Evidence of Benefit
Tobacco Cessation Guidelines
Pharmacotherapy for Smoking Cessation
Pharmacologic interventions to assist in tobacco cessation
A Changing Marketplace for Tobacco Products and Nicotine-Delivery Devices
Many health risks related to tobacco smoking can be reduced by smoking cessation. Smokers who quit smoking before age 50 years have up to half the risk of dying within 15 years compared with people who continue to smoke, and the risk of dying is reduced substantially even among persons who stop smoking after age 70 years. The risk of lung cancer is 30% to 50% lower than that of continuing smokers after 10 years of abstinence, and the risk of oral and esophageal cancer is halved within 5 years of cessation. Smokers who quit also lower their risk of cervical, gastric, and bladder cancer.[1-3]
In a randomized trial of heavy smokers, the long-term follow-up results demonstrated that compared with the nonintervention group (n = 1,964), those randomly assigned to a smoking cessation intervention (n = 3,923) experienced a 15% reduction in all-cause mortality rates (8.83 vs. 10.38 per 1,000 person-years; P = .03). The smoking cessation intervention consisted of a strong physician message plus 12 group sessions and nicotine gum administered during a 10-week period. Decreases in the risk of lung and other cancers, and coronary heart disease, cardiovascular disease, and respiratory disease contributed to the benefit in the group randomly assigned to the smoking cessation intervention.
A number of approaches at the policy, legislative, and regulatory levels have been attempted to effect widespread reduction in or prevention of commencement of tobacco use. Various efforts at the community, state, and national level have been credited with reducing the prevalence of smoking over time. These efforts include, reducing minors’ access to tobacco products, disseminating effective school-based prevention curricula together with media strategies, raising the cost of tobacco products, using tobacco excise taxes to fund community-level interventions including mass media, providing proven quitting strategies through health care organizations, and adopting smoke-free laws and policies.[5,6] School-based interventions alone have not demonstrated long-term impact for smoking prevention. One of the highest quality studies was a large, randomized trial in which children received a theory-based program that incorporated various social-influence approaches from grade 3 through grade 12, with no difference in smoking outcomes observed either at grade 12 or at 2 years after high school between school districts receiving the intervention and those in the control arm.
The Community Intervention Trial for Smoking Cessation (COMMIT) was a National Cancer Institute-funded large-scale study to assess a combination of community-based interventions designed to help smokers cease using tobacco. COMMIT involved 11 matched pairs of communities in North America, which were randomly assigned to an arm offering an active community-wide intervention or a control arm (no active intervention). The 4-year intervention included messaging through existing media channels, major community organizations, and social institutions capable of influencing smoking behavior in large groups of people. The interventions were implemented in each community through a local community board that provided oversight and management of COMMIT activities.
In COMMIT, there was no difference in the mean quit rate of heavy-smokers in the intervention communities (18.0%) compared with the control communities (18.7%). The light-to-moderate smoker quit rates were statistically significantly different: averages of 30.6% and 27.5% for the intervention and control communities, respectively (P = .004). Although no significant differences in quit rates between the sexes were observed, less-educated light-to-moderate smokers were more responsive to the intervention than were college-educated smokers with a light-to-moderate habit.[10,11]
Clinical interventions targeted at individuals have shown more promising results. A meta-analysis of randomized controlled trials shows that 6-month cessation rates are significantly improved with use of nicotine replacement therapy (NRT) products compared with placebo or no intervention (summary relative risk [RR], 1.58; 95% confidence interval [CI], 1.50–1.66). The benefits of nicotine replacement therapy product use have been consistently observed regardless of whether the product used was the patch, gum, nasal spray, inhaler, or lozenge. Smoking cessation counseling alone is also effective; even a brief intervention by a health care professional significantly increases the smoking cessation rate.
An important issue is whether pharmacotherapies are more effective in the presence of counseling. A randomized trial compared the following three levels of intervention that combined free pharmacotherapy (nicotine patch or bupropion) with or without counseling: 1) pharmacotherapy alone; 2) pharmacotherapy plus up to two counseling sessions every 6 months; and 3) pharmacotherapy plus up to six counseling sessions every 6 months. During the 24-month study, each group was offered a randomly assigned intervention at baseline, 6 months, 12 months, and 18 months later. For the primary study endpoint of 7-day point prevalence of smoking abstinence after 24 months of follow-up, no statistically significant differences were observed among the interventions. The results of this study suggest that the combination of pharmacotherapy plus counseling is no better than intervention alone.
