US Pharm. 2007;32(7)(OTC suppl):18-21.

During much of the 20th century, cigarette smoking was tacitly and even overtly romanticized. However, during the 1950s and 1960s, evidence supporting a link between smoking and negative health consequences began to mount. In 1966, the surgeon general of the United States required that all cigarette package labels contain a hazard warning. Today, awareness of nicotine addiction continues to grow. Tobacco smoking is one of the leading causes of morbidity and mortality in the U.S. Several pharmacologic interventions are now available, and many are obtainable without a prescription. Pharmacists are in a unique position to counsel and assist patients who wish to stop smoking, and they can educate patients who smoke about cessation methods and available pharmacologic interventions.

Epidemiology
Each year, approximately half a million Americans die due to causes related to cigarette smoking.1 Cigarette smoking is the leading cause of preventable death in the U.S. It is a habit that typically starts at a young age, with almost 90% of smokers reporting an initial encounter with smoking by age 18. 2 Approximately one out of five adults in the U.S. smokes cigarettes, and of those who smoke, about 80% smoke daily.3 As awareness of the dangers of smoking increases and as public attitudes regarding the "attractiveness" of smoking shift, the prevalence of smoking will continue to decline. According to a recent estimate, about 70% of smokers would like to quit.4 Between 1993 and 2004, the prevalence of heavy smokers (>25 cigarettes/day) declined from 19.1% to 12.1%.5

Nicotine Addiction
According to the World Health Organization, drug dependence is "a behavioral pattern in which the use of a psychoactive drug is given a sharply higher priority over other behaviors that once had significant value."5 Chronic use of tobacco is easily consistent with this definition. The sustained use of tobacco products is contingent on the pharmacologic activity of nicotine.

The molecular structure of the naturally occurring alkaloid nicotine is similar to that of the endogenous neurotransmitter acetylcholine. Nicotine binds to many of the same receptors as does acetylcholine (via cholinergic receptors). Activation of these cholinergic receptors promotes the release of a host of neurotransmitters and hormones associated with the reinforcing effects of nicotine, including acetylcholine, norepinephrine, dopamine, vasopressin, serotonin, and beta-endorphin.6 Dopaminergic effects may be the most salient with regard to the addictive nature of nicotine use. According to recent work from the Institut Pasteur, nicotine stimulates nicotinic acetylcholine receptors (nAChRs) on dopamine-releasing neurons. These dopamine-releasing neurons are an integral part of the reward circuitry.7 It is possible that two specific subunits on the surface of the nAChRs, alpha 7 and beta 2, are necessary for the full sequence of events leading to nicotine reinforcement. These findings may lead to new therapies and a better understanding of nicotine addiction.

The daily cycle of nicotine addiction begins with the first cigarette (or other tobacco form) of the day. The initial daily dose produces significant pharmacologic effects, including a sense of pleasure, arousal, and enhanced performance. At the same time, tolerance begins to escalate.8 The smoker continues to smoke during the day, nicotine accumulates, and tolerance continues to escalate; withdrawal symptoms occur sooner and are more overt with each subsequent cigarette. As the cycle progresses, people tend to smoke more in what is usually an unconscious attempt to relieve the symptoms of withdrawal. However, sleep provides a time of considerable resensitization to the effects of nicotine, and, upon awakening, the cycle begins anew.

Effects of Nicotine Use
Nicotine use causes ganglionic effects, including vasoconstriction, increased blood pressure, and skeletal muscle relaxation.8 Nausea, increased intestinal activity, pallor, and sweating may also be observed. Subjective reports of the effects of nicotine include pleasure and a reduction in anger, depression, and tension. Nicotine has been demonstrated to improve vigilance in repetitive tasks and to augment selective attention.8 In an addicted individual, nicotine withdrawal begins shortly after its last administration, reaches maximal intensity after 24 to 48 hours, and subsides over a period of several weeks. However, some symptoms may persist for months to years.

