The manufacturers’ recommended dosages are listed in Table 91-4. In general, higher
levels of smoking necessitate the use of higher-strength formulations and a longer
duration of therapy. Ultimately, the starting dose, rate of tapering, and total duration
of therapy must be individualized to the patient’s baseline smoking levels,
development of side effects (e.g., nausea, dyspepsia, nervousness, dizziness,
sweating), and the presence or absence of withdrawal symptoms. T.B. currently
smokes 30 cigarettes/day, and thus she should initiate the regimen using the 21-
T.B. should be instructed to apply the patch to a clean, dry, hairless area of skin on
the upper body or the upper outer part of her arm at approximately the same time each
day. To minimize the potential for local skin reactions, the patch application site
should be rotated daily, and the same area should not be used again for at least 1
week. After patch application, T.B. should ensure that the patch adheres well to the
skin, especially around the edges. The clinician should reassure T.B. that water will
not reduce the effectiveness of the nicotine patch if it is applied correctly, and she
may bathe, shower, swim, or exercise while wearing the patch. Finally, T.B. should
be advised to discontinue use of the nicotine patch and contact a healthcare provider
if skin redness caused by the patch does not resolve after 4 days; if the skin swells or
a rash develops; if irregular heartbeat or palpitations occur; or if she experiences
symptoms of nicotine overdose such as nausea, vomiting, dizziness, diarrhea,
sweating, weakness, or rapid heartbeat.
of pink discoloration. Her last cigarette was 2 days ago. How should T.B. be managed at this time?
The most common side effects associated with the nicotine patch are local
reactions (erythema, burning, and pruritus) at the skin application site. These
reactions are generally caused by skin occlusion or sensitivity to the patch adhesives.
Rotating the patch application sites on a daily basis minimizes skin irritation;
nonetheless, skin reactions to the patch adhesives occur in up to 50% of patch users.
Fewer than 5% of patients discontinue therapy because of a skin reaction.
T.B. appears to be experiencing a mild skin reaction and should be reassured that
it is common for the skin to appear erythematous for up to 24 to 48 hours after the
patch is removed. T.B. can apply topical hydrocortisone cream (0.5% or 1%) or
triamcinolone cream (0.5%), or she can take an oral antihistamine for symptomatic
7 Another option would be to try a different brand of patch as the adhesive
may vary. Because the rash on her left arm has nearly resolved, it is reasonable for
T.B. to continue using the nicotine transdermal patch provided that the erythema is
Other less common side effects associated with the transdermal nicotine patch
include vivid or abnormal dreams, insomnia, and headache. Sleep disturbances likely
result from nocturnal nicotine absorption. Patients experiencing troublesome sleep
disturbances should be instructed to remove the patch before bedtime and apply a
new patch as soon as possible after waking the following morning.
The clinician should also provide behavioral counseling support by asking T.B.
about the current quit attempt. Appropriate issues to address include her confidence
in remaining tobacco free, situations in which she has been tempted to smoke and
potential triggers for relapse, nicotine withdrawal symptoms, her social support
system for quitting, and any other questions or concerns she might have. It is
reasonable to review potential coping strategies (behavioral and cognitive; Table
91-4) and schedule a future follow-up call. The clinician should commend T.B. for
her decision to quit, congratulate her for remaining free of cigarettes for 48 hours,
and reassure her that skin irritation is a common, yet generally manageable,
complication with the nicotine patch.
PRODUCT SELECTION CONSIDERATIONS
The primary advantage of the transdermal nicotine patch compared with other NRT
formulations is that the patch is easy to use, releases a continuous dose of nicotine
throughout the day, and requires administration only once daily. Disadvantages of the
patch include a high incidence of skin irritation associated with the patch adhesives
and the inability to acutely adjust the dose of nicotine to alleviate symptoms of
withdrawal. Finally, patients with underlying dermatologic conditions (e.g.,
psoriasis, eczema, atopic dermatitis) should not use the patch because they are more
likely to experience skin irritation.
effective alternative. What options would you recommend? What factors should be considered?
Nicotine polacrilex gum is a resin complex of nicotine and polacrilin in a chewing
gum base that provides slow release and absorption of nicotine across the oral
mucosa. The product is available in 2- and 4-mg strengths, and in multiple flavors.
