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A. Mortality and Morbidity from Smoking [2]

  1. Strongly correlates with amount smoked
  2. Usually quantitated in "pack-years" = number of packs (average/day) x years smoked
  3. Smoking contributes to both cardiovascular (CV)- [2,12] and neoplasia-associated deaths
  4. Smoking approximately doubles mortality rates in men
    1. Total and CV death rates in smokers 33.2 and 15.9 per 1000 person-years
    2. For non-smokers, these rates are 17.8 and 7.5 per 1000 person-years respectively
  5. Smoking increases risk of death ~3 fold between ages 40 and 70 years [7]
    1. In women, deaths occurred in 9% of never-smokers and 26% of heavy-smokers age 40-70
    2. In men, deaths occurred in 14% of never-smokers and 41% of heavy-smokers age 40-70
  6. Current smoking carries 2.95X risk of non-fatal acute myocardial infarction (MI) [2]
  7. Increase in numbers of adolescent smokers >70% in 1990s
  8. Smoking contributes to perioperative complications, morbidity, mortality [3]
  9. Second Hand Smoke (Passive Smoking)
    1. Passive tobacco smoke exposure accelerates atherosclerosis and increases mortality [2]
    2. Increases risk of death due to heart disease [4]
    3. Increases markers of inflammation including CRP, LDL cholesterol, homocysteine [8]
    4. Increases risk of bronchial hyperreactivity and dyspnea on exertion [26]
    5. Impaired endothelial dependent relaxation
    6. Reduction in coronary circulation (reserve blood flow) in healthy adults [42]
    7. No effect on serum IgE levels [26]
    8. Legislative ban on smoking in public places associated with improved pulmonary function in workers [9]
  10. Increased risk of death in smokers who use Oral Contraceptive Pills (OCP) [28]
    1. Death increased 1.2X for smokers 1-14 cigarettes per day
    2. Death increased 2.1X for smokers 15 or more per day
  11. Reducing Health Risks of Smoking
    1. Most excess vascular mortality due to smoking in women eliminated rapidly after cessation [22]
    2. Lung diseases due to smoking become normalized >20 years after cessation [22]
    3. Exercise reduces overall mortality rates in both smokers and non-smokers

B. Toxic Compounds in Tobacco Smoke

  1. Nicotine
    1. Vasoconstrictor activity
    2. Alkaloid Poison with major effects on coronary vessels
    3. Cigarettes contain 6-11mg of nicotine, with 1-3mg absorbed per cigarette
    4. Little variation in nicotine delivery per cigarette independent of package labelling
    5. Nicotine is rapidly absorbed even in smokeless tobacco
    6. Psychological and physical dependence - true craving
    7. Blacks metabolize nicotine more slowly than whites or Mexicans
    8. This (likely genetic effect) may lead to higher risk of nicotine dependence in blacks
  2. Tars
    1. Large number of heterocyclic polyaromatic compounds
    2. Most are mutagenic / carcinogenic and some are teratogens
    3. Include methyl-cholanthrene, benz[a]pyrene, all highly carcinogenic in mice
  3. Gaseous Compounds
    1. Carbon Monoxide - probably responsible for causing hypoxia and polycythemia
    2. Carboxyhemoglobin levels correlate well with amount of cigarette smoking
    3. Nitrogen oxides

