Overview

Key Points

Tobacco smoking leads to a dependence on nicotine that is indistinguishable from other forms of drug dependence. The revised fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) of the American Psychiatric Association (APA, 2000) classifies tobacco dependence as an addiction. In such a dependency, the drug is needed to maintain an optimal state of well-being. Nicotine, the addictive constituent of tobacco, meets these criteria because a typical withdrawal syndrome occurs after smoking cessation, tolerance to its use develops, and most importantly, use persists after developing symptoms attributable to the substance and in the face of its known harm. Some believe that nicotine is more addicting than cocaine or alcohol (Krasnegor, 1979; Lee and D’Alonzo, 1993; Kandel et al., 1997). However, a substantial fraction of daily smokers, perhaps as many as half, do not meet the DSM-IV criteria for nicotine dependence (Hughes et al., 2006; Donny and Dierker, 2007).

Nicotine acts on specific α4β2 nicotinic acetylcholine receptors in the mesocorticolimbic system, through neural pathways that are now seen as a common pathway for addictive drugs. Nicotine modulates the release of dopamine in the brain’s reward centers in the ventral tegmental area and the nucleus accumbens, decreasing the normal rate of degradation of dopamine as well. High concentrations of nicotine are delivered to the central nervous system (CNS) within seconds of a puff during smoking, with complete saturation of nicotinic receptors with as few as three cigarettes, and lasting as long as 3 hours (Brody, 2006).

It may take only one cigarette to hook an adolescent. About one fourth of young people experience a first-inhalation relaxation experience (FIRE) with their first cigarette, a large percentage of whom become addicted (DiFranza et al., 2007).

For tobacco-dependent persons, craving results when nicotine occupancy on receptors declines over time (e.g., during sleep at night). Relief from craving requires that the smoker replenish the nicotine within the receptor as completely as possible, which is why the first cigarette of the morning is often the most “satisfying” to addicted smokers. Since the cigarette is the most efficient rapid-delivery device for nicotine and the concurrent relief of craving, physicians and patients need to understand that medicinal nicotine replacement products are quite inefficient, by comparison, delivering lower concentrations of nicotine and incompletely resolving cravings.

The sheer number of nicotine doses is also highly reinforcing. A typical one-pack-daily smoker receives about 100,000 reinforcing hits a year, much more than with cocaine or heroin (Brunton, 1999).

Tobacco contributes to about 443,000 deaths annually in the United States and has rightly been dubbed the “leading cause of death in the United States” (McGinnis and Foege, 1993; Mokdad et al., 2004). One third of these smoking-related deaths are from cardiovascular disease and cerebrovascular accident (CVA, stroke), 29% from lung cancer, 20% from chronic respiratory disease, and at least 8% from cancers other than lung (Fig. 50-1). Just over 10% of deaths attributable to smoking occur in nonsmokers exposed to secondhand smoke, most from cardiovascular causes (CDC, 2008). Each year, smoking is responsible for 18% of the total deaths in the United States—seven times more Americans than were killed in the Vietnam War. Smoking has killed more Americans during the 20th century than were killed in battle or died of war-related diseases in all U.S. wars ever fought (Pollin and Ravenholt, 1984). Furthermore, cigarettes kill more Americans than alcohol, car accidents, suicide, AIDS, homicide, and illegal drugs combined (ACS, 2005).

Figure 50-1 Deaths attributable each year to smoking.

(From CDC Office on Smoking and Health. http://www.cdc.gov/tobacco/data_statistics/tables/index.htm.)

As shown by the grim, disease-specific facts, most smokers do not understand the implications for longevity involved in continued tobacco use. On the average, male smokers in the United States die 13.2 years earlier and females 14.5 years earlier than nonsmokers (Manson et al., 2000). Half of all continuing adult smokers will die of a cigarette-related illness (Doll et al., 2004). This relative lack of knowledge about tobacco harm may be in part because of the lack of publicity given to celebrities who die from smoking-related diseases (see eTable 50-1), although the death of news anchor Peter Jennings from lung cancer in 2005 received considerable attention and spurred increased interest in cessation.

The Centers for Disease Control and Prevention (CDC; 2009) estimated that in 2007, 19.8% of American adults smoked cigarettes (21.3% of men and 18.4% of women). Smoking prevalence is lowest among Asians (9.6%) and Hispanics (13.3%) and highest among American Indians and Alaska Natives (36.4%). Smoking prevalence is also higher among adults living below the poverty level (28.8%). Higher educational status confers additional protection against smoking, with persons holding a graduate degree smoking the least (6.2%). Thus, cigarette-related disease is increasingly becoming a set of afflictions suffered by the poor and undereducated, persons who understand the least about their risks and who have the poorest access to medical care resources (CDC, 2008).

