INTRODUCTION — Smoking cessation is associated with clear health benefits. Cigarette smoking is the leading preventable cause of death in the United States and worldwide. Tobacco use increases the risk of many acute and chronic diseases, including cancers at many sites.
Medications, including nicotine replacement, varenicline, and bupropion, have demonstrated efficacy as smoking cessation aids [1,2]. These and other pharmacologic options to help patients stop smoking are discussed here.
The likelihood of a successful quit attempt is increased if counseling is provided along with the medications. An overview of smoking cessation management and the benefit of adjuvant behavioral therapies for smoking cessation are discussed separately. (See "Overview of smoking cessation management in adults" and "Behavioral approaches to smoking cessation".)
Smoking cessation treatment in adolescents is discussed separately. (See "Management of smoking and vaping cessation in adolescents".)
OUR APPROACH
Management for all individuals who smoke — All people who smoke should be advised to quit [3].
Assessing a patient’s willingness to quit smoking and options to assist patients who are ready to quit are discussed elsewhere. (See "Overview of smoking cessation management in adults", section on 'Assess readiness to quit' and "Overview of smoking cessation management in adults", section on 'Assist smokers ready to quit'.)
For all people who smoke and are willing to quit, we recommend a combination of behavioral support and pharmacologic therapy. The combination produces higher smoking quit rates than either type of treatment alone [1-3]. Behavioral strategies for smoking cessation are discussed elsewhere. (See "Overview of smoking cessation management in adults" and "Behavioral approaches to smoking cessation".)
For individuals who are considering quitting smoking but are not yet ready to discontinue tobacco use, we suggest offering the option of initiating pharmacotherapy, rather than waiting until they are ready to completely stop tobacco use [4]. We prefer varenicline rather than NRT, although either may be used. (See 'Individuals less committed to quitting' below.)
For adults with nicotine dependence who exclusively use e-cigarettes rather than conventional combustible tobacco, we advise a goal of stopping e-cigarette use when they feel that they can do so without threatening their abstinence from combustible tobacco products. This recommendation is based on the uncertainty about the health effects of long-term e-cigarette use [5]. When the e-cigarette user is ready to stop vaping, our approach is generally the same as it is for those who smoke cigarettes. Although there are few high-quality data informing this strategy [6], indirect evidence from studies of tobacco cessation in conventional smoking supports this approach.
Initial therapy selection — First-line pharmacotherapies for smoking cessation include nicotine replacement therapy (NRT), varenicline, and bupropion (table 1) [1,2,7-9]. These treatments aim to reduce symptoms of nicotine withdrawal, thereby making it easier to stop using cigarettes.
For the general population, the choice among the therapies is based largely on patient preference, with a few notable exceptions for patients with comorbidities or contraindications to certain drugs. (See 'Considerations for special populations' below.)
●For most patients, we suggest treatment with either varenicline or a combination of two nicotine replacement products (a patch plus a short-acting form such as the gum or lozenge) as first-line pharmacologic therapy; the choice depends upon patient preference after shared clinical decision-making.
Combination NRT consists of using both the nicotine patch (a long-acting form of NRT) and a short-acting NRT of the patient’s choice, generally nicotine gum or nicotine lozenge [1]. The patch is used to provide sustained withdrawal symptom relief for 24 hours; the short-acting nicotine product is added to be used “as needed” to control any breakthrough cravings or other withdrawal symptoms. When using NRT, combination NRT is considered standard of care; however, using single-type NRT may be a reasonable alternative based on cost, side effect profiles, and patient preference.
●Combination treatment with varenicline and nicotine patch is also an option when selecting initial therapy, as this may increase smoking abstinence [4,10]. However, there may be a slight increased risk in adverse effects with the use of both medications, including nausea and sleep disturbance, which should be considered in shared clinical decision-making with the patient.
●Bupropion appears to be somewhat less effective than combination NRT or varenicline. However, it is a reasonable alternative first-line choice if the patient had short-term success with bupropion in a previous quit attempt, if cost is an issue, if the patient has depression that would also benefit from treatment, or if the patient wishes to temporarily avoid post-cessation weight gain [1,11] However, bupropion is contraindicated in patients who have a seizure disorder or a predisposition to seizures. (See 'Seizures' below.)
The efficacy of each first-line therapy for smoking cessation has been proven, although studies show differences in their relative efficacy (table 2) [12-18]. Strong evidence was provided by the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) trial, a double-blind randomized controlled trial that directly compared varenicline, bupropion, nicotine patch, and placebo in over 8000 smokers [17]. Each medication was more effective than placebo at six-month follow-up, but varenicline produced higher quit rates than bupropion or the nicotine patch, which were comparable in efficacy.
There is less evidence regarding the relative efficacy of varenicline compared with combination NRT, which was not tested in the EAGLES trial. In another randomized trial including approximately 1000 smokers, there was no difference in biochemically confirmed abstinence rates among users of varenicline, single NRT (nicotine patch), or combination NRT (nicotine patch plus nicotine lozenge therapy) over a shorter period of 12 weeks [14]. Although the American Thoracic Society (ATS) Clinical Practice Guidelines recommends varenicline as first-line pharmacotherapy, we consider patient preference in this decision, as there are few data demonstrating the superiority of varenicline over combination NRT.
The combination of varenicline and nicotine patch may improve smoking abstinence over varenicline alone. In one randomized trial including approximately 450 patients, 12 weeks of combination treatment increased smoking abstinence at six months compared with varenicline treatment alone (odds ratio [OR] 1.98, 95% CI 1.25-3.14) [4,10]. Among those using both medications, there was a slight, but not significant increase in adverse reactions including nausea, sleep disturbance, and constipation.
Several other medications evaluated for smoking cessation have less evidence of efficacy than first-line agents. Nortriptyline is a tricyclic antidepressant that is considered a second-line agent for smoking cessation [19-24]. (See 'Second-line medications' below.)
Cytisine has been used in eastern European countries as a smoking cessation aid for decades. There is increasing evidence of its efficacy, but because it has not yet been evaluated by the US Food and Drug Administration (FDA) or by its European equivalent (European Medications Agency), cytisine is not available in the United States or in most European countries [2]. (See 'Second-line medications' below.)
Details on the efficacy of individual therapies are described below. (See 'First-line agents' below.)
Regardless of initial pharmacotherapy chosen, we schedule a follow-up visit (eg, telemedicine encounter, telephone call, or in-person office visit) one to two weeks after initiation of pharmacotherapy to monitor for adverse effects, reinforce adherence to medication, and provide support for smoking cessation [1]. (See 'Follow-up' below and "Overview of smoking cessation management in adults", section on 'Arrange follow-up'.)
Considerations for special populations — While choice of pharmacotherapy for the general population is typically based on patient preference, the choice of treatment may need to be tailored due to contraindications or comorbidities and for patients in specific settings or populations.
Psychiatric illness — For patients with comorbid psychiatric disease, we suggest initiating varenicline rather than NRT [4].
Absolute tobacco quit rates are somewhat lower in individuals who smoke and also have a psychiatric illness. However, evidence indicates that the same medications are effective for tobacco users with and without psychiatric comorbidity, although among severely mentally ill patients with psychotic disorders, the efficacy of NRT for smoking cessation is unclear.
Despite concerns regarding treatment of those with concomitant mental illness with varenicline and bupropion, evidence suggests that these medications are safe in this population. As an example, in a trial including over 8000 patients with psychiatric disorders, treatment with varenicline and bupropion did not increase the risk of neuropsychiatric adverse effects compared with NRT [17]. (See 'Safety' below.)
