Pharmacotherapy for smoking cessation in adults

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 exceptions for patients with comorbidities or contraindications to certain drugs (see 'Considerations for special populations' below). Each of these medications has proven efficacy although their comparative efficacies differ (table 2) [10-16]. Details on the safety, efficacy, and administration of individual therapies are described below. (See 'First-line agents' below.)

●Varenicline or combination NRT for most patients – We generally 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 because both varenicline and combination NRT appear similarly efficacious. The choice between them depends upon patient preference after shared clinical decision-making.

•Combination NRT – Combination NRT consists of the nicotine patch (a long-acting form of NRT) and a short-acting NRT of the patient's choice (ie, nicotine gum or lozenge) [1]. The patch provides sustained withdrawal symptom relief for 24 hours. The short-acting nicotine product is added "as needed" to control breakthrough cravings or other withdrawal symptoms. When using NRT, combination NRT is preferred over single-type NRT because it is more effective. However, some patients may prefer single-type NRT based on cost, side effect profiles, and patient preference. (See 'Efficacy' below.)

•Varenicline – Studies suggest similar efficacy of varenicline and combination NRT. Varenicline appears superior to other pharmacotherapies for smoking cessation, including bupropion and single agent NRT. Varenicline may also be more effective than e-cigarettes for smoking cessation [15] (see 'Efficacy' below). Less data exist comparing the efficacy of varenicline with cytisine.

Guidelines from the American Thoracic Society (ATS) and a statement from a consensus panel of the American College of Cardiology recommend varenicline over the nicotine patch or bupropion [1,4].

●Reasonable options for certain patients

•Combination treatment with varenicline and nicotine patch – Combining varenicline and the nicotine patch is also an option when selecting initial therapy, as this may increase smoking abstinence compared with varenicline alone [4,17]. We typically reserve this regimen for individuals who continue to smoke despite using one approach, particularly those who are highly motivated and willing to tolerate a potential increased risk of side effects. The safety and efficacy of this combination are discussed elsewhere. (See 'Partial response to treatment' below.)

•Bupropion – Bupropion appears to be less effective than varenicline or combination NRT (see 'Efficacy' below). However, it is a reasonable choice for individuals who have had short-term success with it in a previous quit attempt, have concomitant depression, or wish to minimize post-cessation weight gain [1,18] Bupropion is contraindicated in patients who have a seizure disorder or a predisposition to seizures. (See 'Seizures' below.)

●Other medication options – Several other medications evaluated for smoking cessation have less evidence of efficacy than first-line agents. These include the tricyclic antidepressant nortriptyline and cytisine, a plant derivative whose mechanism of action resembles that of varenicline [2,15,16,19-23]. These are discussed in detail elsewhere. (See 'Second-line medications' 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 [13]. (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 [24]. 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 [1,25-29].

A large study of a general population did not find a difference in major adverse cardiovascular events with use of varenicline, bupropion, or NRT [30]. 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.

Although concern has been raised about the safety of varenicline for patients known to have CVD [31], the available data suggest little or no excess cardiovascular risk [32-35]. (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 [1,36].

•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 [37], a critical trigger of ACS.

•Varenicline – Varenicline has demonstrated efficacy in patients with ACS. In a randomized trial of 302 patients with ACS who smoked, those who started low-intensity counseling and varenicline in-hospital and continued for 12 weeks had higher rates of point abstinence (40 versus 30 percent with placebo) and continuous abstinence (31 versus 21 percent) at 52 weeks [38,39], compared with those allocated to placebo. Both groups experienced similar rates of major adverse cardiovascular events (8.6 versus 9.3 percent) and serious adverse events (25 versus 22 percent). Of the three deaths that occurred among varenicline users, two were attributed to cardiac causes [38]. (See 'Safety' below.)

•Bupropion – In several trials among hospitalized patients with ACS who smoked, bupropion has been safe but not more effective than placebo [40-42]. A possible explanation is that bupropion requires five to seven days to reach steady state. Thus, patients may return home before drug levels are adequate to counter smoking cues that are encountered 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 [43]. 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) [44].

Patients who use NRT in the hospital are more likely to continue it after discharge [45,46] and may be more likely to quit smoking long-term. In a randomized trial in 397 hospitalized patients who smoked that allowed them to choose a smoking cessation medication, most chose NRT products over bupropion or varenicline [47].

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 [48,49]. 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 [48]. 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) [49].

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 patients who smoked and were 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) [50]. 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 [51,52].

