Pharmacotherapy For Smoking Cessation in Adults

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Pharmacotherapy for smoking cessation in adults
Author: Nancy A Rigotti, MD

Section Editors: James K Stoller, MD, MS, Mark D Aronson, MD
Deputy Editor: Judith A Melin, MA, MD, FACP
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2018. | This topic last updated: Jul 10, 2018.
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.
The main medications that have demonstrated efficacy as smoking cessation aids include nicotine replacement, varenicline,
and bupropion [1]. 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 value of also using behavioral therapies for smoking cessation are discussed
separately. (See "Overview of smoking cessation management in adults" and "Behavioral approaches to smoking cessation".)
The treatment of smoking cessation in adolescents is discussed separately. (See "Management of smoking cessation in
adolescents".)
INDICATIONS — All smokers should be advised to quit smoking.
Assessing a patient’s willingness to quit smoking is discussed elsewhere. (See "Overview of smoking cessation management in
adults", section on 'Assess readiness to quit'.)
Mechanisms to assist smokers who are ready to quit are discussed elsewhere. (See "Overview of smoking cessation
management in adults", section on 'Assist smokers ready to quit'.)
For smokers who are willing to quit, we recommend a combination of behavioral support and pharmacologic therapy. The
combination produces higher tobacco quit rates than either type of treatment alone [2]. (See "Overview of smoking cessation
management in adults".)
Behavioral strategies for smoking cessation are discussed elsewhere. (See "Behavioral approaches to smoking cessation".)
INITIAL THERAPY SELECTION
General population — The first-line pharmacotherapies for smoking cessation are nicotine replacement therapy (NRT),
varenicline, and bupropion (table 1) [3-7]. 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 contraindications to certain drugs or comorbidities. (See 'Special
considerations' below.)
For most patients, we suggest 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. 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. However, using single-type NRT is a reasonable alternative based on cost, side effect profiles, and patient preference.
(See 'Nicotine replacement therapy' below.)
Bupropion appears to be somewhat less effective than combination NRT or varenicline, but 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 [8].
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However, bupropion is contraindicated in patients who have a seizure disorder or a predisposition to seizures. (See 'Seizures'
below.)
We recommend providing follow-up in person or by phone one to two weeks after initiation of any pharmacotherapy to monitor
for adverse effects, reinforce adherence to medication, and provide support for smoking cessation. (See "Overview of smoking
cessation management in adults", section on 'Arrange follow-up' and 'Neuropsychiatric effects' below and 'Follow up' below.)
The efficacy of each first-line therapy for smoking cessation has been proven, though studies show differences in their relative
efficacy (table 2) [9-16]. 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 [15]. 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. Another randomized trial of 1086 smokers found 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 [11].
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 [17-23]. (See 'Second-line medications'
below.)
Cytisine is a cost-effective option in the Eastern European countries in which it is available. Because it has not 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. (See 'Second-line medications' below.)
Details on the efficacy of individual therapies are described below. (See 'First-line agents' below.)
Special considerations — While choice of pharmacotherapy for the general population is typically based on patient
preference, pharmacotherapy may need to be tailored due to contraindications or comorbidities and for patients in specific
settings or populations.
Psychiatric illness — Evidence indicates that the same medications are effective for smokers with and without psychiatric
comorbidity; however, for severely mentally ill patients with psychotic disorders, the efficacy of NRT for smoking cessation is
unclear. Special considerations for 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'.)
Absolute tobacco quit rates are somewhat lower in smokers with psychiatric illness. The results of a large trial also suggested
that, in contrast to earlier concerns, varenicline and bupropion have no higher risk of associated adverse psychiatric events than
NRT in smokers with comorbid psychiatric disorders [15]. (See 'Neuropsychiatric effects' below and 'Safety' below.)
Ideally, pharmacotherapy should be coordinated with the patient’s behavioral health provider.
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 [24-32].
A large study of a general population did not find a difference in major adverse cardiovascular events with use of
varenicline, bupropion, or NRT [33]. In the EAGLES study, 11,186 smokers were randomized to receive 12 weeks of
pharmacotherapy. The study included smokers with stable CVD or CVD risk factors; however, it is important to note that
smokers 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 [34], and studies have shown
mixed results, although generally there appears to be little or no excess cardiovascular risk [35-38]. (See 'Cardiovascular
effects' below.)
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● 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 in ACS compared with stable CVD. There are fewer data regarding their efficacy and safety in
smokers hospitalized with ACS, but available studies suggest that they are probably safe to use [39].
• Because of its rapid onset, NRT is generally used to manage nicotine withdrawal 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 smokers 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 [40], a critical trigger of ACS.
• 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 [41,42]. 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 [41]. (See
'Cardiovascular effects' below.)
• Bupropion has been safe but not more effective than placebo in several randomized controlled trials of hospitalized
smokers with ACS [43-45]. 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 smokers' below.)
The approach to smoking cessation in patients after ACS is discussed in detail separately. (See "Overview of the non-acute
management of unstable angina and non-ST elevation myocardial infarction", section on 'Smoking cessation' and
"Overview of the non-acute 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 [46].
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 smokers — NRT is often used to treat nicotine withdrawal symptoms in hospitalized smokers because it has a
rapid onset of action, whereas varenicline and bupropion are slower to reduce these symptoms.
In a meta-analysis of randomized trials comparing intensive counseling alone or combined with various pharmacotherapies for
hospitalized smokers, NRT appeared to improve smoking cessation (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) [47].
Patients who use NRT in the hospital are more likely to continue it after discharge [48] and may be more likely to quit smoking
long-term. A randomized trial in 397 hospitalized smokers that allowed smokers a choice of medication as part of a post-
discharge intervention found that most hospitalized smokers chose NRT products over bupropion or varenicline [49].
Preoperative smokers — 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. Pharmacotherapy in preoperative
smokers has been found to increase smoking cessation rates and decrease postoperative complications [50,51]. 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 in preoperative smokers [50]. In a prospective, randomized trial of 120
smokers awaiting major orthopedic surgery, patients who underwent counseling and nicotine replacement six to eight weeks
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prior to surgery had a lower rate of overall postoperative complications than patients in the control group (18 versus 52 percent)
[51].
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, RR 1.45, 95% CI: 1.01-2.07) [52]. All patients received counseling regarding smoking
cessation.
Pregnant smokers — Pharmacotherapy for smoking cessation in pregnant women is discussed in detail elsewhere. (See
"Cigarette smoking in pregnancy: Cessation strategies and treatment options", section on 'Pharmacotherapy'.)
Light smokers — Evidence about the efficacy of pharmacotherapy for smoking cessation among light smokers (ie, smoking
fewer than 10 cigarettes per day) is limited, but it is reasonable to assume that pharmacotherapies have similar effectiveness for
smoking cessation as they do in heavier smokers.
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 smokers. If varenicline or bupropion
are selected, there is no theoretical need to reduce the dose prescribed for light smokers and standard doses are
recommended. (See 'General population' above.)
Smokers less committed to quitting — Many smokers are not ready to quit in the next month but may be willing to take