Smoking cessation pharmacotherapy, particularly varenicline, should be coordinated with the patient’s behavioral health provider.
Whatever medication is chosen, patients with severe mental illness may benefit from a longer duration of pharmacotherapy to achieve prolonged smoking abstinence [25]. Additional special considerations for comprehensive tobacco cessation treatment for patients with severe mental illness (eg, schizophrenia, bipolar disorder, or major depression) are described separately. (See "Approach to managing increased risk for cardiovascular disease in patients with severe mental illness", section on 'Tobacco smoking'.)
Cardiovascular disease
●Cardiovascular disease – In patients with stable cardiovascular disease (CVD), we use the same treatments as those for the general population. Varenicline, NRT, and bupropion are effective in this population [1,26-30].
A large study of a general population did not find a difference in major adverse cardiovascular events with use of varenicline, bupropion, or NRT [31]. In the EAGLES study, over 8000 people who smoked cigarettes were randomly assigned to receive 12 weeks of pharmacotherapy or placebo. The study included those with stable CVD or CVD risk factors; however, it is important to note that individuals with clinically significant CVD (eg, myocardial infarction or coronary artery bypass grafting) in the two months prior to study entry were excluded. Compared with placebo, treatment with varenicline, bupropion, or NRT was not associated with a difference in major adverse cardiovascular events or hospitalization for unstable angina during or for one year following the pharmacotherapy.
However, concern was raised about the safety of varenicline for patients known to have CVD [32], and studies have shown mixed results, although generally there appears to be little or no excess cardiovascular risk [33-36]. (See 'Safety' below.)
●Acute coronary syndrome – In patients hospitalized with acute coronary syndrome (ACS), the safety of smoking cessation medications, rather than their efficacy, is the major consideration since there is no a priori reason to assume that their efficacy would differ compared with stable CVD. There are fewer data regarding their efficacy and safety in tobacco users hospitalized with ACS, but available studies suggest that they are probably safe to use [1,37].
•NRT – Because of its ability to rapidly relieve nicotine withdrawal symptoms, NRT is generally used to manage these symptoms in hospitalized patients. The general consensus is that the benefits of reducing nicotine withdrawal symptoms and promoting smoking cessation outweigh any potential risks of NRT in most tobacco users with ACS. It is often continued after discharge to promote smoking cessation, although no randomized controlled trials have been done to demonstrate its efficacy in this specific situation.
However, because of the lack of clear evidence, clinicians vary in their willingness to use NRT in the setting of ACS. There is a theoretical concern with the use of NRT in ACS because of nicotine’s adrenergic and vasoconstrictive properties, which could potentially increase cardiac demand. Nevertheless, because NRT does not produce the rapid rise in blood nicotine levels that is produced by inhaling cigarette smoke, the rise in blood pressure and heart rate produced by NRT is more gradual than occurs after smoking a cigarette. Furthermore, NRT does not promote thrombogenesis [38], a critical trigger of ACS.
•Varenicline – Varenicline has demonstrated efficacy in ACS. In a placebo-controlled randomized trial of 302 smokers with ACS, users who started low-intensity counseling and varenicline in-hospital and continued for 12 weeks had higher rates of both point abstinence (39.9 versus 29.1 percent with placebo) and continuous abstinence (31.1 versus 21.2 percent) at 52 weeks [39,40]. Users of varenicline or placebo had similar rates of serious adverse events (24.5 versus 21.9 percent) and major adverse cardiovascular events (8.6 versus 9.3 percent). Of the three deaths that occurred among varenicline users, two occurred within 30 days of drug discontinuation and were attributed to cardiac causes [39]. (See 'Safety' below.)
•Bupropion – Bupropion has been safe but not more effective than placebo in several randomized controlled trials of hospitalized smokers with ACS [41-43]. A possible explanation is that bupropion requires five to seven days to reach steady state. Thus hospitalized patients with ACS may return home before drug levels are adequate to counter smoking cues that the patient encounters at home. (See 'Hospitalized patients' below.)
The approach to smoking cessation in patients after ACS is discussed in detail separately. (See "Overview of the nonacute management of unstable angina and non-ST-elevation myocardial infarction", section on 'Smoking cessation' and "Overview of the nonacute management of ST-elevation myocardial infarction", section on 'Smoking cessation'.)
Seizures — Bupropion is contraindicated in patients with a seizure disorder or a predisposition to seizures, as it reduces the seizure threshold.
In clinical trials of sustained-release bupropion in smoking cessation, the risk of seizure was 0.1 percent [44]. The risk of seizure with bupropion use is dose dependent and is most often described in the setting of overdose and/or in patients with other risk factors for seizures. Varenicline and NRT are options for patients with seizure disorders.
Hospitalized patients — NRT is often used to treat nicotine withdrawal symptoms in hospitalized patients who smoke because it has a rapid onset of action, whereas varenicline and bupropion are slower to reduce nicotine withdrawal symptoms.
In a meta-analysis of randomized trials comparing intensive counseling alone or combined with various pharmacotherapies for hospitalized patients who smoke, NRT appeared to improve smoking cessation (risk ratio [RR] 1.54, CI 1.34-1.79, in six trials), varenicline showed a trend toward improved rates (RR 1.28, CI 0.95-1.74, in two trials), and bupropion did not show additive benefit (RR 1.04, CI 0.75-1.45, in three trials) [45].
Patients who use NRT in the hospital are more likely to continue it after discharge [46,47] and may be more likely to quit smoking long-term. A randomized trial in 397 hospitalized smokers that allowed patients a choice of medication as part of a post-discharge intervention found that most chose NRT products over bupropion or varenicline [48].
Preoperative management — In the preoperative setting, there is often special urgency to stop smoking in order to reduce postoperative respiratory and infectious complications and to promote wound healing. The use of pharmacotherapy preoperatively has been found to increase smoking cessation rates and decrease postoperative complications [49,50]. NRT and varenicline are suggested choices in this population; if surgery will occur within a few days, NRT is favored due to its rapid onset of action.
NRT (combined with behavioral interventions) is effective preoperatively in patients who smoke [49]. In a prospective, randomized trial of 120 patients awaiting major orthopedic surgery, those who underwent counseling and nicotine replacement six to eight weeks prior to surgery had a lower rate of overall postoperative complications than patients in the control group (18 versus 52 percent) [50].
Despite these data, many orthopedic surgeons avoid NRT because of concern that it will impede bone healing, although there is little evidence from human studies that nicotine use impairs bone healing compared with smoking tobacco.
Varenicline has also been shown to be effective in this population. A randomized trial in 286 smokers scheduled for elective noncardiac surgery found that preoperative treatment with varenicline improved the abstinence rate at 12 months compared with placebo (36.4 versus 25.2 percent, relative risk 1.45, 95% CI: 1.01-2.07) [51]. All patients received counseling regarding smoking cessation.
Smoking cessation in the preoperative setting is reviewed in detail elsewhere. (See "Smoking or vaping: Perioperative management" and "Strategies to reduce postoperative pulmonary complications in adults", section on 'Smoking cessation'.)
Pregnancy — Pharmacotherapy for smoking cessation in pregnant individuals is discussed in detail elsewhere. (See "Tobacco and nicotine use in pregnancy: Cessation strategies and treatment options", section on 'Pharmacotherapy'.)
