CIGARETTE SMOKING

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CIGARETTE SMOKING AND NICOTINE ADDICTION Neal L. Benowitz, MD

WHAT IS ADDICTION?

About 54 million Americans smoke cigarettes. 41 According to a July, 1990, Gallup poll, 74% of these smokers would like to quit. 23 Nearly all physicians have treated patients with tobacco-related illnesses who, despite advice, are unable to stop smoking. Most smokers cannot quit because they are addicted to nicotine. An understanding of the role of nicotine in determining smoking behavior and tobacco addiction might help the physician better treat the tobacco-abusing patient. In the broadest sense, addiction indicates a loss of control over drugtaking behavior. The World Health Organization describes drug dependence as "a behavioral pattern in which the use of a given psychoactive drug is given a sharply higher priority over other behaviors which once had a significantly higher value."19 In other words, the drug comes to control behavior to an extent considered detrimental to the individual or to society. A number of criteria for drug dependence (used interchangeably with "addiction" for the purpose of this review) were presented in the Surgeon General's Report, The Health Consequences of Smoking: Nicotine Addiction (Table 1).18 In addition to highly controlled or compulsive use of a drug, the Surgeon General's criteria require that the drug produce psychoactive effects, and there must be evidence that drug-taking behavior is reinforced by effects of the drug. With respect to the latter, for example, people are known to smoke only tobacco that contains nicotine, and a regular smoker modifies his smoking behavior to From the Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, California MEDICAL CLINICS OF NORTH AMERICA VOLUME 76· NUMBER 2· MARCH 1992

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Table 1. CRITERIA FOR DRUG DEPENDENCE Primary criteria Highly controlled or compulsive use Psychoactive effects Drug-reinforced behavior Additional criteria Addictive behavior often involves: Stereotypic patterns of use Use despite harmful effects Relapse following abstinence Recurrent drug cravings Dependence-producing drugs often produce: Tolerance Physical dependence Pleasant (euphoric) effects From US Department of Health and Human Services, Public Health Service: The Health Consequences of Smoking: Nicotine Addiction. A Report of the Surgeon General. Washington, DC, US Government Printing Office, 1988.

maintain a particular level of nicotine in the body.6 The role of nicotine in determining cigarette smoking behavior is discussed in more detail in a later section. A number of additional criteria commonly associated with drug addiction are also listed in the Surgeon General's Report (Table 1). Whereas behaviors meeting these additional criteria are exhibited by most cigarette smokers, they are not universal in smokers. For example, some people, when faced with concerns about harmful effects or social pressures related to smoking, are able to quit and do not relapse. Some smokers who have quit claim the absence of withdrawal symptoms. It is important to note that similar observations have been made in alcoholics and in heroin and cocaine addicts who stop drug use. 18 Other criteria for drug dependence have been developed by the American Psychiatric Association and presented in the DSM-IIIR (Table 2).1 These criteria are quite specific and lend themselves to use in diagnosing individual patients. Again, the major emphasis (items 1 through 5) is loss of control over drug use. Drug addiction has meant different things over the years. At one time, drug addiction involved drugs that produced clear physical dependence (i.e., symptoms of withdrawal when the drug was discontinued) and produced damage not only to the individual but also to society. A prototypic drug with these characteristics was heroin. Drug dependence was distinguished from drug addiction, in which there was thought to be psychological dependence but no physical dependence and no damage to society. Examples of drugs in the former class are cocaine and nicotine. However, subsequent investigation into the human pharmacology of these drugs revealed that the behavioral characteristics and strengths of drug use were similar, that physical dependence could be observed for most or all of these drugs, and that social damage accompanies individual damage. As a result, the distinction has been dropped. In the Surgeon General's Report and this article,

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Table 2. AMERICAN PSYCHIATRIC ASSOCIATION (DSM-IIIR) DIAGNOSTIC CRITERIA FOR PSYCHOACTIVE SUBSTANCE DEPENDENCE A. At least three of the following phenomena are necessary: 1. Substance often taken in larger amounts or over a longer period than the person intended. 2. Persistent desire or one or more unsuccessful efforts to cut down or control substance abuse. 3. A great deal of time spent in activities necessary to get the substance (e.g., theft), taking the substance (e.g., chain smoking), or recovering from its effects. 4. Frequent intoxication or withdrawal symptoms when expected to fulfill major role obligations at work, school, or home (e.g., does not go to work because hung over, goes to school or work "high," takes care of his or her children while intoxicated), or when substance use is physically hazardous (e.g., drives when intoxicated). 5. Important social, occupational, or recreational activities given up or reduced because of substance abuse. 6. Continued substance use despite knowledge of having a persistent or recurrent social, psychological, or physical problem caused or exacerbated by the use of the substance (e.g., keeps using heroin despite family arguments about it, suffers cocaine-induced depression, or makes an ulcer worse by drinking). 7. Marked tolerance; need for markedly increased amounts of the substance (i.e., at least 50% increase) to achieve intoxication or desired effect, or markedly diminished effect with continued use of the same amount. NOTE: The following items may not apply to cannabis, hallucinogens, or phencyclidine (pep): 8. Characteristic withdrawal symptoms (see specific withdrawal syndromes under Psychoactive Substance-Induced Organic Mental Disorders). 9. Substance often taken to relieve or avoid withdrawal symptoms. B. Some symptoms of the disturbance have persisted for at least 1 month or have occurred repeatedly over a longer period of time. From American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 3, revised. Washington, DC, American Psychiatric Association, 1987.

drug dependence and drug addiction are taken to be scientifically equivalent. Confusion also arises concerning distinctions between non-drugrelated habits and addictions. For example, it is argued that strong habits such as compulsive eating or compulsive jogging, which may be extremely difficult to give up and can even result in personal injury, are equivalent to drug addictions. In the case of jogging, the "drug" could be considered to be an endogenous hormone such as an end orphin. Drug addictions can be considered broadly within the sphere of habitual behaviors, which include the habits mentioned above. However, drug addiction is distinguished from other habits in that the behavior is initiated and maintained by pharmacologic effects of a drug. A drug may be defined as a chemical substance that has effects on body functioning but is not a food substance and is not required for normal life. Nicotine is a drug. It seems clear that most if not all people can lead a normal and healthy life without ever consuming nicotine. This article focuses primarily on nicotine as a determinant of addiction to tobacco because the pharmacologic effects of nicotine are essential to sustaining cigarette smoking. However, tobacco addiction