●In a randomized trial of 1510 individuals who were not willing or able to stop smoking entirely but were willing to reduce smoking and make a quit attempt within the next three months, patients on varenicline for 24 weeks had higher continuous abstinence rates than those on placebo during weeks 21 through 24 (37.8 versus 12.5 percent) and weeks 21 through 52 (27 versus 9.9 percent) [51].

●In a meta-analysis of seven randomized trials of almost 2800 participants who smoked, those who received NRT achieved higher rates of sustained abstinence for six months than those on placebo (relative risk 2.06, 95% CI 1.34-3.15) [52]. However, overall quit rates were low (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 concerned about post-smoking cessation weight gain, which bupropion blunts temporarily [18]. (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].

Dedicated 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. Clinicians should individualize follow-up based on patients' needs, success of treatment, side effects, and risk of relapse. (See "Overview of smoking cessation management in adults", section on 'Arrange follow-up'.)

Persistent smoking

Assess and respond to adherence issues and side effects — If a patient does not stop smoking after two to four weeks of pharmacotherapy, clinicians should assess for incorrect use of the medication(s) and nonadherence due to side effects or for other reasons. Clinicians can use targeted strategies to optimize or adjust medication dosing.

●Assess adherence – Clinicians should assess for adherence at every visit because nonadherence to pharmacotherapies for smoking cessation is common and may have a negative impact on a patient's likelihood of quitting smoking [53]. Up to 20 percent of individuals who are prescribed a medication for smoking cessation do not fill the prescription [54]. Those who start an intervention may take lower than prescribed doses, and up to 50 percent of patients who start nicotine replacement therapy (NRT) do not complete the recommended length of treatment [54].

●Incorrect use of medication(s) – We ensure that patients on NRT understand the proper use of short-acting therapy (eg, using the "chew and park" strategy for nicotine gum to avoid nicotine release too rapidly) and how to titrate the short-acting agent they have chosen to use (eg, nicotine gum or nicotine lozenge). We counsel individuals to use these therapies with sufficient frequency to relieve and, optimally, prevent nicotine withdrawal symptoms.

●Other side effects – Patients who experience nonserious side effects can try lowering the dose, since all three first-line medications (varenicline, NRT, and bupropion) can be effective at lower doses. Nighttime symptoms, such as 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.

●Optimizing medication dose – Individuals who are adherent to bupropion or varenicline can increase the dose to the maximally approved doses for smoking cessation (ie, bupropion 300 mg daily; varenicline 1 mg twice daily) if medication side effects are tolerable. If needed, they can also increase the dose of the NRT patch above 21 mg to control symptoms of craving and withdrawal.

No response to treatment — If there has been no response to the initial agent after assessing adherence, optimizing medication dose, and continuing therapy for four to six weeks, we switch to a different medication. (See 'First-line agents' below.)

Partial response to treatment — Several options exist for patients who have a partial response to the initial medication (ie, reducing smoking but not quitting altogether). Clinicians should individualize recommendations based on the type of initial therapy, side effects, patient comorbidities, and patient preference.

●Increase dose of first-line medication – Patients who are already using a first-line oral pharmacotherapy (eg, varenicline or bupropion) and short-acting NRT and still experiencing cravings or other withdrawal symptoms should increase the dose of the first-line medication if it is not yet maximized. (See 'First-line agents' below.)

●Add short-acting NRT – If the patient is not already using adjunctive short-acting NRT, we suggest adding it, with precise instructions on how to use it effectively (see 'Short-acting nicotine replacement therapy' below).

●Combination pharmacotherapy – Combinations of drugs appear to be more effective than monotherapy but can also produce more side effects and are more expensive [8,55-57]. For individuals who have had a partial response to initial medications, combination therapy is a rational choice. Evidence supports the combination of varenicline and nicotine patch.

•Varenicline and nicotine patch – The combination of varenicline and nicotine patch may improve smoking abstinence over varenicline alone but may result in more side effects [4,17]. In a randomized trial of 435 individuals who smoked, treatment with varenicline and nicotine patch for 12 weeks resulted in higher rates of continuous abstinence at six month follow-up, compared with varenicline and placebo patch (49 versus 33 percent; odds Ratio [OR] 1.98, 95% CI 1.25-3.14) [17]. Among those using both medications, there was a slight, but not significant increase in adverse reactions including nausea, sleep disturbance, and constipation. In contrast, a similar trial of 1251 adults found similar abstinence rates with monotherapy versus combination varenicline plus nicotine patch at 52-week follow-up [58].

