Hospital Practice: Volume 38: No.1

Dominique Crain, MD And Abid Bhat, MD

Abstract: Cigarette smoking is the most important modifiable risk factor for premature mortality. Many common and serious diseases, including coronary artery disease, chronic obstructive lung disease, stroke, and cancer, are strongly linked to cigarette smoking. Smoking cessation is difficult due to nicotine addiction and withdrawal symptoms. Comprehensive programs for tobacco control can substantially reduce the frequency of tobacco use. Physicians can improve screening and increase cessation rates by asking patients about tobacco use at every office visit. The spectrum of available smoking cessation interventions ranges from simple advice to intensive behavioral support and pharmacological treatment. Medications currently approved by the US Food and Drug Administration for smoking cessation include nicotine replacement therapy (patch, gum, lozenge, inhaler, and nasal spray), bupropion, and varenicline. Nortriptyline and clonidine have been used in patients who do not tolerate first-line agents. New drug therapies, such as nicotine vaccines, are being developed. The US Public Health Service Guideline, published in 2008, recommends a combination of behavioral support and pharmacologic therapy. In summary, smoking cessation should be based on a patient’s coexisting medical conditions, level of smoking, compliance, previous experience with cessation agents, and the cost of therapy.

Keywords: smoking cessation; counseling; nicotine replacement therapy; varenicline; bupropion

Cigarette smoking is one of the most significant causes of premature death and morbidity worldwide.¹ Tobacco accounts for nearly 435 000 deaths in the United States annually.² Smoking is a known cause of multiple cancers, chronic obstructive pulmonary disease (COPD), heart disease, stroke, and many other illnesses.³ Despite these risks, Americans continue to smoke; a Centers for Disease Control survey published in 2007 revealed that 21% (45.3 million) of the US population are active smokers.⁴ Cigarette smoking is also expensive. The estimated cost of smoking is $167 billion annually, with $92 billion in productivity losses from premature death and $75.5 billion in health care costs.² Quitting smoking at any age leads to significant reduction in the risks associated with smoking.³

Approximately 70% of active smokers choose to quit and 40% make an attempt to quit each year.⁵ However, many of these attempts are without assistance, leading to poor success rates (3%–5%).⁶ Physicians and other health care providers are in a unique position to intervene; yet studies suggest that smokers are not consistently identified or treated in clinical settings.⁷ Successful treatment requires a multifaceted approach. This includes a long-term therapeutic relationship between a health care provider and patient, involving effective counseling and pharmacotherapy.

The first step in smoking cessation is identifying which patients are smoking. In the 1980s, one study revealed that only 50% of smokers were asked by their health care providers whether they were smoking and, if so, were urged to quit.⁸ In 2005, up to 90% of patients were questioned about their smoking, and > 70% had been advised to quit.⁹ The 2008 United States Public Health Service (USPHS) Guideline gives a level “A” recommendation for performing the “5 A’s” on all patients (Table 1).¹⁰ Every patient seen in the doctor’s office should be questioned as to whether they smoke. Those who are smoking should be advised to quit; this message should be clear, strong, and conveyed in a personalized manner. At this point, the smoker’s readiness to quit should be assessed, and the health care provider should assist the patient in making a quit plan. Key items in establishing a quit plan include setting a quit date, telling friends and family about the quit attempt, asking for support by anticipating hurdles to quitting, and removing tobacco from the home. The provider should then arrange for follow-up, which would likely be a contact in the following week and then again within the first month.

Behavioral approach and pharmacotherapy have both shown strong evidence of efficacy for smoking cessation. The combination of counseling and pharmacotherapy is more effective in smoking cessation than pharmacotherapy alone.¹¹

Behavioral treatment is a fundamental component in smoking cessation and several principles should be noted when considering the process of smoking cessation. Smoking should not be considered a “lifestyle choice,” but rather a chronic relapsing condition that is likely to require ongoing intervention.¹² Most smokers attempt cessation several times before they are successful.¹³ A concise period of counseling (< 3 minutes) has been shown to improve the cessation rate when compared with no intervention.¹⁴

In individual counseling, the patient has a face-to-face encounter with a counselor trained to assist patients in smoking cessation. An abstinence rate of 7% is achieved through individual counseling, meaning 1 in 25 patients counseled will achieve abstinence.¹⁵

Group counseling allows more people to be counseled, and therefore most likely serves as a more cost-effective option. It can be effective in a smoker who is in need of support. One Cochrane review, however, concluded that there was no evidence that group therapy was more effective than individual counseling.¹⁶ Group counseling may not be applicable in smokers who have conflict with the timing of the group therapy. Also, health care providers should aid patients who are afraid to be part of a group in developing social support in this environment.17 A spouse, friends, and coworkers should help to support the patient in the quit attempt.¹⁷

