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12:92 Miscellaneous Autonomic Drugs
Nicotine
Introduction
C10H14N2
C10H14N2 x(C10H10C4H6O2)x
Nicotine, a naturally ocurring autonomic drug, is a ganglionic (nicotinic) cholinergic-receptor agonist.
Uses
Smoking Cessation
Buccal (chewing gum, lozenge) nicotine polacrilex or a transdermal system, intranasal spray, or oral
inhaler of nicotine1, 2, 3, 36, 48, 191, 244, 257, 258 is used for nicotine replacement therapy as a
temporary adjunct in the cessation of cigarette smoking either unsupervised188, 189, 190, 246, 257 or
in conjunction with a behavior modification program under medical or dental supervision.1, 2, 5, 6, 7, 8,
9, 10, 11, 29, 30, 31, 96, 97, 191, 192, 193, 194, 195, 196, 244, 245, 257, 258, 263 Although behavioral
modification enhances clinical success and has been considered an integral component of smoking
cessation therapy when any form of nicotine replacement therapy was used, and such modification
generally involved supervised programs of counseling, psychologic support, and education, including
detailed instructions on how to use the gum, lozenge, transdermal system, intranasal spray, or oral
inhaler correctly,1, 2, 7, 9, 43, 67, 68, 76, 77, 96, 97, 101, 102, 103, 104, 115, 116, 119, 126, 131, 144,
148, 149, 167, 192, 194, 195, 196, 244, 245, 257, 258, 263 there is evidence that nicotine replacement
therapy can be effective in many individuals with minimal adjuvant therapy,193, 195, 196, 258, 263 and
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therefore the drug also is available for buccal or transdermal self-medication without such
supervision.188, 189, 190 However, there also is evidence that intensive clinical interventions produce
higher success rates and are more cost effective than less intensive interventions and should be used
whenever possible.257, 258
While the over-the-counter (OTC) availability of nicotine for self-medication has increased the
availability and use of replacement therapy with the drug, this does not reduce the responsibility of
clinicians to intervene with smokers or with insurers and managed-care organizations to cover the costs
of such therapy.257 In addition, OTC availability of these preparations may enhance the capacity of
nonphysician clinicians to intervene comprehensively when treating tobacco dependence.257 All
clinicians have responsibilities regarding OTC nicotine preparations, such as encouraging their use when
appropriate, providing counseling and follow-up, and offering instructions on proper use.257 In
addition, patients should be encouraged to abstain totally from tobacco products, to read the patient
information provided by the manufacturer, and to consult their pharmacist.257 Clinicians also have an
important role in advising patients of their therapeutic options, including the selection and use of OTC
versus prescription therapies, and in providing or recommending counseling when OTC therapy is
chosen.257
Although OTC nicotine replacement therapy employing transdermal systems of the drug has been
reported to nearly double abstinence rates relative to placebo in a pooled analysis of several studies
(the only adjuvant therapy was a self-help manual, the manufacturer's patient information, or written
instructions for use of the transdermal system),257 evidence from one study not included in this
analysis indicates that abstinence rates with OTC therapy may be relatively low.257 Therefore,additional study is needed to determine the extent to which OTC pharmacotherapy is enhanced by
adjuvant therapies such as pharmacist counseling, telephone counseling, computer self-help resources,
and clinical interventions.257 Despite these limitations in current evidence, however, it should be
recognized that OTC replacement therapy with transdermal nicotine has been shown to be more
effective than placebo and should be encouraged as appropriate.257 Because nicotine polacrilex gum or
lozenge or a transdermal system or oral inhaler of nicotine is used as an adjunct to the patient's own
cessation efforts, these preparations should be used in patients who strongly desire to quit smoking.2, 5,
194, 195, 196, 244
Smoking cessation therapies, including nicotine replacement, have been shown to be cost-effective
preventive-health strategies.192, 194, 195, 257, 258, 241, 253 Cost-effectiveness analyses have shown
that smoking cessation therapies compare favorably with routinely reimbursed medical interventions
such as treatment of hypertension and hypercholesterolemia and with preventive screening
interventions such as periodic mammography. 257 In addition, the more intensive the intervention the
lower the cost per quality-adjusted life-year saved, indicating that intensive counseling and adjunctive
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nicotine replacement (e.g., transdermal) therapy have particular merit.241, 257 Use of smoking
cessation services in smokers with health insurance varies according to the extent of coverage for
behavioral and nicotine replacement therapy, with the highest rates of use of such services occurring
among those with full coverage.253 The US Public Health Service (USPHS) currently recommends that
health-care delivery administrators, insurers, and purchasers promote the treatment of tobacco
dependence through a systems approach.257, 258 Purchasers of health care (e.g., employers) should
make tobacco use assessment and treatment a contractural obligation of health-care insurers and/or
providers that sell services to them.257 Because both counseling and pharmacotherapy smoking
cessation treatments are highly cost-effective relative to other reimbursed treatments (e.g., treatment
of hyperlipidemias and mammographic screening), the USPHS recommends that they be provided to all
smokers.257 In addition, because intensive smoking cessation interventions are especially efficacious
and cost-effective, smokers should have ready access to these services as well as to less intensive
interventions.257 Including smoking cessation treatments as a paid or covered benefit by health
benefits plans can improve utilization of such therapy and reduce absenteeism rates and utilization of
health resources.257 In addition, sufficient resources should be allocated for clinician reimbursement
and support services to ensure the delivery of effective tobacco use treatments.257
Guidelines
Nicotine (tobacco) dependence is a chronic relapsing disorder that requires ongoing assessment and
often repeated intervention.196, 257, 258 Because effective nicotine dependence therapies are
available, every patient should be offered effective treatment, and those who are unwilling to attempt
cessation should be provided at least brief interventions designed to increase their motivation to stop
tobacco use.257
US Public Health Service
An expert panel convened by the US Agency for Health Care Policy and Research (AHCPR) (currently the
Agency for Healthcare Research and Quality, AHRQ) had concluded that primary care clinicians were
uniquely positioned to assist individuals who smoke since they have extraordinary access to the smoking
population under their care.194, 195 However, primary care clinicians treat a wide variety of patients
and face severe time constraints.257, 258 At least 70% of smokers visit a physician annually, more than
50% visit a dentist, and the services of other clinicians (e.g., physician assistants, nurse practitioners,
nurses, physical and occupational therapists, pharmacists) are used by many smokers.194, 195, 257, 258
In addition, 70% of smokers indicate that they want to quit and smokers cite a clinician's advice as an
important motivator for attempting to stop.194, 195, 257, 258 Therefore, the current USPHS guideline,
which updates the earlier guideline from AHCPR (now AHRQ), considers all clinicians to be uniquely
positioned to intervene against the use of tobacco by their patients.257, 258
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Delineated in the current USPHS guideline are 5 brief strategies of intervention that can be provided by
any clinician but that are most relevant to primary care clinicians providing service to a wide variety of
patients under the constraint of limited time.257, 258 These strategies consist of asking patients if they
use tobacco, advising those who use tobacco to quit, assessing their willingness to attempt to quit,
assisting those who attempt to quit, and arranging follow-up to prevent relapse.257, 258
Included in the USPHS guideline are recommendations for the use of pharmacotherapy in general, first-
line drugs (i.e., buccal nicotine polacrilex, transdermal nicotine, nicotine nasal spray, nicotine oral
inhaler, bupropion [as extended-release tablets]) that should be considered first as part of treatment for
dependence on tobacco, unless contraindicated, and second-line drugs (i.e., clonidine, nortriptyline).257
Clinicians should encourage all patients attempting to quit smoking to use effective pharmacotherapy,
except in the presence of special circumstances (e.g., medical contraindications, less than 10 cigarettes
smoked daily, pregnancy, breast-feeding, adolescence).257 When pregnant women are not otherwise
able to quit smoking and when the likelihood of cessation, with its potential benefits, outweighs the
risks of the pharmacotherapy and possible continued smoking, clinicians should consider
pharmacotherapy.257 For the treatment of adolescents, nicotine replacement therapy may be
considered when there is evidence of dependence on nicotine and a desire to quit the use of
tobacco.257 For patients receiving treatment for chemical dependence and attempting to quit smoking,
clinicians should provide effective treatments for the cessation of smoking that include both counseling
