Pathophysiology of Tobacco Dependence
An Article By
Jack E. Henningfield, Leslie M. Schuh, and Murray E. Jarvik
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Published On: July 1, 2001
Updated On: August 07, 2001
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Pathophysiology of Tobacco Dependence
Table of Contents
History And Clinical Course
In less than two decades since the first volume in this series, our
understanding of the pathophysiology of tobacco dependence has
progressed enormously. In the first volume, Jaffe and Jarvik (38)
essentially summarized the rational basis for considering cigarette
smoking as a form of drug dependence or "addiction." By the
time the second volume was developed, sufficient new research had been
conducted to enable Jones (42) to describe
many of the functional relationships between nicotine dose and the
behavioral effects that contribute to the dependence process. The field
has continued to progress, enabling us to describe the essential
pathophysiology of tobacco dependence. We contend that this
understanding will provide a rational guide for developing more
A note on the terminology used in this review is necessary.
Consistent with the rest of this volume, we use the term dependence
in the way that the term "addiction" has been more broadly
used to refer to compulsive use of psychoactive drugs in which tolerance
and physiological dependence may also be present. The term physiological
dependence will be used to refer more specifically to the
physiological adaptation manifested by the emergence of withdrawal
symptoms after cessation of use.
The pathophysiological consequences of tobacco smoke exposure include
tissue destruction contributing to lung disease, cellular changes
contributing to cancer, and the cellular and molecular reinforcing
effects leading to dependence. Once the pathophysiological consequences
of tobacco use have occurred, it may be no more a matter of personal
choice to abstain from tobacco than to reverse metastasizing lung cells.
In fact, most smokers identify smoking as harmful and express a desire
to reduce or stop smoking, and nearly 20 million of them (more than
one-third of all smokers) make a serious attempt to quit each year.
Unfortunately, less than 7% of these smokers attempting to quit (or less
than 3% of all smokers) achieve 1-year abstinence each year (17).
The importance, as well as inadequacies, of educational efforts and
motivational contingencies is illustrated by the following statistic:
Approximately 50% of the survivors of myocardial infarctions, lung
removal, and tracheostomy resume smoking (74).
This illustrates two important points. First, powerful motivational
incentives can lead to cessation; no widely used formal treatment
reliably establishes 50% rates of long-term abstinence. Second, this
powerful motivational contingency (i.e., threat of death) is inadequate
for 50% of cigarette smokers; they may also require medications,
behavior modification procedures, or both.
Thus, educational efforts and motivational factors are clearly
limited in their ability to induce remission from tobacco dependence by
the pathophysiological effects of chronic tobacco exposure. As will be
evident from the present review, it is doubtful that complete reversal
of all dependence consequences can be accomplished or that all motivated
people can achieve lasting abstinence with presently approved
medications and medication use guidelines. However, many people can
achieve cessation and reduce their risk of tobacco-caused disease with
currently available treatment. The purpose of this review is to
summarize the present state of knowledge on the pathophysiological basis
of tobacco dependence and advances in treatment (see also Neuronal
Nicotinic Acetylcholine Receptors: Novel targets for Central Nervous
System Therapeutics, Molecularr
Biology: Pharmacology, Brain Distrubution of Subtypes of the Muscarinic
Trandduction, and Structure
and Function of Colonergic Pathways in the Cerebral Cortec, Limbic
System, Basal Gangilia, and Thalamus of the Human Brain, and The
Development of Brain and Behaviour, for related topics).
HISTORY AND CLINICAL COURSE
The cigarette-dependence process, like other pathogenically induced
diseases, is influenced by host or individual factors, environmental
factors, and the level of exposure to the pathogen. Initiation is often
mediated by a variety of social and cultural factors. However, over time
the reinforcing effects of the drug strengthen and the individual's
control over use weakens. Although other factors continue to operate,
cigarette dependence is powerfully and critically driven by the
positively and negatively reinforcing effects of nicotine, as will be
Like other drug dependencies, nicotine dependence is a
"progressive," "chronic," "relapsing"
disorder. Mean age of cigarette smoking onset is 13-14 years (21).
The level of nicotine dependence in adults is inversely related to the
age of smoking initiation when measured by diagnostic criteria of the
American Psychiatric Association (8).
Continued smoke intake is accompanied by the development of tolerance
and physiological dependence. After smoking a few cigarettes, estimates
of people who progress to dependence ranges from roughly 33% to 94%. For
example, a survey of adults in Great Britain in the early 1960s
indicated that 94% of those who smoked more than three cigarettes became
"long-term regular smokers" (62).
However, these data might not be relevant regarding current risks.
Recently collected data in the United States and Great Britain suggest
that between 33% and 50% of people who try cigarettes become regular
smokers (29, 52).
Consistent with these observations, the 1991 U.S. National Health Survey
determined that approximately 70% of adolescents tried smoking, whereas
only 25% smoked each of the 30 days preceding the survey. Improving the
precision of risk estimates is problematic because surveys differ in
their criteria for initial smoking and dependent smoking. Nonetheless,
it seems reasonable to conclude that in the United States, where there
is widespread awareness of smoking hazards, the risk of developing
dependence after smoking more than one cigarette is at least one in
three. Supporting these observations and the low frequency of quitting,
the National Household Survey of the National Institute on Drug Abuse
found that 38% of people who ever smoked cigarettes reported that they
needed tobacco or felt dependent at the time the survey was conducted.
Tobacco use tends to be chronic, with short-lived remission occurring
rarely. In fact, studies have shown that, unlike cocaine, heroin, and
alcohol use, the progression of cigarette smoking was slowed but not
reversed as individuals aged (59!popup(ch163ref59)).
Chronic use is highly resistant to modification. For example, efforts to
reduce intake by smoking fewer cigarettes or cigarettes with lower
nicotine delivery ratings are usually partially or completely thwarted
by compensatory changes in how the cigarettes are smoked (42,
Abstinence is usually short-lived; most individuals resume smoking
within 3 days (34). Providing minimal
assistance prolongs the remission by at least a few more days, and
providing nicotine replacement can extend the mean remission duration by
6 months or more (20). One year later,
nearly one-third of those surveyed had relapsed, a testament to the
persistence of the dependence (17, 74).
These patterns of relapse are similar to those observed with other drug
dependencies (74), but the relapse process
has been studied in even finer detail for cigarette smoking than for
other dependence-producing substances.
There are approximately 45 million cigarette smokers in the United
States, 15-20 million of whom try to quit smoking each year (17).
This represents a substantial reduction in prevalence from 42% of adults
in 1965 to approximately 25% in 1990. Cigarette smoking continues to
account for more than 20% of all deaths in the United States, with more
than 400,000 cigarette smokers dying each year because of their tobacco
intake and more than 50,000 nonsmokers dying from environmental tobacco
The spread of nicotine dependence follows the course of an infectious
disease, with transmission being largely by person-to-person exposure to
cigarettes. More than 33% of those who continue smoking will die
prematurely as a result of this smoking (51);
however, mortality can be significantly reduced by cessation at any age
(76). The causes of death in order of
incidence are cardiovascular diseases (43%), all forms of tobacco-caused
cancer (36%), respiratory diseases (20%), and all other smoking-caused
deaths (1%) (51). The three primary causes
of mortality are similar for men and women: heart disease, cancer, and
stroke, with cigarette smoking being an important contributor to this
Chronic tobacco use and dependence commonly develop during
adolescence and may be considered pediatric medical disorders (69.