Telephone counseling can be reactive (ie, patients call first) or proactive (ie, a counselor initiates calls to patients). The duration of calls is relatively short (5–20 minutes). A Cochrane review meta-analysis that included 48 trials with > 36 000 participants found that quit rates were higher in trials where patients received multiple calls.¹⁸ Smokers who initiated calls had higher abstinence rates (odds ratio [OR], 1.41). Proactive counseling of those who did not initiate contact also increased cessation rates (OR, 1.33). Quit rates directly corresponded to the number and duration of calls to the help lines; those with ≤ 3 contacts had improved rates of cessation (OR, 1.38).¹⁸

Self-help programs consist of written or electronic material to provide advice on how to quit smoking. They are inexpensive and can be tailored to a specific subset of smokers. Various Web- and other computer-based programs have been developed to encourage smoking cessation. The National Cancer Institute has a pamphlet on its Web site that offers education on smoking cessation.¹⁹ A Cochrane review meta-analysis of > 13 000 patients indicated that self-help programs offer a modest improvement in cessation (OR, 1.24).²⁰

Nonpharmacologic approaches that may improve cessation rates include cognitive (learning to reduce negative moods or urges to smoke from nicotine withdrawal), behavioral (changing habits), and motivational (reviewing reasons why not to smoke) therapy. A strong positive correlation exists between the intensity of counseling (total duration of contact) and cessation rates.²¹

Residential (inpatient) programs are used for severely dependent smokers who also have comorbid conditions. During this 8-day program, a physician performs an initial examination and prescribes pharmacotherapy. A tobacco treatment specialist provides behavioral counseling. The 2008 USPHS Guideline defines tobacco treatment specialists as health care providers from various professional backgrounds who view tobacco dependence treatment as a primary professional role.¹⁰ The program includes daily education sessions, group therapy, skills training, and tailored pharmacotherapy. Patients admitted to the residential programs are generally older, have significant tobacco-related medical illnesses, and are in recovery from alcohol or drug dependence.²²

Three medications have been approved by the US Food and Drug Administration (FDA): nicotine replacement therapy (NRT), bupropion, and varenicline (Table 2). Second-line agents (ie, nortriptyline and clonidine) are available for patients who cannot tolerate or fail therapy with first-line drugs.

Nicotine is distilled from cigarette smoke and absorbed into the pulmonary circulation. It readily diffuses into brain tissue, where it binds to nicotinic acetylcholine receptors. Dopamine, norepinephrine, acetylcholine, serotonin, γ-aminobutyric acid, and endorphins are all released, resulting in a myriad of euphoric effects.²³ The central nervous system effects are related to both the absolute blood levels of nicotine and the rate of increase in concentration. Due to nicotine’s short half-life of approximately 2 hours, cravings develop within a few hours of the last cigarette. In addition, withdrawal symptoms develop, including dysphoria or depressed mood, insomnia, irritability, anxiety, and increased appetite. Withdrawal symptoms tend to peak within the first week, but may persist for months.²⁴ Nicotine replacement therapy is geared toward relieving these withdrawal symptoms while the smoker battles the behavioral counterpart.

Nicotine replacement therapy is a well-studied and well-documented pharmacologic approach to helping smokers quit. Currently, there are 5 nicotine replacement formulations available: transdermal patch, gum, lozenge, inhaler, and nasal spray.²⁵ The multiple forms of administration allow the patient to choose which strategy to use, which may facilitate adherence.

A transdermal patch provides a constant, low release of nicotine. The patches are available in several dosages; the highest is typically a 21-mg patch. This provides a nicotine blood level of approximately 40% to 50% of the level consumed when smoking 1.5 packs daily.²⁶ This will reduce, but not completely eliminate, nicotine withdrawal symptoms. Typical treatment with transdermal patch is recommended for 4 to 6 weeks at full dose. Alternatively, the patch may be reduced by 7 mg every 2 to 4 weeks. A meta-analysis of 17 studies (5098 patients) revealed an overall abstinence rate of 27% in nicotine patches versus 13% for placebo and a 6-month abstinence rate of 22% versus 9% for placebo.²⁷ The combined OR for efficacy of nicotine patch versus placebo was 2.6 at the end of treatment and 3.0 at 6 months. Another meta-analysis showed that the OR for abstinence with nicotine patches compared with placebo is 1.81.²⁸

