Smoking Cessation: How to Make Pharmacotherapy Work

Smoking Cessation: How to Make Pharmacotherapy Work

Smoking accounts for more than 400,000 (approximately 1 of every 5) deaths each year in the United States and is the most common cause of preventable disease.1,2 Smoking is a risk factor for the 4 leading causes of death: heart disease, cancer, stroke, and chronic obstructive pulmonary disease (COPD).3 Currently, 24% of the US adult population are smokers.4

Approximately one third to half of all cigarette smokers will die because of their smoking.5 The total mortality rate among current smokers is twice that of persons who never smoked.6 It is estimated that 70% of smokers visit a physician each year; however, only half report ever being advised to quit smoking by their physician.7-9

The main obstacles to quitting smoking are nicotine addiction and withdrawal symptoms. Pharmacotherapy offers assistance for patients who want to quit smoking. Recent developments in the pharmacotherapy for smoking cessation has led the US Public Health Service to update the previous guidelines of the Agency for Health Care Policy and Research (AHCPR).7,8 In this article, I will review the current recommended methods used for smoking cessation and certain issues regarding pharmacotherapy.


Coronary artery disease (CAD) is the leading cause of death in the United States.3 The risk of developing this disease can be reduced by half after 1 year of smoking cessation, and after 2 years, the risk becomes equal to that of persons who never smoked.10 After 5 years or more of smoking abstinence, the mortality rate from CAD decreases to almost the level for persons who never smoked.11 After 10 to 14 years of smoking cessation, the mortality risk decreases to that of persons who never smoked.12

Lung cancer is the leading cause of cancer death among men and women in the United States, and COPD is the fourth leading cause of death overall.3 Smoking can accelerate the normal age-related rate of decline in forced expiratory volume in 1 second, which can revert to a normal rate of decline with smoking cessation.13,14 The risk of lung cancer in former smokers progressively decreases with the number of years of abstinence but always remains higher than that in patients who never smoked.15


Nicotine dependence disorder has been defined as a form of substance abuse that can lead to clinically important impairment or distress.16 Fagerstrom proposed a questionnaire to determine the degree of nicotine dependence.17,18 The Fagerstrom Test for Nicotine Dependence places significant importance on "time to the first cigarette of the day."17,18

Nicotine has a relatively short half-life, and smokers may experience significant discomfort on waking unless they quickly have their first cigarette.19 However, only the number of cigarettes smoked per day has been shown to correlate with the degree of nicotine dependence.20 Therefore, the use of a brief Fagerstrom Test for Nicotine Dependence has been recommended (Table 1).21


The signs and symptoms of tobacco withdrawal include craving for tobacco, irritability, anxiety, difficulty in concentrating, restlessness, insomnia, and increased hunger.22 These signs and symptoms were confirmed in a study of 630 smokers who quit smoking without pharmacologic aid.23 The self-reported and observer-rated signs and symptoms were assessed precessation and postcessation.

The investigators found that anxiety, difficulty in concentrating, irritability, restlessness, and nocturnal awakening returned to precessation levels by 30 days. Hunger symptoms, however, remained elevated at 30 days postcessation.23

In a study conducted by Gritz and colleagues24 of 554 patients who tried to quit smoking without assistance, 87% reported withdrawal symptoms during the first week of follow-up, with restlessness and eating more than usual being the most common symptoms.


In 1996, the AHCPR recommended a 5-step approach known as the 5 A's (Table 2).25

Ask about smoking.

Advise smokers to stop.

Assess the patient's willingness to stop.

Assist patients who are willing to stop.

Arrange close follow-up.

Because of recent developments in the pharmacotherapy for smoking cessation, the US Public Health Service updated the practice guidelines for treating tobacco use and dependence and endorsed the use of this 5-step approach.7,8

The 5 A's outline is a brief clinical intervention that encompasses advice and counseling as major steps in smoking cessation.7,8 Physician communication about the benefits of smoking cessation and encouragement to quit have proved to be successful. Unfortunately, fewer than half of smokers report that they have ever been advised by their physician to quit smoking.9


The impact of even brief, 3- to 5-minute, counseling on smoking cessation has been demonstrated.26,27 Counseling should not be limited to the outpatient setting. In a study evaluating the effects of counseling on smoking cessation among 74 hospitalized patients with COPD, the counseled group had higher quit rates at 6 months' follow-up.28 All patients were advised to quit smoking, and half were provided with a self-help manual and brief, 15- to 20-minute, counseling sessions. A total of 58 patients were available for follow-up at 6 months. Quit rates at 6 months' follow-up were 33% for the counseled group and 21% for the control group.

The effects of counseling can be extended through the use of the telephone. In a study of 233 smokers, Wadland and colleagues29 found that 6 sessions of telephone counseling enhanced smoking cessation rates (21% for the telephone-counseled group vs 8% for the group that received usual care).