A Gallup Survey of cigarette smoking and markers of dependence indicated
that 40% of teenage cigarette smokers begin smoking within 1 hr of
awakening each day (a sign of dependence); 50% of teenage smokers had
tried to quit but relapsed; 70% would not start smoking if they could
"do it again"; and 38% of teenage smokers would be interested
in smoking cessation programs targeted to their needs (21).
These observations are consistent with earlier findings from the 1985
National Institute on Drug Abuse Household Survey which showed that 84%
of 12- to 17-year-olds who smoked a pack or more each day felt that they
"needed" or were "dependent upon" cigarettes (28).
These data also showed that 12- to 17-year-olds develop tolerance,
dependence, needs, graduating usage, and inability to abstain from
nicotine, indicating that the dependence processes are fundamentally the
same as those studied in adults (28, 74).
Thus, tobacco dependence, not just initiation of smoking, is common
during adolescence. Unfortunately, despite the apparent public health
problem of adolescent nicotine dependence and the interest by many
millions of teenagers in obtaining cessation assistance, there has been
little systematic effort to evaluate the efficacy and risks of powerful
adult-targeted treatment strategies such as nicotine replacement
therapy. This is a challenge that must be met because of the poor
prognosis of untreated nicotine dependence.
Severity of Nicotine
Several studies have found nicotine to be as capable of producing
dependence as heroin, cocaine, or alcohol (28,
29). Moreover, a higher percentage of
cigarette smokers consider themselves to be dependent when compared to
users of other abused substances. For example, in a 1990 Gallup Poll,
61% of current smokers reported that they considered themselves to be
"addicted" to cigarettes (21).
These findings are consistent with those of the 1990 National Household
Survey which indicated that, among people who had ever smoked in their
lifetimes, 38% were smoking at the time of the survey and reported that
they needed tobacco or felt dependent at the time the survey was
conducted, and approximately 80% of people who smoked at least a pack
per day felt that they were dependent. By contrast, among people who had
consumed alcoholic beverages in the past year, 30% had consumed at least
once in the past week; and among those who had binged (five or more
drinks in a row) in the past 30 days, 17% reported they felt they needed
to drink or were dependent. For cocaine, the National Household Survey
indicated that among people who had used the drug in the past year, 16%
had used in the past week, and among people who used 11 times or more in
their lives, 7.7% reported they felt they needed the drug or were
The cigarette is distinguished as an abused drug in that the pattern
of occasional or low-level use that characterizes most users of other
abused drugs is relatively rare for tobacco. For example, whereas only
about 10-15% of current alcohol drinkers are considered problem
drinkers, approximately 90% of cigarette smokers smoke at least five
cigarettes every day (27, 29).
Part of the reason that only 2-3% of smokers successfully achieve
abstinence for 1 year on an annual basis (17)
may be that most people who smoke on a daily basis report that they feel
dependent and that they have experienced withdrawal symptoms (28,
Factors unrelated to the drug itself can affect the prevalence of
drug dependence in society as well as the severity in individuals. Some
of the factors are the same as those that determine the prevalence and
severity of other medical disorders resulting from exposure to toxins.
For example, social factors are important determinants of both the
likelihood of initial self-administration and sustained
self-administration until the reinforcing effects of the drug can
maintain self-administration in their own right. Many non-drug-related
factors associated with both achievement of abstinence and relapse
appear similarly operative across dependence-producing drugs and include
drug-dependence-related illness, learning to manage cravings, social
sanctions, availability of the substance, cost of the substance, and
perception of the risks of using the substance (74).
It is now clear that the nicotine delivery vehicle is a determinant
of toxicity and abuse potential (31, 74).
The vehicle determines these characteristics in two ways: First, it
determines the speed of nicotine delivery to the user and also
determines the nicotine concentrations to which body tissues are
exposed. For example, smoke inhalation essentially mimics the effects of
a rapid intravenous injection and exposes the heart, brain, and fetus to
high concentrations that dissipate within a few minutes. Psychoactive
and cardioactive effects are directly related to the speed of nicotine
delivery (4, 31).
Second, the delivery system determines the nature and quantity of other
toxic substances to which the user is exposed.
These issues are not unique to nicotine. Drug dosage form is a
determinant of patient acceptability of a medication and compliance with
instructions for its use; similarly, it is a determinant of the abuse
potential of psychoactive substances (31, 74).
The drug delivery system determines ease and convenience of use as well
as the speed and amount of drug absorbed. For example, tobacco and coca
leaves are rarely swallowed and dependence to swallowed formulations is
uncommon, presumably because the bioavailability of the nicotine and
cocaine is fairly poor via the gastrointestinal system (e.g., 30% of
oral nicotine reaches the systemic circulation); furthermore, the drug
that is absorbed via this route does not produce the rapid onset and
offset of effects that characterize the most powerful
dependence-producing drugs and drug forms (31,
Despite the ability of intravenous nicotine injections to simulate many
of the pleasurable effects of smoking, smoking appears to provide a more
acceptable means of nicotine intake and one in which the individual's
control over dosage is probably superior (74).
Nicotine polacrilex gum and transdermal patch systems have low abuse
liability, in part because rapid absorption is not possible with either
system. Moreover, release of nicotine from polacrilex requires a
substantial work effort—that is, chewing (31,
74). Thus, the cigarette seems to have done
for nicotine dependence what crack did for cocaine dependence; in both
cases, a highly addictive form of the drug was made readily available
and convenient to repeatedly self-administer, and it led to higher rates
of morbidity and mortality than did previously abused forms (29,
For smokeless tobacco products, the nature of the product is a major
determinant of how much nicotine the user obtains and how rapidly
absorption occurs. Those products highly effective in the initiation
process, termed "starter products" by the smokeless tobacco
industry (31), tend to be low in nicotine
concentration and low in pH (thus delaying absorption), and some are in
a unit dosage form ("tobacco pouch") that helps first-time
users avoid placing too much total product in their mouths.
Subsequently, users are encouraged through advertising techniques to
switch to maintenance products (higher in nicotine concentration and pH)
to achieve greater levels of "satisfaction" and
"pleasure" as they become increasingly tolerant (31).
Nicotine is a tertiary amine existing in both isomeric forms, but
tobacco contains only the more pharmacologically active levorotatory
form, namely, (S)-nicotine (4). It
is a water- and lipid-soluble weak base with an 8.0 index of ionization.
Thus, the nicotine present in the mildly alkaline smoke of cigars,
pipes, chewing tobacco, and snuff is readily absorbed across mucosal
membranes of the mouth and nose (72).
Cigarette smoke is mildly acidic and must be inhaled for effective
Effective nicotine absorption from polacrilex is facilitated by
adding a buffer to slightly alkylinate the normally mildly acidic saliva
(16), and consuming acidic beverages such
as coffee, soft drinks, or fruit drinks while using the polacrilex
prevents nicotine absorption (32).
Swallowed nicotine is poorly absorbed, with much of that entering
circulation detoxified in its first pass through the liver (74),
thus providing little therapeutic benefit. Unfortunately, swallowed
nicotine can cause nausea and hiccuping and may lead to patient
dissatisfaction with nicotine polacrilex when improper use leads to
swallowed nicotine-containing saliva (32).
