eMedicine Specialties > Psychiatry > Addiction

Nicotine Addiction

R Gregory Lande, DO, FACN, Clinical Consultant, Army Substance Abuse Program, Department of Psychiatry, Walter Reed Army Medical Center

Updated: Oct 14, 2009

Introduction

Background

Tobacco was first introduced into European society by Hernandez de Toledo in the sixteenth century. The Spaniard discovered the plant while exploring the Yucatan peninsula in 1520. The explorer sent specimens of the plant to Spain and Portugal. Jean Nicot of Portugal received the tobacco plant from Hernandez and eventually sent it to the Queen. For his efforts, the new world species was given the name nicotiana. Sir Walter Raleigh brought tobacco from Virginia to England in 1586, introducing the British to the new recreation called smoking. The exact origin of the word tobacco is lost in time. Some historians suggest the word tobacco refers to the Island of Tobago, or from Tabaco, which was a Mexican Province.¹

Almost immediately after its introduction into Western civilizations, tobacco attracted controversy. Its use was attacked for many reasons, some equating its use with the social problems associated with narcotics while others complained about the hygienic aspects of spit tobacco. Modern concerns about tobacco focus principally on its health-impairing qualities.

Cigarette smoking is a major preventable cause of disease worldwide, and it is the major cause of premature death in North America. In 1912, Adler first suggested that inhalation of cigarette smoke might be a cause of lung cancer. Since then, knowledge about the adverse health effects of smoking has accumulated. The important causes of mortality are atherosclerotic vascular disease, cancer, and chronic obstructive pulmonary disease (COPD). Smoking also can contribute to other diseases, eg, histiocytosis X, respiratory bronchiolitis, obstructive sleep apnea, idiopathic pneumothorax, low birth weight, and perinatal mortality.

Tobacco addiction, the second-leading cause of death in the world, is a culprit for approximately 5 million deaths each year or 1 in 10 adult deaths. Currently, about 1.3 billion smokers live in the world; most (84%) live in developing countries.² With the present smoking trends, tobacco will kill 10 million people each year by 2020.³ 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. These include trade liberalization; direct foreign investment; global marketing; transnational tobacco advertising, promotion, and sponsorship; and international tobacco smuggling.

Research investigating why people smoke has shown that smoking behavior is multifaceted. Factors influencing smoking initiation differ from those of smoking behavior maintenance. Nicotine dependence, genetic factors, and psychosocial factors influence maintenance of smoking behavior.

Nicotine meets the criteria of a highly addictive drug. Nicotine is a potent psychoactive drug that induces euphoria, serves as a reinforcer of its use, and leads to nicotine withdrawal syndrome when it is absent. As an addictive drug, nicotine has 2 very potent issues: it is a stimulant and it is also a depressant. For example, one smoker talked too lovingly about her cigarettes who are called her "best friend." They got her going in the morning, and they chilled her out during the day.

Nicotine in cigarette smoke affects mood and performance and is the source of addiction to tobacco. While cigarette manufacturers have publicly denied that nicotine is an addictive drug, recent documents disclose that they have known and used the addictive properties of nicotine since the 1950s. Unfortunately, this misinformation led to the false belief that nicotine use is a habit and not an addiction.

All health care professionals should be aware of the risks of tobacco smoking, understand tobacco addiction, and assist patients with smoking cessation.

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. Prior to the notice of deployment, he smoked cigarettes only occasionally, maybe 1 or 2 cigarettes a day. As the time for deployment approached, he started smoking more cigarettes and by the time he arrived in Iraq was up to a full pack a day. Throughout the 12-month deployment, he steadily increased his smoking with peak consumption of nearly 40 cigarettes a day. The soldier suffered several significant combat-related traumas resulting in mild physical injuries.

Upon return to the United States, the soldier completed his military obligation and left the service. Although still experiencing some lingering physical and emotional pain from his tour of duty, the former soldier was improving except in one area. His use of tobacco products stubbornly persisted, despite efforts to quit. The 2 packs of cigarettes a day was not only expensive, it was no longer enjoyable. When closely questioned he admitted that only the first cigarette of the day was truly enjoyable. His wife was complaining that the expensive habit was creating an unnecessary financial strain on their meager resources.

Despite his apparent willingness to consider quitting the use of tobacco, the former soldier also readily admitted he was frightened by the prospect. He recognized that his unresolved, but currently under treatment, emotional issues from the war offered a reason not to tackle another problem at this time. The doctor appreciated this frank disclosure but took issue with the patient’s conclusion. The patient appeared motivated, probably contemplating change, but needed an additional boost to consider a smoking cessation program.

At this point, the doctor decided to discuss co-occurring 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. After the traumas suffered in the war, the patient developed posttraumatic stress disorder (PTSD). The continued use of tobacco made it difficult to distinguish the symptoms of nicotine dependence from PTSD, and it delayed recovery from the emotional disorder.

The doctor asked the patient to mull this information over and consider a smoking cessation program. As the doctor further proposed, various medications could alleviate nicotine withdrawal symptoms or reduce tobacco cravings. Medications, when combined with a behavioral strategy, offered the safest and surest route to a tobacco-free life. The patient and the doctor continued to address the issue over a few more visits, including a conjoint meeting with the wife, before he decided to give up smoking. With the doctor’s help, he successfully completed a 3-month smoking cessation program.

