Cigarette Smoking: Health Risks and How to Quit (PDQ®): Prevention - Health Professional Information [NCI]

Overview

Note: A separate PDQ summary on Levels of Evidence for Cancer Screening and Prevention Studies is also available.

The cancer prevention summaries in PDQ refer to cancer prevention, defined as a reduction in the incidence of cancer. The PDQ includes summaries generally classified by histological type of cancer, especially when there are known risk factors for the specific types of cancer. This summary addresses a specific risk factor, tobacco use, which is associated with a large number of different cancers (and other chronic diseases) and unequivocally contains human carcinogens.[1] The focus of this summary is on clinical interventions by health professionals that decrease the use of tobacco.

Effects of Smoking Cessation

Based on solid evidence, cigarette smoking causes cancers of the lung, oral cavity and pharynx, larynx, esophagus, bladder, kidney, pancreas, stomach, uterine cervix, and acute myeloid leukemia.[2] Smoking avoidance and smoking cessation result in decreased incidence and mortality from cancer.

Description of the Evidence

• Study Design: Evidence obtained from a randomized controlled trial.
• Internal Validity: Good.
• Consistency: Good.
• Magnitude of Effects on Health Outcomes: The relative risk (RR) of several cancers is much greater in cigarette smokers compared with nonsmokers (depending on the anatomical site of the cancer and the intensity and duration of smoking, the RR can range from twofold to tenfold or greater in smoking populations). A reduction of 15% is seen in the RR of all-cause mortality in heavy smokers subjected to intensive clinical cessation interventions.
• External Validity: Good.

Counseling and Smoking Cessation

Based on solid evidence, counseling by a health professional improves smoking cessation rates.

Description of the Evidence

• Study Design: Evidence obtained from randomized controlled trials.
• Internal Validity: Good.
• Consistency: Good.
• Magnitude of Effects on Health Outcomes: Counseling improves cessation rates (odds ratio [OR], 1.56; 95% confidence interval [CI], 1.32-1.84).[3,4]
• External Validity: Good.

Physician Advice and Smoking Cessation

Based on solid evidence, simple advice from a physician to stop smoking improves smoking cessation rates.

• Study Design: Evidence obtained from randomized controlled trials.
• Internal Validity: Good.
• Consistency: Good.
• Magnitude of Effects on Health Outcomes: Physician advice improves cessation rates (RR, 1.66; 95% CI, 1.42-1.94).[3]
• External Validity: Good.

Drug Treatment and Smoking Cessation

Based on solid evidence, drug treatments, including nicotine replacement therapies (gum, patch, spray, lozenge, and inhaler), selected antidepressant therapies (e.g., bupropion), and nicotinic receptor agonist therapy (varenicline), result in better smoking cessation rates than placebo.

Description of the Evidence

• Study Design: Evidence obtained from randomized controlled trials.
• Internal Validity: Good.
• Consistency: Good.
• Magnitude of Effects on Health Outcomes: Nicotine replacement therapy treatments, alone or in combination, improve cessation rates over placebo after 6 months (RR, 1.58; 95% CI, 1.50-1.66).[5] Treatment with bupropion improves cessation rates over placebo after 6 months (OR, 1.94; 95% CI, 1.72-2.19).[6] Varenicline therapy treatment improves cessation rates over placebo after 6 months (RR, 2.33; 95% CI, 1.95-2.80).[7]
• External Validity: Good.

References:

1. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans: Tobacco smoke and involuntary smoking. IARC Monogr Eval Carcinog Risks Hum 83: 1-1438, 2004.
2. The Health Consequences of Smoking: A Report of the Surgeon General. Atlanta, Ga: U.S. Department of Health and Human Services, CDC, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2004. Also available online. Last accessed February 9, 2017.
3. Lancaster T, Stead L: Physician advice for smoking cessation. Cochrane Database Syst Rev (4): CD000165, 2004.
4. Lemmens V, Oenema A, Knut IK, et al.: Effectiveness of smoking cessation interventions among adults: a systematic review of reviews. Eur J Cancer Prev 17 (6): 535-44, 2008.
5. Silagy C, Lancaster T, Stead L, et al.: Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev (3): CD000146, 2004.
6. Hughes JR, Stead LF, Lancaster T: Antidepressants for smoking cessation. Cochrane Database Syst Rev (1): CD000031, 2007.
7. Cahill K, Stead LF, Lancaster T: Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev (3): CD006103, 2008.