pharmacotherapy to help them to reduce cigarettes smoked in preparation for quitting in the future. Evidence from randomized
trials indicates that both varenicline and NRT might be used in this way [53,54].
A randomized trial in 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 found that, compared with placebo, patients on
varenicline for 24 weeks had a higher continuous abstinence rate during weeks 21 through 24 (37.8 versus 12.5 percent) and
weeks 21 through 52 (27 versus 9.9 percent) [53].
NRT also appears to be effective for achieving smoking abstinence among smokers who are not ready to abruptly quit. In a
meta-analysis of seven placebo-controlled randomized controlled trials that enrolled a total of 2767 smokers who were not
ready to quit, smokers who received NRT achieved a higher rate of sustained abstinence for six months compared with those
on placebo (RR 2.06, 95% CI 1.34-3.15) [54]. Overall quit rates were low, however. There were no differences in adverse
events except nausea, which was more common with NRT. Most of the trials included regular behavioral support. Whether
using NRT without regular behavioral contact would be as effective is not known.
Smokers concerned about gaining weight — Bupropion may be a good choice for smokers who are especially concerned
about post-cessation weight gain, which bupropion blunts temporarily [8]. (See "Obesity in adults: Drug therapy", section on
'Bupropion-naltrexone'.)
FOLLOW UP
Timing — All patients who initiate pharmacotherapy should have initial follow-up (office visit or telephone call) within one to two
weeks to assess for positive responses, side effects, and opportunities to optimize treatment with first-line therapies, and to
provide reinforcement for smoking cessation when needed. Further follow-up to assess for new side effects, smoking cessation,
or relapse, should be scheduled at three months and one year, and more frequently if necessary. (See "Overview of smoking
cessation management in adults", section on 'Arrange follow-up'.)
Persistent smoking — If a patient does not stop smoking after two to four weeks of medication, 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 suggest providing further precise education about how to use the drug(s).
For example, we assure 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 withdrawal symptoms.
● Intolerance of side effects – Before stopping the medication due to a non-serious side effect, we suggest lowering the
dose. All three first-line medications can be effective at lower doses. For example, unpleasant dreams or insomnia can be
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ameliorated by taking a nicotine patch off at bedtime or by cutting out the evening dose of varenicline. If dose reduction is
not feasible or successful, an alternate first-line agent should be tried.
● Failure of the drug to reduce 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). Smokers who are already using a first-line oral pharmacotherapy along
with appropriate use of short–acting NRT and still experience severe withdrawal symptoms should have the first-line
medication dose increased if the dose is not yet maximized.
If the patient is already using a medication correctly and maximally without sufficient effect at four weeks, the options are to
continue the therapy, switch to a different first-line therapy or nortriptyline (a second-line therapy), or consider combining
medications by adding another first-line agent. If there has been no response to the initial agent, switching to a different
medication is recommended. (See 'First-line agents' below and 'Second-line medications' below.)
However, if the smoker has had a partial response to the initial medication (ie, cutting down on smoking but not quitting
altogether), adding an additional medication is a rational choice. Combinations of drugs appear to be more effective than
monotherapy but can also produce more side effects [55-58]. Options for combination therapy are:
• Nicotine patch and varenicline – 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 [59]. 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. [60]. 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 [RR]
1.19, CI 0.94-1.51) [17].
• 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 (RR 1.21, CI 0.94-1.55). This result is similar to what was found by adding
bupropion to NRT [17].
Duration of therapy — In general, pharmacotherapies for smoking cessation are recommended for two to three months.
However, NRT may be extended and even used indefinitely if needed. Varenicline use may be extended for an additional three
months to prevent relapse [61]. Both varenicline and bupropion use may be extended indefinitely in individual cases, based on
prior quit attempts and patient preference. If bupropion is also being used to treat mood, continuation of therapy should take into
consideration changes in depressive symptoms. (See 'Nicotine replacement therapy' below and 'Varenicline' below and
'Bupropion' below.)
RELAPSE — For patients who successfully quit smoking and then experience relapse, we suggest restarting a pharmacologic
agent that previously worked for the patient. This may be enhanced with more intensive behavioral support and/or intensified
pharmacotherapy (eg, adding another medication). (See "Overview of smoking cessation management in adults", section on
'Relapse' and "Behavioral approaches to smoking cessation".)
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 smoker breaks the behavior of cigarette smoking.
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 [62]. Smokers 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 [55].
Smokers may worry that they will become dependent on NRT, but nicotine dependence rarely occurs, especially with the long-
acting patch [55]. Smokers may also worry that nicotine causes cancer, which it does not.
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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. (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, individual NRT products were found to be superior to placebo, increasing quit rates up to
twofold (table 2) [2,15,55,63]. One randomized trial among the NRT patch, gum, inhaler, and nasal spray found no difference in
efficacy [64]. 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 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. In a meta-analysis of nine 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 [RR] 1.34,
95% CI 1.18 to 1.51) [9]. Combination NRT was also found to be more effective than single-product therapies in other trials
[56,57,65]. However, one randomized trial of 1086 smokers that compared 12 weeks of individual NRT (nicotine patch),
combination NRT (nicotine patch plus nicotine lozenge therapy) and varenicline found no differences in biochemically confirmed
rates of smoking abstinence among the three groups [11].
In some but not all trials, NRT benefits men more than women [66,67].
Administration — For smokers wishing to use NRT, we recommend a combination of long- and short-acting NRT as initial
therapy. Differences in the bioavailability of nicotine replacement products provide a rationale for combining NRT products to
increase efficacy for smoking cessation [2]. 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, smokers have experience titrating their nicotine
intake to avoid both nicotine withdrawal and nicotine overdose, as they have done 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, though NRT use
for as long as a smoker is at high risk for relapse is acceptable because NRT is much safer than continuing to smoke. Some
smokers may need to use the products indefinitely. NRT products can also be used while the smoker is still smoking [68].
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, duration, and instructions for use:
● Dosing is determined by the number of cigarettes smoked daily when the patch is started.
• >10 cigarettes per day and weight >45 kg – Start with the highest dose nicotine patch (21 mg/day) for six weeks,
followed by 14 mg/day for two weeks, and finish with 7 mg/day for two weeks.
• ≤10 cigarettes per day or weight < 45 kg – Start with the medium dose nicotine patch (14 mg/day) for six weeks,
followed by 7 mg/day for two weeks.
● Apply one patch each morning to any non-hairy skin site; rotate the site daily to avoid skin irritation, the most common side
effect. Over-the-counter hydrocortisone 1% cream or ointment topically may be used to relieve skin irritation if it occurs.
● Remove and replace the patch with a new one at bedtime. However, if leaving the patch on overnight is causing the
frequently reported side effects of insomnia and vivid dreams, replace the patch the next morning. Smoking cessation rates
are similar whether the patch is left on for 24 hours or taken off at night [70].
● When the patch is removed at night, substantial plasma levels of nicotine are reached 30 minutes to three hours after a
new patch is applied in the morning [71]. If the patch is removed at night and morning nicotine cravings occur, use a short-
acting NRT (eg, gum, lozenge) while waiting for the nicotine patch to take effect.
Adjusting duration:
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● 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 he or she has 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.
