This course will review the epidemiology of tobacco use, the health risks of smoking, the health benefits of smoking cessation, the role of nicotine in maintaining tobacco dependence, and both pharmacological and nonpharmacological therapies with established efficacy for smoking cessation. With this information, pharmacists should be better able to assist smokers with their cessation attempt, educate smokers on potential adverse effects of these pharmacotherapies, and provide counseling points that include how and when to properly take the medication.
- INTRODUCTION
- EPIDEMIOLOGY OF TOBACCO USE
- HEALTH RISKS ASSOCIATED WITH SMOKING
- HEALTH BENEFITS OF SMOKING CESSATION
- ROLE OF NICOTINE IN TOBACCO DEPENDENCE AND DISEASE RISK
- COUNSELING INTERVENTIONS FOR TOBACCO USE AND DEPENDENCE: AN OVERVIEW
- PHARMACOTHERAPY TO ASSIST WITH THE SMOKING CESSATION ATTEMPT
- INTERACTIONS BETWEEN SMOKING AND MEDICATIONS
- CONCLUSION
- Works Cited
- Evidence-Based Practice Recommendations Citations
This course is designed for nurses, pharmacists, and pharmacy technicians who may intervene to support attempts to quit smoking.
The purpose of this course is to provide nurses, pharmacists, and pharmacy technicians with enhanced knowledge on the health consequences of smoking, the health benefits of quitting, and the medications available to assist with smoking cessation.
Upon completion of this course, you should be able to:
- Describe the epidemiology and changing patterns of tobacco use in the United States.
- Identify the health consequences of smoking and the health benefits of smoking cessation.
- Outline principles of smoking cessation interventions.
- Describe key clinical considerations (such as mechanism of action, dosing, adverse effects, and drug interactions) for medications indicated as aids for smoking cessation.
Katie Blair, PharmD, RPh, is a pharmacist and freelance writer specializing in pharmacy education. She works as a consultant pharmacist in Vancouver, Washington, serving long-term care facilities in the area. She also has over 6 years of experience working as a staff pharmacist at a community pharmacy in Seattle. Katie graduated from Northeastern University in Boston in 2009 with a doctor of pharmacy degree. She has done freelance work writing and revising continuing education programs for pharmacists, pharmacy technicians, and nurses, and written practice questions for various pharmacy technician exams.
Contributing faculty, Katie Blair, PharmD, RPh, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
Candace Pierce, DNP, RN, CNE, COI
The division planner has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
Sarah Campbell
The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.
Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.
It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.
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The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.
Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.
#91810: Pharmacotherapy to Assist with Smoking Cessation
Tobacco use is the leading preventable cause of disease, disability, and death in the United States. In 2021, 11.5% of the adult population smoked cigarettes daily, causing one in every five deaths in the United States each year [1]. While the rate of cigarette smoking has declined by 67% since 1965, approximately 16 million Americans are living with a smoking-related illness, costing over $170 billion annually. Over two-thirds of smokers indicate that they would like to quit smoking, and a majority of smokers make at least one attempt to quit smoking each year, though many smokers require multiple attempts in order to quit smoking completely [2].
To most effectively assist smokers in their cessation attempt, it is necessary for healthcare providers to be aware of the pharmacotherapies currently indicated for smoking cessation, the advantages and disadvantages of each agent, and the instructions for proper use of these medications.
This course is intended to educate healthcare professionals on the health consequences of smoking, the health benefits of quitting, and the medications available to assist with smoking cessation. The course will review the epidemiology of tobacco use, the health risks of smoking, the health benefits of smoking cessation, the role of nicotine in maintaining tobacco dependence, and both pharmacological and nonpharmacological therapies with established efficacy for smoking cessation. With this information, healthcare providers should be better able to assist smokers with their cessation attempt, educate smokers on potential adverse effects of these pharmacotherapies, and provide counseling points that include how and when to properly take the medication.
Cigarette smoking contributes to approximately 480,000 deaths in the United States annually. Despite the known health risks associated with smoking, approximately 11.5% of American adults were identified as current smokers in 2021, with large differences in smoking rates found based on a variety of demographic factors. For example, smoking rates were higher among men than women (13.1% vs. 10.1%), highest among adults between the ages of 45 and 64 (14.9%), highest among low-income adults (18.3%), and lowest among those with a graduate degree (3.2%). Geographically, within the United States, smoking rates were higher in the Midwest (14%) and South (12.4%) than in the West (8.9%) or Northeast (10.4%) [3].
Although the prevalence of smoking continues to be high, the proportion of adults in the United States who smoke has decreased substantially since the 1965 when smoking prevalence among adults was more than 50%. However, the decrease has not been observed consistently among the population, with smoking rates in some subpopulations remaining quite high. Although smoking cessation is difficult, more than 60% of people who have ever smoked have successfully quit [2]. The vast majority of all smokers report first use in adolescence or young adulthood, with 87% of current smokers reporting their first use before the age of 18 and 95% before the age of 21 [4]. These data suggest the importance of preventing tobacco initiation among youth and emphasize the need for public health policies that achieve this goal.
Smoking is a highly social activity that is associated with cancer, coronary artery disease, chronic obstructive pulmonary disease, diabetes, heart disease, cancer, and stroke [5]. The smoking experience is one that is regularly shared with other smokers and is particularly observable with smoking restrictions forcing smokers to leave a building and congregate together outside. Smoking is a learned experience that typically starts in the company of another person teaching the beginner what to do. Growing up in a house with a smoker, having a spouse that smokes, and socializing regularly with smokers are all social situations that contribute to smoking initiation [6].
In addition to smoking initiation, continued use of tobacco products is highly influenced by social circumstances. People from socially disadvantaged communities have more exposure to social situations that promote smoking. These individuals also experience a number of socioeconomic factors that impede smoking cessation, such as stress, financial debt, unemployment, and reduced access to healthcare. This results in a significantly higher concentration of smokers at the bottom of the social ladder, leading to higher rates of the numerous health conditions related to smoking among this group [6].
For individuals with mental health issues, smoking is often perceived as a stress reliever. An estimated 23.1% of American adults with any mental illness are current smokers, compared with 14.5% of adults with no mental health issues [7].
The focus of this continuing education course is on cigarette smoking; however, it is important to be aware of both the wide variety of tobacco products currently available and of the rapid changes that are occurring in the patterns of tobacco product use. In addition to combustible cigarettes, multiple other tobacco products, including electronic nicotine delivery systems (commonly known as e-cigarettes), cigars, smokeless tobacco products, hookah, and pipe tobacco, are being used. In particular, it is important to be aware of the increasing prevalence of e-cigarette use especially among adolescents and young adults. Data from 2023 found that among adolescents, e-cigarette use has surpassed the use of combustible cigarettes, with 7.7% of middle and high school students reporting use of e-cigarettes within the past 30 days compared to 1.6% reporting use of cigarettes [1]. In addition, youth who utilize e-cigarettes are more likely to start smoking combustible cigarettes [8].