Light smoking — Evidence regarding the efficacy of pharmacotherapy for smoking cessation among those who smoke fewer than 10 cigarettes per day is limited [2], but pharmacotherapies may have similar effectiveness for smoking cessation as they do in heavier tobacco users.
NRT has the advantage that its dosage and frequency of use can be adjusted easily during therapy to minimize nicotine withdrawal while also avoiding nicotine toxicity. Generally, lower doses are used in lighter tobacco users.
If varenicline or bupropion are selected, there is no need to reduce the dose of these medications for those with light tobacco use; we treat with standard doses. (See 'Our approach' above.)
Individuals less committed to quitting — For individuals who are considering quitting smoking but are not yet ready to discontinue tobacco use, we suggest offering the option of initiating pharmacotherapy, rather than waiting until they are ready to stop tobacco use [4].
Those who are not ready to quit within the next month may be willing to initiate pharmacotherapy to help reduce cigarettes smoked in preparation for quitting in the future. We prefer varenicline rather than NRT, although either may be used; evidence from randomized trials indicates that both are effective in achieving smoking abstinence when used in patients not ready to abruptly quit [52,53].
●In a randomized trial including 1510 smokers who were not willing or able to make a quit attempt within the next month but who were willing to reduce smoking and make a quit attempt within the next three months, patients on varenicline for 24 weeks had a higher continuous abstinence rate compared with placebo during weeks 21 through 24 (37.8 versus 12.5 percent) and weeks 21 through 52 (27 versus 9.9 percent) [52].
●In a meta-analysis including seven placebo-controlled randomized controlled trials and almost 2800 smokers, those who received NRT achieved a higher rate of sustained abstinence for six months compared with those on placebo (relative risk 2.06, 95% CI 1.34-3.15) [53]. Overall quit rates were low, however, at approximately 7 percent. There were no differences in adverse events except nausea, which was more common with NRT. Most of the trials included adjunctive regular behavioral support. Whether using NRT without the behavioral support would be as effective is not known.
Individuals concerned about gaining weight — Bupropion may be a good choice for those who are especially concerned about post-smoking cessation weight gain, which bupropion blunts temporarily [11]. (See "Obesity in adults: Drug therapy", section on 'Bupropion-naltrexone'.)
FOLLOW-UP
Timing — Following initiation of pharmacotherapy, we schedule a follow-up visit (eg, telemedicine encounter, telephone call, or in-person office visit) in one to two weeks to monitor for adverse effects, reinforce adherence to medication, and provide support for smoking cessation [1].
Further follow-up to assess for new side effects, smoking cessation, or relapse, should be scheduled at three months and at one year, and more frequently if necessary. (See "Overview of smoking cessation management in adults", section on 'Arrange follow-up'.)
Assessment for persistent smoking — If a patient does not stop smoking after two to four weeks of pharmacotherapy, one or more of the following may be occurring:
●Incorrect use of medication(s) – The patient may be using the drug incorrectly (eg, chewing nicotine gum too rapidly or not using gum or lozenge frequently enough). We provide further precise education about how to use the drug(s). For example, we ensure that the patient understands how to titrate the short-acting nicotine replacement therapy (NRT) they have chosen to use (eg, nicotine gum or nicotine lozenge) to prevent as well as relieve nicotine withdrawal symptoms.
●Intolerance of side effects – Before discontinuing the medication due to a non-serious side effect, we suggest lowering the dose, since all three first-line medications (varenicline, NRT, and bupropion) can be effective at lower doses.
For example, unpleasant dreams or insomnia can be ameliorated by removing the nicotine patch at bedtime or by eliminating the evening dose of varenicline.
If dose reduction is not feasible or successful, an alternate first-line agent should be tried.
●Persistent nicotine withdrawal symptoms, despite correct use of the medication – If the patient is not already taking adjunctive short-acting NRT, we suggest adding it, with precise instructions on its effective use. (See 'Short-acting nicotine replacement therapy' below.)
Patients who are already using a first-line oral pharmacotherapy (eg, varenicline or bupropion) along with appropriate use of short-acting NRT and who are still experiencing severe withdrawal symptoms should have the first-line medication dose increased if the dose is not yet maximized. (See 'First-line agents' below.)
If the patient is already using a medication correctly and maximally without sufficient effect at four weeks, the options are to continue the same therapy, switch to a different first-line therapy, or consider combining medications by adding another first-line agent:
If there has been no response to the initial agent, we switch to a different medication. (See 'First-line agents' below.)
However, if the patient has had a partial response to the initial medication (ie, reducing smoking but not quitting altogether), adding an additional medication is a rational choice. In particular, for those who have had partial success with varenicline, adding a nicotine patch may increase smoking abstinence [4,10]. Combinations of drugs appear to be more effective than monotherapy but can also produce more side effects [8,54-56]. Options for combination therapy are:
•Varenicline and nicotine patch – In a randomized trial of 435 smokers, treatment with varenicline and nicotine patch for 12 weeks resulted in a higher rate of continuous abstinence compared with varenicline and placebo patch (49 versus 33 percent) six months after the treatment end [10]. Nicotine or placebo patches were started two weeks before the quit day and varenicline was started one week before the quit day.
•Bupropion and varenicline – In a randomized trial of 506 smokers, 12 weeks of combination therapy with bupropion and varenicline resulted in higher rates of prolonged abstinence at 12 and 26 weeks than varenicline alone. [57]. At 52 weeks, abstinence rates also appeared to be higher with combination therapy, although the difference was not significant. The combination was well tolerated.
•Bupropion and NRT – In a meta-analysis of 12 randomized trials, there was a nonsignificant trend toward higher rates of abstinence with the combination of NRT and sustained-release bupropion than with NRT alone (relative risk 1.19, CI 0.94-1.51) [19].
•Nortriptyline and NRT – In a meta-analysis, adding nortriptyline to NRT (four trials) showed a trend toward higher rates of abstinence compared with NRT alone (risk ratio [RR] 1.21, CI 0.94-1.55). This result is similar to what was found by adding bupropion to NRT [19].
Duration of pharmacotherapy — In general, pharmacotherapy for smoking cessation is recommended for at least three months [4,58].
Both varenicline [59] and bupropion use may be extended up to one year if the patient has quit smoking but still feels at risk for relapse based upon experience with prior quit attempts. If bupropion is also being used to treat mood, continuation of therapy should take into consideration management of depressive symptoms.
NRT may be extended and even used indefinitely if needed. (See 'Nicotine replacement therapy' below and 'Varenicline' below and 'Bupropion' below.)
MANAGEMENT OF RELAPSE — For patients who successfully quit smoking and then experience relapse, we suggest restarting the pharmacologic agent(s) that previously worked for the patient. This may be enhanced with more intensive behavioral support and/or intensified pharmacotherapy (eg, adding another medication).
The approach to managing relapse is reviewed in detail elsewhere. (See "Overview of smoking cessation management in adults", section on 'Relapse'.)
FIRST-LINE AGENTS
Nicotine replacement therapy — The goal of nicotine replacement therapy (NRT) is to relieve nicotine withdrawal symptoms by providing nicotine without the use of tobacco, while the individual breaks the behavior of cigarette smoking. First-line NRT does not include electronic cigarettes.
Safety — Side effects common among all NRT products include gastrointestinal symptoms (nausea, vomiting, abdominal pain, diarrhea), headache, and local irritation depending on the delivery method [60]. Those who experience side effects from NRT products can titrate use of the product to minimize side effects or change products. The side effect profile specific to each type of NRT is discussed below [61].
