Nicotine Addiction
Pathophysiology of Tobacco Dependence

An Article By 
Jack E. Henningfield, Leslie M. Schuh, and Murray E. Jarvik
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Nicotine Addiction
Pathophysiology of Tobacco Dependence
Table of Contents

1.  Introduction

2.  Natural History And Clinical Course

3.  Neuropharmacology

4.  Psychopharmacology

5.  Treatment

6.  Summary And Conclusions

INTRODUCTION

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 effective treatment.

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.

NATURAL 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 discussed below.

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, 74).

Epidemiology and Trends

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 smoke exposure.

Adolescent Nicotine Dependence

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).

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 dependent (28).

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, 42, 74). 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, 74).

NEUROPHARMACOLOGY

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 absorption (4).

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, 14).

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).

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 untreated abstinence.

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 products.

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).

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.

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.

PSYCHOPHARMACOLOGY

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 possible mechanisms.

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 correlate (12).

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.

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).

TREATMENT

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.

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 adolescent treatment).

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 also occur.

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, pp. 150-151).

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.

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 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, 74).

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 these substitutes.

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).

SUMMARY AND CONCLUSIONS

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 disorders.

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