For example, a randomized trial of 568 smokers found that compared with 8 weeks of nicotine patch therapy, extended
therapy (24 weeks) was associated with 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 daily nicotine patch therapy to help control cravings and withdrawal symptoms.
However, short-acting forms require repeated use throughout the day, lead to more variable nicotine levels than the patch, and
require more instructions for correct use. Smokers may be instructed to use the product when they have a craving, but this
generally leads them to underuse the products. An alternative approach is to have the smoker use the short-acting NRT product
at least once every hour while awake and more often as needed.
The choice of a short-acting agent depends on patient preference and comorbidities. The nicotine patch, lozenge, and gum are
available in the United States without a prescription; nasal spray and oral inhaler require a prescription. A nicotine mouth spray
and sublingual tablet are available in some countries, though not in the United States.
Nicotine gum — Nicotine gum is a commonly used short-acting NRT. Chewing the gum releases nicotine to be
absorbed through the oral mucosa, resulting 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, duration and instructions for use:
● Dosing is determined by the number of cigarettes smoked daily.
• ≥ 25 cigarettes per day – 4 mg dose of gum is recommended [55]
• < 25 cigarettes per day – 2 mg dose of gum is recommended [55]
● Chew at least one piece of gum every one to two hours while awake and also whenever there is an urge to smoke.
● Use up to 24 pieces of gum per day for six weeks.
● Gradually reduce use over a second six weeks, for a total duration of three months.
● Proper chewing of gum is important for optimal results. 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. "Chew and park" is recommended: chew the gum until the nicotine taste appears, then
"park" the gum in 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).
● 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.
Smokers with temporomandibular joint disease, with poor dentition, or who use dental appliances 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 that resembles a "Tic Tac" is also on the United States market. It dissolves more rapidly and delivers nicotine more
7 de 22 18/08/2018 19:41
rapidly than the original lozenge.
● Dosing is determined by how soon the first cigarette is typically smoked upon awakening:
• Smokers who smoke within 30 minutes of awakening: 4 mg dose recommended
• Smokers who wait more than 30 minutes after awakening to smoke: 2 mg dose recommended
● Use up to one lozenge every one to two hours for six weeks. The maximum dose is five lozenges every six hours or 20
lozenges per day.
● Gradually reduce number of lozenges used per day over a second six weeks.
● Place lozenge in the mouth and allow it to dissolve for 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 smokers with temporomandibular joint disease, 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 smoker 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.
● Use 6 to 16 cartridges per day for the first 6 to 12 weeks
● Gradually reduce dose over the next 6 to 12 weeks
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 smokers 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 [74]. However, inhaling nicotine into the nasal mucosa produces
side effects that in practice have limited its tolerability by many smokers.
● 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 [75].
Nicotine mouth spray — Nicotine mouth spray is not available in the United States.
Dosing and instructions for use:
8 de 22 18/08/2018 19:41
● 1 mg nicotine is delivered per spray
● Use one or two sprays when cravings occur, up to four sprays per hour [76]
Side effects occurring frequently with the oral spray include hiccups (occurring in more than 55 percent of those treated in one
trial [77]), 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 [78]
Side effects occurring commonly include sore mouth or throat and dryness or burning in the mouth [79].
Varenicline — Varenicline reduces the symptoms of nicotine withdrawal by blocking nicotine from binding to the receptor that
mediates the reinforcing effects of nicotine that lead to nicotine dependence. Through this action, varenicline reduces the
rewarding aspects of cigarette smoking [80-82]. It does this by binding with high affinity and producing partial stimulation of the
alpha-4 beta-2 nicotinic receptor.
Safety — The most common side effects reported are nausea and sleep disorders (eg, insomnia, abnormal 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. (See 'Neuropsychiatric effects' below and
'Cardiovascular effects' below.)
Varenicline is safe for use by smokers with chronic obstructive pulmonary disease (COPD) [83].
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 that they had required in
2009.
Previously, in the initial post-marketing period, there had been concern about the potential for adverse psychiatric effects of
varenicline, 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 [84].
The FDA also required the manufacturers of these drugs 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 EAGLES
double-blind trial enrolled approximately 8000 smokers motivated to quit, half of whom had stable psychiatric disorders (eg,
major depressive, bipolar, or anxiety disorders). It found similar rates of neuropsychiatric adverse events with varenicline,
bupropion, nicotine patch or placebo [15]. In the trial, patients with psychiatric comorbidity had a higher rate of neuropsychiatric
symptoms than patients without this comorbidity, but rates were low for both groups and there was no statistically significant
difference in the rates of neuropsychiatric symptoms among smokers treated with NRT, bupropion, varenicline, or placebo. This
lack of difference in neuropsychiatric symptoms among users of these agents was observed both for patients with and without
underlying psychiatric illness. Based on these data, the FDA removed the boxed barning for varenicline (and bupropion) in
December 2016 [85].
A systematic review and meta-analysis of 39 randomized trials including over 10,000 participants with and without psychiatric
illness also found that varenicline did not increase the risk of suicide or suicide attempts, suicidal ideation, depression,
aggression, or death compared with placebo [16].
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. Overall, 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.
For high-risk patients, the effect of varenicline on cardiovascular event occurrence is less certain. Generally, trials have included
relatively few such patients; however, 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
9 de 22 18/08/2018 19:41
advisory and 2018 labeling update suggested that the known benefits of varenicline for smoking cessation be weighed against
potential harms in patients with CVD [86,87].
The precise risk of cardiovascular events with varenicline is difficult to define because of limitations in the available evidence. In
one randomized double-blind controlled trial of varenicline in 714 smokers with stable CVD, cardiovascular mortality was lower
with varenicline compared with placebo (0.6 versus 1.4 percent) but the rate of non-fatal myocardial infarction was higher with
varenicline compared with placebo (2 versus 0.9 percent) [31]. However, these differences did not reach statistical significance,
precluding a causal inference. Another randomized controlled trial of 302 ACS patients given varenicline or placebo found that
both groups had similar rates of major adverse cardiovascular events [41].
Two large meta-analyses of randomized trials found no differences in the rates of cardiovascular events in patients treated with
varenicline compared with placebo [35,88]. However, the overall rates of cardiovascular events in the trials were low, limiting the
power of the analyses to detect a difference. An earlier meta-analysis excluded trials with no cardiovascular events and did find
an association between varenicline and cardiovascular events (odds ratio [OR] 1.72, 95% CI 1.09-2.71) [89]. However, this
methodology may have also introduced some bias [89,90]. In a large randomized trial that included patients with stable CVD or
cardiovascular risk factors, compared with placebo, use of varenicline was not associated with an increased risk of major
cardiovascular events during treatment or for one year afterward [33].
The majority of observational studies have 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 [91] and another study
showed lower rates of ischemic heart disease and stroke among varenicline than NRT users [92]. However, in a retrospective
database analysis, varenicline initiation was associated with a higher relative risk but small absolute increase in adverse
cardiovascular events [93]. (See 'Cardiovascular disease' above and 'General population' 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 [94]. 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
[80]. However, in a subsequent large observational study in Sweden, varenicline was not associated with an increase in traffic
crimes or transport accidents [95].
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) [9].
Another meta-analysis of open-label randomized controlled trials found that more patients were abstinent at 24 weeks with
