Tobacco use is the leading preventable cause of morbidity and mortality in the United States. Approximately 440,000 deaths each year are attributed to smoking. It is the most common cause of cancer-related deaths in this country, including deaths from lung cancer, laryngeal cancer, esophageal cancer, oral cancer, and bladder cancer. Tobacco use is also a leading cause of heart disease, stroke, and chronic obstructive pulmonary disease. Research suggests that tobacco use results in more than $157 billion in annual health-related costs.

Definition

Nicotine dependence is characterized by both tolerance and withdrawal symptoms in relation to nicotine use. Nicotine dependence can occur with cigarette smoking, smokeless tobacco use, cigar or pipe use. For the purposes of this chapter, the phrases “quitting smoking” will be used to represent complete abstinence from tobacco products, and “success” will be used to represent lifetime abstinence.

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Prevalence and risk factors

Fifty-five percent of Americans have tried smoking. Approximately 22.8% of Americans are current smokers and 30% are ex-smokers. The rates of smoking in the general U.S. population decreased from nearly 42% in 1965 to just over 25% in 1990, but the rate of decline has slowed markedly since 1990. Approximately 20% of all Americans meet criteria for nicotine dependence at some point in their lives. Among smokers, 50% to 80% are estimated to meet criteria for nicotine dependence.

Nicotine dependence is more prevalent in persons with mental disorders, especially mood disorders and schizophrenia. According to DSM-IV-TR, 55% to 90% of those with a mental disorder smoke compared with 22% of the general population.

In 2001, 25.2% of U.S. males and 20.7% of females were smokers. There appear to be genetic factors that contribute to nicotine dependence; the risk for those with a first-degree relative who smokes is three times that of those in a family of nonsmokers. In children, depressed mood, poor grades, and antisocial behavior correlate with smoking rates, but the effects of modeling by peers and family are also likely to be critical factors.

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Pathophysiology

From the first use of nicotine, physical effects increase the likelihood of repeated nicotine consumption. Nicotine binds to cholinergic receptors in the central nervous system. In response to repeated nicotine use, the receptors rapidly desensitize and increase in numbers, and both these phenomena conspire to increase the addictive power of nicotine. Dopaminergic neurons within the nucleus accumbens (a brain structure associated with rewards and reinforcement) are activated by projections from nicotine-stimulated neurons. Cell bodies in the ventral tegmental area (a structure associated with perception and modulation of pleasure) are stimulated directly by nicotine and these neurons project directly to the nucleus accumbens (NAcc). As a result of the widespread neuronal activation, nicotine users experience pleasure, reduced fatigue, increased information-processing ability, reduced anxiety, and other reinforcing effects.

Tolerance develops as the frequency and dose of nicotine use increase. Increasingly desensitized cholinergic receptors on neurons projecting to the NAcc are quickly produced (upregulated) to compensate for the actions of nicotine on the brain. The release of dopamine in the NAcc falls as these desensitized neurons fail to produce the necessary baseline stimulation without the presence of sufficient concentrations of nicotine. Withdrawal symptoms occur when the concentration of nicotine fails to maintain stimulation of the ventral tegmental area and the NAcc. These effects are mediated by increases in noradrenergic outflow from the locus coeruleus and other areas.

Nicotine withdrawal is defined by the DSM-IV-TR as a condition in which a person, after using nicotine daily for at least several weeks, exhibits at least four of the following symptoms within 24 hours after reduction or cessation of nicotine use:

1. Dysphoric or depressed mood
2. Insomnia
3. Irritability, frustration, or anger
4. Anxiety
5. Difficulty concentrating
6. Restlessness
7. Decreased heart rate

Smoking increases the metabolism of several medications, including cyclobenzaprine, naproxen, verapamil, propranolol, and warfarin. Conversely, the blood levels of these medications may increase when smoking cessation is attempted.

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Signs, symptoms, and diagnosis

The first step in treating nicotine dependence is identifying tobacco users. Practice guidelines for nicotine dependence include those from the American Psychiatric Association and the U.S. Department of Health and Human Services. These guidelines suggest asking patients systematically at each visit whether they use tobacco. This question should be part of an expanded vital signs assessment or in a computer reminder system that is part of the electronic medical record. There is strong evidence that documenting smoking status at every visit increases clinician recognition of nicotine dependence and intervention. The criteria for diagnosis of nicotine dependence follow those for other forms of substance dependence.

