NICOTINE REPLACEMENT THERAPY

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TOBACCO USE AND CESSATION

NICOTINE REPLACEMENT THERAPY Reginald V. Fant, PhD, Lucy L. Owen, DPhil, and Jack E. Henningfield, PhD

The Agency for Health Care Policy and Research (AHCPR) Clinical Practice Guideline on Smoking Cessation states that “All physicians should strongly advise every patient who smokes to quit.” Randomized clinical trials have shown that physician advice to quit smoking by itself improves cessation rates by 30%.63Physicians can further aid smokers by recommending nicotine replacement therapy (NRT) to their patients to aid in their quit attempts.63NRT has been shown to be efficaciousin helping smokers quit. In fact, the data to support the efficacy of NRT are strong enough that the AHCPR recommends the following to physicians: ”Patients should be encouraged to use nicotine replacement therapy (patch or gum) for smoking cessation, except in the presence of special circumstances (e.g., cardiovascular disease, pregnancy).” The public health impact of treating smokers is enormous. It has been estimated that 400,000 premature deaths in the United States each year are attributable to cigarette smoking40and that up to one half of all smokers die prematurely from tobacco-related di~ease.4~ Cigarette smoking has been shown to cause myriad diseases and disorders that cost smokers their health and their lives and that cost society approximately $100 billion a n n ~ a l l y . ~ Cigarettes are to lung cancer what contaminated heroin needles are to HIV and hepatitis; in both cases, the role of the highly addictive drug

This paper was written, in part, with financial support from SmithKline Beecham Consumer Healthcare. ~~~~~~~

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From Pinney Associates (RVF, LLO, JEH), Bethesda; and the Division of Behavioral Biology, The Johns Hopkins University School of Medicine (JEH),Baltimore, Maryland

PRIMARY CARE VOLUME 26 *NUMBER 3 *SEPTEMBER 1999

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(nicotine or heroin) is to sustain repetitive use.21That is, the death and disease caused by cigarette smoking is not primarily due to nicotine, but rather the huge number of carcinogens and other toxins produced by the burning and inhalation of tobacco. With one third to one half of occasional users graduating to maladaptive use and physical dependence, cigarettes are one of the most addictive drugs known.16,22 The main cause of death from nicotine and heroin dependence is the contaminated drug delivery system (and not the drug itself), therefore, an important treatment modality for tobacco and heroin dependence is to provide a medication with a favorable risk-to-benefit ratio to replace the drug of abuse, that is, oral methadone for heroin or nicotine medications for tobacco. The vast majority of smokers in the United States report that they would like to quit; however, only about 3%of smokers who quit abruptly on their own (cold It has been repeatedly turkey) remain abstinent for longer than 6 shown that NRT is an effective aid in the treatment of tobacco a b ~ t i n e n c e . ~ ~ This article summarizes the scientific rationale for nicotine replacement medication, describes the clinical features of each of the currently available medications, and offers recommendations as to how nicotine replacement medications might be used in the future to treat tobacco dependence. NICOTINE DEPENDENCE

Two medical disorders are now widely recognized to represent what is generally termed tobacco addiction or dependence: nicotine dependence, which is the disorder of maladaptive and seldom spontaneously remitting tobacco use; and nicotine withdrawal, which is the constellation of withdrawal symptoms that accompany tobacco abstinence in a nicotine-dependent person.' The vast majority of daily cigarette smokers sustain dependence-producing levels of nicotine intake, averaging approximately 20 cigarettes per day, with more than 85%smoking more than 5 cigarettes every day.I6 This level of cigarette smoking provides sufficient nicotine intake to produce a number of physiologic and behavioral effects associated with dependence? Specifically, all widely marketed cigarettes contain between 6 and 13 mg of of which the smoker typically absorbs 1 to 3 mg, irrespective of the nicotine-yield ratings provided on cigarette packages by the tobacco c o m p a n i e ~ .The ~ ~ ,typical ~ ~ pack-per-day smoker absorbs 20 to 40 mg of nicotine each day, achieving nicotine plasma concentrations of 23 to 35 ng/mL by the afternoon? Nicotine has a chemical structure that enables it to readily produce the same kinds of addictive effects as drugs such as heroin, cocaine, and alcoho1.28,60,61 As with these other drugs, the risk and severity of nicotine addiction in an individual and the prevalence of use and dependence in a population are influenced by a range of factors including price, availability, social and legal sanctions, and perceptions of harm.22Nicotine administration can produce psychoactive effects, mood alterations, strong reinforcing effects, physical dependence, and tolerance.61The effects of nicotine that are associated with dependence include increased expression