C. Associated Diseases

  1. Pulmonary Parenchymal Disease
    1. Chronic Bronchitis (COPD) with exacerbations
    2. Exacerbation of asthma (including chronic decline in FEV1)
    3. Frequent infections (pneumonia, tracheobronchitis) [13]
    4. Chronic Hypoxemia - causing right heart failure
    5. Increased risk of invasive pneumococcal disease [10]
    6. Impaired maturation of lung function in adolescents
  2. Smoking Related Interstitial Lung Diseases (ILD) [13]
    1. Respiratory bronchiolitis with ILD (100% are smokers)
    2. Desquamative interstitial pneumonitis (85% are smokers)
    3. Langerhans' cell histiocytosis (95% are smokers)
    4. Usual interstitial pneumonitis (60% are smokers)
    5. Pulmonary hemosiderosis (40% are smokers)
  3. Vascular Disease
    1. Smoking and passive smoke exposure accelerate atherosclerosis [2]
    2. Smoking increases levels of C-reactive protein (CRP), an inflammatory marker [32]
    3. Smoking increases levels of fibrinogen and homocysteine which promote clotting [32]
    4. CAD - Myocardial Infarction (MI), Heart Failure
    5. Cerebrovascular Disease - quitting smoking rapidly reduces risk of stroke
    6. Peripheral Arterial (Vascular) Disease
    7. Second hand (passive) smoke clearly increases risk of cardiac events
    8. All cigarette smoke impairs endothelial relaxation (Whites>Chinese)
    9. Second hand smoke causes a dose dependent, impaired endothelium dependent arterial relaxation in healthy young adults [16]
    10. Inhibition of endothelium-dependent arterial relaxation by smoking is partially reversible [16] and may be due to hyperhomocysteinemia [32]
    11. Passive smoking is associated with ~1.2 fold increase in CAD [17]
    12. Smoking, hypertension and diabetes synergistically accelerate atherosclerosis [2]
    13. Smoking is strongly associated with Buerger's Disease (thromboangiitis obliterans)
  4. Neoplasia
    1. Malignant Pulmonary Disease: squamous > small cell cancer
    2. Head and Neck Cancers: mouth, lip, pharyngeal
    3. Esophageal Cancer: especially in chronic alcohol use
    4. Gastric Carcinoma
    5. Pancreatic Carcinoma: smoking is major risk factor
    6. Colorectal Cancer: >1.6X increased risk in women [22]
    7. Carcinoma of the Urinary Bladder
    8. Histiocytosis X (Langerhan's Cell Histiocytosis)
    9. Overall 7.5X risk for cancers related to smoking; >1.6X risk in "non-related" cancers [22]
  5. Renal Disease
    1. Increased risk in non-diabetics for both both microalbuminuria and reduced renal function
    2. Greatest risks in person who smoke >20 cigarettes (>1 pack) per day
    3. Risks of developing renal dysfunction are >1.8X for >1 pack versus <1 pack per day
    4. These values are in non-diabetics; higher risks in patients with diabetes
  6. Diabetes Mellitus Type 2 [5]
    1. Smoking causes impaired glucose tolerance
    2. Dose-related increase risk in development of type 2 diabetes
    3. Diabetes is synergistic with other factors that cause vascular disease
  7. Alzheimer Disease [18]
    1. Overall risk increased about 2 fold
    2. Risk increase primarily in patients without ApoE e4 genotype
  8. Fetal Distress
    1. CO is especially harmful in the placental circulation
    2. Smoking tobacco and chronic smoke inhalation are serious problems during pregnancy
    3. Smoking 1 pack per day, fetal arterial O2 saturation drops from 75% (normal) to ~58%
    4. Nicotine is also a poison for the fetus, affecting development of major systems
    5. Neurological development may be most affected
    6. Smoking increases risk of spontaneous abortion 1.8X [19]
    7. Smoking increases risk of chromsomal abnormalities in amniocytes from fetus [15]
  9. Age related macular degeneration (ARMD)
  10. Exacerbations of Crohn's Disease
  11. Associated with 1.4X increased rheumatoid arthritis risk, primarily RF+ disease [52]
  12. Gastric Hyperacidity - Reflux symptoms, Gastric or Duodenal Ulceration
  13. Skin Changes - increasing skin lines, nicotine stains
  14. Psychological and Physiological Dependence
  15. Cigarette smoking increases risk of various anxiety disorders 5-15 fold [12]
  16. Reduction in appetite

D. Criteria for Withdrawal Symptoms [20]

  1. Daily use of nicotine for at least 3 weeks
  2. Abrupt cessation or reduction in amount of nicotine, with more than 3 of the following:
    1. Dysmorphic or depressed mood
    2. Insomnia
    3. Irritability, frustration, or anger
    4. Anxiety
    5. Difficulty concentrating
    6. Restlessness
    7. Decreased heart rate
    8. Increased appetite or weight gain
  3. Symptoms cause clinically important distress or impairment in major areas of functioning
  4. Symptoms are not due to a general medical condition
  5. Symptoms are not better accounted for by another mental disorder

E. Cigar and Pipe Smoking

  1. Cigar and pipe smoking is associated with highly increased lung cancer rates
  2. Cigar Smoking Risks [4]
    1. Risk of coronary artery disease (CAD) ~1.3X (up to 2.7X in ApoE e4 carriers [41])
    2. Risk for cancers of upper aerodigestive tract ~2.0X
    3. Risk for lung cancer ~2.1X
    4. Increased risk for impaired fasting glucose and type II diabetes (2-3X) [5,38]
    5. Dose dependent increase in risks is observed

