PSYCHOPHARMACOLOGY
The observation is not recent nor unique to nicotine that abused drugs may provide their users with effects that are clinically useful, or at least users perceive the effects to be beneficial. In fact, most abused drugs have been used in the practice of medicine. For example, opioids continue to be important in pain control, sedatives are helpful in treating anxiety, and stimulants are valuable in treating narcolepsy. Nonetheless, the diverse psychopharmacological actions of abused drugs have long been understood to be important in the etiology and maintenance of drug dependence (74). The abuse liability of a drug that can directly activate neurological mechanisms of reinforcement would appear to be enhanced by its potential to also provide some sort of benefit, even if the long-term consequences of the substance abuse tend to be disastrous. Some of the apparent benefits of drug exposure may be most appropriately conceptualized as reflecting the reversal of withdrawal symptoms, whereas other benefits may be direct effects of drug administration.
Effects That May Contribute to Chronic Use
As discussed earlier, nicotine administration and withdrawal have diverse effects on brain and endocrine function that may be of functional significance in the etiology and treatment of psychiatric and neurological disorders such as affective disorders, Alzheimer's and Parkinson's diseases, Tourette's syndrome, and maintenance of cognitive function (39, 53). Regarding Parkinson's disease, an analysis of 17 studies supports the conclusion that cigarette smoking provides a weak protective effect (53). There is little evidence that nicotine is an effective treatment for the disorder, or even that the protective effect is specific to nicotine, but the relationship is intriguing and has generated new research on 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.
Cognitive Effects
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).
Vulnerability and Psychiatric Comorbidities
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.
TREATMENT
The basic principles of nicotine-dependence treatment are the same as those of other drug abuse treatment, discussed elsewhere in this volume. These include the use of behavioral techniques and medications to reduce or eliminate drug use, alleviate withdrawal symptoms, and prevent relapse. A difference in the population of tobacco users from other drug abusers should be considered because of its implications for understanding the etiology and treatment course; that is, epidemiological information suggests that most tobacco users are employed, well adjusted in society without legal problems, and highly motivated to quit. These factors are prominent correlates of success in the treatment of abusers of other drugs (40, 74), and attention to these factors is a major, if not the primary, target of treatment efforts for them but is probably less important for treatment of most tobacco-dependent persons.
The often severe consequences of untreated nicotine dependence have been important stimuli for the search for more effective treatments. Making effective treatments more widely available is vital, particularly because cancer chemotherapy, surgery, and other medical treatments for tobacco-caused diseases are often less efficacious and are invariably far more toxic than nicotine-dependence treatments that may prevent the development of these disorders. Helping people achieve abstinence is also important from the perspective of containing health care costs because cessation at any age reduces the risk of most forms of tobacco-caused morbidity as well as mortality (76). For example, in 1993 the U.S. Office of Technology Assessment reported to the U.S. Congress that tobacco-attributable health care costs were 68 billion dollars in 1990 and that these costs could be reduced by more effective treatment and prevention.
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.
Diagnostic Advances
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 Treatment Strategies
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).
Pharmacological Treatment Strategies
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.
Nicotine Replacement Therapy: Clinical Issues
Mechanism of Action and Limitations
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.
Rational Basis for Dosing
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.
Efficacy of Nicotine Replacement
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.
Dependence Potential
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).
SUMMARY AND CONCLUSIONS
The pathophysiological consequences of tobacco use produce changes in body tissues that contribute to heart disease, cancer, respiratory diseases, and dependence. These disorders are not inevitable consequences of tobacco exposure, but tobacco exposure is a causal factor in their etiology. Approximately one in three adolescents who smoke a few cigarettes develop nicotine dependence; of these, approximately one in three die of tobacco-related disease. Thus, the relationship between tobacco exposure and death is not unlike that seen with other pathogens such as Mycobacterium tuberculosis, in which approximately one in ten carriers of the bacteria develop tuberculosis disease. Among the disorders resulting from tobacco use, dependence is unique because its primary manifestation is behavioral; this has implications for treatment that were discussed.
Understanding of the pathophysiological basis of tobacco dependence has progressed as rapidly as the understanding of cancer and other tobacco-related disorders. The pathophysiology of nicotine dependence includes tolerance development, receptor up-regulation, physiological dependence, and reinforcing effects, as well as the many other effects of nicotine on behavior and physiological functioning. The reinforcing effects of nicotine, in turn, are related to the method of nicotine delivery. Genetic constitution appears to contribute to the vulnerability to nicotine dependence as well as to the vulnerability to comorbid disorders.
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