were lower and participants taking varenicline continued to show a

higher rate of abstinence (study 1: 22.1%, study 2: 23.0%) than participants taking bupropion

(study 1: 16.4%, P <0.001 compared with varenicline; study 2: 15.0%, P = 0.064 compared with

varenicline) and placebo (study 1: 8.4%, study 2: 10.3%).

A third study examining the efficacy of the drug on smoking relapse prevention used a 12-week,

open-label varenicline phase followed by randomization to 12 weeks of varenicline or placebo

(Tonstad et al. 2006). These investigators found that participants taking varenicline were more

likely to be continuously abstinent during weeks 13–24 (70.5% vs. 49.6%, P <0.001) and weeks

13–52 (43.6% vs. 36.9%, P = 0.02) than those taking placebo. Varenicline was found to reduce

cravings and smoking satisfaction and to be safe and well tolerated. There were similar

discontinuation rates for varenicline and bupropion, and the most common adverse event reported

by the varenicline group was nausea (study 1: 28.1%, study 2: 29.4%).

Off-Label Medications

Nortriptyline

Nortriptyline is a tricyclic antidepressant that has been shown in several double-blind,

placebo-controlled trials to be superior to placebo (Hall et al. 1998; Prochazka et al. 1998) and to

have comparable efficacy to bupropion (Hall et al. 2002). Its efficacy may be improved with higher

rather than lower-intensity behavioral therapies. Its mechanism of action is thought to relate to

norepinephrine and serotonin reuptake blockade. Side effects include dry mouth, blurred vision,

constipation, and orthostatic hypotension. Nortriptyline appears to have some utility for smokers

with past histories of major depression, but its potential for fatal overdose has likely limited its

utilization. Nonetheless, it can be recommended as a second-line agent after nicotine replacement

therapies and bupropion, though more study of this agent is necessary.

Clonidine

Clonidine is a presynaptic 2 receptor agonist that dampens sympathetic activity originating at the

locus ceruleus. It appears to have efficacy for treating opioid withdrawal; thus, it was tested as a

nicotine withdrawal treatment during smoking cessation trials. The most common side effects of

clonidine are dry mouth, sedation, and constipation. Postural hypotension, rebound hypertension,

and depression are rare with clonidine in smoking cessation treatment. Several clinical trials tested

oral or transdermal clonidine in dosages of 0.1–0.4 mg/day for 2–6 weeks with and without

behavior therapy. Results have revealed that clonidine is more effective in women than in men

(Covey and Glassman 1991); however, other studies have failed to find this association (Gourlay

and Benowitz 1995).

In general, the effects of clonidine have not proven to be as robust as those of NRTs. An initial

study of heavy smokers (N = 71) showed that at dosages of up to 0.4 mg/day, cessation rates were

doubled in comparison with placebo (Glassman et al. 1988), and in a follow-up study by the samePrint: Chapter 15. Nicotine and Tobacco http://www.psychiatryonline.com/popup.aspx?aID=347934&print=yes…

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researchers (N = 300) this initial finding was replicated (Glassman et al. 1993). In fact, a

meta-analysis of 9 placebo-controlled studies and 813 patients found short-term quit rates of 39%

by those receiving clonidine versus 21% for those receiving placebo (OR = 2.4, 1.7–32.8) (Covey

and Glassman 1991). These findings suggest that clonidine was effective in the transdermal

preparation and more helpful to female smokers. A meta-analysis by Gourlay and Benowitz (1995)

of four subsequent studies found long-term follow-up quit rates in 31% by those receiving

clonidine and 17% by those receiving placebo (OR = 2.0, 1.3–3.0). Clonidine appears to be useful

in reducing acute nicotine withdrawal symptoms and may play a role for smokers who have high

levels of anxiety during early cessation (Niaura et al. 1996). Recent trials of the transdermal

clonidine preparation (Niaura et al. 1996) and oral clonidine (Nana 1998) have found less

impressive support for clonidine’s efficacy for smoking cessation, but this agent should be

considered as a second-line therapy for smokers failing initial treatment with NRTs or bupropion.