Nicotine polacrilex is available in gum and lozenge forms. The gum contains nicotine bound to a polacrilex resin. It is available in 2- and 4-mg formulas. The gum is chewed until the nicotine taste appears and is placed in the buccal mucosa until the taste disappears. The gum is then chewed a few more times to release more nicotine. This cycle is repeated for 30 minutes, at which point the gum is discarded. Herrera et al²⁹ classified smokers into high- or low-dependency groups. The criterion for high dependence was ≥ 7 points on the Fagerstrom Tolerance Questionnaire.³⁰ The high-dependency smokers were given gum containing 2 or 4 mg of nicotine, and the smokers with low dependence were given gum containing 2 mg of nicotine or a placebo gum. High-dependency smokers needed higher doses of nicotine replacement (4 mg), whereas the 2-mg dose was superior to placebo among low-dependency smokers.

The nicotine lozenge appears to have similar efficacy and is also available in 2- and 4-mg strengths. A randomized placebo-controlled trial of 1818 smokers resulted in significant rates of cessation.³¹ Patients were classified as having high dependency (time from awakening to first cigarette < 30 minutes) or low dependency (> 30 minutes), and were then randomly assigned to take 4-mg or 2-mg nicotine lozenges or placebo. At 6 weeks, quit rates were 46% in the low-dependency group versus 29.7% in the placebo group (OR, 2.1). In the high-dependency group, those treated with the 4-mg lozenges had quit rates of 48.7% at 6 weeks compared with 20.8% in the placebo group (OR, 3.69). The main adverse effects of the lozenges are oral soreness and indigestion.

A nicotine inhaler is available by prescription only. The inhaler consists of a cartridge attached to a mouthpiece that contains 10 mg of nicotine (but only delivers 4 mg) and 1 mg of menthol. The nicotine is released with inspiration, and the majority is deposited in the mouth. It is then transported to the buccal mucosa where it is absorbed. This mode of replacement most closely mimics the act of smoking because it includes active handling of the device and active inhalation through the mouth. The patient should taper use after 6 to 12 weeks. A randomized trial of 247 smokers showed that 28% of participants were smoke-free in the nicotine group compared with 18% in the placebo group (P < 0.05).³² The most common adverse effects from the inhaler are local irritation and cough. Inhaled nicotine may also induce bronchospasm; caution should be used in patients with underlying obstructive lung disease.

Nicotine nasal spray delivers an aqueous solution of nicotine to the nasal mucosa. This is rapidly absorbed at a rate that mimics the rapid rise in serum nicotine levels during smoking. The spray is used ≤ 2 doses per hour or on an as-needed basis for a total of 3 months. A randomized trial showed that significantly more patients in the nicotine group were abstinent for 12 months than in the placebo group (27% vs 15%; OR, 2.16).³³ Nasal irritation is common, occurring in 94% of patients within the first 2 days and continuing in 81% of patients after 3 weeks of therapy.³⁴

In heavy smokers who have previously failed standard-dose nicotine patch therapy, and for those whose nicotine withdrawal symptoms are not relieved sufficiently with standard-dose therapy, use of high-dose nicotine patch therapy (ie, doses of > 21 mg/day) is suggested.³⁵ In patients who smoke > 20 cigarettes per day, high-dose nicotine patch therapy has been shown to be safe and well tolerated.³⁶ The 2008 USPHS Guideline concluded that high-dose nicotine therapy did not show a benefit when compared with a standard dose nicotine patch.¹⁰

The efficacy of NRT in smokers with COPD has been well studied. The Lung Health Study showed that after 12 months of nicotine gum along with counseling, the abstinence rate was higher in smokers who were at increased risk of COPD.³⁷ Nicotine replacement therapy appears to be a safe therapeutic intervention in outpatients with known cardiovascular disease.³⁸ Other studies have noted the lack of association between use of the nicotine patch and cardiovascular events, even in patients who continued to smoke intermittently while using the nicotine patch.³⁹ Limited evidence exists concerning the safety of NRT in critically ill patients and those with acute coronary syndrome. The 2008 USPHS Guideline recommends NRT should be used with caution in patients with underlying serious arrhythmias, those with worsening angina pectoris, and those with a recent (within 2 weeks) myocardial infarction.¹⁰ Women who continue to smoke during pregnancy must be counseled about quitting. They may be motivated to quit smoking by discussing the risks to both mother and fetus.¹⁰ Although quitting smoking prior to conception is optimal, health benefits may result from abstinence at any time. Nicotine prescription formulations have been classified as a Pregnancy Category D drug, indicating that there is evidence of human fetal risks. The 2008 USPHS Guideline does not recommend use of NRT during pregnancy.¹⁰ The safety and efficacy of NRT products has also not been established in smokeless tobacco users and adolescents and are, therefore, not indicated for use in these populations.