Promoting smoking cessation among cancer survivors is essential because the deleterious health effects of cigarette smoking may impact prognosis in both the short term and long term. In a randomized controlled trial of a peer-delivered smoking cessation intervention among childhood cancer survivors, a significantly higher 12-month quit rate was observed in the intervention group (15% vs. 9%; P < .01).Tobacco Cessation Guidelines
In 1996, the Agency for Health Care Policy and Research (AHCPR), now the Agency for Healthcare Research and Quality released a landmark set of clinical smoking-cessation guidelines for helping nicotine-dependent patients and healthcare providers. Now sponsored by the Public Health Service, the updated 2008 guidelines, "Treating Tobacco Use and Dependence" are available online. The broad elements of these guidelines are:
- Clinicians should document the tobacco-use status of every patient.
- Clinicians should assess the readiness to quit of patients who use tobacco and assist those who wish to quit in setting a quit date.
- Patients using tobacco should be provided with at least one of the effective brief cessation interventions that are available.
- In general, more intense interventions are more effective than less intense interventions in producing long-term tobacco abstinence, reflecting the dose-response relationship between the intervention and its outcome.
- One or more of the three treatment elements identified as being particularly effective should be included in smoking-cessation treatment:
- Social support from clinicians in the form of encouragement, assistance.
- Skills training/problem solving (cessation/abstinence techniques).
- Pharmacotherapy, such as nicotine-replacement (e.g., patches, gum).
- To be effective, health care systems must make institutional changes resulting in systematic identification of tobacco users and intervention with these patients at every visit.
For individual interventions, the guidelines  suggest a model based on outcomes from six major clinical trials of physician-delivered smoking intervention conducted in the late 1980s: the ASK, ADVISE, ASSESS, ASSIST, and ARRANGE model. The physician provides a brief intervention that entails asking about smoking status at every visit, advising abstinence, assisting by setting a quit date, providing self-help materials and recommending use of nicotine replacement therapy, and arranging for a follow-up visit. See below for brief and expanded intervention outlines. The recommendations also strongly support the value of referral to more intensive counseling.
Ask, Advise, Assess, Assist, Arrange: Key Elements
- Screen for smoking status at every visit or admission.
- Minimal Advice: “As your physician, I must advise you that smoking is bad for your health, and it would be important for you to stop.”
- Augmented Advice: “Because of your (__________) condition, it is particularly important for you to stop. If you stop now, (briefly educate patient about basic health benefits from quitting).”
- Minimal Assessment: Ask every tobacco user if he/she is willing to make a quit attempt at this time.
- Augmented Assessment: Assess characteristics of smoking history and patterns.
- Amount smoked.
- Quit history.
- Stage of Change:
- Precontemplator: Is not seriously considering stopping smoking.
- Contemplator: Is seriously considering stopping within 3 to 6 months.
- Preparation: Is seriously considering stopping within the next week to month and has already made changes such as cutting back.
- Action: Has recently stopped smoking (within last 6 months).
- Relapse: Has quit for at least 48 hours but is smoking again.
- Maintenance: Has quit for at least 6 months but may still be vulnerable to a relapse up to 1 year.
- Nicotine Addiction: Fagerstrom Test for nicotine dependency.
- Behavioral Patterns: "Why Do You Smoke?" Scale.
- Minimal Assistance: Provide self-help materials; assess interest in quitting; and assess interest in and appropriateness of pharmacological aids.
- Augmented Assistance: Provide brief 5 to 7 minute patient-centered counseling. See below for an outline of the counseling content.
- Arrange Follow-up Support
- Minimal Follow-up Support: Arrange for single follow-up contact by visit or by telephone in about 2 weeks; provide referral to a smoking counselor or group.
- Extended Follow-up Support: Establish “quit smoking” contract with quit date. Arrange three or more follow-up contacts by visit or by telephone.
Patient-Centered Counseling: Key Elements
- Basic Question:
- “How do you feel about smoking?”
- Follow-up Questions:
- “How do you feel about stopping smoking?”
- “Have you ever tried to stop before?” “What happened?”
- “What do you like about smoking?”
- “What do you not like about smoking?”
- Basic Question:
- Anticipated Problems
- Basic Question:
- “What problems will you have if you stop smoking?”
- Follow-up Questions:
- “Anything else?”
