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(Chest. 2000;117:360S-364S.)
© 2000 American College of Chest Physicians

Smoking Cessation*

Stephen I. Rennard, MD, FCCP and David M. Daughton, MS

* From the University of Nebraska Medical Center, Omaha, NE.

Correspondence to: Stephen I. Rennard, MD, FCCP, Department of Internal Medicine, University of Nebraska Medical Center, 600 S 42nd St, Omaha, NE 68198-5300; e-mail: srennard{at}mail.unmc.edu


   Abstract
TOP
 Abstract
Introduction
 Nicotine Addiction
 Smoking Cessation
 Nicotine Replacement
 Summary
 References
 
Cessation of cigarette smoking is the single most important therapeutic intervention that is effective in reducing the symptoms of COPD and in preventing its onset. Smoking cessation is, therefore, a major goal in efforts to mitigate the burden of this disease. This review will consider the pharmacologic and behavioral therapies that have been used to assist smokers in overcoming their addiction. These strategies assist a significant minority of smokers to stop smoking and, thus, they can have an important positive impact on COPD as well as on other health outcomes.

Key Words: COPD • nicotine replacement • smoking cessation


   Introduction
TOP
 Abstract
 Introduction
Nicotine Addiction
 Smoking Cessation
 Nicotine Replacement
 Summary
 References
 
Cigarette smoking is the most important risk factor leading to the development of COPD.1 In the developed world, smoking accounts for as much as 80 to 85% of cases of COPD. Although there is considerable variation among individuals in susceptibility to cigarette smoke,2 3 on the whole, as many as 15% of smokers will develop clinically symptomatic COPD. A larger number will manifest airflow limitation without clinically significant dyspnea. Moreover, symptoms of cough and sputum production can develop independently of airflow limitation.2 Smoking cessation, therefore, is the most important therapeutic intervention both to reduce symptoms in patients who manifest COPD4 and, more importantly, to prevent the development of COPD. In this regard, the Lung Health Study, a large, randomized, prospective clinical trial, clearly demonstrated that smoking cessation is associated with a modest improvement in lung function followed by a reduced rate of decline in smokers with mild COPD (Fig 1 ).5



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  		Figure 1. Lung function (FEV1) in a 5-year follow-up of smokers with mild COPD who quit and remained nonsmokers or who continued to smoke. Data are from the Lung Health Study. Reproduced with permission from Anthonisen et al.5

 

   Nicotine Addiction
TOP
 Abstract
 Introduction
 Nicotine Addiction
Smoking Cessation
 Nicotine Replacement
 Summary
 References
 
Current approaches to smoking cessation recognize that cigarette smoking is not a simple habit but, rather, is a complex physiologic addiction.6 7 The most important active compound in cigarette smoke contributing to addiction is nicotine. This alkaloid is produced by the tobacco plant as a means of chemical defense against insect predators via activation of cholinergic receptors, which leads to dysfunction of the insect nervous system. Receptors sensitive to nicotine, termed nicotinic receptors (as distinct from the other major class of cholinergic receptors, namely, muscarinic receptors), are also present in the mammalian nervous system.

The administration of nicotine is associated with a number of effects. Important among these is the generation of a euphoric sensation. In this regard, nicotine is believed to be active in a way that is similar to opioids, cocaine, and methamphetamine,8 with nicotine becoming active at a much lower dose. All these psychoactive compounds are believed to share some physiologic pathways.9 Specifically, release of dopamine by neurons originating in the ventral tegmental area and projecting to the nucleus accumbens is believed to be crucial for the action of these agents. Nicotine, like opioids and ethanol, increases the release of dopamine by these neurons through the alteration of neuronal activity. Amphetamines increase dopamine release by displacing dopamine from its storage granules, and cocaine can inhibit dopamine reuptake. Once released, dopamine acts on dopaminergic receptors located on the postsynaptic neurons.