varenicline than with nicotine patch (RR 1.25, 95% CI 1.14 to 1.37) [10]. Similarly, a head-to-head double-blinded randomized
controlled trial comparing varenicline, bupropion, nicotine patch, and placebo found that varenicline was more effective in
producing six months of tobacco abstinence than other drugs or placebo [15].
Administration
● Smokers 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 four weeks prior to the quit date is also effective for achieving abstinence.
● The recommended dose of varenicline is 0.5 mg 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 at least moderate renal insufficiency 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) [96].
● Although evidence does not suggest that varenicline causes more neuropsychiatric symptoms than other FDA-approved
smoking cessation aids, the FDA still recommends that any patient started on varenicline who develops neuropsychiatric
symptoms including changes in behavior, hostility, agitation, depressed mood, suicidal ideation, and suicide attempts
should stop the medication, contact their clinician, and seek medical attention, right away.
Adjusting dosing and duration:
10 de 22 18/08/2018 19:41
● The risk of nausea is reduced if the dose of varenicline is titrated upward [97]. 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.
● Dreams that are troubling to the patient can be reduced by taking the evening dose of varenicline earlier in the day or by
lowering the dose by skipping the evening dose.
● 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 with 1236 individuals who had quit smoking after an initial 12-week course of
varenicline, smokers treated with varenicline for an additional 12 weeks had higher rates of continuous abstinence (weeks
13 through 24: 71 versus 50 percent; weeks 13 through 52: 44 versus 37 percent) [61].
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 [15]. 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 [98]. (See 'Neuropsychiatric effects' above.)
Bupropion is safe for use among smokers with stable CVD [24,33] and COPD [18]. Studies suggest that bupropion is safe,
although not effective, for smokers hospitalized for acute myocardial infarction [43-45]. (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 meta-analysis of 44
randomized trials found that rates of smoking cessation are higher with bupropion monotherapy than placebo (RR 1.62, 95% CI
1.49-1.76) [17]. A representative multicenter, randomized trial of 615 smokers comparing sustained-release bupropion (150 mg
twice daily) with placebo found that patients receiving bupropion 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) [99]. A subsequent randomized controlled
trial that enrolled over 8000 smokers confirmed that bupropion was more effective than placebo in patients with and without
psychiatric comorbidity [15]. 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, including African-American smokers, and
smokers who have stable CVD or COPD [18,24,100].
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).
● Bupropion sustained-release is started one week before a smoker's 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 a day thereafter [55].
● We recommend treating for at least 12 weeks.
Adjusting dosing and duration:
● Bupropion 150 mg/day (rather than 300 mg/day) is an option for smokers who do not tolerate the full dose due to side
11 de 22 18/08/2018 19:41
effects.
Two randomized trials found that the 150 mg/day dose was as effective as the 300 mg/day dose and associated with fewer
side effects [99,101].
● 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 smokers who quit smoking after
seven weeks of bupropion compared ongoing treatment for one year with either bupropion 300 mg daily or placebo [102].
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 [9].
Second-line medications
● Nortriptyline – Nortriptyline 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 [17-23]. In a meta-analysis of six
trials, it increased the likelihood of abstinence (relative risk [RR] 2.03, 95% CI 1.48-2.78). 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 [80,103]. 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 [104,105].
In a systematic review and meta-analysis of 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 [106]. 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) [107]. 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 [108-110]. 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 [9].
Adverse effects, such as drowsiness, fatigue, and dry mouth, also limit the use of clonidine as a smoking cessation aid.
● Selective serotonin reuptake inhibitors (SSRIs)/anxiolytics – SSRIs and anxiolytic drugs generally have not been
shown to be effective for smoking cessation [9,17,111].
● 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 [112]. Nicotine that reaches a smoker’s
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 [113,114]. 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. Because tobacco is not burned, these devices are likely to be safer than continuing to smoke conventional
tobacco cigarettes, but their safety is uncertain because they are newer products.
Many e-cigarette products are available that vary in amount of nicotine delivery. The role of e-cigarettes and of heat-not-
12 de 22 18/08/2018 19:41
burn tobacco cigarettes in smoking cessation treatment is unclear; trials are ongoing. (See "E-cigarettes" and "Patterns of
tobacco use", section on 'Heat-not-burn tobacco cigarettes'.)
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
● We recommend that smokers be managed with a combination of behavioral support and pharmacologic therapy (Grade
1B). The combination of counseling and pharmacologic treatment can produce higher quit rates than either one alone.
Referral of smokers to free telephone quitlines (eg, 800-QUIT-NOW in the United States) or to free web-based and text
messaging cessation support (eg, at www.smokefree.gov) are good options for counseling, especially if office-based
behavioral support is not available. (See "Overview of smoking cessation management in adults", section on 'Treatments'
and "Behavioral approaches to smoking cessation".)
● First-line pharmacologic therapies for smoking cessation include nicotine replacement therapy (NRT), varenicline, and
bupropion (table 1). After consideration of specific safety concerns, contraindications (eg, bupropion is contraindicated in
patients who have seizures), and comorbidities, the choice of agent is based largely on patient preference after discussion
with a clinician. For most patients, we suggest either varenicline or a combination of two NRT products (a patch plus a
short-acting form such as the gum or lozenge) (Grade 2B). Bupropion or single NRT products are reasonable alternatives
based on cost, patient preferences, comorbid diseases, and side effect profiles. (See 'First-line agents' above and 'General
population' above.)
● Specific considerations that further impact the choice of pharmacotherapy include psychiatric illness, cardiovascular
disease (CVD), seizure disorder, pregnancy, hospitalization, and level of commitment to smoking cessation. (See 'Special
considerations' above.)
● Medication adjustments for patients who continue to smoke despite pharmacotherapy may be addressed as follows (see
'Persistent smoking' above):
• Before changing medications, patients who are unable to quit smoking on a drug should be interviewed to determine if
the drug was being used correctly and given precise education about usage if the drug was used incorrectly.
• 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.
• For patients using first-line medications (including short-acting NRT) correctly and maximally without sufficient effect at
four weeks, options include combining medications by adding another first- or second-line agent, switching to a
different first-line therapy, or switching to nortriptyline, a second-line therapy. Patients with no response to the initial
agent are typically switched to a different medication. However, if the smoker had a partial response to the initial
medication, adding an additional medication is a rational choice. Options for combination therapy include nicotine
patch plus varenicline, bupropion plus varenicline, bupropion plus NRT, and nortriptyline plus NRT. Combinations of
drugs appear to be more effective than monotherapy but can also produce more side effects. However, patients with
no response to the initial agent are typically switched to a different medication.
● For patients who successfully quit and then relapse, we suggest that treatment with the pharmacologic agent that
13 de 22 18/08/2018 19:41
previously worked for them (Grade 2C). This strategy may be enhanced with more intensive behavioral support or by
adding an additional first- or second-line smoking cessation medication. (See 'Relapse' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Dr. Stephen Rennard, MD, and Mr. David
Daughton, MS, who contributed to an earlier version of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
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hospitalized adults: a randomized clinical trial. JAMA 2014; 312:719.
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complications: a randomised clinical trial. Lancet 2002; 359:114.
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randomized, placebo-controlled trial. Anesthesiology 2012; 117:755.
