- Email: [email protected]
Quitting by Gradual Smoking Reduction Using Nicotine Gum
Quitting by Gradual Smoking Reduction Using Nicotine Gum A Randomized Controlled Trial Saul Shiffman, PhD, Stuart G. Ferguson, PhD, Kenneth R. Strahs, PhD Background: Many smokers express a desire to quit smoking by gradually reducing the number of cigarettes they smoke until they stop completely. This study tested the efficacy of nicotine gum in facilitating cessation through gradual reduction. Design:
This was a multi-center, placebo-controlled, double-blind RCT of 2- and 4-mg nicotine gum versus placebo.
Setting/ 3297 smokers who were interested in quitting gradually. participants: Intervention: Subjects were instructed to gradually reduce their smoking while increasing their gum use over the course of up to 8 weeks. Once they had achieved initial abstinence (no smoking for 24 hours), gum was to be used in accordance with the current FDA-approved directions for cessation. The study was conducted under over-the-counter conditions, with no counseling provided. Continuous abstinence was assessed after 28 days and 6 months. Secondary measures of smoking reduction were also assessed. Analyses were conducted in 1999 –2000 and 2007–2008. Main outcome measures:
Smokers on active gum were significantly more likely to achieve initial cessation (2 mg: OR⫽1.42; 4 mg: OR⫽1.90); 28-day continuous abstinence (2 mg: OR⫽2.01; 4 mg: OR⫽4.66); and continuous abstinence at 6 months (2 mg: OR⫽1.80; 4 mg: OR⫽5.96). During the reduction phase, active gum aided smoking reduction, and participants who reduced their smoking were more likely to achieve abstinence.
Conclusions: These findings demonstrate that smokers who wish to quit smoking by gradual reduction can increase their success by using nicotine gum to facilitate reduction and cessation. (Am J Prev Med 2009;36(2):96 –104) © 2009 American Journal of Preventive Medicine
Introduction
H
alf of all smokers who do not quit will die due to tobacco-related disease.1 Most smokers want to quit smoking, and each year many try without success.2,3 Nicotine dependence hampers smokers’ ability to quit4: the success level for unaided quit attempts is only about 3%.5,6 Treatment with nicotine replacement therapy (NRT) consistently increases success in smoking cessation.7 However, the use of NRT has been restricted to abrupt quitting, when smokers stop smoking all at once and simultaneously start using NRT. Yet, as many as 66% of smokers prefer to quit by gradual reduction,8,9 and about 33% of U.S. smokers who attempt to quit use the From Pinney Associates, Inc., and the University of Pittsburgh (Shiffman, Ferguson), Pittsburgh, Pennsylvania; and GlaxoSmithKline Consumer Healthcare (Strahs), Parsippany, New Jersey Address correspondence and reprint requests to: Saul Shiffman, PhD, Pinney Associates, 201 North Craig Street, Suite 320, Pittsburgh PA 15213. E-mail: [email protected]; cc: gbittner@ pinneyassociates.com.
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gradual method.10 Smokers who want to quit by gradual reduction, rather than abruptly, perceive themselves as more dependent and less successful at quitting.10 Moreover, smokers who state an intention to quit by gradual reduction are less motivated to quit and only half as likely to actually even make a quit effort,11 so inducing them to make a concerted quit attempt and helping them quit may increase quitting success. Thus, allowing NRT use as a support to gradual quitting may increase its public health impact.12 In addition to being attractive to smokers, the concept of gradually reducing smoking as a means of quitting has substantial conceptual appeal: it allows smokers to change their behavior gradually and benefit from “small wins” along the way, helps break the behavioral bonds between smoking and particular situations,13 and may reduce nicotine dependence prior to quitting.14 Unfortunately, although studies using highly structured behavioral reduction methods have shown clinical promise,15,16 outcomes of simpler behavioral reduction methods have proved disappointing.17 It has
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been suggested that as smokers reduce their smoking, they encounter increasing withdrawal symptoms, making reduction progressively more difficult and interfering with cessation.17 Accordingly, NRT may be useful in assisting cessation by gradual reduction, as it reduces craving and withdrawal18,19 and promotes abstinence.7 Indeed, clinical reports20 have suggested that NRT-aided smoking cessation by gradual reduction has promise, but no clinical trial of NRT for cessation by gradual reduction has been reported. This study evaluates the efficacy of NRT in assisting quitting by gradual reduction. Several studies have shown that NRT can help smokers who do not want to quit to reduce their smoking,21 and some studies find that initiating reduction also incidentally increases cessation.22 Based on these data, regulators in the United Kingdom and other countries have approved extended use of NRT for reduction over 6 –9 months by smokers not interested in quitting.23 However, there has not been a trial testing whether NRT might help smokers who are trying to quit but wish to do so by gradual reduction. This article describes a randomized double-blind placebo-controlled clinical trial to test the efficacy of nicotine gum (versus placebo) in assisting cessation through gradual reduction. The reduce-to-quit (RTQ) approach consisted of two treatment phases—a reduction phase and a cessation/maintenance phase. During the reduction phase of treatment, designed to achieve initial abstinence, smokers gradually increased the use of nicotine gum while simultaneously decreasing smoking. Once participants achieved abstinence, they entered the maintenance phase of the study and used nicotine gum in the traditional way to promote continued abstinence. The primary outcome measure was abstinence from smoking, but the analysis also assessed smoking reduction during the reduction phase of the study. The study was designed to evaluate the contribution of active nicotine gum to the efficacy of the entire treatment regime as it might be offered in practice, not to focus just on the addition of a reduction phase to a standard course of nicotine gum. Hence, participants were assigned to receive active or placebo treatment over the entire treatment course.
Methods Participants Participants were recruited using print and radio advertisements for smokers interested in quitting by gradual reduction within 30 days. Prospects called one of 27 study sites across the U.S. Inclusion criteria were: interest in quitting smoking using gradual reduction within 30 days, aged ⱖ18 years, ability to understand English, and capable of providing written informed consent. Exclusion criteria included: use of other nicotine-containing products (e.g., pipes, cigars), bupropion (Zyban or Wellbutrin) or NRT within 30 days of study entry; smoking of any substance other than cigarettes
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within 30 days of study entry; history of heart disease, recent heart attack, or irregular heartbeat; being an insulin-dependent diabetic; involvement in another clinical study, being in the same household as another participant, or being related to study site staff; working during the night hours (i.e., 11:00 PM–7:00 AM, to ensure that daytime carbon monoxide [CO] measurements reflected smoking); being unable to attend visits before 2:00 PM (to ensure CO levels reflected smoking); or being pregnant or nursing or likely to become pregnant during the study. All participants supplied written informed consent prior to being enrolled. This study was approved by IRBs at each of the study sites. (An online appendix is available at www.ajpm-online.net listing the 27 Principal Investigators and their affiliations.)