and pharmacotherapy, since interventions for the cessation of smoking do not appear to interfere with
recovery from chemical dependence.257 Clinicians can consider long-term pharmacotherapy for the
cessation of smoking in certain patients as a strategy to reduce the likelihood of relapse.257
Buccal nicotine polacrilex, transdermal nicotine, nicotine nasal spray, and nicotine oral inhaler are
effective treatments that clinicians should encourage patients to use for the cessation of smoking.257,
263 If nicotine polacrilex gum is used in highly dependent smokers, clinicians should recommend the 4-
mg strength, rather than 2-mg strength, because of evidence of increased efficacy.257 Nicotine
replacement therapy, particularly with nicotine polacrilex gum, or bupropion (as extended-release
tablets) may be most appropriate in patients greatly concerned about gaining weight after cessation of
smoking since these therapies have been shown to result in delay in such gain in weight.257 If
pharmacotherapy with a single first-line drug does not enable patients to quit smoking, clinicians should
encourage the use of transdermal nicotine combined with a self-administered form of nicotine
replacement (i.e., either buccal nicotine polacrilex or nicotine nasal spray) that they administer
independently to themselves.257 Nicotine replacement therapy in such combination is more effective
than when administered as a single nicotine preparation.257
Clinicians should ask all patients if they use tobacco and document their tobacco-use status regularly,
advising patients strongly who use tobacco to quit and assessing their willingness to quit.257 For
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patients unwilling to quit, a motivational intervention to promote cessation attempts should be given by
the clinician.194, 195, 257, 258 For patients who are willing to attempt to quit the use of tobacco,
effective interventions should be initiated.257 The clinician should assist the patient in the effort.194,
195, 257, 258 Help should be provided in developing a plan to quit that encompasses the patient's
preparations for quitting, including setting a date to quit that should ideally be within 2 weeks, telling
family, friends, and coworkers about the attempt to quit, and seeking their understanding and
support.194, 195, 257, 258 Patients should be provided with practical counseling (i.e., problem
solving/skills training).194, 257, 258 Social support should be provided as a part of treatment and the
patient should be aided in obtaining social support outside of treatment.194, 257, 258 The use of
effective pharmacotherapy should be recommended except in special circumstances.257, 258
Supplementary materials should be provided.194, 195, 257, 258 Patients attempting to quit the use of
tobacco should be scheduled for follow-up contact either in person or by telephone soon after the date
set for the patient to quit (e.g., during the first week), again during the month, and then as
indicated.194, 195, 257, 258
Abstinence should be ascertained at the completion of treatment and subsequently during clinical visits
of all patients who receive an intervention against tobacco dependence.257 Treatment to prevent
relapse should be provided to abstinent patients.257 In response to relapse, patients should be assessed
to determine their willingness at another attempt to quit the use of tobacco.257 Additional treatment
should be provided to or arranged for patients willing to attempt again to quit.257 For patients unwilling
to attempt again to quit, an intervention to promote motivation to quit should be given by the
clinician.257
Because chronic relapses are inherent to dependence on tobacco, the clinician should provide brief
treatment to prevent relapse in patients who quit the use of tobacco recently, particularly during the 3
months after they quit.194, 195, 257, 258 Relapse prevention interventions more intensive than
minimal practice interventions may be given by the clinician during dedicated follow-up contact held in
person or over the telephone, or through a specialized clinic or program.194, 195, 257, 258
American Psychiatric Association
The American Psychiatric Association (APA) also has issued guidelines for the treatment of nicotinedependence; while these guidelines should be useful to any clinician caring for a nicotine-dependent
patient, they focus on the groups of smokers most likely to be seen by psychiatrists, including smokers
being seen for a psychiatric disorder other than nicotine dependence or withdrawal, smokers who have
failed initial attempts at cessation and require more intensive treatment that could be provided by a
psychiatrist, and psychiatric patients who smoke and temporarily are confined to a smoke-free
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environment (e.g., hospital, residential care facility).196 The APA guidelines generally apply to all
smokers, not just those meeting the DSM criteria for nicotine dependence.196
Referral or provision of adjunctive psychiatric services, when indicated, and optimizing treatment with
psychosocial therapy or other pharmacologic therapy (e.g., certain antidepressants such as
bupropion)240 also are important responsibilities of the clinician.196
Nicotine Replacement Therapy in Combination with Behavioral and Psychologic Support
Current evidence indicates that use of nicotine replacement therapy in combination with behavioral and
psychologic support is more successful than such pharmacologic therapy alone in achieving smoking
cessation,43, 115, 116, 119, 144, 148, 193, 194, 195, 196, 257, 258 but the use of nicotine replacement
therapy should not be conditioned on concomitant behavioral and psychologic therapy.196, 263
Although transdermal nicotine therapy may be of value even in patients who do not participate in
formal smoking cessation programs,113, 114, 117, 130, 135, 193, 194, 195, 196 many patients receiving
such therapy have been otherwise healthy, nicotine-dependent smokers who were described as
motivated to quit smoking and who often were treated by experienced researchers in specialized clinics
and/or had frequent contact with clinicians.111, 112, 114, 115, 133, 136, 144, 148
The success of nicotine polacrilex gum for smoking cessation in general medical practice, where
intensive behavioral support generally is not feasible and/or patient motivation may be less than
optimal, has been relatively poor,148, 149 and it has been suggested that abstinence rates reportedfrom studies of transdermal nicotine therapy in specialized clinics may not accurately reflect the efficacy
that can be expected in the general community.144 There is some evidence, however, that buccal
replacement therapy with nicotine polacrilex lozenges can be highly effective in achieving smoking
cessation with little face-to-face behavioral support (e.g., limited to simple reinforcement of written
patient information on smoking cessation).263 Different dosing models employed for buccal gum and
lozenge formulations as well as more consistent systemic delivery of the drug from the lozenge may
affect the level of cessation success.263
Current data suggest that rates of smoking cessation in patients receiving transdermal nicotine therapy
are higher and less variable, at least in the short term, when concomitant behavioral support is
provided.101, 144, 194, 195, 196 Therefore, the manufacturers and most clinicians recommend that
transdermal systems of nicotine preferably be used as part of a comprehensive program of multiple
treatment strategies, including behavioral modification, to assist in the cessation of smoking.43, 44, 101,
102, 103, 104, 115, 116, 119, 126, 131, 144, 148, 149, 167, 193, 194, 195, 196, 257, 258 The quality,
intensity, and frequency of such behavioral support appear to influence the outcome of attempts to quit
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smoking,101, 102, 103, 104, 149, 193, 194, 195, 196, 257 although the minimum and/or essential
components of a successful smoking-cessation program have not been clearly defined to date.116, 148
Even clinical interventions by clinicians lasting less than 3 minutes can increase overall tobacco cessation
rates. 257, 258
The efficacy of intranasal191, 196, 202 or orally inhaled244, 245 nicotine replacement therapy as an
adjunct to smoking cessation also has been demonstrated in patients who underwent concomitant
psychosocial interventions (e.g., group support, individualized counseling), and therefore a
comprehensive program of behavioral modification is recommended when this method of nicotine
therapy is employed.
Different strategies of concomitant behavioral support influence the rate of abstinence from smoking
achieved with transdermal nicotine, although evidence against differential outcome also exists.193, 194,195, 196 An analysis of pooled data from several well-designed, controlled studies showed that the rate
of abstinence from smoking was greater with counseling that was of high rather than of low intensity, as
indicated by ratings on an index that reflected the importance of counseling as a goal at meetings with
patients, frequency of meetings during the first 4 weeks of treatment with transdermal nicotine,
number of meetings held during the first 12 weeks of abstinence from smoking, and length of
meetings.257, 258Analysis of individual criteria revealed higher rates of abstinence from smoking when
counseling was a primary goal of meetings with patients, when patients were met with at least weekly
during the first 4 weeks of treatment with transdermal nicotine, and when at least 7 meetings were held
during the first 12 weeks of abstinence. In addition, rates of abstinence from smoking were higher with
group counseling than with individual counseling.