Mecamylamine

Mecamylamine (MEC) is a noncompetitive blocker at the ion channel site of both high-affinity CNS

and peripheral nAChRs (Young et al. 2001). When MEC is given to smokers who are not trying to

stop smoking, they initially increase their smoking in an attempt to overcome the blockade

produced by this drug. MEC does not precipitate withdrawal in humans, perhaps because it is a

noncompetitive nAChR antagonist. Common side effects include abdominal cramps, constipation,

dry mouth, and headaches.

Based on a theory that combined blockade and agonist therapy at the nAChR might be beneficial,

similar to the nAChR partial-agonist profile of varenicline, two randomized trials were conducted

comparing MEC and nicotine patch with placebo and nicotine patch. The rationale for this theory

was that MEC would reduce the rewarding effects of nicotine, and the patch would reduce nicotine

withdrawal symptoms (Rose et al. 1994, 1998). In the first trial (Rose et al. 1994), MEC (up to 10

mg/day; 5 mg two times a day for 5 weeks) or placebo was given in combination with a nicotine

patch (21 mg/day) for up to 8 weeks, and cessation rates were significantly higher in the

combination group than the patch-alone group (12/24 [50.0%] versus 4/24 [16.7%], P <0.05).

MEC was reported to reduce cigarette craving, negative affect, and appetite increases associated

with tobacco withdrawal. In a subsequent study of 80 cigarette smokers (Rose et al. 1998), MEC at

dosages of up to 10 mg/day was given as a pretreatment for 4 weeks prior to nicotine patch

initiation at the target quit date, and the combination of MEC and patch was continued for 6 weeks.

As in the first study, the combination of MEC with NTP increased continuous abstinence rates after

the target quit date compared with NTP alone (19/40 [47.5%] vs. 11/40 [27.5%], P <0.05). These

data indicate the efficacy of the combination of MEC with NTP, and this combination should be

considered a second-line therapy.

Naltrexone

Naltrexone is a long-acting congener of the opioid receptor antagonist naloxone. The rationale for

using naltrexone for smoking cessation is that the performance-enhancing and other positive

effects of nicotine may be opioid mediated (Krishnan-Sarin et al. 1999; Pomerleau 1998). Early

studies revealed that naltrexone monotherapy increases smoking, presumably as an attempt to

overcome blockade; however, a study of naltrexone in heavy-smoking alcoholic individuals showed

that cigarette smoking was decreased modestly (Rosenhow et al. 2003). Adverse events included

elevated liver enzymes, nausea, and vomiting. A trial by Covey et al. (1999) of 68 cigarette

smokers who were highly motivated to quit and were using at least 20 cigarettes/day compared

naltrexone (up to 75 mg/day, initiated 3 days prior to the target quit date) with placebo for a total

of 4 weeks. Cessation rates in the naltrexone group were nonsignificantly higher than in the

placebo group (46.7% vs. 26.3%, P <0.10), and at 6-month follow-up there were no group

differences.

More promising data with naltrexone come from its use in combination with NRT. An initial study

compared the combination of naltrexone (50 mg/day) and NTP (21 mg/day) with naltrexone alone,

NTP alone, and placebo (there being no placebo patch condition) in 100 cigarette smokers for aPrint: Chapter 15. Nicotine and Tobacco http://www.psychiatryonline.com/popup.aspx?aID=347934&print=yes…