The following are DSM-IV-TR criteria for diagnosis of nicotine dependence:

The user must demonstrate at least three of the following criteria occurring at the same time during a 12-month period:

1. Tolerance—Signs of tolerance are a need for a markedly increased amount of nicotine to produce the desired effect or a diminished effect with continued use of the same amount of nicotine.
2. Withdrawal, as manifested by either the characteristic nicotine withdrawal syndrome, or nicotine (or a closely related substance) is taken to relieve or avoid withdrawal symptoms.
3. Nicotine is used in larger amounts or over a longer period than intended.
4. The user has a persistent desire or makes unsuccessful attempts to cut down on tobacco.
5. A great deal of time is spent in obtaining or using the substance (e.g., chain smoking).
6. Important social, occupational, or recreational activities are reduced because of tobacco use.
7. Use of the substance continues despite recurrent physical or psychological problems caused or exacerbated by tobacco—for example, continuing to smoke despite diagnoses such as hypertension, heart disease, cancer, bronchitis, and chronic obstructive lung disease.

Once a diagnosis of nicotine dependence is made, it is useful to characterize the degree to which the patient is physically dependent on smoking. The Fagerström Test for Nicotine Dependence (FTND) (Table 1 ), can be helpful in determining whether nicotine replacement will be necessary and to what degree. The six-question FTND deals with total tobacco intake and craving severity.

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Management

Psychosocial Interventions

Primary care physicians are likely to be most effective in using brief interventions and providing advice and/or prescriptions for pharmacologic interventions. They may also be an important link in providing patients with referrals to more intensive counseling programs and additional education.

Brief Interventions for a Primary Care Setting

“Minimal/brief” interventions require little cost and/or time from the intervener. There is strong evidence that patients who are consistently advised by health care providers to quit smoking are more likely to take steps to stop. Decision trees (Fig. 1) can be helpful in guiding providers through smoking-cessation counseling with patients.

Interventions as short as 3 minutes may substantially increase cessation rates. One common brief intervention designed for health care providers is the “5 A” method, which involves the following:

1. Asking about tobacco status at each visit
2. Advising all tobacco users to quit
3. Assessing the patient's willingness to quit
4. Assisting the patient in quitting
5. Arranging for follow-up contact

Providers can assess a patient's readiness to quit using the transtheoretical model of behavior change. If the patient has not thought about quitting or is considering quitting but not in the next few months, they are in the Precontemplation/Contemplation stage. At this stage, the provider can use motivational interviewing skills to help increase readiness for cessation.

Health care providers can use the “5 Rs” to help enhance a patient's motivation to quit:

1. Discuss why quitting is personally relevant.
2. Identify potential risks associated with smoking.
3. Identify potential rewards and benefits related to quitting.
4. Identify potential barriers or roadblocks that might impede the quitting process.
5. Repeat motivational interventions at each visit.

In general, patients at this stage are unlikely to benefit from advice-giving as much as a non-threatening discussion of what is keeping them from quitting at this time.

Patients who have made plans to quit or who are in the process of quitting are in the Preparation/Action stage. These are the patients who will most benefit from brief interventions such as:

1. Helping the patient identify a “quit date”
2. Asking the patient to elicit support from friends and family
3. Having the patient write down the reasons for quitting or coping strategies
4. Having patients remove tobacco products from their environment
5. Discussing coping strategies such as replacements (sugar-free gum, water) and distraction (keeping busy, exercising)
6. Referring the patient to an intensive smoking cessation counseling program
7. Providing the patient with advice about nicotine replacement and/or discussing use of bupropion as a cessation aid.

Relapse prevention is important for patients in the maintenance stage (those who have quit smoking). Providers at this stage can educate individuals in issues important in preventing relapse, such as being aware of the potential impact of stressful events. In patients who have never smoked, providing reinforcement and encouraging continued abstinence can be effective strategies for prevention. In patients who have relapsed, it is important to deflect guilt and self doubt with reminders about the frequency of relapse and the need for a renewed commitment to abstinence. Consistently working with patients on smoking cessation increases the chances of success.

