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Evidence-based clinical guidelines for smoking cessation were released by the US Public Health Service in 2000 and updated in 2008 (http://www.ahrq.gov/professionals/clinicians-providers/guidelines-recommendations/tobacco/clinicians/update/treating_tobacco_use08.pdf). These guidelines identify two methods, psychosocial counseling and pharmacotherapy, as having strong evidence of efficacy. Each is effective individually, but combining the two produces higher cessation rates. There is no strong evidence to support the efficacy of hypnosis or acupuncture for smoking cessation.
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Effective psychosocial support provides smokers with both practical behavior change strategies and also support and encouragement as part of treatment. Cognitive behavioral treatment methods address the barriers to quitting smoking that are rooted in habit. These methods are effective in aiding smoking cessation. In a typical program, smokers monitor their cigarette intake to identify the things that trigger the smoking, change their habits to break the link between the trigger and smoking, and learn to anticipate and handle the urges to smoke when they occur. The counselor also provides social support to bolster the smoker’s confidence in the ability to stop smoking.
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Psychosocial support was originally developed for delivery in individual or group settings. To broaden the reach of behavioral treatment, in-person methods were adapted for delivery by telephone and found to be effective. Cognitive behavioral treatment techniques can also be packaged into booklets or videotapes for use at home. These techniques have also been adapted for delivery using newer communication tools, including websites, text messaging, mobile phone applications, and social media. Most of these programs are new and their effectiveness is not yet demonstrated.
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Pharmacological Treatment
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Seven products have been approved by the US Food and Drug Administration (FDA) as smoking cessation aids and rated as first-line drugs by the US Public Health Service tobacco treatment guidelines (Table 21-1). These include five nicotine replacement products, bupropion (an atypical antidepressant), and varenicline, a nicotine receptor partial agonist. Nortriptyline and clonidine have also shown efficacy for smoking cessation in clinical trials but have not been submitted for approval by the FDA for this indication and are considered second-line drugs by the US Public Health Service guideline panel.
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Nicotine Replacement Therapy
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The rationale of nicotine replacement therapy (NRT) is to supply nicotine in a form other than a cigarette to block the symptoms of nicotine withdrawal. Nicotine replacement permits the smoker to break the smoking habit first and begin to taper off nicotine. Five forms of nicotine replacement are approved for use in the United States. Nicotine in the form of a gum, a transdermal skin patch, and an oral lozenge are sold without prescription. A nicotine nasal spray and an oral inhaler are prescription-only products. Of all these products, the nicotine patch produces the most constant blood level of nicotine, a substantially different pattern from the fluctuating nicotine levels produced by cigarette smoking. The gum, lozenge, inhaler, and nasal spray produce nicotine levels that vary more than the patch but less than smoking a cigarette. They provide more control over nicotine level. The nicotine supplied by the gum, patch, or nasal spray is sufficient to reduce nicotine withdrawal symptoms, but does not reproduce the rapid rise in nicotine blood levels that results from smoking a cigarette.
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Randomized, placebo-controlled trials demonstrate that nicotine gum, patch, lozenge, inhaler, and nasal spray all reduce symptoms of nicotine withdrawal at approximately double the rates of smoking cessation compared with placebo. Combining the patch with another NRT product is safe and more effective than using a single NRT product. The effectiveness of all products depends on the instruction and counseling that accompany it. This is particularly true for the gum, nasal spray, and inhaler, which require careful instruction for proper use. Adherence is less of a problem with the nicotine patch. Any NRT product is more effective if used with some behavioral smoking cessation support. Clinicians should refer smokers to these resources when they recommend or prescribe NRT products.
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Nicotine replacement is safe to use in smokers with stable coronary artery disease. There are no data on its safety for use in smokers with unstable cardiovascular disease (myocardial infarction in the past 2 weeks, unstable angina, or life-threatening ventricular arrhythmias), although it is clearly safer than continuing to smoke. Nicotine does increase heart rate and blood pressure, causes vasoconstriction, and is thrombogenic. However, a smoker who substitutes NRT for cigarettes avoids exposure to carbon monoxide and to oxidant gases generated by burning tobacco.