Despite these results, transdermal nicotine has been shown to be consistently more effective than
placebo regardless of intensity of any adjuvant psychosocial intervention, which suggests that
transdermal nicotine also is effective with minimal behavioral support.193, 195, 241 A randomized study
of transdermal nicotine combined with minimal (i.e., provision of self-help pamphlet about smoking
cessation), individual (i.e., provision of pamphlet along with motivational message from physician, 3
meetings less than 15 minutes long with nurse), or group (i.e., provision of pamphlet, motivational
message from physician, and 8 weekly sessions of group smoking cessation counseling 1 hour long)
counseling showed that the type of counseling received did not influence the rate of smoking cessation
at the end of treatment with transdermal nicotine for 8 weeks and at follow-up at 26 weeks. Cost-
effectiveness analysis has shown that costs per quitter, life-year saved, and quality-adjusted life-years
saved associated with any degree of counseling provided by a primary-care clinician or smoking
cessation specialist were lower when evaluated in combination with adjunctive transdermal nicotine,
and the more intensive the intervention the lower the cost per quality-adjusted life-year saved.241, 257
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Efficacy of the Various Nicotine Dosage Forms
Therapy with buccal (chewing gum, lozenge) nicotine polacrilex may be useful as a temporary substitute
for smoking and, when used in conjunction with other therapies, may be beneficial in overcoming
manifestations of nicotine withdrawal.43, 86, 97, 195, 196, 263 Unlike nicotine transdermal systems or
intranasal spray, but like orally inhaled nicotine using a smokeless cigarette-like inhaler, buccal nicotine
polacrilex can provide a substitute oral activity during cigarette withdrawal.5, 77, 196, 263 In addition,
buccal administration of nicotine has the potential advantage of allowing smokers to control the amount
and timing of dosing, thus allowing the patient to self-titrate dosage to an appropriate level and to use
acute ("rescue") dosing to combat acute craving episodes.263 By comparison, transdermal systems
potentially may provide some advantages over buccal nicotine polacrilex, such as a reduction in
symptoms of craving, ease of administration, absence of local oral adverse effects, fewer adverse GI
effects, less frequent dosing leading to better compliance, the absence of reinforcement of addictive
behavior obtained from frequent self-administration of nicotine, and effectiveness across diverse
settings and populations and when used with a variety of psychosocial interventions.43, 48, 49, 109,
111, 112, 115, 116, 117, 118, 119, 121, 123, 124, 126, 130, 136, 144, 194, 195, 196
Nicotine oral inhalers provide a method of replacement that most closely mimics the behaviors (i.e.,
handling and inhalation through the mouth) of cigarette smoking,245 although clinical experience
suggests that this mode of administration contributes at most only marginally to efficacy compared with
buccal nicotine polacrilex or intranasal nicotine.245 In addition, the cigarette shape and more obvious
use of the oral inhaler may carry some stigma in certain patients.263 Likewise, use of the nasal inhaler
may carry some stigma in certain patients, and initially is locally very irritating.263
Any of these forms of nicotine provides an alternative source of the drug that is devoid of tars, carbon
monoxide, and respiratory irritants2, 97, 257 and that may help reduce withdrawal symptoms
associated with nicotine dependence.2, 50, 78, 79, 80, 97, 191, 194, 195, 196, 244, 245, 263 Some data
suggest that withdrawal symptoms unrelieved with transdermal nicotine therapy alone may respond to
combined therapy with transdermal nicotine and buccal nicotine polacrilex.43, 166, 196 Some clinicians
state that there are insufficient data from well-designed studies to recommend one method of smoking
cessation therapy (e.g., transdermal nicotine systems, nicotine gum) over another.43, 44, 144, 167, 257,
258
Buccal Nicotine Polacrilex
Buccal nicotine polacrilex has been used widely as a temporary adjunct in smoking cessation therapy263
and has been shown consistently to be more effective than control interventions (e.g., psychosocial
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support alone) regardless of the intensity of adjuvant psychosocial interventions, although efficacy is
enhanced with intensive psychosocial intervention.1, 2, 5, 7, 8, 9, 29, 68, 89, 96, 195 The use of
extemporaneously prepared buccal formulations of nicotine (e.g., nicotine salicylate lozenges
["lollipops"]) is not recommended. (See Extemporaneously Prepared Nicotine Formulations, under Uses:
Smoking Cessation.) The optimal dosage and duration of buccal nicotine polacrilex therapy and optimal
methods for withdrawing buccal therapy have not been clearly established,43, 86 but buccal therapy is
most commonly used during the first few months of an attempt at smoking cessation, and clinicians
should individualize the duration of therapy to meet the needs of the patient.195, 196, 257 There is
some evidence that continuing buccal nicotine polacrilex therapy beyond (e.g., for a year or longer) the
usually recommended period may increase abstinence rates.257 Although weaning from nicotine
replacement therapy should be encouraged,263 continued use of such therapy is clearly preferable to a
return to smoking and its health consequences.257
In several controlled studies in patients participating in behavior modification programs, buccal nicotine
polacrilex has been reported to be more effective than placebo as an adjunct during smoking
cessation.1, 2, 5, 7, 8, 9, 29, 68, 89, 96, 195, 257 In these studies, patients receiving nicotine polacrilex
experienced less severe withdrawal symptoms and achieved higher abstinence rates than patients
receiving placebo.2, 5, 7, 8, 9, 29, 89, 96, 97, 195 Because therapy with buccal nicotine polacrilex may be
associated with problems of compliance,263 ease of use, social acceptability, and unpleasant taste,263
use of this form of nicotine replacement therapy depends in large part on patient preference.195
Abstinence rates in patients using nicotine polacrilex gum therapy are variable,6, 7, 8, 9, 29, 31, 33, 46,
47, 48, 76, 77, 82, 83, 84, 85, 97, 195 but the gum generally improves long-term abstinence rates by 30-80% compared with control interventions.195, 257 In several controlled studies, reported rates of
abstinence for nicotine polacrilex gum vs placebo were 10-63% vs 5-45% at 6 months7, 8, 9, 31, 46, 47,
48, 85 and 10-49% vs 9-37% at 12 months.7, 8, 9, 47, 48, 89, 96 In one study comparing nicotine
polacrilex gum with psychologic behavior modification alone in patients with nicotine dependence,
reported rates of abstinence were 59 vs 22% at 1 month, 51 vs 14% at 3 months, 45 vs 14% at 6 months,
and 38 vs 14% at 1 year, respectively.6 In another study, the abstinence rate at 1 year was about 23% in
patients receiving nicotine polacrilex gum.29 In a large multicenter study, long-term abstinence rates
(i.e., at 6 and 12 months) in patients receiving therapy consisting of verbal and written counseling and
nicotine polacrilex gum were not substantially different from those in patients receiving verbal
counseling alone.48
In highly dependent smokers, the 4-mg nicotine polacrilex gum is more effective than the 2-mg gum as
an aid to smoking cessation.96, 195, 196, 257, 258 In a study in patients receiving gum containing 2 or 4
mg of nicotine and undergoing psychologic behavior modification, abstinence rates in highly dependent
patients at 6 weeks, 1 year, and 2 years were 54.5, 12.1, and 6.1%, respectively, for 2-mg doses and
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81.5, 44.4, and 33.3%, respectively, for 4-mg doses; in those with a low to moderate degree of
dependence, abstinence rates were 73.3, 38.3, and 28.3%, respectively, for 2-mg doses.96
Abstinence rates in patients using nicotine polacrilex lozenges also are variable, but the lozenges
generally improve abstinence rates relative to control interventions.263 In one controlled study
employing little face-to-face behavioral support (e.g., limited to simple reinforcement of written patient
information on smoking cessation), reported rates of abstinence at 6 weeks for nicotine polacrilex
lozenges vs placebo were 46% vs 29.7% for 2-mg doses in low-dependence smokers (dependency
assessed by time to the first cigarette [TTFC] upon awakening) and 48.7% vs 20.8% for 4-mg doses in
highly dependent smokers.263 Abstinence rates for the 2-mg doses were 34.4% vs 21.6%, 24.2% vs
14.4%, and 17.9% vs 9.6% at 12, 24, and 52 weeks, respectively.263 Abstinence rates for the 4-mg doses
were 35.3% vs 14%, 23.6% vs 10.2%, and 14.9% vs 6.2% at 12, 24, and 52 weeks, respectively. 263 In this
study, patients were only provided nicotine polacrilex or placebo lozenges through week 24 and, after a
12-week period of downwardly titrated dosing, were instructed to use them only occasionally (i.e., in
situations when they might be tempted to smoke) during weeks 12-24; patients were instructed to stop
lozenge use after 24 weeks.263 Patients who failed to maintain abstinence at each visit were
discontinued from the study.263 High dependency was defined as a TTFC within 30 minutes of
awakening and low dependency was defined as a more prolonged TTFC.263 Patients who used more
lozenges achieved substantially better treatment effects in both lozenge treatment groups (i.e., low- and
high- dependence patients).263 Active lozenge therapy also reduced craving at weeks 1 and 2 for both
treatment groups vs placebo, but only the 4-mg group exhibited lower withdrawal symptom scores at
week 2; the greater effect on withdrawal symptoms observed with the 4-mg dose probably resulted
from the higher baseline nicotine dependency and associated higher likelihood of withdrawal
precipitation relative to the 2-mg group.263 Most patients in this study had failed previous attempts atpharmacologic smoking cessation therapy.263
The abstinence rate in patients using buccal nicotine polacrilex may depend on the duration of
therapy.5, 33, 257 The manufacturer states that use of buccal nicotine polacrilex for longer than 3
months has not been shown to increase the rate of abstinence,1 although some clinicians suggest that
longer periods of therapy may be necessary to ensure a high abstinence rate.33, 43 257 Although
prolonged use of buccal nicotine polacrilex may increase the risk of patients substituting the drug for
cigarettes as a source of nicotine for their nicotine dependence,1 the risk of dependence on buccal
nicotine polacrilex therapy appears to be low.7, 44, 90 (See Chronic Toxicity.)
Transdermal Nicotine
Transdermal nicotine has been shown to be consistently more effective than placebo regardless of
intensity of any psychosocial intervention, which suggests that transdermal nicotine also is effective
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with minimal behavioral support.193, 195, 241, 257 However, cost-effectiveness of transdermal therapy
appears to increase as the intensity of the cessation intervention increases.241, 257 (See Smoking
Cessation: Nicotine Replacement Therapy in Combination with Behavioral and Psychologic Support.)