Procedure After providing consent, participants completed a smoking history questionnaire and a timeline follow-back24 of daily smoking during the preceding 2 weeks; they also had their breath tested for CO (an indicator of smoke intake25). Participants started treatment the next day. At subsequent study visits (2, 4, and 8 weeks later), participants reported their cigarette and gum consumption since the previous study visit, and provided CO samples. Study visits were scheduled after 2:00 PM so that CO would be near steady state.26 At six of the 27 study sites, participants who smoked ⱖ25 cigarettes per day (CPD) at baseline provided a blood sample for serum thiocyanate (SCN) analysis at the baseline, Week-2, and Week-4 visits. Unlike CO, which has a short half-life, SCN has a relatively long half-life (approximately 1 week27), thus providing a measure of longer-term exposure to tobacco. Although, as with CO, SCN levels can be affected by other inputs, SCN is regarded as a good marker of longer-term tobacco exposure.27 At each visit, subjects were asked about adverse events, and the onset and offset dates of any adverse events were recorded. An adverse event was defined as any unintended change (including physical, psychological, or behavioral changes) from the subject’s pretreatment condition, whether considered related to treatment or not. Study visits were used to monitor for participants’ achievement of initial abstinence. Participants who reported abstinence for at least a day, as verified by CO at ⱕ10 ppm (average of two measurements), were considered to have achieved initial abstinence. Because 8 weeks was considered an adequate time to reduce smoking and achieve abstinence, participants who did not achieve initial abstinence after this time were excused from the remainder of the study and counted as treatment failures in subsequent analyses. Participants who achieved initial abstinence were scheduled for a follow-up visit 28 –35 days after their first day of abstinence to assess 28-day continuous abstinence. At this follow-up visit, participants reported their smoking and gum usage since the previous visit and were specifically asked about their current and recent smoking status to ascertain outcome. Participants who reported continuous abstinence (not even a puff) were subject to confirmation by two CO readings, with an average reading of ⱕ10 ppm verifying abstinence. (Participants who achieved initial abstinence but did not at first maintain 28 days of abstinence could schedule another 28-day follow-up visit if they again achieved another 24-hour period of abstinence—16.9% [85/ 504] of participants who achieved initial abstinence had more than one 28-day follow-up visit.)
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Participants with verified 28-day continuous abstinence were counted as successes on the primary outcome and scheduled for a follow-up visit 6 months from the beginning of treatment, at which time they reported on their smoking, gum use, and adverse events. Participants who reported continuous abstinence (not even a puff) since the 28-day abstinence evaluation were subject to confirmation by two CO readings, with an average reading of ⱕ10 ppm verifying abstinence. Participants who did not demonstrate 28-day abstinence were not scheduled for 6-month follow-up visits and were counted as treatment failures at 6 months. Throughout, participants who did not participate in follow-up visits were counted as treatment failures.
Treatment Consistent with use of an over-the-counter (OTC) medication, participants self-selected their study gum dosage (2 or 4 mg) after reviewing the labels for both doses, which told smokers of ⱖ25 CPD to select the 4-mg dose (per current U.S. Food and Drug Administration [FDA]–approved labeling). Using a 1:1 computer-generated randomization scheme, balanced across study sites and generated separately for the 2and 4-mg groups, participants were randomized on a doubleblind basis to receive active or placebo gum (Nicorette “Original” flavor) and were given 420 pieces of gum with which to initiate treatment. The study was run in a simulated OTC setting: Instructions on quitting and the use of nicotine gum were obtained from only a printed user’s guide and label. Absolutely no instruction, counseling, or intervention was provided by study personnel. The materials instructed smokers to start reducing by not smoking for the first hour of the day and instead using a single piece of gum during that hour. On each subsequent day, participants were to extend their abstinence by adding an additional hour of abstinence, using one additional piece of gum. Once smokers had quit completely (for 24 hours), they were to use the gum in a manner consistent with the current FDA-approved labeling for the following 12 weeks: one piece every 1–2 hours for the first 6 weeks of treatment; one piece every 2– 4 hours for the next 3 weeks; and then one piece every 4 – 8 hours for a final 3 weeks. Participants were then permitted to use the gum “as needed to stay smoke-free” for an additional 12 weeks.
Statistical Analysis The primary endpoint was 28-day continuous abstinence (which was the basis on which other NRT indications have been evaluated by the U.S. FDA28). Active and placebo treatment arms were compared, separately for 2- and 4-mg gum. Reduction in smoking, achievement of initial abstinence (24 hours), and abstinence at 6 months were also examined. Cochran–Mantel–Haenszel tests controlled for study site; analyses pooling 2- and 4-mg groups also controlled for dose (as fixed effects). Results are presented as ORs with 95% CIs. Analysis of variance was used in the analyses of reduction to examine change from baseline to Week 2 in average CPD and in CO concentration. (By a priori plan, the analysis focused on the first 2 weeks of treatment because, as the reduction phase went on, more and more participants achieved abstinence or withdrew from the study and were thus lost to analyses of reduction per se, potentially biasing the analyses.)
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Additionally, successful reduction— defined as a self-reported reduction of ⱖ50% in smoking level verified by a ⱖ25% reduction in CO levels (this measure was constructed to assess significant reduction in cigarette smoking because retrospectively reported smoking level is subject to error and CO is often used to validate self-reports of smoking)—was analyzed as an outcome of treatment and as a mediator of cessation. Finally, reductions in SCN among smokers in the 4-mg gum group were analyzed. Differences between active and placebo conditions in the proportions of subjects experiencing adverse events were tested, by dose. To identify effects of concomitant smoking and nicotine gum use on adverse events, the investigators identified as high-concomitant participants those who were in the upper two thirds for both smoking (CPD) and gum use (pieces per day). To test whether concomitant smoking and use of active gum increased the likelihood of adverse events, a Breslow–Day test was used to determine whether high-concomitant smoking had greater influence on the likelihood of experiencing an adverse event on active versus placebo gum users.