The gum has a distinct, tobacco-like, slightly peppery, minty, or fruity taste and
contains buffering agents to increase the salivary pH, which enhances the buccal
absorption of nicotine. The amount of nicotine absorbed from each piece is variable,
but when used properly, approximately 1.6 and 2.2 mg of nicotine is absorbed from
each 2- and 4-mg piece of gum, respectively.
14 Peak plasma concentrations of
nicotine are achieved approximately 30 minutes after chewing a single piece of gum
and then slowly decline thereafter (Fig. 91-3). Patients using nicotine gum are
significantly more likely to remain abstinent compared with those receiving
Table 91-4 outlines the manufacturers’ recommended dosing schedule for the
nicotine gum. The recommended dosage of the nicotine gum is based on the “time to
first cigarette” (TTFC) of the day. Having a strong desire or need to smoke soon after
waking is viewed as a key indicator of nicotine dependence.
who smoke their first cigarette of the day within 30 minutes of waking are likely to be
more highly dependent on nicotine and require higher dosages than those who delay
smoking for more than 30 minutes after waking (Table 91-4). The “chew and park”
method (Table 91-4) allows for the slow, consistent release of nicotine. Patients can
use additional pieces of gum (to the daily maximum of 24 pieces/day) if cravings
occur between scheduled doses. In general, patients who smoke a greater number of
cigarettes/day will require more nicotine gum to alleviate their cravings than will
patients who smoke fewer cigarettes/day. It is preferable to use the gum on a fixed
schedule of administration, tapering during 1 to 3 months rather than using it only as
Proper chewing technique is crucial when using the nicotine gum, using the “chew
and park” method (Table 91-4). The chew and park steps should be repeated until
most of the nicotine is extracted; this generally occurs after 30 minutes and becomes
obvious when chewing no longer elicits the characteristic taste or tingling sensation.
Patients should be warned that the absorption and therefore the effectiveness of
nicotine gum might be reduced by acidic beverages (e.g., coffee, juices, wine, soft
49 which transiently reduce the salivary pH. To prevent this interaction,
patients should be advised not to eat or drink (except water) for 15 minutes before or
Most of the common side effects (Table 91-4) can be minimized or prevented by
using proper chewing technique.
7 Patients should be warned that chewing the gum too
rapidly may result in excessive release of nicotine, leading to lightheadedness,
nausea, vomiting, irritation of the throat and mouth, hiccups, and indigestion.
PRODUCT SELECTION CONSIDERATIONS
Advantages of nicotine gum include the fact that this formulation may be used to
satisfy oral cravings and the 4-mg strength might delay weight gain.
reasons, the gum may be particularly beneficial for patients who have weight-gain
concerns or for patients who report boredom as a trigger for smoking. The gum might
also be advantageous for patients who desire flexibility in dosing and prefer the
ability to self-regulate nicotine levels to manage withdrawal symptoms. Some
patients may find that the viscous consistency of the gum makes it difficult to use
because it sticks to dental work. Others may find it difficult or socially unacceptable
to chew the gum so frequently. Nicotine gum should not be used by patients with
temporomandibular joint (TMJ) conditions.
The nicotine polacrilex lozenge is a resin complex of nicotine and polacrilin in a
sugar-free, flavored lozenge. The product is available in 2- and 4-mg strengths,
which are meant to be consumed like hard candy or other medicinal lozenges (e.g.,
delivers approximately 25% more nicotine than does an equivalent dose of nicotine
35 Like the nicotine gum, the lozenge also contains buffering agents (sodium
carbonate and potassium bicarbonate) to increase salivary pH, thereby enhancing
buccal absorption of the nicotine. Peak nicotine concentrations of nicotine with the
lozenge are achieved after 30 to 60 minutes of use and then slowly decline thereafter
(Fig. 91-3).The nicotine lozenge approximately doubles 6-month abstinence rates
Table 91-4 outlines the manufacturers’ recommended dosing schedule for the
nicotine lozenge. Like the nicotine gum, the lozenge is dosed based on the TTFC.
Patients are more likely to succeed if they use the lozenge on a fixed schedule rather
than as needed. Patients can use additional lozenges (up to 5 lozenges in 6 hours or a
maximum of 20 lozenges/day) if cravings occur between scheduled doses.