Pathophysiology

Nicotine exerts its neurophysiologic action principally through the brain's reward center. This neuroanatomical 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 monamine oxidase inhibitor enzyme. This enzyme is involved in the metabolism of catecholamines, to include dopamine. The net affect would be a lingering presence of the stimulating dopamine at the nucleus accumbens.⁴

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 are a central component involved in nicotine's widespread influence on brain chemistry. Researchers have identified nAChR subtypes, most prominently labeled as 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, GABA, acetylcholine, dopamine, norepinephrine, and serotonin.⁵

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. Nicotine 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. Nicotine acts on brain reward mechanisms, indirectly through endogenous opioid activity and directly through dopamine pathways.

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 compared to people who do not smoke. A history of major depressive disorder is associated with a decreased ability to quit smoking and an increased likelihood of smoking relapse. Increased relapse rates of major depression after smoking cessation also have been described. In subjects with a history of major depression, smoking may be an attempt to decrease negative affect, and following a quit attempt, they are likely to experience greater symptoms of nicotine withdrawal compared to 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.

Frequency

United States

In 1965, 52% of men and 34% of women were cigarette smokers. Presently, the incidence of cigarette smoking has decreased to 28% and 24%, respectively. The incidence of smoking is highest in blacks, blue-collar workers, less-educated persons, and persons in the lower socioeconomic strata.

• The trend is decreasing in more educated persons. Forty percent of men with less than 12 years of education, 35.9% of high school graduates, and 17.4% of college graduates smoke. Of women, 30.7% with less than 12 years of education, 29.6% of high school graduates, and 15.1% of college graduates smoke.
• Economic status also is related to smoking behavior. Of men with an income of $10,000-20,000 per year, 36.3% smoke, as opposed to 23.2% of men who make $50,000 or more per year. Of women who had a family income of $20,000 or less per year, 29.8% smoke, as opposed to 19.5% who make $50,000 or more per year.
• In 1983, a comparison was made between white-collar workers, of whom 27.9% smoked, and blue-collar workers, of whom 42.7% smoked.
• Twenty-five percent of pregnant women who smoke quit during pregnancy; yet 80% resume smoking after childbirth.
• Recent surveys show that 20% of teenage girls smoke, and 15% of teenage boys smoke.

International

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. Prevalence of smoking in North America is decreasing, currently approximately 25% of North Americans smoke.

Mortality/Morbidity

The health consequences of this 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 $200 billion in future health care costs.

Tobacco accounts for more than 85% of all deaths due to lung cancer. Approximately 10 million people in the United States have died from causes attributed to smoking since the Surgeon General's first report in 1964; 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.

Race

The smoking rate in the United States is higher among blacks than whites and is steadily increasing in Hispanics. In 1987, 39% of the black male population were smokers, compared to 30.5% of white men; 28% of black women were smokers, as opposed to 26.7% of white women. In addition, 30% of Hispanic men and 18% of Hispanic women were smokers.

Sex

In the United States, approximately 28% of men and 24% of women smoke.

Age

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.

Clinical

History

• Nicotine addiction is classified as nicotine use disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). The criteria for this diagnosis include any 3 of the following within a 1-year time span:
  • Tolerance to nicotine with decreased effect and increasing dose to obtain same effect
  • Withdrawal symptoms after cessation
  • Smoking more than usual
  • Persistent desire to smoke despite efforts to decrease intake
  • Extensive time spent smoking or purchasing tobacco
  • Postponing work, social, or recreational events in order to smoke
  • Continuing to smoke despite health hazards
• Nicotine withdrawal is classified as a nicotine-induced disorder according to the DSM-IV-TR. Symptoms include difficulty concentrating, nervousness, headaches, weight gain due to increased appetite, decreased heart rate, insomnia, irritability, and depression. These symptoms peak in the first few days but eventually disappear within a month.
• Symptoms of nicotine toxicity, otherwise known as acute nicotine poisoning, include nausea, vomiting, salivation, pallor, abdominal pain, diarrhea, and cold sweat.
• A previous history of depression, use of antidepressants in the past, and onset of depression during previous quit attempts should be obtained.

Physical

• Physical effects of nicotine use include increased heart rate, accelerated blood pressure, and weight loss.
• Physical effects of nicotine withdrawal and smoking cessation include weight gain due to increase in appetite, decreased heart rate, and improvement in the senses of taste and smell.

Mental Status Examination

• Aside from the physical effects, nicotine exerts a strong behavioral influence. A complete mental status examination would begin with a general observation of the patient that commonly discloses the odor of smoke, tar-stained teeth, and premature skin aging.
• Nicotine may enhance an individual's level of alertness, although tobacco abuse and dependence may simulate a frantic, almost manic, picture. The speech may also be accelerated in line with the behavior. Tobacco use can contribute to irritability, often soothed by a dose of nicotine. The early phases of withdrawal can present with more irritability, anxiety, and agitation.
• People ostensibly use tobacco for the pleasure derived from the nicotine, but anxiety and depression commonly coexist.
• Tobacco use by itself would not be a significant risk factor for suicide. The co-occurring disorders such as depression and anxiety do increase the risk of suicide. The clinician should inquire about the patient's safety and probe further if the patient endorses suicidal ideation. The clinician should investigate if the suicidal ideation has matured to include a plan, and if so, what factors either aggravate or mitigate the patient's propensity to convert ideation to actual attempt.
• Nicotine would not normally produce perceptual or thought disorders such as visual hallucinations or delusions.
• The use of nicotine should not negatively impact memory, the ability to perform simple calculations, abstract thinking, or judgment.
• Tobacco use disorders should not cause delirium or dementia.

