the Anatomy of Nicotine Addiction

The Anatomy of Nicotine Addiction

ABSTRACT. Cigarette smoking is a severe form of drug addiction claiming a higher death toll than all other addictions combined. Recent research has increased our understanding of nicotine addiction and has provided effective strategies for treatment. It is now clear that the persistence of cigarette smoking behavior is not explained simply by the tolerance that develops to nicotine, but rather, by a complex array of nicotine-mediated effects in the smoker. These effects compose what maybe termed the anatomy of nicotine addiction. The purpose of the paper is to provide a brief overview of this anatomy to provide guidance to the rational use of nicotine-replacement therapies.

Despite the fact that most people who smoke cigarettes believe that smoking is harmful to their health and would like to quit, most cigarette smokers die as smokers, many because of their smoking.( 1) Why don't more people quit? Why do most of those who do quit quickly relapse? We now know that tobacco consumption delivers addicting doses of nicotine to the brain. Thus, tobacco-delivered nicotine is to lung cancer what intravenously delivered heroin is to AIDS. In beth cases, the addicting drug ensures that users repeatedly and persistently expose themselves to a highly contaminated drug-delivery system. The 1988 Surgeon General's Report( 2) documented in considerable detail the diverse actions of nicotine that contribute to tobacco addiction, as well as the ways in which the tobacco cigarette itself contributes to the addiction process. These observations together constitute what may be called the anatomy of tobacco addiction or, more technically, the pathophysiological basis of cigarette smoking. In this paper, we will briefly sketch this anatomy.

Nomenclature

The terms drug addiction or drug dependence are widely used to refer to various medical and social disorders related to the compulsive ingestion of psychoactive chemicals. More technically, the American Psychiatric Association differentiates two medical disorders pertaining to nicotine addiction:( 3)

Nicotine dependence, which is a type of a Psychoactive Substance Use Disorder. The essential feature of this type of disorder is a "a cluster of cognitive, behavioral, and physiologic symptoms that indicate that the person has impaired control of psychoactive substance use and continues use of the substance despite adverse consequences." In the case of nicotine it is concluded that the most common form Is cigarette smoking, in part due to the rapidly onsetting effects of nicotine via this route, which "facilitate the conditioning of an intensive habit."
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, and pipes, chewing tobacco, or nicotine gum) that includes craving for nicotine; irritability; frustration, or anger; anxiety; difficulty concentrating; restlessness; decreased heart rate; and increased appetite or weight gain."
Two other commonly used terms are tolerance and physical dependence. Tolerance refers to the decreased responsiveness to the same dose of the drug as a function of repeated drug exposure. This is often, as is the case with tobacco, accompanied by increased drug-taking over time. A toxicologic consequence of tolerance to nicotine is that cigarette smokers expose themselves to much higher levels of tobacco-borne toxins than they would off they had not become tolerant and able to ingest many cigarettes per day. The cellular and neurological adaptations that result in tolerance also result in the body's coming to need continued drug intake to function relatively normally. At this point, the organism is said to be physically (or) physiologically dependent; acute drug deprivation will precipitate a syndrome of responses, including some that are opposite of those produced by drug administration. Depending on the Individual and the duration and amount of drug intake, it may take from a few days to many months for recovery to a state at which the person feels normal in the absence of the drug. For nicotine the acute withdrawal phase appears to last about four weeks on average.

Epidemiology of Cigarette Smoking Compared to That of Other Drug Addictions.

Tobacco kills more people than all other addictions combined, with more than one in four cigarette smokers dying prematurely due to their addiction.( 4) The 1990 National Household Survey on Drug Abuse found that 17% of people who had consumed five or more alcoholic drinks in a row in the past 30 days felt that they needed to drink or were dependent; for cocaine, 8% of people who had used the drug 11 or more times in their lives felt that they needed the drug or were dependent. In contrast, among people who had ever smoked cigarettes in their lifetime, 38% were smoking at the time of the survey, and the majority of these people reported that they needed tobacco or felt dependent at the time that the survey was conducted.( 5) Moreover, cigarettes are unique among addicting drugs in that the vast majority of users may be considered to be at some level of dependence smoking at least five cigarettes every day. For example, less than 15% of people who drink alcohol appear to have problems with alcohol and less than one in six people who have consumed cocaine in the past year have used in the past week, whereas approximately 90% of all cigarette smokers smoke more than five cigarettes every day.( 2, 5)