Other options for combination therapy are:

•Bupropion and varenicline – The combination of varenicline and bupropion may be more effective in helping people quit smoking than using varenicline alone [16,59]. A meta-analysis (four studies; 1057 participants) found a nonsignificant trend toward increased smoking cessation rates for participants on combination bupropion and varenicline therapy compared to varenicline alone (RR 1.21; 95% CI .95-1.55) [16]. The combination was well tolerated.

•Bupropion and NRT – In a meta-analysis of 15 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 1.17, CI 0.95-1.44) [16].

•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 [16].

Duration of pharmacotherapy — In general, pharmacotherapy for smoking cessation is recommended for at least three months [4,60]. Patient response to treatment and preference may dictate longer treatment durations. Duration of treatment for specific agents is reviewed below. (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 [61]. 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 [62].

Patients may worry that they will become dependent on NRT, but nicotine dependence rarely occurs, especially with the long-acting patch [62]. 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. For individuals who wish to use NRT, we suggest combination therapy with a long- and short-acting formulation.

●Versus placebo – Individual NRT products are superior to placebo, increasing quit rates up to twofold (table 2) [13,14,63,64]. In a meta-analysis of 133 studies of 64,640 participants, any form of NRT resulted in higher abstinence rates than placebo (16 versus 10.5 percent, respectively; RR 1.55; 95% CI 1.49-1.61) [65].

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'.)

In some, but not all trials, NRT benefits men more than women [66,67].

●Different types of NRT – Few trials have directly compared one NRT product with another. 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 [68].

●Single-agent versus combined NRT – Evidence from most trials suggests 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) [69]. Combination NRT was also found to be more effective than single-product therapies in other trials [55,56,70]. However, one randomized trial of 1086 individuals who smoked found no differences in biochemically confirmed rates of smoking abstinence between the nicotine patch and combination NRT (nicotine patch plus lozenge) [10].

Nicotine replacement products can safely be combined because each agent produces a lower blood nicotine level than does smoking one pack of cigarettes daily [63]. In addition, individuals who smoke already have experience titrating their nicotine intake to avoid nicotine withdrawal and overdose, so they can effectively do so with NRT products.

Administration — For tobacco users wishing to use NRT, we suggest a combination of long- and short-acting NRT as initial therapy.

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 [52,69].

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 [71] 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.

●Initial dosing and instructions for use – 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

Patients should remove and replace the patch with a new one each morning, applying it to any nonhairy skin site and rotating the site daily to avoid skin irritation.

Address side effects – Skin irritation and sleep disturbances are the most common side effects of NRT.

•Skin irritation – If skin irritation persists despite site rotation, patients can use topical hydrocortisone (1% cream or ointment).

•Insomnia, vivid dreams – To address sleep disturbances, patients can remove the patch at bedtime and replace with a new one the next morning. After an overnight hiatus, adequate plasma levels of nicotine are reached 30 minutes to three hours after applying the new patch [72]. If morning nicotine cravings occur before plasma nicotine levels rise, we advise use of a short-acting NRT (eg, gum, lozenge).

Smoking cessation rates are similar whether the patch is left on for 24 hours or taken off at night [73].

●Dose tapering – Although patches are typically marketed with instructions to taper the dose over 12 weeks, tapering does not improve smoking cessation rates [1]. Tapering the dose is optional and can be used if patients feel that cravings and withdrawal symptoms are well controlled, and 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.

•For patients using the 14 mg/day patch successfully, 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.

•Alternatively, patients can continue either the 21 mg/day or 14 mg/day doses for the duration 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 the person feels stabilized without smoking. 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 individuals who smoked that compared eight with 24 weeks of nicotine patch therapy, 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) [74]. Similarly, a subsequent randomized trial evaluated nicotine patch therapy for eight, 24, or 52 weeks and found that the longer treatment durations were superior to eight weeks at 24-, but not at 52-, week follow-up [75].

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.

•Use – 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.

•Dose – Dosing is determined by how soon the first cigarette is typically smoked upon awakening [76]:

-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.

•Side effects – Side effects primarily arise from excess nicotine release with overly vigorous chewing. They include 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.

•Duration of therapy – Gradually reduce use over the next six weeks, for a minimum treatment duration of three months.

●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. The lozenge can be used in those with temporomandibular disorders, poor dentition, or dentures.

•Use – Place lozenge in the mouth and allow it to dissolve over 30 minutes. The lozenge should not be chewed.

•Dose – Dosing is determined by how soon the first cigarette is typically smoked upon awakening [77]:

-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.