E-cigarettes are available in multiple flavors including a wide variety of fruit and candy flavors. A particular concern regarding the availability of fruit- and candy-flavored e-cigarette liquid is that these flavors may be especially appealing to adolescents. Nearly 90% of adolescents who used e-cigarettes in 2023 reported using flavored e-cigarettes in flavors such as candy, mint, or menthol [1]. This could perhaps explain (at least in part) the increasing popularity of e-cigarettes among youth.
An in-depth review of e-cigarettes is beyond the scope of this course. However, due to their increasing popularity, it is important for healthcare professionals to be aware of these products and to remain up to date with the rapidly changing information regarding their effects on health and how the increasing popularity of e-cigarettes is affecting overall tobacco use patterns. In brief, an e-cigarette generally consists of a battery, a heating element, and a container that holds a liquid. The liquid typically consists of a solvent containing vegetable glycerin and/or propylene glycol, nicotine, and flavorings. The liquid is heated by the heating element, which generates an aerosol that is inhaled by the user. There are a wide variety of e-cigarettes currently available on the market with some resembling cigarettes, some larger tank models, and others resembling devices such as USB drives. Some devices allow the user to adjust the battery output voltage, and others allow the user to modify the e-liquid to contain varying amounts of nicotine [2].
The U.S. Preventive Services Task Force recommends that primary care clinicians provide interventions, including education or brief counseling, to prevent initiation of tobacco use among school-aged children and adolescents.
(https://jamanetwork.com/journals/jama/fullarticle/2765009 Last Accessed: August 28, 2026)Level of Evidence: B (There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.)
The health effects of e-cigarettes are an active area of research. Although the risks to an individual from e-cigarette use are likely substantially lower than from smoking cigarettes, the overall public health impact of e-cigarettes is unclear because these products may be attracting adolescents or maintaining nicotine addiction in those who might otherwise have quit smoking entirely [9]. Furthermore, there is concern that nicotine exposure in adolescent brains can negatively impact functions such as attention, learning, memory, and susceptibility to addiction. Concern about the increased use of these products in youth has led the FDA to launch a campaign in 2018 to decrease youth e-cigarette use, aiming to challenge the risk-free attitude teens may have about using e-cigarettes [8]. As new data regarding the risks and use patterns of e-cigarettes become available, this information will likely shape regulatory actions that the FDA may take regarding the availability, marketing, and manufacturing of these products and will likely influence public opinion regarding the use of e-cigarettes. Healthcare providers and pharmacy professionals should stay up to date with these developments so they can provide patients with accurate information regarding the safety of these products and regarding the role (if any) they may have in assisting with smoking cessation.
The clinical practice guidelines stress that even brief interventions (3 minutes) can significantly increase smoking cessation rates. Therefore, it is important that every tobacco user should be offered at least brief counseling. The 5 As are the key components (Ask, Advise, Assess, Assist, Arrange) of a brief counseling program designed for use in the primary care setting [18].
According to the U.S. Department of Health and Human Services, brief tobacco dependence treatment is effective. Individual, group, and telephone counseling are effective, and their effectiveness increases with treatment intensity. Two components of counseling are especially effective, and clinicians should use these when counseling patients making a quit attempt: practical counseling (problem-solving/skills training) and social support delivered as part of treatment.
(https://www.ncbi.nlm.nih.gov/books/NBK63952 Last Accessed: August 28, 2026)Level of Evidence: Expert Opinion/Consensus Statement
The 5 As include asking all patients at each encounter regarding tobacco use (Ask). Those who are identified as tobacco users should be advised to quit (Advise). The advice provided should be clear, strong, and personalized. The clinical practice guidelines provide example statements that can be used to advise patients to quit such as the following [18]:
"It is important that you quit smoking now and I can help you."
"Occasional or light smoking is still dangerous."
"As your clinician, I need you to know that quitting smoking is the most important thing you can do to protect your health now and in the future."
"Continuing to smoke makes your asthma worse and quitting may dramatically improve your health" (as an example of personalized advice).
"Quitting smoking may reduce the number of ear infections your child has" (as another example of personalized advice).
The next component of the 5 As is to determine the patient's willingness to make a quit attempt (Assess). For those willing to make a quit attempt, the next step is to provide assistance to the patient to maximize the probability of quitting (Assist). The final component of the 5 As is to arrange for follow-up contact, preferably within the first week of cessation, either in person or by telephone. At the follow-up, the clinician should identify and help troubleshoot any problems the smoker has encountered. The clinician should congratulate those smokers who are abstinent or review circumstances and elicit a recommitment to tobacco abstinence for those who lapsed [18].
As noted previously, approximately 480,000 deaths annually in the United States are attributable to cigarette smoking [3]. Smokers are nearly three times more likely than nonsmokers to die prematurely from cardiovascular disease; this risk is highest among those who started smoking before age 15 [10]. Smoking affects nearly every organ system and results in increased morbidity and mortality from a wide variety of illnesses. Although smoking is most commonly associated with increased risk of cancer, cardiovascular disease, and respiratory disease, it has been established as a risk factor for numerous other diseases, and the list of diseases continues to grow.
In the United States, tobacco use results in approximately 660,000 new cancer cases and 343,000 cancer deaths annually. The number of cancer diagnoses attributable to tobacco use represents approximately 40% of all cancer deaths in the United States [11]. Smoking results in an approximately 25-fold increase in lung cancer risk and it has been estimated that 90% of all lung cancers are attributable to smoking. Although smoking is most closely associated with increased lung cancer incidence, it is also a risk factor for numerous other cancers, including cancers of the esophagus, larynx, stomach, liver, pancreas, bladder, kidney, and colon [12].
In addition to the number of deaths due to cancer, the American Heart Association estimates that there are approximately 160,000 deaths annually from cardiovascular disease due to smoking. Chemicals in cigarette smoke can alter the blood chemistry and increase the accumulation of plaque in the arteries, leading to atherosclerosis, which increases the risk of blood clots that can cause heart attacks, strokes, or death [13].
The other major disease category that smoking is commonly associated with is pulmonary disease, with smokers having 12 to 13 times the risk of dying from chronic obstructive pulmonary disease (COPD) than nonsmokers. Cigarette smoking is the most common cause of COPD in the United States, and approximately 80% of all deaths from COPD are attributable to smoking [12].
Smoking during pregnancy is associated with preterm delivery, low infant birthweight, and sudden infant death syndrome. In addition to the health risks to the smoker, exposure of nonsmokers to secondhand tobacco smoke has been linked to multiple diseases such as cancer, respiratory disease, cardiovascular disease, and adverse health effects in children and infants [2]. Secondhand smoke exposure is associated with 30,000 coronary heart disease deaths annually in the United States [13].
The health benefits of smoking cessation are considerable, with both short-term and long-term health effects observed after cessation. Within 24 hours of quitting, nicotine levels in the blood drop to zero. Several days after quitting, carbon monoxide levels drop to the same level as nonsmokers. Within a year of quitting, coughing and shortness of breath decrease. The risk of heart attack drops sharply after 1 to 2 years have passed since quitting. After 3 to 6 years, the risk of coronary heart disease is approximately half that of a continuing smoker. Within 5 to 10 years of quitting smoking, risk for stroke decreases to approximately that of a nonsmoker, as does the risk of cancers of the mouth, throat, and voice box. Within 10 years of quitting, the added risk of lung cancer drops by half, and the risk of bladder, esophagus, and kidney cancers decreases. Approximately 15 years after quitting, the risk of coronary heart disease drops to approximately that of a nonsmoker [14].