In 2008, about one in five (20.4%) high school seniors smoked, the lowest level since monitoring started in the 1970s. Boys smoke more than girls in high school, (21.3% vs. 18.7%), and many more boys use smokeless tobacco (13.6% vs. 2.2%). The tobacco industry spends more than $12 billion annually on marketing (>$42 million/day) (Campaign for Tobacco-Free Kids, 2008).

Although few people start smoking as adults, each day 4000 children and adolescents try smoking for the first time, and 3000 of them become regular users of tobacco. Half of high school seniors who smoke started by age 14. Most smokers start smoking before 18, and only 5% start after age 20. Each year, 70% of those who smoke say that they would like to stop, and about 50% attempt to quit, but less than 5% succeed (Fiore et al., 2008). The likelihood of success in smoking cessation increases with the number of attempts, and those with a college education are twice as likely to succeed as less educated smokers. Family physicians must view tobacco addiction as a chronic disease that requires frequent intervention.

Health Risks Associated with Smoking

Toxins from cigarette smoke go everywhere the blood goes and cause disease in almost every organ of the body.

Cancer

Key Points

• A dose-response relationship exists between the number of cigarettes smoked and the risk of cancer. Those smoking more than one pack a day have 20 times the risk of nonsmokers.

• Smoking formerly labeled “low-tar” and “low-nicotine” cigarettes provides no benefit over smoking regular cigarettes.

• Less than half of all smoking deaths are from cancer; the rest are from heart disease, chronic lung disease, and stroke.

• Tobacco use increases the risk of cancer in most organs.

About 30% of all cancer deaths are attributable to cigarette smoking, with the evidence increasingly stronger. Box 50-1 lists diseases, including many cancers, for which the evidence is sufficient to infer a causal relationship, as well as those for which the evidence is sufficient only to suggest a causal relationship. Reviewing tobacco’s role in carcinogenesis, Hecht (2008) discusses several mechanisms that contribute to cancer, including metabolic changes in DNA and formation of DNA-carcinogen adducts, leading to mutation; inhibition of genes such as p53, a tumor suppressor; and mutations in the K-RAS oncogene (Fig. 50-2).

Box 50-1 Evidence-Based Relationship between Smoking and Disease

From US Surgeon General. The Health Consequences of Smoking: a Report of the Surgeon General, 2004. Rockville, Md, US Department of Health and Human Services, Public Health Service, Office of the Surgeon General, 2004.

The evidence is sufficient to infer a causal relationship between smoking and:

Cancer of the bladder, cervix, esophagus, kidney, larynx, lung, oral cavity, pharynx, pancreas, stomach

Acute myeloid leukemia

Abdominal aortic aneurysm

Subclinical atherosclerosis

Stroke (cerebrovascular accident)

Coronary heart disease

Chronic obstructive pulmonary disease (COPD)

Acute respiratory infections, including pneumonia

Reduced lung function in infants

Impaired lung growth during childhood and adolescence

Respiratory symptoms in children and adolescents, including cough, phlegm, wheezing, and dyspnea

Asthma-related symptoms (e.g., wheezing) in childhood and adolescence

Premature onset of age-related decline in lung function

All respiratory symptoms among adults, including coughing, phlegm, wheezing, and dyspnea

Poor asthma control

Sudden infant death syndrome (SIDS)

Reduced fertility in women

Fetal growth restriction and low birth weight

Premature rupture of membranes, placenta previa, and placental abruption

Preterm delivery and shortened gestation

Cataracts

Increased absenteeism from work

Adverse surgical outcomes related to wound healing and respiratory complications

Hip fractures

Low bone density in postmenopausal women

Peptic ulcer disease

The evidence is suggestive of a causal relationship between smoking and:

Colorectal cancer

Liver cancer

Increased prostate cancer mortality

Acute respiratory infections in persons with COPD

Increased lower respiratory tract illnesses during infancy

Impaired lung function in childhood and adulthood (with maternal smoking)

Poorer prognosis for children and adolescents with asthma

Increased nonspecific bronchial hyperresponsiveness

Ectopic pregnancy

Spontaneous abortion

Cleft palate

Low bone density in older men

Dental caries

Erectile dysfunction

Macular degeneration

Graves’ disease

Figure 50-2 Mechanisms that contribute to tobacco-caused cancer.