Differential Diagnoses

Other Problems to Be Considered

Fetal growth retardation
Atherosclerotic vascular disease
Cancer
Histiocytosis X
Respiratory bronchitis
Obstructive sleep apnea
Idiopathic pneumothorax
Low birth weight
Perinatal mortality

Treatment

Medical Care

Smoking Cessation Guidelines

• Ask about tobacco use.
• Advise to quit through personalized messages. 
• Assess willingness to quit.
• Assist with quitting.
• Arrange follow-up care and support.

Brief behavioral counseling (ie, under 10 min) and pharmacotherapy are each effective alone—although they are most effective when used together.⁷

The task force also advises clinicians to ask all pregnant women, regardless of age, about tobacco use. Those who currently smoke should receive pregnancy-tailored counseling supplemented with self-help materials.

Understanding the benefits and limitations of the available medications provides an important foundation for such a successful smoking cessation program.

• Assess smoking history, level of addiction, and the health status of the patient (see Media file 1). After the assessment, intervene with education and advice.
  
  

  

  Smoking cessation strategies for clinicians.

  
  
• Educate patients about the benefits of smoking cessation and the cessation process. Provide a description of the expected withdrawal syndrome. Continue with a discussion of the possible cessation methods, which include counseling, nicotine replacement, antidepressant medications, behavioral training, group therapy, hypnosis, and quitting "cold turkey."
  • More than 90% of patients who attempt to quit smoking stop cold turkey.
  • Professional group therapy or counseling achieves a 60-100% initial cessation rate and a 1-year cessation rate of approximately 20%.
  • Hypnosis and acupuncture are popular programs that might encourage renewed attempts by people who failed other techniques, but they are no different from placebo.
  • Verify successful cessation by measuring cotinine or carbon monoxide levels.
• A cigarette delivers 1.2-2.9 mg of nicotine, and the typical one pack-per-day smoker absorbs 20-40 mg of nicotine each day, raising the plasma concentrations to between 23-35 ng/mL. Nicotine produces increased expression of brain nicotine receptors, changes in regional brain glucose metabolism, the release of catecholamines, tolerance, and physiologic dependence. Nicotine addiction results from positive reinforcement (with the administration of nicotine) and withdrawal symptoms that start within a few hours of the last cigarette. The time to first cigarette and total cigarettes per day are the two strongest predictors of nicotine addiction. The nicotine dependence and nicotine withdrawal could be treated by the following:^8,9
  • Other forms of nicotine delivery
  • Drugs that selectively target one or more of the underlying mechanisms
  • Behavioral treatments, acupuncture, and other therapies

Smoking Cessation Therapies and Medications

Nicotine replacement therapy¹⁰

Nicotine replacement therapy works by making it easier to abstain from tobacco by partially replacing the nicotine previously obtained from tobacco. At least 3 mechanisms by which NRT could be effective include (1) reducing either general withdrawal symptoms, thus allowing people to learn without cigarettes, (2) reducing the reinforcing effects of tobacco-delivered nicotine, and (3) providing some psychological effects on mood and attention states.

Nicotine replacement medications should not be viewed as stand-alone medications that make people stop smoking. Reassurance and guidance from health professionals can be critical to achieve and sustain abstinence. Six types of nicotine replacement products are on the market. These include nicotine transdermal patch systems; nicotine nasal spray; and nicotine delivery through the oral mucosa including gum, lozenge, sublingual tablet, and vapor inhaler. Common adverse events that are common to all NRT products include dizziness, nausea, and headache.

