CHAPTER •••

21 : :., .. Nicotine Use ••• Disorder

Nicotine addiction from cigarette smoking and smokeless tobacco use is the most prevalent form of chemical dependence in the United States. Cigarette smoking is the primary preventable cause of morbidity and mortality in the United States: an estimated 434,000 premature deaths each year are attributed to smoking-related illnesses, and 50,000 additional deaths of nonsmokers to exposure to environmental tobacco smoke. Smoking causes 90% of all lung cancers and 80% to 90% of all chronic obstructive pulmonary diseases and correlates with a two times greater than average risk of death from stroke and coronary heart disease. Smoking is also associated with increased incidences of cancer at a number of extra pulmonary sites, including the larynx, oral cavity, esophagus, cervix, bladder, pancreas, and kidneys, and with complications of pregnancy and negative effects on the fetus, including low birth weight.

COMORBIDITY

Nicotine dependence and smoking are more common in persons with comorbid psychiatric disorders than in the general population.': 2 Some 55% to 90% of those with psychiatric disorders smoke, as compared with approximately 25% of the general population. The prevalence of smoking is especially high in persons with schizophrenia, those with affective disorders, and those with alcoholism or other substance use disorders. There is also

270

evidence that affective, anxiety, and substance use disorders may be more common in smokers than in those who do not or who have never smoked.f Finally, there is evidence that as many as 75% of smokers with a history of major depressive disorder acquire depressed mood during the first week of withdrawal, as compared with only 30% of smokers with no depressive history, and that the withdrawal syndrome may be more severe in smokers who have a history of depression." The presence of depressive symptoms during withdrawal is also associated with failed attempts at quitting.v " Several studies suggest a genetic predisposition to both nicotine dependence and intercurrent depression.P: 7

ETIOLOGY AND PATHOPHYSIOLOGY

Nicotine, the primary psychoactive agent in tobacco smoke and smokeless tobacco, has powerful addictive properties." One third to half of all children and adolescents who smoke one cigarette progress to become habitual users. Some consider nicotine to be a "gateway drug" to the use of other substances, and it is the first substance used by a large majority of alcohol and substance abusers." Nicotine is readily absorbed in the lungs from tobacco smoke or, with smokeless tobacco, through the mucous membranes. Nicotine enters the bloodstream and is available to the brain within 7 to 9 seconds (sooner than when administered

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intravenously). Its peak effect occurs within 1 minute, and effects are present after a single puff of smoke. With a half-life of approximately 2 hours, the level of nicotine in the bloodstream gradually accumulates during the day, dropping but persisting overnight.

Nicotine has a multitude of effects. It acts in two principal areas of the brain-the mesolimbic dopaminergic system, which is related to the euphoriant effects of the drug, and the locus ceruleus, which mediates stress reactions and vigilance and relates to the higher mental and cognitive functions. There are specific nicotine receptor sites (the nicotinic cholinergic receptors) throughout the central nervous system in the hypothalamus, hippocampus, thalamus, midbrain, brain stem, and cerebral cortex. In addition, nicotine affects nearly all aspects of the endocrineneuroendocrine system, including the catecholamine, serotonin, corticosteroid, and pituitary hormones. Its endocrine effects are mediated via the hypothalamic-pituitary axis and the adrenal medullary cortex. Centrally it causes release of acetylcholine, norepinephrine, serotonin, dopamine, vasopressin, growth hormone, corticotropin, cortisol, prolactin, and ~-endorphins.

Nicotine has stimulant and depressive effects on both the central and the peripheral nervous systems. It also affects the cardiovascular system (increased heart rate and blood pressure), gastrointestinal system, and skeletal motor system. Nicotine alters brain metabolism and stimulates the peripheral cholinergic nervous system (sympathetic and parasympathetic). Through this variety of central and peripheral actions, nicotine improves mood and decreases anxiety, decreases distress in response to stressful stimuli, and decreases aggression; improves overall cognitive function and performance (improves reaction time, concentration, vigilance, and stimulus-processing capacity); and decreases the appetite for simple carbohydrates, decreases stress-induced eating, and increases resting metabolic rate.

