Pathophysiology of Tobacco Dependence

Jack E. Henningfield, Leslie M. Schuh, and Murray E. Jarvik

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.

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 Receptor, Cholinergic 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).

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).

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 smoke exposure.

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 similarity.

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.

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).

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, 74).

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, 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).

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 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 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, 40, 43). 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 untreated abstinence.

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 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).

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.

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).

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 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).

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, 74).

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 medications.

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.

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.

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 smoking.

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 disorders.

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.

published 2000