Nicotin, AHFS

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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

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Nicotin, AHFS