The tobacco cigarette is the most toxic and addictive widely used
vehicle for nicotine delivery. Nicotine is distilled at the tip of a
burning cigarette where it is carried by particulate matter
("tar" droplets) deep into the lungs with inspired air. The
nearly 2000°F microblast at the cigarette's tip is also the source of
carbon monoxide and many other toxicologically significant pyrolysis
products. Nicotine is rapidly absorbed in the alveoli of the lung,
concentrated in the pulmonary veins as a bolus, and pumped by the left
ventricle of the heart throughout the body. Absorption characteristics
are similar to those of gases (such as oxygen) that are exchanged in the
lung from inspired air to venous blood (33).
Thus, smoke inhalation produces arterial boli that may be 10 times more
concentrated than the levels measured in venous blood (33).
A similar phenomenon of arterial boli occurs when cocaine is smoked,
adding to the addictiveness and toxicity of "crack" cocaine (13).
Most cigarettes contain about 8-9 mg of nicotine, of which the smoker
generally obtains 1-3 mg (4). The typical
pack-per-day smoker obtains 20-40 mg of nicotine each day and may
achieve venous plasma levels that are substantially higher than values
produced by nicotine transdermal systems (6,
Nicotine is primarily eliminated through metabolism in the liver,
with less than 5% typically excreted unchanged in the urine (74).
The major initial nicotine metabolite is cotinine, which has
pharmacological activity at the cellular and behavioral level but
appears about one-hundredth to one-twentieth as potent as nicotine (23,
Cotinine provides a useful marker of nicotine intake because it has an
approximately 20-hr half-life and is readily measurable in blood, urine,
or saliva. Carbon monoxide (CO) is eliminated through the lung as a
function of respiration rate. The half-life of CO is 4-7 hr; thus,
measurement of expired air CO or COHb provides a useful marker of recent
cigarette smoke exposure (74).
Nicotine tolerance appears to be substantially acquired during youth
as smokers progress from a few to many cigarettes to obtain the same
effects (42, 75).
Administering nicotine to a tobacco-deprived smoker can substantially
increase heart rate and euphoria measures and decrease knee-reflex
strength. With repeated doses, heart rate stabilizes at a level
intermediate to that produced by the first dose and that occurring when
nicotine-deprived, subjective effects are minimal, and the knee reflex
may appear normal (11, 74).
Tolerance to a variety of the behavioral, physiological, and subjective
effects of nicotine have been studied (74).
There are several physiological mechanisms of nicotine tolerance,
including decreased responsiveness to the drug at the site of drug
action and increased nicotine receptor number and some degree of
increased metabolism (7, 74).
Cigarette smokers lose a substantial degree of tolerance while
sleeping each day and regain it upon resumption of smoking. A single
nicotine exposure induces short-lived tolerance to its psychoactive,
cardiovascular, and other effects and is thus referred to as tachyphylaxis
(71). The rapid pharmacodynamic development
of tolerance may contribute to the disappointment with nicotine
replacement systems expressed by many patients. Specifically, they lose
the ability to obtain desirable nicotine effects as quickly as when
smoking, thus preventing the desirable moment-to-moment manipulation of
mood possible with cigarettes.
After at least "several weeks" of nicotine exposure (1),
physical dependence on nicotine develops, and, when deprived for more
than a few hours, withdrawal symptoms that are generally opposite to the
effects initially produced by nicotine are reported (74).
The cellular and neurological adaptations that produce tolerance also
lead to physical dependence. In actuality, compared to nonsmokers, the
cigarette smoker has an elevated pulse (5-7 beats per minute), elevated
circulating catecholamines, lower body weight (5-8 pounds), and
increased nicotine receptor binding sites (7).
Such increases in brain nicotine receptors may affect the smoker's
subsequent risk for neuropsychiatric disorders.
Nicotine administration to animals and humans produces altered
spontaneous electroencephalogram (EEG) (producing signs of
electroencephalographic activation such as increased beta power,
decreased alpha and theta power, and increased alpha frequency), evoked
brain electrical potentials, and local cerebral glucose metabolism,
increased adrenal hormone release (including adrenocorticotropic
hormone, b-endorphin, b-lipotropin,
growth hormone, vasopressin, and neurophysin), increased heart rate, and
caused changes in skeletal muscle tension (55,
74). Most, if not all, of these effects are
related to the dose of nicotine, and tolerance develops to differing
degrees across effects.
The nicotine withdrawal syndrome has been described in detail (1).
Onset begins within a few hours of the last cigarette; symptoms include
increased craving, anxiety, irritability, and appetite; decreased
cognitive capabilities and heart rate; and increased tendency to smoke (37,
55). Altered brain electrical potentials
and hormonal output are primarily opposite in direction to those
produced by acute nicotine administration, and decrements in evoked
electrical potentials of the brain indicate impaired information
processing capabilities (57, 74).
The severity of the syndrome and specific prominent symptoms vary
across individuals, but it is generally unpleasant and frequently
intolerable (74), with most patients
relapsing before the syndrome begins to subside (31,
37). The time course varies across
individuals and responses, but withdrawal symptoms usually peak within a
few days and then begin to subside over the next several weeks. For
example, certain measures of brain function (e.g., P300 evoked
electrical potential) recover within a few days, whereas others may take
weeks or more (e.g., N100 evoked potential) (37,
74), and powerful urges to smoke may recur
for many years (37, 74).
Nicotine replacement therapy does not appear to shorten the course of
the syndrome but can reduce symptom severity to the generally more
tolerable levels that are typically reported after about 4-5 weeks of
Withdrawal severity is related to prior nicotine intake, although
differences in just a few cigarettes may not have an effect (74).
It is precipitated by an approximately 50-60% reduction in smoking (78).
Similarly, withdrawal symptoms can be relieved by readministering
nicotine. In general, the degree of relief appears to be related to the
nicotine dose (74): Significant relief of
physical withdrawal signs is provided by 60% replacement of plasma
nicotine, and greater relief is provided by higher levels of replacement
(55). Laboratory studies of the nicotine
withdrawal syndrome (55, 74)
show the time course of measures of brain and cognitive function
parallel each other, and symptoms were completely reversed (in
dose-related fashion) by nicotine polacrilex gum. Nonlaboratory studies
suggest that nicotine given transdermally is similarly effective in
alleviating withdrawal symptoms (14),
although studies of electrical brain activity have yet to be conducted.
Nicotine absorption curves vary across types of delivery systems.
Nicotine absorption is rapid for cigarettes, and levels fall quickly
because about half of the nicotine is redistributed throughout body
compartments within 15-20 min of the last puff from a cigarette. Further
decline is more gradual, with a terminal half-life averaging 2 hr, but
highly variable across individuals (6).