Primary care physicians may also choose to refer their patients to intensive counseling programs for smoking cessation. “Intensive” interventions are recommended by national guidelines as effective treatments and refer to specifically tailored educational programs involving repeated face-to-face contact in an individual or group setting and including a psychotherapy component. More intensive programs appear to generate better outcomes. Intensive programs help patients cope with nicotine withdrawal through a number of behavioral strategies including using social supports, relaxation training, and cognitive restructuring.

Medical Options

National guidelines recommend that pharmacologic therapy be considered for all smokers attempting to quit unless medically contraindicated. Pharmacologic interventions include nicotine replacement strategies and antidepressant treatment.

Nicotine Replacement Therapies.

Nicotine replacement therapies (NRTs) work by delivering nicotine into the body to ease withdrawal while allowing the smoker to break the behavioral habits associated with the cigarette itself. The fact that 50% of all quitters report withdrawal symptoms makes clear the value in reducing or eliminating the likelihood that these symptoms will impair a quitter's ability to remain abstinent. Behavioral counseling (either brief or intensive) is an important adjunct to any pharmacologic intervention for smoking cessation.

Nicotine gum is available in 2-mg and 4-mg pieces and is sold without a prescription. Patients must be instructed to soften the gum and “park” it between the cheek and gum rather than chewing it. Chewing the gum continuously or drinking acidic beverages will reduce nicotine absorption. Advantages include rapid absorption of nicotine with resultant reduction in withdrawal symptoms.

Nicotine patches have the advantage of a delivery system that maintains nicotine levels throughout a longer period than any other system. Patches are designed to deliver nicotine transdermally over a 16- or 24-hour period. The most common side effects are rash and insomnia. Switching from 24-hour to 16-hour release systems can often solve sleep problems associated with longer-release patches. Patients usually use patches at a steady dose daily for 6 to 12 weeks, then taper slowly over an additional 6 to 12 weeks. Nicotine nasal sprays, inhalers, and lozenges are also available.

Bupropion hydrochloride (Zyban) also has demonstrated efficacy in smoking cessation. Bupropion is an atypical antidepressant with noradrenergic and dopaminergic effects. Numerous studies have shown that bupropion therapy, given in the context of a comprehensive smoking cessation program, doubled the number of subjects reporting no nicotine use in the week before the follow-up contact. The recommended and maximum dose of bupropion is 300 mg a day, given as 150 mg twice daily. Dosing should begin at 150 mg a day—given every day for the first 3 days—followed by a dose increase for most patients to the recommended usual dose of 300 mg a day.

Therapy is typically begun 1 to 2 weeks before the patient's predetermined smoking quit date. Treatment should continue for 12 weeks. Its use is contraindicated in those with a seizure disorder, those with anorexia/bulimia, or those who have used a monoamine oxidase inhibitor (e.g., selegiline [Eldepryl], tranylcypromine [Parnate], or phenelzine [Nardil]) within the previous 14 days. Health care providers interested in prescribing Zyban should thoroughly review the manufacturer's product information before deciding to initiate therapy.

Varenicline was approved by the FDA in 2006 for the treatment of nicotine dependence. This medication appears to represent a partial agonist that binds with high affinity to the neuronal nicotinic acetylcholine receptor. Nicotine stimulation of this particular receptor, with which varenicline binds with high specificity, is associated with significant mesolimbic dopamine release, which serves to reinforce nicotine ingestion. The high affinity with which varenicline binds to this receptor prevents nicotine itself from stimulating the receptor, thereby reducing the reinforcing properties of nicotine ingestion.

In three studies comparing varenicline with buproprion, placebo or both, varenicline 1 mg BID resulted in 52-week continuous abstinence rates of 21% to 23% (95% confidence intervals ranging from 17% to 28%), whereas buproprion and placebo produced rates of 14% to 16% (95% confidence interval 11%-20%) and 4% to 10% (95% confidence interval 1%-13%), respectively. ^1,2,3 The most commonly reported side effects have been nausea, insomnia, and headache. While disturbing or bizarre dreams have been reported at higher rates than placebo, these have rarely been so severe as to lead to treatment discontinuation. More recently, the FDA has advised clinicians to monitor patients taking varenicline for changes in behavior, agitation, depressed mood, suicidal thoughts or behavior, as well as worsening of preexisting psychiatric illnesses.

