Nicotine addiction is the second-leading cause of death worldwide. Cigarette smoking kills more than 480,000 Americans each year, with an estimated 49,000 of these deaths from exposure to secondhand smoke. 
Signs and symptoms
The time to first cigarette and total cigarettes per day are the 2 strongest predictors of nicotine addiction.
The physical effects of nicotine use include accelerated heart rate, increased blood pressure, and weight loss.
In addition to its physical effects, nicotine exerts a strong behavioral influence. Nicotine may enhance an individual’s level of alertness, although tobacco abuse and dependence may simulate a frantic, almost manic, picture. Speech may also be accelerated in line with behavior. Tobacco use can contribute to irritability, which is often soothed by a dose of nicotine.
See Clinical Presentation for more detail.
Nicotine addiction is now referred to as tobacco use disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). 
There are 11 possible criteria, of which at least 2 must be present in the last 12 months:
1. Tobacco taken in larger amounts or over longer periods of time
2. Persistent desire or unsuccessful efforts to cut down or control use
3. A great deal of time is spent on activities necessary to obtain or use tobacco
4. Craving or a strong desire or urge to use tobacco
5. Recurrent tobacco use resulting in a failure to fulfill major role obligations at work, school, or home
6. Continued tobacco use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by effects of tobacco (eg, arguments with others about tobacco use)
7. Important social, occupational, or recreational activities are given up or reduced because of tobacco use
8. Recurrent tobacco use in situations in which it is physically hazardous (eg, smoking in bed)
9. Tobacco use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by tobacco
10. Tolerance, as defined by one of the following:
a. The need for markedly increased amounts of tobacco to achieve the desired effect
b. A markedly diminished effect with continued use of the same amount of tobacco
11. Withdrawal, as manifested by either of the following:
a. The characteristic withdrawal syndrome for tobacco
b. Tobacco (or a closely related substance, such as nicotine) is taken to relieve or avoid withdrawal symptoms
See Workup for more detail.
Tobacco use remains the single largest preventable cause of death and disease in the United States.
Nicotine replacement therapy
Nicotine replacement therapy (NRT) works by making it easier to abstain from tobacco by partially replacing the nicotine previously obtained from tobacco.  All of the commercially available forms of NRT increase the chances of successful smoking cessation. Overall, NRT increases the quit rate by 50-70%, and the increase appears to be independent of any additional support provided.
Types of NRT products on the market today include the following:
Transdermal nicotine patch
Nicotine nasal spray
Sublingual nicotine tablet
The medications bupropion and varenicline have demonstrated efficacy for smoking cessation.
Bupropion acts by alleviating some of the symptoms of nicotine withdrawal. Like NRT products, bupropion has been endorsed by the US Clinical Practice Guideline as a first-line therapy.  Compared with placebo, bupropion approximately doubles smoking cessation rates, and it is equally effective for men and women.
Varenicline is a partial agonist that is selective for alpha-4, beta-2 nicotinic acetylcholine receptors (nAChRs). The drug helps smokers quit by preventing withdrawal symptoms while moderate levels of dopamine are maintained in the brain.
Some reviews have found that patients receiving varenicline are at an increased risk for serious adverse cardiovascular events. On the basis of study findings, extreme caution should be used when considering varenicline for patients with known cardiovascular problems.
Combination treatment with varenicline and bupropion may be more effective than single-drug therapy for smoking cessation in those smokers motivated to quit.
Nicotine addiction is the second-leading cause of death worldwide. The important causes of smoking-related mortality are atherosclerotic vascular disease, cancer, and chronic obstructive pulmonary disease (COPD). Smoking also can contribute to other diseases, such as histiocytosis X, respiratory bronchiolitis, obstructive sleep apnea, idiopathic pneumothorax, low birth weight, and perinatal mortality.
Currently, there are about 1.3 billion smokers the world, most (84%) of them in developing countries.  If current smoking trends continue, tobacco will kill 10 million people each year by 2020.  Through direct healthcare costs and loss of productivity from death and illness, tobacco will cost governments an estimated US $200 billion per year. A third of these costs will be borne by the developing countries. Many factors have led to increased global smoking rates, including the following:
Direct foreign investment
Transnational tobacco advertising, promotion, and sponsorship
International tobacco smuggling
Research investigating why people smoke has shown that smoking behavior is multifaceted. Factors influencing initiation of smoking differ from those influencing maintenance of smoking behavior. Nicotine dependence, genetic factors, and psychosocial factors all influence maintenance of smoking behavior.