Similar to the gum, the nicotine lozenge is a specially formulated nicotine delivery
system that must be used properly for optimal results. The lozenge should be allowed
to dissolve slowly in the mouth; when nicotine is released, a warm, tingling sensation
may be experienced. The patient should occasionally rotate the lozenge to different
areas of the mouth to reduce the potential for mucosal irritation. When used correctly,
the lozenge should completely dissolve within 30 minutes. Patients should be
counseled not to chew or swallow the lozenge because this increases the incidence of
gastrointestinal-related side effects.
As with the gum, patients should be cautioned that the effectiveness of the nicotine
lozenge may be reduced by acidic beverages such as coffee, juices, wine, or soft
49 Patients should be advised not to eat or drink (except water) for 15 minutes
before or while using the nicotine lozenge.
In general, the nicotine lozenge is well tolerated. The most common side effects
include nausea, hiccups, cough, dyspepsia, headache, and flatulence. Patients who
use more than one lozenge at a time, continuously use one lozenge after another, or
chew or swallow the lozenge are more likely to experience dyspepsia or hiccups.
PRODUCT SELECTION CONSIDERATIONS
The nicotine lozenge is similar to the nicotine gum formulation in that it may be used
to satisfy oral cravings, the 4-mg strength might delay weight gain,
self-titrate therapy to acutely manage withdrawal symptoms. Because the lozenge
does not require chewing, many patients find this to be a more discreet nicotine
delivery system. The disadvantages of the lozenge are the fact that it requires frequent
dosing, and the gastrointestinal side effects (nausea, hiccups, and heartburn) may be
T.B. has expressed interest in either the nicotine gum or lozenge formulation for
her quit attempt. Both agents are effective, and the choice of therapy is dependent on
the patient’s perceptions and expectations regarding treatment, including the ability to
comply with the regimen, previous experience with cessation medications, and other
concerns (e.g., adverse effects, weight gain, cost of medications). T.B. would be a
candidate for either agent provided she is able to comply with the frequent dosing
schedule (one lozenge or piece of gum every 1–2 hours while she is awake). T.B.
smokes her first cigarette of the day immediately after waking in the morning and she
smokes approximately 30 cigarettes/day; this smoking pattern suggests a higher
degree of nicotine dependence, and therefore T.B. would benefit from a higher dose
of NRT. T.B. should initiate treatment with the 4-mg strength of either the nicotine
lozenge or nicotine gum dosed every 1 to 2 hours while she is awake and tapered
according to the schedule outlined in Table 91-4.
gain common after quitting, and if so, how can this be prevented?
Most tobacco users gain weight after quitting, and clinicians should neither deny
the likelihood of weight gain nor minimize its significance.
the health risks associated with postcessation weight gain are negligible compared
with the risks of continued smoking.
Most quitters gain fewer than 10 lb, but there is a broad range of weight gain
reported, with up to 10% of quitters gaining as much as 30 lb.
tend to gain more weight than men. In a study of nearly 6,000 smokers who were
followed for 5 years after quitting, the average weight gain during the follow-up
period was 19.2 and 16.7 lb among women and men, respectively.
The weight-suppressing effects of tobacco are well known. However, the
mechanisms to explain why most successful quitters gain weight are not completely
understood. Smokers have been found to have an approximately 10% higher
metabolic rate compared with nonsmokers.
Increased postcessation caloric intake
might result from an increase in appetite, improved sense of taste, or a change in the
hand-to-mouth ritual through the substitution of tobacco with food.
In general, a patient is less likely to be successful if he or she attempts to change
multiple behaviors at once. For most patients, strict dieting to prevent weight gain,
especially during the early stages of quitting, is generally not recommended.
should be counseled that the average weight gain of fewer than 10 lb is less
detrimental to her overall health than is continued smoking. Although exercise
interventions have not been shown to reduce weight gain among quitters,
not be ruled out as a recommendation for T.B. because she expresses significant
concern about weight gain, and this might be a barrier to her quitting. Modest
increases in activity can help with weight gain and exercise can serve as a
behavioral substitution for tobacco use. Furthermore, T.B. should be advised to plan
her meals in advance to avoid binge eating, increase her water intake to create a
feeling of fullness, chew sugarless gum, and limit alcohol consumption. T.B. may
consider pharmacotherapy options that have been shown to delay weight gain
including NRT, varenicline, or sustained-release bupropion.
note, however, that none of the medications have been shown to prevent weight gain
for more than a month. How should the clinician respond?