(From American Chemical Society, for Stephen S. Hecht. Progress and Challenges in Selected Areas of Tobacco Carcinogenesis.)

Lung

A clear dose-response relationship exists between lung cancer risk and daily cigarette consumption. From 1950 to 1990, the U.S. mortality rate for lung cancer increased fourfold for men and sevenfold for women. Although the mortality rates in men have been declining since 1990, lung cancer is still the principal cause of cancer death for both genders. In 1988, lung cancer passed breast cancer as the leading cause of death from cancer in women (Fig. 50-3). Although the lung cancer death rate has leveled off in U.S. women, in some states it is still increasing (Fig. 50-4).

Figure 50-3 A, Annual age-adjusted cancer death rates among males for selected cancers, United States, 1930–2005 (rates are age-adjusted to the 2000 U.S. population). Because of changes in International Classification of Disease (ICD) coding, numerator information has changed over time. Rates for cancers of the lung and bronchus, colon and rectum, and liver are affected by these changes. B, Annual age-adjusted cancer death rates among females for selected cancers, United States, 1930–2005 (rates are age-adjusted to the 2000 U.S. standard population). ∗Uterus includes uterine cervix and uterine corpus. Because of changes in ICD coding, numerator information has changed over time. Rates for cancers of the uterus, ovary, lung and bronchus, and colon and rectum are affected by these changes.

(A from US mortality data, 1960 to 2005, US Mortality 1930–1959. National Cancer Institute, CDC, 2008. CA Cancer J Clin 59:233, 2009; B from US mortality data, 1960 to 2005, US Mortality 1930–1959, National Center for Health Statistics, CDC, 2008. CA Cancer J Clin 59:234, 2009.)

Figure 50-4 Trends in age-standardized lung cancer death rates for the United States and select states by gender, 1975–2005.

(From Cokkinides V et al. CA Cancer J Clin 59:357, 2009.)

Unfortunately, early detection does not improve the survival rate for lung cancer. The 5-year survival rate is only 15% and has improved only slightly since the early 1960s (ACS, 2005). Almost 60% of lung cancer patients die within a year and 85% within 5 years. By the time the diagnosis is made, three of four patients already have metastases. However, the risk of death from lung cancer is substantially reduced when smoking is discontinued. Reducing smoking from an average of 20 cigarettes a day to less than 10 per day reduces the lung cancer risk by 25% (Godtfredsen et al., 2005). A diminished risk for lung cancer is experienced in former smokers after 5 years of cessation; however, the risk remains higher than that of nonsmokers for as long as 15 to 20 years (US Surgeon General, 2004).

Although the amount of tar in cigarettes has declined in recent years, the risk of lung cancer has not changed. Smoking formerly labeled “low-tar” and “low-nicotine” cigarettes provides no benefit over smoking regular cigarettes, and the uptake of carcinogens is no different in “regular,” “light,” and “ultralight” smokers (Hecht et al., 2005), as previously marketed. However, surveys show that most people believed “light” cigarettes to be less dangerous than regular cigarettes and regular cigarettes much more likely to cause illness. The recent federal legislation banning the use of words such as “light” from tobacco advertising is beginning to dispel this myth.

Increasing data regarding the genetic predisposition to lung cancer are emerging (see Smoker’s Genetics). Family aggregation related to lung cancer is likely multifactorial, including exposure to secondhand smoke, major genetic factors (e.g., chromosome 6p locus, CYP1A1 gene), other genes that modify risk of lung cancer, and genes that may enhance nicotine addiction or modify nicotine metabolism (D’Amico, 2008; US Surgeon General, 2004).

Larynx

The risk for laryngeal cancer is 20 to 30 times greater in smokers. About 70% of oral and 85% of laryngeal cancer deaths are directly attributable to smoking. The risks of cancer of the oral cavity, pharynx, and larynx drop sharply during the first 10 years after smoking cessation. There appears to be a synergistic, multiplicative effect between smoking and drinking, such that the risk for development of cancer of the larynx is as much as 75% higher in people who use tobacco and alcohol versus those exposed to either substance alone (US Surgeon General, 1990, 2004).

Esophagus

Cigarette smoking is a casual factor in both squamous cell carcinoma and adenocarcinoma of the esophagus. Heavy smokers (more than one pack per day) have 10 times the mortality from esophageal cancer as do nonsmokers.