Considering how quickly some health benefits of cessation are observed, it is important to stress to smokers that there are health benefits to quitting at any age regardless of how long they have been smoking. Indeed, data has shown that smokers who quit between the ages of 25 and 34 gain 10 years of life (i.e., their lifespan is essentially comparable to a never smoker), smokers who quit between the ages of 35 and 44 gain approximately 9 years of life, those who quit between the ages of 45 and 54 gain 6 years of life, and those who quit between the ages of 55 and 64 gain 4 years of life as compared to those who continue to smoke [2].
The following case study will be revisited throughout this course.
Patient J is a 28-year-old single mother of two children who has been considering quitting smoking cigarettes. Her 2-year-old daughter was recently diagnosed with asthma, and the patient is concerned about the effects of secondhand smoke impacting her child's breathing. Even though she keeps her smoking away from her kids, she is worried that the scent on her clothes or irritants remaining in the air may be contributing to worsening her asthma. She wants to be a good role model to her children and support her daughter's journey in optimizing her asthma treatment. Patient J started smoking when she was 16 years old and is concerned that quitting will be difficult, especially while she is going to school part time, working, and taking care of her young children.
Nicotine has been shown in behavioral studies in both animals and humans to be an addictive compound and is the primary constituent of tobacco smoke responsible for maintaining the addiction to smoking [2]. The addictiveness of nicotine is evidenced in part by the difficulty that many smokers have in successfully quitting even after being diagnosed with tobacco-related diseases (such as cardiovascular disease or COPD). For example, a study found that after experiencing an acute myocardial infarction (AMI), approximately 50% of patients do not quit smoking [15].
After being inhaled, nicotine is absorbed rapidly into the pulmonary venous circulation and then quickly enters the brain. In the brain, nicotine binds to presynaptic nicotine cholinergic receptors, resulting in the release of a variety of neurotransmitters, including dopamine, in the reward pathways of the brain. This release of dopamine is responsible for many of the pleasurable effects of nicotine (as well as other drugs of abuse). Nicotine's effects on numerous other neurotransmitters, including glutamate and γ-aminobutyric acid (GABA), are also thought to contribute to its addictive properties [16].
Despite its role as the primary addictive compound in tobacco, nicotine is a relatively small contributor to the overall health risks associated with smoking. It is rather many of the other constituents in tobacco smoke that are responsible for the negative health effects. Tobacco smoke contains thousands of chemicals that are deposited in the large and small airways when inhaled. Although the relative contribution of each individual compound to the development and progression of disease is not clear, some compounds' role in contributing to disease has been better studied. The presence of oxidant chemicals and particulates is thought to lead to inflammation whereas the presence of carbon monoxide leads to reduced oxygen availability—both of these then lead to increased cardiovascular morbidity and mortality. The presence of tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons, aromatic amines, and other carcinogens likely contributes to the development of cancer [2].
Unfortunately, many smokers mistakenly believe that nicotine is responsible for many of smoking's health effects and are therefore reluctant to use nicotine replacement therapy (NRT) to help them quit smoking. Approximately 80% of American adults believe that nicotine is the main cause of disease from tobacco products [17]. This misconception can lead to concerns about the safety of nicotine replacement, preventing smokers from utilizing evidence-based smoking cessation aids. Education is critical to combat these incorrect perceptions. It is therefore important that healthcare providers reassure patients that the health risks of using medicinal nicotine during a quit attempt are small compared to the health risks of continued smoking.
The most recent clinical practice guidelines published by the Agency for Healthcare Research and Quality (AHRQ) that address the treatment of tobacco use and dependence were updated in 2008 [18]. As there have been no new medications approved since that time (varenicline, approved in 2006, is the most recent medication approved as an aid to smoking cessation treatment), much of the information from these clinical practice guidelines is still relevant.
Approximately 70% of smokers report that they would like to quit smoking and over 50% of adult daily smokers try to quit each year. An increasing number of people are quitting smoking successfully; in 2020, 8.5% of smokers successfully quit in the past year, compared to 7.5% in 2019 [19]. In clinical studies in which smokers receive both behavioral and pharmacological interventions, quit rates are substantially higher, but unfortunately even in these circumstances fewer than 30% of those who try to quit smoking are able to achieve long-term abstinence [18]. There is therefore clearly a need for knowledgeable healthcare professionals who can suggest appropriate pharmacotherapy for patients and instruct them on how to properly use it so as to maximize smoking cessation success rates.
The clinical practice guidelines stress that even brief interventions (3 minutes) can significantly increase smoking cessation rates. Therefore, it is important that every tobacco user should be offered at least brief counseling. The 5 As are the key components (Ask, Advise, Assess, Assist, Arrange) of a brief counseling program designed for use in the primary care setting [18].
According to the U.S. Department of Health and Human Services, brief tobacco dependence treatment is effective. Individual, group, and telephone counseling are effective, and their effectiveness increases with treatment intensity. Two components of counseling are especially effective, and clinicians should use these when counseling patients making a quit attempt: practical counseling (problem-solving/skills training) and social support delivered as part of treatment.
(https://www.ncbi.nlm.nih.gov/books/NBK63952 Last Accessed: August 28, 2026)Level of Evidence: Expert Opinion/Consensus Statement
The 5 As include asking all patients at each encounter regarding tobacco use (Ask). Those who are identified as tobacco users should be advised to quit (Advise). The advice provided should be clear, strong, and personalized. The clinical practice guidelines provide example statements that can be used to advise patients to quit such as the following [18]:
"It is important that you quit smoking now and I can help you."
"Occasional or light smoking is still dangerous."
"As your clinician, I need you to know that quitting smoking is the most important thing you can do to protect your health now and in the future."
"Continuing to smoke makes your asthma worse and quitting may dramatically improve your health" (as an example of personalized advice).
"Quitting smoking may reduce the number of ear infections your child has" (as another example of personalized advice).
The next component of the 5 As is to determine the patient's willingness to make a quit attempt (Assess). For those willing to make a quit attempt, the next step is to provide assistance to the patient to maximize the probability of quitting (Assist). The final component of the 5 As is to arrange for follow-up contact, preferably within the first week of cessation, either in person or by telephone. At the follow-up, the clinician should identify and help troubleshoot any problems the smoker has encountered. The clinician should congratulate those smokers who are abstinent or review circumstances and elicit a recommitment to tobacco abstinence for those who lapsed [18].
Patients unwilling to quit may respond to brief interventions that are based on principles of motivational interviewing. Motivational interviewing is a directive, patient-centered counseling intervention with the goal of eliciting behavioral change by helping to explore and resolve ambivalence. This approach is intended to increase the likelihood that a smoking cessation attempt will be made. Its four general principles are express empathy, develop discrepancy, roll with resistance, and support self-efficacy [18]. Table 1, taken from the practice guidelines, details approaches and statements that can be used when counseling a smoker [18].