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randomized clinical trial. JAMA 2015; 313:687.
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smoking: systematic review and meta-analysis. BMJ 2009; 338:b1024.
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randomized trial. Ann Intern Med 2009; 150:447.
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varenicline alone for smoking cessation: a randomized clinical trial. JAMA 2014; 312:155.
60. Ebbert JO, Hatsukami DK, Croghan IT, et al. Combination varenicline and bupropion SR for tobacco-dependence
treatment in cigarette smokers: a randomized trial. JAMA 2014; 311:155.
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controlled trial. JAMA 2006; 296:64.
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65. Cahill K, Stevens S, Lancaster T. Pharmacological treatments for smoking cessation. JAMA 2014; 311:193.
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cessation: differences between men and women. J Consult Clin Psychol 2004; 72:712.
67. Perkins KA, Donny E, Caggiula AR. Sex differences in nicotine effects and self-administration: review of human and
animal evidence. Nicotine Tob Res 1999; 1:301.
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69. Hartmann-Boyce J, Aveyard P. Drugs for smoking cessation. BMJ 2016; 352:i571.
70. Daughton DM, Heatley SA, Prendergast JJ, et al. Effect of transdermal nicotine delivery as an adjunct to low-intervention
smoking cessation therapy. A randomized, placebo-controlled, double-blind study. Arch Intern Med 1991; 151:749.
71. Fant RV, Henningfield JE, Shiffman S, et al. A pharmacokinetic crossover study to compare the absorption characteristics
of three transdermal nicotine patches. Pharmacol Biochem Behav 2000; 67:479.
72. Schnoll RA, Patterson F, Wileyto EP, et al. Effectiveness of extended-duration transdermal nicotine therapy: a randomized
trial. Ann Intern Med 2010; 152:144.
73. Schnoll RA, Goelz PM, Veluz-Wilkins A, et al. Long-term nicotine replacement therapy: a randomized clinical trial. JAMA
Intern Med 2015; 175:504.
74. Hughes JR, Goldstein MG, Hurt RD, Shiffman S. Recent advances in the pharmacotherapy of smoking. JAMA 1999;
281:72.
75. Nicotrol NS® Product Information. In: Physician's Desk Reference 1998, Medical Economics, Montvale, NJ 1998.
76. www.medicines.org.uk/emc/medicine/24257 (Accessed on September 03, 2013).
77. Tønnesen P, Lauri H, Perfekt R, et al. Efficacy of a nicotine mouth spray in smoking cessation: a randomised, double-blind
trial. Eur Respir J 2012; 40:548.
78. Glover ED, Glover PN, Franzon M, et al. A comparison of a nicotine sublingual tablet and placebo for smoking cessation.
Nicotine Tob Res 2002; 4:441.
79. http://www.quit.org.au/downloads/Background%20Briefs/25SublingTab.pdf (Accessed on October 04, 2013).
80. Hays JT, Ebbert JO. Varenicline for tobacco dependence. N Engl J Med 2008; 359:2018.
81. Coe JW, Brooks PR, Vetelino MG, et al. Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking
cessation. J Med Chem 2005; 48:3474.
82. Henningfield JE, Fant RV, Buchhalter AR, Stitzer ML. Pharmacotherapy for nicotine dependence. CA Cancer J Clin 2005;
55:281.
83. Tashkin DP, Rennard S, Hays JT, et al. Effects of varenicline on smoking cessation in patients with mild to moderate
COPD: a randomized controlled trial. Chest 2011; 139:591.
84. https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm169988.htm (Acces
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systematic review and meta-analysis. CMAJ 2011; 183:1359.
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5, 2012).
91. Svanström H, Pasternak B, Hviid A. Use of varenicline for smoking cessation and risk of serious cardiovascular events:
nationwide cohort study. BMJ 2012; 345:e7176.
92. Kotz D, Viechtbauer W, Simpson C, et al. Cardiovascular and neuropsychiatric risks of varenicline: a retrospective cohort
study. Lancet Respir Med 2015; 3:761.
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Smoking Cessation. Am J Respir Crit Care Med 2018; 197:913.
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95. Molero Y, Lichtenstein P, Zetterqvist J, et al. Varenicline and risk of psychiatric conditions, suicidal behaviour, criminal
offending, and transport accidents and offences: population based cohort study. BMJ 2015; 350:h2388.
96. Hajek P, McRobbie HJ, Myers KE, et al. Use of varenicline for 4 weeks before quitting smoking: decrease in ad lib smoking
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Engl J Med 1997; 337:1195.
100. Ahluwalia JS, Harris KJ, Catley D, et al. Sustained-release bupropion for smoking cessation in African Americans: a
randomized controlled trial. JAMA 2002; 288:468.
101. Swan GE, McAfee T, Curry SJ, et al. Effectiveness of bupropion sustained release for smoking cessation in a health care
setting: a randomized trial. Arch Intern Med 2003; 163:2337.
102. Hays JT, Hurt RD, Rigotti NA, et al. Sustained-release bupropion for pharmacologic relapse prevention after smoking
cessation. a randomized, controlled trial. Ann Intern Med 2001; 135:423.
103. Karnieg T, Wang X. Cytisine for smoking cessation. CMAJ 2018; 190:E596.
104. Rigotti NA. Cytisine--a tobacco treatment hiding in plain sight. N Engl J Med 2014; 371:2429.
105. Zatoński W, Zatoński M. Cytisine versus nicotine for smoking cessation. N Engl J Med 2015; 372:1072.
106. Hajek P, McRobbie H, Myers K. Efficacy of cytisine in helping smokers quit: systematic review and meta-analysis. Thorax
2013; 68:1037.
107. Walker N, Howe C, Glover M, et al. Cytisine versus nicotine for smoking cessation. N Engl J Med 2014; 371:2353.
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109. Prochazka AV, Petty TL, Nett L, et al. Transdermal clonidine reduced some withdrawal symptoms but did not increase
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114. LeSage MG, Keyler DE, Hieda Y, et al. Effects of a nicotine conjugate vaccine on the acquisition and maintenance of
nicotine self-administration in rats. Psychopharmacology (Berl) 2006; 184:409.
Topic 16635 Version 57.0
18 de 22 18/08/2018 19:41
GRAPHICS
First-line medications used to treat tobacco dependence in adults
Common Disadvantages
Other
Drug OTC?(US) Dosing Administration † adverse Advantages and
notes
effects precautions
Nicotine Yes 21 mg for Apply one new patch Skin irritation, Provides steady User cannot alter If removed
patch >10 daily insomnia, vivid nicotine level nicotine level in before
cigarettes/day May start patch dreams Easiest nicotine case of craving bedtime,
14 mg for before quit date product to use takes 0.5
≤10 to three
Rotate application
cigarettes/day hours after
site
reapplication
7 mg used
to reach
when tapering
effective
levels
Nicotine Yes 2 mg for <25 One piece every hour Mouth irritation, User controls Unpleasant taste Proper
gum cigarettes/day Maximum: ≤24 jaw soreness, nicotine dose Can damage dental chewing
4 mg for ≥25 pieces/day heartburn, Oral substitute work technique
cigarettes/day hiccups, or for cigarettes required
No food or drink for Difficult for denture
nausea (chew and
30 minutes before wearers to use
(gastrointestinal park)
and during use
side effects
usually due to
overly vigorous
chewing)
Nicotine Yes 2 mg if first One piece every one Mouth irritation, User controls Unpleasant taste
lozenge cigarette ≥30 to two hours hiccups, nicotine dose
min after Maximum: heartburn, or Oral substitute
waking nausea for cigarettes
Five lozenges/six
4 mg if first hours Can be used by
cigarette <30 smokers with
20 lozenges/day
min after poor dentition
waking No food or drink for
or dentures
30 minutes before
and during use
Nicotine No 10 mg per Inhale as needed (eg, Mouth and User controls Device visible when Frequent
inhaler cartridge every one to two throat irritation nicotine dose being used puffing
hours) Oral substitute Use caution in required
Maximum: 16 for cigarettes reactive airway
cartridges/day disease
Nicotine No 0.5 mg per Apply one spray to Nasal and User controls Local irritation to
nasal spray each nostril every one throat irritation, nicotine dose nasal mucosa is
spray (10 mg/mL) to two hours rhinitis, Most rapid difficult for many to
Maximum: sneezing, delivery of tolerate
cough, or teary nicotine among
10 sprays/hour
eyes nicotine-
80 sprays/day
replacement
products
Varenicline No 0.5 mg pill 0.5 mg/day for three Nausea, Dual action: Reduced dose in
days, then 0.5 mg insomnia, relieves severe renal
twice a day for four abnormal nicotine insufficiency
days, then 1 mg dreams, withdrawal and Avoid in patients
twice a day headache, skin blocks reward with unstable
Start one to rash (≤3%) from smoking psychiatric status
two weeks before quit Oral agent (pill) or history of
date suicidal ideation
May be started up to Monitor for
four weeks prior to neuropsychiatric
quit date symptoms*
19 de 22 18/08/2018 19:41
Bupropion No 150 mg pill 150 mg/day for three Insomnia, Blunts Monitor for A lower
sustained days, then 150 mg agitation, dry postcessation neuropsychiatric dose of 150
release twice a day mouth, weight gain symptoms* mg per day
Start one to headache while being Contraindicated in is an option
two weeks before quit used patients with for patients
date Oral agent (pill) seizure disorder or who do not
predisposition tolerate the
full dose
OTC: over-the-counter (nonprescription) sale; US: United States.