In 1997, the FDA approved bupropion for smoking cessation, making it the first non-nicotine agent to demonstrate efficacy in smoking cessation. A 150-mg sustained-release tablet (Zyban^®) twice daily has been approved for smoking cessation alone.⁴⁰ Treatment is started with sustained-release bupropion 150 mg daily for 3 days, then 150 mg twice daily for ≤ weeks. A Cochrane review meta-analysis that focused on 19 trials with bupropion concluded that it doubles the chances of successful smoking cessation when compared with placebo.⁴¹ When used as monotherapy, bupropion doubled the odds of smoking cessation. One center performed a randomized, placebo-controlled trial of 615 smokers comparing sustained-release bupropion (150 mg twice daily) with placebo.⁴² At the end of 7 weeks, 44% of those treated with bupropion were smoke-free compared with 19% in the placebo group. When re-evaluated after 1 year, abstinence rates remained higher in the treatment group (23% in the bupropion group compared with 12% in the placebo group). The most common side effects reported with bupropion are insomnia and dry mouth. Risk of seizures has been reported, with rates up to 1 in 1000.⁴³ For this reason, bupropion is contraindicated in patients with underlying seizure disorders. Bupropion is also contraindicated in patients with anorexia or bulimia nervosa and in patients who are undergoing abrupt discontinuation of alcohol and sedatives. In 2009, the FDA issued a black-box warning highlighting the risks of serious neuropsychiatric symptoms, including change in behavior, hostility, agitation, depressed mood, suicidal thoughts, and attempted suicide.⁴⁴

Varenicline (Chantix^®) is the most recent addition to the list of pharmaceutical options for smoking cessation. It is a partial agonist of the nicotinic acetylcholine receptor subtype α4β2, stimulating dopamine turnover in the nucleus accumbens to between 32% and 45% of the level induced by nicotine.⁴⁵ This mediates the nicotine craving and withdrawal symptoms. The partial agonist action is also useful in patients who lapse and return to smoking, as its competitive binding inhibits the dopamine release (and therefore positive feedback) triggered by smoking.⁴⁶

Varenicline is prescribed at 0.5 mg daily for 3 days, then 0.5 mg twice daily for 4 days, and then 1 mg twice daily for 12 weeks. An additional 12 weeks of treatment for patients who have quit smoking may be helpful in preventing relapses. Two similarly designed, randomized, double-blind, placebo-controlled trials compared varenicline 1 mg twice daily, bupropion 150 mg twice daily, and placebo.^47,48 At the end of 12 weeks, quit rates had increased nearly 4-fold in the varenicline group when compared with placebo and nearly doubled when compared with the bupropion group. At 1 year, abstinence rates were 23% in the varenicline group, 16% in the bupropion group, and 9% in the placebo group. An additional trial randomly assigned healthy smokers to varenicline 0.5 mg twice daily, 1 mg twice daily, and placebo.^49,50 Quit rates were highest in the 1-mg group (49.4%), followed by the 0.5-mg group (44%). Placebo quit rates were 11.6%. At 52 weeks, the 1-mg group continued to have a higher quit rate compared with the other 2 groups.

Several safety concerns have emerged with the use of varenicline. In November 2007, the FDA received reports of erratic behavior and suicidal ideation in patients who had been prescribed varenicline.⁵¹ Serious neuropsychiatric symptoms have occurred, including changes in behavior, agitation, depressed mood, suicidal ideation, and attempted and committed suicides.⁵² Initially, it was thought that some of these symptoms were attributable to nicotine withdrawal; however, not all of the patients had stopped smoking. In most cases, symptoms developed while on varenicline therapy, although some patients developed symptoms following withdrawal of varenicline therapy. In 2008, the FDA reported that it was increasingly likely that varenicline is associated with neuropsychiatric symptoms and a warning was added.⁵³ The current prescribing information recommends patients should be observed for the development of these symptoms, and family and health care providers should be informed of the need to monitor for said symptoms.⁵⁴

Combining 2 types of NRT with different types of delivery—one rapid (gum, lozenge, and inhaler) and the other passive (eg, the patch)—has been shown to improve the abstinence rate.⁵⁵ Improved efficacy with combination therapy is attributed to the 2 forms of nicotine (rapid and slow), and not to the increased amounts of nicotine.⁵⁶ The 2008 USPHS Guideline also recommends a combination of nicotine patch with short-acting NRT formulations (ie, gum, nasal spray, or inhaler).¹⁰ More recent data suggest that aggressive regimens in the form of triple-combination therapy (eg, patch, inhaler, and sustained-release bupropion) are a safe and effective treatment approach.⁵⁷ Preliminary data also suggest varenicline in combination with NRT or bupropion may be efficacious and well tolerated.^58,59 However, future controlled trials are required to confirm these findings.