Whether transdermal nicotine administered at a higher dosage is superior to standard dosages is
uncertain.196 At steady state, the percentage of nicotine replacement, in terms of blood cotinine
concentration, provided by transdermal nicotine at a dosage of 44 mg/24 hours was slightly above 100%
but was less than 100% with dosages of 11 and 22 mg/24 hours. At the end of treatment for 8 weeks,
the likelihood of smoking cessation was increased with each increment in dose of 11 mg and with each
increase of 25% in percentage of cotinine replaced, although such associations were not discerned at
follow-up at 6 months or 1 year. However, evaluation of the efficacy in achievement of smoking
cessation with 8 weeks of transdermal nicotine at an initial dosage of 22 or 44 mg/24 hours did not
indicate the superiority of the higher dose at follow-up at 6 months. Desire to smoke, one of 8
withdrawal symptoms assessed, was less severe with transdermal nicotine at a dosage of 44 mg/24
hours than at 22 mg/24 hours during the first 4 weeks of treatment, although such difference between
these dosages in the suppression of this withdrawal symptom was not discerned at subsequent
evaluation and was, furthermore, not related to the rate of smoking cessation. Other data showed that
during the first 6 days of treatment, severity of withdrawal symptoms (i.e., anger/irritability/frustration,
anxiety or nervousness, awakening at night, difficulty concentrating, depression, hunger, impatience or
restlessness, desire to smoke) considered as a whole was less with transdermal nicotine at a dosage of
44 mg/24 hours than at 22 or 11 mg/24 hours on the first day of treatment and was less with 44 or 11
mg/24 hours than with 22 mg/24 hours on the fourth day of treatment.
Although the optimal duration, dosage, and long-term efficacy and safety of transdermal nicotine
therapy have not been established fully,43, 144, 148, 149, 177 current evidence indicates that extending
the duration of transdermal nicotine therapy beyond 8 weeks does not appear to increase efficacy.193,
195, 196 However, based on evidence with nicotine polacrilex gum, continued therapy for periods
longer than usually recommended may be appropriate for certain patients to promote extended
abstinence. 257
In controlled studies of 3-6 months or less in otherwise healthy adults who generally were considered
highly motivated to quit smoking and who smoked at least 0.5-1 pack of cigarettes daily, therapy with
transdermal systems of nicotine has been more effective than placebo in achieving smoking
cessation,43, 101, 102, 103, 109, 111, 112, 133, 136, 143, 144, 193, 194, 195 although abstinence rates
with such therapy have varied considerably.144 Smoking cessation usually was defined as total
abstinence from smoking as determined by patient diary and, in most studies, was verified by
measurement of expired carbon monoxide concentration. 101, 102, 103, 104, 109, 111, 112, 113, 115,
118, 136, 144 With concomitant behavioral support, rates of smoking abstinence at 6 or 7 weeks
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generally ranged from about 20-60% (reportedly up to 92%)2 in smokers who received therapy with
either 24- or 16-hour transdermal systems of nicotine compared with about 3-46% for placebo
recipients.101, 102, 103, 104, 109, 136, 144 Abstinence rates of approximately 30-53% within the first 6
weeks of treatment also have been reported in a few studies in which concomitant behavioral support
was not provided.14, 18, 113, 144 Data from trials that assessed abstinence at 6 months generally
indicate lower rates of smoking cessation.2, 3, 4, 11, 15, 36 Patients receiving a transdermal system of
nicotine and behavioral support experienced less severe withdrawal symptoms, including less craving
for cigarettes, as indicated by patients' ratings of symptom severity, and achieved higher abstinence
rates than patients receiving placebo.101, 102, 103, 104, 109, 111, 112, 133, 136, 137 Reductions in the
severity of symptoms such as irritability, anger, restlessness, dizziness, difficulty concentrating, and
dysphoria have been reported with transdermal nicotine therapy, although hunger and weight gain do
not appear to be attenuated substantially.111, 112, 136, 148, 149
Clinical studies indicate that abstinence rates in patients receiving transdermal nicotine therapy
generally exceed those in placebo recipients for at least 6 months,111, 118, 136, 149, 193 but early
relapse is common.118, 136, 144, 257 Although initial rates of smoking cessation with transdermal
nicotine therapy may be substantial,118, 144, 148, 193 long-term (e.g., 1-year) abstinence rates in
smokers receiving transdermal therapy with behavioral support generally have averaged about 25%,
similar to those observed with the use of nicotine gum for comparable periods.148 In one randomized,
multicenter study, the abstinence rate with transdermal nicotine therapy and behavioral support was
61% following 6 weeks of treatment with the full dosage of 21 mg/day but, while still exceeding placebo
rates, had declined to 39% at 3 months following weaning with dosages of 14 and 7 mg/day and to 26%
3 months after completion of transdermal nicotine therapy.133, 136 Therefore, while abstinence rates
with transdermal nicotine therapy are approximately double those in patients who receive placebo,additional measures to prevent relapse and optimize the long-term success of nicotine-replacement
therapy are needed.115, 121, 148, 149, 195, 257 However, in a few studies, addition of specific relapse-
prevention strategies (e.g., self-observation and recording of temptation situations, role playing,
thought blocking) to therapy with transdermal nicotine systems plus behavioral support has not
produced substantial improvements in long-term abstinence rates.126, 141
Because transdermal systems of nicotine do not replace the pleasurable and habitual aspects of
smoking,144, 149 some clinicians suggest that transdermal nicotine therapy, combined with another
more rapid-acting, titratable form of nicotine replacement (e.g., buccal nicotine polacrilex, nicotine
inhaler or spray) to facilitate dosage tailoring and/or prevent relapse, may constitute the most
successful treatment approach; additional study is needed.43, 147, 148, 149
Reported rates of abstinence and severity of nicotine craving in patients using transdermal systems of
nicotine are variable, presumably because of differences in patient motivation, concurrent illnesses,
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number of cigarettes smoked daily and duration of the smoking habit, exposure to or influence of other
smokers, socioeconomic status, and differences among smoking cessation clinics.101, 102, 103, 104,
113, 136 However, in a multicenter study of 9 clinics, the number of cigarettes smoked daily at baseline,
number of years of smoking cigarettes, or clinic site were not predictive of response to treatment in
patients receiving transdermal nicotine therapy.111, 136 Abstinence rates for patients older than 60
years of age were comparable to those for younger individuals,101, 102, 103, 104, 144 and efficacy of
the transdermal nicotine systems also appears to be similar regardless of gender.113, 121, 136, 144
However, while women appear to benefit from the same smoking cessation therapies as men, women
may face different stressors and barriers to quitting (e.g., greater likelihood of depression, greater
weight control concerns, hormonal cycles), and there is some evidence that nicotine replacement
therapy may be less effective in women.257 Although reduction in most nicotine-withdrawal symptoms
does not appear to be clearly related to the dosage of nicotine delivered by transdermal systems of
nicotine,43, 136, 159 limited evidence suggests that reduction in craving may be greater with higher
transdermal nicotine dosages (e.g., 21 mg/24 hours).136 In some studies, reductions in craving have
been apparent only after several days or weeks of therapy, rather than early in treatment when craving
is most severe.113, 114, 118, 144, 167
Comparative studies currently are limited, but some evidence suggests that abstinence rates and
adverse effects are similar whether a nicotine transdermal system is applied over 16 or 24 hours.44,
111, 144, 148 Nicotine transdermal systems that deliver the drug over 24 rather than 16 hours
theoretically offer the advantage of maintenance of plasma nicotine concentrations adequate to
minimize withdrawal symptoms in the morning,105, 123, 132, 134 while use of 16-hour transdermal
systems of nicotine is intended to reduce adverse effects (e.g., insomnia) and the potential for
tolerance.144, 148 However, in one randomized study in which a prototype44 transdermal system ofnicotine designed to provide 24-hour systemic delivery of nicotine was applied for either 24 hours daily
or only while patients were awake (approximately 16 hours daily), severity of withdrawal symptoms
during the 4-week treatment period and abstinence rates 6 months after the completion of therapy
were similar for both regimens, as was the frequency of adverse effects.111, 132
Some clinicians149, 195 state that nicotine replacement therapy generally should be discontinued after
6-12 weeks. Alternatively, it has been suggested that smokers optimally should receive such therapy for
as long as needed to overcome the addiction,43, 116, 143, 257 although skin irritation from a
transdermal system potentially may preclude such long-term use in some patients.43, 112, 115, 167,
195 (See Cautions: Local and Sensitivity Reactions.) In addition, some evidence indicates that
transdermal therapy of 8 weeks or less may be as effective as longer therapy, but therapy, including
duration, should be individualized.257 Complete abstinence from smoking generally is the goal of
transdermal nicotine therapy.101, 102, 103, 104, 123, 195, 257 In clinical studies of such therapy, most
patients who stopped smoking did so during the first month;101, 102, 103, 104, 115, 121 therefore, the
manufacturers state that transdermal nicotine therapy probably should be discontinued in patients who
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continue to smoke 4 weeks after initiating such treatment.101, 102, 103, 104 Adjunctive transdermal
nicotine therapy may be used again in subsequent attempts to quit smoking,101, 102, 103, 104, 121
although the efficacy of such therapy following initial failure has not been demonstrated to date.43,
162, 167 If another trial of transdermal nicotine therapy is contemplated, such therapy should be
initiated only after identifying and addressing reasons for failure so that success is more likely.43, 101,
102, 103, 104
It has been suggested that use of nicotine-replacement therapy to facilitate a reduction in cigarette
smoking, rather than complete cessation, may be a reasonable objective in patients in whom abstinence
is not possible (harm reduction therapy).123, 148 Many patients who have been unable to quit smoking
entirely have experienced a substantial (e.g., 60%), dose-related reduction in cigarette consumption, or
in nicotine intake during smoking, with transdermal nicotine therapy.113, 136, 148, 158, 160 However,
reduction in disease (e.g., lung cancer, emphysema) associated with a reduction in the intake of tobacco
smoke has not been demonstrated to date.43, 167 Additional data on the long-term safety of nicotine
replacement therapy and on patterns of smoking behavior in patients receiving such therapy are needed
to determine the merits of achieving a reduction in smoking as a harm reduction strategy, rather than
complete cessation,43, 123, 257 and such use of transdermal nicotine therapy generally should not be
encouraged.43, 144, 167, 257
Nicotine Nasal Spray
Nicotine nasal spray with or without concomitant psychosocial treatment (e.g., group therapy, individual
counseling) was more effective than placebo in achieving smoking cessation in controlled studies.191,201, 202, 203, 257 Enrollment did not include patients with severe or symptomatic cardiovascular
disease, hypertension, asthma, diabetes, or severe allergy.191, 201, 202 Nicotine nasal spray was used
for up to 1 year at a dosage determined by the patient of up to 40 mg daily, although 3 months was
recommended generally as the duration of therapy.191, 201, 202, 203 Smoking cessation usually was
defined as total abstinence from smoking as reported by the patient and verified by measurement of
expired carbon monoxide concentration.191, 201, 202, 203 Abstinence was achieved with nicotine nasal
spray in 49-58, 41-45, 31-35, and 23-27% of patients at 6 weeks, 3 months, 6 months, and 1 year,
respectively, compared with 21-32, 17-20, 12-15, and 10-15% at the respective follow-up in recipients of
placebo.191, 201, 202, 203 Outcome at 1 year did not distinguish use of nicotine nasal spray limited to 6
months from therapy of longer duration.191, 203 Withdrawal symptoms and craving for cigarettes wereexperienced to a lesser extent with nicotine nasal spray than with placebo.191, 201 The risk of
developing dependence on nicotine nasal spray appears to be greater than that with other nicotine
replacement therapy but less than that with cigarette smoking.191, 196, 201, 202, 257 (See Chronic
Toxicity.)