Evidence of Benefit

Background

In the United States, smoking-related illnesses accounted for an estimated 480,000 deaths each year.[1,2] (Also available online.) On average, these deaths occur 12 years earlier than would be expected, so the aggregate annual loss exceeds 5 million life-years.[3] These deaths are primarily due to smoking's role as a major cause of cancer, cardiovascular diseases, and chronic lung diseases. The known adverse health effects also include other respiratory diseases and symptoms, nuclear cataract, hip fractures, reduced female fertility, and diminished health status. Maternal smoking during pregnancy is associated with fetal growth restriction, low birth weight, and complications of pregnancy.[4] About 32% of cancer deaths [1] and 20% of all premature deaths in the United States are attributable to smoking.[5]

Tobacco products are the single, major avoidable cause of cancer, causing more than 155,000 deaths among smokers in the United States annually due to various cancers.[6] The majority of cancers of the lung, trachea, bronchus, larynx, pharynx, oral cavity, nasal cavity, and esophagus are attributable to tobacco products, particularly cigarettes. Smoking is also causally associated with cancers of the pancreas, kidney, bladder, stomach, and cervix and with myeloid leukemia.[4,7]

Smoking also has substantial effects on the health of nonsmokers. Environmental or secondhand tobacco smoke is implicated in causing lung cancer and coronary heart disease.[8] Among children, secondhand smoke exposure is causally associated with sudden infant death syndrome, lower respiratory tract illnesses, otitis media, middle ear effusion, exacerbated asthma, and respiratory effects such as cough, wheeze, and dyspnea.[8]

Environmental tobacco smoke has the same components as inhaled mainstream smoke, although in lower absolute concentrations, between 1% and 10%, depending on the constituent. Carcinogenic compounds in tobacco smoke include the polycyclic aromatic hydrocarbons (PAHs), including the carcinogen benzo[a]pyrene (BaP) and the nicotine-derived tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).[9] Elevated biomarkers of tobacco exposure, including urinary cotinine, tobacco-related carcinogen metabolites, and carcinogen-protein adducts, are seen in passive or secondhand smokers.[8,10,11,12]

In 2014, 18.8% of adult men and 14.8% of adult women in the United States were current smokers.[13] (Also available online.) Cigarette smoking is particularly common among American Indians and Alaska Natives. The prevalence of smoking also varies inversely with education, and was highest among adults who had earned a General Educational Development diploma (43.0%) and generally decreased with increasing years of education.[13] (Also available online.) From 2011 to 2014, significant declines occurred in the use of cigarettes among middle school (4.3% to 2.5%) and high school (15.8% to 9.2%) students.[14] Cigarette smoking prevalence among male and female high school students increased substantially during the early 1990s in all ethnic groups, but in 2015, it declined to 9%.[1,15,16] (Also available online.)

The effect of tobacco use on population-level health outcomes is illustrated by the example of lung cancer mortality trends. Smoking by women increased between 1940 and the early 1960s, resulting in a greater than 600% increase in female lung cancer mortality since 1950. Lung cancer is now the leading cause of cancer death in women.[15,17] In the last 30 years, prevalence of current cigarette use has generally decreased, though far more rapidly in males. Lung cancer mortality in men peaked in the 1980s, and has been declining since then; this decrease has occurred predominantly in squamous cell and small cell carcinomas, the histologic types most strongly associated with smoking.[15] Variations in lung cancer mortality rates by state also more or less parallel long-standing state-specific differences in tobacco use. Among men, the average annual age-adjusted lung cancer death rates from 2010 to 2014 were highest in Kentucky (90 per 100,000),[1] where 29.1% of men were current smokers in 1997, and lowest in Utah (25 per 100,000), where only 10.4% of men smoked. Among women, lung cancer death rates were highest in Kentucky (55 per 100,000), where 28.0% of women were current smokers, and lowest in Utah (16 per 100,000), where only 9.3% of women smoked.[1,15] However, in 2015, 26% of adults, including both men and women, were current smokers in Kentucky, and 9% of adults were current smokers in Utah.[1]