Arterial blood nicotine levels produced by smoking a single cigarette
are 3-5 times greater than the maximal levels produced by nicotine
transdermal systems (33). Nicotine
absorption from smokeless tobacco and noninhaled pipe or cigar smoke is
absorbed less rapidly than from inhaled cigarette smoke, and presumably
without an arterial bolus. By contrast, plasma levels increase much more
slowly when nicotine transdermal systems are used, generally requiring
several hours to achieve the venous levels produced in a few minutes by
one cigarette. Nicotine polacrilex is capable of somewhat more rapid
delivery than transdermal systems but is also slow compared to tobacco
Over the course of a day, transdermal systems produce a much less
variable pattern of nicotine plasma levels than that associated with
cigarette smoking. In general, the pack-per-day cigarette smoker obtains
more nicotine than will be obtained from any of the transdermal systems
and from typical levels of 2 mg polacrilex use, although there is
considerable individual variability. Nicotine levels fall rapidly
overnight during smoking abstinence, but fall more slowly when a
transdermal system is removed before sleeping. This is consistent with
the 4- to 5-hr half-life of transdermally delivered nicotine, which is
approximately double that of cigarette-delivered nicotine (14).
It may take several days on transdermal nicotine for daily plasma levels
to stabilize as the possibly higher nicotine levels obtained from
smoking decline (4) and cumulative effects
of transdermal dosing develop (61).
There are no medications known to adversely interact with nicotine
replacement medications in patients who had already been exposed to
daily doses of nicotine from tobacco. However, achieving tobacco
abstinence decreases the need for many other medications. Cigarette
smoke is a powerful hepatic enzyme inducer, which frequently means that
higher doses of many drugs must be administered to smokers than to
nonsmokers to obtain similar plasma levels (74).
For example, caffeine concentrations can increase by more than 250%
during smoking cessation attempts (5).
Nicotine replacement medications may not produce the same level of
hepatic induction as cigarette smoke; for example, theophylline
metabolism is increased by tobacco smoke but not by nicotine only (47).
These findings suggest that patients in treatment for nicotine
dependence should be warned not to increase their caffeine intake;
follow-up evaluations of patient status should include questions about
caffeine and other drug intake. It is also worth noting that acute
caffeine abstinence results in its own withdrawal syndrome (68)
that might complicate simultaneous tobacco withdrawal.
Nicotine produces a cascade of behavioral and physiological effects
mediated through receptors (C6) at autonomic ganglia, the adrenal
medulla, and sensory nerve endings, through neuromuscular (C10)
receptors on muscle endplates, and by brain receptors. The powerful
conditioning action of nicotine is mediated, at least in part, by (a)
the activation of nicotinic cholinergic receptors in the brain (74)
and (b) the modulation of levels of hormones such as epinephrine
("adrenalin") and cortisol (57, 74).
The mesolimbic dopaminergic reward system, which mediates the ability of
cocaine to produce dependence, has also been implicated in nicotine's
ability to produce dependence (57, 74).
The cells of this system are located in the ventral tegmental area of
the midbrain. Axons project to the limbic system—specifically, to the
nucleus accumbens, olfactory tubercle, nuclei of the stria terminalis,
and parts of the amygdala. Behaviors followed by such neural activation
can become extremely persistent. Cortical effects of nicotine
administration include changes in local cerebral metabolism (49)
and EEG (42). Prominent endocrine effects
include release of catecholamines, serotonin, prolactin, growth hormone,
arginine vasopressin, b-endorphin, and
adrenocorticotropic hormone (57, 74).
These effects mediate both (a) the positive nicotine reinforcement
sought by smokers and even animals (10, 30,
56, 74) and
(b) the negative reinforcement of withdrawal symptoms that also fuel the
compulsion to smoke (37, 57).
Nicotine's observed effects on any given response can appear either
stimulant-like or sedative-like depending upon dose administered, time
since the last dose, level of tolerance, and degree of physical
dependence (31, 58).
For example, the initial cigarettes of the day produce autonomic
arousal, abrupt activation of EEG, and clearly discriminable (often
pleasurable) effects. Subsequent cigarettes may produce little change in
physiology or behavior (67). The
sedative-like effects, however, may be indirect, for example, dependent
upon withdrawal relief or behavioral conditioning processes.
Although some nicotine effects may depend little on rate of delivery,
the contribution of rapid delivery to dependence-producing psychoactive
and reinforcing effects appears to be as important for nicotine as it is
for coca-derived products, barbiturates, minor tranquilizers, and
opioids, where dependence is directly related to speed of onset. For
example, whereas rapid intravenous injections or cigarette smoke
inhalation produce psychoactive effects that may be pleasurable, slow
infusions or delivery by the transdermal systems produce little, if any,
discriminable psychoactive response (31)
and blunted or eliminated physiological responses (14).
Tolerance and dependence development are not sufficient to establish
compulsive smoking of cigarettes, or any other drug for that matter (73).
The drug also must be self-administered frequently enough for its
reinforcing effects to condition the behavior. Such conditioning
processes are maximally effective when the drug effect is discrete,
paired with readily discriminable stimuli, and follows a specific
behavior within a few seconds (73). The
paradigm is optimal for smoking to become powerfully conditioned because
each cigarette provides approximately 10 nicotine reinforcers, each
carried by a sensorally sating cloud of smoke and delivered to the brain
in seconds. Tolerance and physical dependence potentiate the process by
establishing a motivational state in the individual which did not
preexist. Thus, smoking is reinforced both by the direct positively
reinforcing actions of nicotine on the brain and by the necessity of
continued nicotine administration to prevent withdrawal symptoms.
In addition to the direct actions of nicotine to strengthen behavior
and alleviate withdrawal symptoms, cigarette smokers commonly report
benefits that may be at least partially attributable to nicotine. It may
not be possible to completely dissociate transient relief of withdrawal
from nicotine effects that people with certain vulnerabilities or
deficits find addressed by nicotine, but it is important to be aware
that smoking cessation will lead to a variety of potential unfulfilled
needs that can contribute to relapse. For example, some people claim
that smoking enhances their ability to handle stress, helps to control
appetite and weight, increases the pleasure of leisure activities such
as reading and listening to music, and facilitates social interactions.
At least three kinds of nicotine effects, then, can contribute to the
development of dependence: (i) Nicotine delivery produces reinforcing
effects mediated by reward systems in the brain; (ii) tolerance and
physical dependence are produced such that nicotine abstinence is
accompanied by adverse effects; and (iii) at least those dependent on
nicotine may derive useful effects on mood, appetite, and cognition.
These effects are not mutually exclusive, and they often interact.
When nicotine replacement therapy is viewed from the foregoing
perspective, we see that very little of the cigarette is actually
replaced by the nicotine delivery medications. Therefore, patients may
be disappointed when they find that the medications are neither as
pleasurable nor as quickly satisfying as cigarettes. Nonetheless, our
understanding of the pathophysiology of tobacco dependence has
progressed to the point that it has been possible to develop nicotine
replacement pharmaceuticals with impact on the disease process. These
medications may not satisfy all the wants and desires of the cigarette
smoker, but they can provide many patients with what they need to
achieve tobacco abstinence.
The observation is not recent nor unique to nicotine that abused
drugs may provide their users with effects that are clinically useful,
or at least users perceive the effects to be beneficial. In fact, most
abused drugs have been used in the practice of medicine. For example,
opioids continue to be important in pain control, sedatives are helpful
in treating anxiety, and stimulants are valuable in treating narcolepsy.
Nonetheless, the diverse psychopharmacological actions of abused drugs
have long been understood to be important in the etiology and
maintenance of drug dependence (74). The
abuse liability of a drug that can directly activate neurological
mechanisms of reinforcement would appear to be enhanced by its potential
to also provide some sort of benefit, even if the long-term consequences
of the substance abuse tend to be disastrous. Some of the apparent
benefits of drug exposure may be most appropriately conceptualized as
reflecting the reversal of withdrawal symptoms, whereas other benefits
may be direct effects of drug administration.