F. Assessing Patients [1,6,46]

  1. Physicians must play an aggressive role in getting patients to quit smoking
  2. Clinical Practive Guideline [45]
    1. Primary care physician plays major role
    2. Treat every smoker with cessation or motivational intervention
    3. Counseling (physician guidance) combined with pharmacotherapy strongly recommended
    4. Referral to smoking cessation specialist should be considered
  3. Ask about tobacco use
  4. Advise to quit
    1. Be as personal but strong as possible
    2. "Quitting smoking is the MOST important action you can take to stay healthy [45]
  5. Assess willingness to make cessation attempt and determine date for cessation
    1. Self-help programs are only marginally effective [14]
    2. Assist in cessation attempt - see Therapy below
    3. Pharmacologic intervention is about 2X as effective as placebo [14]
  6. Arrange followup, usually within first week after cessation date
  7. Cancer screening should be aggressive in all smokers, particularly heavy smokers
  8. Public Health Service Guideline http://www.surgeongeneral.gov/tobacco

G. Pharmacotherapy [6,21,46]

  1. Overview [1,14]
    1. Bupropion (Zyban®), an atypical antidepressant, should be considered
    2. Nicotine replacement should also be offerred to most patients
    3. Varenicline (Chantix®), an acetylcholine receptor agonist, likely more effective than buproprion
    4. Strong message to patients who smoke from their physicians is a critical component of smoking cessation [11]
  2. Bupropion (Zyban®, Wellbutrin® SR) [14,21,24]
    1. Atypical antidepressant with clear efficacy
    2. In several trials, higher abstinance rates than nicotine replacement therapy [21,23]
    3. As single agent, probably as effective as any nicotine replacement therapy [45]
    4. May combine with nicotine gum or patch therapy, but also effective alone
    5. Sustained release 150mg po qd x 3 days then bid for 7 to >12 weeks recommended
    6. At 12 months, abstinence 30.3% with bupropion alone, 35% combined with patch [23]
    7. In COPD patients, Bupropion SR treatment had 16% abstinence versus placebo 9% at week 26 [39]
    8. Bupropion (300mg/d) maintained for 52 weeks leads to 55% abstinence compared with 42% abstinence over 7 weeks of treatment [43]
    9. Quit rates in African Americans at 6 months were 21% for Buproprion SR 150mg qd and 13.7% with placebo; depression symptoms also reduced [47]
    10. Generally well tolerated, but insomnia (~25%), dry mouth, anaphylactoid reactions occurred
    11. In patients receiving 300mg/day, mean weight gain after 7 weeks was 1.5kg (3.3 lbs)
  3. Varenicline (Chantix®) [53,54]
    1. Alpha4-Beta2 nicotinic acetylcholine receptor (nAChR) partial agonist
    2. nAChR reinforces effects of nicotine, enhancing dopamine release
    3. Varenicline causes ~50% of dopamine release as nicotine in animal models
    4. Varenicline 1mg bid significantly more effective than placebo in 12 week smoking cessation
    5. Varenicline significantly more effective than buproprion SR at 12 and 24 weeks smoking cessation phase III study
    6. Superior to placebo for maintaining abstinence from smoking in patients who quit [44]
    7. Main side effect is nausea, occurred in ~30% of patients taking varenicline
    8. Abnormal dreams, contipation, also occur
    9. Increased neuropsychiatric symptoms, particularly in those with pre-existing conditions, have been reported in observational but not randomized studies [56]
  4. Nicotine - Overview [14]
    1. Peak serum nicotine levels after smoking occur at 10 minutes ~16ng/mL
    2. Half-maximal nicotine levels at ~60 minutes after smoking
    3. Different nicotine formulations provide different profiles of nicotine replacement
    4. Nicotine nasal spray, inhaler and gum provide peak levels in 10-30 minutes
    5. Nicotine patch provides prolonged sustained nicotine levels (14ng/mL at 2 hours)
  5. Nicotine Inhalers (Nicotrol® Inhaler) [25]
    1. Inhalers are easy to use and increase 1 year quit rates by about 50%
    2. Quit rate at 12 months was 28% compared with 18% for control
    3. Weight gain in 10-14 pound range was seen over 1 year in treated and control groups
  6. Nicotine Patch (Nicoderm® CQ, Nicotrol®) [20]
    1. Most patches are worn 24 hours per day
    2. Some patches are worn only 18 hours per day to similate usual smoking patterns
    3. Typical doses are 14-22mg/day nicotine (patch) to begin with
    4. Starting dose is usually selected based on current smoking useage
    5. A particular dose is usually maintained for 2-3 weeks, then lowered
    6. Final dose is 7mg/day (5mg for the 18 hour patches)
    7. Smoking is contraindicated during patch wearing
    8. 44mg patch is safe but appears no more effective than 22mg/day patch in long term
    9. Note that ~12-18 hours are required to absorb all nicotine from skin after patch removal
    10. Patch increased patients not smoking after 1 year: from 9% (placebo) to 25% patch
    11. However, abstinance rates in another study was similar to (16%) placebo (15%) [23]
    12. May be combined with nicotine gum when urges are very high
    13. Addition of nicotine nasal spray prn to patch improved overall responses [29]
    14. Abstinence rates at one year for patch combined with buproprion >20% [23]
    15. Appears to be cost-effective, <$1000 per life year saved
  7. Nicotine Nasal Spray (Nicotrol® NS)
    1. Provides very rapid peak serum nicotine levels (6ng/mL nicotine with 1mg nasal spray)
    2. Addition of nicotine nasal spray prn to patch improved overall responses [29]
    3. Abstinence rates with patch + spray 27% at one year versus 11% for patch alone [29]
  8. Nicotine Nasal Spray versus Patch [50]
    1. Abstinence rates at 6 months 12.2% with spray, 15.0% with patch
    2. Low to moderate dependence, non-obesity, white race did better with transdermal patch
    3. Highly dependent, obese, or minority race did better with spray
  9. Nicotine Gum (Nicorette®) [31]
    1. Both 2mg and 4mg gums are available
    2. Delivery is ~50% of nicotine level, approximately equivalent to one cigarette
    3. Extremely poor taste but fairly effective in reducing and/or eliminating smoking
    4. ~30% reduction in withdrawal symptoms
    5. Probably best used in patients to prevent "next" cigarette (to get over "craving")
    6. Now available over the counter in USA
  10. Contraindications to Nicotine Medications
    1. Recent MI is a relative contraindication
    2. Known hypersensitivity or allergy to nicotine
    3. Presence of CAD is not a major contraindication [33]
  11. Nortriptyline [34]
    1. Tricyclic Antidepressant (secondary amine)
    2. Initial dose 25mg po qhs, titrated to 75-100mg/d or maximal tolerated dose
    3. Initiate therapy 10-28 days prior to proposed quit date
    4. Significant reduction in withdrawal symptoms
    5. Cessation rate at 6 months was 14% with nortriptyline and 3% with placebo
    6. Dry mouth occurred in 64% and dysgeusia occurred in 20%
  12. Other Agents
    1. Buspirone (BuSpar®, 5 tid initial, to 20mg po tid) may help anxiety and improve quit rates
    2. Clonidine 0.1-0.3mg/d for 3-10 weeks second line
    3. Hypnotism has been effective in some patients
    4. Acupuncture has not been effective in randomized trials
    5. Vitamin A (as ß-carotene) of no benefit and may be harmful in smokers [30]
    6. Vitamin E is of little benefit in preventing CV disease in smokers [30]
    7. Nicotine vaccines are in clinical trials
  13. Anxiety and depression should be treated agressively as needed
  14. A 10 week smoking cessation program lead to ~22% abstinence at 5 years (compared with ~5% with usual care) and lead to reduction in mortality [11]