Patients may worry that they will become dependent on NRT, but nicotine dependence rarely occurs, especially with the long-acting patch [61]. Patients may also worry that nicotine causes cancer, which it does not.
NRT is safe to use in patients with known stable cardiovascular disease (CVD). While there is limited information regarding its use after acute coronary syndrome (ACS), it is generally used to reduce nicotine withdrawal symptoms in the hospital when needed [1]. (See 'Cardiovascular disease' above and "Cardiovascular effects of nicotine", section on 'Safety of nicotine replacement therapy'.)
Efficacy — Studies show that NRT is effective for smoking cessation. Few trials have directly compared one product with another; however, in randomized trials, all individual NRT products were found to be superior to placebo, increasing quit rates up to twofold (table 2) [17,18,62,63]. In one randomized trial evaluating NRT (including patch, gum, inhaler, and nasal spray) in a general adult population, there was no difference in efficacy between products [64]. The efficacy of NRT for patients with severe mental illness is described separately. (See "Modifiable risk factors for cardiovascular disease in patients with severe mental illness", section on 'Nicotine replacement treatment'.)
The consensus among experts, supported by evidence from most clinical trials, is that single-agent NRT is less effective than combining the long-acting patch with a short-acting form such as gum, lozenge, or inhaler [1,2]. In a meta-analysis of 14 randomized trials, use of a nicotine patch combined with a short-acting NRT product (gum, spray, or inhaler) was more effective than a single type of NRT (relative risk 1.25, 95% CI 1.15-1.36) [65]. Combination NRT was also found to be more effective than single-product therapies in other trials [54,55,66]. However, in one randomized trial of 1086 smokers that compared 12 weeks of individual NRT (nicotine patch), combination NRT (nicotine patch plus nicotine lozenge), and varenicline, there were no differences in biochemically confirmed rates of smoking abstinence among the three groups [14].
Additionally, in some, but not all trials, NRT benefits men more than women [67,68].
Administration — For tobacco users wishing to use NRT, we suggest a combination of long- and short-acting NRT as initial therapy.
Differences in the bioavailability of NRT products provide the rationale for combining NRT products to increase efficacy for smoking cessation [62]. NRT products can be used in combination because each agent produces a lower blood nicotine level than does smoking one pack of cigarettes daily. In addition, individuals who smoke already have experience titrating their nicotine intake to avoid both nicotine withdrawal and nicotine overdose; they have performed this titration throughout their years as cigarette smokers.
The initial dosing of most NRT products is based on the number of cigarettes smoked daily, as discussed below. NRT dose is then gradually tapered. In general, NRT use is recommended for two to three months after smoking cessation, although NRT use for as long as an individual is at high risk for relapse is acceptable because NRT is much safer than continuing to smoke. Some people may need to use the products indefinitely. In addition, NRT products, particularly the transdermal patch, can be used while the person is still smoking in anticipation of smoking cessation [53,65].
Nicotine transdermal patch (long-acting) — The nicotine patch provides the most continuous nicotine delivery among all NRT products and is the simplest NRT to use. The patch has a long-acting, slow-onset pattern of nicotine delivery, which produces relatively constant relief from withdrawal over 24 hours [69] but requires several hours to reach peak levels. Compliance with the patch is high; however, the user cannot adjust the dose of nicotine being released to respond to nicotine cravings and withdrawal symptoms. The patch is available over the counter and by prescription in the United States.
●Dosing and instructions for nicotine patch – Initial patch dosing is determined by the number of cigarettes smoked daily when the patch is started as well as the patient's weight:
•>10 cigarettes per day: apply 21 mg/day patch
•≤10 cigarettes per day: apply 14 mg/day patch
Remove and replace the patch with a new one each morning to any non-hairy skin site; rotate the site daily to avoid skin irritation, the most common side effect. Over-the-counter topical hydrocortisone (1% cream or ointment) may be used to relieve skin irritation if it occurs.
If leaving the patch on overnight causes the frequently reported side effects of insomnia and vivid dreams, remove the patch at bedtime and replace with a new one the next morning. Smoking cessation rates are similar whether the patch is left on for 24 hours or taken off at night [70].
If the patch is removed at night and replaced with a new one in the morning, adequate plasma levels of nicotine are reached 30 minutes to three hours after the new patch is applied [71]. If morning nicotine cravings occur before plasma nicotine levels rise, we advise use of a short-acting NRT (eg, gum, lozenge) while waiting for the new nicotine patch to take effect.
Although patches are typically marketed with instructions to taper the dose over 12 weeks, in clinical trials and experience, tapering has not improved smoking cessation rates [1]. Tapering the dose is not required, but optional; this approach can be used if patients feel that cravings and withdrawal symptoms are well controlled, but they wish to reduce the dose. As examples:
●For patients using the 21 mg/day patch successfully, the dose may be lowered to 14 mg/day after six weeks. For patients who prefer to lower the dose further, this can be followed by the 7 mg/day patch for the duration of therapy, although continuation of the 21 mg/day or the 14 mg/day dose for the duration of therapy is reasonable.
●For patients using the 14 mg/day patch successfully, the dose may be continued for the duration of treatment. For patients who prefer, the dose can be lowered to 7 mg/day after the initial six weeks, and this dose may be continued for the remainder of therapy.
●Duration of nicotine patch therapy - Longer duration (more than 8 to 10 weeks) of treatment with the nicotine patch may lead to improved smoking cessation rates.
Generally, NRT is used until a patient feels that they have stabilized as a nonsmoker. The patch may be continued longer, even indefinitely if needed, as NRT is safer than continued smoking. NRT is often used for a longer period in patients with comorbid psychiatric illness or other substance use disorders.
In a randomized trial of 568 smokers that compared eight weeks of nicotine patch therapy with extended therapy (24 weeks), longer treatment resulted in higher rates of seven-day point-prevalence abstinence at 24 weeks (odds ratio [OR] 1.81, 95% CI 1.23-2.66) [72]. A subsequent randomized trial in 525 smokers who received 12 sessions of smoking cessation behavioral counseling along with the nicotine patch for 8, 24, or 52 weeks found benefit at 24 weeks to using the nicotine patch for 24 or 52 weeks rather than for 8 weeks. However, there were no differences in abstinence rates at 52 weeks [73].
Short-acting nicotine replacement therapy — A short-acting form of NRT (lozenge, gum, inhaler, or nasal spray) can be used as a single agent or can be added to nicotine patch therapy to help control cravings and manage withdrawal symptoms. However, short-acting preparations require repeated use throughout the day, lead to more variable nicotine levels than the patch, and require more instructions for correct use.
Patients can be instructed to use the product when they have a craving, although this generally leads them to underuse the products. A preferred approach for those in whom this "as needed" use of short-acting NRT fails to control cravings is to have the individual use the product at least once every hour while awake and more often if needed.
The choice of a short-acting agent depends on patient preference and comorbidities (eg, reactive airways, temporomandibular disorders, poor dentition). The nicotine patch, lozenge, and gum are available in the United States without a prescription; nasal spray and oral inhaler require a prescription. Nicotine mouth spray and a sublingual tablet are available outside the United States.
Nicotine gum — Nicotine gum is a commonly used short-acting NRT. Chewing the gum releases nicotine, which is absorbed through the oral mucosa. This results in peak blood nicotine levels 20 minutes after starting to chew. Nicotine gum is available in several flavors that most users find preferable to the original flavor.