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of brain nicotine receptors, changes in regional brain glucose metabolism, electroencephalographicchanges, the release of catecholamines, tolerance, and physiologic dependence.61These effects increase the compulsion to smoke by producing positive reinforcement (with the administration of nicotine) and withdrawal symptoms (with abstinence). Effects and symptoms vary within individuals over time. Additional determinants of the effects of nicotine, desired and undesired, are dose, speed of administration, and sensory factors associated with the formulation. Because nicotine is a small water- and lipid-soluble molecule, it is readily absorbed by various routes of administration. Speed of nicotine in blood levels varies widely by formulation. As shown in Figure 1, cigarettes and smokeless tobacco produce high levels of nicotine very rapidly. In fact, arterial levels can be ten times higher than venous levels during the smoking of the ~ i g a r e t t e .In ~ ,contrast, ~~ with the exception of nicotine nasal spray, nicotine replacement medications are very slow in their delivery of nicotine relative to cigarette smoking; nasal spray is somewhat faster than other nicotine replacement medications. As a psychoactive drug, nicotine produces effects that are readily identified by humans and animals and are reinforcing even in the absence of tobacco. For example, human abuse liability studies show that rapid administration of nicotine (e.g., by way of cigarette smoke or intravenous administration) produces dose-related increases in scores on liking scales. These are similar to those observed in comparable studies for drugs such as cocaine and morphine.1s,28,61 Slower delivery forms of pure nicotine formulated as medications are much lower in abuse liability (Fig. 2) and

t C A g a r e t t e (nicotinedekry, 1-2 mg)

*Oral

Snuff

tNasal spray (nicotinedelivery 1mg)

x Polacrilex(nicotinedelivery,4mg) +Nicoderrn

-+- Ncotrol

-10 0 10 20 30 40 50 60 70 80 90 100 110 120

Minutes Figure 1. Venous blood concentrations in nanograms of nicotine per millimeter of blood as a function of time for various nicotine delively systems. (Data from 2, 6,51 .)

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Cigarette 3 T

1

0

Smokeless Tobacco

I.V. Nicotine

3T

3 T

0

3

2

1

2

3

0

1

2

3

':b Nicotine Gum

4

Nfcotlne Patch

~

a 1 4 0

0

2

4

6

0

22

44

Figure 2. Mean liking scores from studies in which subjective effects and other data were collected as a function of nicotine dosing condition. (Data from 8, 19, 20, 26,45, 52.)

do not produce such elevated scale scores. Physiologic actions that are associated with, and possibly mediate, the abuse potential of nicotine include alteration of function and structure of the nervous system including increased expression and reduced turnover of nicotine receptors in the brain and other parts of the body, alteration of brain EEG and regional cerebral glucose metabolism, and activation of dopaminergic reinforcement systems in the brain.3'jT6' The involvement of dopaminergic neurotransmitters in the reinforcement of nicotine self-administrationis another quality shared with cocaine, and perhaps other drugs of a b u ~ e . ' ~Data ,~~,~~ by Fowler et all5show that brains of living smokers show a 40% decrease in the level of monoamine oxidase B (MA0 B), compared with non-smokers or former smokers. M A 0 B is involved in the breakdown of dopamine;

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thus M A 0 B inhibition is associated with enhanced activity of dopamine and antidepressant effects. Such effects are related to the dose and speed of nicotine d e l i ~ e r y . ~ , ~ ~ Nicotine has other physiologic actions that may be reinforcing to smokers. Nicotine increases general metabolic rate, may reduce the hunger for sweet tasting foods, and can decrease body This is clinically important in smoking cessation efforts, because self-reported smoking for weight control reasons is associated with a lack of intention to quit smoking.@In smokers who are attempting to quit, nicotine enhances certain types of performance and mood that may contribute to the reasons that people find it difficult to abstain from nicotine.17 Nicotine may be capable of enhancing certain types of performance related to attention in non tobacco user^.'^,^ These improvements in performance and mood, however, appear to be primarily related to reversal of withdrawal-related decrements in performance and mood rather than actual improvements. PHYSIOLOGIC BASIS FOR NICOTINE REPLACEMENT THERAPY