Nicotine in cigarette smoke affects mood and performance and is the source of addiction to tobacco. It meets the criteria of a highly addictive drug, in that it is a potent psychoactive substance that induces euphoria, reinforces its own use, and leads to nicotine withdrawal syndrome when it is absent. As an addictive drug, nicotine has 2 very potent effects, being both a stimulant and a depressant. Thus, cigarettes may both get a smoker going in the morning and “chill out” the smoker during the day.
All healthcare professionals should be aware of the risks of tobacco smoking, understand nicotine addiction, and assist patients with smoking cessation.
In their 2010 guidelines, the American Heart Association (AHA) and the American Stroke Association (ASA) strongly recommended that smokers consider smoking cessation because of the direct correlation between smoking and both ischemic stroke and subarachnoid hemorrhage. Clinicians should provide counseling, nicotine replacement, and oral smoking cessation medications as options. Avoiding exposure to environmental tobacco smoke is reasonable. 
Illustrative case study
A young adult man met his primary care physician for the first time, during which his prior military history came to light. The young man recalled the anxiety he experienced when he received his military orders for deployment to Iraq. Before being notified of deployment, he smoked cigarettes only occasionally, perhaps 1 or 2 cigarettes a day.
As the time for deployment approached, the young man started smoking more cigarettes, and by the time he arrived in Iraq, he was up to a full pack a day. Throughout the 12-month deployment, the soldier steadily increased his smoking, reaching a peak consumption of nearly 40 cigarettes a day. He sustained several significant combat-related traumas resulting in mild physical injuries.
After returning home, the young man completed his military obligation and left the service. Although experiencing some lingering physical and emotional pain from his tour of duty, he was improving, except in 1 area: He continued to smoke 2 packs a day, despite efforts to quit. The former soldier’s wife complained that the expensive habit was creating an unnecessary financial strain on their meager resources. Furthermore, the young man himself no longer derived much pleasure from smoking, admitting that only the first cigarette of the day was truly enjoyable.
Despite his apparent willingness to consider quitting the use of tobacco, the former soldier also readily admitted that he was frightened by the prospect. He recognized that his unresolved emotional issues from the war, though currently being addressed in treatment, gave him a reason not to tackle another problem at this time. The doctor appreciated the frank disclosure but took issue with the patient’s conclusion. The patient appeared motivated and open to change but needed additional encouragement to consider a smoking cessation program.
At this point, the doctor decided to discuss concomitant disorders by explaining the common association of a mental disorder with substance misuse. The doctor further explained how tobacco use, at least in the beginning, helped the former soldier cope with anxiety. Trauma suffered in the war led to the developed of posttraumatic stress disorder (PTSD). The continued use of tobacco made it difficult to distinguish the symptoms of nicotine dependence from those of PTSD and delayed recovery from the emotional disorder.
The doctor asked the patient to think about this information and consider a smoking cessation program. Various medications were described that could alleviate nicotine withdrawal symptoms or reduce tobacco cravings. Such medications, combined with a behavioral strategy, offered the safest and surest route to a tobacco-free life. Discussions continued over a few more visits (including a meeting with the wife) before the patient decided to give up smoking. With the doctor’s help, he successfully completed a 3-month smoking cessation program.
Nicotine exerts its neurophysiologic action principally through the brain’s reward center. This neuroanatomic complex, otherwise known as the mesolimbic dopamine system, stretches from the ventral tegmental area to the basal forebrain. The nucleus accumbens, a dopamine-rich area, is an intersection where all addictive behaviors meet. The release of dopamine at this site promotes pleasure and reinforces the associated behaviors, such as the use of alcohol and drugs, to replicate the positive experience.
Other factors may also promote nicotine dependence, such as nicotine’s reduction in the monoamine oxidase inhibitor enzyme. This enzyme is involved in the metabolism of catecholamines, including dopamine. The net effect would be a lingering presence of the stimulating dopamine at the nucleus accumbens. 