●Dosing is determined by how soon the first cigarette is typically smoked upon awakening [74]:
•For people who smoke within 30 minutes of awakening: the 4 mg dose is recommended
•For people who wait more than 30 minutes after awakening to smoke: the 2 mg dose is recommended
●Chew at least one piece of gum every one to two hours while awake and also whenever there is an urge to smoke.
●Patients may use up to 24 pieces of gum per day for the first six weeks of treatment.
●Gradually reduce use over the next six weeks, for a minimum treatment duration of three months.
●Proper chewing of gum is important for optimal results. "Chew and park" is recommended: chew the gum until the nicotine taste appears, then "park" the gum against the buccal mucosa until the taste disappears, then chew a few more times to release more nicotine. Repeat this for 30 minutes, then discard the gum (because all nicotine in the gum has been released).
In addition, gastric and esophageal irritation can occur if the gum is chewed too rapidly, because nicotine is released faster than it can be absorbed by the buccal mucosa and the nicotine is thus swallowed. Nicotine absorbed from the gastrointestinal tract is largely metabolized by the liver and is therefore relatively ineffective for smoking cessation.
●Acidic beverages (eg, coffee, carbonated drinks) should be avoided before and during gum use, as acidic beverages lower oral pH, which causes nicotine to ionize and reduces nicotine absorption.
Side effects are mostly a consequence of excess nicotine release with overly vigorous chewing and consist of nausea, vomiting, abdominal pain, constipation, hiccups, headache, excess salivation, a sore jaw, and mouth irritation or ulcers.
Chewing gum may exacerbate temporomandibular joint disease and the gum can damage or adhere to dental appliances. Those with temporomandibular joint disease, with poor dentition, or who use dental appliances (eg, removable orthodontic appliances, dentures) may do better with an alternative short-acting form of NRT such as the lozenge or inhaler.
Nicotine lozenge — Nicotine lozenges are a commonly used short-acting NRT product, with pharmacokinetics similar to nicotine gum. Lozenges are easier to use correctly than nicotine gum and are also available in different flavors. A smaller mini-lozenge is also on the United States market. It dissolves more rapidly and delivers nicotine more rapidly than the original lozenge and in our clinical experience is preferred by most people who smoke.
●Dosing is determined by how soon the first cigarette is typically smoked upon awakening [75]:
•For those who smoke within 30 minutes of awakening: the 4 mg dose is recommended
•For those who wait more than 30 minutes after awakening to smoke: the 2 mg dose is recommended
●Patients may use up to one lozenge every one to two hours for the first six weeks of treatment. The maximum dose is five lozenges every six hours or 20 lozenges per day.
●Gradually reduce number of lozenges used per day over the next six weeks.
●Place lozenge in the mouth and allow it to dissolve over 30 minutes. The lozenge does not need to be chewed.
An advantage of the lozenge over the gum is that it can be used in those with temporomandibular disorders, poor dentition, or dentures.
Side effects include mouth irritation or ulcers, in addition to nicotine-related side effects of abdominal pain, nausea, vomiting, diarrhea, headache, and palpitations.
Nicotine inhalers — These consist of a mouthpiece and a plastic, nicotine-containing cartridge. The inhaler addresses not only physical dependence but also the behavioral and sensory aspects of smoking (ie, having a cigarette between one's fingers and inhaling from the cigarette).
When the individual inhales through the device, nicotine vapor (not smoke) is released, deposited primarily in the oropharynx, and absorbed through the oral mucosa. Nicotine vapor does not reach the lungs to an appreciable extent.
The ad lib use of the nicotine inhaler produces plasma nicotine levels that are roughly one-third of those that occur with cigarette smoking. The pharmacokinetics of the inhaler resemble those of nicotine gum.
Initial dosing of the nicotine inhaler is individualized "as needed" and tapered over the course of therapy:
●Patients may use 6 to 16 cartridges per day for the first 6 to 12 weeks of treatment
●Gradually reduce dose over the next 6 to 12 weeks
When using the nicotine inhaler, it is important to puff in short breaths or inhale into back of throat (not the lungs). Twenty minutes of continuous puffing may yield the best effect, but patients may individualize dosing. Nicotine in the inhaler is used up after 20 minutes of puffing (eg, puffing on inhaler for 10 minutes gives enough nicotine for two uses). Once opened, cartridge remains effective for 24 hours.
Side effects occurring commonly include localized irritation of the mouth or throat, particularly during the early stages of use. Because inhaled nicotine may cause bronchospasm, it may be less appropriate for individuals with a history of severe airway reactivity.
Nicotine nasal spray — The nicotine nasal spray delivers an aqueous solution of nicotine to the nasal mucosa.
Absorption via nasal mucosa results in peak nicotine levels 10 minutes after nasal spray use, which is a more rapid rise in plasma nicotine concentration than that produced by agents absorbed via the oral mucosa (eg, gum, inhaler, or lozenge). Nasal spray more closely mimics changes in nicotine concentration that occur while smoking, although the nasal spray does not increase nicotine levels nearly as fast as smoking a cigarette [76]. However, inhaling nicotine into the nasal mucosa produces side effects, particularly nasal irritation, that have limited its tolerability.
Dosing, duration, and instructions for use:
●Dose is one or two sprays per hour
●Use for about three months
●The maximum dose is 10 sprays per hour, not to exceed 80 total sprays per day
Side effects include nasal and throat irritation, rhinitis, sneezing, and tearing. Nasal irritation is extremely common, occurring in 94 percent of patients during the first two days of use and continuing in 81 percent of patients after three weeks of therapy [77].
Nicotine mouth spray — Nicotine mouth spray is not available in the United States.
Dosing and instructions for use:
●1 mg nicotine is delivered per spray
●Use one or two sprays when cravings occur, up to four sprays per hour [78]
Side effects occurring frequently with the oral spray include hiccups (occurring in more than 55 percent of those treated in one trial [79]), throat irritation, and nausea.
Nicotine sublingual tablet — The nicotine sublingual tablet is not available in the United States.
Dosing and instructions for use:
●Allow one 2 mg tablet to dissolve sublingually (typically over 30 minutes) every one to two hours
●Patients who are heavily nicotine-addicted can use two tablets sublingually (4 mg total) for each dose [80]
Side effects occurring commonly include sore mouth or throat and dryness or burning in the mouth [81].
Varenicline — Varenicline reduces the symptoms of nicotine withdrawal by binding with high affinity and acting as a partial agonist at the alpha-4 beta-2 nicotinic receptor. It blocks nicotine from binding to the receptor, interrupting the reinforcing effects of nicotine that lead to nicotine dependence. Through this action, varenicline reduces the rewarding aspects of cigarette smoking [82-84]. Through its stimulating effects of the receptor, it also reduces withdrawal and cravings.
Safety — The most common side effects reported are nausea and disordered sleep, including insomnia and abnormal (vivid, unusual, or strange) dreams.
There were early concerns about neuropsychiatric and cardiovascular side effects of varenicline, but subsequent studies have not supported these concerns, and varenicline is generally considered safe.
Varenicline is safe for use by tobacco users with chronic obstructive pulmonary disease (COPD) [85].
●Neuropsychiatric effects – Despite earlier concerns, subsequent data indicate that varenicline does not cause an excess of neuropsychiatric side effects compared with nicotine replacement or bupropion. In December 2016, the US Food and Drug Administration (FDA) removed the boxed warning about potential neuropsychiatric side effects.