Results Participant Characteristics and Disposition In total, 3297 participants were enrolled and randomized to treatment (Figure 1); 1636 participants selfselected the 2-mg gum, and 1661 self-selected the 4-mg gum. Self-selection conformed to label instructions 88.3% of the time. Accordingly, as expected, smokers in the 4-mg arm smoked more heavily and were more nicotine dependent than those using 2-mg gum (Table 1). Otherwise, the study arms were similar on baseline characteristics. The average participant was white, 44 years old, and had some college education. The majority of participants (57%) were women. Randomization within dose group resulted in well balanced groups. Treatment outcomes: initial abstinence and 28-day and 6-month continuous abstinence. Active treatment significantly increased the probability of achieving initial cessation: 26% of participants on active treatment achieved initial 24-hour abstinence, compared to 18.5% on placebo (OR⫽1.60, 95% CI⫽1.36, 1.90). This effect held for both the 2- and 4-mg dose groups (Figure 2). The rate at which participants first achieved abstinence was fairly constant over the 8 weeks of the reduction period. Among those who achieved abstinence, the median time to initial abstinence was 29 days, with no differences between the active and placebo groups (p⬎0.25). Active treatment increased both 28-day (10.3% vs 3.9%; OR⫽2.83, 95% CI⫽2.10, 3.81) and 6-month (5.9% vs 2.1%; OR⫽2.86, 95% CI⫽1.93, 4.24) continuous abstinence rates. The effects were strongest in the 4-mg group but significant for both doses (Figure 2). Once initial abstinence had been achieved, treatment with active gum improved the odds of participants remaining abstinent. Among participants who achieved initial abstinence, 28-day abstinence rates were significantly higher
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6923 screened
vs 11.2%; OR⫽1.81, 95% CI⫽1.49, 2.21). Regardless of treatment (active or placebo), the odds of achieving 28 days of continuous abstinence were approximately nine times higher among those who successfully reduced by this criterion, compared to those that did not (Figure 4).
3626 excluded 926 failed screening 509 refused 2191 did not enrolla
3297 enrolled
2 mg n=1636
Self-selected group
Randomly allocated
817 placebo
4 mg n=1661
819 active
24-hour abstinence
195 succeeded 622 failed
252 succeeded 567 failed
28-day abstinence
45 succeededb 150 failed 148 terminatedc 2 discontinuedd
86 succeeded 166 failed 159 terminated 7 discontinued
831 placebo
109 succeeded 722 failed 21 succeeded 88 failed 87 terminated 1 discontinued
830 active
184 succeeded 646 failed 88 succeeded 96 failed 92 terminated 4 discontinued
Gum Use
Gum use increased progressively during the first 40 completed 75 completed 18 completed 78 completed 6-month follow-up 4 weeks of the study in 5 did not completee 11 did not complete 3 did not complete 10 did not complete both treatment arms and Figure 1. Participant flow and disposition. Screening data presented are estimates generated both dose groups. Particifrom the records from 12 of the 27 study sites; the remaining sites did not adequately record pants in the 4-mg dose subject screening information. groups tended to use a Qualified for the study and did not explicitly decline, but did not schedule or did not keep an more gum than those in enrollment appointment b the 2-mg groups, but Includes two subjects who demonstrated 24-hour abstinence before 28 days postquit and five subjects who quit more than 9 weeks after the randomization date (includes a 1-week window there was little difference around the Week-8 visit). These seven subjects were considered failures in the primary efficacy between the active and analysis but were continued into the follow-up phase. placebo treatment arms c Terminated includes adverse events, lack of efficacy, withdrawal of consent, and nonspecified within each dose group. factors contributing to failure of abstinence. d By the end of the first Subjects were discontinued for failing to follow the protocol. e Did not complete 6-month follow-up phase for reasons of adverse events, were lost to follow-up week of the study, participhase, or withdrew consent pants in the 2-mg group were using 3.8 (SD⫽3.8) pieces of gum per day, whereas those in the 4-mg group among those randomized to active gum treatment (38.8% were using 5.1 (SD⫽5.0) pieces per day. By the end of vs 21.1%; OR⫽2.29, 95% CI⫽1.62, 3.25), with both the the fourth week of the study, consumption of gum had 2-mg (33.3% vs 22.6%; OR⫽1.79, 95% CI⫽1.14, 2.79) risen to 5.7 (SD⫽4.9) and 7.5 (SD⫽5.9) pieces per day, and the 4-mg gum (46.2% vs 18.4%; OR⫽3.36, 95% respectively, for the 2- and 4-mg groups. CI⫽1.88, 5.99). Similarly, among this subset of participants, Smokers who used more pieces of gum achieved 6-month abstinence rates were significantly higher among substantially higher initial abstinence rates: Collapsed those on active gum treatment (overall: 22.3% vs 11.5%; across dose group, and controlling for both study site OR⫽2.07, 95% CI⫽1.36, 3.17; 2 mg: 18.3% vs 13.3%; and treatment group (active or placebo), those particOR⫽1.45, 95% CI⫽0.85, 2.49; 4 mg: 27.7% vs 8.3%; ipants who used more than the median amount of gum OR⫽3.58, 95% CI⫽1.71, 7.53). per week for the first 2 weeks were more than twice as likely to achieve 28-day continuous abstinence (13.8% Smoking Reduction vs 5.9%; OR ⫽2.66, 95% CI⫽1.96, 3.61). The interacAfter 2 weeks in the study, smokers on active treatment tion between treatment group and gum use was not reported greater reductions in number of cigarettes significant (p⫽0.471). smoked than those on placebo treatment (Figure 3); however, the difference between treatment groups was Adverse Events only significant in the 4-mg group. Participants randomized to active treatment (both doses) demonDuring the first 8 weeks of the study, 42.4% of particistrated significantly greater reductions in CO, indicatpants reported an adverse event (a total of 2515 ing reduced smoke intake. Finally, in the 4-mg group, events). Participants on active gum were more likely to active treatment resulted in significantly greater reducexperience an adverse event than participants taking tions in SCN. placebo gum (48.2% vs 36.6%; p⬍0.001). Among those Participants using active gum were significantly more on active gum, similar proportions of participants using likely to achieve successful reduction (ⱖ50% in smok2- or 4-mg gum reported adverse events (48.7% vs ing level and ⱖ25% in CO level) after 2 weeks (18.6% 47.7%). The most frequently reported adverse events February 2009