MOTIVATIONAL INTERVIEWING STRATEGIES
| Express empathy |
Use open-ended questions to explore:
Use reflective listening to seek shared understanding:
| |||
| Develop discrepancy |
Highlight the discrepancy between the patient's present behavior and expressed priorities, values, and goals (e.g., "It sounds like you are very devoted to your family. How do you think your smoking is affecting your children?"). Reinforce and support "change talk" and "commitment" language:
Build and deepen commitment to change:
| |||
| Roll with resistance |
| |||
| Support self-efficacy |
Help the patient to identify and build on past successes: "So you were fairly successful the last time you tried to quit." Offer options for achievable small steps toward change:
|
Patients who appear unwilling to attempt to quit smoking may lack information on the benefits of quitting and harmful effects of tobacco use, may have concerns or fears surrounding quitting, may be put off by a prior relapse, or may lack the financial resources to quit. Motivational interviewing can help increase conversation on these topics and uncover the core reasoning behind a patient's reluctance to quit (Table 2). Motivational interviewing has been shown to be effective in increasing future quit attempts [18].
THE 5 Rs OF MOTIVATIONAL INTERVIEWING
| Relevance | Encourage the patient to indicate why quitting is personally relevant, being as specific as possible. Motivational information has the greatest impact if it is relevant to a patient's disease status or risk, family or social situation (e.g., having children in the home), health concerns, age, gender, and other important patient characteristics (e.g., prior quitting experience, personal barriers to cessation). | ||||
| Risks |
| ||||
| Rewards |
The clinician should ask the patient to identify potential benefits of stopping tobacco use. The clinician may suggest and highlight those that seem most relevant to the patient. Examples of rewards follow:
| ||||
| Roadblocks |
The clinician should ask the patient to identify barriers or impediments to quitting and provide treatment (problem-solving counseling, medication) that could address barriers. Typical barriers might include the following:
| ||||
| Repetition | The motivational intervention should be repeated every time an unmotivated patient visits the clinic setting. Tobacco users who have failed in previous quit attempts should be told that most people make repeated quit attempts before they are successful. |
After a thorough discussion with Patient J, she decides she is ready to start treatment for smoking cessation. She is concerned that it will be incredibly difficult; she shares that she tried quitting several times during her pregnancies, but she always struggled with abstaining after stressful arguments with the father of her children. She does not know how she is going to manage all of the responsibilities of her life without being able to take breaks to smoke cigarettes and do something selfish for herself. She is worried that she is going to put a lot of effort into a quit attempt, just to fail at it.
There are currently seven medications approved in the United States to assist smokers with a smoking cessation attempt. Five of these are various dosage forms of nicotine. The other two are bupropion sustained release and varenicline. The clinical practice guidelines list two medications (i.e., nortriptyline, clonidine) that can be used as second line agents; however, their use in smoking cessation is limited due to their lack of indication for this purpose and an increased risk for adverse effects. The second-line agents will therefore not be reviewed in this course.
In general, pharmacotherapy should be recommended for all smokers trying to quit except in special circumstances such as if there are contraindications to the medications, in light smokers, adolescents, or women who are pregnant or breastfeeding. In light smokers and adolescents, there is not sufficient data to state that all such smokers should receive pharmacotherapy, but it may be appropriate in individual cases. Similarly, although it would be preferable for women who are pregnant or breastfeeding to quit without using medication, since smoking during pregnancy increases the risk for pregnancy complications and is harmful to the fetus, it may be appropriate to use medication after weighing the potential risks and benefits [18].
For smokers interested in cessation, most programs (including the clinical practice guidelines) suggest setting a target quit date on which they will completely stop smoking. The target quit date can be one of personal significance to the smoker such as a birthday, a New Year's resolution, or a child's birthday. The data regarding the relative effectiveness of abrupt versus gradual cessation is somewhat inconsistent. For example, a meta-analysis of 10 studies did not find large differences between the two methods, whereas a more recent study found abrupt cessation to be more effective in achieving successful cessation [20,21]. Both the gradual and abrupt approaches, however, generally ask smokers to pick a date at which they will stop smoking completely. The difference between these approaches is whether there is a scheduled period of reduction first. Smokers should therefore be advised to pick a date on which they will stop smoking all cigarettes regardless of whether they choose to start cutting down prior to that date or not. On their target quit date, smokers should ensure that they dispose of all cigarettes and that they have developed strategies to deal with cravings that are likely to occur during parts of their daily routine when they would normally be smoking.
The focus of this course is on the pharmacotherapies that are available to help with the smoking cessation attempt, and the following sections review the medications currently available. It is important to note that medications are most effective when combined with counseling. The clinical practice guidelines found that relative to medication alone, the odds ratio (95% confidence interval) of successful cessation when medication was combined with counseling was 1.4 (1.2 to 1.6). Smokers should therefore either be provided or referred to counseling in addition to educating them regarding the proper use of medications.
There are currently five dosage forms of NRT (gum, lozenge/mini-lozenge, patch, inhaler, nasal spray) available in the United States. The patch, gum, and lozenge dosage forms are available over the counter, whereas the inhaler and nasal spray require a prescription. The over-the-counter dosage forms are used far more commonly than the prescription forms and provide an optimal opportunity for pharmacy professionals to ensure that patients selecting these products are counseled about how to properly use them.
All of the dosage forms of NRT are designed such that absorption occurs either through the oral mucosa (nicotine gum, nicotine lozenge, nicotine inhaler), the nasal mucosa (nicotine nasal spray), or the skin (nicotine patch). None of the dosage forms are meant to be absorbed through the gastrointestinal tract. There are several reasons for this. First, nicotine undergoes first-pass metabolism in the liver, thereby reducing the nicotine concentrations that would be achieved in the systemic circulation were nicotine to be swallowed. Second, nicotine can cause irritation and if swallowed can result in gastrointestinal side effects. It is important to consider these properties of nicotine when instructing patients on how to properly use the various dosage forms of NRT. For example, nicotine gum and lozenge if used improperly are likely to result in large amounts of nicotine being swallowed. As described previously, this would result in low nicotine concentrations (and therefore decreased efficacy) but high rates of gastrointestinal adverse events. It is also important to note that none of the dosage forms of NRT deliver nicotine nearly as quickly as smoking cigarettes does, which may in part contribute to the relatively low success rates and the relatively low addiction potential associated with these products [18,22].
As can be expected, there are many similarities among the NRT formulations. The primary differences are in patient preference, tolerability, and the rate at and location from which nicotine is absorbed. In terms of efficacy, the quit rates for the five dosage forms are similar among the products. For example, a review of 136 studies found that the relative risk of abstinence for any form of NRT compared to the control group, which included either a placebo or a non-NRT group, was 1.55 with a 95% confidence interval (CI) of 1.49 to 1.61. A relative risk of greater than 1 means that abstinence is more likely to occur in the experimental group relative to the control group. Examining each individual NRT dosage form, this review found the relative risks of successful cessation as follows [23]:
Nicotine gum: 1.49 (95% CI 1.40 to 1.60) based on 56 studies.