The clinician should thank T.B. for being honest about her smoking and ask
whether she is comfortable discussing the circumstances during which the smoking
occurred. At the time of her smoking, where was she, who was she with, how did she
get access to cigarettes, and how was she feeling at the time? What, specifically,
were the triggers for her relapse (e.g., alcohol, depression, friends who were
smoking around her)? It is important that the clinician help the patient to use this
information as part of the learning process, but it also is important to focus on the
“positive,” such as T.B.’s ability to have remained tobacco free for more than 1
month. Four weeks after quitting, most physical effects of nicotine withdrawal have
completely resolved, and thus, the relapse trigger for T.B. likely was psychological
or situational and could be abated through application of effective coping techniques.
After an informative discussion about the situation in which the smoking occurred, it
is important that the clinician works with the patient in identifying strategies for
avoiding relapse in the future (Table 91-3).
Smoking and Cardiovascular Disease
QUESTION 1: P.J. is a 62-year-old man admitted for an elective coronary artery bypass graft (CABG)
medical conditions may be caused or exacerbated by his tobacco use?
A wealth of evidence suggests that cigarette smoking is a major cause of
cardiovascular disease and is responsible for approximately 128,000 premature
cardiovascular-related deaths each year.
There are numerous plausible pathophysiologic mechanisms by which tobacco
smoking contributes to the development of cardiovascular disease.
and other compounds in tobacco smoke are believed to induce a hypercoagulable
state characterized by increased platelet aggregation and thrombosis, which
substantially increases the risk of myocardial infarction (MI) and sudden death.
The carbon monoxide in smoke reduces the amount of oxygen available to tissues and
organs, including myocardial tissue, and may reduce the ventricular fibrillation
53 Smoking may accelerate atherosclerosis through effects on serum lipids;
smokers tend to have higher levels of total cholesterol, LDL-C, and triglycerides and
3 Smoking increases the levels of inflammatory
mediators (C-reactive protein, leukocytes, and fibrinogen), which might contribute to
the development and progression of atherosclerosis.
55 Finally, smoking stimulates the
release of neurotransmitters (e.g., epinephrine, norepinephrine) that increase
myocardial workload and induce coronary vasoconstriction, leading to ischemia,
arrhythmias, and sudden death.
P.J.’s hospital admission for a CABG procedure for coronary heart disease and
angina, and previous procedures for peripheral vascular disease (angioplasty with
stent placement) and cerebrovascular disease (bilateral carotid endarterectomy) are
all conditions associated with chronic tobacco use. His elevated total cholesterol,
cardiovascular risk factors (hypertension, dyslipidemia) has synergistically
increased his risk for serious cardiovascular disease.
3,53 Fortunately, the effects of
smoking on lipids, coagulation, myocardial workload, and coronary blood flow
appear to be reversible, and P.J.’s risk of developing further cardiovascular-related
complications will markedly decrease if he is able to quit smoking.
Smoking cessation is associated with a 36% reduction in the risk of death among
patients with established coronary heart disease. The reduced mortality risk
associated with quitting smoking is comparable to that observed with other
established secondary preventative approaches such as therapies for hyperlipidemia
57 The clinician should approach this hospitalization as an
opportunity to assist P.J. with quitting smoking.
7 Furthermore, published data suggest
that initiation of intensive cessation counseling interventions for hospitalized patients
is effective in achieving long-term abstinence.
The adverse health effects of cigar smoking have been well described and include
an increased risk of cancer of the lung, oral cavity, larynx, esophagus, and pancreas.
In addition, cigar smokers who inhale deeply are at increased risk for developing
cardiovascular disease and chronic obstructive pulmonary disease (COPD).
Cigarette smokers who switch to smoking only cigars decrease their risk of
developing lung cancer, but their risk is markedly higher than if they were to quit
Cigar weight and nicotine content vary widely from brand to brand and from cigar
to cigar. Most cigars range in weight from about 1 to 22 g, and a typical cigarette
weighs less than 1 g. The nicotine content of 10 commercially available cigars
studied in 1996 ranged from 10 to 444 mg. In comparison, US cigarettes have a
relatively narrow total nicotine content range (mean, 13.5 ± 0.1 mg)/cigarette.
possible for one large cigar to contain as much tobacco as an entire pack of cigarettes
and deliver enough nicotine to establish and maintain dependence.