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Percent abstinent
were the mild adverse Table 1. Demographic and smoking history of sample, by treatment group (% unless events characteristic of otherwise indicated) nicotine gum use, such 2-mg group 4-mg group as nausea, hiccups, and Placebo Active Placebo Active heartburn. The most com(nⴝ817) (nⴝ819) (nⴝ831) (nⴝ830) monly affected body systems were the gastrointes- Gender Female 65.5 62.8 52.2 47.6 tinal (active: 26% of Age subjects, placebo: 14.5%; M 42.2 42.1 46.3 46.1 p⬍0.001) and respiratory SD 13.3 13.0 11.4 11.3 Race (active: 12%, placebo: Caucasian 83.2 84.5 91.0 90.8 8.6%; p⫽0.002) systems, Black 8.2 8.9 4.8 5.7 consistent with adverse Asian 1.7 1.0 0.5 0.7 events previously reported Hispanic 5.0 4.3 2.5 1.7 for nicotine gum. Adverse Other 1.8 1.3 1.2 1.1 Education events affecting other Some college or more 79.8 78.2 72.0 74.0 body systems occurred in Income ($) ⬍10% of participants in ⬍25,000 28.4 30.1 31.7 29.1 either study group. Ad25,000–49,999 40.4 40.9 39.2 38.8 verse events affecting the ⬎50,000 31.1 29.0 29.1 32.0 cardiovascular system were Cigarettes per day ⱖ25 9.8 9.0 85.4 84.3 very rare and were equally M 17.6 17.7 32.5 32.0 distributed across treatSD 6.1 6.0 10.0 9.6 ment arms: cardiovascular Years smoked disorders (active: 0.4%, plaM 24.3 24.1 29.5 29.2 SD 13.6 12.8 11.7 11.3 cebo: 0.4%); heart rate and Fagerstrom Test for Nicotine rhythm disorders (active: Dependence 0.4%, placebo: 0.4%). M 4.4 4.4 6.9 6.9 To examine the effects SD 2.1 2.1 1.7 1.7 of concomitant smoking Time to first cigarette ⱕ30 minutes 70.3 70.1 92.3 91.7 and nicotine gum use on adverse events, the first 4 Note: There were no significant differences between active and placebo treatments within group (2 mg or weeks of treatment were 4 mg) on any of these variables. focused on, as this is the period with greatest concompare the odds of an adverse event among high- versus comitant smoking and gum use. In each week, the low-concomitant users, while taking into account the use analysis compared the probability of experiencing an of active versus placebo gum (Figure 5). If concomitant adverse event among participants who engaged in high use increased the probability of adverse events, then levels of concomitant use versus those engaged in low among those on active gum, high-concomitant users or no concomitant use. The investigators classified as should be more likely to experience adverse events than high-concomitant users those who were in the 33rd low-concomitant users. However, significant differences percentile or higher on both smoking and gum use. This classified roughly 40% of participants as high40 6.0 1.8 2.0 4.7 1.4 1.9 concomitant users, but results were similar when the 35 (1.1, 2.9) (2.9, 12.2) (1.4, 2.9) (2.8, 7.7) (1.1, 1.8) (1.5, 2.5) top 20% of concomitant users were analyzed. In the 30 Placebo 25 2-mg arm, the high-concomitant group averaged 12.38 20 Active cigarettes (SD⫽5.47) and 6.78 pieces of gum 15 (SD⫽4.85) per day, and the low-concomitant group 10 averaged 8.49 cigarettes (SD⫽7.20) and 3.69 pieces of 5 gum (SD⫽4.54) per day. In the 4-mg arm, high0 2 mg 4 mg 2 mg 4 mg 2 mg 4 mg concomitant users averaged 22.26 cigarettes (SD⫽9.03) and 8.91 pieces of gum (SD⫽5.85) per day, and lowInitial abstinence 28-day abstinence 6-month abstinence concomitant users averaged 15.64 cigarettes Figure 2. Initial abstinence percentages and 28-day and (SD⫽11.46) and 5.17 pieces of gum (SD⫽5.79) per 6-month continuous smoking cessation percentages, by day. treatment and dose group. Figures above each set of bars To assess the effects of concomitant use on adverse events, represent the OR for active treatment versus placebo, and a Breslow–Day test for homogeneity of ORs was used to its 95% CI. 100
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Figure 3. Percentage reduction (and SE) in carbon monoxide (CO; n⫽2250), cigarettes per day (CPD; n⫽2260), and serum thiocyanate (SCN; 4 mg only; n⫽205) from baseline to week 2, by treatment and dose groups. Asterisks indicate a significant difference between treatment groups: *p⬍0.05; **p⬍0.01; ***p⬍0.001.
in the likelihood of adverse events between high- and low-concomitant users on active gum were not observed. (In fact, for high-concomitant users, there was a trend toward lower likelihood of reporting an adverse event.) Further, if concomitant use and the consequent increased nicotine intake caused adverse events, the differences between active and placebo gum should be more marked among high-concomitant users than among low-concomitant users. However, this interaction was not observed (p values ⬎0.10 for all weeks and both doses); the combination of chewing active gum and smoking did not increase the likelihood of adverse events.
Comments This study is the first to test the efficacy and safety of using nicotine gum to assist smoking cessation by gradual reduction. Treatment with nicotine gum en-
Figure 4. 28-day continuous smoking-cessation rates, by treatment group and successful smoking reduction. Figures above each set of bars represent the OR for those who successfully reduced (n⫽492) versus those who did not (n⫽2805), and its 95% CI. Successful reduction is defined as a ⱖ50% reduction in smoking rate combined with a ⱖ25% reduction in carbon monoxide (CO) between baseline and Week-2 values.