A closer inspection of nicotine’s neurophysiology reveals a much more complex system. In particular, researchers continue to study the brain’s neuronal nicotinic acetylcholine receptors (nAChRs).The nAChRs play a central role in nicotine’s widespread influence on brain chemistry.
Researchers have identified several nAChR subtypes, broadly classified in terms of alpha and beta subunits; the alpha-4 and beta-2 subunits are the most widely expressed in the brain. Acting through the nAChRs, nicotine influences glutamate, gamma-aminobutyric acid (GABA), acetylcholine, dopamine, norepinephrine, and serotonin. 
Nicotine also releases corticosteroids and endorphins that act on various receptors in the brain. Nicotine use results in more efficient processing of information and reduction of fatigue. In addition, nicotine has a sedative action, reduces anxiety, and induces euphoria. Nicotine effects are related to absolute blood levels and to the rate of increase in drug concentration at receptors.
Nicotine stimulates the hypothalamic-pituitary axis; this, in turn, stimulates the endocrine system. Continually increasing dose levels of nicotine are necessary to maintain the stimulating effects. With regards to dependence, some experts rank nicotine ahead of alcohol, cocaine, and heroin. A teenager who smokes as few as 4 cigarettes might develop a lifelong addiction to nicotine.
Small, rapid doses of nicotine produce alertness and arousal, as opposed to long-drawn-out doses, which induce relaxation and sedation. Nicotine has a pronounced effect on the major stress hormones. It stimulates hypothalamic corticotropin-releasing factor (CRF), and it increases levels of endorphins, adrenocorticotropic hormone (ACTH), and arginine vasopressin in a dose-related manner. Corticosteroids also are released in proportion to plasma nicotine concentration.
Nicotine alters the bioavailability of dopamine and serotonin and causes a sharp increase in heart rate and blood pressure. It acts on brain reward mechanisms, both indirectly (through endogenous opioid activity) and directly (through dopamine pathways).
A cigarette delivers 1.2-2.9 mg of nicotine, and the typical 1 pack–per-day smoker absorbs 20-40 mg of nicotine each day, raising the plasma concentrations to between 23-35 ng/mL. Nicotine addiction results from positive reinforcement (with the administration of nicotine) and withdrawal symptoms that start within a few hours of the last cigarette.
Association with depression
The association between depression and smoking is well established. A lifetime history of major depression is more than twice as common in people who smoke than in people who do not. A history of major depressive disorder (MDD) is associated with a decreased ability to quit smoking and an increased likelihood of smoking relapse.
As shown by the National Institute on Alcohol Abuse and Alcoholism’s National Epidemiologic Survey on Alcohol and Related Conditions, current daily smokers with lifetime MDD and current MDD were more likely to report a continuation of smoking than those without a diagnosis of MDD. Former daily smokers with current MDD were also less likely to report continued abstinence. 
In subjects with a history of major depression, smoking may be an attempt to decrease negative affect. After an attempt to quit, such patients are likely to experience greater symptoms of nicotine withdrawal than smokers without a history of depression. Therefore, in patients who are attempting to quit smoking, inquiring about present or past symptoms of depression and anxiety is advisable, and specific therapy may be indicated.
Association with insomnia
Insomnia is an unrelenting problem affecting 10-35% of Americans.  As might be expected, the use of nicotine affects sleep. Nicotine reduces total sleep time, interferes with sleep initiation, and reliably fragments the sleep cycle. 
Association with posttraumatic stress disorder (PTSD)
The rates of smoking range from 40-86% among individuals with PTSD.  The co-occurrence of PTSD and nicotine use should be assessed among all current and former military service members. Roughly one third of current military service members smoke cigarettes.  The use of tobacco products increases with combat deployment, including the initiation of smokeless tobacco.  The strong relationship between smoking and combat-related PTSD may in part be explained by nicotine’s role in reducing the trauma-induced emotional numbness. 
United States statistics
In 1965, 52% of men and 34% of women were cigarette smokers. In 2013, an estimated 66.9 million Americans aged 12 or older were current (past month) users of a tobacco product. Also, 55.8 million persons (21.3% of the population) were current cigarette smokers; 12.4 million (4.7%) smoked cigars; 8.8 million (3.4%) used smokeless tobacco; and 2.3 million (0.9%) smoked tobacco in pipes. 