Smoking Cessation Interventions

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.[18] 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.[18] Smokers who quit also lower their risk of cervical, gastric, and bladder cancer.[4,17,18]

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.[19,20]

The Lung Health Study

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).[21] 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.

School-based interventions

School-based interventions alone have not demonstrated long-term impact for smoking prevention.[22] 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.[23]

Minimum legal age of access to tobacco products

Raising the minimum legal age of access (MLA) to tobacco products is a tobacco control policy option that has gained momentum. Currently, the MLA set by the federal government is 18 years of age, but states and municipalities can raise the MLA to older ages. In 2015, Hawaii became the first state to raise the MLA to 21 years, and many municipalities, including Boston and New York City, have enacted MLA 21-years legislation. An Institute of Medicine report thoroughly evaluated public health implications of raising the MLA.[24] In the absence of direct evidence on this topic, the report was based on a series of assumptions about the impact of raising the MLA on reducing and delaying initiation of smoking. These assumptions were entered into statistical models that forecast the impact of increasing the MLA on smoking prevalence and smoking-caused premature deaths during the 21st century. Even the results of the more conservative Cancer Intervention and Surveillance Modeling Network estimated that an increase of the MLA to 21 years in 2015 would avert 249,000 smoking-caused premature deaths in a hypothetical U.S. birth cohort by 2100.

Despite the strong hypothetical evidence of benefit implied by the Institute of Medicine report, the dearth of direct evidence on raising the MLA makes it challenging to discern the actual impact of raising the MLA in real-world settings. Needham, Massachusetts became the first U.S. municipality to raise the MLA to 21 years in April of 2005. To evaluate the impact of raising the MLA, researchers used a post-intervention only time series approach to compare area-level smoking prevalence among high school students in Needham with 16 surrounding municipalities that had a constant MLA of 18 years.[25] The source of smoking prevalence data was a biennial survey administered to students in grades 9 through 12; data from 2006, 2008, 2010, and 2012 were presented. During this 6-year period, the decrease in prevalence of current smoking in Needham (7.4%) was only slightly larger than the 16 surrounding municipalities (6.3%). Numerous limitations weaken the evidence provided by this study, including the assessment of evidence only more than a year after the MLA 21 years was enacted; this is especially important in the Needham example because the MLA had been gradually increased to MLA 19 years in 2003 and MLA 20 years in 2004 and ignoring these previous MLA increases would bias the findings toward the null. The lack of high-quality direct evidence evaluating the public health impact of raising the MLA accentuates the future need for stronger direct evidence on this topic.

Community Intervention Trial for Smoking Cessation (COMMIT)

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).[26] 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.[27,28]

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 the 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).[29] The benefits of NRT product use have been consistently observed regardless of whether the product used was the patch, gum, nasal spray, inhaler, or lozenge.[29] Smoking cessation counseling alone is also effective;[30] even a brief intervention by a health care professional significantly increases the smoking cessation rate.[31]

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.[32] 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).[33]

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 health care providers. Now sponsored by the U.S. Public Health Service, the updated 2008 guidelines, "Treating Tobacco Use and Dependence" are available online.[34] The broad elements of these guidelines are:

