NCI/PDQ^® Health professionals: Cigarette Smoking: Health Risks and How to Quit (PDQ®)

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National Cancer Institute
Last Modified: February 3, 2012

TABLE OF CONTENTS

• Summary of Evidence
  • Effects of Smoking Cessation
  • Counseling and Smoking Cessation
  • Physician Advice and Smoking Cessation
  • Drug Treatment and Smoking Cessation

• Significance

• Evidence of Benefit
  • Background
  • Tobacco Cessation Guidelines
  • Pharmacotherapy for Smoking Cessation
    • Pharmacologic interventions to assist in tobacco cessation
      • Nicotine replacement therapy
      • Nonnicotine products
        • Bupropion HCl
        • Fluoxetine
        • Lobeline
        • Other Agents
  • Smoking Reduction

• Changes to This Summary (02/03/2012)

• Questions or Comments About This Summary

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
  • Contact Us

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Summary of Evidence

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], 1.321.84). 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 (relative risk [RR], 1.66; 95% CI, 1.421.94). 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, 1.501.66). 5 Treatment with bupropion improves cessation rates over placebo after 6 months (OR, 1.94; 95% CI, 1.722.19). 6 Varenicline therapy treatment improves cessation rates over placebo after 6 months (RR, 2.33; 95% CI, 1.952.80). 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. [PUBMED Abstract]
2. U.S. Department of Health and Human Services.: 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. Available online [PUBMED Abstract]
3. Lancaster T, Stead L: Physician advice for smoking cessation. Cochrane Database Syst Rev (4): CD000165, 2004. [PUBMED Abstract]
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. [PUBMED Abstract]
5. Silagy C, Lancaster T, Stead L, et al.: Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev (3): CD000146, 2004. [PUBMED Abstract]
6. Hughes JR, Stead LF, Lancaster T: Antidepressants for smoking cessation. Cochrane Database Syst Rev (1): CD000031, 2007. [PUBMED Abstract]
7. Cahill K, Stead LF, Lancaster T: Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev (3): CD006103, 2008. [PUBMED Abstract]

Significance

In the United States, smoking-related illnesses accounted for an estimated 443,000 deaths each year between 2000 and 2004. 1 On average, these deaths occur 12 years earlier than would be expected, so the aggregate annual loss exceeds 5 million life-years. 2 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. 3 It has been estimated that at least 30% of cancer deaths and 20% of all premature deaths in the United States are attributable to smoking. 1

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. 4 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. 3 5

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. 6 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. 6

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). 7 Elevated biomarkers of tobacco exposure, including urinary cotinine, tobacco-related carcinogen metabolites, and carcinogen-protein adducts, are seen in passive or secondhand smokers. 6 8 9 10

In 2007, 22.3% of adult men and 17.4% of adult women in the United States were current smokers. 11 (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 (44.0%) and high school dropouts (33.3%) and generally decreased with increasing years of education. 11 (Also available online.) Cigarette smoking prevalence among male and female high school students increased substantially during the early 1990s in all ethnic groups but appears to have been declining since approximately 1996. 12 13 (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. 12 14 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. 12 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 2001 to 2005 were highest in Kentucky (111.5 per 100,000), where 29.1% of men were current smokers in 1997, and lowest in Utah (33.7 per 100,000), where only 10.4% of men smoked. Among women, lung cancer death rates were highest in Kentucky (55.9 per 100,000), where 28.0% of women were current smokers, and lowest in Utah (16.9 per 100,000), where only 9.3% of women smoked. 12

References:

1. American Cancer Society.: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online [PUBMED Abstract]
2. Nelson DE, Kirkendall RS, Lawton RL, et al.: Surveillance for smoking-attributable mortality and years of potential life lost, by state--United States, 1990. Mor Mortal Wkly Rep CDC Surveill Summ 43 (1): 1-8, 1994. [PUBMED Abstract]
3. U.S. Department of Health and Human Services.: 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. Available online [PUBMED Abstract]
4. Centers for Disease Control and Prevention.: Targeting Tobacco Use: The Nation's Leading Cause of Death 2005. Atlanta, Ga: CDC, 2005. [PUBMED Abstract]
5. Ontario Task Force on the Primary Prevention of Cancer.: Recommendations for the Primary Prevention of Cancer. Toronto, Canada: Queen's Printer for Ontario, 1995. [PUBMED Abstract]
6. U.S. Department of Health and Human Services.: The Health Consequences of Involuntary Exposure to Tobacco Smoke: A Report of the Surgeon General. Atlanta, Ga: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Coordinating Center for Health Promotion, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2006. Also available online [PUBMED Abstract]
7. Cinciripini PM, Hecht SS, Henningfield JE, et al.: Tobacco addiction: implications for treatment and cancer prevention. J Natl Cancer Inst 89 (24): 1852-67, 1997. [PUBMED Abstract]
8. Finette BA, O'Neill JP, Vacek PM, et al.: Gene mutations with characteristic deletions in cord blood T lymphocytes associated with passive maternal exposure to tobacco smoke. Nat Med 4 (10): 1144-51, 1998. [PUBMED Abstract]
9. Benowitz NL: Cotinine as a biomarker of environmental tobacco smoke exposure. Epidemiol Rev 18 (2): 188-204, 1996. [PUBMED Abstract]
10. Hecht SS: Human urinary carcinogen metabolites: biomarkers for investigating tobacco and cancer. Carcinogenesis 23 (6): 907-22, 2002. [PUBMED Abstract]
11. Centers for Disease Control and Prevention (CDC).: Cigarette smoking among adults--United States, 2007. MMWR Morb Mortal Wkly Rep 57 (45): 1221-6, 2008. [PUBMED Abstract]
12. Jemal A, Thun MJ, Ries LA, et al.: Annual report to the nation on the status of cancer, 1975-2005, featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst 100 (23): 1672-94, 2008. [PUBMED Abstract]
13. Johnston LD, O'Malley PM, Bachman JG: Monitoring the Future: National Survey Results on Drug Use, 1975-2001. Volume I: Secondary School Students. Bethesda, Md: National Institute on Drug Abuse, 2002. NIH Pub. No. 02-5106. Also available online. [PUBMED Abstract]
14. U.S. Preventive Services Task Force.: Guide to Clinical Preventive Services: Report of the U.S. Preventive Services Task Force. 2nd ed. Baltimore, Md: Williams & Wilkins, 1996. [PUBMED Abstract]