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(like all drug addictions) is a complex process involving the interplay of pharmacology, learned or conditioned factors, personality, and social settings. The pharmacologic reasons for drug use can be considered as enhancement of mood or functioning. Drugs might enhance mood directly or do so by relieving negative consequences of prior drug usethat is, the relief of withdrawal symptoms. The pharmacologic actions of nicotine are involved in tobacco addiction in several ways6; Smokers report positive effects such as pleasure, arousal, and relaxation. Smoking may improve attention and reaction time and improve performance on certain tasks. Smokers may also experience the relief of aversive emotional states, including the reduction of anxiety or stress, relief from hunger and prevention of weight gain, and relief of symptoms of withdrawal from nicotine. Whether the positive rewards-that is, enhanced performance and mood after smoking-are due to the relief of symptoms of abstinence or to an intrinsic enhancement effect of nicotine (or both) is unclear. All drug-taking behavior is learned, a result of conditioning. Drugtaking behavior is made more probable (reinforced) by the consequences of the pharmacologic actions of the drug, as discussed for nicotine above. At the same time, the drug abuser begins to associate specific moods, situations, or environmental factors with the rewarding effects of the drug. The association between such cues and anticipated drug effects and the resulting urge to use the drug is another type of conditioning. Cigarette smoking is maintained in part by such conditioning. People often smoke cigarettes in specific situations, such as after a meal, with a cup of coffee or an alcoholic beverage, or with friends who smoke. The association between smoking and these other events, repeated many times, causes the environmental situations to become powerful cues for the urge to smoke. Likewise, aspects of the drugtaking process, such as the manipulation of smoking materials, or the taste, smell, or feel of smoke in the throat, become associated with the pleasurable effects of smoking. Even unpleasant moods can become conditioned cues for smoking. For example, a smoker may learn that not having a cigarette provokes irritability (one of the common symptoms of the nicotine-abstinence syndrome). Smoking a cigarette relieves withdrawal symptoms. After repeated experience(s) of this sort, a smoker may come to regard irritability from any source (such as stress or frustration) as a cue for smoking. Although conditioning becomes an important element of drug addiction, conditioning develops only because of a pairing of the pharmacologic actions of the drug with behaviors. Conditioning loses its power without the presence of an active drug. Conditioning is a major factor that causes relapse to drug use after a period of cessation. It must be addressed as a component of behavioral therapy of drug addiction. Other factors in drug addiction include personality and social setting. Not every person experiments with drugs, and not everyone who experiments becomes addicted. Personality factors such as rebelliousness, risk-taking, and possibly affective disorders appear to in-

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crease the likelihood of addiction to drugs. There are no clear guidelines linking specific personalities with substance abuse. Interactions between drug abuse and a patient's personality need to be examined to design optimal treatment. Personal imagery may contribute to drug abuse, as seen, for example, in cigarette smoking by adolescents who view smoking as adult, sophisticated behavior or a behavior linked with physical attractiveness (such as the advertising image of slim, attractive women). Finally, sociologic factors may be determinants of substance abuse risk and drug abuse patterns. Drug-taking behavior within a family or among friends is a strong motivator and reinforcer of drug use. An understanding of the complexity of factors motivating drug addiction is essential to understand why smokers smoke and to implement successful therapy. ADDICTION AND THE PHARMACOLOGY OF NICOTINE

Some of the behavioral effects of cigarette smoking that reinforce tobacco addiction have been mentioned above. In this section, the pharmacology of nicotine as it contributes to the addictive process is discussed in detail. The pharmacology of nicotine dependence can be discussed in relation to four processes: (1) absorption of nicotine into the body, (2) distribution of nicotine within the body, (3) pharmacologic effects of nicotine on target organs, and (4) translation of pharmacologic effects into behavior. Absorption of Nicotine

Nicotine is a tertiary amine composed of a pyridine and a pyrrolidine ring. It is a weak base with a pKa of 8.0, soluble both in water and in lipids. At physiologic pH, about 31 % of nicotine is not ionized and readily crosses cell membranes. The pH of tobacco smoke is important in determining the absorption of nicotine from different sites within the body. The pH of smoke from flue-cured tobaccos found in most cigarettes is acidic. At this pH, most of the nicotine is ionized and does not rapidly cross membranes. As a consequence, there is little buccal absorption of nicotine from cigarette smoke, even when it is held in the mouth. Tobacco smoke is inhaled into the lungs, from which it is absorbed into the systemic circulation. Absorption of nicotine is facilitated by a huge alveolar surface area, thin alveolar epithelial and endothelial layers, and an extensive capillary bed. 3 As a result of these ana to mic factors, nicotine moves rapidly from the alveolar spaces into the systemic circulation. In addition, pulmonary capillary blood flow is high, with the entire blood volume passing through the lung every minute. Thus, drugs that are absorbed are carried quickly to various

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parts of the body and to target organs. After absorption through the lungs, blood concentrations of nicotine rise quickly and peak at the completion of cigarette smoking. The absorption of nicotine from nicotine polacrilex gum or smokeless tobacco is gradual, with blood levels peaking at the end of the chewing or snuff-taking period. 14 Nicotine gum is buffered to an alkaline pH to facilitate absorption of nicotine through the mucous membranes of the mouth. In addition to absorption through the buccal mucosa, a considerable amount of nicotine is swallowed while chewing nicotine gum.]] Nicotine that is swallowed is also absorbed but undergoes presystemic metabolism by the liver so that its bioavailability is relatively low (about 30%). Distribution of Nicotine