Consistent with the findings of a high incidence of dependence among users of cigarettes compared to users of other addicting substances, the likelihood of escalating from casual use to regular or compulsive use Is also much higher for cigarettes. Recent surveys in the United States and United Kingdom suggest that approximately 50% of those who smoke any cigarettes escalate to regular usage, whereas it appears that only a small minority of people who have tried any form of cocaine, heroin, or alcohol graduate to addictive patterns of use.( 6-8) As has been discussed elsewhere,( 6) the high likelihood of development of dependence and the extensive prevalence of nicotine addiction compared to other forms of drug addiction do not mean that nicotine is more addictive than cocaine or heroin; rather, it would appear that factors, such as availability, the severity of legal and social consequences for use, and sophisticated marketing and advertising techniques by tobacco companies, appear to be important determinants of the pervasiveness of tobacco addiction.( 6)

The Drug DeLivery System

The tobacco cigarette would appear to be the most highly addictive and toxic form of nicotine delivery that has ever been widely used. The low pH of the smoke delivered and the small doses of nicotine delivered per puff require users regularly and frequently to inhale tobacco smoke to maintain their addiction. Cigarette tobacco containing toxins, as well as the other taxi produced in the nearly 2,000-degree micro-blast furnace at the burning tip of the cigarette, is inhaled deeply into the lungs approximately 300 Hines each day by the pack-and-one-half-per-day cigarette smoker. Such repetition occurs because the acute effects of the smoke-delivered nicotine desired by the smoker last only a few minutes. Most cigarettes in the U.S. market contain about 8-9 mg of nicotine, of which the smoker usually obtains about 1-2 mg per cigarette.( 9) In general, the type of cigarette or the nicotine delivery rating reported by tobacco manufacturers bears almost no relation to the amount of nicotine obtained per cigarette by the typical smoker.( 2) Exceptions are the so-called ultra low nicotine delivering cigarettes that are highly ventilated and deliver such a high volume of air along with the smoke that it may be more difficult for smokers to obtain a milligram or more of nicotine per cigarette unless they cover the ventilation holes with their lips. In the early 1990s, two non-nicotine delivering tobacco cigarettes were also test marketed, although at this writing one of them has already been withdrawn from the market.

Smokeless tobacco products are also highly addictive and toxic, but these toxins are not inhaled into the lungs and do not include carbon monoxide and other pyrolysis products of burning cigarettes. It may be easier for young people to become addicted to smokeless tobacco, however, because the products that tend to be marketed to young people (termed "starter products" by the tobacco industry) deliver nicotine in doses that are lower and more slowly delivered than those from maintenance smokeless products or cigarettes; the starter tobacco products are also heavily sweetened and flavored.( 10)

The Addicting Chemical

Nicotine is a naturally occurring alkaloid present in the many strains of tobacco leaf cultivated to produce cigarettes. Because nicotine is a small molecule that is both lipid and water soluble, it is rapidly absorbed through the skin or lining of the mouth and nose. Rate of absorption is enhanced in a mildly alkaline environment and severely reduced in an acidic environment. Because of the massive area for gas exchange in the alveoli of the lungs, nicotine delivered by smoke inhalation is almost immediately extracted from the smoke and funnelled from the alveoli into the pulmonary veins; then It is pumped through the left ventricle of the heart into the arterial circulation where this highly concentrated wave of nicotine-laden blood reaches end organs such as the brain, in less than 10 seconds and is transmitted to the fetus of a pregnant woman via the umbilical artery. These arterial nicotine boll may be 10 times or more concentrated than the levels produced by use of nicotine polacrilex gum or nicotine transdermal patches.( 11) Smokeless tobacco products do not produce this explosive arterial bolus; however, smokeless tobacco users who repeatedly put fresh material, "pinches" or "pouches", into their mouth during the day can achieve relatively stable levels of nicotine that are higher than those typically observed in cigarette smokers.