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Transdermal Nicotine Patch
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The nonprescription nicotine patch contains a reservoir of nicotine that is released at a fixed dose and is absorbed through the skin. On the morning of the quit day, the smoker applies the first patch and removes it 24 hours later. A new patch is applied to rotating skin sites each morning afterward for 2–3 months, although there is evidence that prolonging use beyond 3 months produces better long-term results. Smokers who smoke 10 or more cigarettes (half of a pack) daily start with the 21-mg patch; lighter smokers start with the 14-mg patch. After 4–6 weeks, the smokers progressively switch to a lower dose patch. The most common side effect is local skin irritation, which rarely requires discontinuation of treatment and can often be managed with topical steroids. Vivid dreams or insomnia can be managed by removing the patch at bedtime. Long-term dependence on the nicotine patch rarely occurs.
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Nicotine gum is available without prescription in 2-mg and 4-mg strengths and in several flavors. Smokers who smoke more than 25 cigarettes daily use the 4-mg gum; all others use the 2-mg gum. Proper chewing technique is essential for the nicotine released by chewing to be absorbed through the oral mucosa as intended, rather than being swallowed. The gum should not be chewed like regular gum. Initially, it should be chewed only long enough to release the nicotine, producing a peppery taste, and then placed between the gums and buccal mucosa to allow for nicotine absorption. When the taste disappears, the gum is chewed again until the taste reappears, then “parked” again. After 30 minutes, it is discarded. The smoker should not eat or drink while the gum is in the mouth, and should avoid beverages, especially acidic beverages (e.g., coffee) for 30 minutes of gum use. Common side effects include those related to nicotine (nausea, dyspepsia, hiccups, dizziness) and to chewing (sore jaw, mouth ulcers). The product is approved for use as needed to handle urges to smoke, but its onset of action is slower than smoking. Most patients chew fewer than the recommended 9–12 pieces daily. Consequently, many experts use fixed-dose schedules (e.g., chewing one piece for the first 30 minutes of every hour) to achieve blood nicotine levels adequate to prevent withdrawal. It is used for 3 months. Long-term dependence on the gum is uncommon.
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A nicotine lozenge whose pattern of nicotine delivery resembles the gum is sold without prescription in 2-mg and 4-mg doses. Smokers whose first cigarette of the day is smoked within 30 minutes of awakening should use the 4-mg dose; others use the 2-mg dose. In randomized controlled trials, it doubles cessation rates compared with a placebo lozenge. It is placed in the mouth between cheek and gum. Nicotine in the lozenge is gradually absorbed through the oral mucosa over 30–40 minutes. The user should not eat or drink when the tablet is in the mouth. The lozenge differs from the gum in that no chewing is required, making it easier to use properly. People with dentures or poor dentition who generally cannot use the gum can use the lozenge. A smoker uses a lozenge as needed to control cravings, usually every hour or two, and uses it for 3–6 months. A mini-lozenge formulation that is smaller and dissolves more rapidly than the original nicotine lozenge is now available.
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The nicotine inhaler, sold only by prescription in the United States, is a handheld device containing nicotine in a plug that is vaporized when the smoker inhales. The nicotine is absorbed by the oral mucosa rather than in the lungs. Therefore, the inhaler delivers nicotine in a pattern similar to the gum or lozenge with peak nicotine levels reached 20 minutes after the start of use. The inhaler mimics the hand-to-mouth behavior of cigarette smoking, a feature that appeals to some smokers. The inhaler doubles the cessation rate compared to placebo in randomized trials. Side effects are minimal; throat irritation and cough are the most common.
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Nicotine nasal spray is sold only by prescription. Nicotine is more rapidly absorbed from the nasal mucosa than it is through the oral mucosa, but less rapidly absorbed than through the lungs when a cigarette is smoked. The nicotine nasal spray doubles cessation rates compared with a placebo spray in randomized controlled trials, but has a high incidence of side effects (nose and throat irritation, watery eyes, sneezing, and cough). Careful instruction is required for its proper use. The dose is one spray in each nostril as needed; this delivers a dose of 1 mg of nicotine. It is used for 3–6 months.