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total of 12 weeks (Wong et al. 1999). Cessation rates for placebo alone and naltrexone alone

groups were 19% and 22%, and for NTP alone and NTP plus naltrexone, 48% and 46%,

respectively, suggesting only a main effect of NTP treatment and no effects of naltrexone on

smoking cessation, either alone or in combination. In addition, there was no effect of naltrexone on

amount smoked or cigarette craving. However, a preliminary study by Krishnan-Sarin et al. (2003)

revealed that the combination of naltrexone and NTP is superior to NTP alone, if NTP administration

precedes that of naltrexone (presumably to decrease naltrexone-related withdrawal). In a larger

trial of the combination of nicotine patch (21 mg/day) with four active doses of naltrexone (0, 25,

50, and 100 mg/day), it was shown that the highest dosage of naltrexone-plus-patch significantly

improves continuous smoking abstinence rates compared with placebo (O’Malley et al. 2006), but

these effects appeared to be confined to the first weeks of treatment. Further studies of naltrexone

either alone or in combination with the patch are needed, including studies of patients with

concurrent alcohol misuse.

Monoamine oxidase inhibitors

The use of monoamine oxidase (MAO) inhibitors is a potentially useful strategy for smoking

cessation, given that blockade of the metabolism of neurotransmitters such as DA (MAO B), and

serotonin and norepinephrine (MAO A) leads to increased synaptic levels of these transmitters,

which are reduced during acute withdrawal. A trial of the MAO A inhibitor moclobemide (Berlin et

1. 1995) was conducted that indicated short-term increases in smoking cessation in smokers (N =

88).

Furthermore, the results of a small trial by George et al. (2003) involving 40 smokers suggested

the short-term efficacy of the MAO B inhibitor selegiline hydrochloride (10 mg/day), for smoking

cessation. Moreover, results of a trial of the combination of selegiline and nicotine patch compared

with the patch alone suggested the superiority of this combination in smokers (N = 109), but this

difference was not significant (Biberman et al. 2003). Finally, a trial with the reversible MAO B

inhibitor lazabemide showed promising effects for smoking cessation compared with placebo, but

this agent demonstrated liver toxicity in other trials and was thus withdrawn from subsequent

development (Berlin et al. 2002). Larger controlled trials of these agents are warranted before firm

recommendations for the use of these agents for smoking cessation can be made.

Rimonabant and nicotine vaccine

Two important novel pharmacological strategies that are not yet approved in the United States may

offer some additional strategies for smoking cessation and smoking relapse prevention. The

cannabinoid receptor (CB1) antagonist, rimonabant (Accomplia), demonstrated promising results in

clinical trials in the United States and Europe, and at 20 mg/day doubled the chance of quitting

compared with placebo. Most notably, it potently suppresses smoking cessation–related weight

gain (Gelfand et al. 2006). Side effects include nausea, vomiting, and tremors, which are dose

dependent. Although the drug is likely to be approved for the treatment of obesity, it was not

approved specifically for the indication of smoking cessation, but may have a particular role in the

treatment of weight-concerned smokers. The nicotine vaccine (Hatsukami et al. 2005) is being

developed by several companies. It appears to be well tolerated and enhances smoking abstinence

rates; higher abstinence rates are observed as a function of higher serum antibody titres. The

nicotine vaccine may also hold promise for the prevention of smoking relapse or initiation of

smoking and will likely be tested for these indications. Side effects include soreness at the injection

site and hypersensitivity reactions to vaccine components.

INTEGRATION OF TOBACCO DEPENDENCE TREATMENT IN MENTAL HEALTH

CARE SETTINGS

As the high rates of tobacco use and dependence and low rates of smoking cessation are becoming

increasingly appreciated in psychiatric and addicted populations (Grant et al. 2004; Kalman et al.

2005; Lasser et al. 2000), it is increasingly emphasized that mental health and addiction clinics

have done little to address the tobacco culture that permeates institutional environments.

However, smoking bans are becoming increasingly common in psychiatric hospitals and addictionPrint: Chapter 15. Nicotine and Tobacco http://www.psychiatryonline.com/popup.aspx?aID=347934&print=yes…

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treatment programs, and the bans appear to be successfully implemented in the majority of

reported cases (Lawn and Pols 2005).