Nicotine patch: 1.64 (95% CI 1.53 to 1.75) based on 51 studies.
Nicotine lozenge/oral tablet: 1.52 (95% CI 1.32 to 1.74) based on 8 studies.
Nicotine inhaler: 1.90 (95% CI 1.36 to 2.67) based on 4 studies.
Nicotine nasal spray: 2.02 (95% CI 1.49 to 2.73) based on 4 studies.
Although the estimates for the effectiveness of the nicotine inhaler and nasal spray appear to be higher than those of the other dosage forms, it is important to note that the estimates for these two products are based on a smaller number of studies with wider confidence intervals around the estimate. Furthermore, this meta-analysis includes some products or dosages (e.g., nicotine sublingual tablets, nicotine oral spray, certain strengths of nicotine patches) that are not currently available in the United States. Nonetheless, these estimates demonstrate that the various dosage forms of NRT are of approximately equal efficacy and that NRT increases the probability of quitting by approximately 50% to 60%. Considering that this translates into cessation rates (at six months) of approximately 30% or lower, most patients will require multiple quit attempts before they can achieve successful long-term cessation. Tobacco dependence should therefore be treated as a chronic disease that often requires multiple interventions and repeated quit attempts before sustained cessation is achieved [18].
Although NRT is appropriate for most smokers, nicotine activates the sympathetic nervous system, which leads to increases in heart rate, blood pressure, and myocardial contractility. For this reason, NRT should be used with caution among certain patients with cardiovascular disease, specifically those who have had a myocardial infarction within the preceding two weeks, have serious arrhythmias, or have unstable angina pectoris. When considering the risks and benefits of NRT use, it is important to consider the risk of continued smoking, which is almost certainly more dangerous than the use of NRT since in addition to nicotine, smoking cigarettes exposes smokers to numerous other toxic compounds. The decision is therefore not whether smokers should be left untreated, but rather if NRT is the most appropriate treatment for a particular patient or if another treatment, such as medication or behavioral counseling, would be more appropriate. For all dosage forms of NRT, overuse or use by nonsmokers can lead to symptoms of nicotine overdose such as nausea, vomiting, dizziness, diarrhea, weakness, and rapid heartbeat. Although it is important for smokers to be aware of these side effects, smokers are generally more likely to underuse these medications (resulting in low efficacy) than to overuse them, leading to the recommendation that all dosage forms of nicotine replacement be used on a scheduled basis if used as monotherapy [18,22].
The recommended duration varies among products due to differences in the design of studies that were conducted establishing each product's efficacy rather than specific characteristics of each product. Some smokers, however, may not be ready to completely stop using NRT at the end of the recommended period of use and may benefit from an extended duration of therapy. For example, there is data that among patients given free access to nicotine gum, 15% to 20% of successful abstainers continue to use the gum for a year or longer [18]. Although patients should not be encouraged to use nicotine gum (or other NRT dosage forms) indefinitely, any risks associated with its long-term use are small relative to the risks associated with continued smoking. In recognition of the need for some smokers to use NRT beyond a 3-month period, the FDA in recent years changed the labeling on over-the-counter NRT products from stating that NRT must be stopped within 3 months regardless of the smoker's progress toward cessation to stating that NRT may be used for a longer period of time after consultation with a healthcare provider [18].
For all dosage forms of NRT, the recommendation is that smokers start using NRT on their quit date, although there has been some research examining if starting NRT prior to the quit date might result in increased efficacy. The rationale for such an approach is that pre-loading with nicotine might result in decreased craving and withdrawal symptom severity and allow smokers to become familiar with the medication. A meta-analysis of seven studies found that starting to use NRT for a brief period prior to the quit date did not lead to significantly higher quit rates versus starting NRT on the quit date (risk ratio [RR] 1.18, 95% CI 0.98 to 1.41). An analysis limited to only the nicotine patch did, however, find a significant effect based on six studies (RR 1.34; 95% CI 1.08 to 1.65) [24]. The data for pre-treatment is therefore somewhat mixed and may be dependent on the NRT dosage form.
All of the available dosage forms of NRT work in part by alleviating or minimizing nicotine withdrawal symptoms that typically occur after cessation of tobacco. Withdrawal symptoms generally peak within one to two weeks after quitting but may persist for months. The time course of these symptoms may help explain why most lapses occur within the first week of cessation (and many within the first 24 hours). Nicotine withdrawal symptoms include irritability, anxiety, difficulty concentrating, increased appetite, restlessness, depressed mood, and insomnia. Use of nicotine replacement therapy decreases the intensity of these symptoms relative to use of placebo or no treatment. In addition to decreasing withdrawal symptoms, nicotine from NRT might provide some of the perceived benefits that smokers experience from cigarettes. For example, smokers often report that smoking decreases stress or anxiety (although smoking may in fact be relieving withdrawal symptoms). To the extent that these perceived benefits are due to nicotine, replacing the nicotine from cigarettes with another source may result in similar effects and thereby reduce the likelihood of smoking lapses [18,22].
The nicotine gum is available in two strengths (2 mg, 4 mg), in multiple flavors (such as original, mint, and cinnamon, among others), and in both brand-name and generic form. Dosing for the nicotine gum is based on the time to first cigarette, which is a surrogate measure for the degree of nicotine dependence. If the first cigarette of the day is smoked within 30 minutes of waking, the 4-mg dose should be used. Otherwise, the 2-mg dose should be used. Nicotine concentrations peak approximately 30 minutes after nicotine gum use is started. This relative rapid increase means that unlike the nicotine patch (described subsequently), the nicotine gum can be used to decrease craving and withdrawal symptom severity when smokers find that they are experiencing an urge to smoke, although for many smokers craving relief may not occur quickly enough to avoid a lapse.
For efficacy to be maximized and side effects minimized, the gum should be used in a manner that results in as much nicotine as possible being absorbed via the buccal mucosa rather than being swallowed. It is therefore important that patients are counseled as to how to properly use nicotine gum, particularly since using this product properly is different than how regular chewing gum is used. To maximize nicotine absorption, the "chew and park" technique is recommended. This entails chewing the gum until a peppery taste appears (or a tingling is felt), then parking the gum between the cheek and gum until the taste (or tingling) stops. This is repeated for about 30 minutes until the taste dissipates. Since an acidic environment reduces the absorption of nicotine, drinking anything but water should be avoided for 15 minutes prior to and during gum use. Acidic beverages such as coffee or carbonated drinks should particularly be avoided [18,22].
Utilizing nicotine gum requires a different technique than regular chewing gum—the gum should be parked between the cheek and gum to allow the nicotine to be absorbed through the oral mucosa. Patients should be counseled on this "chew and park" technique to maximize effectiveness. They should also be counseled to avoid acidic drinks while using the gum, such as coffee, orange juice, and carbonated sodas [18].