The rate of tobacco use has been declining slowly since 2002. Between 2002 and 2013, past month use of any tobacco product among persons aged 12 or older decreased from 30.4 to 25.5%, and past month cigarette use declined from 26.0 to 21.3%. 
In 2013, young adults aged 18 to 25 had the highest rate of current use of a tobacco product (37%), followed by adults aged 26 or older (25.7%), then by youths aged 12 to 17 (7.8%). 
In 2013, current use of a tobacco product among persons aged 12 or older was reported by a higher percentage of males (31.1%) than females (20.2%). 
In 2013, the prevalence of current use of a tobacco product was 40.1% for American Indians or Alaska Natives, 31.2% for persons reporting two or more races, 27.7% for whites, 27.1% for blacks, 25.8% for Native Hawaiians or Other Pacific Islanders, 18.8% for Hispanics, and 10.1% for Asians. 
Worldwide, approximately 1.1 billion people smoke. In China, more than 70% of men older than 25 years smoke. Smoking is more prevalent in developing countries and is continuing to increase. The prevalence of smoking in North America is decreasing; currently, approximately 25% of North Americans smoke.
Studies reveal that the average age of first-time smokers is 14.5 years and the average age of daily smokers is 17.7 years. Approximately 20% of high school seniors smoke.
Early onset of tobacco use contributes to greater rates of addiction, making adolescence a particularly vulnerable age. Specific neurobiologic factors may contribute to adolescent vulnerability.  In a study by Bandiera et al, an association between the effects of secondhand smoke and various mental disorders in children and adolescents was reported. 
The 2012 US Surgeon General’s report concluded that prevention efforts must focus on both adolescents and young adults because among adults who become daily smokers, nearly all first use of cigarettes occurs by age 18 years (88%), with 99% of first use occurring by age 26 years. 
The Surgeon General’s report also states that tobacco use among adolescents and young adults has decreased substantially, especially since 1998. However, this decrease has begun to level off, particularly since 2007. Some groups have demonstrated increases in the prevalence of tobacco use (eg, the growth of smokeless tobacco use among white males). Some groups of young people continue to smoke more than others, notably American Indians and Alaska Natives but also whites and Hispanics.
With the introduction of new tobacco products and the promotion of smokeless tobacco products, use of multiple tobacco products is common. Among tobacco users, more than 50% of white and Hispanic high-school males and nearly 50% of Hispanic high-school females use more than one product.
According to the latest data from the U.S. Centers for Disease Control and Prevention and the U.S. Food and Drug Administration's Center for Tobacco Products, 3 million middle and high school students reported using e-cigarettes in 2015, compared with 2.46 million in 2014. 
Sex- and race-related demographics
In the United States, approximately 34% of men and 22% of women smoke. American Indians or Alaskan Natives have the highest rates of tobacco use, followed by whites. 
Mortality and morbidity
The health consequences of nicotine addiction are enormous. Tobacco smoking is responsible for 1 of every 5 deaths and is the most common cause of cancer-related deaths in the United States. Children smoke 1.1 billion packs of cigarettes yearly. This accounts for more than $300 billion in future health care costs.
Tobacco accounts for more than 85% of all deaths due to lung cancer. Since the Surgeon General’s first report in 1964, approximately 10 million people in the United States have died from causes attributed to smoking; 2 million of these were from lung cancer alone. Furthermore, tobacco also has been identified as the leading cause of emphysema, COPD, bronchitis, and heart disease.
Laryngeal cancer is uncommon; however, in 1988, it accounted for 1.1% of cancer-related deaths in men and 0.3% of cancer-related deaths in women. Oral cancer accounted for approximately 2.1% of male cancer-related deaths and 1.2% of female cancer-related deaths in 1988. Cigarette smoking and tobacco chewing are major causes of this disease. Esophageal cancer accounted for 2.6% of male cancer-related deaths and 1% of female cancer-related deaths. Approximately 50% of overall esophageal cancer mortality is due to cigarette smoking.
Bladder cancer accounted for 2.4% of male cancer-related deaths and 1.3% of female cancer-related deaths in 1988; approximately one third of these deaths were related to cigarette smoking. Pancreatic cancer accounted for approximately 5% of cancer-related deaths in 1990; one third of these deaths were associated with cigarette smoking. Kidney cancer accounted for 2.3% of male cancer-related deaths and 1.8% of female cancer-related deaths.