1. Clinicians should document the tobacco-use status of every patient.
2. Clinicians should assess the readiness to quit of patients who use tobacco and assist those who wish to quit in setting a quit date.
3. Patients using tobacco should be provided with at least one of the effective brief cessation interventions that are available.
4. 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.
5. One or more of the three treatment elements identified as being particularly effective should be included in smoking-cessation treatment:
   1. Social support from clinicians in the form of encouragement and assistance.
   2. Skills training/problem solving (cessation/abstinence techniques).
   3. Pharmacotherapy, such as nicotine-replacement (e.g., patches, gum).
6. 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 [34] suggest a model based on outcomes from six major clinical trials of physician-delivered smoking intervention conducted in the late 1980s:[35] 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 NRT, 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

1. Ask
   • Screen for smoking status at every visit or admission.
2. Advise
   • 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)."
3. Assess
   • 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.
4. Assist/Counsel
   • 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.
5. 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

• Motivation
  • 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?"
• 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?"
• 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?"

Pharmacotherapy for Smoking Cessation

Pharmacological agents have been used successfully to aid in the cessation of smoking in the general population.[36] Since the original AHCPR guidelines [37] 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.[38,39,40,41] Pharmacotherapy of smoking cessation, including NRTs (gum, patch, spray, lozenge, and inhaler) and non-nicotine medications (e.g., bupropion and varenicline), results in statistically significant increases in smoking cessation rates over those of a placebo. Based on a synthesis of the results of 110 randomized trials, the researchers found that NRT treatments, alone or in combination, improved cessation rates over placebos after 6 months (RR, 1.58; 95% CI, 1.50-1.66).[29] The results of a meta-analysis of three randomized controlled trials that tested combination NRT versus single NRT interventions suggested that combining another type of NRT, such as nicotine lozenges, with the nicotine patch was more efficacious than the nicotine patch alone (odds ratio [OR], 1.43; 95% CI, 1.08-1.91).[42] However, this result was not confirmed in a subsequent randomized trial that compared an intervention of nicotine patch plus nicotine lozenge to nicotine patch alone.[43] There was little difference in 7-day point-prevalence abstinence after 26 weeks of follow-up (27% vs. 23%; P = .25) and no added benefit after 52 weeks of follow-up (20% vs. 21%; P = .86) between participants in the combination NRT intervention and those in the nicotine patch-alone intervention.

There are also non-nicotine 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 OR, 1.94; 95% CI, 1.72-2.19).[44] There is insufficient evidence to support the idea that combining bupropion plus NRT increases smoking cessation rates over those of NRT alone (summary OR, 1.37; 95% CI, 0.65-2.91).[44]

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.[45,46] 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.[45,46] 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).[45] The other study also showed a 46% higher continuous abstinence in the varenicline group (OR, 1.46; 95% CI, 0.99-2.17).[46] 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).[47] The prevalence of nausea in the varenicline group (37%) was more than triple that in the transdermal nicotine group (10%). However, this result was not confirmed in a subsequent randomized trial that compared varenicline with the nicotine patch.[43] There was little difference in 7-day point-prevalence abstinence after 26 weeks (24% vs. 23%; P = .82) or 52 weeks (19% vs. 21%; P = .61) between those randomly assigned to the varenicline intervention and those assigned to the nicotine patch intervention.

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."[48] 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."[48] 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).[49] 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.[50] 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).[51]

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.[52,53]

Non-nicotine products

Bupropion HCl

Also used as an antidepressant, bupropion HCl is a non-nicotine 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.

Fluoxetine

Although Zyban (bupropion HCl) is the only antidepressant approved by the FDA for smoking cessation, Prozac (fluoxetine HCl) has been shown to be effective.[54]

Cytisine

Cytisine is a naturally occurring compound isolated more than 50 years ago from the plant Cytisus laburnum, a partial nicotinic acetylcholine receptor agonist.[55] It has a long history of use for smoking cessation in Bulgaria and other eastern European nations, including clinical trials published in the 1970s. As this older evidence has been uncovered, it has led to more recent trials in western nations; a systematic review and meta-analysis showed clear benefit for cytisine compared with placebo.[55] For all trials combined (n = 9 trials; 2,141 cytisine participants, 1,879 placebo participants), the pooled RR for abstinence from smoking at the longest follow-up for cytisine was 1.59 (95% CI, 1.43-1.75), compared with placebo. When the analyses were limited to two high-quality trials published since 2008, the pooled RR for smoking abstinence was 3.29 (95% CI, 1.84-5.90).[55] There has been no evidence of serious adverse events, but gastrointestinal symptoms have been more common in the cytisine (12%) group compared with the placebo (7%) group.[55]