* Neuropsychiatric symptoms include: behavioral changes, hostility, agitation, depressed mood, suicidal ideation and attempts.
† All pharmacologic agents may be continued for three to six months.
1. Rigotti NA. Strategies to help a smoker who is struggling to quit. JAMA 2012; 308:1573.
2. Shahab L, Brose LS, West R. Novel delivery systems for nicotine replacement therapy as an aid to smoking cessation and for harm
reduction: rationale, and evidence for advantages over existing systems. CNS Drugs 2013; 27:10079
Graphic 97259 Version 3.0
20 de 22 18/08/2018 19:41
Effectiveness of methods used to treat tobacco dependence
Nonpharmacologic methods Pharmacologic methods
Versus minimal or usual care Versus placebo unless

Method Method
unless otherwise noted otherwise noted
(number of trials) (number of trials)
Risk ratio (95% CI) Risk ratio (95% CI)
Behavioral counseling First-line pharmacotherapies *
Individual counseling [1] (22) 1.39 (1.24-1.57) Nicotine replacement [5]
Group counseling [2] (13) 1.98 (1.60-2.46) Combination [versus 1.34 (1.18-1.51)
individual products] [6]
Telephone quit line 1.37 (1.26-1.50)
(9)
counseling [3] (9)
Patch (43) 1.64 (1.52-1.78)
Physician counseling [4]
Gum (56) 1.49 (1.40-1.60)
Brief advice (17) 1.66 (1.42-1.94)
Lozenge (7) 1.95 (1.61-2.36)
Brief counseling (11) 1.86 (1.60-2.15)
Inhaler (4) 1.90 (1.36-2.67)
Brief counseling [versus brief 1.37 (1.20-1.56)
advice] (15) Nasal spray (4) 2.02 (1.49-2.73)
Varenicline [6] (14) 2.27 (2.02-2.55)
Bupropion SR [6] (36) 1.69 (1.53-1.85)
SR: sustained release.