Smoking is a unique form of systemic drug administration in that entry into the circulation is through the pulmonary rather than the portal or systemic venous circulations. Entry via the lung influences the rate and pattern of delivery of drugs to body organs. For example, nicotine can be expected to move quickly from inhaled cigarette smoke to the brain. 3 It is estimated that it takes 19 seconds or less from the start of a puff to the delivery of nicotine to the brain. This estimation assumes a 2-second puff, negligible time for diffusion of nicotine across alveolar membranes, and negligible time for movement from the arterial blood into the brain. Brain concentrations decline quickly as nicotine is distributed to other body tissues. Using partition coefficients (the ratio of drug concentration in tissue compared with blood at steady state) derived from experiments in rabbits, along with organ weights and blood flows in people, one can use perfusion models to simulate the concentrations of nicotine in various organs after smoking a cigarette. 3 Concentrations of nicotine in arterial blood and the brain are seen to increase sharply following exposure, then to decline over 20 to 30 minutes as nicotine is redistributed to other body tissues, particularly skeletal muscle. Venous blood concentrations, reflecting outflow of nicotine from body tissues, are predicted to be considerably lower than arterial concentrations for the duration of the infusion and for several minutes afterward. This discrepancy has been observed in rabbits following rapid intravenous injection of nicotine 46 and in people after cigarette smoking. 28 The ratio of nicotine in the brain to that in venous blood is highest during and at the end of the exposure period and gradually decreases as the elimination phase is entered. In contrast to inhalation, the buccal-oral route of absorption is expected to result in a gradual increase in concentrations of nicotine in the brain, with relatively little arterial-venous disequilibrium. In summary, inhalation of a drug such as nicotine allows for rapid transfer into the arterial circulation and into the brain. Rapid passage

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into the brain provides for the possibility of rapid behavioral reinforcement from smoking and for the smoker to precisely control the concentrations of nicotine in the brain and hence to modulate pharmacologic effects. Buccal-oral absorption results in gradual passage into the brain and provides less opportunity for behavioral reinforcement. To better understand the reinforcement process, one must examine the relationship between levels of nicotine in the body and its effects on the brain. Pharmacodynamics of Nicotine

Nicotine acts on nicotinic cholinergic receptors in the brain and other organs of the body.16 The drug appears to act predominantly presynaptically to enhance release of neurotransmitters such as acetylcholine, norepinephrine, dopamine, and serotonin. The physiologic consequences of nicotine include behavioral arousal and sympathetic neural activation (Table 3). Release of specific neurotransmitters has been speculatively linked to the reported reinforcing effects of nicotine. 44 For example, enhanced release of dopamine and norepinephrine may be associated with pleasure as well as anorexia, the latter of which may contribute to lower body weight. Release of acetylcholine may be associated with improved performance on behavioral tasks and improvement of memory. Release of beta-endorphin may be associated with reduction of anxiety and tension. Table 3. HUMAN PHARMACOLOGY OF NICOTINE Primary Effects' Pleasure Arousal, enhanced vigilance Improved task performance Relief of anxiety Reduced hunger Body weight reduction EEG desynchronization Increased circulating levels of catecholamines, vasopressin, growth hormone, ACTH, cortisol, prolactin, beta-endorphin Increased metabolic rate lipolYSis, increased free fatty acids Heart rate acceleration Cutaneous and coronary vasoconstriction Increased cardiac output Increased blood pressure Skeletal muscle relaxation

Withdrawal Irritability, restlessness Drowsiness Difficulty concentrating; impaired task performance Anxiety Hunger Weight gain Sleep disturbance Cravings or strong urge for nicotine Decreased catecholamine excretiont

Heart rate slowingt

'Some of these effects are due in part to relief of withdrawal symptoms. tMay represent a return to baseline rather than true withdrawal.

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Although smokers give different explanations for their smoking, most agree that smoking produces arousal, particularly with the first few cigarettes of the day, and relaxation, particularly in stressful situations. Consistent with reports of arousal, electroencephalographic de synchronization with an upward shift in the dominant alpha frequency and decreased total alpha and theta power follows cigarette smoking or the administration of nicotineY Many smokers report that smoking helps them concentrate and lifts their mood. A number of studies of the effects of cigarette smoking or nicotine administration on the behavior of abstinent smokers have been conducted. 56 Many such studies show improvement in attention, reaction time, and problem-solving. Nicotine has been shown to increase vigilance in the performance of repetitive tasks and to enhance selective attention. Smokers commonly report pleasure and reduced anger, tension, depression, and stress after a cigarette. Whether the enhanced performance and mood after smoking are due to the relief of symptoms of abstinence or to an intrinsic enhancement effect on the brain is unclear. A few studies showing improvement in the performance of nonsmokers after taking nicotine tablets suggest at least some direct enhancement. 56 Smoking and nicotine also have sympathomimetic action, producing brief increases of blood pressure, heart rate, and cardiac output, with cutaneous vasoconstriction. Nicotine causes muscle relaxation by stimulating discharge of the Renshaw cells and/or pulmonary afferent nerves, with inhibition of activity of motor neurons and relaxation of certain muscles. However, not all muscles are relaxed; increased electromyographic activity and tonicity of the trapezius muscle have been observed after smoking. 21 The time course of nicotine absorption strongly influences its actions, although it is not clear whether this is a result of a more rapid rate of rise or higher absolute levels of nicotine in the brain. We and others have found that heart rate acceleration, which reflects the level of sympathetic neural discharge and is a sensitive physiologic response, correlates with the magnitude of subjective effects. 48 , 57 Heart rate acceleration appears to be mediated by the CNS either through actions on chemoreceptor afferent pathways or via direct effects on the brain stem. Drug dosing by inhalation results in higher brain concentrations and greater psychological effects than does giving the same dose by routes with slower absorption. The possibility of titrating the level of a drug in the brain to achieve a desired mental state is, therefore, facilitated by inhalation compared with oral dosing. This explains why inhaling nicotine is preferred by most people over the oral route of administration. NICOTINE TOLERANCE AND WITHDRAWAL The Addiction Cycle

With prolonged or repetitive exposure to nicotine, neuroadaptation occurs. In animals, chronic nicotine exposure results in an increased