The most well studied and well documented pharmacologic approach to help smokers manage the signs and symptoms of nicotine dependence and withdrawal is therapeutic use of nicotine replacement medications. Since the 1970s, hundreds of studies have been conducted on the safety, efficacy, and mechanisms of action of this class of medications. Nicotine medications enable the tobacco-dependent person to abstain from tobacco by replacing, at least partially, the nicotine formerly obtained from tobacco. Nicotine replacement therapy provides nicotine-mediated neuropharmacologic effects, such as increased expression and reduced turnover of nicotine receptors in the brain and other parts of the body, alteration of brain EEG and regional cerebral glucose metabolism, and activation of dopaminergic reinforcement systems in the brain.61There appear to be at least three major mechanisms by which NRT enhances smoking-cessation efforts.2,18 First, medications may reduce either general withdrawal symptoms or at least prominent ones, thus enabling people to function normally while they learn to live without cigarettes. Second, medications may also reduce the reinforcing effects of tobacco-delivered nicotine. Finally, nicotine medications may provide some effects for which the patient previously relied on cigarettes, such as sustaining desirable mood and attention states and making it easier to handle stressful or boring situations. AVAILABLE NICOTINE MEDICATIONS

Currently, there are four types of nicotine replacement medications on the market: gum, patch, nasal spray, and vapor inhaler. Table 1 shows that these products are all very much different from cigarettes in terms of

m

W

QI

-

High High High Low Low High

High High High High

Cigarette

Mod Mod Low Mod Low Mod Mod Low High Mod Low

2-mg Gum

Mod Mod Mod Mod Low Mod Mod Low High Mod Low

4-mg Gum

Mod High Mod Low Low Low Low Low High High Low

16-hr Patch

Mod High Mod Low Low Low Mod Low High High Low

24-hr Patch

Data from Nicotine Replacement Guidance Working Group (1999):choosing a nicotine replacement product: A guide. London, 1999

Ease of access Convenienceof use Nicotine dose typically obtained Can control how much nicotine you receive Similarity to smoking behavior Behavioral ritual Morning coverage Palatability/desirability to smokers Safety Discreetness/social acceptability Dependence potential

Feature

Table 1. CLINICAL FEATURES OF CIGARETTES AND NICOTINE REPLACEMENT MEDICATIONS

Low(Rx) Mod Mod Mod Low Mod Mod Low High Mod Mod

Spray

Low(Rx) Mod Low Mod Mod Mod Mod Low High Mod Low

Inhaler

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their dependence potential and consumer appeal. Meta-analyses demonstrate that smoking cessation rates have been approximately twice as high for smokers quitting with the aid of smoking cessation medications compared with those observed in smokers treated with p l a ~ e b o .The ~ ~ rates ,~~ of cessation in individual trials are related to a number of factors, including overall level of treatment intensity and level of nicotine dependence among patients. The following section offers a brief description of each of these four medications and includes their instructions for use, their sideeffect profiles, and other information that might be of use for physicians and patients. Because each of these medications has been shown to be effective, and because there have been no head-to-head trials of efficacy among these medications, the following information may be useful in helping patients decide which product might be the most effective in helping them to quit smoking. Gum

The first NRT that was made available to consumers was transmucosally-delivered nicotine polacrilex (nicotine gum). The 2-mg formulation of nicotine gum was first marketed in the United States in 1984 as a prescription medication. The 4-mg form was marketed in 1992 to enable patients to achieve higher plasma nicotine concentrations with less effort. In 1996, both the 2- and 4-mg forms were marketed as over-the-counter medications in the United States, which has made the products much more widely available to consumers. In 1999, a mint flavored gum was marketed in the United States in an effort to increase compliance with use instructions among patients who found the original (peppery) flavor to be unpalatable. About 50% of the nicotine in gum is absorbed into the mouth.2Thus, when gum is chewed on a fixed schedule of 10 pieces per day, a smoker receives about 10 mg or 20 mg of nicotine per day using the 2-mg or 4-mg gum formulations, respectively. The average systemic intake of nicotine from cigarettes is about 30 mg/d.8 Thus, most gum chewers do not match the daily nicotine levels achieved through smoking cigarettes. Furthermore, because of the relatively slow absorption of nicotine from gum compared with smoke inhalation, individual doses do not produce the extremely high arterial levels of nicotine produced by smoke inhalation.ls Smokers who use fewer pieces of gum achieve much lower concentrations of nicotine, which may reduce the efficacy of the treatment. Because of the importance of replacing nicotine in adequate quantities, success with nicotine gum treatment depends in part on how many pieces of gum the smoker chews per day.%More dependent smokers have been shown to improve their chances of achieving abstinence with the 4-mg rather than the 2-mg Compliance with nicotine gum is reduced in some people by the demands of oral manipulation, the unappealing flavor, jaw fatigue, jaw and mouth soreness, and headaches.4I These detrimental effects can be re-