Smoking has been established as an independent risk factor for uterine cervical cancer. Anal cancer in both heterosexual men and women also was due largely to cigarette smoking. Interactions between viral factors and tobacco exposure increase cancer risk.
Nonsmokers exposed to environmental tobacco smoke have a significantly higher risk of developing cancers and pulmonary diseases. Concentrations of toxins and carcinogens are higher in sidestream smoke. Children exposed to secondhand smoke develop a variety of respiratory disorders and morbidity.
An association between nicotine addiction and depression is well established. Previous studies also have demonstrated that dependent smokers have lower monoamine oxidase A and B activity than nonsmokers do. Smokers with a past history of major depression also were found to have significantly lower resting plasma norepinephrine levels. A history of depression also was found to be more frequent in female smokers.
Reports of severe major depressive episodes after smoking cessation indicate that the onset of severe depressive symptoms ranges from 2 days to 6 weeks after abstinence from smoking.
In some cases, depression after smoking cessation was resolved with the use of nicotine replacement therapy or the use of antidepressants; in others, depressive symptoms dissipated after a relapse to smoking. The significant predictors of major depressive episodes were as follows:
Having a history of major depression
Experiencing elevated withdrawal symptoms at the end of treatment
Obtaining information about any history of depressive symptoms is important, and when such a history is present, remaining alert to the possible onset of depression even weeks after smoking cessation treatment has ended is also important.
Antidepressants (eg, fluoxetine and sertraline) may be a useful cessation aid for smokers with prior major depression, and other authors have suggested that smokers with prior major depression benefit from mood management counseling and nortriptyline as cessation aids. Whether these treatments also prevent the onset of postcessation depression remains to be determined. It also remains to be seen whether effective management of withdrawal symptoms prevents postcessation depression.
Concerns about weight gain after smoking cessation are a well-known barrier to discontinuing tobacco use. In fact, many patients forego tobacco cessation fearing the subsequent weight gain. Such contentions often involve the comparative health risks of continued nicotine use versus weight gain. Current research offers little guidance concerning postcessation weight gain. Bupropion, nicotine replacement therapy (NRT), and varenicline appear to minimize weight gain only when prescribed, an effect that dissipates with the conclusion of pharmacologic treatment. Exercise can reduce weight over the long run. 
Smokers with weight concerns are more likely to relapse. Smoking for weight control reasons has been associated with being female, smoking more cigarettes per day, lower motivation to quit smoking, body image dissatisfaction, and higher Fagerstrom scores. 
All patients who smoke should receive education regarding the health effects of smoking. Patients should be provided with a variety of options and a range of advice that will allow them to escape the harmful effects of tobacco use and the addiction to nicotine.
Family education should be a primary recommendation every clinician undertakes in an effort to reduce teen smoking. Preliminary results from well-designed randomized controlled studies suggest that family interventions can reduce teen smoking. 
School-based smoking prevention programs educate students about tobacco use. Although such programs are widely seen in school curricula, the scientific evidence supporting their utility is limited. 
Both print and visual media are saturated with antismoking messages. A systematic review of the scientific literature shows that such messages have only a weak impact on smoking rates. 
Work-based smoking cessation programs that provide both behavioral treatment and medication support can be effective interventions with good quit rates. 
Naturally, many patients quit smoking on their own. (These probably would not be the typical patients seen in the office in the precontemplative or contemplative stage of change.) Such patients may be referred to various self-help materials (eg, books or pamphlets). The evidence that self-help materials lead to smoking cessation when used as the sole treatment strategy is weak.  Such materials are probably better used as tools to encourage personal education and to facilitate later dialogue between the clinician and the patient.
Patients interested in Web-based smoking cessation programs may find the following links helpful:
“ Freedom from Smoking,” available from the American Lung Association
The Tobacco Control Research Branch of the National Cancer Institute
The Smoking Quitline of the National Cancer Institute (NCI), which makes smoking cessation counselors available to answer smoking-related questions in English or Spanish by telephone or confidential online chat
The American Cancer Society website, which provides educational materials and can direct interested individuals to a community-based smoking cessation program called FreshStart
Nicotine Anonymous ,a fellowship-based program structured along the same lines as Alcoholics Anonymous
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