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number of nicotine receptors in the brain. 39 The time course of change and the number of brain nicotinic receptors and tolerance to various effects of nicotine are similar. At autopsy, the number of nicotinic receptors is greater in the brains of cigarette smokers than in those of nonsmokers.15 In humans, substantial tolerance develops to the behavioral arousal and cardiovascular effects of nicotine within the course of a single day. Smokers regain sensitivity to the effects of nicotine, at least in part, after overnight abstinence from smoking. Another consequence of neuroadaptation is the emergence of nicotine withdrawal symptoms when nicotine use is abruptly stopped (Table 3). In carefully controlled studies in humans, withdrawal symptoms including restlessness, irritability, anxiety, drowsiness, impatience, confusion, and impaired concentration have been described. 30 Abstaining smokers (at least acutely) also gain weight, and some performance measures, such as reaction time, are impaired. There is a strong desire, sometimes termed a craving, to smoke a cigarette. Most symptoms of the withdrawal syndrome reach maximal intensity 24 to 48 hours after cessation and gradually diminish in intensity over a period of 2 weeks. Other symptoms, such as a desire to smoke, particularly in stressful situations, persist for months or even years after cessation. That the abstinence symptoms are due to effects of nicotine is shown by the appearance of these symptoms after withdrawal from the use of smokeless tobacco or nicotine gum and the relief of these symptoms by the administration of nicotine. The pharmacokinetic and pharmacodynamic considerations discussed thus far help us understand the development of nicotine dependence, human cigarette smoking behavior, and the adverse effects of cigarette smoking. The daily smoking cycle can be conceived as follows (Fig. 1): The first cigarette of the day produces substantial pharmacologic effects, primarily arousal, but at the same time tolerance begins to develop. A second cigarette may be smoked later, at a time when the smoker has learned there is some regression of tolerance. With subsequent cigarettes, there is accumulation of nicotine in the body, resulting in a greater level of tolerance, and withdrawal symptoms become more pronounced between successive cigarettes. Transiently high brain levels of nicotine after smoking individual cigarettes may partially overcome tolerance, but the primary (euphoric) effects of individual cigarettes tend to lessen throughout the day. Overnight abstinence allows considerable resensitization to the actions of nicotine. Because of the dose-response and tolerance characteristics, most habitual smokers tend to smoke a certain number of cigarettes (usually 10 or more) and consume 10 to 40 mg of nicotine per day to achieve the desired effects of cigarette smoking and to minimize withdrawal discomfort throughout the day. Evidence indicates that smokers regulate intake of nicotine. Role of Nicotine in Maintaining Cigarette Smoking

Considerable behavioral and pharmacologic evidence supports the role of nicotine in maintaining and determining the pattern of cigarette

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Hour Figure 1. Model for the nicotine addiction cycle during daily cigarette smoking. The solid line represents venous plasma concentrations of nicotine as a cigarette is smoked (systemic dose of nicotine, 1 mg) every 40 minutes from 8:00 A.M. to 9:00 P.M. The upper dashed line indicates the threshold concentration for nicotine to produce pleasure or arousal. The lower dashed line indicates the concentrations at which symptoms of abstinence from nicotine occur. The shaded area represents a zone of nicotine concentrations (the "neutral" zone) in which the smoker is comfortable without experiencing either pleasure/arousal or abstinence symptoms. Note that the threshold levels for both pleasure/arousal and abstinence rise progressively during smoking owing to neuroadaptation (development of tolerance). The magnitude of pleasure/arousal is seen to be greatest with the first cigarette of the day and becomes less intense with subsequent cigarettes. Late in the day, cigarettes produce little primary pleasure/arousal but are smoked primarily to relieve abstinence symptoms. Cessation of smoking overnight allows resensitization of drug responses (i.e., loss of tolerance). This model is based on a mathematical simulation using the pharmacokineticpharmacodynamic model of Porchet et al. 45 Dr. Shi Jun performed the mathematical simulations.

smoking. 6, 49 First, as discussed, nicotine is delivered to the brain and is psychoactive; that is, it acts on the brain and affects mood and cognitive function. Second, the subjective and physiologic effects of intravenous nicotine and cigarette smoking are similar. Third, only tobacco that contains nicotine has been consumed habitually by people over long periods of time. Neither tobacco from which nicotine has been removed nor ultralow-yield cigarettes have received general public acceptance. In contrast, chewing tobacco and snuff, which deliver substantial amounts of nicotine, are widely used. Fourth, nicotine functions as a positive reinforcer-that is, animals and people administer intravenous nicotine to themselves. In addition, deprivation of nicotine, totally or in part, over a period of time results in an increase in nicotine-seeking behavior. Furthermore, smokers tend to adjust their smoking behavior to compensate for changes in the rate of elimination of nicotine from the body, to regulate body levels of nicotine. Finally, breaking the smoking habit is facilitated by replacing the nicotine

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derived from tobacco with nicotine administered in the form of chewing gum or transdermal nicotine. That smokers regulate their intake of nicotine has been dearly demonstrated. 6 , 49 Smokers change the way they puff a cigarette depending on nicotine yield, as determined by the cigarette smoking machine. They puff lower-yield cigarettes more frequently or more intensely than higher-yield cigarettes, presumably to obtain more nicotine. Smokers who switch from higher-yield to lower-yield cigarettes consume more nicotine from the lower-yield cigarettes than is predicted by smoking machine tests. Conversely, smokers consume less nicotine than predicted from higher-yield cigarettes. The intake of nicotine, with blood cotinine or nicotine concentrations used as markers of nicotine intake, has been studied in large groups of people smoking their chosen brand of cigarettes. 12 In such studies, nicotine intake correlates only weakly with the machine-determined yield. The slope of the regression line is quite shallow, indicating that only small differences in intake are seen with widely differing nicotine yields. The regulation of nicotine intake is dearly apparent when the number of cigarettes available to a smoker is restricted. ID When that number was reduced from unlimited (average, 39 per day) to 5 cigarettes per day, the average intake of nicotine per cigarette tripled. As a result, reducing the number to 15 cigarettes per day had very little effect, and reducing it to 5 cigarettes per day reduced only by 50% the daily exposure to tobacco smoke toxins. The administration of nicotine by infusion has been shown to reduce cigarette smoking. 8 , 38 Intravenous infusion of nicotine in doses similar to those consumed during regular cigarette smoking resulted in an average 25% suppression of nicotine intake from ad libitum cigarette smoking. 8 Suppression of cigarette smoking has also been observed with nicotine replacement by nicotine gum or transdermal nicotine. 32,50 Finally, compensatory responses in smoking have been observed when the rate of elimination of nicotine is accelerated. 9 The rate of renal elimination of nicotine is influenced by acidification or alkalinization of the urine. Acid loading, which results in a large increase in real excretion of nicotine, led to an 18% increase in the intake of nicotine from cigarette smoking, replacing about 50% of the excess lost in the urine. Thus, many studies using different experimental approaches show a strong tendency for persons to regulate levels of nicotine in the body within certain limits. Considering that the concentrations of nicotine in low-yield and high-yield cigarette tobacco are similar/ that smokers can manipulate their intake of nicotine by the manner in which they smoke, and that the deliveries of nicotine and tar are highly correlated, it is not surprising to find that the use of low-yield cigarettes has no effect on the risk of some smoking-related diseases, such as coronary heart disease. 34 Addiction Versus Free Will It is often argued that smokers smoke cigarettes of their own free will because they enjoy smoking and that they could stop at any time.