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duced by using the instructed "chew and park" method of chewing in which the patient chews the gum until a peppery taste emerges, then parks the gum between the cheek and gum until it no longer produces a tingle. Other side effects of nicotine gum use include hiccuping, burping, and nausea although these effects are generally mild and transient when they do occur. There are several instructions for use that physicians should be particularly aware of when recommending nicotine gum to their patients. As mentioned above, success with nicotine gum therapy largely depends on how many pieces of gum the patient chews per day. For this reason, the patient should be encouraged to use at least 9 pieces of gum per day, at least at the beginning of therapy4' Gum should be used at a rate of one piece every 1 to 2 hours, although an additional piece may be used during the hour if a strong nicotine craving arises. The patient should be encouraged not to smoke while using nicotine gum; however, if a patient lapses, they should be instructed to resume gum use as soon as possible. Acidic beverages have been shown to interfere with buccal absorption of ni~otine'~; therefore, patients should avoid acidic beverages (e.g., soda, coffee, beer) for 15 minutes before and during gum chewing (Table 2).

Patch In the United States, prescription-only marketing of four transdermal-delivery ("nicotine patch) systems began in late 1991 and 1992. In 1996, two brands of nicotine patches were marketed as over-the-counter medications to increase availability to consumers. The transdermal patch delivers nicotine throughout the day. Compliance is based on whether or not the patient places the patch on the body in the morning, rather than on the patient's actively using a product throughout the day, as with the gum. As Figure 1 shows, the nicotine patch delivers nicotine more slowly than the gum does, although nicotine plasma concentrations can get higher during the day with patch use than with gum use, especially if the patient uses few pieces of gum. The wide variability in patch systems has been described in reviews3 Table 3 illustrates some of the key differences in the absorption kinetics of the patches as reported in the Physician's Desk Referen~e.~~ There is a wide variation between nicotine patch systems in terms of the plasma levels achieved and the speed of nicotine absorption. The maximum plasma concentrations range from 13 to 23 ug/L and the times taken to reach maximum plasma concentration range from 4 to 9 hours, depending on the patch. The most frequently reported side effects occurring with nicotine patch use are local skin reactions?' Cutaneous hypersensitivity and disseminated or contact sensitization have been reported with all 24-hour patches, although not with the 16-hour patch. Moving the site of patch application daily as instructed can reduce the incidence of skin reactions

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Table 2. SUGGESTIONS FOR THE CLINICAL USE OF NICOTINE GUM Parameter of Clinical Use

Dosage

Adverse effects

Patient instructions

Suggestion

Nicotine gum is available in doses of 2-mg and 4-mg per piece. The 2-mg dose should be recommended to those who smoke under 25 cigarettes per day. The 4-mg dose should be recommended to those who: use over 24 cigarettes per day; are highly dependent on nicotine; express a preference for a higher dose; or failed with the 2-mg gum, but remain motivated to quit smoking and prefer to quit with the aid of gum. Patients should not exceed 24 pieces of gum per day. Common adverse effects include mouth soreness, hiccups, dyspepsia, and jaw ache. These effects are generally mild and transient and can often be alleviated by correcting the patient’s chewing technique.

Scheduling of dose: A common problem with gum therapy is that patients d o not use enough gum to get the maximum benefit they chew too few pieces per day and do not use the gum for a sufficient number of weeks. Instructions to chew the gum on a fixed schedule (at least 1 piece every 1 to 2 hours) for at least 1 to 3 months may be more beneficial than instructions to use the gum as needed. Patients should by advised to use an extra piece of gum within the hour if strong cravings for nicotine arise. Chewing technique: The gum should be chewed slowly until a ”peppery” taste emerges, then “parked” between cheek and gum to facilitate nicotine absorption through the oral mucosa. Gum should be slowly and intermittently chewed and parked for about 30 minutes, then discarded. Absorption: Acidic beverages (e.g., coffee, juices, soft drinks) interfere with the buccal absorption of nicotine, so eating and drinking anything except water should be avoided for 15 minutes before and during chewing. ~

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Adapted from The Smoking Cessation Clinical Practice Guideline Panel and Staff The Agency for Health Care Policy and Research Smoking Cessation Clinical Practice Guidelines. JAMA 2751270,1996; with permission.

Table 3. PHARMACOKINETICSOF FOUR CURRENTLY AVAILABLE NICOTINE PATCHES MARKETED IN THE UNITED STATES

Cmax (ug/L) Cmin (ug/L) Tmax (hr) AUC (ug . hr/L)

Habitrol

Nicoderm

Prostep

Nicotrol

17 9 6 312

23 11 4 410

16 5 9 276

13 2 8 158

Data from Medical Economics Inc.: Physicians’ Desk Reference, ed 51. Montvale, NJ, Medical Economics Company, Inc, 1997.