The utilization of standard tobacco dependence treatments such as behavioral therapies, NRT, and

bupropion has been increasingly reported in psychiatric and substance-abusing smokers. For

example, various formulations of NRT, including NTP (Addington et al. 1998; Chou et al. 2004;

George et al. 2000), nasal spray (Williams et al. 2004), and bupropion SR (Evins et al. 2001, 2005;

George et al. 2002) have been reported to be well tolerated and efficacious in increasing rates of

both smoking reduction and cessation in patients with schizophrenia when combined with CBT and

motivational enhancement therapy. Both NRTs and bupropion have also been studied in smokers

with major depression (Chengappa et al. 2001; Hayford et al. 1999; Kinnunen et al. 1996),

posttraumatic stress disorder (Hertzberg et al. 2001; McFall et al. 2005), and alcohol (Hughes et al.

2003; Hurt et al. 1995; Kalman et al. 2004) and opioid (Shoptaw et al. 2002) dependence and found

to be well tolerated and effective. Moreover, a recent study that compared integration of behavioral

and pharmacological treatments in a mental health setting for smokers with posttraumatic stress

disorder found enhanced quit rates compared to nonintegrated smoking cessation therapies (McFall

et al. 2005, 2006), which suggests that provision of integrated mental health and tobacco

treatment produces enhanced cessation outcomes.

Finally, a better understanding of the pathophysiology of mental disorders may lead to improved

treatments for this population. For example, schizophrenia is associated with a broad range of

cognitive deficits, particularly those related to prefrontal lobe dysfunction; atypical antipsychotic

drugs (e.g., clozapine, olanzapine) that improve certain cognitive deficits associated with

schizophrenia may facilitate reduction of smoking (George et al. 1995; McEvoy et al. 1995;

Procyshyn et al. 2002) or smoking cessation with standard pharmacotherapies such as the nicotine

patch or bupropion SR (George et al. 2000). The development of novel medications that target the

underlying pathophysiology of psychiatric or substance use disorders may well lead to important

advances in the management of tobacco dependence in these special populations of smokers.

CONCLUSION

Tobacco dependence remains one of the leading preventable causes of morbidity and mortality in

the Western world. Nonetheless, smoking cessation therapies are among the most cost-effective

and proven therapies in psychiatry and medicine, yet most health care providers do not identify

tobacco use in their patients. In fact, a survey of psychiatric practices found that only 9.1% of

smokers under the care of psychiatrists received treatment for nicotine dependence (Montoya et al.

2005). Nonetheless, the American Psychiatric Association has recently published an update of its

Clinical Practice Guidelines for Nicotine Dependence (Kleber et al. 2006), which should provide

standards for the field of psychiatry in the assessment and treatment of tobacco dependence.

Furthermore, although medication and behavioral treatments have documented efficacy in treating

tobacco dependence, it is important that these therapies be used in combination to achieve the best

overall results and to ensure adequate skill acquisition and treatment adherence. Future challenges

include developing safer and more effective smoking cessation therapies and making these

therapies available to all individuals who want to quit smoking.

KEY POINTS

Tobacco dependence rates have decreased substantially, but many people who smoke appear to have

comorbidities, such as psychiatric and substance use disorders, that reduce their chance of quitting.

Identification of smokers in clinical settings is of critical importance to the treatment of tobacco

dependence.

There are effective pharmacological and behavioral therapies for tobacco dependence, which work best

when used in combination.

A better understanding of the pathophysiology of mental health and addictive disorders may lead to

improved treatment approaches for tobacco dependence in these smoking populations.Print: Chapter 15. Nicotine and Tobacco http://www.psychiatryonline.com/popup.aspx?aID=347934&print=yes…

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Smokers with psychiatric and substance use comorbidity may best be treated in settings that integrate

smoking cessation treatments with mental health and addiction treatment.

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