Second-line agents have been studied as aids in smoking cessation. However, they have not been approved by the FDA for smoking cessation, typically because of the increased concern for adverse effects when compared with first-line agents. Second-line agents are recommended for patients unresponsive or intolerant to first-line therapy.

Clonidine is an α₂-adrenergic agonist that acts in the central nervous system, decreasing sympathetic output. In smoking cessation, it is believed to counter nicotine withdrawal symptoms.⁶⁰ Clonidine should be started 3 days prior to the quit date at 0.15 to 0.75 mg daily, and continued for 3 to 10 weeks. The dose will need to be tapered down because rebound hypertension may result from abrupt discontinuation. In a meta-analysis of 6 trials in which clonidine was administered orally at 0.15 to 0.45 mg per day or transdermally at 0.1 to 0.3 mg per day, results showed an almost 2-fold improvement in cessation rates at 12 weeks when compared with placebo (OR, 1.89).⁶¹ Adverse effects include sedation, postural hypotension, dry mouth, and constipation. Transdermal clonidine can also lead to skin reaction.

Nortriptyline is a tricyclic antidepressant and is believed to act through inhibition of the reuptake of serotonin and norepinephrine. A meta-analysis of 6 trials indicated that treatment with nortriptyline (75–100 mg/day) doubles the chances of successful cessation (OR, 2.34).⁶² Nortriptyline treatment should start 10 to 28 days prior to the quit date at a dose of 25 mg daily, which may be increased to 75 to 100 mg daily. Treatment duration is typically 12 weeks. Common adverse effects include dry mouth, blurred vision, sedation, urinary retention, and postural hypotension.

There are ≥ 3 companies that are in the early clinical stages of vaccine development: TA-NIC (Xenova, Slough, United Kingdom), NicVAX^® (Nabi Pharmaceuticals, Rockville, MD), and Nicotine-Qbeta (Cytos, Schlieren, Switzerland). In randomized trials with rats, all 3 vaccines elicited immunologic responses and increased quit rates when compared with placebo. The vaccine works by inducing antibodies to nicotine. When nicotine is ingested, the antibodies bind to it, resulting in particles too large to cross the blood-brain barrier. The amount of nicotine that reaches the brain is reduced rather than completely eliminated; therefore, it is possible that some smokers would actually increase tobacco consumption, at least in the short-term, to achieve the levels of nicotine normally obtained when smoking. Results of phase 1 studies of TA-NIC and NicVAX^® suggest that these vaccines are safe and well tolerated.⁶³

Rimonabant is a selective cannabinoid type 1 (CB₁) receptor antagonist designed for the treatment of obesity and tobacco dependence. A meta-analysis demonstrated that rimonabant 20 mg increases the risk of quitting by almost 1.5-fold.⁶⁴ The drug had been approved in Europe for obesity, but safety concerns resulted in suspension of sales and the discontinuation of ongoing trials.⁶⁵ The FDA has also declined to approve rimonabant for any indication, pending more information about its safety.⁶⁶ Concern regarding the rate of depression and suicidal tendency has led to a call for more studies to investigate the overall efficacy and safety of this drug.

Tobacco use continues to be a major source of morbidity and mortality in the United States (Figure 1). Many people attempt to quit smoking without formal intervention, but these efforts are usually unsuccessful. The 2008 USPHS Guideline recommends that smokers be managed with a combination of behavioral support and pharmacologic therapy. Repeated attempts to quit smoking should be encouraged for all smokers at every opportunity. First-line agents for smoking cessation include nicotine replacement products, bupropion, and varenicline. There is a great deal of clinical experience with nicotine replacement products and they have favorable safety profiles. Bupropion is at least comparable to nicotine replacement in efficacy. With its novel mechanism of action, varenicline provides smokers with a new therapeutic option to reduce cravings and physical dependence. However, citing recent concerns about depression and suicidality associated with varenicline, some patients and health care providers may prefer to use an agent with longer clinical experience. In patients who are unable to quit with individual agents, combination pharmacologic therapy is suggested. The combination of nicotine patch and a short-acting NRT product (eg, gum or nasal spray) has been shown to be more effective than monotherapy. Other alternatives include NRT and bupropion. Inadequate evidence is available regarding the combination of varenicline with either nicotine replacement or bupropion. For patients who are still unsuccessful with or cannot tolerate first-line therapy, clonidine or nortriptyline may also be used. Results from early trials of the nicotine vaccines appear promising and may be available in the near future.

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