Weight gain is a common problem that can negatively affect rates of successful smoking cessation. Weight gain in patients following smoking cessation can be attributable to replacing the oral nicotine habit with another oral habit-consuming food. Patients undergoing cessation are also likely to be able to taste and smell food better following smoking cessation, which may contribute to weight gain. Other mechanisms contributing to weight gain after smoking cessation include increased caloric intake, decreased resting metabolic rate, and decreased physical activity. Estimated average weight gain as a result of smoking cessation is approximately 4 pounds for both men and women.

To help alleviate weight gain concerns, health care providers can discuss healthy replacement strategies for nicotine including drinking water, exercising, and eating healthful foods such as raw fruits and vegetables. Many patients also benefit from a discussion of the benefits of quitting smoking versus the risks of the small amount of actual weight gain.

Alternative therapies for smoking cessation include a wide range of strategies from herbal supplements to laser treatments. Two popular alternative therapies include hypnosis and acupuncture. Currently, both acupuncture and hypnosis should be considered as supplements to well-established treatments rather than first-line recommendations because the research has not been conclusive concerning the effectiveness of these treatments.

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Treatment outcomes

Fully 70% of smokers report wanting to quit, and 46% attempt to quit each year. Only 5% to 7% of them are abstinent from smoking for an entire year after quitting. Several factors appear to affect rates of abstinence in different groups. Women have less success with quitting smoking and higher rates of relapse. Patients with higher levels of nicotine dependence (as evidenced by higher FTND scores) and those with a history of depression also have lower abstinence rates. African Americans and Chinese Americans have lower smoking cessation numbers than Euro-Americans. The primary care provider should consider referring patients in these groups to a more intensive smoking cessation program and adding nicotine replacement or bupropion (or both) to increase the likelihood of successful abstinence.

Bupropion and nicotine gum have been shown to double the rate of abstinence. Meta-analysis of multiple research studies suggests that intensive counseling programs also significantly increase cessation rates. Research suggests that “more is better,” with more frequent counseling leading to better cessation rates.

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Prevention and screening

Considering the highly addictive nature of cigarette smoke and the difficulties smokers face in becoming abstinent, perhaps the best approach to reducing smoking rates is to educate the public regarding the dangers of smoking and to prevent exposure to nicotine before an addictive pattern establishes itself. Physicians can have an effect on the formation of attitudes regarding smoking in young people by clearly explaining the negative health effects and costs of exposure to cigarettes. Reviewing available practice guidelines such as the 2006 version (available in print or free on-line) produced by the American Psychiatric Association can help physicians stay up to date on the current state of understanding of this significant public health problem.

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Summary

• Ask every patient about tobacco use.
• Engage patients in brief counseling.
• Discuss pharmacologic options including nicotine replacement and bupropion therapy.
• Consider referral to intensive smoking cessation treatments.

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Suggested Readings

• Meta-analytic review of the efficacy of smoking cessation interventions. Drug alcohol Rev. 13: 1994; 157-170.
• Both smoking reduction with nicotine replacement therapy and motivational advice increase future cessation among smokers unmotivated to quit. J Consult Clin Psychol. 72: 2004; 371-381.
• Treating Tobacco Use and Dependence, U.S. Department of Health and Human Services, 2000. Available at: www.surgeongeneral.gov/tobacco/default.htm
• The health benefits of smoking cessation: A report of the Surgeon General. DHHS pub. #(CDC) 90-8416. 1990; ;Washington, DC.
• Diagnostic and Statistical Manual of Mental Disorders. 4th ed., text rev 2000; ;Washington DC.
• Methods used to quit smoking in the United States: Do smoking cessation programs help?. JAMA. 263: 1990; 2760-2765.
• The Fagerström test for nicotine dependence: A revision of the Fagerström tolerance questionnaire. Br J Addict. 86: 1991; 1119-1127.
• Nicotine-related disorders. Sadock B, Sadock A. Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 8th ed 2005; ;Philadelphia. 1257-1264.
• Treating nicotine addiction. BMJ. 327: 2003; 1394-1395.
• American Psychiatric Association, 2006. Available at: www.psychiatryonline.com/pracGuide/pracGuideChapToc_5.aspx