• Transdermal nicotine patches¹¹
  • Nicotine patches deliver nicotine through the skin at a relatively steady rate. Currently, 4 patch formulations are on the market; they vary widely in their design, pharmacokinetics, and duration of wear (ie, 24- and 16-h wear). For some products, progressively lower doses can be used to provide weaning over a period of several weeks or longer to enable gradual adjustment to lower nicotine levels and ultimately to a nicotine-free state. Smokers who use more than 10 cigarettes per day should use the 21-mg/d patch for the first 6 weeks, move to the 14-mg/d strength for 2 weeks, then use the 7-mg dose for the final 2 weeks. Nicotine patches have higher compliance than other NRT products but may not adequately protect against craving provoked by smoking-related stimuli. For breakthrough cravings not adequately controlled by transdermal nicotine alone, acute therapies may be added.
  • A study tested the efficacy of nicotine patches in combination with behavioral therapy for the treatment of adolescent spit tobacco addiction. The usual care group's spit tobacco cessation rate was 11.4%; placebo patch, 25.0%; and active patch, 17.3%. The cessation rates for active and placebo patch were not significantly different, proving that behavioral intervention is twice as successful and that nicotine patch did not offer additional improvement.¹²
• Acute dosing forms
  • The amount and timing of these products can be titrated by the user, thus allowing the use of NRT medications as rescue medication for cravings. Ongoing craving in a quitter is associated with acute episodes of more intense craving called breakthrough craving. Provoked by situational stimuli, such as seeing someone smoke, or experiencing emotional upset, are associated with very high risk of relapse.
  • These therapies may also be used when a situation is expected to produce a craving, such as a demanding meeting, rush-hour traffic, commute, or social situation with cigarette smokers.
• Nicotine gum¹³
  • First available in the 1980s, nicotine polacrilex (nicotine gum) is available without a prescription. The gum is available in doses: 2 mg and 4 mg, delivering approximately 1 mg and 2 mg of nicotine. Users are instructed to use a piece of gum every 1-2 hours for the first 6 weeks, then to reduce use to one piece every 2-4 hours for 3 weeks, and one piece every 4-8 hours for 3 weeks. In highly dependent smokers, the 4-mg gum is superior to the 2-mg gum. Since about 50% of the nicotine in gum is absorbed, a fixed schedule of 10 pieces per day, a smoker receives about 10 mg or 20 mg of nicotine per day using the 2-mg or 4-mg gum, respectively.
  • The slow absorption of nicotine from gum doses does not produce the extremely high levels of nicotine. Acidic beverages interfere with buccal absorption of nicotine; patients should avoid acidic beverages (eg, soda, coffee, beer) for 15 minutes before and during chewing gum. Nicotine gum chewing may cause jaw soreness; therefore, the smoker should chew the gum to release nicotine, then move the gum between the cheek and gum for a minute or so. Gum can also cause a mild burning sensation in the mouth and throat, which may be undesirable.
  • In an open, randomized trial of 314 daily smokers, Etter et al found that starting nicotine gum 4 weeks prior to the quit date did not improve smoking cessation rates compared with initiating gum on the quit date. At follow-up 8 weeks after the target quit date, self-reported 4-week abstinence rates were 41.6% for the pre-quit date treatment group compared with 44.4% in the usual care group. Biochemically verified cessation occurred at 1 year following the quit date for participants, and no difference was found between the 2 groups (20.8% for the pre-quit date group vs 19.4% for the usual care group).^14,15
• Lozenge: Available in 2- and 4-mg formulations since 2002, nicotine from the lozenge is absorbed slowly through the buccal mucosa. The lozenge should not be chewed, and the amount of nicotine absorbed per lozenge is somewhat higher than that delivered by gum.
• Inhaler
  • Currently marketed as a prescription medication in the United States, the inhaler consists of a mouthpiece and a plastic cartridge containing nicotine. When the inhaler is "puffed," nicotine is drawn into the mouth of the smoker and satisfies the behavioral aspects of smoking, namely, the hand-to-mouth ritual.
  • Each inhaler cartridge contains 10 mg nicotine, of which 4 mg can be delivered and 2 mg are absorbed. Nicotine is not delivered to the bronchi or lungs, but rather it is deposited and absorbed in the mouth, like nicotine gum. Most people use between 6 and 16 cartridges a day, the recommended duration of treatment is 3 months, after which patients may be weaned by gradual reduction over the following 6-12 weeks.
• Nasal spray: Marketed as a prescription medication, the nasal spray delivers nicotine more rapidly than other NRTs and delivers acute craving relief. The multidose bottle with a pump delivers 0.5 mg of nicotine per 50-µL squirt. Each dose consists of 2 squirts, one to each nostril. The dose of nasal spray should be individualized for each patient based on the patient's level of nicotine dependence. Most patients are started with 1 or 2 doses per hour, which may be increased up to the maximum of 40 doses per day.
• Sublingual tablet: A small nicotine tablet has been developed but is not yet available in the United States. The product is designed to be held under the tongue, where the nicotine in the tablet is absorbed sublingually. The levels of nicotine obtained by use of the 2-mg tablet and 2-mg nicotine gum are similar. It is recommended that smokers use the product for at least 12 weeks, after that the number of tablets used is gradually tapered.

Smoking cessation treatments with NRT enable smokers to cease tobacco use and subsequently to withdraw from nicotine altogether. However, for some smokers, withdrawing from smoking completely may be difficult. In those individuals, there may be benefit by continuing to use NRT for longer periods, even indefinitely, to prevent relapse to smoking. This strategy is currently used in methadone maintenance programs for heroin-dependent patients, where patients may be maintained on daily doses of methadone for years. Although nicotine is not entirely without risk, nicotine maintenance is clearly safer than cigarette smoke-delivered nicotine with its numerous toxins. Therefore, indefinite NRT to prevent resumption of smoking may be considered for some individuals.

A Cochrane meta-analysis of 132 trials where any type of NRT and a placebo or non-NRT control group showed risk ratio of abstinence for any form of NRT relative to control at 1.58 (95% confidence interval [CI], 1.50-1.66). The pooled RR for each type were 1.43 (95% CI: 1.33 to 1.53, 53 trials) for nicotine gum; 1.66 (95% CI, 1.53-1.81, 41 trials) for nicotine patch; 1.90 (95% CI, 1.36-2.67, 4 trials) for nicotine inhaler; 2.00 (95% CI, 1.63-2.45, 6 trials) for oral tablets/lozenges; and 2.02 (95% CI, 1.49-3.73, 4 trials) for nicotine nasal spray. Therefore, all of the commercially available forms of NRT (gum, transdermal patch, nasal spray, inhaler, and sublingual tablets/lozenges) increase the chances of successful smoking cessation. Overall NRTs increase the rate of quitting by 50-70% and appear to be independent of the additional support.