H. Effects of Smoking Cessation

  1. Reduces overall risk of death from any cause
  2. Mortality reduction 36% in patients with CAD who quit smoking [49]
  3. Cardiovascular Effects
    1. Slows progression of atherosclerosis, but does not reverse it [2]
    2. Reduces risk of and death from MI
    3. Reduces risk of recurrent MI to non-smoker levels within 3 years of cessation [48]
  4. Effects on Lung Disease
    1. Over 18% overall reduction in mortality at 14.5 years in patients with asymptomatic airway obstruction [11]
    2. Reduces progression of COPD / emphysema
    3. Reduced lung cancer risk: In patients who smoked >15 cigarettes per day, quitting reduces the risk of lung cancer by >50% [27]
    4. Reduces risk of developing oral cancer by >50% [51]
    5. Long term use of non-steroidal anti-inflammatory drugs (NSAIDS) reduced risk of oral cancers in smokers [51]
  5. Perioperative Smoking Intervention
    1. Intervention 6-8 weeks prior to surgery reduced complications from 52% in control to 18% in intervention group
    2. Perioperative smoking intervention strongly recommended
  6. Weight Gain Associated with Smoking Cessation
    1. Cessation often associated with an increase in 5-10 pounds (3-4.5 kg) weight [24,25,35]
    2. Exercise and careful attention to diet help mitigate weight gain [45]
  7. Smokers with a history of depression who refrain from smoking have high risk of depression relapse and should be closely followed [40]

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