Effects That May
Contribute to Chronic Use
As discussed earlier, nicotine administration and withdrawal have
diverse effects on brain and endocrine function that may be of
functional significance in the etiology and treatment of psychiatric and
neurological disorders such as affective disorders, Alzheimer's and
Parkinson's diseases, Tourette's syndrome, and maintenance of cognitive
function (39, 53).
Regarding Parkinson's disease, an analysis of 17 studies supports the
conclusion that cigarette smoking provides a weak protective effect (53).
There is little evidence that nicotine is an effective treatment for the
disorder, or even that the protective effect is specific to nicotine,
but the relationship is intriguing and has generated new research on
By contrast, cigarette smoking appears to be positively associated
with Alzheimer's disease development, although evidence is far from
conclusive (53). Preliminary data
suggesting that nicotine administration might be of benefit to
Alzheimer's patients (53, 65)
are also intriguing but at present fall far short of supporting a
clinical application of nicotine.
Although sufficient epidemiological data are still lacking to
determine the relationship between cigarette smoking and Tourette's
syndrome, a trial administering nicotine polacrilex and haloperidol to
treatment-resistant Tourette's patients produced a therapeutic effect (66).
These results are particularly interesting considering data implicating
dopaminergic neurons in the reinforcing effects of nicotine as well as
in Tourette's syndrome (10, 66).
One of the increasingly studied potential therapeutic applications of
nicotine is to treat ulcerative colitis. The gastrointestinal tract is
rich in receptors for neurotransmitters and is quite responsive to
environmental factors. Several studies have now documented that
nicotine, administered in tobacco smoke, polacrilex, or transdermal
system, can reduce symptoms of ulcerative colitis (70).
Continuous nicotine administration appears to suppress the reemergence
of colitis symptoms (70).
One of the most common reasons females give for beginning to smoke
and for relapsing upon cessation is their belief that tobacco helps
control their appetite and body weight (74);
this factor appears somewhat less important for males. In fact, there is
now a substantial literature that documents the robust effect of
nicotine exposure to reduce body weight and prevent developmental weight
gain in animals and humans (46).
Furthermore, the results of a twin study support the hypothesis that the
relationship is a consequence of cigarette smoking and not simply a
Several mechanisms have been postulated to account for the
appetite-and weight-suppressing effect of cigarettes (46,
74). Those that appear specific to nicotine
include a selective decrease in appetite for sweet carbohydrates,
increased metabolic rate, and decreased appetite through serotonergic
mechanisms. Interestingly, the slowly releasing form of nicotine
provided by the transdermal medications does not provide the weight
attenuating effect of either continued smoking or nicotine polacrilex
use (14). This is not because the total
daily dose is inadequate; no weight-suppressing effect was found with up
to 22 mg of transdermal nicotine, whereas the effect of nicotine
polacrilex appears reliable at a daily intake of approximately 5-8 mg
(the expected dose received from the consumption of 6-9 units of
2-mg-containing polacrilex) (24). The more
pronounced catecholamine-releasing effects of faster forms of nicotine
delivery (4) might account for cigarettes
appearing to be particularly efficacious anorectants, polacrilex less
so, and transdermal systems without such an effect.
A prominent component of the nicotine withdrawal syndrome is impaired
cognitive performance; readministration of nicotine provides rapid
relief, thus providing a potentially powerful source of reinforcement
for continued smoking. It has even been suggested that nicotine does not
really produce dependence but that instead people self-administer
cigarettes primarily to provide cognitive benefit (77);
however, the presence or lack of therapeutic efficacy is not a criterion
for the determination of addiction liability. Furthermore, the only
conditions under which reliable cognitive benefits of nicotine
administration have been documented are in persons who are cognitively
impaired during nicotine withdrawal or possibly by Alzheimer's disease.
In nonsmokers, nicotine administration can increase finger-tapping
rate and slightly (but significantly in some studies) attenuate the
deterioration in attention that occurs during protracted testing. These
effects are scientifically interesting but do not appear to be of either
the type or magnitude to explain why at least one in three people
exposed to a few cigarettes becomes dependent (74).
Moreover, complex cognitive performance may be impaired by nicotine in
cigarette smokers as well as in nonsmokers (26).
A corollary of the possibility that nicotine can provide certain
benefits that then contribute to its overall abuse is that individuals
vary in their vulnerability to nicotine dependence. Several studies
suggest that the risk of dependence, following the smoking of a few
cigarettes, is present in most people. For example, as discussed
earlier, in a study in the United Kingdom, 94% of adolescents who smoked
at least four cigarettes graduated to regular use persisting for at
least 5 years (62). Furthermore, until the
1960s, most male adults in the United States smoked cigarettes;
presently, in Japan and other countries, most men smoke cigarettes. On
the other hand, with present antismoking educational efforts and
policies in the United States, smoking prevalence among men has declined
to approximately 27%. This decline cannot be explained by a reduction in
biologically conferred vulnerability occurring within three decades.
Rather, it would seem more plausible that most people are vulnerable but
that education and prevention efforts can reduce the likelihood of
exposure and the progression to dependence after exposure.
Individuals vary in their vulnerability to dependence on nicotine and
other drugs just as they vary in their vulnerability to other medical
disorders: Some people show a high degree of resistance to the disorder
despite multiple exposures to the carrier, whereas others very quickly
become dependent or otherwise sick (74).
Prominent social and environmental factors have been identified—for
example, smoking by a household member, stressful environment, and cost
of cigarettes (74). In addition,
personality characteristics determined by age 6 (44),
as well as genetic heritage (45), are
associated with the risk of dependence.
Certain psychiatric comorbidities have also been identified as
significant concomitants of cigarette smoking. Depression, possibly
certain anxiety disorders, and other forms of drug abuse or dependence
occur in approximately one in three cigarette smokers (9).
Particularly interesting is the direct relationship between nicotine
dependence severity, as determined using Diagnostic and Statistical
Manual III-R criteria (DSM-III-R; 1), and depression, anxiety, and
other drug abuse (9).
There are several potential explanations for the co-incidence of
these disorders that are not mutually exclusive. Most plausible are that
common factors (inherited or environmental) may elevate the risk of
developing nicotine dependence as well as the comorbid disorder, the
risk of smoking may have been elevated by early premorbid symptoms of
another disorder (which could have been alleviated to some degree by
smoking), or chronic alteration of dopaminergic and endocrine function
resulting from chronic smoking during adolescence may alter the risk of
developing certain comorbid disorders.
The basic principles of nicotine-dependence treatment are the same as
those of other drug abuse treatment, discussed elsewhere in this volume.
These include the use of behavioral techniques and medications to reduce
or eliminate drug use, alleviate withdrawal symptoms, and prevent
relapse. A difference in the population of tobacco users from other drug
abusers should be considered because of its implications for
understanding the etiology and treatment course; that is,
epidemiological information suggests that most tobacco users are
employed, well adjusted in society without legal problems, and highly
motivated to quit. These factors are prominent correlates of success in
the treatment of abusers of other drugs (40,
74), and attention to these factors is a
major, if not the primary, target of treatment efforts for them but is
probably less important for treatment of most tobacco-dependent persons.