In the initial post-marketing period, there had been concern about the potential for varenicline's adverse psychiatric effects, especially in patients with underlying psychiatric comorbidities. Based on its review of post-marketing case reports, the FDA in 2009 had required varenicline (and bupropion) to carry a boxed warning about possible serious neuropsychiatric side effects, including suicide and suicidal ideation, associated with these medications [86].
The FDA also required the drug manufacturers to conduct a large randomized controlled trial of the two drugs’ efficacy and safety in patients with and without psychiatric illness (largely depression and anxiety disorders). The resulting double-blind trial, Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES), enrolled approximately 8000 smokers motivated to quit, half of whom had stable psychiatric disorders (eg, major depressive, bipolar, or anxiety disorders) [17]. Although patients with a psychiatric comorbidity had higher rates of neuropsychiatric symptoms than patients without this comorbidity, rates were low for both groups, and there was no difference between those treated with NRT, bupropion, varenicline, or placebo. Based on these data, the FDA removed the boxed warning for varenicline (and bupropion) in December 2016 [87].
In addition, in a previous meta-analysis including 39 randomized trials and over 10,000 participants with and without psychiatric illness, varenicline did not increase the risk of suicide or suicide attempts, suicidal ideation, depression, aggression, or death compared with placebo [88].
●Cardiovascular effects – Although concern has been raised that varenicline might increase the risk of adverse cardiovascular events, the bulk of the evidence does not indicate an increased risk. For patients at low risk for an acute coronary event, it appears unlikely that varenicline is associated with a clinically meaningful increase in cardiovascular events. In addition, for high-risk patients, the effect of varenicline is less certain, although no large increase in risk has been observed. Further, it is likely that any cardiovascular risk of taking varenicline, if it exists, is likely to be far smaller than the risk of continuing to smoke cigarettes. A 2011 FDA advisory and a 2018 labeling update suggested that the known benefits of varenicline for smoking cessation be weighed against potential harms in patients with CVD [89,90].
The precise risk of cardiovascular events with varenicline in different populations is difficult to define because of limitations in the available evidence, although many trials suggest no increased risk. As examples:
•Two large meta-analyses of randomized trials found no differences in the rates of cardiovascular events in patients treated with varenicline compared with placebo [33,91]. However, the overall rates of cardiovascular events in the trials were low, limiting the power of the analyses to detect a difference. In an earlier meta-analysis in which trials without cardiovascular events were excluded from the analysis, there was an association between varenicline and the cardiovascular events (OR 1.72, 95% CI 1.09-2.71) [92]; however, methodologic issues limit the conclusions of this study [93].
•In a randomized double-blind controlled trial evaluating 12 weeks of varenicline therapy in 714 smokers with stable CVD, there was no difference in mortality or major cardiovascular events at 52 weeks compared with placebo [29]. The study conclusions are limited, however, by the small trial size and the limited follow-up.
•In another randomized controlled trial including approximately 300 patients hospitalized with ACS, there were similar rates of major adverse cardiovascular events among those treated with 12 weeks of varenicline and placebo at 52 weeks [39].
•In the EAGLES trial that included patients with stable CVD or cardiovascular risk factors, treatment with varenicline was not associated with an increased risk of major cardiovascular events up to one year compared with placebo [31].
In addition, the majority of observational studies have generally not shown an increase in cardiovascular events with use of varenicline. One study found similar rates of major cardiovascular events among smokers who took varenicline or bupropion [94], another showed similar rates of major cardiovascular events among those who used varenicline or NRT patches [95], and another showed lower rates of ischemic heart disease and stroke among varenicline compared with NRT users [96]. However, in a retrospective database analysis, varenicline initiation was associated with a higher relative risk but small absolute increase in adverse cardiovascular events [97]. (See 'Cardiovascular disease' above and 'Our approach' above.)
●Driving or flying advisory – Some concern has been raised about varenicline’s effect on an operator of a motor vehicle. A review of adverse drug reports by the Institute for Safe Medication Practices had found an unusually high rate of accidental injuries from road accidents and falls in patients taking varenicline [98]. Based on this report, the FDA issued a public health advisory stating that patients taking varenicline may experience impairment of the ability to drive or operate heavy machinery [82]. However, in a subsequent large observational study in Sweden, varenicline was not associated with an increase in traffic crimes or transport accidents [99].
Efficacy — The efficacy of varenicline for smoking cessation has been demonstrated in many studies. A meta-analysis of randomized trials found that varenicline was more effective for smoking cessation than placebo (RR 2.27, 95% CI 2.02-2.55) [12]. In another meta-analysis of randomized controlled trials, more patients were abstinent at 24 weeks with varenicline compared with both placebo and nicotine patch (RR 2.24, 95% CI 2.06-2.43; and RR 1.25, 95% CI 1.14-1.37 respectively) [13]. Similarly, in a head-to-head double-blinded randomized controlled trial comparing multiple agents (varenicline, bupropion, nicotine patch) and placebo, varenicline was more effective in producing six months of tobacco abstinence than other drugs or placebo [17].
Combining varenicline with nicotine patch or utilizing extended duration of treatment does not seem to improve results; in a 2x2 factorial design trial among 1251 adults comparing varenicline monotherapy with varenicline plus nicotine patch, and comparing 12-week with 24-week treatment duration, abstinence rates at 52 weeks were similar across all four treatment groups [100].
Administration
Dosing, duration, and instructions for use:
●Patients are instructed to quit smoking one week after starting varenicline, by which time stable blood levels are achieved. However, a longer preloading period of up to five weeks prior to the quit date is also effective for achieving abstinence [75]. Although abruptly quitting smoking appears to be more effective, gradual smoking reduction (50 percent smoking reduction by week 4, another 50 percent reduction by week 8, then quitting by week 12) is an acceptable alternative [101].
For patients not yet ready to commit to a quit date, varenicline may be initiated to help with smoking reduction in advance of a quit attempt [4]. (See 'Individuals less committed to quitting' above.)
●The recommended dose of varenicline is 0.5 mg once daily for three days, then 0.5 mg twice daily for four days, and then 1 mg twice daily for the remainder of a 12-week course. The up-titration of varenicline dose is done to minimize gastrointestinal side effects, especially nausea. Dose reduction is required for those with creatinine clearance <30 mL/minute because varenicline is excreted almost entirely by the kidney.
A four-week preload of varenicline produced higher abstinence rates at 12 weeks in a trial of 101 smokers, compared with those assigned to three weeks of placebo followed by one week of varenicline (47 versus 21 percent) [102].
●Although evidence does not suggest that varenicline causes more neuropsychiatric symptoms than other FDA-approved smoking cessation aids, any patient started on varenicline who develops concerning neuropsychiatric symptoms (eg, changes in behavior, hostility, agitation, depressed mood, suicidal ideation, or suicide attempts) should stop the medication, contact their clinician, and seek medical attention right away.
Adjusting dosing and duration:
●The risk of nausea is reduced if the dose of varenicline is titrated upon initiation [103]. Nausea can also be minimized by taking varenicline with food and a full glass of water. Alternately, the dose can be reduced to 0.5 mg twice daily if nausea occurs at the 1 mg dose.
●Dreams that are troubling to the patient may be reduced by taking the evening dose earlier in the day, by lowering the dose, or by skipping the evening dose if necessary.