* First-line drugs as recommended by the 2008 US Public Health Service guideline.
References:
1. Lancaster T, Stead LF. Individual behavioural counselling for smoking cessation. Cochrane Database Syst Rev 2005; 2:CD001292.
2. Stead LF, Lancaster T. Group behaviour therapy programmes for smoking cessation. Cochrane Database Syst Rev 2005; 2:CD001007.
3. Stead LF, Hartmann-Boyce J, Perera R, Lancaster T. Telephone counselling for smoking cessation. Cochrane Database Syst Rev 2013;
8:CD002850.
4. Stead LF, Buitrago D, Preciado N, et al. Physician advice for smoking cessation. Cochrane Database Syst Rev 2013; 5:CD000165.
5. Stead LF, Perera R, Bullen C, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 2012;
11:CD000146.
6. Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-
analysis. Cochrane Database Syst Rev 2013; 5:CD009329.
Graphic 97255 Version 3.0
21 de 22 18/08/2018 19:41
Contributor Disclosures
Nancy A Rigotti, MD Grant/Research/Clinical Trial Support: Pfizer [Smoking cessation (Varenicline)]. Consultant/Advisory
Boards: Achieve Life Sciences [Smoking cessation (Cytisine)]. James K Stoller, MD, MS Grant/Research/Clinical Trial
Support: CSL Behring [Alpha-1 antitrypsin detection (Pooled human alpha-1 antiprotease)]. Consultant/Advisory Boards: CSL
Behring; Grifols; Shire [Alpha-1 antitrypsin detection (Pooled human alpha-1 antiprotease)]; Arrowhead Pharmaceuticals
[Alpha-1 antitrypsin deficiency]; Vertex; Inhibrx; 23andMe [Alpha-1 antitrypsin deficiency]; Alpha-1 Foundation [Member, Board
of Directors (Alpha-1 antitrypsin deficiency)]; American Respiratory Care Foundation [Member, Board of Directors (Respiratory
therapy issues)]. Mark D Aronson, MD Nothing to disclose Judith A Melin, MA, MD, FACP Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting
through a multi-level review process, and through requirements for references to be provided to support the content.
Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy
22 de 22 18/08/2018 19:41