- “On the ‘Why Do You Smoke?’ questionnaire, you scored high on (_______). How do you think you can handle that type of situation?”
- Basic Question:
- Resources for Coping with Problems
- Basic Question:
- “How do you think you can handle that?”
- Follow-up Questions:
- “What else could you do?”
- “How do you expect your (family/spouse/friends) to help you?”
- Basic Question:
Pharmacological agents have been used successfully to aid in the cessation of smoking in the general population. Since the original AHCPR guidelines  were published in 1996, various nicotine replacement products have been approved for over-the-counter sale, and additional evidence of the effectiveness of therapies for smoking cessation has been published.[21-24] Pharmacotherapy of smoking, including nicotine replacement therapies (gum, patch, spray, lozenge, and inhaler) and nonnicotine medications (e.g., bupropion and varenicline) result in statistically significant increases in smoking cessation rates compared with a placebo. Based on a synthesis of the results of 110 randomized trials, nicotine replacement therapy treatments, alone or in combination, improve cessation rates over placebos after 6 months (RR, 1.58; 95% CI, 1.50–1.66).
There are also nonnicotine pharmacotherapies that have been efficacious for smoking cessation, including bupropion and varenicline. Based on the results of 31 randomized trials that compared the antidepressant bupropion to placebo, after 6 months of follow-up, bupropion was associated with a statistically significant increase in the likelihood of quitting smoking (summary odds ratio [OR], 1.94; 95% CI, 1.72–2.19). There is insufficient evidence to support the idea that combining bupropion plus NRT increases smoking cessation rates compared to NRT alone (summary OR, 1.37; 95% CI, 0.65–2.91).
Varenicline is a selective alpha-4-beta-2 nicotinic acetylcholine receptor partial agonist. In two randomized controlled trials for smoking cessation, varenicline titrated to a dose of 1.0 mg twice a day and was compared with bupropion sustained-release (SR) 150 mg twice a day and with a placebo group.[26,27] Treatment lasted for 12 weeks, with an additional 40 weeks of posttreatment follow-up. In both studies, varenicline was more efficacious than bupropion and placebo for continuous abstinence from smoking at 9 to 12 weeks and at 9 to 24 weeks of follow-up. For 9 to 52 weeks of follow-up, varenicline was more efficacious than placebo in both studies.[26,27] At 52 weeks of follow-up, the 7-day point prevalence of smoking abstinence was 46% higher in the varenicline group than in the bupropion SR group (OR, 1.46; 95% CI, 1.04–2.06). The other study also showed a 46% higher continuous abstinence in the varenicline group (OR, 1.46; 95% CI, 0.99–2.17). Approximately 30% of the participants who were randomly assigned to receive varenicline reported nausea, more than double that in the bupropion groups, and triple that seen in the placebo groups. In a randomized trial comparing varenicline with transdermal nicotine, continuous abstinence was greater in the varenicline group than in the transdermal nicotine group at the end of treatment (56% vs. 43%; P < .001) and during posttreatment follow-up (26% vs. 20%; P = .06). The prevalence of nausea in the varenicline group (37%) was more than triple that in the transdermal nicotine group (10%).
Based on postmarketing surveillance, on July 1, 2009, the U.S. Food and Drug Administration (FDA) required additions to the Boxed Warnings for both bupropion and varenicline to describe the risk of serious neuropsychiatric symptoms associated with these products. Symptoms include: “changes in behavior, hostility, agitation, depressed mood, suicidal thoughts and behavior, and attempted suicide.” The FDA goes on to advise that the important health benefits of quitting smoking “should be weighed against the small, but real, risk of serious adverse events with the use of varenicline or bupropion.” A meta-analysis of double-blind, placebo-controlled, randomized trials of varenicline administered for at least 1 week (N = 14 trials) indicated that varenicline was associated with an increased risk of serious adverse cardiovascular events (RR, 1.72; 95% CI, 1.09–2.71). This finding is particularly noteworthy because almost all of the randomized trials included in the meta-analysis had the following in common: they excluded patients with cardiovascular disease (CVD) at baseline; the usual average age of the patient populations (early 40s) was young for CVD; varenicline was usually administered for only 12 weeks or less; and, varenicline is efficacious for smoking cessation, which would act to decrease CVD risk.