Evidence of Benefit

Background

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. 1 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. 1 Smokers who quit also lower their risk of cervical, gastric, and bladder cancer. 1 2 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). 4 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. 7 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. 8

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). 9 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], 1.501.66). 12 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. 12 Smoking cessation counseling alone is also effective; 13 even a brief intervention by a health care professional significantly increases the smoking cessation rate. 14

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. 15 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). 16

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. 17 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, 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 17 suggest a model based on outcomes from six major clinical trials of physician-delivered smoking intervention conducted in the late 1980s: 18 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
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. 19 Since the original AHCPR guidelines 20 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 22 23 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, 1.501.66). 12

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, 1.722.19). 25 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, 0.652.91). 25

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, 1.042.06). 26 The other study also showed a 46% higher continuous abstinence in the varenicline group (OR, 1.46; 95% CI, 0.992.17). 27 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). 28 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. 29 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. 29 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, 1.092.71). 30 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 pharmacotherapiessuch as polymorphisms in genes encoding enzymes involved in nicotine metabolismthis information could eventually be integrated into smoking cessation treatment planning. 31 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). 32

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 (2224 weeks vs. 8 weeks) improves quit rates. 33 34

Nonnicotine products

Bupropion HCl

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.

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. 35

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. 36

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, 1.73.6) than smokers who received a placebo to remain abstinent from smoking after 6 months. 37

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 healthand ultimately the public's healthif 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. 40 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. 38

References:

1. U.S. Department of Health and Human Services.: The Health Benefits of Smoking Cessation. A Report of the Surgeon General. Rockville, Md: 1990. DHHS Publ No. (CDC) 90-8416. [PUBMED Abstract]
2. U.S. Preventive Services Task Force.: Guide to Clinical Preventive Services: Report of the U.S. Preventive Services Task Force. 2nd ed. Baltimore, Md: Williams & Wilkins, 1996. [PUBMED Abstract]
3. U.S. Department of Health and Human Services.: 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. Available online [PUBMED Abstract]
4. Anthonisen NR, Skeans MA, Wise RA, et al.: The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann Intern Med 142 (4): 233-9, 2005. [PUBMED Abstract]
5. Wingo PA, Ries LA, Giovino GA, et al.: Annual report to the nation on the status of cancer, 1973-1996, with a special section on lung cancer and tobacco smoking. J Natl Cancer Inst 91 (8): 675-90, 1999. [PUBMED Abstract]
6. Koh HK: The end of the "tobacco and cancer" century. J Natl Cancer Inst 91 (8): 660-1, 1999. [PUBMED Abstract]
7. Thomas R, Perera R: School-based programmes for preventing smoking. Cochrane Database Syst Rev 3: CD001293, 2006. [PUBMED Abstract]
8. Peterson AV Jr, Kealey KA, Mann SL, et al.: Hutchinson Smoking Prevention Project: long-term randomized trial in school-based tobacco use prevention--results on smoking. J Natl Cancer Inst 92 (24): 1979-91, 2000. [PUBMED Abstract]
9. Community Intervention Trial for Smoking Cessation (COMMIT): summary of design and intervention. COMMIT Research Group. J Natl Cancer Inst 83 (22): 1620-8, 1991. [PUBMED Abstract]
10. Community Intervention Trial for Smoking Cessation (COMMIT): I. cohort results from a four-year community intervention. Am J Public Health 85 (2): 183-92, 1995. [PUBMED Abstract]
11. Community intervention trial for smoking cessation (COMMIT): II. Changes in adult cigarette smoking prevalence. Am J Public Health 85 (2): 193-200, 1995. [PUBMED Abstract]
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