US Pharm. 2020;45(2):33-35.

Most smokers become addicted to nicotine, a drug naturally occurring in tobacco. Tobacco smoke contains a mixture of harmful chemicals that can cause lung cancer and many other diseases. About one-half of individuals who smoke regularly will die of smoking-related health problems. More people are addicted to nicotine in the United States than in any other country. Tobacco is the cause of roughly 435,000 deaths in the U.S. each year, correlating to approximately one in every five deaths.1

People who stop smoking greatly reduce their risk of disease and early death, no matter how old they are when they quit. The risk of developing cancer decreases with each year that an individual remains smoke-free.1

Smoking cessation is difficult and may require several attempts. It can cause bothersome short-term effects, such as weight gain, irritability, and anxiety. Soon after a smoker quits, however, the circulation begins to improve and blood pressure returns to normal. The senses of smell and taste improve, and breathing becomes easier. However, people who stop smoking often start again because of withdrawal symptoms.1

There are a number of methods individuals can employ to stop smoking. Some people quit abruptly; others quit gradually, using step-by-step manuals, counseling, medications, or products that help reduce nicotine addiction.1,2

In the last decade, the use of electronic cigarettes (e-cigarettes) has increased in the U.S. Some people switch to e-cigarettes in the belief that these products can help them quit smoking, but that has not been proven. Further research is warranted to determine the safety and effectiveness of long-term use of e-cigarettes.1,2

This article briefly reviews the neurobiology of nicotine addiction and withdrawal and discusses nicotine-addiction therapies and patient education.

Nicotine Pharmacology

It is primarily the pharmacologic effect of nicotine that produces addiction. However, other components of cigarette smoke cause most of the toxicity of smoking. As a result, researchers continue to investigate how nicotine produces addiction and what the best intervention is to reduce the toxicity.3

Nicotine, a tertiary amine that consists of a pyridine and a pyrrolidine ring, forms two stereoisomers. (S)-nicotine, which is found in tobacco, binds stereoselectively to nicotinic cholinergic receptors. (R)-nicotine occurs in small quantities in cigarette smoke, owing to racemization during the pyrolysis process; it is a weak agonist at cholinergic receptors.3

When a person inhales smoke from a cigarette, nicotine is distilled from the tobacco and is carried via smoke particles into the lungs, where it is absorbed rapidly into the pulmonary venous circulation. The nicotine then enters the arterial circulation and moves quickly to the brain, where it binds to nicotine cholinergic receptors, which are ligand-gated ion channels. When a cholinergic agonist binds to the outside of the channel, the channel opens, allowing the entry of cations, including sodium and calcium. These cations further activate voltage-dependent calcium channels, allowing further calcium entry. This process enhances dopamine, glutamate, and gamma-aminobutyric acid release in the brain. The release of dopamine is thought to be the source of the pleasurable sensations experienced during smoking, including relaxation and release of tension.3

The enjoyable sensation derived from smoking takes place rapidly, but in a process known as neuroadaptation, eventually more nicotine is needed to achieve the same sensation. Smoking addiction results from the developing need to smoke more cigarettes, and to smoke more often, in order to keep experiencing that sensation.3,4

Nicotine stimulates the nervous system to release neurotransmitters and hormones, such as epinephrine, that act on various parts of the body. The inhalation of nicotine causes a feeling of stimulation induced by the epinephrine release, resulting in increased heart rate and blood pressure as well as other effects.4


Three drug classes have been FDA-approved for smoking cessation: nicotine replacement products, which come in inhaler, spray, gum, patch, and lozenge form; sustained-release bupropion (Zyban); and varenicline.4 The efficacy of all of these agents has been demonstrated in controlled clinical trials. Absolute smoking-cessation rates of 5% to 35% have been found, varying according to the drug and to the intensiveness of concurrent patient counseling.4

Nicotine Replacement Therapy

Acting on nicotine cholinergic receptors, nicotine replacement medications replace or mimic the effects of the nicotine in tobacco. There are a number of ways in which nicotine replacement agents, which are first-line therapy, are thought to promote smoking cessation. Relief of withdrawal symptoms when a person ceases using tobacco is the main action of these products. Amelioration of withdrawal symptoms occurs with fairly low nicotine blood levels.4

Positive reinforcement, particularly for the arousal and stress-relieving effects, is another beneficial mechanism. The peak nicotine level in arterial blood and the rapidity of absorption influence the degree of reinforcement. Positive reinforcement is most pertinent to nicotine nasal sprays and other rapid-delivery formulations; it has less of an effect with nicotine gum, inhalers, and lozenges. When patients feel the need to smoke cigarettes, they may use these agents to dose themselves with nicotine. Little positive reinforcement is provided by the nicotine patch, which delivers nicotine more slowly and maintains a steady nicotine level throughout the day.3,4

The ability of nicotine agents to desensitize nicotinic receptors may be another mechanism. Desensitization reduces the effect of nicotine from cigarettes; that is, when a patient receiving nicotine replacement therapy smokes, the cigarette is less pleasurable and continued smoking is less likely.4

Transdermal patches deliver the dose over 24 hours for 8 to 10 weeks, starting with a 21-mg patch, followed by a 14-mg and then a 7-mg patch. Nicorette gum works by buccal absorption, and there are special chewing instructions; therapy exceeding 11 months may be associated with hyperinsulinemia or insulin resistance. Nicorette lozenges, also absorbed bucally, are available as 2 mg or 4 mg per piece; the dosage is one piece every 1 to 2 hours for 6 to 12 weeks, then tapered. The lozenge should be moistened, then parked in the buccal mucosa.