The amount of nicotine delivered by one to two cigars/day is capable of sustaining
his dependence on nicotine. Furthermore, former cigarette smokers are more likely to
inhale deeply, which further increases the risk of cancer and cardiovascular and
pulmonary disease. The clinician should strongly advise P.J. to quit smoking
cigarettes and that switching to cigars is not a safe alternative.
P.J. has inadequately responded to treatment with the transdermal patch and
experienced intolerable jaw soreness with the nicotine gum. Newer formulations of
the nicotine gum are less viscous, and therefore easier to chew, than earlier
formulations of the gum; however, other options are available. First-line treatment
options that he has not tried include the nicotine lozenge (see Case 91-1, Question 3),
nicotine nasal spray, nicotine inhaler, sustained-release bupropion, varenicline, or an
effective combination of first-line agents (see Case 91-3, Question 1).
50-μL spray containing 0.5 mg of nicotine. Nicotine in the nasal spray is more
rapidly absorbed than other NRT formulations (Fig. 91-3), with peak venous nicotine
concentrations achieved within 11 to 18 minutes after administration.
nicotine nasal spray more than doubles long-term abstinence rates when compared
Table 91-4 outlines the manufacturers’ recommended dosing schedule for the
nicotine nasal spray. A dose of nicotine (1 mg) is administered as two sprays, one
(0.5-mg spray) in each nostril. For best results, patients should be encouraged to use
at least eight doses/day during the initial 6 to 8 weeks of therapy because less
frequent administration may be less effective. The initial regimen may be increased,
as needed, to a maximum recommended dosage of five doses/hour or 40 mg/day.
After 6 to 8 weeks, the dose should be gradually decreased during an additional 4 to
Before using the nasal spray for the first time, the nicotine nasal spray pump must be
primed. This is done by actuating the device into a tissue until a fine spray is visible
(about 6–8 times). When administering a dose, the patient should tilt the head back
slightly and insert the tip of the bottle into the nostril as far as is comfortable. After
actuation of the pump, the patient should not sniff, swallow, or inhale through the
nose because this increases the irritant effects of the spray. The spray increases the
likelihood of tearing, coughing, and sneezing, so patients should wait 5 minutes
before driving or operating heavy machinery.
In clinical trials, 94% of patients report moderate–severe nasal irritation during the
first 2 days of therapy; 81% of patients still reported mild to moderate nasal irritation
after 3 weeks of therapy. Nasal congestion and transient changes in taste and smell
7 Despite the high incidence of local adverse effects (Table
91-4), most patients become tolerant to the irritant effects of the spray during the first
PRODUCT SELECTION CONSIDERATIONS
The primary advantage in using the nicotine nasal spray is the ability to rapidly titrate
therapy to manage withdrawal symptoms. However, because nicotine from the spray
more rapidly penetrates the central nervous system, there may be a higher likelihood
of developing dependence during treatment. The nicotine nasal spray has a
dependence potential intermediate between tobacco products and other NRT
products. Individuals with chronic nasal disorders (e.g., rhinitis, polyps, sinusitis) or
severe reactive airway disease should not use the nicotine nasal spray because of its
irritant effects. Exacerbation of asthma has been reported after use of the nicotine
The nicotine oral inhaler consists of a plastic mouthpiece and a disposable cartridge
containing a porous plug containing 10 mg of nicotine and 1 mg of menthol. Menthol
is added to reduce the irritant effect of nicotine.
Given that the usual pack-a-day smoker repeats the hand-to-mouth motion up to
200 times per, it is not surprising that many smokers
find they miss the physical manipulation of the cigarette and associated behaviors
that accompany smoking. The nicotine inhaler was designed to provide nicotine
replacement in a manner similar to smoking while addressing the sensory and
ritualistic factors that are important to many patients who smoke.
As a patient inhales through the mouthpiece, nicotine vapor is released from the
cartridge and is distributed throughout the oral cavity. When the inhaler is used
correctly, approximately 4 mg of nicotine vapor is released from the cartridge and 2
mg is absorbed across the buccal mucosa.