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Nicotine Oral Inhaler
Nicotine inhalation therapy using an oral inhaler, with intensive (e.g., group therapy) or minimal (limited
individual advice and support) concomitant psychosocial treatment, was more effective than placebo in
achieving smoking cessation in controlled studies.244, 245, 246 257 Orally inhaled nicotine was used for
up to 6 months at a dosage determined by the patient, but generally with a recommended minimumdosage of 4 inhaler cartridges (designed to deliver a maximum of about 4 mg each) daily and a
maximum dosage of 20 cartridges daily; the recommended duration of inhalation therapy was 3 months,
although patients could continue therapy for up to 6 months if they desired, preferably at reduced
dosage.244, 245 Patients who continued to smoke cigarettes during nicotine replacement therapy with
the oral inhaler were encouraged to continue their inhaler use and increase the dosage.256 Smoking
cessation was defined as total abstinence from smoking after the initial 2 weeks of oral inhaler therapy
as reported by the patient and verified by measurement of expired carbon monoxide concentration.244,
245
Abstinence was achieved with nicotine oral inhaler in 44-46, 31-37, 20-35, and 11-28% of patients at 6
weeks, 3 months, 6 months, and 1 year, respectively, compared with 14-33, 8-23, 6-19, and 5-18% at the
respective follow-up in recipients of placebo.244, 245 The urge to smoke, a nicotine withdrawal
symptom, was reduced during the first week of nicotine oral inhalation therapy relative to placebo.244,
245 Although not compared directly, 1-year abstinence rates with the oral inhaler were similar to those
observed with nicotine polacrilex gum or intranasal nicotine in similarly designed clinical studies.245
After 2, 3, or 6 weeks of oral inhaler therapy, the percentage of nicotine replacement, in terms ofsalivary cotinine concentration, provided by oral inhalation of usual dosages of nicotine inhaler was
about 37-43, 30-34, or 20-24%, respectively, of that provided by cigarette smoking, representing the
lower availability of nicotine from the inhaler compared with cigarette smoking as well as downward
self-titration of nicotine replacement during continued use of the inhaler.245, 246 Small increases (3.8
mg/dL) in serum high-density lipoprotein (HDL) cholesterol concentrations were associated with orally
inhaled nicotine therapy at 3 and 6 months; similar increases were observed in placebo recipients at 3
but not 6 months.245
Extemporaneously Prepared Nicotine Formulations
The US Food and Drug Administration (FDA) has become aware of the increasing promotion of certain
extemporaneous formulations of nicotine salicylate intended to be used as nicotine replacement
therapy to assist in the cessation of smoking.259 Such extemporaneous formulations have included
buccal lozenges ("lollipops") and topical ointments for lips ("lip balm") that contain nicotine salicylate,
natural sweeteners, and flavorings in a sugar-free base.259 It should be noted, however, that a
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commercially available buccal (lozenge) formulation of nicotine polacrilex (Commit Lozenges) has been
approved by FDA for marketing and use in the US. (See Buccal Nicotine Polacrilex, under Uses: Smoking
Cessation.) The promotions on pharmacy websites that sold the extemporaneously prepared products
suggested to consumers that these products help alleviate the "hand-to-mouth fixation" associated with
smoking and are a "convenient, tasty way" to replace the cigarette habit.259 After careful investigation
and assessment of these websites, the FDA has determined that the extemporaneously prepared
nicotine "lollipop" and "lip balm" preparations are intended for use as drugs, and the agency has taken
appropriate regulatory actions to remove such preparations from the US market.259 FDA is concerned
that these formulations may pose a health risk to consumers because they appear to be compounded
and dispensed without a prescription, contain a form of nicotine that is not used in FDA-approved
commercially available nicotine dosage forms, and because these candy-like preparations present a risk
of accidental use by children.259
Weight Gain and Smoking Cessation
Weight gain occurs in most smokers who quit.194, 195, 196, 245, 257, 263 Although most smokers will
gain less than 4.5 kg following cigarette cessation,194, 195, 196, 245, 246, 257, 263 there is a broad
range of weight gain, with up to 10% of smokers gaining up to 13.5 kg following cessation.194, 195, 257
Women tend to gain more weight than men, and blacks, individuals younger than 55 years of age, and
heavy smokers (more than 25 cigarettes daily) are at increased risk of substantial weight gain.194, 195,
257
Patients generally should be advised not to take strong measures (e.g., strict dieting) to counteractweight gain during smoking cessation therapy since such simultaneous measures may undermine the
attempt at smoking cessation.194, 195, 196, 257 Although no strategy or treatment has been shown
unequivocally to prevent postcessation weight gain, nicotine replacement (particularly with the
gum)194, 195, 196, 243, 257 or bupropion smoking cessation therapy243, 257 appears to be effective in
delaying postcessation weight gain.194, 195, 196, 257 In fact, there appears to be a dose-response
relationship between gum use and weight suppression, although once nicotine polacrilex gum is
discontinued, the ultimate weight gain appears to be about the same as if the patient had never used
the gum.195 Therefore, for patients concerned greatly about gaining weight after cessation of smoking,
it may be most appropriate to implement or recommend nicotine replacement therapy, particularly with
nicotine polacrilex gum, or alternatively bupropion therapy.257
Postcessation weight gain appears to result both from increased caloric intake (e.g., eating, alcohol
consumption) and by metabolic adjustments.257 Involvement of metabolic mechanisms suggests that
patients will on average gain some weight following smoking cessation even if they do not increase their
caloric intake.257 Because many patients believe that they can do little to prevent postcessation weight
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gain except to return to smoking, a belief that is consistent with research findings, such concerns may be
difficult to address clinically.257 However, clinicians should recommend a healthy diet and physical
activity and emphasize that the health risks of postcessation weight gain are small compared with the
risk of continued smoking.257 Clinicians also should recommend that patients concentrate principally on
smoking cessation rather than weight control until they are confident that they will not return to
smoking.257
Nicotine Replacement Therapy in Patients with Pulmonary and Cardiovascular Disease
Because smokers with pulmonary disease appear to be highly nicotine dependent, nicotine replacement
therapy is particularly important in such patients.196 Current evidence in patients with stable coronary
artery disease indicates that transdermal nicotine therapy is effective and does not exacerbate cardiac
complications (e.g., angina, arrhythmias) in such patients.102, 144, 149, 156, 196, 200, 211, 221, 242,
257 Although adverse cardiovascular effects, including myocardial infarction, have been reported rarely
in patients receiving nicotine replacement therapy (e.g., in those who continued to smoke while
receiving transdermal nicotine),144, 149, 164, 165, 167, 211, 212, 213, 214, 215 nicotine replacement
therapy with transdermal systems does not appear to be associated with particular risk in patients with
cardiovascular disease (even in patients who continue to smoke intermittently) but can be beneficial if
the smoking cessation attempt were successful, and smoking cessation is considered essential as a
secondary long-term prevention measure in such patients (e.g., those surviving a myocardial
infarction.102, 156, 196, 200, 211, 221, 242, 256, 257 (See Cautions: Other Systemic Effects.) Because of
inaccurate media coverage in the past linking transdermal nicotine replacement therapy and
cardiovascular risk, it may be important to inform patients who are reluctant to use nicotine
replacement therapy that there currently is no evidence of increased cardiovascular risk. 257
Nonetheless, the risks versus benefits should be considered, particularly in patients with acute
cardiovascular conditions.1, 97, 101, 102, 103, 104, 144, 148, 149, 191, 257 (See Cautions: Precautions
and Contraindications.)