The often severe consequences of untreated nicotine dependence have
been important stimuli for the search for more effective treatments.
Making effective treatments more widely available is vital, particularly
because cancer chemotherapy, surgery, and other medical treatments for
tobacco-caused diseases are often less efficacious and are invariably
far more toxic than nicotine-dependence treatments that may prevent the
development of these disorders. Helping people achieve abstinence is
also important from the perspective of containing health care costs
because cessation at any age reduces the risk of most forms of
tobacco-caused morbidity as well as mortality (76).
For example, in 1993 the U.S. Office of Technology Assessment reported
to the U.S. Congress that tobacco-attributable health care costs were 68
billion dollars in 1990 and that these costs could be reduced by more
effective treatment and prevention.
Pharmacological approaches to treating nicotine dependence were
surely one of the important medical advances of the 1980s and 1990s.
However, pharmacological approaches are generally viewed as medications
to supplement some type of behaviorally oriented approach because the
goal is to assist in modifying smoking behavior. This is not meant to
imply, however, that medications should only be used by persons trained
in behavior modification techniques or that extensive behavioral
counseling is necessary to incur some level of benefit. Several studies
have documented long-term benefits of nicotine polacrilex and
transdermal systems in general practice settings that administered only
a brief behavioral intervention package (64).
The basic elements of such interventions will be summarized below.
The first step in determining the appropriate treatment course is to
diagnose the severity of the nicotine dependence and determine if
complicating comorbidities are present. No strong rational basis exists
for prescribing nicotine replacement therapy if there is little or no
nicotine dependence or withdrawal symptoms. If this is the case or if
the patient has never tried to quit, the patient should be strongly
advised to attempt to quit without medication. Some patients will
succeed; those who do not will at least be able to provide useful
diagnostic information about their degree of dependence. This is also
one of the ways patients learn to cope with life without cigarettes.
Several potential predictive measures of dependence severity tend to
co-vary. These include: cotinine level in biological fluid such as
saliva, blood, or urine; number of cigarettes smoked per day (e.g., 16
versus 25 may be significant, whereas 21 versus 25 may not be
significant); score on the Fagerstrom Tolerance Questionnaire; and
number of symptoms from the American Psychiatric Association's DSM-III-R
(1). As discussed in the 1988 Report of the
Surgeon General (74), these measures tend
to predict the following: difficulty achieving abstinence, severity of
withdrawal symptoms, rapidity of relapse, and efficacy of replacement
therapy. The probability of spontaneous remission (i.e., quitting
without formal treatment intervention) is inversely related to the
predicted strength of the dependence.
Each of the aforementioned measures has a particular area of utility.
The Fagerstrom Tolerance Questionnaire takes only a minute or two to
administer and provides remarkably predictive information about the
level of dependence and appropriateness of nicotine replacement therapy.
Expired air carbon monoxide (or carboxyhemoglobin) provides a
quantitative marker of smoke intake and may be useful in monitoring
treatment efficacy and potential reduction in smoke-delivered toxins
over the course of treatment. Cotinine (assessed in saliva, urine, or
blood) may be the single most useful measure of dependence but is not
generally worth the expense of collection except in cases where nicotine
replacement will be used, and it is especially important to document
that the overall exposure to nicotine is lower during therapy than
during pretreatment smoking (e.g., pregnancy, active heart disease, and
The two medical disorders pertaining to nicotine dependence are
identified by the American Psychiatric Association:
1. Nicotine dependence, which is a type of psychoactive-substance-use
disorder. The essential feature is "a cluster of cognitive,
behavioral, and physiologic symptoms that indicate the person has
impaired control of psychoactive substance use and continues use of the
substance despite adverse consequences" (1,
p. 166). The most common form is cigarette smoking, in part due to the
rapid onset of nicotine effects via this route which "facilitate
the conditioning of an intensive habit" (1,
pp. 181-182). However, it is noted that dependence to other forms of
nicotine delivery, including smokeless tobacco and nicotine gum, may
2. Nicotine withdrawal, which is a type of psychoactive-substance-induced
organic mental disorder. The essential feature is "a
characteristic withdrawal syndrome due to the abrupt cessation of, or
reduction in, the use of nicotine-containing substances (e.g.,
cigarettes, cigars, pipes, chewing tobacco, or nicotine gum) that has
been at least moderate in duration and amount. The syndrome includes
craving for nicotine, irritability, frustration, anger, anxiety,
difficulty concentrating, restlessness, decreased heartrate, and
increased appetite or weight gain." (1,
The American Psychiatric Association criteria are useful in
estimating the likely severity of withdrawal symptoms (if the patient
can accurately remember symptoms from prior cessation attempts) and
appear most useful in predicting the likelihood of comorbid depression
and anxiety (9).
Behavioral intervention is the cornerstone of all forms of effective
smoking cessation intervention. Even high-dose administration of
nicotine to smokers not attempting to quit does not induce spontaneous
cessation and generally produces reductions in smoke intake that,
although scientifically important, are probably of little health benefit
(e.g., reduction of cigarette intake from 27 to 23 cigarettes per day).
Several behavioral forms of intervention varying both in type and
intensity have been demonstrated to substantially enhance cessation
rates above the 3-7% baseline cessation rate detected in several
population studies. These interventions range from briefly administered
physician advice and guidance to intensive behavior modification (63).
The more widely studied forms are summarized in this section.
Individual behavioral counseling often includes the provision
of self-help materials providing strategies for achieving and sustaining
remission. Dependence level, possible withdrawal severity, and putative
relapse factors that vary across individuals (e.g., weight gain, stress,
friends who smoke, and alcohol consumption) are important factors in the
development of a behavioral prescription. Setting a target quit date 1-3
weeks from the initial intervention appears critical to give the person
time to prepare for the possible trauma, but it is critical not to leave
the quit date's occurrence open-ended. Behavioral approaches may also
include skills training, relaxation training, recommendations for
exercise, and contingency contracting.
Group counseling approaches are used in a variety of health
care settings and by many voluntary agencies. Specific protocols vary,
but there appear to be at least three important elements: information
about smoking risks and the benefits of quitting to provide additional
motivation; strategies to cope with relapse situations and sustain
abstinence; and social settings which may constitute a contingency
program for achieving and sustaining cessation. The latter factor is
probably subsumed under what is often referred to as group dynamics
and appears to be powerful in some groups and weak or counterproductive
in others. A major problem with this approach is that it appears that
less than 10% of cigarette smokers who want to quit would actually
participate in a group program.
Nicotine fading approaches attempt to achieve gradual
reduction of smoke intake by decreasing puffs per cigarette, number of
cigarettes smoked per day, and smoking brands of cigarettes that deliver
lower doses of nicotine. Special cigarette filters and approaches to
dilute the smoke may also be incorporated. Although nicotine fading can
be helpful when done carefully, the main problem with these approaches
is that the goal of reduced tobacco intake may be easily defeated by
subtle changes in how each cigarette is smoked because it is possible to
extract several milligrams of nicotine from nearly any brand of
cigarettes sold in the United States (74).
Aversion treatments are designed to condition a cigarette
aversion by pairing smoking with either unpleasant imagery (covert
sensitization), electric shock, or unpleasant effects of smoking itself
through directed smoking procedures. Directed smoking techniques include
satiation, rapid smoking, and focused smoking. The usefulness of
aversion procedures is limited because the aversions are rarely
permanent, and it is difficult to condition aversion to a substance that
has had repeated past use.