Similar to the nicotine gum, nicotine lozenges are available in 2 mg and 4 mg strengths, in multiple flavors, and in both brand-name and generic form. As with the nicotine gum, the dosage is determined by whether the first cigarette of the day is smoked within 30 minutes of awakening, in which case the 4 mg lozenge is to be used. The pharmacokinetics of nicotine lozenges is similar to that of nicotine gum, and therefore the dosing is similar for these products. Dosing, based on the product labeling, is to use one lozenge every 1 to 2 hours for the first six weeks with at least nine lozenges used per day during this time period. The number of lozenges used per day is then gradually decreased for the subsequent six weeks. As with nicotine gum, it is advisable for smokers to initially use the lozenge on a scheduled basis and supplement with extra doses as needed to treat craving and withdrawal symptoms when they arise. The labeling cautions that no more than 5 lozenges should be used in a 1-hour period and not more than 20 pieces used within a 24-hour period. Side effects of nicotine lozenge include hiccups, cough, and heartburn.
As with the nicotine gum, it is imperative that nicotine lozenges are used correctly to ensure that nicotine absorption occurs through the buccal mucosa and to minimize side effects. The lozenge should be placed in the mouth and allowed to slowly dissolve over approximately 20 to 30 minutes. Occasionally the lozenge should be moved from one side of the mouth to the other until it completely dissolves. The lozenge should not be chewed or swallowed whole and as with the nicotine gum, acidic beverages should be avoided for 15 minutes prior to and during nicotine lozenge use [18,22].
The nicotine patch is different from all of the other dosage forms of NRT in that it delivers a constant amount of nicotine over a prolonged period of time. Nicotine concentrations following the application of the nicotine patch increase gradually over several hours and then remain relatively steady for the duration that it is worn. An advantage of this pharmacokinetic profile is that smokers need only to remember to place the patch once per day. A disadvantage is that the patch cannot be used for acute relief of craving and withdrawal symptoms.
As is the case with the nicotine gum and lozenge, the patch is available over the counter in both brand and generic forms. The patch comes in three dosages (21-mg, 14-mg, and 7-mg). The initial dose, per the labeling, is based on the number of cigarettes that are smoked per day. Those that smoke fewer than 10 cigarettes per day start with the 14-mg patch, whereas those smoking more than 10 cigarettes per day start with the 21-mg patch. The labeled dosage of the patch is the amount of nicotine delivered over a 24-hour period. The nicotine patch is designed to be worn for 24 hours; smokers who have sleep disturbances while wearing the patch overnight may benefit from removing the patch at bedtime.
For those starting with the 21-mg patch, the labeling states that this dose should be used for four weeks with the dose then reduced at two-week intervals until the patch is discontinued, for a total course of eight weeks. As with the other dosage forms, it is important that smokers use the patch correctly. Patients should be instructed to apply a new patch daily to a hairless location on the upper body. The skin site should be rotated to minimize the possibility of skin reactions. Since the patch can be placed on areas that are normally covered by clothes, an advantage of this dosage form is that its use is least obvious to others. Side effects associated with the patch include skin reactions, insomnia, and vivid dreams [18,22].
The nicotine inhaler is a product that is available only by prescription. Although the name inhaler suggests that nicotine is absorbed through the lungs (as is the case when smoking cigarettes), the absorption of nicotine actually occurs through the buccal mucosa, with very little of the nicotine reaching the lower respiratory tract. The instructions cautioning patients regarding drinking anything but water for 15 minutes prior to and during use of the nicotine lozenge and gum therefore also applies to the nicotine inhaler. An advantage of the nicotine inhaler is that it mimics some of the hand-to-mouth ritual of smoking.
The dosing for the nicotine inhaler, based on the product labeling, is that patients use at least 6 cartridges per day and up to 16 cartridges per day. The nicotine inhaler consists of a mouthpiece and a plastic nicotine-containing cartridge that delivers 4 mg of nicotine over 80 inhalations. Most successful patients in clinical trials used between 6 and 16 cartridges a day, with the best effect achieved by frequent continuous puffing over 20 minutes. The duration of treatment per product labeling is 3 months, after which patients may gradually reduce the daily dose over the subsequent 6 to 12 weeks (for a total length of treatment of 6 months). The nicotine inhaler is temperature dependent, with temperatures below 40 degrees Fahrenheit resulting in significantly decreased delivery of nicotine; therefore, patients should be instructed to keep the inhaler and cartridges in an inside pocket or warm area. Although use of the nicotine inhaler is designed to be similar to smoking a cigarette, this product is used relatively infrequently.
To use the inhaler, the top and bottom of the mouthpiece are first separated by lining up the markings on the mouthpiece. The cartridge is then placed into the top of the mouthpiece and pushed in until it pops into place. The markings on the two parts of the mouthpiece are then lined up again and the two parts are pushed together so they fit tightly. To secure the unit, the mouthpiece is then twisted to misalign the marks. Once the cartridge is assembled, it is ready to be used. To use the inhaler, the patient should inhale deeply into the back of the throat or puff in short breaths. The nicotine in the cartridge is depleted after about 20 minutes of use. Side effects most commonly experienced while using the inhaler include irritation of the mouth or throat, cough, and rhinitis. Because nicotine is an airway irritant and might cause bronchospasm, the nicotine inhaler should be used with caution in patients with bronchospastic disease [18,22].
Absorption of nicotine after using the nasal spray is via the nasal mucosa and is substantially more rapid than other dosage forms of NRT, with peak concentrations occurring within approximately 10 to 15 minutes after use. Although faster than other dosage forms of NRT, this is still significantly slower than occurs after cigarette smoking. An advantage of the more rapid nicotine absorption is that withdrawal symptom relief should occur more quickly than with other NRT dosage forms. Nonetheless, usage of this product is limited due to a high rate of adverse events.
The nicotine nasal spray is currently only available by prescription [18,22]. Each actuation of the nicotine nasal spray delivers a 50-microliter spray containing approximately 0.5 mg of nicotine. The recommended dose is one spray in each nostril (1 mg), approximately half of which reaches the systemic circulation. The dosing for the nicotine nasal spray, based on the product labeling, is that patients should be started with 1 or 2 doses per hour for a minimum of 8 doses per day, which may be increased up to a maximum of 5 doses per hour and 40 doses (i.e., 80 sprays) per day. The dosage can be adjusted based on signs or symptoms of nicotine withdrawal or excess. Although not specifically mentioned in the labeling, as with the nicotine lozenge, gum, and inhaler, smokers are most likely to benefit if the nicotine nasal spray is initially used on a schedule. The duration of treatment per product labeling is up to eight weeks at the selected dosage before being discontinued over the next four to six weeks, with length of use limited to 6 months.
Use of the nasal spray is limited by the frequency with which side effects are experienced, with nasal irritation occurring most commonly. Over the first two days of treatment, over 90% of users report nasal irritation, with the majority of users rating it as either moderate or severe. Although the frequency and severity of this side effect decreases with continued use, over 80% of users continue to experience mild to moderate nasal irritation after three weeks of use. Other commonly experienced side effects include throat irritation, rhinitis, sneezing, coughing, and watering eyes. Because exacerbation of bronchospasm in patients with pre-existing asthma has been reported, use of nicotine nasal spray in patients with severe reactive airway disease is not recommended [18,22].