●Patients who have successfully quit at 12 weeks may benefit from continuing on varenicline for an additional 12 weeks to prevent relapse. In a randomized trial including 1236 individuals who had quit smoking after an initial 12-week course of varenicline, those treated with varenicline for an additional 12 weeks had higher rates of continuous abstinence compared with those not continuing the medication (weeks 13 through 24: 71 versus 50 percent; weeks 13 through 52: 44 versus 37 percent) [59].
Increasing the dose of varenicline has not been shown to improve smoking cessation rates.
Bupropion — Bupropion is believed to act by enhancing central nervous system noradrenergic and dopaminergic release.
Safety — Bupropion is contraindicated in patients with a seizure disorder or predisposition to seizure because it reduces the seizure threshold. The risk of seizure is dose-dependent and is most often described in the setting of overdose and/or in patients with other risk factors for seizures.
The FDA removed the boxed warning it had earlier required about potential neuropsychiatric side effects. Removal of the warning was based on a randomized trial that found no difference in adverse neuropsychiatric events comparing bupropion with nicotine patch or placebo in patients with or without a coexisting psychiatric disorder [17]. The concern about serious neuropsychiatric side effects associated with bupropion had been raised earlier by post-marketing case reports associating bupropion with increased risks of suicidal/self-injurious behavior or depression [104]. (See 'Psychiatric illness' above.)
Bupropion is safe for use among individuals with stable CVD [26,31] and COPD [20]. Studies suggest that bupropion is safe, although not effective, for those hospitalized for acute myocardial infarction [41-43]. (See 'Cardiovascular disease' above.)
The most common side effects of bupropion are insomnia, agitation, dry mouth, and headache. Other side effects of bupropion are discussed separately. (See "Atypical antidepressants: Pharmacology, administration, and side effects", section on 'Bupropion'.)
Efficacy — Randomized trials have demonstrated the efficacy of bupropion in smoking cessation. A 2020 meta-analysis of 46 randomized trials found that rates of smoking cessation are higher with bupropion monotherapy than placebo or no treatment (RR 1.64, 95% CI 1.52-1.77) [105]. In an included trial, patients receiving sustained-release bupropion (150 mg twice daily) had greater rates of point-prevalence abstinence at the end of a seven-week course (44 versus 19 percent) and at one year (23 versus 12 percent) compared with placebo [106]. Another randomized controlled trial including over 8000 smokers confirmed that bupropion was more effective than placebo in patients with and without psychiatric comorbidity [17]. In that study, varenicline produced higher quit rates than bupropion, while nicotine patch produced comparable cessation rates to bupropion.
Other studies have demonstrated the efficacy of bupropion in specific populations of tobacco users, including African Americans and those with stable CVD or COPD [20,26,107].
The use of bupropion in patients with CVD is discussed above. (See 'Cardiovascular disease' above.)
Administration — Several formulations of bupropion are available, including a sustained-release formulation (Zyban, which is licensed as an aid to smoking cessation and is identical to the antidepressant forms: generic sustained-release bupropion and Wellbutrin SR).
Dosing, duration, and instructions for use:
●Bupropion sustained-release is started one week before the target quit date, since it takes five to seven days to reach steady-state blood levels.
●Abruptly quitting smoking appears to be more effective, although gradual smoking reduction (50 percent smoking reduction by week 4, another 50 percent reduction by week 8, then quitting by week 12) is an acceptable alternative [101].
●The recommended dose of bupropion is 150 mg/day for three days, then 150 mg twice daily thereafter [61].
●We recommend treating for at least 12 weeks.
Adjusting dosing and duration:
●Although it is less studied, bupropion 150 mg/day (rather than 300 mg/day) is an option for those who do not tolerate the full dose due to side effects.
One randomized trial found that the 150 mg/day dose was as effective as the 300 mg/day dose and associated with fewer side effects [106].
●Longer duration of treatment can be considered in individual cases, based on the patient’s previous quit attempts and patient preference. However, if the rationale for longer treatment is improved mood, it is important to assess the change in depressive symptoms from the initiation of treatment and to make dosing adjustments accordingly. (See "Unipolar major depression in adults: Choosing initial treatment", section on 'Dose'.)
Longer-duration therapy may prevent relapse in successful quitters. A randomized trial of 461 individuals who quit smoking after seven weeks of bupropion compared ongoing treatment for one year with either bupropion 300 mg/day or placebo [108]. Patients taking bupropion for one year had a higher abstinence rate at one year (51 versus 42 percent) that persisted 16 weeks after discontinuation of therapy (47 versus 37 percent), a longer median time to relapse after cessation of therapy (156 days versus 65 days), and less weight gain at two years (4.1 versus 5.4 kg). However, the abstinence rate at two years was the same in both groups (41 versus 40 percent).
OTHER PHARMACOTHERAPIES — A number of other pharmacologic agents have been evaluated as aids to smoking cessation, all of which have lesser or uncertain efficacy compared with first-line agents [12].
Second-line medications
●Nortriptyline – Nortriptyline, a tricyclic antidepressant, is a second-line therapy that has shown moderate efficacy in aiding smoking cessation for individuals who cannot use a first-line agent or who need an adjunct to first-line therapy [19-24,109]. In a meta-analysis of six trials and almost 100 patients, it increased the likelihood of abstinence compared with placebo (risk ratio [RR] 2.03, 95% CI 1.48-2.78) [19]. However, patients receiving nortriptyline were more likely to report side effects including dry mouth and sedation.
●Cytisine – Cytisine is a plant derivative that, like varenicline, is a partial agonist at the alpha-4 beta-2 nicotinic acetylcholine receptor [82,110]. Cytisine appears to be a reasonable option for smoking cessation where available and may offer a low-cost pharmacologic alternative to therapies such as varenicline. It has been used for smoking cessation in Eastern Europe for decades and is not available in the United States or Western Europe [111,112].
In a meta-analysis including two high-quality trials, the efficacy of cytisine appears to be comparable to other pharmacologic therapies, although there were more gastrointestinal side effects with cytisine [113]. In a randomized trial of 1310 adult daily smokers, self-reported continuous abstinence was higher with cytisine than with nicotine replacement therapy (NRT) at one month (40 versus 31 percent) and at six months (22 versus 15 percent) [114]. More adverse events were reported with cytisine; the most common adverse events were nausea, vomiting, and sleep disorders.
Therapies with limited or unproven benefit
●Clonidine – Despite promising initial studies, clonidine is now generally regarded as having limited efficacy for smoking cessation [115-117]. Although a meta-analysis suggested that clonidine was superior to placebo in facilitating smoking cessation, the majority of individual studies evaluating the drug have not demonstrated statistically significant efficacy [12]. Adverse effects, such as drowsiness, fatigue, and dry mouth, also limit the use of clonidine as a smoking cessation aid.
●Selective serotonin reuptake inhibitors/anxiolytics – Selective serotonin reuptake inhibitors (SSRIs) and anxiolytic drugs generally have not been shown to be effective for smoking cessation [12,19,118].
●Nicotine vaccine – A nicotine vaccine is a novel experimental approach to treating tobacco dependence. Nicotine is bound to an adjuvant that stimulates the body to generate specific anti-nicotine antibodies [119]. Nicotine that reaches the bloodstream from inhaled cigarette smoke is bound by the antibody, producing a nicotine-antibody complex that is too large to cross the blood-brain barrier. Thus, nicotine from tobacco smoke is unable to reach the central nervous system nicotinic receptors to produce the rewarding effects of smoking [120,121]. Theoretically, a decrease in the rewarding effects of nicotine will lead to smoking cessation. Several companies have taken candidate vaccines into clinical trials, but none have generated adequate antibody responses or demonstrated efficacy versus placebo.