Several lines of evidence suggest that smokers vary in their underlying genetic susceptibility to becoming addicted smokers. Studies of twins show a higher concordance for smoking among same-sex monozygotic twins than in same-sex dizygotic twins.10 11 12 13 In addition, several candidate genes, including polymorphisms, in dopamine metabolism have been associated with smoking behavior.9 A known mutation in the P450 oxidase CYP2A6, which normally metabolizes nicotine, results in a marked decrease in nicotine metabolism. Individuals with a known mutation are much less likely to become smokers and, if they do smoke, they are likely to smoke significantly fewer cigarettes.14 While these studies have not yet led to specific therapeutic approaches to achieve smoking cessation, they do provide evidence that smoking is a heterogeneous disorder.

In addition to the euphoric effects of nicotine, smokers likely derive additional perceived benefits through the psychoactive properties of nicotine. These benefits include both an antidepressant effect15 and possibly an ability to enhance task performance,16 particularly for tasks requiring memory and attention in relatively unstimulating circumstances. Some of the antidepressant effects associated with smoking, for example the inhibition of monoaminoxidase activity, appear to be due to factors in cigarette smoke other than nicotine.17

Taken together, the actions due to nicotine may represent significant benefits for some smokers, and their loss may represent a significant problem for some smokers wishing to quit. In addition, nicotine is clearly an addicting substance. Nicotine withdrawal is associated with a well-described syndrome characterized by irritability, awakening from sleep, bradycardia, anxiety, impaired concentration, impaired reaction time, restlessness, drowsiness, impotence, confusion, hunger, weight gain, and, consistent with nicotine’s actions as an antidepressant, with depression.18

In addition to the biological basis of nicotine addiction and cigarette smoking, environmental cues can be very important. In this regard, cigarette advertising, the general perception of smoking by family and peers, and the availability of cigarettes can all effect smoking initiation.7 19 20 21 22 As might be expected, the presence of other smokers in the household and in the immediate environment can prove to be a problem for a smoker wishing to quit. Conversely, appropriate social support can be a significant advantage in aiding cessation.


   Smoking Cessation
TOP
 Abstract
 Introduction
 Nicotine Addiction
 Smoking Cessation
Nicotine Replacement
 Summary
 References
 
Smoking cessation efforts fit into two broad categories: pharmacologic and behavioral.6 Pharmacologic approaches currently include two general strategies: nicotine replacement and bupropion therapy.

As noted above, nicotine is associated with psychoactive effects that may be perceived as beneficial by the smoker. As with other psychoactive drugs, the potency of nicotine depends both on the levels of nicotine in the brain and on the rate at which they rise.23 Smoking is a particularly effective means of delivering a psychoactive drug. Nicotine, for example, is lipid soluble and crosses rapidly from the inhaled air into the pulmonary capillary blood. It then transmits directly into the arterial blood and to the brain. As a result, rapid peaks in nicotine level are achieved following smoking. These are believed to be associated not only with the psychoactive effects of nicotine, but also with the reinforcement required for developing and maintaining addiction. Withdrawal symptoms, in contrast, appear to depend, at least in part, on steady-state nicotine levels. In this regard, following the inhalation of cigarette smoke nicotine levels initially fall through redistribution and then more slowly, over hours, through metabolism.


   Nicotine Replacement
TOP
 Abstract
 Introduction
 Nicotine Addiction
 Smoking Cessation
 Nicotine Replacement
Summary
 References
 
These pharmacokinetic effects underlie the concept of nicotine replacement as an aid to smoking cessation, providing that steady-state levels of nicotine can prevent a smoker from experiencing intense withdrawal while not providing the reinforcing peaks achieved with smoking. Smokers can, therefore, achieve abstinence by dealing with the various behavioral aspects of smoking. Once abstinence is achieved, the smoker can taper off nicotine by gradual reduction.