There is a growing number of smoking cessation pharmacotherapies that have been shown to be efficacious in significantly increasing rates of smoking cessation. The choice of therapy should be individualized based on a number of factors, including past experience, patient and/or physician preference, and potential agent side effects. As more is learned about specific genetic variants that influence a smoker's response to smoking cessation pharmacotherapies—such as polymorphisms in genes encoding enzymes involved in nicotine metabolism—this information could eventually be integrated into smoking cessation treatment planning. Presently, the evidence is not yet sufficient to be integrated into clinical practice.
The following sections summarize available pharmacologic interventions to assist in tobacco cessation. More comprehensive information is available from product package inserts.Pharmacologic interventions to assist in tobacco cessation
Nicotine replacement therapy
These products are designed to aid in the withdrawal symptoms associated with nicotine. Several precautions are warranted before initiating therapy, but it should be noted that these precautions do not constitute absolute contraindications. In particular, special considerations are necessary in some patient groups (e.g., those with medical conditions such as arrhythmias, uncontrolled hypertension, esophagitis, peptic ulcer disease, insulin-treated diabetes, or asthma, pregnant or breast-feeding women, and adolescent smokers).Table 1. Nicotine Patches
|d = day; OTC = over the counter; Rx = prescription; wk = week.|
|Rx||Habitrol||7–21 mg/d||Erythema||Use for 6–12 wk|
|OTC||Nicoderm CQ||7–21 mg/d||Pruritus||Use for 6–12 wk|
|OTC||Nicotrol||5–15 mg/d||Burning at site||Use for 14–20 wk|
|Rx||ProStep||11–22 mg/d||Local irritation||Use for 6–12 wk|
Current guidelines recommend 8 weeks of transdermal nicotine therapy. Findings from two randomized placebo-controlled trials of transdermal therapy are divergent in their findings as to whether extended therapy (22–24 weeks vs. 8 weeks) improves quit rates.[33,34]Table 2. Nicotine Polacrilex Gums
|d = day; OTC = over the counter.|
|OTC||Nicorette||18–24 mg/d||Stomatitis, sore throat||Max 30 pieces/d; decrease 1 piece every 4–7 d|
|OTC||Nicorette DS||36–48 mg/d||Jaw ache||Max 20 pieces/d; decrease 1 piece every 4–7 d|
Table 3. Nicotine Lozenges
|d = day; h = hour; OTC = over the counter; wk = week.|
|OTC||Commit||40–80 mg/d||Local irritation (warmth and tingling)||Use for 12 wk; max 20 pieces/d. Wk 1–6: 1–2 lozenges every 1–2 h; wk 7–9: 1 lozenge every 2–4 h; wk 10–12: 1 lozenge every 4–8 h|
Table 4. Nicotine Inhalers
|Rx = prescription; wk = week.|
|Rx||Nicotrol Inhaler||Individualized||Local irritation||Use up to 24 wk|
Table 5. Nicotine Nasal Sprays
|d = day; mo = month; Rx = prescription.|
|Rx||Nicotrol NS||Max 40 mg/d||Nasal irritation||Max use 3 mo|
Also used as an antidepressant, bupropion HCl is a nonnicotine aid to smoking cessation. It is a relatively weak inhibitor of the neuronal uptake of norepinephrine, serotonin, and dopamine, and does not inhibit monoamine oxidase. The exact mechanism by which bupropion HCl enhances the ability of patients to abstain from smoking is unknown; however, it is presumed that this action is mediated by noradrenergic or dopaminergic mechanisms.Table 6. Bupropion Hydrochloride
|d = day; Rx = prescription; wk = week.|
|Rx||Zyban||150 mg/d X 3 d then increase to 300 mg/d X 7–12 wk||Insomnia, dry mouth, dizziness, rhinitis||Do not take with Wellbutrin or Wellbutrin SR|
|Higher incidence of seizures in patients treated for bulimia, anorexia|
|Do not prescribe >300 mg/d for patients being treated for bulimia|
Table 7. Varenicline
|d = day; Rx = prescription; wk = week.|
|Rx||Chantix||0.5 mg/d, d 1–3; 0.5 mg twice a d, d 4–7; then 1.0 mg twice a d through wk 12||Nausea, insomnia||Risk of toxicity greater in patients with impaired renal function|
|Not tested in children and pregnant women|
Although Zyban (bupropion HCl) is the only antidepressant approved by the FDA for smoking cessation, Prozac (fluoxetine HCl) has been shown to be effective.Table 8. Fluoxetine
|d = day; Rx = prescription.|
|Rx||Prozac||30–60 mg/d||Insomnia, dizziness, anorexia, sexual dysfunction, confusion||Limited data available on its use in combination with cognitive-behavioral therapy|
Lobeline (Bantron) is classified as a category III agent by the FDA, safe but no proven effectiveness. This product is not recommended for use in any smoking cessation program due to its lack of efficacy.Other Agents