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hanced success levels at every step of the process: Smokers using active nicotine gum were more likely to substantially reduce their smoking, more likely to achieve initial abstinence, and more likely to maintain abstinence, both in the short run and for up to 6 months. Although the absolute quit rates achieved in this trial appear modest (with 10% of active gum users achieving 28-day abstinence and 6% maintaining abstinence at the 6-month follow-up visit), it must be recalled that this trial included no behavioral instruction or intervention whatsoever. The quit rates observed are comparable to those observed in abrupt quitting with nicotine gum under similar conditions (Shiffman et al.29 reported 6-month quit rates of 8%). In assessing the quit rates in this study, it is important to keep in mind that smokers who prefer quitting by gradual reduction differ from those who elect abrupt cessation. For example, smokers planning to quit by gradual reduction are less motivated to quit and are less than half as likely as abrupt quitters to even attempt quitting.11 Indeed, those saying they would quit gradually were no more likely to make a quit attempt than smokers who said they wanted to only reduce, not quit, smoking. Thus, smokers preferring to quit by gradual reduction are not comparable to those who want to quit abruptly, as in most cessation trials, and may be expected to have lower quit rates. Indeed, very low rates of quitting in the placebo group (4% at 28 days and 2% at 6 months) were observed. Against that background, treatment with active gum tripled the odds of quitting for 28 days, an advantage that was maintained at the 6-month follow-up visit. Indeed, the 6-month OR (2.86) is at the high end of those typically observed in trials of nicotine gum for abrupt smoking cessation (which average 1.667). The data suggest that for smokers quitting gradually, using nicotine gum can offer a very
Figure 5. Percentage (and 95% CI) of participants who reported adverse events (AEs) by concomitant use and treatment groups, during Weeks 1 (n⫽2265), 2 (n⫽2366), 3 (n⫽2027), and 4 (n⫽1841). High-concomitant smokers were those who were in the upper two thirds of the distribution on both daily cigarette consumption and daily gum use (see text). The “Low” group includes all other participants.
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substantial advantage. Interestingly, in a nonrandomized population study, Cheong et al.10 similarly found that using medication was associated with success in quitting by gradual reduction (OR⫽2.6), consistent with the findings from this RCT. The reduce-to-quit (RTQ) approach described here is not the only approach using an NRT-assisted reduction phase to promote cessation. The RTQ approach engages smokers who are ready to quit on a relatively time-limited program of structured reduction explicitly aimed at a quitting endpoint. A contrasting approach, described as “cut down to quit” (CDTQ),30 encourages smokers who are not currently interested in quitting to use NRT for reduction over a period of up to 12 months. Meta-analysis30 suggested that this approach was efficacious but less cost effective than abrupt cessation. In any case, the RTQ and CDTQ approaches address different populations with different propositions, making results difficult to compare. Treatment with active nicotine gum facilitated reductions in reported smoking and biochemical markers of smoke exposure. Although use of active 2-mg gum did not show significantly greater reductions in self-reports of cigarettes smoked, it did yield significantly greater drops in CO, demonstrating greater reductions in smoke intake. Smokers on placebo gum may have compensated for some of their reductions by smoking more intensely,31 whereas treatment with nicotine gum reduced the use of this compensation. Indeed, a measure of biochemically verified reduction, requiring a ⱖ50% reduction in cigarettes smoked and a ⱖ25% reduction in CO level, showed significant effects for active treatment in both doses. Assays based on SCN, which has a longer half-life than CO, confirmed significant reductions in those using 4-mg gum. Many purely behavioral approaches to reducing smoking have been tested previously (e.g., keeping a strict schedule, elimination of least-favored cigarettes).32 It is not known which procedures are optimal for promoting reduction. In this study, smokers were instructed to progressively increase their gum use while simultaneously decreasing their smoking on an hour-by-hour basis.20 However, the pattern of gum use observed in the study, and the fact that smokers in the study did not necessarily achieve abstinence after 16 days (as would be expected if they followed the regimen and added a waking hour of abstinence each day), suggests that smokers did not strictly follow the hour-by-hour instruction. Further research is needed in order to determine whether alternate procedures more effectively promote reduction and cessation. However, it is clear that participants benefited from having 8 weeks to establish abstinence, as new participants continued to achieve initial abstinence each week throughout this 8-week period. This suggests that allowing a longer period for reduction might have led to higher quit rates. 102
Process analyses shed light on the ways in which active treatment helped smokers achieve abstinence. Nicotine gum was expected to help smokers reduce smoking effectively, and thus to promote achievement of initial abstinence. Indeed, the analysis showed that active treatment with nicotine gum promoted smoking reduction, which, in turn, promoted initial cessation. Once smokers achieved initial abstinence, active treatment with nicotine gum promoted maintenance of abstinence for 28 days– 6 months. Thus, active treatment provided a benefit at each step in the process of quitting by gradual reduction. As noted by Shiffman et al.,33 achievement of initial abstinence is an important but often ignored key step in successful quitting. In this study of quitting by gradual reduction, achieving initial cessation for 24 hours appeared to be the greatest hurdle—treatment with active gum helped increase the proportion who reached that milestone by 37%, from 19% (on placebo) to 26%. This demonstrates the contribution of active treatment during the reduction phase in bringing smokers to the point of quitting. After initial cessation was achieved, active treatment further demonstrated its well known ability to sustain abstinence, increasing 28-day abstinence by 40%, from 28% (placebo) to 39%. Further work is needed on behavioral and pharmacologic treatment regimens to increase achievement of initial quitting in the context of gradual reduction regimens. It is possible that a more structured approach to cessation, or selection of smokers who are more committed to complete cessation, would yield substantially higher initial quit rates. The data suggest that behavioral as well as pharmacologic processes are at work in determining success. Notably, whereas other studies have demonstrated a benefit of more NRT use in the active group only,34 in this study, smokers who used more gum early in the reduction phase were more likely to achieve 28-day abstinence, regardless of whether they used active or placebo gum. This could reflect nonspecific behavioral benefits of just chewing gum (chewing gum and candy is often recommended for quitting35), or it could be a marker distinguishing those smokers who were more motivated and prepared to make greater efforts to achieve and maintain abstinence. In either case, this suggests the importance of behavioral processes, even in the context of pharmacologic treatment. Nicotine gum has been used safely for cessation in clinical trials and in actual use for over 20 years.7 This study was unique in directing that smokers use nicotine gum while still smoking, for up to 8 weeks. The results were reassuring: Adverse events were generally mild and were consistent with those seen with nicotine gum used for abrupt quitting. Moreover, there was no evidence of increased risk among smokers who engaged in the most concomitant smoking and gum use. Even smokers who smoked an average of 18 CPD along with
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seven pieces of 4-mg nicotine gum (more than is used by the typical quitter36) did not experience an increased likelihood of adverse events. Nicotine regulation mechanisms37 likely limited exposure, causing smoking to decline as nicotine intake from the gum increased. The safety of concomitant smoking and NRT use seen in this study is consistent with analyses of long-time users of nicotine gum38 and with a study of myocardial perfusion during concomitant smoking and NRT use.39 Using nicotine gum while smoking carries little to no incremental risk. The study’s limitations include a lack of highly detailed data about how subjects used nicotine gum to quit and a lack of detailed information regarding subjects who were screened out of participation. The study also did not include some groups of smokers, such as those with cardiovascular disease, who may be at greater risk for adverse events; thus, the adverse event profile described in the study cannot be generalized to all smokers. The study’s strengths include a very large and diverse sample, studied under real-world conditions with no counseling or instruction; detailed data on cigarette and gum consumption; and biochemical measures of smoke exposure. This is the first study to demonstrate that smokers wanting to quit by gradual reduction can substantially increase their success by using nicotine gum to facilitate reduction and cessation. Nicotine gum helped smokers reduce smoking, achieve initial abstinence, and maintain abstinence. The advantage of active NRT treatment is particularly evident for heavy smokers treated with the 4-mg nicotine gum, for which treatment increased the odds of quitting for 6 months sixfold. This expands treatment options for the substantial proportion of smokers who prefer quitting gradually,8 who have relatively low chances of quitting, and who have heretofore been implicitly excluded from the use of NRT to help them quit. Offering this new way to use NRT may enhance the appeal and reach of a treatment that increases success, and thereby have positive public health impact. Given the ongoing extraordinary health toll from smoking, consideration should be given to novel approaches that increase success in quitting. This study was supported by SmithKline Beecham Consumer Healthcare, now GlaxoSmithKline Consumer Healthcare (GSKCH), which markets nicotine replacement medications for smoking cessation. Dr. Strahs is employed by GSKCH. Through their work at Pinney Associates, Drs. Shiffman and Ferguson serve as consultants to GSKCH on matters related to smoking control and/or nicotine replacement medications. Dr. Shiffman also has a financial interest in a venture to develop new nicotine replacement medications. The authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The authors wish to thank Mark Sembower and Gina Bittner for their assistance with analyzing the data and
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preparing the manuscript for publication. The authors owe a debt of gratitude to the 27 study-site Principal Investigators (listed in an online appendix at www.ajpm-online.net) who collected the data.