Medications

• Bupropion (Zyban)^16,17
  • Bupropion acts by alleviating some of the symptoms of nicotine withdrawal, which includes depression. One clinical trial demonstrated that highly nicotine-dependent smokers who receive bupropion are more likely to experience a decrease in depressive symptoms during active treatment. Like NRT products, bupropion has been endorsed by the US Clinical Practice Guideline as a first-line therapy.⁸
  • Bupropion has been shown to approximately double rates of cessation compared with placebo, and the medication is equally effective for men and women. It has also been shown that bupropion combined with nicotine replacement medications may increase cessation rates relative to bupropion alone. The recommended and maximum dose of bupropion is 300 mg/d, given as 150 mg bid. Dry mouth and insomnia are the most common adverse events associated with use. A very small risk of seizure exists, which can be reduced by not prescribing the medication to persons with a history of seizure or a predisposition toward seizure.
• Varenicline (Chantix)
  • Varenicline (Chantix) is a partial agonist selective for alpha-4, beta-2 nicotinic acetylcholine receptors. Action is thought to result from activity at a nicotinic receptor subtype, where its binding produces agonist activity while simultaneously preventing nicotine binding. Agonistic activity is significantly lower than nicotine.
  • Varenicline, developed as a nicotine receptor partial agonist, help smokers quit by preventing withdrawal symptoms as moderate levels of dopamine are maintained in the brain. Cochrane meta-analysis included 5 trials of varenicline compared with placebo and 3 of these also included a bupropion as comparator. The pooled odds ratio (OR) for continuous abstinence for varenicline versus placebo at 12 months was 3.22, (95% CI, 2.43-4.27). The pooled OR for varenicline versus bupropion was 1.66 (95% CI, 1.28-2.16). The main adverse effect of varenicline was nausea, which was mostly at mild to moderate levels and usually subsided over time. Varenicline increased long-term smoking cessation rates by 3-fold compared with unassisted quit attempts.¹⁸
• Other medications: Besides NRT products and bupropion, nortriptyline and clonidine are endorsed by the US Clinical Practice Guideline as second-line therapies.
  • Nortriptyline¹⁶ : As a second-line therapy, studies have demonstrated the potential efficacy of nortriptyline for smoking cessation in smokers without history of major depression. Nortriptyline in combination with transdermal nicotine was also shown to enhance the cessation rates above levels seen with transdermal nicotine alone. The tricyclic antidepressant doxepin has also been shown in a small human study to improve cessation rates. The most commonly encountered side effects associated with nortriptyline include fast heart rate, blurred vision, urinary retention, dry mouth, constipation, weight gain or loss, and low blood pressure on standing.
  • Clonidine: An alpha-2-noradrenergic agonist used to treat hypertension, clonidine has been shown to diminish symptoms of both opiate and alcohol withdrawal symptoms. In one study of heavy smokers who had failed in previous quit attempts found that those treated with clonidine had twice the rate of abstinence as those treated with placebo at the end of the 4-week treatment, and the effect persisted for the 6-month follow-up period. Although clonidine may be efficacious in the treatment of nicotine addiction, the conditions under which it is most appropriately used are not well defined. The most common side effects of clonidine are constipation, dizziness, drowsiness, dryness of mouth, and unusual tiredness or weakness.

Combination products

• To improve smoking cessation, medications can be combined, such as passive nicotine delivery (eg, transdermal patch) with another medication that permits acute nicotine delivery (eg, gum, nasal spray, inhaler). Combining the nicotine patch (which may prevent the appearance of severe withdrawal) with acute dosing forms (which can provide relief in trigger-to-smoke contexts) may provide an excellent treatment option over either therapy alone.^19,20
• Bupropion in combination with a nicotine patch appears to be more efficacious than a nicotine patch alone, possibly because the 2 medications act via different pharmacologic mechanisms. Despite the possibility of increased efficacy concluded in the Clinical Practice Guideline, these therapies should be prescribed under the direction of an experienced clinician or the specialty clinic.²¹

Novel therapies

Since success of most pharmacological and behavior therapies is rather limited, alternative and improved treatments are needed. One novel approach is provided by immunization against nicotine. Antibodies induced by the vaccine bind nicotine in the blood, thus preventing it from reaching the nicotine receptors in the brain and breaking the cycle of nicotine addiction. A prototype vaccine against nicotine has been developed and studied in a randomized trial where 229 subjects received 5 intramuscular injections of the nicotine vaccine and 112 placebo. The vaccine was safe and generally well tolerated, despite failure to significantly increase continuous abstinence rates; results were significant in subgroup analyses. Although more studies are needed, immunotherapy appears to have opened a new avenue to the treatment of nicotine addiction.²²

Mecamylamine is a nicotine antagonist that, in principle at least, would seem to have a role in smoking cessation. As much as opiate antagonists prevent the user from achieving a high, so would mecamylamine block any pleasurable affects from nicotine. The research supporting the clinical use of mecamylamine awaits further study.²³

Consultations

Patients may be referred for group therapy or behavioral counseling. If an affective disorder is suspected, evaluation by a psychiatrist may be indicated.

Diet

Patients who quit smoking tend to gain weight; therefore, encourage patients to follow a low-calorie diet and exercise regimen during and after cessation.

Activity

While attempting smoking cessation, exercise has been shown to help curb weight gain and to help alleviate nicotine withdrawal symptoms.

Medication

Two types of medications are available as part of a smoking cessation program. Types include nicotine replacement therapy in the form of cutaneous patches, inhaled or nasal delivery, or chewing gum and the non–nicotine-containing tablet bupropion. These medications ameliorate withdrawal symptoms while the smoker deals with behavioral aspects of smoking cessation.

Nicotine chewing gum, if chewed correctly, increases quit rates up to 2-fold. At 1 year, the abstinence rate with the patch is 20%. At 4 years, the abstinence rate is 12.4% compared to 4.5% with placebo.

Nicotine replacement therapy (patches)

Nicotine patches are sold under the following trade names: NicoDerm, Nicotrol, and Habitrol. The dosing schedule of each is a graduated decrease of drug over 9-12 wk.

Nicotine transdermal system (NicoDerm CQ)

Works best when used in conjunction with a support program such as counseling, group therapy, or behavioral therapy.