Acupuncture and hypnosis are two widely marketed techniques
that have never been proven efficacious as specific procedures to induce
lasting cessation. However, clinics offering such services range from
those that apply the procedure with little additional support to those
that apply the procedure ancillary to extensive individual or group
counseling. It is plausible that clinics offering a comprehensive
approach (some hypnosis programs even incorporate nicotine-delivering
medications) may be effective, although there has been little systematic
study of this possibility. Controlled clinical trials of acupuncture
have not demonstrated significant efficacy (63,
The major pharmacological approaches are nicotine replacement,
symptomatic treatment, nicotine blockade, and deterrent
treatment. Nicotine replacement and symptomatic treatment have
become part of general medical practice. Until further information is
collected, blockade and deterrent treatment must still be considered
experimental. These will be summarized in what we believe is reverse
order of their presently known efficacy.
Nicotine blockade therapy is based on the rationale that if
one blocks the rewarding aspects of nicotine by administering an
antagonist, the person who smokes for the pleasant effects nicotine
produces will be more likely to stop smoking. To be effective, the drug
must be centrally active. Thus, mecamylamine, which acts at both central
and peripheral nervous system sites, may increase rates of abstinence,
whereas hexamethonium and pentolinium, which block peripheral receptors
only, should have no effect on abstinence. Preliminary data suggest that
mecamylamine might be used to antagonize the nicotine-mediated
reinforcing effects of smoking (40.
Unfortunately, there are presently no pure nicotine antagonists
clinically available. Drugs like mecamylamine produce side effects such
as sedation, low blood pressure, and fainting that probably limit their
role to experimental tools but not for clinical treatment (40).
The rationale for deterrent therapy is that pretreatment with
a drug may transform smoking from a rewarding experience to an aversive
one if the unpleasant consequences are immediate and strong enough.
Disulfiram treatment for alcoholism is an example of this type of
treatment. After pretreatment, even a small quantity of alcohol can
produce discomfort and acute illness. Silver acetate administration is a
potential deterrent treatment for smokers. When silver acetate contacts
the sulfides in tobacco smoke, the resulting sulfide salts are very
distasteful to most people. Although many over-the-counter deterrent
smoking prevention treatments are available, their effectiveness has not
been scientifically validated. Additionally, a severe limitation to this
treatment is compliance. It has been difficult to ensure that patients
continue to take the medication as needed (74).
Nicotine administration and withdrawal produce a number of
neurohormonal and other physiological effects. Symptomatic treatment
methods are nonspecific pharmacotherapies to relieve the discomforts and
mood changes associated with withdrawal. If the potential quitter
relapses to escape withdrawal, these methods should help to prevent such
relapse. There is a long history of pharmacological treatment of
smokers. Sedatives, tranquilizers, anticholinergics, sympathomimetics,
and anticonvulsants have all been used to reduce withdrawal, but they
failed to increase chances of quitting relative to placebo. Clonidine
has been used in attempts to treat withdrawal discomfort. Glassman et
al. (22) administered clonidine to heavy
smokers on days they abstained from smoking and found that clonidine
reduced anxiety, irritability, restlessness, tension, and cigarette
craving. Moreover, there was a significantly greater rate of smoking
cessation among women, but not among men, 6 months after clonidine
treatment. The mechanism of the gender difference was not elucidated.
For example, it was not clear whether this lack of efficacy in men was
due to gender or insufficient dose (the same doses were given to all
subjects regardless of body weight). Before recommending clonidine for
smokers, potential side effects such as drowsiness, hypotension, and
discontinuation-related hypertension must also be considered.
Among nicotine's effects is the regulation of mood. Smokers have been
shown to smoke more during stressful situations, and people trying to
quit often relapse during stressful situations. These observations
suggest that treating the mood changes associated with abstinence with,
for example, benzodiazepine tranquilizers, antidepressants, or
psychomotor stimulants may improve abstinence rates. The benzodiazepine
tranquilizer alprazolam was also examined by Glassman et al. (22)
and found to reduce anxiety, irritability, tension, and restlessness,
but it had no effect on cravings in heavy cigarette smokers abstaining
from smoking for one day. Although clonidine and other medications with
potential utility in treating symptoms of nicotine abstinence do not
have Food and Drug Administration (FDA) approval, they may still merit
attention for some people not helped by other means (40).
The rationale for administering nicotine replacement medications
is to substitute a safer, more manageable, and, ideally, less addictive
form of the drug to alleviate withdrawal symptoms and facilitate
abstinence. The ability of health professionals to effectively treat
nicotine dependence was greatly enhanced by the appearance of nicotine
replacement medications. The first generation of such medications was
nicotine polacrilex ("gum"), approved by the FDA for marketing
in 1984. The second generation was the transdermal delivery system, four
of which were approved from December 1991 to August 1992. Another
generation is in development, encouraged by the proven utility as well
as limitations of the first two generations. This includes a nicotine
vapor inhaler, nasal nicotine spray (gel droplets), and lozenge.
The scientific foundations for administering nicotine as a substitute
for cigarette smoke included work by Johnston (41)
in the 1940s and Luchessi et al. in the 1960s (50).
However, it was not until the 1970s that the first non-tobacco
nicotine-delivering formulation intended as a medicinal replacement for
tobacco, a chewable nicotine resin complex (nicotine polacrilex), was
developed by the Swedish pharmaceutical company A.B. Leo (16).
The main limitation of nicotine polacrilex is difficulty maintaining
adequate self-administration to provide a viable means of nicotine
replacement for smoking (40).
The constraints on the utility of nicotine polacrilex were partially
addressed by the transdermal delivery system. The transdermal nicotine
delivery approach was initially developed to treat nicotine dependence
in research supported by the National Institute on Drug Abuse (60).
By August 1992, four pharmaceutical companies in the United States
received approval by the FDA to market their transdermal systems.
Lobeline is a putative nicotine agonist present in several aids for
smoking cessation such as CigArrestTM, BantronTM,
and NicobanTM. These and other such aids were
removed from the market in December 1992 by the FDA until they are
established to be efficacious in scientific studies. Lobeline is a weak
nicotinic receptor agonist, but it is of unproven efficacy for smoking
cessation treatment; it appears to act at cholinergic receptor sites
other than those mediating the discriminative effects of nicotine (40).
It is possible that higher doses than those tested might be helpful, but
studies have yet to be conducted.
The clinical use of nicotine replacement medication may be advanced
by considering research on the correlates of efficacy of methadone
treatment of heroin dependence. Particularly valuable is the information
provided by the study of Ball and Ross (2),
which showed that heroin treatment efficacy was related to factors such
as daily methadone dose, duration of treatment, level of support, and
characteristics of the counselors themselves. Similar factors appear
important in treating nicotine dependence using nicotine-delivering
Mechanism of Action
The goal of nicotine replacement therapy is to help the patient
establish remission and sustain it long enough to develop prophylactic
strategies to avoid relapse. The physiological mechanisms of action of
nicotine replacement must be understood to predict the possible benefits
as well as probable limitations of the medication. Nicotine replacement
is used to facilitate the cessation of tobacco use, but there is no
evidence that nicotine replacement would induce smoking cessation in
persons not attempting to quit. In fact, spontaneous smoking in persons
not attempting to quit is only slightly reduced (54,
There appear to be three pharmacological mechanisms by which nicotine
facilitates smoking cessation. Nicotine replacement reduces withdrawal
symptoms that can motivate relapse. This mechanism provides a secondary,
albeit controversial, indication for nicotine replacement—that is,
relief of withdrawal symptoms in those who must undergo intermittent
periods of abstinence but who are not attempting to cease smoking (e.g.,
this application is practiced in many hospitals for short-term
inpatients and by some military pilots). Nicotine replacement also
partially sates the appetite for cigarettes by sustaining nicotine
tolerance and thereby reduces the acute reinforcing effects of
smoke-delivered doses (74).