References 1. Peto R. Smoking and death: the past 40 years and the next 40. BMJ 1994;309:937–9. 2. CDC. Cigarette smoking among adults—United States, 2000. MMWR 2002;51:642–5. 3. Shiffman S, Brockwell SE, Pillitteri JL, Gitchell JG. Use of smokingcessation treatments in the United States. Am J Prev Med 2008;34:102–11. 4. Fiore MC. Treating tobacco use and dependence: an introduction to the U.S. Public Health Service Clinical Practice Guideline. Respir Care 2000;45:1196 –9. 5. Garvey AJ, Bliss RE, Hitchcock JL, Heinold JW, Rosner B. Predictors of smoking relapse among self-quitters: a report from the Normative Aging Study. Addict Behav 1992;17:367–77. 6. Hughes JR, Gulliver SB, Fenwick JW, et al. Smoking cessation among self-quitters. Health Psychol 1992;11:331– 4. 7. Silagy C, Lancaster T, Stead L, Mant D, Fowler G. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 2004(3): CD000146. 8. Hughes JR, Callas PW, Peters EN. Interest in gradual cessation. Nicotine Tob Res 2007;9:671–5. 9. Shiffman S, Hughes JR, Ferguson SG, Pillitteri JL, Gitchell JG, Burton SL. Smokers’ interest in using nicotine replacement to aid smoking reduction. Nicotine Tob Res 2007;9:1177– 82. 10. Cheong Y, Yong HH, Borland R. Does how you quit affect success? A comparison between abrupt and gradual methods using data from the International Tobacco Control Policy Evaluation Study. Nicotine Tob Res 2007;9:801–10. 11. Peters EN, Hughes JR, Callas PW, Solomon LJ. Goals indicate motivation to quit smoking. Addiction 2007;102:1158 – 63. 12. Shiffman S, Gitchell J, Pinney JM, Burton SL, Kemper KE, Lara EA. Public health benefit of over-the-counter nicotine medications. Tob Control 1997;6:306 –10. 13. Rose JE, Behm FM. Extinguishing the rewarding value of smoke cues: pharmacological and behavioral treatments. Nicotine Tob Res 2004;6:523–32. 14. Carpenter MJ, Hughes JR, Keely JP. Effect of smoking reduction on later cessation: a pilot experimental study. Nicotine Tob Res 2003;5:155– 62. 15. Cinciripini PM, Lapitsky LG, Wallfisch A, Mace R, Nezami E, Van Vunakis H. An evaluation of a multicomponent treatment program involving scheduled smoking and relapse prevention procedures: initial findings. Addict Behav 1994;19:13–22. 16. Cinciripini PM, Lapitsky L, Seay S, Wallfisch A, Kitchens K, Van Vunakis H. The effects of smoking schedules on cessation outcome: can we improve on common methods of gradual and abrupt nicotine withdrawal? J Consult Clin Psychol 1995;63:388 –99. 17. Levinson BL, Shapiro D, Schwartz GE, Tursky B. Smoking elimination by gradual reduction. Behavior Therapy 1971;2:477– 87. 18. West R, Shiffman S. Effect of oral nicotine dosing forms on cigarette withdrawal symptoms and craving: a systematic review. Psychopharmacology (Berl) 2001;155:115–22. 19. Shiffman S, Ferguson SG, Gwaltney CJ, Balabanis MH, Shadel WG. Reduction of abstinence-induced withdrawal and craving using high-dose nicotine replacement therapy. Psychopharmacology (Berl) 2006;184:637– 44. 20. Cooper T, Clayton R. New hope for heavy smokers: the cooper/clayton method for stop smoking. Lexington: SBC Publishers, 1988. 21. Hughes JR, Carpenter MJ. The feasibility of smoking reduction: an update. Addiction 2005;100:1074 – 89. 22. Fagerstrom KO. Can reduced smoking be a way for smokers not interested in quitting to actually quit? Respiration 2005;72:216 –20. 23. Committee on Safety of Medicines and Healthcare Products Regulatory Agency (CSMHPRA). Report of the committee on safety of medicines working group on nicotine replacement therapy 2006. London, CSM & MHRSA. www.mhra.gov.uk. 24. Brown R, Burgess E, Sales S, Whitely J, Evans D, Miller I. Reliability and validity of a smoking timeline follow-back interview. Psychol Addict Behav 1998;12:101–12. 25. Shields PG. Tobacco smoking, harm reduction, and biomarkers. J Natl Cancer Inst 2002;94:1435– 44.