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According to this argument, persons who continue smoking are not addicts but persons who have made a conscious decision, whether they admit it or not, not to quit. Evidence that most smokers who quit smoking do so spontaneously, and that at least some report quitting without difficulty, is taken as support for the argument for free will and against addiction. A motivational model is a way to incorporate these observations into current concepts of drug addiction (Fig. 2). In such a model, smoking versus quitting is determined by the relative strengths of motivations to continue or stop smoking. The motivations to continue smoking include the pleasure and other perceived cognitive benefits of smoking, body weight control, avoiding discomfort from not smoking, social or peer pressures, and environmental cues (conditioning). Mo-

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Figure 2. A motivational model for tobacco addiction. The decision to smoke or not to smoke is determined by a balance of factors (motives) that reward or punish smoking behavior. When the level of motivation to quit exceeds the level of motivation to smoke, a person will quit. If quitting causes too much discomfort, a person will be unable to quit or, after quitting, will relapse to smoking. This state in which the personal cost of quitting is too high is the nicotine addiction state. The symbol N refers to motivation factors that are determined by pharmacologic actions of nicotine.

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tives to quit may include concern for one's health, social pressures, or economic factors (cigarettes cost a lot). According to this model, when the level of motivation to quit exceeds the level of motivation to smoke, a person quits. If the balance remains on the quit side, quitting is permanent. If quitting causes too much personal discomfort (cost), then the motivation to smoke increases and relapse occurs. Thus, nicotine addiction can be viewed as a state in which the personal cost of quitting is too high; i.e., quitting is too uncomfortable or too greatly impairs personal functioning. The extent of addiction depends on the strength of the motivations to smoke and hence how costly it is for a smoker to quit. The drug addiction concept is central to this motivation model because most of the motivations to smoke are related to pharmacologic effects of nicotine; i.e., the motivations are driven by the drug. Advocates of smoking as a free choice point out that smokers enjoy smoking and are simply choosing to do what they enjoy. That smoking is pleasurable to the smoker is not inconsistent with the addiction concept but rather reinforces the concept. Most drugs of abuse, most notably cocaine, are pleasurable to use. Memory of intense pleasure from taking a drug like cocaine may be so strong that uncontrollable urges to take the drug recur, even in the absence of physical dependence or much conditioning. Thus, the fact that people derive pleasure from their drugs does not make the drug less but rather more potentially addictive. In summary, habitual smoking is associated with a variety of nicotine-mediated or nicotine-initiated effects that maintain further smoking. Although smoking may be viewed by others, or even by the smoker himself, as a freely chosen behavior, much of the behavior is controlled by a prior history of exposure to nicotine and is sustained because ceasing the consumption of nicotine produces an unacceptable degree of discomfort in the smoker. Thus, apparent free choice is really drug addiction.

COMPARISON OF ADDICTION TO NICOTINE AND TO OTHER DRUGS

The previous discussion has mentioned several ways in which addiction to nicotine or tobacco resembles addiction to other drugs of abuse. A detailed review of the comparison of nicotine and other drug addictions is contained in the 1988 Surgeon General's Report. Is A summary comparison of various attributes of drug addiction in different drugs of abuse is shown in Table 4. It is obvious that all drugs of abuse share psychoactivity, produce pleasure, and are shown to reinforce drug-taking behavior. The nature of nicotine's psychoactivity, which is generally subtle and is consistent with high levels of cognitive performance, is considerably different from that of heroin and cocaine, which

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Table 4. ATTRIBUTES OF DRUG ADDICTION: COMPARISON OF DRUGS OF ABUSE Psychoactive effects Drug-reinforced behavior Compulsive use Use despite harmful effects Relapse after abstinence Recurrent drug cravings Tolerance Physical dependence Agonist useful in treating dependence

Nicotine

Heroin

Cocaine

Alcohol

Caffeine

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produce more intense euphoria and may be disruptive to performance. This difference has been taken to argue against the addictive nature of nicotine. However, a subtle psychoactive effect, especially when experienced hundreds of times (puffs) per day, may surely be expected to exert a powerful effect on behavior over time. Compulsive use can be observed with each of the drugs in Table 4; however, it has been argued that the degree of compulsion to use nicotine or tobacco is less than that to use other drugs. After all, smokers can forego their cigarettes at work or in other public places where smoking is proscribed. Smokers rarely go more than a day without nicotine, however, and may need to take numerous breaks throughout the day to smoke when smoking is prohibited concomitantly with work. In contrast, other drugs such as cocaine and heroin are used by some addicts only intermittently, that is, every few days or even at longer intervals. Yet the compulsion to use the drug repeatedly persists. Thus, in some situations nicotine and other drugs of abuse do not behave strictly according to a physical dependence model in which drug use is continually compelled by the need to reverse withdrawal symptoms. Nonetheless, these behaviors can be strongly controlled by drug-related factors. Use despite harmful effects reflects the difficulty in quitting drug use for many addicts. This is clearly evident to clinicians who deal with alcoholics with chronic liver disease, heroin addicts with infective endocarditis, and cigarette smokers. For example, of smokers who suffer acute myocardial infarction, only 50% quit despite a physician's universal admonition to do SO.2 It has been argued that many activities that entail risk, such as sex, sunbathing, and skiing, are situations in which an individual assumes a risk and makes a free choice, and that the same is true of cigarette smoking. However, life-long smoking results in the premature death of one in four smokers and the disability of a great number of smokers from chronic lung disease, indicating a substantially different level of risk compared with that of sex, sunbathing, and skiing. Relapse rates after abstinence appear to be similar for tobacco, heroin, and alcohol; about 60% of quitters relapse in 3 months and 75%