Patient J is ready to start treatment for smoking cessation. She has never utilized nicotine replacement therapy but notes that this may be helpful for her to reduce her cravings that were difficult to deal with during past quit attempts. Patient J smokes about a pack of 20 cigarettes per day and typically smokes her first cigarette within the first 10 minutes of waking up in the morning.
Bupropion was the first non-nicotine medication to be approved for use as an aid for smoking cessation. Bupropion's mechanism of action is unclear, but it is thought that it is related to its activity blocking the reuptake of dopamine and norepinephrine in the central nervous system. Although effective in the treatment of major depressive disorder, bupropion increases cessation rates in those who do and in those who do not have symptoms of depression. Its efficacy as an aid for smoking cessation is therefore independent of its effect as an antidepressant. As further evidence that bupropion's effects are not secondary to its antidepressant effects, there have been several studies demonstrating that unlike bupropion, selective serotonin reuptake inhibitors (SSRIs), which are also effective antidepressants, are not effective at increasing smoking cessation rates [25].
Smokers should begin taking bupropion one to two weeks prior to their quit date to allow steady-state concentrations to be achieved. Because a dose-related incidence of seizures has been reported, bupropion is contraindicated in those with a seizure disorder or who are at increased risk for seizures, for example, those with a current or prior diagnosis of eating disorders or after acute discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. Consistent with the labeling of all antidepressants, bupropion carries a black box warning regarding an increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults.
When used as an aid to smoking cessation treatment, the sustained release dosage form of bupropion is initiated at 150 mg daily for the first three days, then increased to 150 mg twice daily separated by at least 8 hours. Treatment should continue for at least 7 to 12 weeks and can be extended for up to 6 months if appropriate. The most common side effects of bupropion include insomnia and dry mouth, with other side effects such as headache, agitation, dizziness, nausea, and constipation also reported. To prevent insomnia, it is sometimes recommended that the evening dose of bupropion is given several hours before bedtime (but at least 8 hours after the first dose of the day). In some patients, bupropion can cause increases in blood pressure. Although in most cases these increases are relatively small, blood pressure should be monitored, particularly in those who use bupropion with the nicotine patch as the increases may be larger in these patients. Bupropion is metabolized by CYP2B6, and therefore bupropion concentration may be affected by drugs that alter the activity of this isoenzyme. Bupropion is also known to be an inhibitor of the CYP2D6 isoenzyme, which is responsible for the metabolism of many medications. When both starting and discontinuing bupropion, it is therefore necessary to determine if the patient is taking any medications metabolized via this route to determine if increased monitoring or dose adjustments may be needed [18,22].
In a large study called the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) trial, over 8,000 smokers were randomized to varenicline, bupropion, nicotine patch, or placebo. Approximately one-half of the randomized participants had stable psychiatric disorders such as major depressive disorder, bipolar disorder, an anxiety disorder, or a psychotic disorder. The primary endpoint of this study was to compare the incidence of a composite measure of moderate and severe neuropsychiatric adverse events. More participants in the psychiatric cohort experienced neuropsychiatric adverse events than in the nonpsychiatric cohort; however, the data did not suggest that that the rates of these symptoms were higher in either the bupropion or varenicline group compared to the placebo group. The results of this study contributed to changes in the labeling of both bupropion and varenicline, decreasing the prominence of the warning regarding neuropsychiatric adverse events. Although no longer a boxed warning, neuropsychiatric adverse events are still listed as a warning and should be monitored for when taking these medications.
The EAGLES study, in addition to assessing safety outcomes, also allowed for a direct comparison of efficacy among these four treatments and for information regarding the effectiveness of smoking cessation medication in those with mental illness. Overall cessation rates were lower in participants in the psychiatric cohorts; however, all three medications were more effective than placebo at increasing cessation rates in both the psychiatric and non-psychiatric cohorts. Furthermore, those treated with varenicline achieved higher cessation rates than those treated with either bupropion or nicotine patch, with no differences found between bupropion- and patch-treated participants [26].
Varenicline is a partial agonist at the α4β2 nicotinic acetylcholine receptor, which is thought to be the major receptor involved in nicotine addiction. As a partial agonist, varenicline could relieve the symptoms of nicotine withdrawal while also blocking the effects of nicotine from any cigarettes that are smoked. This would thereby decrease the chance that a smoking lapse would lead to a relapse. The efficacy of varenicline has been confirmed in multiple studies, with an analysis of 27 trials finding that the relative risk for abstinence at 6 months or longer for varenicline-treated smokers relative to those receiving placebo is 2.24 (95% CI 2.06 to 2.43). This effect is larger than those previously described for either bupropion or NRT, and indeed a meta-analysis has found that varenicline is more effective than either bupropion (relative risk of 1.39; 95% CI 1.25 to 1.54) or NRT (relative risk of 1.25; 95% CI 1.14 to 1.37) at increasing cessation rates [27].
Varenicline should be started a week before the target quit date. The dosing for varenicline is 0.5 mg once daily for three days followed by 0.5 mg twice daily for the subsequent four days, which is then increased to 1 mg twice daily for the duration of therapy. The recommended duration of therapy is 12 weeks and for those who have successfully quit during this time, treatment can be extended for an additional 12 weeks to decrease the risk of relapse. Since varenicline is almost exclusively excreted unchanged in the urine, dosing adjustments are needed for those with severe renal impairment. The most common side effects associated with varenicline use are nausea, abnormal dreams, and insomnia. Neuropsychiatric side effects, which include changes in mood (including depression and mania), psychosis, aggression, agitation, anxiety, and suicide, were identified in post-marketing reports and resulted in a boxed warning in the labeling of varenicline. However, rates of these side effects in the EAGLES study did not occur more frequently in varenicline-treated smokers than in those receiving placebo [26]. The boxed warning was therefore removed, although these potential side effects are still listed as a warning and patients should be monitored for them, particularly since smoking cessation can also result in some of these symptoms. The cardiovascular safety of varenicline has been questioned due to reports of increased cardiovascular adverse events, particularly in those with underlying cardiovascular disease, but studies have not found an increase in cardiovascular events when used in generally healthy individuals. As a result, the current labeling states that those with underlying cardiovascular disease may be at increased risk of cardiovascular events but that these concerns should be balanced with the health benefits of smoking cessation [18,22].
Despite the documented efficacy of the first-line pharmacotherapies described previously, smoking cessation rates when using any of them remain relatively low, leading researchers and clinicians to examine if quit rates can be increased by combining several of the medications. Perhaps the most commonly used combination is the nicotine patch used on a scheduled basis combined with one of the other dosage forms (i.e., gum, lozenge, inhaler, nasal spray) of nicotine replacement therapy used on an as-needed basis. This combination allows for a basal level of nicotine to be obtained from the patch with additional nicotine provided by short-acting NRT formulations when smokers experience withdrawal symptoms or for situational urges for tobacco. A meta-analysis evaluating the data regarding this combination has confirmed its increased efficacy relative to use of a single NRT. Based on the results of nine trials, it was found that treatment with two types of NRT was more effective than the use of a single NRT product (relative risk = 1.34, 95% CI 1.18 to 1.51), with the resultant efficacy rates similar to treatment with varenicline. This approach is therefore recommended as a first-line treatment approach in some guidelines [18,24].