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to the patch. Sleep disturbances have also been reported with 24-hour patches, and a dose effect has been noted, with 21-mg patches producing higher rates of sleep disturbance than 14- or 7-mg patches.58Physicians can recommend that persons who have sleep disturbances either use a 16hour patch, or remove the 24-hour patch soon before bedtime (Table 4). Nasal Spray

Nicotine nasal spray was first marketed in the United States as a prescription smoking-cessation medication in 1997. The nasal spray was designed to deliver doses of nicotine to the smoker more rapidly than was possible with use of the gum or patch. The device currently available to consumers is a multidose bottle with a pump mechanism fitted to a nozzle Table 4. SUGGESTIONS FOR THE CLINICAL USE OF NICOTINE PATCH Parameter of Clinical Use

Dosage

Adverse effects

Patient instructions

Suggestion

Treatment with nicotine patch of 8 weeks or less has been shown to be as effective as longer treatment periods. Based on this finding, the AHCPR suggests the following step-down treatment schedules as reasonable for most smokers. Clinicians should consult the package insert for other treatment suggestions. Clinicians should also consider individualizing treatment based on specific patient characteristics, such as previous experience with the patch, number of cigarettes smoked per day, and degree of addiction. Duration Dose Brand (weeks) trrtglh) Nicoderm and 4 21 /24 Habitrol then 2 14/24 then 2 7/24 4 22 / 24 Prostep 11/24 then 4 Nicotrol 4 15/16 then 2 10/16 then 2 5/16 Up to 50% of patients using the nicotine patch will have a local skin reaction. Skin reactions are usually mild and self-limiting, but may worsen over the course of therapy. Local treatment with hydrocortisone cream (5%)or triamcinolone cream (0.5%)and rotating patch sites as instructed may ameliorate such local reactions. In fewer than 5% of patients do such reactions require the discontinuation of nicotine patch treatment. Locution: At the start of each day, the patient should place a new patch on a relatively hairless location between the neck and waist. Time: Patches should be applied as soon as patients awaken on their quit day, and on every day of therapy thereafter.

Adapted from The Smoking Cessation Clinical Practice Guideline Panel and Staff The Agency for Health Care Policy and Research Smoking Cessation Clinical Practice Guideline: JAMA 2751270, 1996; with permission.

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that delivers 0.5 mg of nicotine per 50-uL squirt. Each dose consists of two squirts, one to each nostril. As Figure 1 shows, nicotine nasal spray is absorbed into the blood rapidly relative to gum and patch. Whereas the rate of plasma nicotine absorption with the spray approaches that of cigarettes and oral snuff, the magnitude of the increase in plasma nicotine concentrations is lower. According to labeling, the dose of nasal spray should be individualized for each patient based on the patient’s level of nicotine dependence and the occurrence of symptoms of nicotine excess. Patients should be started with 1 or 2 doses per hour, which may be increased to the maximum of 40 doses per day. One dose of nasal spray per hour (1-mg nicotine) for 10 hours produces average plasma concentrations of 8 ng/mL. There are a number of side effects associated with the use of nicotine nasal spray.41The most common side effects are nasal and throat irritation. Other side effects include coughing, sneezing, watery eyes, and runny nose. Nasal irritation occurs in the vast majority of users during the first few days of use and may reduce treatment compliance. Reports of moderate to severe nasal and throat irritation usually dissipate or diminish to mild symptoms within a few days of treatment; however, physicians should warn patients of these likely side effects and inform them that they should become bearable within a few days. As with nicotine gum, patients should be informed that success with therapy is largely related to how much of the product is used. Product labeling states that patients should use at least 8 doses (16 sprays) per day for optimal efficacy (Table 5).41 Table 5. SUGGESTIONS FOR THE CLINICAL USE OF NICOTINE NASAL SPRAY Parameter of Clinical Use

Dosage

Adverse effects

Patient instructions

Suggestion

Each actuation of nicotine nasal spray delivers 0.5 mg of nicotine. One dose of nicotine nasal spray is 1 mg (2 sprays, one in each nostril). Patients should start with one or two doses per hour. Patients may increase or decrease use as needed, but should not exceed 40 doses (80 sprays) per day. During the first 2 days of treatment, nasal irritation was reported by nearly all of the patients using the nicotine spray, the majority of whom rated the irritation as either moderate or severe. The frequency and severity of nasal irritation declined with continued medication use, but was still experienced by most patients after 3 weeks of treatment. Other common adverse events include runny nose, watering eyes, sneezing, and cough. Administration: Patients who do not use adequate amounts of spray will not get the maximum benefit. Patients should be encouraged to use at least 8 sprays per day. Patients should use extra doses within the hour if strong cravings for nicotine arise (up to 5 doses per hour).