The FDA has approved 5 products for smoking cessation, including nicotine gum; nicotine transdermal patch; nicotine nasal spray; nicotine inhaler; and a nonnicotine agent, sustained-release bupropion.30,31 The US Public Health Service recommends that all smokers, with the exception of women who are pregnant or breast-feeding, adolescents, and those with medical contraindications, should consider pharmacotherapy for smoking cessation.7,8 Medical contraindications include severe reactive airways disease in patients considering nicotine nasal spray.7,8 Pregnant smokers should first be encouraged to quit without pharmacologic aid.7,8

Cost and lack of insurance coverage may be a barrier for some patients in obtaining pharmacologic aid for smoking cessation. The Box lists the typical costs of drug therapy.

Nicotine gum. Nicotine polacrilex gum is available over the counter in 2- and 4-mg strengths. The gum can be chewed every 1 to 2 hours for a maximum of 60 mg/d.30 The typical dose is 10 pieces per day. The recommended duration of therapy is 1 to 3 months.7,8

The gum should be chewed slowly until a peppery, minty taste becomes apparent and then "parked" between the cheek and gum to facilitate nicotine absorption. Chewing is resumed when the taste fades, and the "chew/park" steps should be repeated until the taste completely fades. Approximately 50% of the nicotine is released in the mouth and is absorbed through the mucosa. The gum should be chewed and parked for about 30 minutes.7,8 Common side effects of nicotine gum include jaw ache and dyspepsia.30

One study found an increased cessation rate with the 4-mg dose compared with the 2-mg dose for high-dependence smokers, but not for low-dependence smokers.32 The participants were classified as high-nicotine-dependent or low-nicotine-dependent based on the Fagerstrom test. They were randomly assigned to receive placebo or 2- or 4-mg nicotine gum.

Of the 608 persons, 92 were abstinent at 1 year. One-year quit rates for the low-nicotine-dependent smokers were as follows: 11% for placebo, 18% for 2-mg gum, and 17% for 4-mg gum. One-year quit rates for the high-nicotine-dependent smokers were as follows: 8% for placebo, 20% for 2-mg gum, and 26% for 4-mg gum.

Nicotine patch. There are 3 major brands of nicotine patch. Generic nicotine patches are now available also. Habitrol and Nicoderm CQ are intended for 24-hour use. The patches are available in 21-, 14-, and 7-mg doses. The dose can be progressively weaned over 2 to 4 months.7,8 The recommended taper is 21 mg for 4 weeks, then 14 mg for 2 weeks, then 7 mg for 2 weeks. The Nicotrol patch is intended for 16-hour daytime use and should be removed before bedtime. The patch is available as a 15-mg dose. The recommended duration of treatment is 6 weeks.30

The nicotine patch should be applied to a clean hairless area of the skin. A common side effect of the patch is skin irritation, such as mild itching or burning, which can be reduced by rotating the patch site.31

A randomized, placebo-controlled trial reported 1-year quit rates of 19% for nicotine patch versus 12% for placebo patch.33 A meta-analysis of 17 studies involving a variety of nicotine patches showed abstinence rates at 6 months of 22% for the treatment group compared with 9% for the group that received the placebo patch.34 In a study evaluating the efficacy of varying doses of nicotine patch, patients assigned to the 21-mg patch had higher abstinence rates at long-term follow-up.35 The self-reported continuous quit rates at 48 months of follow-up were 20% for the 21-mg patch, 10% for the 14-mg patch, 12% for the 7-mg patch, and 7% for the placebo patch.

In another study, a 24-hour transdermal nicotine patch yielded better control of morning craving symptoms than a 16-hour patch. The 24-hour patch also yielded longer abstinence rates.36

Two separate randomized controlled trials demonstrated that a 44 mg/d dose of nicotine patch therapy appears to be safe and effective for use in smokers who have high nicotine dependence.37,38

The use of nicotine patches combined with counseling treatments has been shown to increase quit rates.39

Another study by Paoletti and colleagues40 found that patients with high cotinine levels at baseline had lower cessation rates with the use of nicotine patch therapy. Patients with low baseline cotinine levels (less than 250 ng/mL) had higher cessation rates when compared with patients who had baseline cotinine levels of greater than 250 ng/mL.40 Thus, determination of baseline plasma cotinine levels may be helpful in identifying smokers who may have difficulty with smoking cessation.