Besides reducing the pharmacological reinforcing effects of
cigarettes, nicotine replacement may provide some of the effects the
smoker had come to rely upon cigarettes to provide, such as sustaining
desirable mood and attentional states and handling stressful or boring
situations. Nicotine gum, but not transdermal systems, also reduces the
weight gain accompanying smoking cessation (14).
These effects are at least partially related to withdrawal reduction,
but many other uses of cigarettes do not involve withdrawal relief.
There is little reason to believe that nicotine replacement would reduce
these pressures to smoke. Most apparent may be the social situations in
which smoking had come to serve as a lubricant and common bond. Equally
prominent would be the private pleasures of sensorium satisfaction
established over hundreds of thousands of smoking episodes. For many,
these pleasures may be no more satisfied by nicotine polacrilex or
transdermal systems than were the pleasures of eating satisfied by
nutritional substitutes for normal food in volunteers kept healthy by
There do not appear to be any residual pharmacological effects of
nicotine replacement to protect against relapse; unfortunately, the
pressures to relapse are constant, and the likelihood of cigarette smoke
exposure is virtually guaranteed for most people in remission.
Therefore, establishing new patterns of behavior (i.e., of learning to
handle life without cigarettes) during the replacement-aided period of
remission would act as the primary protection from relapse.
Rational Basis for
Diagnosis of nicotine dependence level and determination whether
previous cessation attempts have resulted in withdrawal symptoms are
essential to provide individualized guidance to the patient, as well as
provide a rational basis for dosing decisions. The need for appropriate
dosing is the same as that for other medications—namely, to ensure
adequate doses to provide therapeutic benefit while minimizing the risks
associated with doses that are too high. The importance of the latter
concern is that smokers are a high-risk population for
nicotine-attributable mortality, and risks do not immediately cease with
the cessation of smoking. Thus, clinicians should perform an appropriate
diagnosis to confirm that their prescribed dosing regimen does not
expose patients to higher levels of nicotine than they obtained by
Efficacy of Nicotine
Nicotine polacrilex and transdermal systems have been approved by the
FDA as safe and effective, and the medications have been suggested as
important and cost-effective components of an emerging health care
system (3). The efficacy of the medications
in helping to achieve cessation and manage withdrawal symptoms has been
repeatedly demonstrated under a broad range of conditions, although some
level of structured behavioral support is critical (14,
18, 40). In
addition, several reviews have concluded that 1-year quit rates
following transdermal medications are approximately 20-30%, or double
those of placebo treatment and approximately five times greater than
spontaneous quitting rates (14, 18,
19). Similar short- and moderate-term
success rates have been reported with nicotine polacrilex, but long-term
efficacy with this medication appears to be more dependent on its
incorporation into a systematic behavioral treatment approach than are
transdermal systems (36).
In treatment trials, the level of behavioral intervention is
generally correlated with efficacy rates among both nicotine-medicated
and placebo-receiving groups (25). What is
unclear, however, is the level of behavioral intervention beyond which
no further reliable benefit occurs, or if certain kinds of interventions
are generally more effective than others (63).
Two studies have reported increased withdrawal relief by combining a
nicotine transdermal system with polacrilex (15,
48). Rationale for this combination is that
the transdermal system provides stable nicotine levels that can then be
supplemented as needed by polacrilex. Although long-term benefits are
not yet known, this regime appears reasonable for highly dependent
patients and those not helped by either alone.
Nicotine polacrilex and transdermal systems can sustain
tolerance and some degree of physical dependence but do not produce the
highly reinforcing effects of rapid delivery systems (31,
74). In fact, transdermal systems deliver
nicotine so slowly that they are almost devoid of the psychoactive effects
characteristic of drugs with significant abuse potential (31,
74). Nicotine polacrilex takes considerable
effort to produce such a limited response compared to tobacco products and
has proven to be low in abuse liability (31).
In addition, there is no evidence that the widespread availability of
nicotine replacement systems has led to dependence in people not already
dependent on nicotine. Among people prescribed nicotine polacrilex, less
than 5% continue their use for a year of more, and approximately 20% of
people who have sustained abstinence continue to use the polacrilex. When
there appears to be minimal danger of smoking relapse, available data
suggest that most of these persons can end their nicotine medication usage
without undue difficulty (35).
The pathophysiological consequences of tobacco use produce changes in
body tissues that contribute to heart disease, cancer, respiratory
diseases, and dependence. These disorders are not inevitable consequences
of tobacco exposure, but tobacco exposure is a causal factor in their
etiology. Approximately one in three adolescents who smoke a few
cigarettes develop nicotine dependence; of these, approximately one in
three die of tobacco-related disease. Thus, the relationship between
tobacco exposure and death is not unlike that seen with other pathogens
such as Mycobacterium tuberculosis, in which approximately one in
ten carriers of the bacteria develop tuberculosis disease. Among the
disorders resulting from tobacco use, dependence is unique because its
primary manifestation is behavioral; this has implications for treatment
that were discussed.
Understanding of the pathophysiological basis of tobacco dependence has
progressed as rapidly as the understanding of cancer and other
tobacco-related disorders. The pathophysiology of nicotine dependence
includes tolerance development, receptor up-regulation, physiological
dependence, and reinforcing effects, as well as the many other effects of
nicotine on behavior and physiological functioning. The reinforcing
effects of nicotine, in turn, are related to the method of nicotine
delivery. Genetic constitution appears to contribute to the vulnerability
to nicotine dependence as well as to the vulnerability to comorbid
These recent advances in knowledge have contributed to our
understanding of nicotine dependence as a chronic disorder. Insufficient
motivation or inadequate knowledge of risks do not adequately explain why
most cigarette smokers continue tobacco use. Most tobacco users are aware
of the risks, and they frequently attempt abstinence; however, they
usually fail, even when motivated by the near-death experience of a heart
attack. It seems reasonable to conclude that once nicotine dependence is
established, the seemingly irrational behavior of continued tobacco use is
no more governed by free choice and rational decision-making than is the
behavior of metastasizing cells once cancer onset has occurred. In both
cases, systematic treatment can enhance the individual's prognosis.
However, treatments for nicotine dependence are generally more effective
and less toxic than treatments for heart disease and cancer. Therefore,
greater availability of nicotine-dependence treatment will be an important
means of lowering the overall health cost burden of a nation.
Gorski and Other Members of the GORSKI-CENAPS Team Are Available To Train
& Consult On Areas Related To Addiction & Mental Health
Gorski - CENAPS, 17900 Dixie Hwy, Homewood, IL
60430, 708-799-5000 www.tgorski.com, www.cenaps.com,