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26. Benowitz NL, Kuyt F, Jacob P III. Circadian blood nicotine concentrations during cigarette smoking. Clin Pharmacol Ther 1982;32:758 – 64. 27. Junge B. Changes in serum thiocyanate concentration on stopping smoking. Br Med J (Clin Res Ed) 1985;291:22. 28. U.S. Food and Drug Administration. Transcript of the Joint Meeting of the Non-prescription Drugs Advisory Committee and the Drug Abuse Advisory Committee of the Food and Drug Administration. 29. Shiffman S, Rolf CN, Hellebusch SJ, et al. Real-world efficacy of prescription and over-the-counter nicotine replacement therapy. Addiction 2002;97:505–16. 30. Wang D, Connock M, Barton P, Fry-Smith A, Aveyard P, Moore D. Cut down to quit with nicotine replacement therapies in smoking cessation: a systematic review of effectiveness and economic analysis. Health Technol Assess. 2008;12:iii–iv, ix–xi, 1–135. 31. Hammond D, Fong GT, Cummings KM, Hyland A. Smoking topography, brand switching, and nicotine delivery: results from an in vivo study. Cancer Epidemiol Biomarkers Prev 2005;14:1370 –5. 32. Schwartz JL. Review and evaluation of smoking cessation methods: the United States and Canada, 1978 –1985. Washington DC: U.S. Government Printing Office, 1987.
33. Shiffman S, Scharf DM, Shadel WG, et al. Analyzing milestones in smoking cessation: illustration in a nicotine patch trial in adult smokers. J Consult Clin Psychol 2006;74:276 – 85. 34. Shiffman S. Use of more nicotine lozenges leads to better success in quitting smoking. Addiction 2007;102:809 –14. 35. Abrams DB, Niaura R, Brown RA, Emmons KM, Goldstein MG, Monti PM. Tobacco dependence treatment handbook: a guide to best practices. New York: Guilford Press, 2003. 36. Shiffman S, Paty JA, Rohay JM, Di Marino ME, Gitchell J. The efficacy of computer-tailored smoking cessation material as a supplement to nicotine polacrilex gum therapy. Arch Intern Med 2000;160:1675– 81. 37. Nemeth-Coslett R, Henningfield JE. Effects of nicotine chewing gum on cigarette smoking and subjective and physiologic effects. Clin Pharmacol Ther 1986;39:625–30. 38. Murray RP, Bailey WC, Daniels K, et al. Safety of nicotine polacrilex gum used by 3,094 participants in the Lung Health Study. Lung Health Study Research Group. Chest 1996;109:438 – 45. 39. Mahmarian JJ, Moye LA, Nasser GA, et al. Nicotine patch therapy in smoking cessation reduces the extent of exercise-induced myocardial ischemia. J Am Coll Cardiol 1997;30:125–30.
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Appendix Study-Site Principal Investigators Wanda D. Angueira, MD Sciman Biomedical Research San Antonio TX Robert Bettis, MD Edmonds Family Medicine Clinic Edmonds WA Stephen A. Braden, MD Sciman Biomedical Research Bryan TX David Brown, MD Community Clinical Research, Inc. Austin TX Michael Cassar, MD TKL Research, Inc. Paramus NJ Paul Cinciripini, PhD UT MD Anderson Cancer Center Houston TX Clinton N. Corder, PhD, MD COR Clinical Research Oklahoma City OK
Lawrence V. Larsen, PhD Intermountain Clinical Research Salt Lake City UT Samuel Lederman, MD Hill Top Research, Inc. West Palm Beach FL Robin Mermelstein, PhD University of Illinois at Chicago Chicago IL John S. Muchmore, MD Lynn Health Science Institute Oklahoma City OK Mitch Nides, PhD LA Smoking Research Center Los Angeles CA Stephen Rennard, MD University of Nebraska Medical Center Omaha NE Harvey Resnick, MD R/D Clinical Research, Inc. Lake Jackson TX Ernie Riffer, MD Central Phoenix Medical Clinic Phoenix AZ
Thomas Fiel, DO Tempe Primary Care Associates Tempe AZ
Nancy Rigotti, MD General Internal Medicine Unit Massachusetts General Hospital Boston MA
David Gonzales, PhD Oregon Health Sciences University Portland OR
Sid Rosenblatt, MD, FACP Irvine Clinical Research Center Irvine CA
Dorothy Hatsukami, PhD University of Minnesota Minneapolis MN
Joseph Salvatore, MD Vista Medical Research, Inc. Mesa AZ
F. Charles Hiller, MD University of Arkansas for Medical Sciences Little Rock AR
Teresa S. Sligh, MD Sciman Biomedical Research Euless TX
Larysa Hun, MD Research Testing Laboratories, Inc. Huntington NY
Kevin Tack, MD Research Testing Laboratories, Inc. Great Neck NY
Sharad Lakhanpal, MD Metroplex Clinical Research Dallas TX
Gerald Wolfley, MD Hill Top Research Scottsdale AZ
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This was a multi-center, placebo-controlled, double-blind RCT of 2- and 4-mg nicotine gum versus placebo.
Setting/ 3297 smokers who were interested in quitting gradually. participants: Intervention: Subjects were instructed to gradually reduce their smoking while increasing their gum use over the course of up to 8 weeks. Once they had achieved initial abstinence (no smoking for 24 hours), gum was to be used in accordance with the current FDA-approved directions for cessation. The study was conducted under over-the-counter conditions, with no counseling provided. Continuous abstinence was assessed after 28 days and 6 months. Secondary measures of smoking reduction were also assessed. Analyses were conducted in 1999 –2000 and 2007–2008. Main outcome measures:
Smokers on active gum were significantly more likely to achieve initial cessation (2 mg: OR⫽1.42; 4 mg: OR⫽1.90); 28-day continuous abstinence (2 mg: OR⫽2.01; 4 mg: OR⫽4.66); and continuous abstinence at 6 months (2 mg: OR⫽1.80; 4 mg: OR⫽5.96). During the reduction phase, active gum aided smoking reduction, and participants who reduced their smoking were more likely to achieve abstinence.