A randomized trial in New Zealand compared cytisine (n = 655) with NRT (n = 655).[56] Compared with the group who received NRT, the cytisine group had higher continued abstinence at 1 month (40% vs. 31%; risk difference 9%; 95% CI, 4%-15%), 2 months (31% vs. 22%; risk difference 9%; 95% CI, 4%-14%), and 6 months (22% vs. 15%; risk difference 7%; 95% CI, 2%-11%).[56] With respect to adverse events, there was no difference between groups for serious adverse events, but comparing the cytisine group with the NRT group, nausea and vomiting (28 events vs. 2 events) and sleep disorders (28 events vs. 2 events) were more common in the cytisine group.[56] This trial is noteworthy because of the following results:

1. It considerably strengthened an already substantial body of evidence indicating that cytisine is an efficacious smoking cessation pharmacotherapy.
2. It showed that cytisine is more efficacious than NRT products that are known to be effective.

Lobeline

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.[57]

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.[58]

Smoking Reduction

Among smokers who are interested in quitting but not ready to make an immediate quit attempt, gradually decreasing the number of cigarettes smoked per day leading up to a quit attempt may prove to be a viable intervention strategy. This "reduce to quit" approach was tested in the context of a randomized controlled trial. In this study, both the intervention group and control group received counseling with the goals of reducing the number of cigarettes smoked per day by 75% or greater by week 8 and to quit smoking entirely by week 12.[59] The intervention group (n = 760) also received smoking cessation pharmacotherapy (varenicline at a maintenance dose of 1 mg bid for 24 weeks), whereas the control group (n = 750) received placebo tablets. For the primary endpoint of self-reported smoking abstinence during weeks 15 through 24, a statistically significant risk difference of 25.2% (varenicline group, 32.1% vs. placebo group, 6.9%; 95% CI, 21.4%-29.0%) was observed. The clinical significance of this finding is that it provides evidence of benefit for a pharmacotherapy-enhanced intervention aimed to motivate smokers who are interested in quitting, but not yet ready to quit, to start by cutting down on the number of cigarettes per day as a lead-in to a subsequent quit attempt.

For a smoker who wants to quit, an important practical question is whether a quit attempt is more likely to successfully result in smoking cessation if it involves abruptly stopping smoking or gradually decreasing the number of cigarettes smoked per day leading up to a quit attempt. U.S. evidence-based guidelines recommend abrupt quitting as the preferred approach,[60] but guidelines from other countries vary on this matter. A systematic review of this topic revealed substantial heterogeneity in the results across studies, but the results showed that gradual cessation was associated with a 6% lower likelihood of smoking cessation than abrupt cessation that was not statistically significant (RR, 0.94; 95% CI, 0.79-1.13).[61] To directly test this question, 697 smokers who wanted to quit were recruited from 31 primary care clinics in England, and randomly assigned to either a gradual or abrupt smoking cessation intervention.[62] In this noninferiority trial, both groups were provided with access to nicotine replacement therapy during the two weeks before the planned quit date. In the gradual cessation group, plans were made to cut down the number of cigarettes per day by 75% by the planned quit date; however, the abrupt cessation group was advised to follow usual smoking patterns until stopping smoking entirely on the planned quit date. Both groups were provided with nicotine replacement therapy after the quit date and throughout the trial. For the primary endpoint of prolonged validated smoking abstinence at 4 weeks, the gradual cessation arm was less likely to quit smoking than the abrupt cessation arm (39.2% vs. 49.0%); a difference that was statistically significant (risk difference, -9.8%; 95% CI, 2.5%-17.1%). The statistically significantly lower likelihood of smoking cessation in the gradual versus abrupt intervention arms persisted during follow-up at 8 weeks (29.2% vs. 36.6%; risk difference, -7.4%; 95% CI, 0.4%-14.3%) and 6 months (15.5% vs. 22.0%; risk difference, -6.5%; 95% CI, 0.7%-12.2%). Baseline patient preferences for a gradual or abrupt quit attempt indicated that smokers who preferred the gradual quitting approach had a lower likelihood of smoking abstinence at 4 weeks (38% vs. 52%), suggesting that patient preferences for these methods may be a marker for other factors associated with successful quitting, such as motivation to quit; however, even when stratified by baseline patient preferences, the gradual cessation method resulted in lower likelihood of cessation both among those who preferred the gradual approach (34.6% vs. 42.0%) and those who preferred the abrupt approach (45.8% vs. 58.1%). The overall clinical significance of this study is that it provides evidence that in the setting of a pharmacotherapy-aided quit attempt among smokers interested in quitting, quitting abruptly is a more effective smoking cessation strategy than gradually cutting down on the number of cigarettes smoked before making a quit attempt; this holds true regardless of smoker preferences in methods. A quit attempt regardless of method should never be discouraged, but abrupt cessation appears to be the most effective strategy. In this context, abrupt cessation is distinct from making an unaided quit attempt (i.e., quitting "cold turkey").[61]