The chronic effects of tobacco use are usually devastating. In 2004, the U.S. surgeon general reported that virtually every organ system in the body is impacted by tobacco use.9 Chronic cigarette smoke, and even secondhand smoke, increases the risk of lung cancer, other potentially fatal respiratory conditions, and cardiovascular disease. Other adverse health consequences of smoking include nonpulmonary cancers, reduced fertility in women, higher infant mortality rates, osteoporosis, and poor surgical outcomes.9

Benefits of Smoking Cessation
The positive effects of smoking cessation are measurable almost immediately. As soon as 20 minutes after the last cigarette, blood pressure decreases and peripheral vasoconstriction is reduced, causing the temperature of the hands and feet to return to normal.10 After eight hours, carbon monoxide levels drop to normal. After just 24 hours, the chance of a heart attack is reduced. After one to nine months, ciliary function in the lungs returns to normal; this allows for appropriate clearance of mucus, which in turn clears the lungs of excess mucus and particulate matter and reduces the chance for infection. Coughing, sinus congestion, fatigue, and shortness of breath are also reduced. Risk of coronary heart disease will drop to half of that of a smoker after one year and to the level of a nonsmoker after 15 years. After five to 15 years, risk of stroke is reduced to the level of a nonsmoker. After 10 years, risk of cancer and cancer-related death is significantly lower. One study suggested that an individual who quit smoking at age 30 could expect to live an average of 10 years longer than one who continued to smoke.11  

Approach to Treatment
First, the pharmacist must remember that most attempts to stop using tobacco end in relapse. The CDC reported that only about 5% of those who attempted cessation were able to actually do so for three to 12 months.4 While even short counseling periods with a clinician, as the sole intervention, are associated with improved rates of cessation, the most effective approach is multipronged. Since behavioral and social factors have a role in nicotine addiction, in addition to pharmacologic factors, treatment modalities addressing each of these factors is likely more effective and should include pharmacologic therapy; counseling; support from family, friends, and coworkers; and support from health care providers.

The CDC suggests that "patients who are willing to quit should be provided with effective intervention, including brief interventions by clinicians at every visit." 5 They recommend using the five A's: Ask about tobacco use; Advise to quit; Assess willingness to make a quit attempt; Assist in the quit attempt; and Arrange for a follow-up. In addition, the CDC recommends pharmacotherapies for smoking cessation, including prescription medications such as bupropion (Zyban), nicotine nasal spray, nicotine inhaler, and the various forms of OTC nicotine (patch, gum, and lozenge). One new prescription-only medication for smoking cessation, Chantix (varenicline) was approved by the FDA after the above-cited CDC recommendation was published and is an appropriate alternative. The CDC also recommends that patients who are not ready to quit should be provided with messages to increase the motivation to quit.

OTC Products
The FDA-approved OTC products for smoking cessation constitute nicotine replacement therapy (NRT) in the form of nicotine patches, gum, and lozenges (Table 1). NRT should be used in conjunction with behavioral support. NRT produces less severe physiologic alterations than tobacco-based systems and provides patients with lower overall levels of nicotine than they would receive from tobacco.12 NRTs are useful and beneficial in several ways. First, they have little abuse potential, because they do not produce the same pleasurable effects as tobacco products.13 Second, they do not contain the carcinogens or other toxic gases contained in tobacco smoke. All of the NRTs available provide a controlled dose of nicotine; reduce withdrawal symptoms, including cravings; and allow the patient to gradually taper off tobacco. Patients who use NRT are twice as likely to be successful in their attempt to stop smoking as similar individuals treated with a placebo.13


While NRT is safer than continuing to smoke, there are several warnings that should be considered. First, patients should not continue to smoke while using NRT. The effects of more than one delivery device for nicotine are additive, and the patient may experience untoward effects due to high serum levels of nicotine. Second, patients with serious underlying cardiovascular disease should be advised to use NRT under the supervision of a primary care provider. Last, pregnant or breast-feeding patients and those younger than 18 should use NRT only under the supervision of a primary care provider. While in all of these situations NRT probably has a much greater safety margin than does smoking, the current labeling is worded in such a way that the pharmacist recommending one of these products to one of the above-mentioned "high risk" patients could be exposing him/herself to liability. However, there is currently a push from tobacco researchers and policy makers to tone down the warnings on pharmaceutical nicotine, which may eventually result in the removal of warnings targeting pregnant or breast-feeding women and individuals younger than 18.14

Nicotine Gum: Nicotine gum was the first FDA-approved form of NRT. It was approved in 1984 as a prescription item and in 1996 as an OTC product.12 Nicotine gum is a resin complex of polacrilin and nicotine in a sugarless chewing-gum base.15 The product is available in two dosage strengths: 2 and 4 mg.