Sustained-Release Bupropion

Before it was made available as a smoking-cessation agent, the antidepressant bupropion was observed to lead to spontaneous smoking cessation in veterans receiving the drug for depression. Brain levels of dopamine and norepinephrine are increased with bupropion use, simulating nicotine’s effects on these neurotransmitters. Additionally, bupropion’s nicotine receptor–blocking activity might contribute to reduced reinforcement from a cigarette during a lapse. The dosage of sustained-release bupropion is 300 mg per day for 7 to 12 weeks, with maintenance up to 24 weeks.5


Varenicline, a selective nicotine receptor partial agonist, is an analogue of the plant alkaloid cytisine. Although cytisine has been noted to have certain benefits for smoking cessation, it is believed to have poor oral bioavailability overall. Varenicline prevents nicotine stimulation of the mesolimbic dopamine system associated with nicotine addiction. It also stimulates dopamine activity, but to a much lesser degree than nicotine, resulting in fewer cravings and withdrawal symptoms. In addition, varenicline blocks the effects of any nicotine added to the system. In clinical trials, varenicline was superior to bupropion in furthering smoking cessation, and prolonged varenicline administration lessened relapse in patients who were abstinent from smoking 12 weeks following initial therapy. Patients with a history of depression, anxiety, or heart disease must discuss varenicline use with their provider before taking it. Varenicline can increase the effects of alcohol in some people, so it is wise to limit drinking while taking varenicline. The initial dosage is 0.5 mg once daily on days 1 to 3, and on days 4 to 7, the dosage is 0.5 mg twice daily; maintenance (starting on day 8) is 1 mg twice daily for 11 weeks. Caution should be exercised in patients with preexisting psychiatric illness.6


Although clonidine is not approved by regulatory authorities for smoking cessation, clinical trials have demonstrated its efficacy, and it is considered a second-line drug. FDA-approved clonidine aids in smoking cessation.4 Clonidine, an alpha-2 adrenergic agonist, is used primarily as an antihypertensive agent. Its role in smoking cessation involves decreasing the acute symptoms of withdrawal from nicotine, specifically irritability, anxiety, tension, cravings, restlessness, and trouble thinking clearly.4

Patient Evaluation and Intervention

Successful intervention is based on the patient’s willingness to quit. The five major steps to intervention are the “5 A’s”7:

Ask—Identify and document tobacco-use status for every patient at every visit.
Advise—In a clear, strong, and personalized manner, urge every tobacco user to quit.
Assess—Is the patient willing to make a quit attempt at this time?
Assist—If the patient is willing to make a quit attempt, use counseling and pharmacotherapy to help him or her quit.
Arrange—Schedule follow-up contact, in person or by other means, preferably within the first week after the quit date.

Patient Education

Although a number of drugs effectively enhance smoking cessation, success rates remain relatively low, and most smokers require multiple attempts before successfully quitting for good. The characteristics of tobacco addiction differ from person to person. There are individual differences in the benefits derived from smoking; therefore, there has been much interest in the individualization of smoking-cessation therapy. The goal is to select medications and dosages based on the individual characteristics of the smoker.8

Quitting smoking can lower a person’s risk of developing or dying from heart disease, lung disease, kidney failure, infection, or cancer. Smoking cessation will improve a patient’s health at any age without regard to how long or how much he or she has smoked.8

Many people believe that electronic cigarettes or vaping might help them quit smoking. However, clinicians do not recommend e-cigarettes in place of medications and counseling. That is because e-cigarettes contain liquid nicotine as well as other potentially harmful substances.8

The word “START” can help patients remember the steps to take in attempting to quit smoking8:

S: Set a quit date.
T: Tell family, friends, and others around you that you plan to quit.
A: Anticipate or plan ahead for the difficulties you’ll face while quitting.
R: Remove cigarettes and other tobacco products from your home, car, and workplace.
T: Talk to your doctor about getting help to quit.

Individuals who smoke have the best chance of quitting if they take medications to help them quit and work with a counselor. It might also be helpful to combine nicotine replacement with one of the prescription medications that help people quit. In some cases, it might make sense for the patient to take bupropion and varenicline together.8 Counseling and medication are both proven to be effective for treating tobacco dependence, and it is generally believed that using them together is more effective than using either one alone.8


1. MedlinePlus. Nicotine and tobacco. Accessed January 24, 2019.
2. American Cancer Society. How to quit smoking or smokeless tobacco. Accessed January 24, 2019.
3. Benowitz NL. Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics. Annu Rev Pharmacol Toxicol. 2009;49:57-71.
4. Benowitz NL. Nicotine addiction. N Engl J Med. 2010;362(24):2295-2303.
5. Slemmer JE, Martin BR, Damaj MI. Bupropion is a nicotinic antagonist. J Pharmacol Exp Ther. 2000;295(1):321-327.
6. Gray KM, Baker NL, McClure EA, et al. Efficacy and safety of varenicline for adolescent smoking cessation: a randomized clinical trial. JAMA Pediatr. 2019 Oct 14; [Epub ahead of print].
7. Five major steps to intervention (the “5 A’s”). Accessed January 24, 2019.
8. Rigotti NA. Patient education: quitting smoking (beyond the basics). Accessed January 24, 2019.

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