●Electronic cigarettes – Electronic cigarettes (e-cigarettes) are nicotine delivery devices that use a battery to aerosolize nicotine. Many e-cigarette products are available that vary in the rate and amount of nicotine delivery. Because tobacco is not burned, these devices are likely to be safer than continuing to smoke conventional tobacco cigarettes. However, their safety with long-term use is uncertain.
Some e-cigarette devices have been authorized by the US Food and Drug Administration (FDA) as tobacco products whose net benefits exceed harms at a population level. However, no e-cigarette has been evaluated or approved by the FDA as a medical product for smoking cessation [122]. (See "Vaping and e-cigarettes", section on 'Adverse health effects' and "E-cigarette or vaping product use-associated lung injury (EVALI)", section on 'Pathogenesis and risk factors'.)
The role of e-cigarettes in smoking cessation treatment is unclear. The results of randomized trials are mixed, although a meta-analysis concluded that there is moderately good evidence that e-cigarettes were more effective for smoking cessation than nicotine replacement products or e-cigarettes without nicotine [18]. In some [123-125] but not all [126,127] included trials, increased rates of smoking abstinence at 6 and 12 months were observed with the use of nicotine containing e-cigarettes compared with non-nicotine (placebo) devices or NRT. In addition, in several of these trials as well as in another meta-analysis [128], a large proportion of study participants continued to use of e-cigarettes after the intervention. While this reduces health harms relative to continued use of combustible tobacco products, the long-term health effects of e-cigarettes are not yet known. (See "Vaping and e-cigarettes", section on 'Role in smoking cessation'.)
The role in smoking cessation treatment is unclear also for heat-not-burn tobacco cigarettes, which are another type of electronic nicotine delivery system (ENDS). (See "Patterns of tobacco use", section on 'Heat-not-burn tobacco products'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Smoking cessation, e-cigarettes, and tobacco control".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Quitting smoking (The Basics)" and "Patient education: Cough in adults (The Basics)")
●Beyond the Basics topic (see "Patient education: Quitting smoking (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Combination pharmacotherapy and behavioral support recommended
•Individuals who smoke combustible (traditional) cigarettes – All individuals who smoke should be advised to quit smoking. For those who are willing to quit, we recommend a combination of behavioral support and pharmacologic therapy (Grade 1B). The combination produces higher smoking quit rates than either type of treatment alone. (See 'Management for all individuals who smoke' above and "Overview of smoking cessation management in adults", section on 'Treatments'.)
•Individuals who use e-cigarettes – For adults with nicotine dependence who exclusively use e-cigarettes rather than conventional combustible tobacco, we advise a goal of stopping e-cigarette use when they feel that they can do so without threatening their abstinence from combustible tobacco products. When the e-cigarette user is ready to stop vaping, our approach is generally the same as it is for those who smoke cigarettes. (See 'Management for all individuals who smoke' above.)
●Initial pharmacotherapy: Our approach – Pharmacologic therapies for smoking cessation include nicotine replacement therapy (NRT), varenicline, and bupropion (table 1). For the general population, the choice among the therapies reflects patient preference, with a few notable exceptions for patients with comorbidities or contraindications to certain drugs. (See 'Initial therapy selection' above.)
•For most patients, we suggest treatment with either varenicline or NRT as first-line pharmacologic therapy rather than bupropion or other pharmacotherapy (Grade 2B). The choice depends upon patient preference after shared clinical decision-making.
•For patients wishing to use NRT, we suggest a combination of long- and short-acting NRT (eg, nicotine patch plus nicotine gum or lozenges) rather than single-agent NRT (Grade 2C). Differences in the bioavailability of nicotine replacement products provide the rationale for combining NRT products to increase efficacy for smoking cessation.
•Combination treatment with varenicline and nicotine patch is also an option when selecting initial therapy, as this may increase smoking abstinence. However, there may be a slight increased risk in adverse effects with the use of both medications, such as nausea and sleep disturbance.
•Bupropion appears to be somewhat less effective than combination NRT or varenicline. However, it is a reasonable alternative first-line choice if the patient had short-term success with bupropion in a previous quit attempt, if cost is an issue, if the patient has depression that would also benefit from treatment, or if the patient wishes to temporarily avoid post-cessation weight gain. Bupropion is contraindicated in patients with a seizure disorder or a predisposition to seizures, as it reduces the seizure threshold.
•For patients with comorbid psychiatric disease, we suggest initiating varenicline rather than NRT (Grade 2B). Evidence indicates that the same medications are effective for individuals with and without psychiatric comorbidity, although among severely mentally ill patients with psychotic disorders, the efficacy of NRT for smoking cessation is unclear. Smoking cessation pharmacotherapy should be coordinated with the patient’s behavioral health provider. Patients with severe mental illness may benefit from a longer duration of pharmacotherapy to achieve prolonged smoking abstinence. (See 'Psychiatric illness' above.)
●For individuals who are contemplating but not yet ready to quit – For individuals who are considering quitting but are not ready to discontinue tobacco use, we suggest initiating pharmacotherapy rather than waiting until they are ready to stop tobacco use (Grade 2B). We prefer varenicline rather than NRT, although either may be used; both are effective in achieving smoking abstinence when used in patients not ready to abruptly quit. (See 'Individuals less committed to quitting' above.)
●Follow-up after initiating pharmacotherapy
•Following initiation of pharmacotherapy, we schedule a follow-up visit (eg, telemedicine encounter, telephone call, or in-person office visit) in one to two weeks to monitor for adverse effects, reinforce adherence to medication, and provide support for smoking cessation. (See 'Timing' above.)
•If a patient does not stop smoking after two to four weeks of pharmacotherapy, one or more of the following may be occurring: incorrect use of medication(s), intolerance of side effects, or persistent nicotine withdrawal symptoms. (See 'Assessment for persistent smoking' above.)
●Management of persistent withdrawal symptoms or persistent smoking – For patients who continue to experience withdrawal symptoms despite correct use of a first-line pharmacotherapy, and who are not already taking a short-acting NRT, we suggest adding short-acting NRT (Grade 2C). In addition, the dose of the first-line medication should be increased if it is not yet maximized. (See 'Assessment for persistent smoking' above.)
•If there has been no response to the initial agent, we switch to a different first-line pharmacotherapy.
•If the individual has had a partial response to the initial medication (ie, reducing smoking but not quitting altogether), adding an additional medication is reasonable. In particular, for those who have had partial success with varenicline, adding a nicotine patch may increase smoking abstinence. Other combination therapy options include bupropion and varenicline, bupropion and NRT, and nortriptyline and NRT. Combinations of drugs appear to be more effective than monotherapy but can also produce more side effects.
●Duration of pharmacotherapy – Pharmacotherapy for smoking cessation is recommended for at least three months. (See 'Duration of pharmacotherapy' above.)
●Pharmacotherapy for relapse – For patients who successfully quit smoking and then experience relapse, we suggest restarting the pharmacologic agent(s) that previously worked for the patient (Grade 2C). This may be enhanced with more intensive behavioral support and/or intensified pharmacotherapy (eg, adding another medication). (See 'Management of relapse' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Dr. Stephen Rennard, MD, and Mr. David Daughton, MS, who contributed to an earlier version of this topic review.