Data from Medical Economics Inc.: Physician’s Desk Reference, ed 51. Montvale, NJ, Medical Economics Company, Inc, 1997.

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Vapor Inhaler

The nicotine vapor inhaler, which consists of a mouthpiece and a plastic cartridge containing nicotine, was first marketed in the United States in 1998 as a prescription smoking cessation medication. The vapor inhaler was designed to satisfy behavioral aspects of smoking, namely, the hand-to-mouth ritual, while delivering nicotine to combat physiological withdrawal symptoms produced by tobacco withdrawal. Each inhaler cartridge contains 10 mg nicotine, of which 4 mg can be delivered and 2 mg are The majority of nicotine is delivered into the oral cavity (36%)and into the esophagus and stomach (36%).37 Very little nicotine is delivered to the lung (4%).Because absorption is primarily through the oral mucosa, the rate of absorption is similar to that of nicotine gum. Patients may self-titrate with the inhaler to the level of nicotine they require. However, as with nicotine gum, success largely depends on the number of doses taken per day. In clinical trials, most smokers who successfully abstained from smoking used between 6 and 16 cartridges per day. The side effects of nicotine inhaler therapy primarily involve local irritation such as burning sensations in the throat, coughing, sneezing, and Although local irritation is generally mild, it may produce problems with compliance in that a patient is less likely to inhale deeply enough to deliver adequate amounts of nicotine if the irritation is construed as aversive. Moreover, because a large number of puffs are required, any of these side effects may produce less use of the product, which may reduce efficacy. As with nicotine gum, health care providers should emphasize the need for the patient to use enough cartridges per day to achieve levels of nicotine adequate to alleviate withdrawal symptoms and craving. The majority of people who successfully quit smoking used 6 to 16 cartridges per day.41Nicotine delivery also is related to the number and depth of inhalations. Labeling states that 80 deep puffs of the inhaler delivers 4 mg of nicotine; however, fewer or shallower puffs may not replace adequate amounts of nicotine. Moreover, the amount of nicotine absorbed from the inhaler is temperature with higher temperatures delivering larger amounts of nicotine and lower temperatures delivering smaller amounts. Thus physicians should warn patients that using the product in very cold temperatures may not allow them to receive adequate amounts of nicotine (Table 6). GENERAL PRECAUTIONS FOR NICOTINE REPLACEMENT MEDICATIONS Concomitant Use of Tobacco

Patients should be instructed to stop using tobacco products as soon as they begin using a nicotine replacement medication. Concomitant use

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Table 6. SUGGESTIONS FOR THE CLINICAL USE OF NICOTINE VAPOR INHALER Parameter of Clinical Use

Dosage Adverse effects

Patient instructions

Suggestion

An intensive inhalation regimen (80 deep inhalations over 20 minutes) releases approximately 4 mg of nicotine, of which about 2 mg is absorbed into the bloodstream. The most common adverse effects of the nicotine vapor inhaler include irritation of the mouth and throat, coughing, and running nose. The majority of these reactions were rated as mild and the frequency and severity of these symptoms typically declines with continued use of the treatment. Administration: Patients who d o not use the inhaler frequently enough to reduce nicotine withdrawal will not get the maximum benefit of the treatment. Most successful patients in the clinical trials used between 6 and 16 cartridges per day. Clinicians should advise patients to use at least 6 cartridges per day for the first 3 to 6 weeks of treatment. Additional doses may be needed to control the urge to smoke, with a maximum of 16 cartridges per day for up to 12 weeks. During the 6-12 weeks following the initial therapy, gradual reduction can be used, if needed. Temperature:The delivery of nicotine from the inhaler is related to temperature. Low temperatures may prohibit the inhaler from delivering adequate amounts of nicotine. Therefore, patients should be advised that they should not use the inhaler in cold temperatures.

Data from Medical Economics Inc.: Physicians’ Desk Reference, ed 51. Montvale, NJ, Medical Economics Company, Inc, 1997.

of NRTs and tobacco may increase a patient’s nicotine plasma concentration to a higher level than seen during tobacco use alone. For this reason, concomitant use is not recommended. If a patient does smoke a cigarette during NRT use, he or she should be encouraged to stop smoking immediately and resume NRT use as soon as possible to avoid full relapse. Use During Pregnancy