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in 6 months. 31 These relapse rates have been observed in clients discharged from treatment programs. It has been argued that the relapse rate for tobacco among spontaneous quitters might be lower than these rates. Few data on self-quitters are available, but most smokers report multiple quit attempts before they succeed, suggesting that relapse is very common. Recurrent drug cravings have been described for each of the addicting drugs, although there has been considerable debate about the use of the term craving. 36 A better term might be strong desire to use a drug. When desires for different drugs were compared among polydrug abusers, most of whom smoked cigarettes, the reported intensity of desire for cigarettes when they are not available was as high as or higher than for heroin, alcohol, or cocaine when the latter were not available. 35 Tolerance to the various drugs of abuse has been well documented, although the time course varies. Different time courses of tolerance might influence the pattern of drug use. For example, tolerance to many effects of nicotine develops quickly, within the day, and there is resensitization of many responses overnight. Intermittent high levels of nicotine in the brain from individual puffs might also overcome tolerance to some extent so that effects can be experienced from individual cigarettes. Presumably because of the daily cycle of tolerance and resensitization, daily doses of nicotine tend to stabilize, and, after a period of dose escalation in the first few years, many smokers smoke the same number of cigarettes each day. In contrast, in an alcoholic who drinks all day and whose brain is more or less continually exposed to alcohol throughout the day, tolerance lasts longer. Tolerance likewise occurs during cocaine binges when progressively larger doses are used in an attempt to maintain a cocaine high. However, between binges, sensitivity to cocaine may be regained. Physical dependence has been well characterized for smokers as well as for other drug abusers. It has been argued that there is a marked stereotypic syndrome after stopping heroin or alcohol, whereas the withdrawal symptoms after stopping smoking vary widely in nature and magnitude and are not present in 25% of quitters. Although it is true that smoking does not result in seizures or delirium tremens, withdrawal from smoking can be extremely disruptive to personal life. Nicotine withdrawal may be viewed as closer to that of withdrawal from other stimulants such as cocaine: The withdrawal syndrome is not life-threatening but it profoundly affects behavior and remains a strong impetus to recurrent drug use. Conversely, some heroin or alcohol addicts stop their drug use abruptly without marked withdrawal symptoms. Agonist drug "replacement" to modify withdrawal symptoms or to facilitate cessation has been used with narcotic abuse (methadone and L-acetylmethadol) and alcoholism (benzodiazepines) as well as with tobacco addiction (nicotine gum and transdermal nicotine). In all cases the agonist relieves withdrawal symptoms. Methadone and nicotine can be used over several months, with gradual tapering, to facilitate

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cessation. Methadone is also used in the long term to maintain abstinence. While such use is not recommended for nicotine replacement, 5% to 10% of nicotine gum users do continue to use the gum for more than a year after stopping smoking,29 which appears to function as a sort of maintenance treatment. The consideration of caffeine and coffee use in comparison to smoking is also informative with respect to understanding drug addiction. Caffeine clearly has psychoactive and pleasurable effects, and drug-reinforced behavior has been demonstrated. 4, 27 Tolerance to various effects of caffeine develops rapidly, which explains why regular users can drink coffee before bedtime without disrupting sleep, whereas those who do not drink coffee regularly may be up all night. Physical dependence is evident, with headache, fatigue, and irritability following caffeine withdrawal, even at low doses. Despite these characteristics common to other drugs of abuse, compulsive use of caffeine is relatively uncommon. Most people drink only one or two cups of coffee or tea per day and can change to decaffeinated beverages quite easily in response to personal health concerns or after requests to do so by a physician. There are, to be sure, some coffee drinkers, typically those who drink 6 to 10 cups of coffee per day or more, who appear to be addicted to caffeine and cannot forego their coffee or switch to decaffeinated coffee without severe disruption of their lives. However, these seem to represent a small fraction of all coffee drinkers. The reason for the low addiction liability is most likely that the psychoactive effects of caffeine have gradual onset after a dose, in contrast to the immediate reinforcement seen after smoking a cigarette. In contrast to coffee drinkers, the vast majority of cigarette smokers exhibit addictive behavior. The comparison of patterns of alcohol and cigarette use among the population illustrates another important characteristic of nicotine addiction. Whereas alcohol addiction and abuse are well known, fewer than 15% of alcohol users develop alcohol abuse problems. Most can drink an alcoholic beverage now and then and can easily skip drinking without a significant personal cost. Thus, most people can drink alcohol without becoming compulsive alcohol consumers. Cigarette smoking is quite the opposite. Most people who smoke cigarettes on a regular basis smoke 10 or more cigarettes per day and smoke every day. Fewer than 10% of smokers smoke 5 cigarettes per day or fewer or smoke intermittently, i.e., on some days but not others. 51 Thus, for the general population the addiction liability of nicotine is much greater than that of alcohol. Another interesting comparison can be made between tobacco and heroin. During the Viet Nam War, many soldiers became addicted to both tobacco and heroin. After the end of the war, most, upon return to the United States, discontinued heroin use, despite withdrawal symptoms, but tobacco addiction persistedY It is hard to distinguish the intrinsic level of the addiction versus the social influences on drug use, but in any case nicotine use can be seen to be a powerful and persistent addiction.

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IMPLICATIONS OF NICOTINE PHARMACOLOGY FOR TREATMENT Pharmacotherapy of Tobacco Addiction