Changes in Brain Structure and Function Due to Nicotine Exposure

Both animal and human studies have shown that chronic nicotine administration induces changes in the physical make-up of brain and other parts of the nervous system by stimulating the expression of excess nicotine receptors on neurons ("up-regulation"). Even prenatal exposure to nicotine can produce such nicotine receptor up-regulation.( 12) Postmortem studies of smokers have revealed elevated concentrations of nicotine receptors as well as other changes in brain tissue due to cigarette smoking.( 13-15) Such morphological changes in the nervous system are being investigated for their possible contribution to the development of nicotine tolerance and physical dependence.( 2, 16-18)

Nicotine also produces a wide range of changes in the function of the central nervous system, which include changes in brain metabolism and energy utilization in various regions similar to those produced by other addictive drugs, changes in spontaneous EEG, and changes in evoked electrocortical potentials.( 2) Functioning of the endocrine system is also altered markedly in ways that appear related to the addiction process.( 2, 19) These diverse physiological actions of nicotine appear to contribute to the addiction process by providing a variety of mechanisms by which behavior may be reinforced by tobacco use (e.g., control of mood, appetite, and attention, as well as avoidance of withdrawal symptoms that occur only because of physiologic changes produced by nicotine exposure).

Development of Dependence

Although the distinction between physiological dependence and psychological (or behavioral) dependence is useful heuristically and in the development of treatment protocols, the dichotomy is blunted upon closer analysis. For example, the subjective pleasure reported in studies and advertised by tobacco manufacturers is due, in part. to the physiological actions of nicotine in the brain. These actions, related to the dose of nicotine administered and the time since the last dose, can be blocked by chemicals that block the actions of nicotine in the brain, such as mecamylamine. Conversely, nicotine withdrawal symptoms include so called psychological symptoms, such as anxiety, irritability, and impaired cognition. These can be prevented or immediately reversed by administration of nicotine, and their magnitude is a function of time since the last nicotine dose and level of nicotine that the person had been taking up to the point of abstinence. Most people who smoke regularly have probably become dependent on nicotine, both physiologically and psychologically. The time course of development of addiction has not been well studied, but it is assumed to take at least several weeks to become physically dependent to nicotine.( 3) Many people continue to escalate their smoking rates over more than eight years.(20)

Physical Dependence

As discussed earlier, repeated exposure to nicotine leads to the development of tolerance and physical dependence. Tolerance of several types develope and contributes in different ways to the nicotine addiction process. Over time with chronic nicotine use, many of the physiological and behavioral responses to acute doses become blunted. Thus, the same dose of nicotine routinely inhaled by the smoker would have a much more profound effect in the non smoker; for example, many first-time smokers become ill ("green") and intoxicated for several hours. Upon rapidly smoking a cigarette, even the experienced cigarette smoker who has been deprived of cigarettes for several days may also experience some signs of acute toxicity, such as nausea and dizziness, indicating that some of the tolerance has been lost. It is extremely rare, however, in such persons to produce the level of sickness that is sometimes observed in first-time smokers. This appears to reflect both the experienced smokers' acquisition of tolerance and their experience in regulating their nicotine intake.

Within each day some degree of tolerance is lost overnight, such that the first cigarettes of the day are reported as the strongest and/or the best cigarettes. Over the course of the day tolerance increases, and the subsequent nicotine effects diminish. For example, the first few cigarettes of the day may produce a substantial increase in heart rate lasting for only a few minutes beyond the duration of the cigarette; thereafter, heart rate over the course of the day follows the same diurnal rhythm of nonsmokers and is elevated about seven beats per minute when compared to the heart rate of nonsmokers.( 2) These observations indicate that with nicotine as with other addicting drugs, tolerance development is only partial.

The withdrawal syndrome varies somewhat across tobacco users although certain symptoms are pervasive (e.g., cognitive impairment. Other symptoms are not part of the generally recognized syndrome of withdrawal but may be related to psychiatric co-morbidities; for example, people with histories of major depression may develop a deeper depression. During prolonged period of abstinence, most symptoms of nicotine withdrawal do not return to pre-abstinence levels until four to six weeks after cessation, and increased hunger and craving for tobacco may persist for 6 months or longer.(21,22) Nicotine-replacement attenuates the severity of withdrawal symptoms in abstinent cigarette smokers, confirming that tobacco smoke-produced nicotine arterial boll and sensory effects of smoking are not critical to the physical dependence process.

A clinically important but poorly understood feature of the nicotine withdrawal syndrome is "craving for tobacco." Cravings or urges to smoke cigarettes and use smokeless tobacco have been described, both clinically and theoretically, as major obstacles confronting tobacco users attempting to quit, and appear to be one of the most prominent symptoms of nicotine withdrawal.(23-25) The etiology of urges may vary. For example, both positively motivated ("pleasure seeking") and negatively motivated ("avoiding withdrawal") urges to use tobacco have been characterized.(26,27) Although craving is a widely discussed aspect of drug dependence in general, there is little direct evidence that suppressing craving with medications enhances quitting success.(28) One implication of this is that people given nicotine-replacement medication should not be told that the primary benefit will be to relieve their craving.