Head and Neck

Cancers of the head and neck account for about 5% of all cancers diagnosed and 3% of cancer mortality each year. Tobacco use, whether smoking or chewing, is a key causal factor, with excess risks ranging from 5 to 25 times that of persons not using tobacco. Smoking accounts for 45% to 75% of all head and neck cancers (Freedman et al., 2007). The risks are dose dependent, and concurrent alcohol use multiplies the risks of developing head and neck cancer.

Pancreas

An equally dismal picture occurs with cancer of the pancreas, for which the 5-year survival rate is only 2%. Because of the nonspecific nature of the initial symptoms and the difficulty in making a diagnosis, the mean survival time after diagnosis of pancreatic cancer is less than 6 months. Smokers have two to three times the risk of pancreatic cancer as nonsmokers, and the risk is proportional to the amount smoked. Increased risk persists at least 10 years after quitting. More than one fourth of pancreatic cancer cases (27%) are attributable to cigarette smoking (Silverman et al., 1994; US Surgeon General, 2004).

Cervix Uteri and Ovary

Women who smoke cigarettes have four times the risk of cervical cancer as nonsmokers. Even women who smoke only 100 cigarettes during their lifetime more than double their risk of cervical cancer. The risk from smoking is greater in women younger than 30 than in those older than 30 (Slattery et al., 1989). Constituents from cigarette smoke, including mutagens and the carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), have been detected in the cervical mucus of smokers at levels 40 to 50 times those in serum. Smoking is a risk factor for cervical intraepithelial neoplasia (CIN) and cervical cancer among women who test positive as well as negative for human papillomavirus (HPV). The relative risks for CIN and cervical cancer are two to four times greater for current and former smokers compared with never-smokers (US Surgeon General, 2004). Although the risk of some types of ovarian cancer has been shown to be as much as three times greater in women who smoke cigarettes (Qian et al., 1989; Tworoger et al., 2008), the evidence is inadequate to confer a causal relationship (US Surgeon General, 2004).

Bladder and Kidney

Forty percent of bladder cancers are smoking-related, and higher rates of kidney cancers are also noted in smokers. Smokers have two to four times the risk of bladder cancer as those who never smoked. The risk for kidney cancer is strongly dose dependent. Even one to nine cigarettes per day creates a 60% excess risk of renal cell cancer in men, and the risk doubles for men smoking more than a pack a day. Overall, the relative risk (RR) for women smokers is about 1.38, and for men 1.54 (Hunt et al., 2005). Smoking accounts for most cancers of the renal pelvis and ureter in the United States (McLaughlin et al., 1996; US Surgeon General, 2004). The kidneys and bladder are the final common pathway for the concentration of toxic products of tobacco smoke and provide the longest direct exposure to carcinogens and radioactive substances, such as polonium 210, in tobacco smoke (Winters and DiFranza, 1982).

Colon and Rectum

A strong relationship has been noted between smoking and colorectal cancer, but the induction period is about 35 years. This lengthy induction would explain why it is just beginning to show up in women and indicates that efforts to prevent smoking among young people should be intensified (Giovannucci et al., 1994). The increased risk is about 20% higher for current smokers, and appears to be stronger for rectal cancer. Although the evidence is suggestive but not conclusive, a causal relationship would mean that about 12% of the colorectal cancer burden would be attributable to smoking (Tsoi et al., 2009; US Surgeon General, 2004).

Liver

Although the 2004 Surgeon General’s Report concludes that the relationship between smoking and liver cancer is suggestive but not causal, a meta-analysis from the World Health Organization (WHO) International Agency for Research on Cancer found an RR of 1.55 among current smokers and 1.2 among former smokers for development of liver cancer (Lee et al., 2009).

Leukemia

Overall, smoking cigarettes increases a person’s risk for leukemia by 30%. Mortality from leukemia is increased 50% in cigarette smokers (RR, 1.53), and the response is dose related. The risk is greatest for myeloid leukemia. The potent carcinogen benzene, a constituent of cigarette smoke, seems to be the major toxin responsible for leukemia among smokers. Approximately 14% of all cases of leukemia in the United States may be caused by cigarette smoking (Brownson et al., 1993).

Second Primary/Recurrent Cancers

Continued smoking interferes with both radiotherapy and chemotherapy used for cancer treatment. An increase in second primary tumors among continuing smokers is seen in lung (Lin et al., 2005) and head and neck cancer (Chuang et al., 2008). The emergence of contralateral breast cancer has also been linked to continued smoking among women (Li et al., 2009).

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