Cigarette smoking has been shown to be harmful to fetal health.62 Whereas cigarette smoke delivers a number of toxins to the fetus other than nicotine (e.g., carbon monoxide, carcinogens, etc.), nicotine may be responsible for some of the association between smoking and poor fetal outcome.46Because of the potentially harmful effects of nicotine on the fetus, nicotine gum, as a prescription medication, was rated by the FDA as a Category C drug; nicotine patch, vapor inhaler, spray have been rated as Category D drugs. These ratings allow physicians to determine the riskto-benefit ratio of recommending or prescribing nicotine replacement medications to pregnant women. Although there is a risk associated with nicotine use during pregnancy, it is likely much less than the risk associated with cigarette smoking. The AHCPR recommends that pregnant women be offered intensive counseling to quit smoking.63For pregnant

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women who cannot stop smoking without the aid of replacement therapy, NRTs should be used only if the increased likelihood of smoking cessation, with its potential benefits, outweighs the risk of nicotine replacement and potential concomitant smoking. Physicians play an important role in encouraging pregnant women who smoke to quit by helping them choose the safest and most effective means of quitting.

TAILORING OR RECYCLING WITH NICOTINE REPLACEMENT MEDICATIONS

There has been little research to support the use of one form of nicotine replacement medication over another, although patient preference and tolerability of the effects of each medication are appropriate to consider. Because of the lack of data-driven information, patient preference should be a physician's main consideration in recommending a particular medication. For example, if a patient complains of missing something in the mouth, nicotine gum may be a first consideration. If a patient wears dentures, however, a physician would be remiss in recommending nicotine gum. Similarly, if a patient complained of not knowing what to do with his or her hands, the inhaler might be a good first option. A heavily dependent smoker who needs symptomatic relief of withdrawal symptoms might prefer the nasal spray or gum, which provide on-demand nicotine delivery. Recycling refers to treating a patient who failed to quit smoking with nicotine replacement therapy for a second time. A patient's experience and preference should be taken into account in the patient and physician decisions to choose a smoking cessation medication for the second attempt. A physician can assist the patient by asking about previous experience with nicotine replacement medication and making a decision based in part on those experiences. If patients have a positive experience with a medication, physicians might recommend that they try that therapy again, but perhaps at a higher dose. If the patient had only some success with a medication, a different nicotine replacement medication more suitable to alleviating the more aversive experiences seen during the earlier experience should be recommended.

THE FUTURE OF NICOTINE REPLACEMENT MEDICATIONS

Although nicotine replacement medications have been shown to be effective in treating smokers, there is much room for improvement. Following are novel ways in which nicotine replacement medications could be used or improved to enhance their ability to aid smokers who are trying to achieve abstinence.

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Combined Use of Existing Medications

Studies have examined the effects of combining patch and gum34,49 and patch and nasal spray7as means of increasing abstinence rates during cessation attempts. There is a good scientific rationale for studying such a combination according to Fagerstrom et al.I4Smokers may need both a constant level of nicotine to relieve nicotine craving and tobacco withdrawal symptoms (patch) in addition to a self-administered, self-titrated, faster-acting preparation (gum, nasal spray) for more immediate relief of craving and withdrawal symptoms. Transdermal nicotine provides a general reduction of withdrawal symptoms and craving after application. This steady-state nicotine dosing, however, does not allow users to respond to break-through cravings with acute nicotine doses, whereas nicotine gum can have an effect within 10 to 15 minutes of chewing initiation. The speed of onset may be particularly important first thing in the morning, when the withdrawal symptoms and craving are at a peak for many smokers. The patch provides nicotine in a steady-state and passive form, whereas gum or nasal spray can be manipulated to accommodate the smoker’s needs. Thus combining nicotine patch, which may prevent the appearance of severe withdrawal, with a faster-delivery nicotine replacement medication, which can provide relief in trigger-to-smoke contexts (e.g., stressful situations, being around other smokers), may provide an excellent treatment option over either therapy alone. Possible Alterations to Existing Medications

There are alterations that could be made to improve the consumer appeal or efficacy of existing nicotine replacement medications. These improvements could be affected by modifying the amount of nicotine delivered, the rate of delivery, or the nonpharmacologic features of the products. As previously noted, currently available products generally do not deliver doses of nicotine that fully replace those seen during cigarette smoking. Therefore, increasing the dose of nicotine delivered by currently existing products, or the ease with which smokers can comfortablyachieve and sustain adequate nicotine concentrations, may lead to a higher rate of successful cessation attempts. Increasing the rate of nicotine delivery may also improve efficacy of the products. Cigarettes deliver a large bolus of nicotine to the smoker. Nicotine nasal spray is the only currently-available product that delivers moderate doses of nicotine to the smoker in a bolus fashion. Although arterial plasma levels of nicotine delivered by the nasal spray do not come close to measuring up to the huge levels seen during cigarette smoking, there is a slightly higher concentration of nicotine in the arterial blood relative to venous blood soon after administration. Although nicotine nasal spray mimics the bolus dosing seen during smoking to some degree, other products do not do so in their current form. There are, however,