•Side effects – Side effects include mouth irritation or ulcers, in addition to nicotine-related side effects of abdominal pain, nausea, vomiting, diarrhea, headache, and palpitations.

•Duration of therapy – Gradually reduce number of lozenges used per day over the next six weeks.

●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 [78]. However, inhaling nicotine into the nasal mucosa produces side effects, particularly nasal irritation, that limit its tolerability.

•Dose – Dose is one or two sprays per hour. The maximum dose is 10 sprays per hour, not to exceed 80 total sprays per day.

•Side effects – 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 [79].

•Duration of therapy – Use for about three months.

●Nicotine inhalers – As of September 2023, the product's sole manufacturer discontinued sale of the nicotine inhaler, so its availability is uncertain [80]. Nicotine inhalers 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). 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.

•Use – 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.

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.

•Dose – 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.

•Side effects – Common side effects 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.

•Duration of therapy – Gradually reduce dose over the next 6 to 12 weeks.

●Nicotine mouth spray — Nicotine mouth spray is not available in the United States.

•Dose – Use one or two sprays when cravings occur, up to four sprays per hour [81]. 1 mg nicotine is delivered per spray.

•Side effects – Common side effects include hiccups (in more than 55 percent of those treated in one trial [82]), throat irritation, and nausea.

●Nicotine sublingual tablet – The nicotine sublingual tablet is not available in the United States.

•Dose – Allow one 2 mg tablet to dissolve sublingually (typically over 30 minutes) every one to two hours. Patients are heavily nicotine-addicted can use two tablets sublingually (4 mg total) for each dose [83].

•Side effects – Side effects occurring commonly include sore mouth or throat and dryness or burning in the mouth [84].

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 [85-87]. 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) [88].

●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 [89].

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 individuals who were motivated to quit smoking, half of whom had stable psychiatric disorders (eg, major depressive, bipolar, or anxiety disorders) [13]. 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 [90].

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 [91].

●Cardiovascular effects – The preponderance of the evidence suggests that varenicline does not increase the risk of adverse cardiovascular events. Any potential cardiovascular risk from varenicline is likely smaller than the risk of continued smoking.

For patients at low risk of an acute coronary event, varenicline is unlikely to cause a clinically meaningful increase in cardiovascular events. For high-risk patients, the cardiovascular risk of varenicline is less certain although existent data has not shown a large increase in risk.

The precise risk of cardiovascular events with varenicline is difficult to define because of limitations in the available evidence. As examples:

•A 2023 meta-analysis of 18 randomized controlled trials comprising 7151 participants found an increased point estimate of cardiovascular side effects (RR 1.20; 95% CI .79-1.85) with varenicline compared to placebo but not compared to bupropion or dual-form NRT. All conclusions were limited by imprecision since the confidence intervals were compatible with both benefit and harm [15]. Two large meta-analyses of randomized trials found no differences in the rates of cardiovascular events in patients treated with varenicline compared with placebo but, again, low rates of cardiovascular events in the trials limited their power to detect a difference [32,92].

•Varenicline does not appear to increase the risk of cardiovascular events in patients with established CVD. A randomized trial of 714 individuals who smoked and had stable CVD found no difference in mortality or major cardiovascular events at 52 weeks in those allocated to 12 weeks of varenicline or placebo [28]. Although the small trial size and limited follow-up limited the strength of these conclusions, additional trials of varenicline in individuals with CVD or multiple cardiovascular risk factors had similar results [30,39].

•Most observational studies have not shown an increase in cardiovascular events with use of varenicline [93-96]. (See 'Cardiovascular disease' above and 'Our approach' above.)

•A 2011 FDA advisory and a 2018 labeling update suggested weighing the benefits of varenicline for smoking cessation against potential harms in patients with CVD [97,98].

●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 [99]. 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 [85]. However, in a subsequent large observational study in Sweden, varenicline was not associated with an increase in traffic crimes or transport accidents [100].

Efficacy — The efficacy of varenicline for smoking cessation has been demonstrated in many studies.

●Versus placebo – In a meta-analysis of 41 studies with 17,395 participants, those allocated to varenicline were more likely to be abstinent at six months than those allocated to placebo (estimated absolute risks 23 versus 9.9 percent) [15]. Similarly, a 2022 network meta-analysis of 34 studies of varenicline and 11 other interventions concluded that varenicline (both as monotherapy or in combination with other pharmacotherapies, particularly bupropion) was more effective in achieving smoking cessation than counseling or placebo [101].