Other combinations of approved medications have received less study although there is some evidence that they may be helpful. A review of the combination of varenicline with NRT concluded (based on three studies) that the combination is more effective than varenicline alone, with similar rates of adverse events except for skin reaction that occurred more commonly in the combination therapy group [28].
The data regarding the efficacy of the combination of bupropion and NRT are also unclear, although this combination is listed in the bupropion labeling as acceptable. The clinical practice guidelines, based on a meta-analysis of three studies, found the combination to be more effective than NRT alone (odds ratio = 1.3; 95% CI 1.0 to 1.8); however, a more recent meta-analysis of 12 studies did not find this effect to be significant (relative risk = 1.19, 95% CI 0.94 to 1.51) [18,25]. Considering that the estimate of the effect is similar in both analyses, this suggests that there is variability among studies.
The most commonly used combination NRT is the patch combined with one of the other dosage forms. In addition to providing additional nicotine when subjects feel they need it, this combination also provides a behavioral component to the treatment by allowing smokers to take action (i.e., use the faster-acting NRT product) at a time when they feel they are most likely to have a smoking lapse. Other combinations have either less data or data that is somewhat inconsistent, although the combination of bupropion with nicotine patch is approved in the bupropion labeling. These other combinations may therefore be considered for smokers who have failed previous attempts and would like to try different medications for their subsequent attempt. Side effects from the combinations are those that would be expected based on the side effects of the individual agents [18].
Combination therapy with medication and behavioral therapy has been shown to be the most effective in maintaining smoking cessation. Behavioral interventions to consider for smoking cessation include the following [29]:
Brief interventions: Since many patients have difficulties seeking face to face behavioral therapy, brief counseling on smoking cessation can occur with providers regardless of their specialty. Counseling can focus on education, identifying coping skills to address triggers, and techniques to manage stress.
Individual counseling: Formal counseling can be initiated before the patient's quit date. A follow-up visit should occur within a week of the quit date and can continue for at least 3 months to support the patient through the quitting process. Individual counseling has been shown to improve quit rates by 40% to 80%.
Group counseling: Allows patients to support one another through quitting while learning behavioral techniques to help themselves. Patients using group counseling experienced 1-year quit rates of around 20%, significantly higher than quitting without assistance.
Telephone counseling: Phone counseling can be incorporated into a multimodal approach or be used as the primary behavioral therapy. Proactive phone counseling, where a counselor calls the smoker on a prearranged schedule, has been shown to be more effective than reactive counseling, where the patient needs to call the counselor. Free proactive phone counseling is available in the United States by calling 1-800-QUIT-NOW.
Text messaging: Text messaging services that consist of personalized smoking cessation support can suggest behavioral changes, provide positive feedback, and allow patients to request additional help if needed.
Internet resources and interventions: Abstinence rates are increased when interventions are delivered in more than one format. A number of organizations provide patient resources or learning centers with additional materials and web-based tools that can be tailored to the smoker.
Mobile phone apps: Smartphone apps can be used as an additional tool to help smokers remain motivated to quit, though studies show that many apps have low adherence to clinical practice guidelines.
Self-help: Materials such as pamphlets and videos are slightly more effective than no treatment intervention and can be used as an adjunct to alternative methods of treatment.
In addition to drug/drug interaction that can occur (e.g., due to bupropion's inhibitory effect on CYP2D6), it is important to be aware of how smoking, and therefore quitting, can impact medications that a smoker may be taking. Interactions between smoking and medications may be either pharmacokinetic (i.e., smoking impacts concentrations of the impacted drug) or pharmacodynamic (i.e., smoking impacts the effect of the impacted drug). A mechanism by which smoking can impact the concentrations of concurrently used medications is via the induction of the cytochrome P450 1A2 isoenzyme (CYP1A2). Polycyclic aromatic hydrocarbons in cigarette smoke increase the activity of this isoenzyme, which therefore results in lower concentrations of medications metabolized via this route [30]. Conversely, smoking cessation results in the reversal of this induction and can therefore lead to increases in the concentrations of medications metabolized via this route. A number of medications, such as clozapine and olanzapine among others, are known to be metabolized via CYP1A2.
A review of product labels found that the labeling of 34 medications lists some kind of interaction with smoking [31]. It is therefore important for healthcare professionals to be aware of how smoking cessation (or smoking resumption in the instance of a former smoker who relapsed) might affect the concentrations of any concurrent medications that the smoker is taking in order to properly monitor the efficacy and side effects of these medications and to recommend dose adjustments if necessary.
One compound that is metabolized by CYP1A2 and commonly used by smokers is caffeine. Accordingly, the concentration of caffeine (after controlling for caffeine intake) is substantially higher in nonsmokers than in smokers. Upon cessation, the clearance of caffeine decreases, which leads to increased concentrations of caffeine if the amount of caffeine intake is not adjusted. Although it is not clear how higher caffeine concentrations impact cessation success, it is possible that the effects of increased caffeine concentrations (e.g., insomnia and irritability) may be interpreted by some smokers as withdrawal symptoms and thereby lead to smoking lapses. It is also possible that these symptoms of caffeine withdrawal are interpreted by smokers to be side effects of the medications that they are taking to help with the smoking cessation attempt. If this is the case, smokers may decrease the dose of these medications or discontinue taking them, thereby decreasing the probability of successful cessation. Smokers therefore should be informed that after quitting, they may experience greater caffeine effects despite there being no changes in their caffeine intake [32].
Smoking is considered to be the single largest preventable cause of morbidity and mortality; it is responsible for approximately 480,000 deaths in the United States annually [3]. It is therefore necessary for all clinicians to intervene to improve cessation rates among smokers. A general principle of tobacco cessation treatment is that all smokers should be offered treatment (i.e., behavioral and/or pharmacotherapy). For most smokers, pharmacotherapy would be appropriate, and there are currently seven medications available that have been approved for use as aids to smoking cessation. However, for these medications to be effective, they have to be used properly. For some medications such as the nicotine gum and lozenge, reviewing proper use is particularly important since their instructions for use differ from the way one would normally chew gum or use a lozenge. Additionally, to be most effective, medications should be combined with behavioral counseling.
When used as monotherapy, all of the medications are comparably effective. The exception is varenicline, which appears to be more effective than the other products [26,27]. Additionally, there is some data that combination NRT (i.e., nicotine patch combined with one of the other NRT dosage forms) is more effective than use of single NRT or bupropion [24,27]. The choice of medication to be used for an individual patient will largely depend on patient-specific factors such as patient preference (perhaps based on previous experience with these medications), comorbid conditions, drug interactions, cost considerations, and so on. It is helpful to keep in mind that patients might require multiple cessation attempts before achieving long-term abstinence. An attempt that leads to relapse should therefore be viewed not as a failure but as part of the process in treating a chronic condition that requires repeated interventions. It is important to consider drug/drug interactions and drug/smoking interactions since smoking cessation (or relapse after cessation) may alter the effects of other medications the patient is taking.
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