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Bupropion is an antidepressant with dopaminergic and noradrenergic activity. In its sustained-release form (Zyban, Wellbutrin SR), bupropion doubles smoking cessation rates compared with a placebo and is FDA approved for smoking cessation. The most serious side effect is a reduction in the threshold for seizure. The risk of seizure is 1 in 1000 patients or less, but the drug is contraindicated in patients with a seizure disorder or predisposition. Common side effects are insomnia, agitation, headache, and dry mouth. Doses of 150–300 mg/day for 7–12 weeks are effective for smoking cessation. The drug is started 1 week before the smoker’s quit date to allow for blood levels to stabilize before quitting occurs. Bupropion reduces but does not eliminate weight gain after smoking cessation (see section below “Weight and Smoking Cessation”), but the effect disappears when the medication is stopped. Nonetheless, this effect may appeal to smokers who are concerned about postcessation weight gain.
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Varenicline is a selective partial agonist at the α4β2 nicotinic receptor, the subtype of nicotine receptor in the brain that appears to mediate nicotine dependence. It is thought to have a dual mechanism of action. As a partial agonist, it partly relieves nicotine withdrawal symptoms. In addition, if a smoker using varenicline smokes a cigarette, the drug blocks the nicotine in cigarette smoke from binding to the nicotine receptor, thereby making smoking less rewarding. In randomized controlled trials comparing the drug with placebo and with bupropion, varenicline produced a higher long-term cessation rate than both and nearly tripled the cessation rate compared with placebo. Nausea is the most common side effect, occurring in nearly 30% of subjects in clinical trials. In practice, it can often be managed successfully by taking with food and a full glass of water. Varenicline is used for 12 weeks at a dose of 1-mg bid, starting with a 1-week gradual up-titration in dose to minimize nausea. The quit date should be set at least 1 week after starting the drug to allow blood levels to stabilize before quitting occurs, but delaying the quit date until 4 weeks after starting the drug might produce even better results.
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Concerns about varenicline’s safety appeared after the drug was marketed in 2008. In 2009, the FDA reviewed case reports for all smoking cessation drugs and reported that varenicline and bupropion, but not NRT, were “associated with reports of changes in behavior such as hostility, agitation, depressed mood, and suicidal thoughts or actions.” Bupropion and varenicline were both required to add boxed warnings about this to their labels. So far, an association between varenicline and behavior changes has not been observed in randomized clinical trials or observational studies of smokers starting varenicline. In 2011, the FDA reaffirmed their position that the benefits outweigh the risks in most cases. An association of varenicline with an increased incidence of cardiovascular outcomes such as heart attack was observed in one meta-analysis, but not in the second one. In both studies, the absolute risk of an adverse cardiovascular event was very low, with or without varenicline. Clinicians who prescribe varenicline should monitor patients’ behavior and mood, especially those with current or past psychiatric diagnoses. Combination NRT is an alternative for individuals in whom varenicline is considered potentially risky.
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Nortriptyline, a tricyclic antidepressant, has demonstrated efficacy for smoking cessation in randomized controlled trials. A meta-analysis found that its efficacy resembled that of the atypical antidepressant bupropion. Nortriptyline is not FDA approved as a smoking cessation aid. Hypotension and dry mouth are the most common side effects. There is no evidence to support the use of any other antidepressants or any antianxiety agents for smoking cessation.
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Clonidine, a centrally acting α-adrenergic agonist, is used to treat craving for psychoactive drugs other than nicotine. In randomized, placebo-controlled trials, both oral and transdermal clonidine reduced withdrawal symptoms and increased rates of cessation. Clonidine is not FDA approved for smoking cessation, and side effects (sedation, dizziness, and dry mouth) generally limit its use in practice.