Pharmacotherapy For Smoking Cessation in Adults - UpToDate PDF

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Official reprint from UpToDate®

Author: Nancy A Rigotti, MD

INDICATIONS — All smokers should be advised to quit smoking.

INITIAL THERAPY SELECTION

Dosing, duration, and instructions for use:

Dosing, duration and instructions for use:

● Dosing is determined by the number of cigarettes smoked daily.

• ≥ 25 cigarettes per day – 4 mg dose of gum is recommended [55]

• < 25 cigarettes per day – 2 mg dose of gum is recommended [55]

● Use up to 24 pieces of gum per day for six weeks.

rapidly than the original lozenge.

Dosing, duration and instructions for use:

• Smokers who smoke within 30 minutes of awakening: 4 mg dose recommended

Dosing, duration and instructions for use:

● Use 6 to 16 cartridges per day for the first 6 to 12 weeks

● Gradually reduce dose over the next 6 to 12 weeks

Dosing, duration, and instructions for use:

● Dose is one or two sprays per hour

● Use for about three months

Dosing and instructions for use:

● 1 mg nicotine is delivered per spray

Dosing and instructions for use:

Dosing, duration, and instructions for use:

Adjusting dosing and duration:

Dosing, duration and instructions for use:

● We recommend treating for at least 12 weeks.

Adjusting dosing and duration:

Therapies with limited or unproven benefit

SUMMARY AND RECOMMENDATIONS

Use of UpToDate is subject to the Subscription and License Agreement.

97. www.pfizer.com/files/products/uspi_chantix.pdf (Accessed on October 17, 2011).

Topic 16635 Version 57.0

First-line medications used to treat tobacco dependence in adults

OTC: over-the-counter (nonprescription) sale; US: United States.

Graphic 97259 Version 3.0

Effectiveness of methods used to treat tobacco dependence

Nonpharmacologic methods Pharmacologic methods

Versus minimal or usual care Versus placebo unless

Behavioral counseling First-line pharmacotherapies *

Individual counseling [1] (22) 1.39 (1.24-1.57) Nicotine replacement [5]

Varenicline [6] (14) 2.27 (2.02-2.55)

Bupropion SR [6] (36) 1.69 (1.53-1.85)

SR: sustained release.

Graphic 97255 Version 3.0

Conflict of interest policy

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