Reinforcing Effects

The reinforcing effects of tobacco use are often dichotomized into pharmacological (i.e., "nicotine") and nonpharmacological components, but these distinctions become blurred under scrutiny. For example, the pleasure derived from smoking may be modulated by the dose of nicotine taken, the time since the last dose, and actors such as social setting.( 2) Similarly, severity of the physiological withdrawal symptoms is a preabstinencee levels of nicotine intake and the environmental setting.( 2) Where the distinction may be most meaningful is in the of the nicotine dependence process. Presumably a variety of non pharmacological factors operate to sustain the nicotine self-administration over the days, weeks, or months that may be required for the effects of nicotine to become critical to addiction.( 2,29) Once the effects of nicotine become critical in the addiction process, the tobacco user appears to be "trapped" within a crude boundary of ideal nicotine requirements by the adverse effects that may accompany either too much or too little nicotine.(30) It must be kept in mind, however, that the boundary is broad. such that makers tend to change their smoking behavior to sustain plasma nicotine concentration within a broad range, but are not necessarily driven to sustain pinpoint dose control ("titration").( 2)

Cigarette smoking is a complex behavior that becomes powerfully conditioned by several types of biobehavioral mechanisms. To use a metaphor, the nicotine-addicted cigarette smoker may be viewed as a person held by many chains, some of which hold much more strongly than others. For some people, eliminating one or two of the chains is sufficient for them to break the addiction. This metaphor could be taken more lightly except for the fact that of the nearly 20 million people who attempt to quit smoking each year, less than 7% remain abstinent for a year; of those who do remain abstinent for a year, nearly 1/3 relapse thereafter!( 1)

Let us briefly review the ways that the behavior of the smoker becomes controlled. Through conditioning processes, sensory stimuli associated with the effects of nicotine become immediately and powerfully reinforcing to the user in their own right.( 2,31) These include the sight, feel, and taste of cigarettes, as well as the effects of various smoke constituents including nicotine in the mouth, nose, and throat.( 2,31) Environmental stimuli may come to signal the occasion for smoking, such as friends who smoke, the ringing of the telephone, tobacco advertisements, or a cup of coffee. In some people such stimuli do more than set the occasion; they elicit powerful urges, and these occur throughout the day even in the person who has been smoking throughout the day. Such effects of environmental stimuli have also been documented as important factors in addictions to heroin, cocaine, and alcohol.( 2,32)

Nicotine itself directly reinforces the behavior of tobacco smoking by the stimulation of nicotine receptors in the brain and, very likely, by activation of the ventral tegmental dopamine system, which also appears to be involved in cocaine addiction.( 2) Because such reinforcements occur hundreds of times per day and tens of thousands of times per year in people smoking a pack or more per day, the behaviors of seeking, lighting, and self-administering cigarettes become exceedingly entrenched. This behavior becomes conditioned both through positively and negatively driven reinforced. Specifically, the stimulation of nicotine receptors in the brain and the activation of the dopaminergic reward system appear to mediate the ability of nicotine to produce pleasurable effects and positive reinforcement. Such reinforcements "stamp in" nicotine self-administration in both humans and animals.( 2) It is plausible that cigarette smoke inhalation optimizes these reinforcing effects of nicotine because the arterial bolus of nicotine maximizes the rapidity and magnitude of the effects produced at brain nicotine receptors, as well as the release of hormones.( 2, 19)

Finally, nicotine administration provides relief of negative symptoms of withdrawal, which begin to emerge within a few hours alter the last cigarette. Nicotine gum and the transdermal patch systems reduce withdrawal symptoms, but with much less pleasure than is provided by smoke inhalation. Thus, the cigarette smoker, may get what is needed to avoid withdrawal with nicotine gum or patch, but not necessarily what is wanted with respect to pleasure and euphoria.( 2, 10)

In addition to the direct reinforcing effects of nicotine, the cigarette smoker has learned to live under the influence of a drug that has become functional in the modulation of mood, appetite, energy metabolism, as well as in the ability to deal with stress and boredom.( 2, 19) Others find that they no longer enjoy activities that have been important, such as socializing with friends who continue to smoke. Still others whose occupational demands mandate optimal performance find themselves (or at least perceive themselves) unable to perform to the best of their abilities or to the demands of their Job after they have quit smoking. Thus, the anecdotes abound of surgeons who devised their own nicotine patches prior to the commercial marketing of such systems, of fighter pilots removing their respirators to insert a fresh "chew" of tobacco, and of parents who stay at home with the children all day reporting that if they could not intermittently break for a cigarette. their children would suffer for it.