It should be clear from the previous discussion that tobacco addiction is a very complex process. Although many smokers are able to quit by themselves or with behavioral therapies, a substantial number of smokers are unable to do so. Because the pharmacologic action of nicotine is a substantial factor in maintaining smoking behavior, the application of pharmacologic therapies to some patients makes intuitive sense. The most successful pharmacologic therapy to date has been nicotine substitution therapyY, 55 The idea is that taking nicotine from a medicinal preparation diminishes the need to smoke cigarettes. Nicotine chewing gum and transdermal nicotine delivery systems are now licensed drugs. Formulations under development include nasal and inhaled nicotine delivery systemsY Pharmacodynamic considerations make it obvious that the pharmacologic effects of nicotine gum and transdermal nicotine differ substantially from those of cigarette smoking. Because absorption of nicotine from the former preparations is gradual, uptake into the brain is not rapid. Consequently, more time is available for neuroadaptation (development of tolerance) as concentrations of nicotine in the brain are rising. The stimulant and euphoric effects of nicotine derived from cigarette smoking do not occur. On the other hand, maintaining a fairly constant level of nicotine in the body from nicotine substitution therapy prevents the decline in nicotine levels which is seen after smoking cigarettes and which is associated with abstinence symptoms. Thus, abstinence symptoms are relieved, which is probably the basis for the efficacy of nicotine substitution therapy. The pharmacodynamics of gum and the transdermal systems differ somewhat. 5 The gum causes gradually rising and falling levels of nicotine in the body throughout the day. The user must repeatedly chew the gum to obtain nicotine over time, and nicotine levels fall overnight as the person sleeps. As with cigarette smoking, there is a daily cycle of neuroadaptation and abstinence with use of the chewing gum, but the amplitude of the cycles is blunted. Gum use has certain advantages and disadvantages. Advantages include providing the smoker with a behavior that can be employed when there is an urge to smoke, which offers a person some active control over nicotine-related mood changes. With intermittent use, allowing time for resensitization, the pharmacologic effects of nicotine persist in a stable manner from day to day. Disadvantages include the considerable effort needed to chew enough pieces of gum to obtain a reasonable level of nicotine in the body, side effects including jaw fatigue, unpleasant taste, and gastrointestinal upset, and the risk (about 10%) of becoming dependent on nicotine gum and not being able to discontinue its use. Transdermal nicotine delivery systems result in levels of nicotine

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that rise gradually and plateau for most of the day.40 Whether there is a circadian rise and fall depends on the dosing regimen and the delivery characteristics of the particular system. Advantages of transdermal systems include the ease of application and minimal side effects. This should result in improved compliance and therefore better treatment outcome. Theoretical disadvantages include the development of complete tolerance to the effects of nicotine such that therapeutic benefits are lost and the potentially adverse health consequences of maintaining sustained levels of nicotine in the body 24 hours a day. The nasal and inhaled nicotine preparations have a potential to deliver nicotine to the circulation rapidly,33 similar to cigarette smoking, and should allow more direct substitution of one form of nicotine dosing for another. A concern with such rapid-delivery preparations is that, with regular use, individuals will become dependent on them as they had been on cigarettes. Combinations of occasional use of rapiddelivery preparations and regular use of slow-delivery preparations may provide a better pharmacokinetic!pharmacodynamic profile for smoking cessation therapy. Other pharmacologic therapies have also been employed to facilitate smoking cessation. These include receptor antagonists (such as mecamylamine), nonreceptor antagonists (such as clonidine), and antidepressants. Mecamylamine reduces the satisfaction and other effects of cigarette smoking. However, in short-term trials it appears to produce higher rates of smoking, presumably to overcome the effects of blockade. 52 Mecamylamine has been administered for up to 6 weeks in an open trial as an adjunct to treatment to help smokers stop smoking,53 but the drug is probably not useful for most patients because of potential complications of ganglionic blockade which include orthostatic hypotension, ileus, and urinary retention. Clonidine has been reported to reduce tobacco withdrawal symptoms, including the intensity of craving for tobacco, presumably by acting on the alpha 2-adrenergic receptors of the central nervous system. 25, 42 In one small controlled clinical trial, oral clonidine treatment for up to 6 weeks was found to be more effective than placebo as an aid to smoking cessation, although the benefit was seen primarily in women. 26 Other recent trials of oral or transdermal clonidine have found small or no benefit in the promotion of smoking cessation in primary care settings. I?, 22 An assessment of the utility and safety of clonidine for routine treatment awaits the results of recent large clinical trials. Based on observations that cigarette smokers are more likely to have a history of major depression than nonsmokers,26 antidepressant drug therapy for smoking cessation has aroused interest. Recent small trials of doxepin and oral buspirone treatment look promising. 20, 24 For example, Edwards et aFo treated nondepressed subjects with doxepin (150 mg) or placebo at bedtime for 3 weeks. One week after instructions to stop smoking, no doxepin-treated subjects were smoking, compared with 9 of 10 placebo-treated subjects. In the buspirone trial,24 which was not placebo-controlled, 7 of 8 subjects receiving 60 mg of buspirone

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per day reported reduced craving for cigarettes and less difficulty reducing smoking than in prior cessation attempts. Four subjects stopped smoking completely and 3 reduced their cigarette consumption. Other trials of these and other antidepressant drugs are ongoing. Stepped-Care Approach to Cessation

The details of clinical trials and practical use of nicotine substitutes and their integration into a comprehensive smoking cessation treatment program are discussed by other authors in this issue. This discussion proposes a stepped-care approach to smoking cessation, based on concepts of nicotine addiction that have been discussed (Fig. 3). Initial therapy for a smoker who has never tried to quit should be nonpharmacologic. Some smokers are able to pick a quit date and just stop (cold turkey). Others may require more formal behavioral therapies, such as those available in specialized smoking cessation clinics. Individuals who fail nonpharmacologic therapy are those most likely to be more dependent on nicotine and to be candidates for nicotinereplacement therapies. As discussed, slow-release preparations (nicotine gum or transdermal nicotine) are effective in relieving nicotine withdrawal symptoms and in facilitating smoking cessation. For nicotine gum therapy, smokers with a high level of nicotine dependence, as evaluated by the greater number of cigarettes smoked per day or by the Fagerstrom questionnaire, generally do better with a higher dose. 54 Presumably, the same would be true for transdermal nicotine. For the highly dependent smoker in whom relief of withdrawal symptoms is insufficient to promote cessation, one might consider alternative pharmacotherapies or rapid-release nicotine preparations.

Other Pharmacologic Therapy -

Clonidine; Antidepressants t

3 Nicotine Replacement: Rapid Release -

21 Nicotine Replacement: * Slow Release -

AerOSOl, Nasay Spray

Nicotine Gum, Transdermal

Nonpharmacologic Therapy: Cold Turkey; Behavioral Therapy

" Higher Dependence

t

-

History of Depressive Illness

Higher Nicotine Dose -

Antidepressants

Figure 3. Step· care approach to smoking cessation. The diagram depicts a series of

ascending steps in the treatment of tobacco addiction. Characteristics of individual patients, such as the level of nicotine dependence or a history of depressive illness, might influence the selection of treatments as noted.