●Versus other pharmacotherapies – Varenicline appears superior to bupropion, single agent NRT, and cytisine, and equivalent to combination NRT [15,101].

•A meta-analysis of five randomized trials (2344 participants) that compared varenicline with combination NRT found no significant difference in quit rates (RR 1.02; 95% CI .87-1.20) [15]. Another randomized trial of approximately 1000 participants showed no difference in biochemically confirmed abstinence rates among users of varenicline, single NRT (nicotine patch), or combination NRT (nicotine patch plus nicotine lozenge therapy) for 12 weeks [10].

•A meta-analysis of 75 randomized trials reported higher quit rates with varenicline than with bupropion (RR 1.36; 95% CI 1.25-1.49) and single form NRT (RR 1.25; 95% CI 1.14-1.37) [15]. Similarly, the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) trial directly compared varenicline, bupropion, nicotine patch, and placebo in over 8000 individuals who smoked [13]. At six-month follow-up, varenicline produced higher quit rates than bupropion or the nicotine patch, which were comparable in efficacy, and all medications were more effective than placebo.

●Versus e-cigarettes – Evidence comparing varenicline to e-cigarettes is limited. One study found higher quit rates at six or more months in the varenicline than the e-cigarette group (48 versus 15 percent, respectively) [15].

Administration

Dosing, duration, and instructions for use:

●Initiation and titration – 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.

Increasing the dose of varenicline has not been shown to improve smoking cessation rates.

●When to stop smoking – 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 quit date is also effective for achieving abstinence [77]. A four-week preload of varenicline produced higher abstinence rates at 12 weeks in a trial of 101 persons who smoked, compared with those assigned to three weeks of placebo followed by one week of varenicline (47 versus 21 percent) [102].

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.)

●Duration of treatment – The optimal duration of varenicline therapy is not clear. We recommend that patients use for at least 12 weeks; individuals who experience benefit and feel at risk for relapse can continue therapy for up to one year. In a trial of 1251 individuals who smoked at least 5 cigarettes daily, treatment durations of 12 and 24 weeks showed no difference in continuous abstinence at 52 weeks (24.3 vs 24.8 percent, respectively [58]. In contrast, in a randomized trial of 1236 individuals who had quit smoking after a 12-week course of varenicline, those treated in an open-label fashion 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) [103].

Addressing side effects:

●Counseling about side effects – Evidence does not suggest that varenicline causes more neuropsychiatric symptoms than other FDA-approved smoking cessation aids. Nonetheless, clinicians should counsel patients that if they develop concerning neuropsychiatric symptoms (eg, changes in behavior, hostility, agitation, depressed mood, suicidal ideation, or suicide attempts), they should stop the medication and immediately contact their clinician.

●Minimizing nausea – The risk of nausea is reduced if the dose of varenicline is titrated upon initiation [104]. 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.

●Minimizing insomnia or disturbing dreams – 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.

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 [13]. 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 [105]. (See 'Psychiatric illness' above.)

Bupropion is safe for use among individuals with stable CVD [25,30] and COPD [19]. Studies suggest that bupropion is safe, although not effective, for those hospitalized for acute myocardial infarction [40-42]. (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 across a variety of patient populations, including those with psychiatric comorbidities, chronic obstructive lung disease (COPD), and cardiovascular disease. The use of bupropion in patients with CVD is discussed above. (See 'Cardiovascular disease' above.)

●Versus placebo – A meta-analysis of 50 randomized trials with 18,577 participants found higher rates of smoking cessation at six month follow-up with bupropion monotherapy than placebo or no treatment (19 versus 12 percent, respectively; RR 1.60, 95% CI 1.49-1.72) [16]. 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].

Studies have demonstrated the efficacy of bupropion in specific populations of tobacco users, including African Americans and those with stable CVD or COPD [19,25,107].

Another randomized controlled trial including over 8000 participants who smoked confirmed that bupropion was more effective than placebo in patients with and without psychiatric comorbidity [13].

●Versus other agents – Comparative meta-analyses suggest that bupropion is equivalent to single agent NRT but inferior to varenicline and combination NRT [16]. (See 'Efficacy' 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:

●Initiation and titration – 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. The recommended dose of bupropion is 150 mg/day for three days, then 150 mg twice daily thereafter [62].

●When to stop smoking – Individuals take bupropion for at least one week prior to quitting smoking.

●Duration of treatment – We recommend treating for at least 12 weeks. Longer duration of treatment can be considered in individual cases, based on the patient’s previous quit attempts and patient preference. 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). Abstinence rates at two years were the same in both groups (41 versus 40 percent).