Dosing

Adult

One 21-mg patch qd for 6 wk, then one 14-mg patch qd for 2 wk, followed by one 7-mg patch qd for 2 wk

Pediatric

Not established

Interactions

May decrease diuretic effects of furosemide and decrease cardiac output; may decrease absorption of glutethimide; may increase circulating cortisol and catecholamines; do not use if patient continues to smoke, use snuff, chew tobacco, or use other nicotine products because may increase toxicity of nicotine

Contraindications

Documented hypersensitivity; nonsmokers, children, pregnancy, life-threatening arrhythmias, severe or worsening angina pectoris

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution in peptic ulcer, coronary artery disease, angina, hypertension, peripheral arterial disease, diabetes, severe renal dysfunction, and hepatic dysfunction; may cause skin irritation

Nicotine transdermal system (Nicotrol)

Works best when used in conjunction with a support program such as counseling, group therapy, or behavioral therapy.

Dosing

Adult

One 15-mg patch qd for 6 wk, then one 10-mg patch qd for 2 wk, followed by one 5-mg patch qd for 2 wk

Pediatric

Not established

Interactions

May decrease diuretic effects of furosemide and decrease cardiac output; may decrease absorption of glutethimide; may increase circulating cortisol and catecholamines; do not use if patient continues to smoke, use snuff, chew tobacco, or use other nicotine products because may increase toxicity of nicotine

Contraindications

Documented hypersensitivity; nonsmokers, children, pregnancy, life-threatening arrhythmias, severe or worsening angina pectoris

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution in peptic ulcer, coronary artery disease, angina, hypertension, peripheral arterial disease, diabetes, severe renal dysfunction, and hepatic dysfunction; may cause skin irritation

Nicotine transdermal system (Habitrol)

Works best when used in conjunction with a support program such as counseling, group therapy, or behavioral therapy.

Dosing

Adult

One 21-mg patch qd for 3-4 wk, then one 14-mg patch qd for 3-4 wk, followed by one 7-mg patch qd for 3-4 wk

Pediatric

Not established

Interactions

May decrease diuretic effects of furosemide and decrease cardiac output; may decrease absorption of glutethimide; may increase circulating cortisol and catecholamines; do not use if patient continues to smoke, use snuff, chew tobacco, or use other nicotine products because may increase toxicity of nicotine

Contraindications

Documented hypersensitivity; nonsmokers, children, pregnancy, life-threatening arrhythmias, severe or worsening angina pectoris

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in peptic ulcer, coronary artery disease, angina, hypertension, peripheral arterial disease, diabetes, severe renal dysfunction, and hepatic dysfunction; may cause skin irritation

Nicotine replacement therapy (chewing pieces)

These are marketed in 2 strengths (2 mg and 4 mg). An individual who smokes 1 pack per day should use 4-mg pieces. The 2-mg pieces are to be used by individuals who smoke less than 1 pack per day. Instruct the patient to chew hourly and for their initial cravings for 2 wk, then gradually reduce amount chewed over the next 3 mo.

Nicotine polacrilex (Nicorette)

Comes in boxes containing 96 pieces and costs approximately US $20-30. The nicotine is absorbed through the oral mucosa. Quickly absorbed and closely approximates time course of plasma nicotine levels observed after cigarette smoking.

Dosing

Adult

1 piece of gum (2 mg) per h as needed to abstain from smoking; not to exceed 30 mg/d

Pediatric

Not established

Interactions

May decrease diuretic effects of furosemide and decrease cardiac output; may decrease absorption of glutethimide; may increase circulating cortisol and catecholamines; do not use if patient continues to smoke, use snuff, chew tobacco, or use other nicotine products because may increase toxicity of nicotine

Contraindications

Documented hypersensitivity; nonsmokers, children, pregnancy, life-threatening arrhythmias, severe or worsening angina pectoris

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in peptic ulcer, coronary artery disease, angina, hypertension, peripheral arterial disease, diabetes, severe renal dysfunction, and hepatic dysfunction; dental problems may become exacerbated with this dosage form

Nicotine replacement therapy (nasal spray)

Provides nicotine delivery through nasal mucosa

Nicotine polacrilex nasal spray (Nicotrol NS)

Intranasal nicotine may closely approximate time course of plasma nicotine levels observed after cigarette smoking.

Dosing

Adult

1-2 puff/h, each spray contains 0.5 mg of nicotine, not to exceed more than 10 puff/h (5 mg)

Pediatric

Not established

Interactions

May decrease diuretic effects of furosemide and decrease cardiac output; may decrease absorption of glutethimide; may increase circulating cortisol and catecholamines; do not use if patient continues to smoke, use snuff, chew tobacco, or use other nicotine products because may increase toxicity of nicotine

Contraindications

Documented hypersensitivity; nonsmokers, children, pregnancy, life-threatening arrhythmias, severe or worsening angina pectoris

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in peptic ulcer, coronary artery disease, angina, hypertension, peripheral arterial disease, diabetes, severe renal dysfunction, and hepatic dysfunction

Nicotine replacement therapy (inhaler)

Delivers nicotine through oral mucosa.

Nicotine polacrilex inhaler (Nicotrol Inhaler)

Quickly absorbed and closely approximates time course of plasma nicotine levels observed after cigarette smoking.