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Alternative pharmacotherapies such as antidepressants are logical when smoking cessation results in depression or there is a prior history of major depression. Rapid-release nicotine preparations such as nicotine aerosol or nicotine nasal spray are still experimental. The rationale for the use of these preparations is that they might stimulate the same rapid delivery of nicotine to the brain as cigarettes and might provide some of the direct stimulation and other psychological effects sought by the smoker. Thus, the smoker would have a medicinal preparation that would provide the pharmacologic effects of a cigarette but would be dissociated from the rituals of smoking, the smell and taste of tobacco, and so forth. The highly dependent smoker can then stop cigarette use and begin behavioral modification therapy. In most situations, rapid-release nicotine preparations would be added to a slowrelease preparation. The rapid-release preparation would be tapered and discontinued first; then the slow-release preparation would be tapered as the patient learns to replace cigarette smoking with other behaviors. SUMMARY

Smokers smoke in large part because of the addictive effects of nicotine. Nicotine affects mood and performance and has been clearly implicated as the source of addiction to tobacco. People smoke to deliver desired doses of nicotine to their bodies, with certain rates of delivery and intervals between doses; these behaviors tend to be consistent for a person from day to day. Rational treatment of the pharmacologic aspects of tobacco addiction includes nicotine substitution therapy. New formulations of nicotine substitutes will provide more options to the physician for tailoring treatment to the needs of individual smokers. Other pharmacotherapies, particularly antidepressant drugs, hold promise for certain smokers. ACKNOWLEDGMENTS Supported in part by USPHS grants DA02277 and DA01696.

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4. Benowitz NL: Clinical pharmacology of caffeine. Annu Rev Med 41:277, 1990 5. Benowitz NL: Pharmacodynamics of nicotine: Implications for rational treatment of nicotine addiction. Br J Addict 86:495, 1991 6. Benowitz NL: Pharmacologic aspects of cigarette smoking and nicotine addiction. N Engl J Med 319:1318, 1988 7. Benowitz N1, Hall SM, Herning RI, et al: Smokers of low yield cigarettes do not consume less nicotine. N Engl J Med 309:139, 1983 8. Benowitz NL, Jacob P Ill: Intravenous nicotine replacement suppresses nicotine intake from cigarette smoking. J Pharmacol Exp Ther 254:1000, 1990 9. Benowitz NL, Jacob P Ill: Nicotine renal excretion rate influences nicotine intake during cigarette smoking. J Pharmacol Exp Ther 234:153, 1985 10. Benowitz N1, Jacob P Ill, Kozlowski 1, et al: Influence of smoking fewer cigarettes on exposure to tar, nicotine, and carbon monoxide exposure. N Engl J Med 314:1310, 1986 11. Benowitz NLO, Jacob P Ill, Savanapridi C: Determinants of nicotine intake while chewing nicotine polacrilex gum. Clin Pharmacol Ther 41:467, 1987 12. Benowitz NL, Jacob P Ill, Yu L, et al: Reduced tar, nicotine, and carbon monoxide exposure while smoking ultralow- but not low-yield cigarettes. JAMA 256:241, 1986 13. Benowitz NL, Porchet H, Jacob P Ill: Nicotine dependence and tolerance in man: Pharmacokinetic and pharmacodynamic investigations. In Nordberg A, Fuxe K, Homstedt B, et al (eds): Progress in Brain Research, Vol 79. Amsterdam, Elsevier Science Publishers, 1989, p 279 14. Benowitz NL, Porchet H, Sheiner L, et al: Nicotine absorption and cardiovascular effects with smokeless tobacco use: Comparison with cigarettes and nicotine gum. Clin Pharmacol Ther 44:23, 1988 15. Benwell MEM, Balfour DJK, Anderson JM: Evidence that tobacco smoking increases the density of (- H 3H]nicotine binding sites in human brain. J Neurochem 50:1243, 1988 16. Clarke PBS: Nicotine and smoking: A perspective from animal studies. Psychopharmacology 92:135, 1987 17. Davison R, Kaplan K, Fintel 0, et al: The effect of clonidine on the cessation of cigarette smoking. Clin Pharmacol Ther 44:265, 1988 18. Department of Health and Human Services, Public Health Service: The Health Consequences of Smoking: Nicotine Addiction. A Report of the Surgeon General. DHHS (CDC) Publication No 88-8406. Washington DC, US Government Printing Office, 1988 19. Edwards G, Arif A, Hodgson R: Nomenclature and classification of drug and alcoholrelated problems: A shortened version of a WHO memorandum. Br J Addict 77:3, 1982 20. Edwards NB, Murphy JK, Downs AD, et al: Doxepin as an adjunct to smoking cessation: A double-blind pilot study. Am J Psychiatry 146:373, 1989 21. Fagerstrom KO, Gotestam KG: Increase in muscle tonus after tobacco smoking. Addict Behav 2:203, 1977 22. Franks P, Harp J, Bell B: Randomized, controlled trial of clonidine for smoking cessation in a primary care setting. JAMA 262:3011, 1989 23. Gallup G Jr, Newport F: Many Americans favor restrictions on smoking in public places. Gallup Poll Monthly 298:19, 1990 24. Gawin F, Compton M, Byck R: Buspirone reduces smoking. Arch Gen Psychiatry 46:288, 1989 25. Glassman AH, Jackson WK, Walsh BT, et al: Cigarette craving, smoking withdrawal and clonidine. Science 226:864, 1984 26. Glassman AH, Stetner F, Walsh BT, et al: Heavy smokers, smoking cessation, and clonidine. JAMA 259:2863, 1988 27. Griffiths RR, Woodson PP: Caffeine physical dependence: A review of human and laboratory animal studies. Psychopharmacology 94:437, 1988 28. Henningfield JH, London EO, Benowitz NL: Arterial-venous differences in plasma concentrations of nicotine after cigarette smoking (letter). JAMA 263:2049, 1990 29. Hughes JR: Dependence potential and abuse liability of nicotine replacement therapies. In Pomerleau OF, Pomerleau CS (eds): Progress in Clinical and Biological Research. New York, Alan R. Liss, 1988, P 261

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