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.[63,64] However, the impact of NRT on smoking reduction appears not to be sustained in the long run.[65] 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.[64,66] 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.[63]

Financial Incentive Programs for Smoking Cessation

Financial incentive programs can offer additional support for smoking cessation efforts. Results from a recent randomized trial suggest that the efficacy of such programs may be influenced greatly by the way rewards are disbursed.[67,68]

The trial randomly assigned 2,538 participants to either one of four incentive programs or usual care. The four programs were combinations of scope (two programs targeted individuals, and two targeted groups of six participants) and incentive structure (one of the individual-focused programs and one of the group-focused programs provided rewards of approximately $800 to participants who achieved cessation at 6 months; the others required an initial refundable deposit of $150, supplemented with $650 in reward payments for successful cessation). The rationale for the four intervention arms was based on behavioral observations that 1) people are more loss averse than gain seeking and 2) collaboration/competition with others can bolster intervention efficacy.[67]

Two main dimensions of the intervention effects were explored:

1. Acceptance of the intervention.
2. Efficacy of the intervention.

Both intent-to-treat and per-protocol analyses were performed, with an in-depth sensitivity analysis for potential biases accompanying the latter. In the intent-to-treat analyses (which evaluated the overall efficacy of the interventions), all of the financial incentive arms demonstrated significantly higher 6-month abstinence rates than did usual care (9.4%-16%, compared with 6% for usual care). The 6-month abstinence rates were similar between the group-focused and individual-focused arms (13.7% and 12.1%, respectively; P = .29), but the reward-based programs were associated with higher abstinence rates than were the deposit-based ones (15.7% vs. 10.2%; P < .001).[67]

However, per-protocol analyses that accounted for the dramatically lower acceptance rate for the deposit-based interventions than for the reward-based interventions (14% vs. 90%) estimated that 6-month abstinence rates could be 13.2 percentage points (95% CI, 3.1-22.8) higher in the deposit-based programs than in the reward-based programs among the estimated 13.7% of participants who would participate in either type of program. That is, deposit-based interventions may be more efficacious than reward-based interventions but harder to get people to commit to.[67]

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.[69,70,71,72,73] 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.[69,70] 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 with the use of 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.[74] 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).[74]

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Changes to This Summary (04 / 27 / 2017)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Evidence of Benefit

Added American Cancer Society as reference 1.

Added text to state that in 2015, 26% of adults, including both men and women, were current smokers in Kentucky, and 9% of adults were current smokers in Utah.

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About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the prevention and cessation of cigarette smoking and the control of tobacco use. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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