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modifications to gum, patch, and inhaler that could achieve this end. For example, nicotine gum could be formulated with a buffer that would increase the pH of the oral mucosa, which would increase absorption rates. Patches could be designed to deliver nicotine more rapidly to the smoker by delivering it by way of electrophoresis. The vapor inhaler could be formulated relatively easily to deliver larger doses of nicotine per puff. Moreover, modifying the nonpharmacologic features of the products may increase compliance with treatment regimens. For example, one of the barriers to successful treatment with nicotine gum has been the poor palatability of the product. Although the recent introduction of mint flavoring was designed to improve compliance, it is likely that further product improvements could increase compliance even more without significantly altering the abuse potential of the product. New Nicotine Replacement Medications

It has been suggested that the best way to treat smokers with a wide variety of needs is to offer a wide variety of nicotine replacement medications. According to the Pharmaceutical Research and Manufacturers of America (PhRMA), there are several nicotine replacement medications currently in development. These include nicotine oral lozenges and oral transmucosal nicotine formulations. Tobacco-flavored chewing gum and tobacco-specific nitrosamine-freecigarettes also are in development. These products and other new nicotine formulations may make a significant contribution to public health, because they may offer treatment to a significant proportion of smokers who were not reachable by other nicotine replacement medications. PUBLIC HEALTH POLICY ISSUES

One of the main problems with tobacco dependence treatments stems from how nicotine replacement medications are regulated in comparison to tobacco productsz9Warner et aP6 highlighted the irony of the current status of nicotine product regulation: Although tobacco products, the deadly form of nicotine delivery, are the most widely available and least stringently regulated, nicotine replacement medications for the treatment of tobacco dependence are strongly regulated. The toxicity and addictiveness of nicotine varies widely as a function of the dosing characteristics and other constituents of a given nicotine delivery system. This raises the possibility that alternate forms of nicotine delivery could be fully or partially substituted for cigarette^.^^,^^ Presently, tobacco companies are permitted to make claims of reduced toxin delivery for low tar cigarettes, even though these companies have provided no evidence of actual human exposure reduction for such cigarettes.Nicotine replacement medications, on the other hand, cannot be advertised as partial smoking substitutes or as means to reduce smoking. This is not to

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imply that nicotine replacement medications are without some risk of unintended effects or that claims by pharmaceutical companies should be exempt from supportive data. Rather, tobacco and pharmaceutical companies should be held to similar standards to defend their claims and should endeavor to minimize risks. If they are not held to similar standards, the companies with the poorest records in public health will likely continue to be the sole commercial suppliers of putative harm reduction approaches because of their less restricted ability to develop products and make claims with fewer restriction^.^^ SUMMARY

Physicians can help their patients quit smoking by recommending to all of their patients that they quit smoking, and recommending that they quit with the help of nicotine replacement medications. Nicotine replacement medications aid smokers in their cessation efforts by relieving the physiologic symptoms of nicotine withdrawal. Because nicotine medications do not deliver myriad toxins and carcinogens that cigarettes deliver, these medications are safe when used as directed. Although the efficacy of nicotine medications in helping smokers to quit has been well documented, there is much room for improvement. There are improvements that could be made to the products themselves, but there are also improvements that could be made in the way that these products are regulated, compared with tobacco products. Cigarettes are highly appealing to smokers, inexpensive, and easy to produce, whereas nicotine medications are generally unappealing to smokers, expensive, and often require a prescription. In addition, cigarettes are available at gas stations, convenience stores, grocery stores, and vending machines, whereas nicotine replacement medications currently are available only in stores that sell pharmaceuticals. So long as these barriers to effective treatment exist, many smokers are likely to continue to use the more appealing, and deadly, cigarettes. References 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. DSM-IV, Fourth Edition. Washington DC, American Psychiatric Association, 1994 2. Benowitz NL: Nicotine replacement therapy: What has been accomplished-Can we do better? Drugs 45:157, 1993 3. Benowitz NL: Clinical pharmacology of transdermal nicotine. Eur J Pharm Biopharm 41:168, 1995 4. Benowitz NL, Henningfield JE: Establishing a nicotine threshold for addiction. N Engl J Med 331:123, 1994 5. Benowitz NL, Jacob P 111: Daily intake of nicotine during cigarette smoking. Clin Pharmacol Ther 35:499,1984 6. Benowitz NL, Porchet H, Sheiner L, et al: Nicotine absorption and cardiovascular effects with smokeless tobacco use: Comparison with cigarettes and nicotine gum. Clin Pharmacol Ther 4493,1988

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