Patients should not use more than 24 pieces per day and should be told not to eat or drink 15 minutes prior to or while chewing the gum. Also, patients should rinse their mouths out with water prior to using this product if they have recently consumed acidic drinks or foods (cola, fruit juices, coffee, wine, citrus fruits, tomatoes, or vinegar-containing foods), since the pH shift caused by these substances may interfere with the absorption of nicotine across the mucosal layer. The patient should be instructed to

1. Chew the gum slowly until noticing a peppery, minty, citrus taste or a tingling sensation in the mouth (usually about 15 chews).13,15
2. When this occurs, place the gum between the cheek and the gums (this allows for absorption).
3. After one or two minutes, when the taste or tingling has stopped, resume chewing.
4. When the taste or tingling sensation returns, place the gum in a different area between the gums and the cheek.
5. Repeat steps 3 and 4 until the taste or tingling does not return (usually 30 minutes).

Problems encountered by patients using nicotine gum include irritation of the mouth, fatigue of the jaw, hypersalivation, hiccups, and dyspepsia. In addition, the gum's adhesive properties make it likely that the gum will stick to fillings, bridges, crowns, dentures, and braces.13 Furthermore, if the patient chews the gum too fast or vigorously, he or she may experience dizziness, nausea, vomiting, throat irritation, hiccups, or dyspepsia. Properly educating the patient about the correct technique for chewing the gum could mitigate these problems. If the gum sticks to or damages dental work, patients should be advised to stop using the product, visit their dentist, and use an alternate form of therapy, such as a patch or a lozenge.

Nicotine Patches: In 1991 and 1992, the FDA approved four transdermal nicotine patches for prescription-only use. In 1996, several transdermal nicotine patches were approved for OTC use.

Patients electing to use the patch should be instructed to apply the patch to a dry, clean, hairless area on the upper body or upper part of the arm at about the same time each day. 13 The application site for the patch should be rotated daily, with each site being used only once per week to avoid skin irritation. After use, a slight redness at the site of the patch may occur. If erythema persists for more than four days, or if swelling or a rash develops at the site, the patient should be told to discontinue use of the patch and contact a health care provider. Use of the product should also be discontinued and medical attention sought if palpitations occur, or if the patient develops symptoms of nicotine toxicity (i.e., nausea, vomiting, dizziness, diarrhea, sweating, or weakness). Other adverse effects, which are uncommon but seem to be unique to the transdermal patch, include insomnia, headache, and vivid or troublesome dreams. These problems seem to be associated with the continuous release of nicotine. If these problems are encountered and are intolerable, the patient should be counseled to use an alternative form of NRT. 

Nicotine Lozenges: Like nicotine gum, nicotine lozenges are a resin complex of nicotine and polacrilin. They are sugar free and have a slight mint flavor. The lozenges should be allowed to dissolve slowly in the mouth and should occasionally be rotated to different areas in the mouth to avoid discomfort.13 The patient may experience a warm, tingling sensation in the mouth. The lozenges typically take about 30 minutes to dissolve and should not be chewed or swallowed. No more than five lozenges should be used in a six-hour period, and no more than 20 should be used per day. Patients should follow the same guidelines regarding use of the lozenges with food and beverages as they would with nicotine gum.15 Nicotine lozenges are typically well tolerated but may cause dyspepsia, nausea, headache, or flatulence. Side effects are more common in patients who use too many lozenges.