Smoking Cessation Therapy in Inpatients and Residents of Long-term Care Facilities
Because hospitals must be smoke-free environments to meet Joint Commission on Accreditation of
Healthcare Organizations (JCAHO) standards, hospitalization may provide a good opportunity to attempt
smoking cessation, depending on the patient's condition.194, 195, 257 For smokers who experience
nicotine withdrawal manifestations during hospitalization, nicotine replacement therapy during
hospitalization can reduce such symptoms and may promote continued use of replacement therapy for
patients desiring to prolong their abstinence beyond the period of hospitalization.194, 195 In addition to
reducing or preventing withdrawal manifestations, there is evidence that smoking cessation
interventions that are undertaken in hospitalized patients increase abstinence rates.195, 257
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The use of nicotine replacement therapy to alleviate nicotine withdrawal manifestations may be
considered for inpatients who smoke and who will not consent to hospitalization without treatment for
nicotine withdrawal because of concern about its occurrence.196 Such prophylactic use may be
advantageous compared with allowing breaks for smoking since nicotine replacement therapy is of low
risk.196 Among the advantages of buccal nicotine polacrilex are that patients can titrate the dosage of
nicotine and that use can stop immediately before intermittent smoking (e.g., at breaks).196, 263 Daily
use of a few doses of buccal nicotine polacrilex is sufficient in many patients to prevent manifestations
of nicotine withdrawal.196 Transdermal nicotine offers the advantages of better compliance and stable
delivery of nicotine, which may by especially advantageous in differentiating nicotine withdrawal from
other psychiatric symptoms.196 A disadvantage of either route of administration is that patients may
smoke during such therapy.196 However, substantial adverse effects do not appear to be likely with this
undesirable combination.196, 200
Prophylactic pharmacotherapy generally is not a consideration for inpatients who smoke because
nicotine withdrawal is often less severe than they anticipated because of such factors as the absence of
cues that elicit smoking, distraction of the primary problem, and the effects of drugs.196 The use of
nicotine replacement therapy (e.g., transdermal system, buccal dosage form) to alleviate nicotine
withdrawal manifestations usually should be considered only when such manifestations stimulate
complaints from the patient or are observed.196 Although inpatients who decide to stop smoking may
not need nicotine replacement therapy while hospitalized, they should be followed carefully after
discharge to determine whether such therapy is indicated because many patients experience nicotine
withdrawal manifestations when they return to their usual environment.196
Nicotine replacement therapy is not recommended for use in patients while hospitalized for
management of acute myocardial infarction because of the potentially deleterious effects of the
sympathomimetic effects of nicotine.256 However, because the dose of nicotine in the gum and
transdermal systems of the drug is substantially lower than that provided by cigarettes, nicotine
replacement therapy may be considered preferable to cigarette smoking in patients experiencing
nicotine withdrawal.256 (See Cautions: Cardiovascular Effects and also Precautions and
Contraindications.) Smoking cessation, however, is essential as a secondary long-term (i.e., following
hospital discharge) prevention measure in patients surviving a myocardial infarction.256
Residents in long-term care facilities also should receive effective tobacco dependence interventions.
257
Efficacy for Noncigarette Tobacco Cessation
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The efficacy of nicotine as an adjunct in cessation therapy for other forms of nicotine dependence (e.g.,
smoking a pipe or cigar, chewing tobacco) has not been established to date.43, 44, 144 Specifically,
studies conducted with nicotine polacrilex gum or transdermal nicotine have failed to show increased
abstinence rates in users of smokeless tobacco.257 Despite the lack of current evidence establishing
efficacy of nicotine replacement therapy of other pharmacotherapies for tobacco cessation in patients
dependent on noncigarette forms of tobacco, smokeless/spit (chewing tobacco, snuff) tobacco users,
and those using cigars, pipes, or other noncigarette combustible forms of tobacco should be identified,
strongly urged to quit, and treated with the same counseling cessation interventions recommended for
cigarette smokers.257 In addition, clinicians delivering dental health services should provide at least
brief interventions to all smokeless/spit tobacco users.257 Like cigarette smoking, smokeless or spit
tobacco produces addiction to nicotine and has serious health consequences; health risks include teeth
abrasion, gingival recession, periodontal bone loss, leukoplakia, oral cancer, and cardiovascular
disease.257 Cigar smoking also poses serious health risks, including coronary heart disease, chronic
obstructive pulmonary disease (COPD), and lung and other cancers.257 Additional study is needed to
determine the efficacy of pharmacotherapy, alone or combined with counseling and behavioral
therapies, in promoting tobacco abstinence among users of noncigarette tobacco.257
Nicotine Dependence and Withdrawal
Some evidence indicates that nicotine replacement therapy may be most likely to be effective in
patients with a high degree of dependence on nicotine (i.e., heavy smokers)1, 2, 8, 30, 33, 67, 68, 263
and a high degree of motivation.5 However, the decision to use nicotine replacement as an adjunct to
smoking cessation does not depend on establishing a diagnosis of nicotine dependence.195, 196 In a
study comparing buccal nicotine polacrilex gum vs placebo, 6-week abstinence rates were 46% vs 9% in
patients highly dependent on nicotine and 29% vs 13% in those with a low degree of dependence.68
However, it currently is unclear whether the likelihood of achieving smoking cessation with transdermal
nicotine systems depends substantially on the patient's degree of nicotine dependence.111, 113, 114,
136, 144 Neither the number of cigarettes smoked per day, nor scores on the Fagerstrom Tolerance
Questionnaire, at baseline appeared to influence the rate of smoking cessation after 8 weeks of
treatment with transdermal nicotine at a dosage of 22 or 44 mg/24 hours and at follow-up at 26 weeks.
Limited data suggest that highly dependent smokers may benefit from therapy with nicotine nasal
spray.191, 201
Some clinicians suggest that dependence on nicotine is probable in patients who smoke more than 15
cigarettes per day, smoke cigarettes with a nicotine yield greater than 0.9 mg/cigarette, usually inhale
the smoke frequently and deeply, smoke their first cigarette within 30 minutes of arising,263 find that
the first cigarette in the morning is the most difficult to give up, smoke more frequently during the
morning than the rest of the day, find it difficult to refrain from smoking in places where it generally is
not permitted (e.g., church), or smoke even when they are so ill that they are confined to bed.1, 2, 8
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Although most individuals who have quit smoking have done so spontaneously without the aid of an
organized smoking cessation program such as one that includes therapy with nicotine polacrilex or
transdermal nicotine,35, 74, 75, 86, 97 without social support procedures directed specifically at
maintenance of abstinence, abstinence rates generally have been low.34, 35, 42, 56, 63, 97 Individuals
most likely to quit spontaneously or with minimal intervention appear to be psychologically healthier,
smoke less heavily and for fewer years, are generally more skillful in controlling their own behavior, and
are well motivated.34, 35 Light smokers who may not be dependent on nicotine may only require
psychologic behavior modification to discontinue cigarette smoking.5, 11, 34, 48, 56
Other Uses
Nicotine polacrilex reportedly has provided temporary relief (for about 1 hour after chewing a piece of
the gum) of hemidystonia in a patient with severe dystonia of the left hand and athetoid movements of
both feet.71
Nicotine also has been administered transdermally in the management of ulcerative colitis.125, 204,
205, 206, 207, 208, 209, 210 Transdermal nicotine appeared to produce therapeutic benefit in patients
who also were receiving conventional pharmacologic therapy (e.g., mesalamine with or without
corticosteroids) for active ulcerative colitis.204, 205, 206, 207, 235, 236, 237 Clinical improvement, as
indicated by scores on a disease activity index, was observed in a greater proportion of patients treated
with transdermal nicotine at a dosage titrated up to 22 mg daily for 4 weeks than with placebo.204
Improvement from baseline in stool frequency, sigmoidoscopic results, and global assessment by the
physician were each distinctive of the superiority of transdermal nicotine over placebo after 4 weeks ofsuch treatment.204 Transdermal nicotine in a dosage of up to 25 mg daily for 6 weeks produced greater
improvement than did placebo in the global clinical grade, daily stool frequency, abdominal pain, and
fecal urgency in patients with active ulcerative colitis that relapsed during conventional pharmacologic
therapy.206, 208, 209 In addition, improvement in the histologic score of rectal biopsies was greater
with transdermal nicotine than with placebo after 6 weeks of treatment.206, 208, 209 Transdermal
nicotine alone was not effective in the maintenance of patients with ulcerative colitis in remission.205,
208, 210 The number of relapses that occurred during 6 months of treatment in such patients did not
distinguish transdermal nicotine from placebo.205, 210 Additional study is needed to adequately
determine the role of nicotine in the management of this condition.204, 205, 208, 209, 210
Dosage and Administration
Administration
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Buccal Administration
Buccal nicotine polacrilex is administered orally as a chewing gum or lozenge; the gum or lozenge should
not be swallowed.1 In addition, the lozenge should not be bitten or chewed like a hard candy.260, 263,
264 To obtain optimum results, patients should be provided self-help materials, advice, and instructions
in the proper use of the gum or lozenge.1, 194, 195, 196, 198, 241, 257 Patients should be given a copyof the patient information provided by the manufacturer and should be instructed to read and keep this
information.1, 190, 264 Patients should be instructed to stop smoking immediately prior to initiating
buccal nicotine polacrilex therapy and to not eat or drink anything other than water for 15 minutes
before and during chewing of the gum or sucking on the lozenge.1, 190, 257, 263, 264 However, some
clinicians suggest that some carefully selected heavy smokers may benefit from a cessation program
that includes a gradual reduction in cigarette smoking and concomitant use of nicotine polacrilex;58
additional evaluation of such concomitant use is needed.257
Patients receiving buccal nicotine polacrilex therapy with the gum should chew one piece of gum
whenever they have the urge to smoke.1 They should be instructed to chew the gum very slowly until
the distinctive peppery taste of nicotine, minty or orange taste of the flavored gum, or a slight tingling in
the mouth is perceived, and to then stop chewing and park the gum between the cheek and gum; once
this tingling is almost gone (usually within about 1 minute), this chewing procedure should be repeated
intermittently for about 30 minutes or until the taste dissipates.1, 257 The initial taste or tingling usually
is perceived after about 15 chews but its onset exhibits interindividual variation.1 This chewing
technique provides constant, slow, buccal absorption of nicotine from the gum.1, 257 Patients should be
advised that chewing the gum will not provide the same rapid satisfaction that smoking tobacco
provides.1 Chewing the gum too rapidly can cause excessive release of nicotine, resulting in adverse
effects similar to those of oversmoking (e.g., nausea, hiccups, irritation of the throat).1
Patients receiving buccal nicotine polacrilex therapy with the lozenge should be instructed to suck on
the lozenge until it dissolves.263, 264 The lozenge should be allowed to dissolve slowly in the mouth
over 20-30 minutes, periodically moving the lozenge (e.g., with the tongue) from one side of the mouth
to the other; patients should be advised to minimize swallowing while the lozenge is dissolving in the
mouth.263, 264 The lozenges are self-administered in response to the patient's cravings for nicotine
during the day, with the frequency of administration expected to decline over time as nicotine cravings
and/or withdrawal symptoms decline.263, 264 (See Dosage: Buccal Dosage in Dosage andAdministration.)