Nicotine nasal spray. This spray delivers nicotine more rapidly than the gum or the patch.41 It is available by prescription in a quantity of 10 mL. Each spray of 0.05 mL delivers 0.5 mg of nicotine.30 The dose may be titrated up to a maximum of 40 mg/d.30

The recommended dosage is 1 or 2 sprays every hour for 6 to 8 weeks. The minimum recommended treatment is 8 doses per day, with a recommended duration of 3 to 6 months.7,8 Patients should not exceed 5 sprays per hour or 40 sprays per day. Tapering of doses in the subsequent 4 to 6 weeks is optimal for avoiding withdrawal symptoms. Side effects often reported from nicotine nasal spray include nasal irritation, rhinorrhea, throat irritation, sneezing, and coughing.31

The results of a randomized, double-blind, placebo-controlled trial showed that 32% of patients who used active spray were abstinent at 6 months compared with 12% who received the placebo spray.42 The abstinence rates at 1 year of follow-up were 26% for the group that received active spray and 10% for the group that received placebo spray.

Nicotine inhaler. The inhaler is available by prescription and consists of a mouthpiece and a plastic cartridge that contains 4 mg of nicotine. Approximately 80 inhalations are needed to equal the amount of nicotine obtained from 1 cigarette.30 Common side effects include throat irritation and coughing.31 The recommended dosage is 6 to 16 cartridges per day for 6 to 12 weeks, with tapering over the subsequent 3 months.7,8 The vapor should not be inhaled deeply into the lungs because the nicotine is primarily absorbed through the oral cavity, rather than through the lungs.21

In a randomized, double-blind, placebo-controlled trial of 247 smokers, abstinence rates of 28% were reported for the nicotine inhaler group and 18% for the placebo group at 1 year of follow-up.43 Another double-blind, placebo-controlled trial found that the inhaler is useful for short-term smoking cessation with some potential for long-term cessation.44 The respective cessation rates for the active inhaler and placebo groups were 46% versus 28% at 1 week, 24% versus 10% at 3 months, and 13% versus 8% at 1 year of follow-up.

Bupropion. This drug is recommended as a first-line agent by the US Public Health Services guidelines. The recommended dosage is 150 mg once daily for 3 days, then 150 mg twice daily for up to 12 weeks.30 The quit date should be set 1 to 2 weeks after initiating therapy. Common side effects include dry mouth, agitation, insomnia, headaches, and dizziness. Bupropion is contraindicated in patients with seizure disorder.45

In a double-blind, placebo-controlled trial, the quit rates increased with the dose of bupropion.46 The quit rates at 7 weeks' follow-up were 19% for the placebo group, 29% for the 100-mg group, 39% for the 150-mg group, and 44% for the 300-mg group. The 1-year abstinence rates were 12% for the placebo group, 20% for the 100-mg group, 23% for the 150-mg group, and 23% for the 300-mg group.46


A comparative trial evaluating the efficacy of the 4 types of nicotine replacement products found no significant difference in rates of abstinence.47 The continuous abstinence rates at 12 weeks' follow-up were 20% for gum, 21% for patch, 24% for spray, and 24% for inhaler.

A study evaluating whether smokers' preference for a nicotine replacement product correlated with abstinence rates found no difference at 15 weeks' follow-up.48 Participants were allowed to rank their preference among gum, patch, nasal spray, and inhaler. The heavier smokers preferred the spray or inhaler, but the patch was the most preferred product overall. There was no significant difference in cessation rates for smokers who received their preferred product. The overall continuous abstinence rates at 15 weeks' follow-up were 23% for gum, 23% for patch, 23% for spray, and 28% for inhaler.


There has been concern about the safety of nicotine replacement in patients with cardiovascular disease. In a study by Joseph and colleagues,49 584 patients with cardiovascular disease were randomized to receive a 10-week course of transdermal nicotine or transdermal placebo. Primary end points after 14 weeks of follow-up included death; myocardial infarction; cardiac arrest; and admission to the hospital for angina, arrhythmia, or congestive heart failure. This study failed to show a significant increase in cardiovascular events for patients receiving nicotine replacement therapy.49

In a similar study, 156 patients with CAD who smoked at least 1 pack of cigarettes per day were randomized to receive transdermal nicotine or transdermal placebo.50 After 5 weeks' follow-up, the study failed to show any significant difference in the rate of cardiac events. Thus, nicotine replacement therapy is safe in smokers with CAD.


In one double-blind, placebo-controlled trial that evaluated bupropion, nicotine patch, and combined bupropion and nicotine patch, combination therapy was superior to both therapies alone and placebo. Quit rates were 16% for placebo, 16% for bupropion, 30% for nicotine patch, and 36% for combined bupropion and nicotine patch at 1 year of follow-up.51

Another double-blind, placebo-controlled study found higher abstinence rates for persons who received both nicotine patch and nicotine gum compared with those who received nicotine patch and placebo gum.52

Nicotine nasal spray delivers nicotine at a much faster rate than any other nicotine replacement product (for example, peak plasma concentrations are achieved at a much faster rate, usually less than 10 minutes). Blondal and colleagues53 randomized 237 smokers to receive either nicotine patch and spray or patch and placebo spray and found that 1-year cessation rates were better for the patients who received the combined therapy.


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