Dosing

Adult

Each inhaler cartridge delivers 4 mg of nicotine; once activated, may be used over several min to simulate smoking, although drug generally is absorbed from oral mucosa

Pediatric

Not established

Interactions

May decrease diuretic effects of furosemide and decrease cardiac output; may decrease absorption of glutethimide; may increase circulating cortisol and catecholamines; do not use if patient continues to smoke, use snuff, chew tobacco, or use other nicotine products because may increase toxicity of nicotine

Contraindications

Documented hypersensitivity; nonsmokers, children, pregnancy, life-threatening arrhythmias, severe or worsening angina pectoris

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution in peptic ulcer, coronary artery disease, angina, hypertension, peripheral arterial disease, diabetes, severe renal dysfunction, and hepatic dysfunction

Antidepressants

The drug bupropion is used as a non–nicotine-containing aid to smoking cessation. Acts by enhancing the central nervous nonadrenergic function. A recent study demonstrated a 23% sustained cessation rate with bupropion tablets at 1 year, compared to a 12% sustained cessation rate with placebo. Bupropion also is effective for patients in whom nicotine replacement therapy fails.

Bupropion hydrochloride (Zyban)

Used in conjunction with a support group and/or behavioral counseling. Inhibits neuronal dopamine reuptake in addition to being a weak blocker of serotonin and norepinephrine reuptake.

Dosing

Adult

150-mg tab PO qd for 3 d, then increase to 150 mg PO bid with at least 8 h between each dose for 7-12 wk

Pediatric

Not established

Interactions

Carbamazepine, cimetidine, phenytoin, and phenobarbital may decrease effects; toxicity increases with concurrent administration of levodopa and MAOIs

Contraindications

Documented hypersensitivity; seizure disorder, anorexia nervosa, concurrent use with MAOIs

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal or hepatic insufficiency; doses >450 mg/d significantly decrease seizure threshold; pruritus, angioedema, dyspnea, insomnia, and delusions and/or hallucinations may occur in depressed patients

Nicotinic acetylcholine receptor partial agonists

Bind to nicotine receptors and elicit mild nicotine central effects to ease withdrawal symptoms. Also decrease stimulatory effect from consuming nicotine products by blocking nicotine receptors.

Varenicline (Chantix)

Partial agonist selective for alpha4, beta2 nicotinic acetylcholine receptors. Action is thought to result from activity at a nicotinic receptor subtype, where its binding produces agonist activity while simultaneously preventing nicotine binding. Agonistic activity is significantly lower than nicotine. Also elicits moderate affinity for 5-HT3 receptors. Maximum plasma concentrations occur within 3-4 h after oral administration. Following regular dosing, steady state reached within 4 d.

Dosing

Adult

Initiate 1 wk before date chosen to stop smoking
Days 1-3: 0.5 mg PO qd pc
Days 4-7: 0.5 mg PO bid pc
Day 8 to end of treatment: 1 mg PO bid pc
Continue treatment for 12 wk; if successfully stopped smoking at end of 12 wk, an additional 12-wk course is recommended; take pc with full glass of water
Severe renal impairment (ie, CrCl <30 mL/min): Not to exceed 0.5 mg PO bid
End-stage renal disease (ESRD) with hemodialysis: Not to exceed 0.5 mg PO qd

Pediatric

<18 years: Not established

Interactions

Data limited; coadministration with nicotine replacement therapy (NRT) may increase incidence of nausea, headache, vomiting, dizziness, and dyspepsia compared with NRT alone

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Common adverse effects include nausea, headache, vomiting, flatulence, insomnia, abnormal dreams, and dysgeusia; decrease dose with severe renal impairment (ie, CrCl <30 mL/min) or ESRD undergoing hemodialysis;
Serious neuropsychiatric symptoms have been reported during postmarketing surveillance and may include changes in behavior, agitation, depressed mood, suicidal ideation, and attempted and completed suicide; these adverse events have been exhibited in patients without pre-existing psychiatric illness, and patients with pre-existing psychiatric illness have reported worsening symptoms during varenicline treatment; for more information, see the FDA MedWatch Safety Information

Follow-up

Further Outpatient Care

Long-term follow-up is recommended because individuals who successfully quit smoking are at high risk for relapse. The health care deliverer should make provisions for support, measurement of progress, and a mechanism to deal with relapse. For motivated patients who have failed smoking cessation, consider referral to an expert for the treatment of a relapse.

Deterrence/Prevention

• More than 90% of first-time use of tobacco occurs before high school graduation. Because the average age at first use is 14.5 years, smoking prevention must start early.
• Approximately 40% of teenagers who smoke eventually become addicted to nicotine.
• Social attitudes and policies toward smoking can have a major impact on smoking behavior. Healthcare associations, public health organizations, and consumer groups should lobby for the following:
  • Restriction of access to tobacco products for minors
  • Restriction of smoking in public places
  • Restriction of advertisements
  • Increased prices through taxation
  • Increased awareness about the harmful health effects of smoking
• Tobacco industry marketing and public health tobacco-control activities are 2 of the major determinants of cigarette smoking behavior. These vie with each other to influence the proportion of each generation who initiate smoking, the intensity level reached by smokers, and the time before smokers are able to quit successfully. The evidence for causality in this association is considered convincing. Strong evidence supports the notion that tobacco-control programs reduce smoking behavior.