For information on buccal administration via oral inhalation of nicotine, see Administration: Oral
Inhalation, in Dosage and Administration.
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Transdermal Administration
If the protective pouch containing a transdermal nicotine system is damaged, the system should not be
used because of the possibility that tampering has occurred.101, 102, 103, 104 To expose the adhesive
surface of a nicotine transdermal system, the protective liner should be peeled and discarded just prior
to application.101, 102, 103, 104, 129 The transdermal system should be applied immediately after
removal from its protective pouch and removal of the protective liner to avoid loss of nicotine through
volatilization.101, 102, 103, 104
Nicotine transdermal systems should be applied to clean, dry, hairless areas of skin on the trunk or
upper outer arm at the same time each day, usually after awakening.101, 102, 103, 129, 167, 188, 189,
257 The application site should not be oily, damaged, or irritated;43, 101, 129 if necessary, hair may be
clipped, but the area should not be shaved.167 The transdermal system usually is applied as soon as thepatient wakes up; for patients who experience sleep disruption while receiving a 24-hour transdermal
system, the system can be removed prior to bedtime or the patient can be switched to application of a
16-hour system after awakening.257 The manufacturer states that each Nicotrol transdermal system
should not be applied for longer than 16 hours daily; patients who forget to remove these systems at
bedtime may experience vivid dreams or other sleep disturbances.262
With the adhesive side touching the skin, the transdermal system should be pressed firmly in place with
the palm of the hand for about 10 seconds, ensuring good contact, particularly around the edges.101,
129, 167 If the system should inadvertently come off during the period of use, the manufacturers
recommend that a new system be applied;101, 102, 103, 104, 167 the application schedule employed
may either be continued or changed so that the next system would be applied 24 hours later.129
To minimize and/or prevent potential skin irritation, application sites for the transdermal systems
should be rotated; an interval of at least 1 week should be allowed between application at a given
site.101, 102, 103, 129 After removal, used transdermal systems should be folded so that the adhesive
side adheres to itself, placed in the empty protective pouch of the system just applied, and then
disposed of immediately to prevent access by children or pets.101, 102, 103, 104, 129, 264 (SeeCautions: Precautions and Contraindications.) After handling a nicotine transdermal system, patients
should wash their hands with water alone since soap reportedly may enhance percutaneous absorption
of the drug; patients should avoid touching their eyes prior to handwashing.43, 101, 102, 103, 104, 129,
167
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Intranasal Administration
Nicotine nasal solution is administered intranasally via a metered-dose spray pump.191 A 1-mg dose is
delivered by administering 1 metered spray into each nostril (i.e., 2 sprays total).191, 257 (See Dosage:
Intranasal Dosage, in Dosage and Administration.) Patients should be instructed carefully regarding the
proper use of the nasal spray and their questions should be answered.191 They should be advised to tilttheir head back slightly when administering nicotine nasal spray and to not sniff, swallow, or inhale
nasally during administration since these may increase the irritating effects.191, 257 Comprehension by
the patient of the directions for the use of nicotine nasal spray and safe disposal of spent containers
should be ensured.191 Patients should be instructed to stop smoking completely upon initiation of
therapy with nicotine nasal spray.191
Oral Inhalation
Nicotine oral inhaler is administered as an inhaled vapor from cartridges containing porous plugsimpregnated with the drug.244, 245, 246, 247, 248 Patients should be carefully instructed in the proper
use of the oral inhaler.244, 250 To obtain optimum results, patients also should be given a copy of the
patient instructions provided by the manufacturer and should be instructed to stop smoking
completely.244, 250
Only a small portion of the dose is released from the inhaler with each inhalation, and the amount of
nicotine released depends on the volume and temperature of the air passing through the inhaler.244,
245, 246, 247, 248 At room temperature, the inhaler releases approximately 13 ng of nicotine per rapid
shallow (about 50-mL) inhalation or about 1 mg per 80 inhalations;245 however, intense deep
inhalations can release up to 4 mg of the drug from the plug per 80 inhalations.244, 247
Patients should be advised that puffing on the inhaler for about 5 minutes at a time will provide about 4
uses per inhaler cartridge.250 Oral inhalation over 5 minutes using rapid shallow sucking/puffing
("buccal mode") has been shown to produce delivery of the drug comparable to that using slow deep
inhalation ("pulmonary mode").248 Therefore, because the deep inhalation technique requires
considerable effort but does not result in substantially increased drug delivery or other benefits,248 the
shallow puffing method generally is preferred.244, 248, 250 257
Patients should be advised that while use of the oral inhaler mimics that of smoking cigarettes, deep
inhalation via the inhaler is not necessary for effective absorption of nicotine but more frequent puffing
of the inhaler generally is required.244, 245, 248 Patients also should be advised that optimum results
generally are achieved by frequent continuous puffing of the inhaler over 20 minutes.244 Patient
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tolerance of the local irritant effects of orally inhaled nicotine generally improves with continued
therapy.244
Nicotine is used up from each cartridge after about four 5-minute sessions of inhalation or one 20-
minute session of active puffing.250 After a few days of use, patients will become aware of what
method and frequency of oral inhalation works best for them as well as knowing when the cartridge is
used up.250 After complete use of a given cartridge, the mouthpiece should be separated carefully from
the inhaler and the cartridge removed and disposed of properly.244, 250 (See Cautions: Precautions and
Contraindications.) After use, the mouthpiece should be stored in the plastic storage case for further
use.244 The mouthpiece is reusable and should be cleaned regularly with soap and water.244
Dosage
Buccal Dosage
Dosage of nicotine polacrilex is expressed in terms of nicotine.1, 264 Dosage of nicotine polacrilex
should be individualized by the patient after careful instruction and, unless self-administered without
supervision,190 should be assessed periodically by the clinician.1, 43, 195 Supervised or unsupervised
(self-medication) nicotine polacrilex therapy can be initiated with either the 2- or 4-mg (of nicotine) gum
or lozenge, but should be individualized depending on the patient's degree of nicotine dependence.1,
190, 195, 257, 263, 264
Nicotine Polacrilex Gum
In most cases, nicotine replacement therapy with nicotine polacrilex gum is initiated with the 2-mg (of
nicotine) gum.195 Initial therapy with the 4-mg gum generally is preferred for heavy (highly dependent)
smokers (e.g., as determined by a Fagerstrom Tolerance Questionnaire [FTQ] score of 7 or greater,
current smoking history of more than 20-25 cigarettes per day, smoking within 30 minutes of
awakening, or difficulty refraining from smoking in places where it is forbidden). In addition, some
patients initially receiving the 2-mg gum may benefit from substitution of the 4-mg gum (e.g., those who
fail to stop smoking with the 2-mg gum, those whose withdrawal symptoms with the 2-mg gum remains
so strong as to threaten relapse).