There are currently four formulations of nicotine that are available for replacement therapy (gum, patch, inhalers, and nasal spray), which have been reviewed elsewhere.24 25 26 27 28 29 30 31 32 As might be expected, these forms of partial nicotine replacement therapy do not completely eliminate withdrawal symptoms,6 although in large clinical trials a reduction in symptom intensity has been reported.33 Importantly, nicotine replacement can increase quit rates,6 approximately doubling quit rates compared with placebo.34

The availability of several modes of nicotine replacement permits the clinician to adjust treatment for individual preference. While available data are limited, there may be some advantages for combined modalities of nicotine replacement in selected individuals.35 36 Of the formulations available, the transdermal nicotine patch has the slowest rate of nicotine delivery (Table 1 ). Perhaps for this reason, it may have the lowest addiction potential. Both the nicotine gum and the inhaler depend on nicotine absorption across the buccal mucosa. Despite a rate of nicotine delivery that is slower than that with smoking, nicotine addiction can be sustained with the gum37 38 and, possibly, with the inhaler. It seems likely that the nasal spray, by virtue of its more rapid nicotine delivery and absorption across the nasal mucosa, also will be able to sustain a nicotine addiction. Whether these modes of delivery will represent an addiction potential in their own right remains to be determined.


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  		Table 1. Pharmacokinetics of Forms of Nicotine Replacement Therapy

 
Bupropion
Bupropion is an antidepressant, active on dopaminergic pathways in the CNS. An empiric observation that depressed smokers using bupropion lost their craving for smoking led to two large randomized prospective clinical trials,39 40 and, subsequently, to the approval of bupropion for use as an aid to smoking cessation. In one of the clinical trials, bupropion was combined with nicotine replacement therapy via a transdermal system, and the combination had the highest quit rates.40 Bupropion has some risk of precipitating seizures, particularly in individuals with an underlying seizure disorder or bulimia and should be used with caution. Nevertheless, bupropion may be a particularly attractive alternative for smoking cessation in some individuals.

Behavioral Therapy
A variety of behavioral approaches are available to aid smokers in quitting.6 41 These approaches range from very brief interventions to extensive programs conducted by specialized counselors. A series of meta-analyses suggest that quit rates increase within an increasing intensity of the intervention6 and that several sessions of >= 10 min will optimize benefits (Fig 2 ). The most aggressive programs, in general, achieve quit rates of approximately 20%, and, as noted above, these quit rates can be further augmented by the addition of pharmacologic therapy. High quit rates achieved by intense programs may reflect a selection bias. Only a minority of smokers who accept a referral to such programs will actually attend.42 As a result, many practitioners may have become discouraged with referrals for smoking cessation. A minimal intervention that can be conducted in the course of a routine office visit is generally regarded as a much more appropriate first-line intervention. The National Cancer Institute recommends the program of "four As": Ask about smoking; Advise about smoking cessation; Assist with smoking cessation intervention; and Arrange for follow-up. This is recognized as a readily implemented and effective program in a general-practice setting.43



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  		Figure 2. Smoking cessation rates as a function of intervention. Data are adapted from Agency for Health Care Policy and Research guidelines.6

 

   Summary
TOP
 Abstract
 Introduction
 Nicotine Addiction
 Smoking Cessation
 Nicotine Replacement
 Summary
References
 
Smoking cessation is generally regarded as a health-maintenance activity. The clinician may be able to exploit windows of opportunity in which smoking cessation interventions are much more likely to be effective. Data are emerging that acute health problems are associated with increasing cessation rates.43 44 45 46 A reasonable assumption is that this may be due to an increased motivation to quit that is related to concurrent health status. Even with modest smoking cessation rates, however, intervention in the course of routine practice, because of the high prevalence of smoking and its high association with significant disease, can have a major impact on public health.

Currently available smoking-cessation methodologies can assist a significant minority of smokers in quitting. Ongoing studies designed to understand the nature of nicotine addiction hold a promise both for more individualized treatments and treatments exploiting additional pathophysiologic mechanisms. The currently available therapies, however, are appropriate for use in routine practice and can have a positive impact on health outcomes.


   References
TOP
 Abstract
 Introduction
 Nicotine Addiction
 Smoking Cessation
 Nicotine Replacement
 Summary
 References
 

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