Patient Education

• Patient education with regard to the health effects of smoking should occur with all patients who smoke. Patients should be provided with a variety of options and advice that will allow them to escape the harmful effects of tobacco use and the highly addictive drug, 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.²⁴
• School-based smoking prevention programs educate students about tobacco use. Although widely seen in school curricula, the scientific evidence supporting this approach is limited.²⁵
• Both print and visual media are saturated with antismoking messages. A systematic review of the scientific literature shows a weak impact in preventing smoking.²⁶
• Work-based smoking cessation programs that provide both behavioral treatment and medication support can be effective interventions with good quit rates.²⁷
• Naturally, many patients quit smoking on their own by going cold turkey. This would probably not be the typical patient seen in a clinician's office in the precontemplative or contemplative stage of change. For these patients, many clinicians may refer them to a variety of self-help materials such as books or pamphlets. As a sole treatment strategy, the evidence that self-help materials lead to smoking cessation is weak.²⁸ A better approach would use self-help materials as a tool 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:
  • The American Lung Association offers " Freedom from Smoking."
  • Another helpful Web site is the Tobacco Control Research Branch of the National Cancer Institute.
  • Smoking cessation counselors are available to answer smoking-related questions in English or Spanish by telephone or confidential online chat at the National Cancer Institute’s (NCI) Smoking Quitline.
  • The American Cancer Society's website provides educational materials and can direct interested individuals to a community based smoking cessation program called FreshStart.
  • Nicotine Anonymous is a fellowship-based program modeled along the same lines as Alcoholics Anonymous.

Miscellaneous

Medicolegal Pitfalls

• Relapse during the first year after achieving smoking cessation occurs in approximately 50% of patients, irrespective of therapeutic regimen.
• The changes in the central nervous system, eg, neurone genetics, cell structure, and cell function, induced by smoking do not reverse with pharmacological therapy.
• Highly nicotine-dependent smokers may require an initial therapy for 6 months or longer. Some individuals may require low-dose maintenance therapy for years.
• Controlled studies are required to help guide management of relapses and prolonged tapering periods. Immediately restarting nicotine medication might be helpful if a relapse occurs.
• According to Gro Harlem Brundtland, the director of the World Health Organization, "A tax increase is the single most important intervention by governments to curb tobacco consumption." A 10% tax increase worldwide could inspire 42 million people to stop smoking and would prevent approximately 10 million premature deaths.

Special Concerns

• Tobacco use is the greatest potentially remedial problem throughout the world, and it is the number-one preventable cause of death in the developed world. Clinicians have a particularly important role as patient advocates in health promotion, discouraging smoking initiation, encouraging and assisting smoking patients to quit, and participating in social efforts designed to curb smoking at various levels.
• The gains in understanding the neuropathology of nicotine addiction have already opened new frontiers, including effective nicotine replacement and oral therapy. Greater therapeutic advances are anticipated in the next few years.
• Smoking and weight gain
  • Concerns about weight gain following smoking cessation are a well-known barrier. 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 Fagerström.²⁹
  • Interventions designed specifically for weight-concerned smokers such as on-site exercise program improved smoking abstinence rates and delayed weight gain. Cognitive-behavioral therapy to reduce weight concerns improved smoking cessation success and reduced weight gain.
  • NRT can have an additional, positive effect on weight gain as another significant barrier to smoking cessation. NRTs can attenuate postcessation weight gain, although upon termination of nicotine replacement use, weight continues to increase to the level of exsmokers who used placebo.³⁰
• Smoking and depression
  • 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. Smokers with a past history of major depression also were found to have significantly lower resting plasma norepinephrine levels. Past 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 having a history of major depression and 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 also is important.
  • Antidepressants such as 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 examined. It also remains to be known whether effective management of withdrawal symptoms prevents postcessation depression.

Multimedia

Media file 1: Smoking cessation strategies for clinicians.

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Keywords

smoking cessation, lung cancer, cigarettes, cigarette smoking, chronic obstructive pulmonary disease, COPD, emphysema, atherosclerotic vascular disease, atherosclerosis, nicotine addition, quitting smoking, tobacco addiction, lung disease

Contributor Information and Disclosures

Author

R Gregory Lande, DO, FACN, Clinical Consultant, Army Substance Abuse Program, Department of Psychiatry, Walter Reed Army Medical Center
R Gregory Lande, DO, FACN is a member of the following medical societies: American Osteopathic Academy of Addiction Medicine and American Osteopathic Association
Disclosure: Nothing to disclose.

Medical Editor

Sarah C Aronson, MD, Associate Professor, Departments of Psychiatry and Medicine, Case Western Reserve School of Medicine/University Hospitals of Cleveland
Sarah C Aronson, MD is a member of the following medical societies: American Academy of Family Physicians, American Medical Association, and American Psychiatric Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
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Managing Editor

Eduardo Dunayevich, MD, Adjunct Assistant Professor, Department of Psychiatry, University of Cincinnati; Clinical Research Physician, Neuroscience, Lilly Research Laboratories
Eduardo Dunayevich, MD is a member of the following medical societies: American Psychiatric Association
Disclosure: Nothing to disclose.

CME Editor

Harold H Harsch, MD, Program Director of Geropsychiatry, Department of Geriatrics/Gerontology, Associate Professor, Department of Psychiatry and Department of Medicine, Froedtert Hospital, Medical College of Wisconsin
Harold H Harsch, MD is a member of the following medical societies: American Psychiatric Association
Disclosure: lilly Honoraria Speaking and teaching; Forest Labs Honoraria Speaking and teaching; AstraZeneca Honoraria Speaking and teaching; Pfizer Grant/research funds Speaking and teaching; Northstar Grant/research funds Research; Novartis Grant/research funds research; Pfizer  Speaking and teaching; Sanofi-avetis Grant/research funds research; Otsuke Grant/research funds reseach; GlaxoSmithKline Grant/research funds research

Chief Editor

Stephen Soreff, MD, President of Education Initiatives, Nottingham, NH; Faculty, Metropolitan College of Boston University, Boston, MA
Stephen Soreff, MD is a member of the following medical societies: American College of Mental Health Administration and American Psychosomatic Society
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The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors Sat Sharma, MD, FRCPC and Morley Lertzman, MD, FRCP(C) to the development and writing of this article.

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