However, if bupropion is also being used for treatment of a mood disorder, clinicians should monitor changes in depressive symptoms and adjust doses accordingly. (See "Unipolar major depression in adults: Choosing initial treatment".)

●Addressing side effects – Lower-dose bupropion (150 mg/day) is an option for those who do not tolerate the full dose due to side effects. Although this dose is less studied, one randomized trial found that 150 mg/day was as effective as 300 mg/day and caused fewer side effects [106].

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 [109].

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 [16,19-23,110]. In a meta-analysis of six trials and 975 participants, it increased the likelihood of abstinence compared with placebo (RR 2.03, 95% CI 1.48-2.78) [16]. However, patients receiving nortriptyline were more likely to report side effects including dry mouth and sedation.

●Cytisine – Cytisine, known as cytisinicline in the United States, is a plant derivative that, like varenicline, is a partial agonist at the alpha-4 beta-2 nicotinic acetylcholine receptor [85,111]. It appears more effective than placebo and single-agent NRTA [15,112,113].

Cytisine is 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; however, cytisine is not available in the United States or Western Europe because it has not yet been evaluated by the US Food and Drug Administration (FDA) or its European equivalent (European Medications Agency) [2,114,115].

•A meta-analysis found that cytisine was more effective than placebo (RR 1.30; 95% CI 1.15-1.47) and single-product NRT (RR 1.43; 95% CI 1.134-1.80). The same meta-analysis suggested that cytisine may be inferior to varenicline (RR .83; 95% CI .66-1.05), but results were imprecise [15]. Nausea, a common side effect, occurred less often with cytisine than with varenicline and more often than with NRT.

Subsequently, the ORCA-2 trial randomized 810 participants who smoked daily (mean of 19.4 cigarettes per day) to 6- or 12-week courses of a different dose of cytisine than that used in prior trials (cytisinicline 3 mg taken 3 times daily) or placebo [113]. All participants underwent intensive behavioral counseling. Participants allocated to the 12-week course of cytisinicline had higher continuous rates of abstinence during weeks 9 to 24 (21 percent) than those allocated to placebo (5 percent) (odds ratio [OR] 5.3; 95% CI 2.8-11.1). Continuous abstinence rates among participants allocated to the 6-week course were less robust but still higher than those with placebo. Cytisinicline was well-tolerated, with side effects of insomnia and abnormal dreams occurring in fewer than 10 percent of the intervention groups.

Therapies with limited or unproven benefit

●Clonidine – Despite promising initial studies, clonidine is now generally regarded as having limited efficacy for smoking cessation [116-118]. 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 [109]. 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 [16,119].

●Nicotine vaccine – A nicotine vaccine is a novel experimental approach to treating tobacco dependence. Theoretically, the vaccine would generate antinicotine antibodies that prevent nicotine from interacting with nicotine receptors in the central nervous system and thereby decrease the rewarding effects of smoking [120-122]. Several companies have previously evaluated candidate vaccines, but none have demonstrated efficacy. It is not clear that this strategy remains under active investigation.

●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 that can be sold as consumer products because their 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 [123]. (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 emerging due to limited evidence regarding their efficacy and long-term safety. A meta-analysis concluded that there is strong evidence that e-cigarettes are more effective for smoking cessation than nicotine replacement products and moderate evidence that they are superior to e-cigarettes without nicotine [124]. In some [125-127] but not all [128,129] 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. Most existing trials used older types of e-cigarettes that had lower nicotine delivery than currently available e-cigarette options. The efficacy and safety of these newer types of e-cigarettes requires additional investigation.

A large proportion of clinical trial participants continue to use e-cigarettes after the intervention [130]. 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 heated tobacco products, 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 5^th to 6^th 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 10^th to 12^th 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 combination NRT as first-line pharmacologic therapy rather than bupropion, single-agent NRT, or other medications (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 products (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 for initial therapy. This may increase smoking abstinence but may also increase the risk of adverse effects, such as nausea and sleep disturbance.

•Bupropion appears to be less effective than combination NRT or varenicline. However, it is a reasonable choice if cost is an issue or the patient had short-term success with bupropion in a previous quit attempt, has concomitant depression, or wishes to 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) or other reasons for nonadherence, intolerance of side effects, or persistent nicotine withdrawal symptoms. (See 'Assess and respond to adherence issues and side effects' 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 'Assess and respond to adherence issues and side effects' 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.