Nicotine is a highly addictive substance that causes physical and psychological dependence similar to that of opiates and other substances of abuse. 10-12 It is powerfully reinforcing, leading to compulsive use. 13 Effects are

Chapter 21 • Nicotine Use Disorder 271

related to dose, and tolerance to its actions develop rapidly, resulting in increased intake. Smokers adjust smoking behavior to regulate and maintain the level of nicotine in the bloodstream. A withdrawal syndrome develops in response to reduced intake or total abstinence and involves both physiological and psychological symptoms." Withdrawal symptoms overlap with those of alcohol and other substances of abuse. 14 In addition to the physiologically addictive aspects of nicotine, smoking is strongly conditioned to cues in the environment.

COURSE AND NATURAL HISTORY

Smokers who attempt to quit are at high risk of relapse. The relapse curve parallels that for opiates: 65% of those who stop smoking relapse in 3 months and another 10% in 3 to 6 months. The relapse rate is 80% by 1 year.

Fewer than 25% of smokers who quit are successful on their first attempt. Repeated failures are common before successful abstinence is achieved: the average smoker attempts cessation two or three times before succeeding.

Withdrawal symptoms are most severe within the first 1 to 3 days of abstinence, often continue for 3 to 4 weeks, and in some persons last 6 months or longer. Current depressive symptoms and a history of depression are predictors of relapse. Weight gain may also contribute to relapse, particularly in women. In contrast, several factors have been found to predict success at smoking cessation. These predictors include individual factors, manifestations of the addiction such as severity of withdrawal symptoms, and social and environmental circumstances.

Treatment of nicotine addiction with resultant abstinence can result in very beneficial health effects. Short-term effects (within a month) include a significant reduction in respiratory symptoms and infections such as influenza, pneumonia, and bronchitis. Excess risk of death from coronary heart disease is reduced after 1 year and continues to decline over time. In patients with coronary heart disease, smoking cessation decreases the risk of recur-

272 Section V • Adult Psychiatric Disorders

rent myocardial infarction and cardiovascular death by 50%. After 10 to 15 years of abstinence, the mortality rate from all causes returns to that of a person who never smoked. Pulmonary function can also return to normal if chronic obstructive changes have not already occurred at the time of cessation.

TREATMENT

The general approach to the treatment of nicotine dependence must be viewed as having three primary components: physiological, psychological, and behavioral. The physiological dependence parallels the characteristics of other physiologically addicting substances: compulsive use, dose-related effects, rapid tolerance leading to increased intake, and a withdrawal syndrome. Psychological dependence involves the reasons a person smokes, for example, to regulate affect, to improve mood and sense of well-being, to satisfy craving, and to provide stimulation and relaxation. The behavioral component involves environmental and social cues that become associated with smoking cigarettes, for example, drinking coffee or alcohol, talking on the telephone, taking a work break, or smoking at parties or social functions. The direct beneficial effects of nicotine, for example, on mood become highly positive reinforcements, as do the associated behaviors or activities, which can act as powerful triggers for relapse during attempts at quitting.

Four different approaches with different foci have been used for pharmacological treatment of nicotine addiction (Table 21-1). Of the

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Blockade therapy (antagonist administration) Nonspecific attenuation therapy

Deterrent therapy

four pharmacotherapeutic interventions, nicotine replacement is most widely used. Nicotine replacement is also indicated for extreme physiological dependence.

The substituted nicotine initially prevents significant withdrawal symptoms, which could lead to relapse during the early period of smoking cessation. The dose is then gradually tapered until nicotine is discontinued. Replacement produces a lower overall plasma level of nicotine than that experienced from smoking. Not only does replacement avoid the strongly reinforcing peaks in plasma level, but it also prevents emergence of withdrawal symptoms by maintaining the nicotine plasma level above a threshold.

The second pharmacological approach to treating nicotine addiction involves blockade therapy or antagonist administration. The advantage of this approach over nicotine replacement is that it does not continue the reinforcing effects of nicotine or maintain exposure to its potentially damaging effects. Several agents have been used, but mecamylamine, which has central and peripheral blockade effects, is the only agent shown presently to be effective. Although mecamylamine initially increases smoking behavior by decreasing the effective level of nicotine available from smoking, overall, it mitigates the reinforcing properties of nicotine.

The third pharmacological approach involves nonspecific attenuation therapy. In this approach, a pharmacological agent is used to mitigate abstinence symptoms in a manner similar to the use of clonidine to reduce withdrawal symptoms of opioid dependence. The agent most commonly used has been clonidine, in both oral and transdermal forms. Clonidine is an antihypertensive drug with central sympatholytic activity.