65 Peak plasma nicotine concentrations with
the inhaler are achieved after approximate 30 minutes of use
decline thereafter (Fig. 91-3). Use of the nicotine inhaler approximately doubles
long-term abstinence rates when compared with placebo (Table 91-4).
Table 91-4 outlines the manufacturers’ recommended dosing schedule for the
nicotine inhaler. During the initial 3 to 6 weeks of treatment, the patient should use 1
cartridge every 1 to 2 hours while awake. This should be increased, as needed, to a
maximum of 16 cartridges/day. The manufacturer recommends that each cartridge be
depleted of nicotine by frequent continuous puffing for 20 minutes. The recommended
duration of treatment is 3 months, after which patients may be weaned from the
inhaler by gradual reduction of the daily dose during the following 6 to 12 weeks.
To minimize the likelihood of throat irritation, patients should be instructed to inhale
shallowly (as if puffing a pipe). When used correctly, 100 shallow puffs from the
inhaler mouthpiece during 20 minutes approximate 10 puffs from one cigarette during
36 The release of nicotine from the inhaler is temperature dependent and
significantly reduced at temperatures less than 40°F.
should store the inhaler and cartridges in a warm place (e.g., inside pocket).
Conversely, under warmer conditions, more nicotine is released/puff. However,
nicotine plasma concentrations achieved using the inhaler in hot climates at maximal
doses will not exceed levels normally achieved with smoking.
As with all forms of NRT that are absorbed across the buccal mucosa, the
effectiveness of the nicotine inhaler is reduced by acidic foods and beverages, such
as coffee, juices, wine, or soft drinks. Therefore, patients should be instructed not to
eat or drink anything (except water) for 15 minutes before or while using the inhaler.
The most common side effects associated with the nicotine inhaler include mouth or
throat irritation (40%) and cough (32%).
7 Most patients rated cough and mouth and
throat irritation symptoms as mild, decreasing with continued use. Other less common
side effects are rhinitis, dyspepsia, hiccups, and headache. Adverse reactions
necessitating discontinuation of treatment occurred in less than 5% of patients using
PRODUCT SELECTION CONSIDERATIONS
Patients who express a preference for therapy that can be easily titrated to manage
withdrawal symptoms or one that mimics the hand-to-mouth ritual of smoking may
find the nicotine inhaler to be an appealing option. Patients with underlying
bronchospastic conditions should use the nicotine inhaler with caution, because the
nicotine vapor can be irritating and might induce bronchospasm.
Sustained-release bupropion increases long-term abstinence rates relative to
placebo. (RR 1.62; Table 91-4).
Because approximately 1 week of treatment is necessary to achieve steady state
blood levels, sustained-release bupropion should be initiated while the patient is still
smoking (Table 91-4). Patients should set a target quit date that falls within the first 2
dose is tolerated, the dosage should be increased on the fourth day to the
recommended maximal dosage of 300 mg/day (150 mg BID). Therapy should be
continued for 7 to 12 weeks after the quit date.
Patients experiencing insomnia should avoid taking the second dose close to bedtime.
Patients should be informed that bupropion might cause dizziness or drowsiness, and
should exercise caution when driving or operating machinery. Patients should avoid
or drink alcohol only in moderation while taking bupropion as alcohol use can
increase the risk of seizures. Abrupt cessation of alcohol use while taking bupropion
might increase the risk of seizure. Patients should also be advised not to take Zyban
The most common adverse effects associated with bupropion therapy include
insomnia (35%–40%) and dry mouth (10%)
; these usually lessen with continued use.
Taking the second daily dose in the early evening, but no sooner than 8 hours after the
first dose, might reduce insomnia. Less common side effects include headache,
nausea, tremors, and rash. Seizures are a dose-related toxicity associated with
bupropion therapy. For this reason, bupropion is contraindicated in patients with
underlying seizure disorders and those receiving concurrent therapy with other forms
of bupropion (Wellbutrin, Wellbutrin SR, and Wellbutrin XL). Bupropion also is
contraindicated in patients with anorexia or bulimia nervosa, patients undergoing
abrupt discontinuation of alcohol or sedatives (including benzodiazepines), and
patients currently taking monoamine oxidase inhibitors owing to the increased
potential for seizures in these populations.