These diverse means by which the behavior of the tobacco user is controlled by nicotine administration and deprivation, as well as by nonpharmacological factors, are the reasons that multifaceted treatment strategies involving nicotine replacement are more efficacious than nicotine-replacement therapies given alone.( 2,33) The importance of nonpharmacologic factors is not unique to nicotine. The benefits of many medications (e.g., calcium channel blockers for heart disease, drugs for ulcers) are enhanced when appropriate behavior change takes place. Similarly, many medications, like nicotine replacement, can be powerful aids in establishing remission, but prolongation of remission may require a change in behavior that may be difficult. Thus, as is discussed elsewhere in this volume, Just as nicotine is only part of the tobacco addiction problem, nicotine-replacement therapy is only part of the solution. ( 2,33)

Nicotine Gum and Patch Systems Less Toxic and Addictive Than Cigarettes.

The scientific basis for answering two commonly asked questions about nicotine gum and patch has been at least partially provided by this review. The questions are: Are these therapies addictive? Do they cause heart attacks? With respect to addiction potential, nicotine gum and patch preparations are substantially lower in addiction potential than are cigarettes and smokeless tobacco. In brief, as we have seen nicotine gum and patch medications can stabilize mood, behavior, and physiological function while maintaining a generally lower level, of nicotine intake than was produced by smoking, thereby maintaining a relatively low level of physical dependence. This is accomplished without the highly toxic and addictive bullet-like arterial boli produced by smoke inhalation. Furthermore, these systems provide little of the sensory stimuli that also contribute to the strength of the addiction. Thus, the vast majority of users of these products stop using them, and only a minority of people who started using them use them much longer than was intended.( 10,34)

With respect to coronary artery disease, low-level nicotine administration is considered to be a risk factor; however, the benefits of replacement therapy appear to greatly outweigh the risks of unabated smoking in most people.( 2,34,35) In part, this is because when people do continue to smoke while using the replacement system, it would appear that most of them smoke less than they did before they started the therapy; they have also considerably decreased the frequency of arterial spikes of nicotine.(34,35) Another factor is that these nicotine-replacement systems do not deliver the carbon monoxide that also contributes to coronary artery disease and that is delivered in high levels by cigarette smoke inhalation. Finally, the actual incidence of heart attacks among people who have been prescribed nicotine transdermal patches has been found to be surprisingly low: Epidemiologic data would have predicted the occurrence of approximately 2,250 myocardial infarctions among the initial 3 million smokers who used patches during any 1.5-month period; in fact, only(33) "serious adverse cardiovascular events" were reported to the FDA during the first seven months that the transdermal patches were marketed.(35)

SUMMARY

The anatomy of nicotine addiction is complex, multifaceted, and varies somewhat from individual to individual; this perspective may help health professionals to better understand the severity of the addiction, and the challenges faced by people attempting to quit smoking. Quitting smoking is more than giving up a companion; it is more than learning to live without repetitive stimulation of nicotine receptors; it is learning a new way of living. Most people will have more time to live and learn than had they not quit, however.

Understanding that lasting morphological changes in the brain, as well as changes in the function of the brain and endocrine system, are produced by nicotine exposure also helps to explain why many people need repeated and long-term treatments. From this perspective, it can be seen that the addiction is no more eliminated when the nicotine is cleared from the body than is the pain and dysfunction of the trauma that snapped a leg bone over when the trauma is over. In both cases, physical healing may take weeks, months, or even years. In both cases, adjustments in behavior will be required. Finally, in both cases, medications and other aids may be essential if healing is ever to occur. It is possible that some people may require lifelong nicotine replacement therapy.(31) For most people, however, the wonder is that the marvelous ability of the body and behavior to heal and recover will eventually enable them to achieve freedom from tobacco and to reverse much of the damage incurred by their addiction.

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