Clonidine and nortriptyline have been suggested as possibly useful second-line pharmacotherapies, but are not approved for smoking cessation by the FDA. Nortriptyline is an antidepressant that does not contain nicotine. A meta-analysis of five randomized controlled trials found that smokers who received nortriptyline were 2.4 times more likely (95% CI, 1.7–3.6) than smokers who received a placebo to remain abstinent from smoking after 6 months.Smoking Reduction
Among dependent smokers, complete abstinence from smoking is the ultimate goal. Even in instances when complete abstinence from smoking is not achieved, smoking cessation pharmacotherapies may benefit individual health—and ultimately the public’s health—if the smoker reduces the number of cigarettes smoked. The relationship between cigarette smoking and lung cancer, and other smoking-associated malignancies, is strongly dose-dependent. Thus, an individual smoker who is unable to achieve abstinence or who is not motivated to quit smoking may benefit by using pharmacotherapies (or other means) to reduce the number of cigarettes smoked per day. NRT has thus generated attention as a viable means of “harm reduction.” In studies that randomly assigned smokers who were not trying to quit to NRT or placebo, a greater proportion of those randomly assigned to NRT compared with placebo reduced the number of cigarettes per day.[38,39] However, the impact of NRT on smoking reduction appears not to be sustained in the long run. Less evidence is available for bupropion, varenicline, and psychosocial interventions as a means of harm reduction. A potential problem with such a harm reduction strategy would be if it prevented cessation among smokers who would have otherwise quit smoking. Evidence shows that smoking reduction is actually associated with increased likelihood of future cessation.[39,41] Another potential negative aspect of harm reduction would be if smokers reduced the number of cigarettes smoked per day but modified the way the cigarettes were smoked in such a way that exposure to tobacco toxins was not actually reduced (e.g., by inhaling more deeply). Compensatory behaviors such as inhaling more deeply or smoking more of a cigarette are attempts by the smoker to try to maintain nicotine levels, so the use of supplemental NRT presumably safeguards against this. Evidence from studies of smoking reduction with NRT that measured smoking biomarkers indicates that compensation occurs, but not to such an extent that it would be expected to outweigh the reduction in exposure from the reduced number of cigarettes per day.A Changing Marketplace for Tobacco Products and Nicotine-Delivery Devices
The expansion in the marketplace of tobacco products and devices that deliver nicotine poses new challenges to tobacco control.[42-46] Examples of nontraditional tobacco products in the U.S. market include small cigars, water pipe tobacco smoking (“hookah”), and new types of flavored, smokeless tobacco products modeled after Swedish snus. Prominent among non–tobacco-containing nicotine delivery devices are electronic cigarettes (or “e-cigarettes”) that have experienced a rapid upsurge in use and are now marketed by the major U.S. tobacco companies.[42,43] Monitoring this expansion in products, how the products are used (e.g., product switching, multiple use, and use for tobacco cigarette smoking cessation), and the harms and benefits associated with their use compared to tobacco cigarettes is critical to the development of more effective tobacco control strategies.
Research to determine the potential risks and benefits of these new products is just beginning to emerge. In a three-arm trial in New Zealand, 657 adult tobacco cigarette smokers who wanted to quit smoking were all referred to a smoking cessation quit line and randomly assigned to receive nicotine e-cigarettes, nicotine patches, or placebo e-cigarettes. After 3 months of intervention and 3 additional months of follow-up, the primary outcome of 6-month continuous abstinence was 7.3%, 5.8%, and 4.1%, respectively. These quit rates were low in all three arms of the study, and the differences were not statistically significant but provide preliminary evidence that e-cigarettes resulted in rates of smoking cessation comparable to those of the nicotine patch, a smoking cessation pharmacotherapy of established efficacy. The trial results also suggested that nicotine e-cigarettes could expand the reach of smoking cessation interventions. Compared with the group assigned to the nicotine patch, the group assigned to e-cigarettes had higher adherence to treatment (78% vs. 46%; P < .0001) and were more likely to report that they would recommend their assigned product to a friend wanting to quit (88% vs. 56%; no P-value reported).References
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