Antidepressants have been used in attempts to attenuate withdrawal symptoms, to treat or prevent emergent depressive symptoms or episodes in the early phase of cessation, and to prevent relapse of depressive episodes in patients with a history of depression. Antidepressants may provide significant benefits in special populations of patients with current or prior major depression or dysthymic

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disorder or with current depressive symptoms when these factors predict a poor outcome. Because negative affect is the most common antecedent of a smoking relapse, this approach appears promising. If antidepressants are used, pretreatment is necessary because the benefit of the medication may not be apparent for 1 to 3 weeks.

The fourth pharmacological approach to treating nicotine dependence and withdrawal is deterrent therapy or use of a drug to produce an aversive effect when nicotine is used, similar to the use of disulfiram (Antabuse) for alcohol dependence. The primary drug used has been silver acetate in a gum or lozenge preparation. If a cigarette is smoked, sulfite salts are produced when silver acetate contacts the sulfides in tobacco smoke, producing an unpleasant taste. Unfortunately, there is not an acceptable preparation because the existing gum has a short duration of action.

Combined or serial pharmacotherapeutic approaches may also be beneficial, especially in more difficult to treat cases of nicotine addiction. Examples of such combinations include the following:

• Nicotine replacement (gum and/or transdermal) combined with clonidine to cover any emergent withdrawal symptoms (no controlled studies of this approach exist presently)

• Pretreatment with an antidepressant followed by the use of nicotine replacement to cover acute withdrawal symptoms

• Pretreatment with an antidepressant, with clonidine added for acute withdrawal symptoms

In addition to pharmacological approaches, an incredible variety of psychosocial interventions has been developed to help people quit smoking. A number of the more commonly used psychosocial treatments are reviewed in Table 21-2. Psychosocial interventions, particularly behavioral therapy, have been shown to increase abstinence rates significantly.

Chapter 21 • Nicotine Use Disorder 273

• Psychological Interventions for the Treatment of Nicotine Addiction

Self-help

Brief advice from the physician Nicotine fading

Aversive techniques Cognitive-behavioral therapies Social support

Hypnosis

Acupuncture

SPECIAL CONSIDERATIONS IN mEATMENT: PSYCHIATRIC COMORBIDITY

The prevalence of smoking is much greater in psychiatric patients than in the general population. Psychiatric patients also are generally much less likely to be able to stop smoking. The strongest association of smoking is with schizophrenia. Several reasons for this powerful association have been postulated, including the effect of nicotine in decreasing drug-induced side effects and in increasing dopamine in the frontal and prefrontal brain areas, which could positively influence negative symptoms or improve prefrontal cognitive function.

Both epidemiological studies and studies of clinical populations have found a strong association between smoking and depression. There is a higher lifetime prevalence of major depressive disorder in smokers than in nonsmokers. Furthermore, persons with a history of depression and those currently experiencing a major depressive disorder have higher prevalences of cigarette smoking than patients with no history of major depressive disorder. Finally, smokers with a history of major depressive disorder experience a much greater frequency of this disorder and increased severity of depressive symptoms occurring during cessation. Depression is also associated with increased risk of relapse and difficulty maintaining abstinence.

An 80% to 90% rate of smoking has also been found in persons with active alcoholism.

274 Section V • Adult Psychiatric Disorders

Some data suggest that smokers with alcoholism may be more behaviorally, but not physically, dependent on nicotine than are other smokers. In addition, it appears that successful smoking cessation in persons with active alcoholism is much less likely than in individuals recovering from alcoholism, whose cessation rate is similar to that for the general population of smokers.

Clinical Vignette

A 32-year-old married, man, Mr. N, consulted his internist and stated that he wished to stop smoking but had been unable to do so on numerous prior attempts. During the past 2 years, he had twice tried to quit "cold turkey" and was able to abstain from smoking for only 2 days before starting again. During these periods of. abstinence, he. experienced severe nicotine withdrawal symptoms, including irritability, insomnia, restlessness, and trouble concentrating that interfered with his ability

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couragement and feedback on how his cessation attempt was progressing.

After stopping smoking, Mr. N experienced minimal withdrawal symptoms and was supported in his cessation effort by his wife. His work performance did not suffer significantly. The dose of the .. transdermal patch was reduced from 21 fig during the first month to

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References

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10. TIl tic M SE

11. H. or

12. JE m B

Chapter 21 • Nicotine Use Disorder 275

10. The Health Consequences of Smoking: Nicotine Addiction: A Report of the U.S. Surgeon General. Rockville, MD: Office on Smoking and Health. U.S. Public Health Service; 1988. DHHS publication CDC 88:8406.

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