Conclusion
Cigarette smoking and other forms of tobacco use are a major cause of morbidity and mortality in the U.S. Chronic use of tobacco is due to nicotine addiction, and the addicted patient must be motivated to quit before cessation attempts will be successful. Motivation is sometimes created by education about the dangers of nicotine addiction and the mere offer of help by someone with knowledge about cessation methods, such as the pharmacist. Nicotine addiction is best treated using a multimodal approach that includes counseling, support, pharmacotherapy, and follow-up. While several prescription-only medications for tobacco cessation are available, a number of effective OTC products are also available. By counseling patients and recommending appropriate smoking cessation products, the pharmacist can have an important role in improving the quality and longevity of the lives of tobacco users who wish to quit. Pharmacists wishing to set up pharmacy-based smoking cessation programs can find helpful information at the University of California, San Francisco's Rx for change Web site, located at rxforchange.ucsf.edu.16

References
1. Centers for Disease Control and Prevention. Annual smoking-attributable mortality, years of potential life lost, and productivity losses-United States, 1997-2001. MMWR Morb Mortal Wkly Rep. 2005;54:625-628.
2. US Dept of Health and Human Services. Preventing Tobacco Use among Young People: A Report of the Surgeon General. Atlanta, GA: National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 1994.
3. Johnston LD, O'Malley PM, Bachman JG, et al. Monitoring the Future National Survey Results on Drug Use, 1975-2003. Volume 1: Secondary School Students . Bethesda, Md: National Institute on Drug Abuse; 2004. NIH Publication 04-5507.
4. Centers for Disease Control and Prevention. State specific prevalence of cigarette smoking and quitting among adults--United States, 2004. MMWR Morb Mortal Wkly Rep . 2005;54:1124-1127.
5. Centers for Disease Control and Prevention. Cigarette smoking among adults-United States, 2004. MMWR Morb Mortal Wkly Rep. 2005;54:1121-1124.
6. Pomerleau OF, Pomerleau CS. Neuroregulators and the reinforcement of smoking: towards a biochemical explanation. Neuroscience Behavioral Reviews. 1984;8:503-513.
7. Mameli-Engvall M, Evrard A, Pons S, et al. Hierarchical control of dopamine neuron-firing patterns by nicotinic receptors. Neuron. 2006;50:911-921
8. National Academy of Sciences. Growing Up Tobacco Free. The Nature of Nicotine Addiction. 2000. Available at: www.nap.edu/openbook.php?record_id=4757&page=31. Accessed February 25, 2007.
9. US Department of Health and Human Services. The Consequences of Smoking: A Report of the Surgeon General. Center for Disease Control and Prevention. Office on Smoking and Health. Bethesda, Md. 2004
10. US Department of Health and Human Services. The Health Benefits of Smoking Cessation: A Report of the Surgeon General. Bethesda, Md: Centers for Disease Control and Prevention and Health Promotion. Office on Smoking and Health; 1990. DHHS Publication no. (CDC) 90-8416.
11. Doll R, Peto R, Boreham J, et al. Mortality in relation to smoking: 50 years' observation on male British doctors. BMJ. 2004;328:1519-1527
12. National Institute on Drug Abuse. Research Report Series. Tobacco Addiction. National Institutes of Health publication number 06-4342, 2006.
13. Corelli RL, Hudmon KS. Tobacco use and dependence. In: Koda-Kimble MA, Young LY, Kradjan WA, et al., eds. Applied Therapeutics: The Clinical Use of Drugs. Philadelphia, Pa: Lippincott Williams & Wilkins; 2004:Chapter 85, 1-27.
14. Helliker K. Battle heats up over nicotine therapy. Wall Street Journal. Feb 27, 2000; D1-D2.
15. Hudmon KS, Kroon LA, Corelli RL. Smoking Cessation. In: Berardi RR, DeSimone MM, Newton GD, et al, eds. Handbook of Nonprescription Drugs. Washington, DC: American Pharmaceutical Association; 2004:1021-1044.
16. Rx for change: clinician assisted tobacco cessation. University of California, San Francisco Web site. Available at: rxforchange.ucsf.edu. Accessed February 26, 2007.

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