In clinical trials for smoking cessation,
seizure frequency with sustained-release bupropion was less than 0.1% (seven
seizures among 8,000 bupropion-treated patients), which is comparable to the
reported incidence of seizures (0.1%) with the sustained-release formulation when
used for the treatment of depression.
68 For this reason, bupropion should be used with
extreme caution in patients with a history of seizures or cranial trauma, in individuals
taking medications that may lower the seizure threshold, and in patients with
underlying severe hepatic cirrhosis. The manufacturer recommends that patients
space the doses at least 8 hours apart and limit the total daily dose to no more than
300 mg. Although a boxed warning has been removed, clinicians should monitor
patients for serious psychiatric symptoms while taking bupropion.
PRODUCT SELECTION CONSIDERATIONS
Sustained-release bupropion may be the drug of choice for patients who prefer to
take oral medications (an alternative oral option is varenicline, described below).
Because sustained-release bupropion tablets require twice daily administration, this
agent may be preferable for patients with adherence concerns (e.g.,
those unable to consistently use short-acting NRT formulations that require multiple
daily doses). Sustained-release bupropion might be beneficial for use in patients with
coexisting depression or in individuals with a history of depressive symptoms during
a previous quit attempt. Finally, sustained-release bupropion has been found to
reduce postcessation weight gain during treatment,
7,52 and this might be of short-term
benefit in selected patients with concerns about weight gain after quitting.
Disadvantages of sustained-release bupropion include a high prevalence of insomnia
and several contraindications and precautions mentioned above.
Data from meta-analyses indicate that varenicline significantly increases long-term
abstinence rates relative to placebo,
46 and sustained-release bupropion.
The pooled risk ratio for long-term abstinence (≥6 months) for varenicline compared
with placebo was 2.24 (95% CI, 2.06-2.43). The pooled risk ratio for varenicline
versus sustained-release bupropion at 1-year follow-up was 1.39 (95% CI, 1.25 -
1.54). At 24 weeks, the pooled risk ratio for varenicline compared to NRT was 1.25
46 Lower doses and longer durations of varenicline have been
shown to be safe and effective in clinical trials.
Varenicline absorption is virtually complete after oral administration, and oral
bioavailability is unaffected by food. Once absorbed, varenicline undergoes minimal
metabolism, with 92% excreted unchanged in the urine. Renal elimination is
primarily through glomerular filtration, along with active tubular secretion.
half-life is approximately 24 hours, and following administration of multiple oral
doses, steady state conditions are reached within 4 days.
Treatment with varenicline (Table 91-4) should be initiated 1 week before the
patient stops smoking. This dosing regimen allows for gradual titration of the dose to
minimize treatment-related nausea and insomnia. The recommended dosage titration
for varenicline is as follows: 0.5 mg daily days 1 to 3, 0.5 mg twice daily days 4 to
7, and 1 mg twice daily weeks 2 to 12. For patients who have successfully quit
smoking at the end of 12 weeks, an additional course of 12 weeks may be considered
to increase the likelihood of long-term abstinence. An alternative approach is to set a
quit date 8 to 35 days after starting varenicline. Patients should be advised to
decrease their smoking over the first 12 weeks and then continue varenicline for 12
69 Varenicline should be used with caution in patients with
impaired renal function. For patients with severe renal dysfunction (estimated
creatinine clearance <30 mL/minute), the recommended maximal dose of varenicline
is 0.5 mg twice daily. In patients with end-stage renal disease undergoing
hemodialysis, a maximal dose of 0.5 mg daily is recommended.
The tablets are to be taken after eating and with 8 ounces of water. Nausea and
insomnia are side effects that are usually temporary. Patients should be advised to
discontinue varenicline and contact their healthcare provider immediately if they
experience agitation, hostility, depressed mood, or changes in behavior or thinking
that are not typical for them (see adverse reactions below).
Varenicline is generally well tolerated. Common side effects (≥5% and twice the
rate observed in placebo-treated patients) include nausea (30%), sleep disturbance
(insomnia 18%; abnormal dreams 13%), constipation (8%), flatulence (6%), and
vomiting (5%). Nausea is dose dependent and generally described as mild or
moderate and often transient; however, for some patients, it persists for several
months. Initial dose titration was beneficial in reducing the occurrence of nausea.
Approximately 3% of subjects receiving varenicline 1 mg BID discontinued
treatment prematurely because of nausea. For patients with intolerable nausea, dose
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