Patients often do not use enough nicotine polacrilex gum to obtain maximum benefit; they chew too
few pieces daily and do not use the gum for a sufficient number of weeks. 257 Because of evidence that
abstinence rates may be improved when nicotine polacrilex gum is administered on a regular schedule
rather than on an as-needed ("prn") basis, it may be preferable to follow a fixed dosing schedule such as
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instructing patients to chew at least one piece of gum at 1- to 2-hour intervals for at least 1-3
months.257 Alternatively, when nicotine polacrilex therapy is initiated, patients can be instructed to
chew one piece of gum whenever the urge to smoke a cigarette occurs,1 and to titrate their daily use of
the gum according to tolerance and response.1 To minimize adverse effects, it is important that patients
be instructed carefully regarding the need to self-titrate their dosage of the gum and to chew the gum
slowly (see Dosage and Administration: Administration), since adverse effects are related principally to
the balance between the individual's degree of nicotine tolerance and the rate and extent of absorption
of nicotine from the gum.1
During the first month of smoking-cessation therapy with nicotine polacrilex, most patients require
approximately 9-12 pieces of 2-mg (of nicotine) gum (18-24 mg of nicotine) daily, one piece at a time.1
This dosage has been reported to approximate usual nicotine doses attained from smoking 20 cigarettes
daily.5, 43 Most patients receiving the 4-mg gum respond to 9-12 pieces (36-48 mg of nicotine) daily.
The maximum dosage of nicotine polacrilex should not exceed 30 pieces (60 mg of nicotine) of 2-mg
gum daily under the supervision of a clinician1, 195 or 24 pieces (48 mg of nicotine) daily when
unsupervised during self-medication,190, 257 and maximum dosage of the 4-mg gum should not exceed
24 pieces (96 mg of nicotine) daily, whether supervised or not.190 When supervised, patients should be
evaluated at intervals of no more than 1 month to determine their smoking status and whether
adjunctive therapy with nicotine polacrilex gum should be continued.1 As the patient's urge to smoke
decreases, the number of pieces of gum used each day should be reduced gradually.1, 190
Attempts to gradually reduce nicotine polacrilex dosage generally should begin after 2-3 months of
successful smoking abstinence. In patients who are successfully abstaining from smoking after 3 months
of therapy, nicotine polacrilex generally should be discontinued or, when the patient is using more than
2 pieces of gum daily at this time, gradually withdrawn.1 In general, gradual withdrawal of the gum can
be accomplished by instructing the patient to reduce their consumption by one or more pieces daily at
4- to 7-day intervals as tolerated. Alternatively, patients can reduce the chewing time for each piece of
gum from the usual 30-minute duration (see Dosage and Administration: Administration) to 10-15
minutes for 4-7 days, and to subsequently begin reducing the daily consumption of pieces of gum as
described. Some patients also may benefit from a withdrawal schedule that involves decreasing the
number of daily pieces of gum chewed while increasing the duration of chewing for each piece to
periods that exceed 30 minutes. Substituting nonmedicated sugarless chewing gum for discontinued
doses of nicotine polacrilex gum may aid in successful withdrawal of the drug. For patients receiving the
4-mg gum, substitution of the 2-mg gum for individual doses and any of the previously described
procedures also could be followed. Some clinicians state that it may be possible to discontinue nicotine
polacrilex therapy prior to 3 months in some patients (e.g., those who are confident that they can
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remain abstinent if therapy is discontinued, those who have titrated their dosage of the gum to 2 or
fewer pieces daily).43
When nicotine polacrilex gum is used for self-medication, the manufacturer recommends a 12-week
schedule of gradually decreasing dosage.190 In this schedule, the usual initial dosage of the gum in
adults 18 years of age or older is one 2- or 4-mg piece chewed at 1- to 2-hour intervals during weeks 1-6,
followed by this dose administered at 2- to 4-hour intervals during weeks 7-9 and then at 4- to 8-hour
intervals during weeks 10-12.190 If the patient feels the need for continued use of the gum after this
period, a clinician should be consulted.190 If problems of the mouth, jaw, or teeth develop during self-
medication with buccal nicotine polacrilex, use of the gum should be stopped and a clinician
consulted.190Use of the gum also should be stopped and a clinician consulted if an irregular heart beat
or palpitations develop or if manifestations of nicotine overdosage (e.g., nausea, vomiting, dizziness,
weakness, rapid heartbeat) develop.190
Use of the gum for longer than 3 months is discouraged by the manufacturer and the benefit of
continued therapy should be weighed against the risk of nicotine dependence.1, 81 If the drug is used
for 3 months or longer, withdrawal from the gum should be gradual and should be completed by 6
months; use of nicotine polacrilex for longer than 6 months is not recommended by the manufacturer.1
(See Chronic Toxicity.) Since most patients who have returned to smoking during participation in a
smoking-cessation program that included nicotine polacrilex therapy have done so within 6 months
after initiation of the gum and because the efficacy of continuing therapy with the gum has not been
established, the manufacturer recommends that nicotine polacrilex be withdrawn gradually in patients
who have not spontaneously reduced their consumption of the gum after 6 months of therapy.1Although use of nicotine polacrilex for longer than 6 months is not recommended by the manufacturer,1
many clinicians state that therapy for longer than 6 months may be beneficial in some patients and the
need for continued use should be determined mainly by the patient's preference, since such continued
use is not associated with substantial risk and almost all patients eventually will discontinue use of the
gum.9, 43, 65, 96, 98, 195, 196, 257 In addition, there is some evidence that continuing nicotine
polacrilex therapy beyond (e.g., for a year or longer) the usually recommended period may promote
long-term abstinence in some patients.257 Although weaning from nicotine replacement therapy should
be encouraged, continued use of such therapy is clearly preferable to a return to smoking and its health
consequences.257
Nicotine Polacrilex Lozenges
The initial replacement dosage of nicotine polacrilex lozenges for self-administration should be
determined by the patient's level of nicotine dependency as indicated by the time to smoking their first
cigarette [TTFC] upon awakening.263, 264 Patients who smoke their first cigarette within 30 minutes of
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awakening are considered to have high dependence and should initiate therapy with the 4-mg lozenges,
and those who smoke their first cigarette later than 30 minutes after awakening are considered to have
low dependence and should initiate therapy with the 2-mg lozenges.263, 264
During the first 6 weeks of therapy with nicotine polacrilex lozenges, low- or high-dependence smokers
should receive 2 or 4 mg of nicotine, respectively, every 1-2 hours, with a recommended minimum use
of 9 lozenges daily.263, 264 Taking at least 9 lozenges daily during this initial phase of therapy appears
to optimize the likelihood of success.263, 264 During weeks 7-9, low- or high-dependence smokers
should receive 2 or 4 mg of nicotine, respectively, every 2-4 hours, and during weeks 10-12, they should
receive the respective dose every 4-8 hours.263, 264
Generally, patients should discontinue nicotine polacrilex replacement therapy with the lozenges after
12 weeks,263, 264 although some patients may require occasional use of the lozenges over weeks 12-24for situations when they might be tempted to smoke.263 In addition, the patient's clinician may
recommend a regimen that extends beyond the initial 12 weeks.264 Patients should be advised to
contact their clinician if they feel the need for continued nicotine replacement therapy beyond the usual
12-week regimen.264
Patients should be instructed not to exceed 5 nicotine polacrilex lozenges in any 6-hour period nor to
exceed 20 lozenges daily.263, 264 In addition, patients should be instructed not to use more than one
lozenge simultaneously nor to use them in uninterrupted sequence since the risk of certain adverse
effects (e.g., hiccups, dyspepsia, nausea) may be increased with such administration.264
Transdermal Dosage
Transdermal systems of nicotine are applied only once daily; after the prescribed duration of daily use
(e.g., 16 or 24 hours), the system in use is removed and discarded and a new system is applied at a
different site.101, 102, 103, 104, 129, 167, 188, 189, 257 The Nicotrol transdermal system is designed
to provide systemic nicotine delivery of nicotine over 16 hours; this system is applied daily after
awakening and removed before retiring.104, 257 Patients should be instructed not to use the same
Nicotrol transdermal system for longer than 16 hours.188 The duration of daily use for NicoDerm CQ
is 16- 24 hours; patients who crave a cigarette upon awakening should wear this transdermal system for
24 hours.189 Patients who experience vivid dreams or other disturbances of sleep with application of
NicoDerm CQ for 24 hours should remove the transdermal system after about 16 hours of application,
before retiring.189, 257, 262 Patients should be instructed not to use the same NicoDerm CQ
transdermal system for longer than 24 hours.189
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Self-medication
For self-medication as a temporary adjunct in the cessation of cigarette smoking in adults who smoke
more than 10 cigarettes daily, transdermal nicotine therapy with NicoDerm CQ is initiated with the
21-mg/day strength.189 The usual dosage schedule consists of 4-6 weeks of therapy with a transdermal
system delivering 21 mg/day of nicotine, followed by 2 weaning periods in which systems delivering 14
and 7 mg/day are each used for 2 weeks, for a total duration of therapy of 10 weeks; therapy is then
discontinued.189, 257 In adults who smoke 10 or fewer cigarettes daily, therapy with NicoDerm CQ is
initiated with the 14-mg/day s