Conclusions: These findings demonstrate that smokers who wish to quit smoking by gradual reduction can increase their success by using nicotine gum to facilitate reduction and cessation. (Am J Prev Med 2009;36(2):96 –104) © 2009 American Journal of Preventive Medicine
Introduction
H
alf of all smokers who do not quit will die due to tobacco-related disease.1 Most smokers want to quit smoking, and each year many try without success.2,3 Nicotine dependence hampers smokers’ ability to quit4: the success level for unaided quit attempts is only about 3%.5,6 Treatment with nicotine replacement therapy (NRT) consistently increases success in smoking cessation.7 However, the use of NRT has been restricted to abrupt quitting, when smokers stop smoking all at once and simultaneously start using NRT. Yet, as many as 66% of smokers prefer to quit by gradual reduction,8,9 and about 33% of U.S. smokers who attempt to quit use the From Pinney Associates, Inc., and the University of Pittsburgh (Shiffman, Ferguson), Pittsburgh, Pennsylvania; and GlaxoSmithKline Consumer Healthcare (Strahs), Parsippany, New Jersey Address correspondence and reprint requests to: Saul Shiffman, PhD, Pinney Associates, 201 North Craig Street, Suite 320, Pittsburgh PA 15213. E-mail: [email protected]; cc: gbittner@ pinneyassociates.com.
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gradual method.10 Smokers who want to quit by gradual reduction, rather than abruptly, perceive themselves as more dependent and less successful at quitting.10 Moreover, smokers who state an intention to quit by gradual reduction are less motivated to quit and only half as likely to actually even make a quit effort,11 so inducing them to make a concerted quit attempt and helping them quit may increase quitting success. Thus, allowing NRT use as a support to gradual quitting may increase its public health impact.12 In addition to being attractive to smokers, the concept of gradually reducing smoking as a means of quitting has substantial conceptual appeal: it allows smokers to change their behavior gradually and benefit from “small wins” along the way, helps break the behavioral bonds between smoking and particular situations,13 and may reduce nicotine dependence prior to quitting.14 Unfortunately, although studies using highly structured behavioral reduction methods have shown clinical promise,15,16 outcomes of simpler behavioral reduction methods have proved disappointing.17 It has
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been suggested that as smokers reduce their smoking, they encounter increasing withdrawal symptoms, making reduction progressively more difficult and interfering with cessation.17 Accordingly, NRT may be useful in assisting cessation by gradual reduction, as it reduces craving and withdrawal18,19 and promotes abstinence.7 Indeed, clinical reports20 have suggested that NRT-aided smoking cessation by gradual reduction has promise, but no clinical trial of NRT for cessation by gradual reduction has been reported. This study evaluates the efficacy of NRT in assisting quitting by gradual reduction. Several studies have shown that NRT can help smokers who do not want to quit to reduce their smoking,21 and some studies find that initiating reduction also incidentally increases cessation.22 Based on these data, regulators in the United Kingdom and other countries have approved extended use of NRT for reduction over 6 –9 months by smokers not interested in quitting.23 However, there has not been a trial testing whether NRT might help smokers who are trying to quit but wish to do so by gradual reduction. This article describes a randomized double-blind placebo-controlled clinical trial to test the efficacy of nicotine gum (versus placebo) in assisting cessation through gradual reduction. The reduce-to-quit (RTQ) approach consisted of two treatment phases—a reduction phase and a cessation/maintenance phase. During the reduction phase of treatment, designed to achieve initial abstinence, smokers gradually increased the use of nicotine gum while simultaneously decreasing smoking. Once participants achieved abstinence, they entered the maintenance phase of the study and used nicotine gum in the traditional way to promote continued abstinence. The primary outcome measure was abstinence from smoking, but the analysis also assessed smoking reduction during the reduction phase of the study. The study was designed to evaluate the contribution of active nicotine gum to the efficacy of the entire treatment regime as it might be offered in practice, not to focus just on the addition of a reduction phase to a standard course of nicotine gum. Hence, participants were assigned to receive active or placebo treatment over the entire treatment course.
Methods Participants Participants were recruited using print and radio advertisements for smokers interested in quitting by gradual reduction within 30 days. Prospects called one of 27 study sites across the U.S. Inclusion criteria were: interest in quitting smoking using gradual reduction within 30 days, aged ⱖ18 years, ability to understand English, and capable of providing written informed consent. Exclusion criteria included: use of other nicotine-containing products (e.g., pipes, cigars), bupropion (Zyban or Wellbutrin) or NRT within 30 days of study entry; smoking of any substance other than cigarettes
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within 30 days of study entry; history of heart disease, recent heart attack, or irregular heartbeat; being an insulin-dependent diabetic; involvement in another clinical study, being in the same household as another participant, or being related to study site staff; working during the night hours (i.e., 11:00 PM–7:00 AM, to ensure that daytime carbon monoxide [CO] measurements reflected smoking); being unable to attend visits before 2:00 PM (to ensure CO levels reflected smoking); or being pregnant or nursing or likely to become pregnant during the study. All participants supplied written informed consent prior to being enrolled. This study was approved by IRBs at each of the study sites. (An online appendix is available at www.ajpm-online.net listing the 27 Principal Investigators and their affiliations.)
Procedure After providing consent, participants completed a smoking history questionnaire and a timeline follow-back24 of daily smoking during the preceding 2 weeks; they also had their breath tested for CO (an indicator of smoke intake25). Participants started treatment the next day. At subsequent study visits (2, 4, and 8 weeks later), participants reported their cigarette and gum consumption since the previous study visit, and provided CO samples. Study visits were scheduled after 2:00 PM so that CO would be near steady state.26 At six of the 27 study sites, participants who smoked ⱖ25 cigarettes per day (CPD) at baseline provided a blood sample for serum thiocyanate (SCN) analysis at the baseline, Week-2, and Week-4 visits. Unlike CO, which has a short half-life, SCN has a relatively long half-life (approximately 1 week27), thus providing a measure of longer-term exposure to tobacco. Although, as with CO, SCN levels can be affected by other inputs, SCN is regarded as a good marker of longer-term tobacco exposure.27 At each visit, subjects were asked about adverse events, and the onset and offset dates of any adverse events were recorded. An adverse event was defined as any unintended change (including physical, psychological, or behavioral changes) from the subject’s pretreatment condition, whether considered related to treatment or not. Study visits were used to monitor for participants’ achievement of initial abstinence. Participants who reported abstinence for at least a day, as verified by CO at ⱕ10 ppm (average of two measurements), were considered to have achieved initial abstinence. Because 8 weeks was considered an adequate time to reduce smoking and achieve abstinence, participants who did not achieve initial abstinence after this time were excused from the remainder of the study and counted as treatment failures in subsequent analyses. Participants who achieved initial abstinence were scheduled for a follow-up visit 28 –35 days after their first day of abstinence to assess 28-day continuous abstinence. At this follow-up visit, participants reported their smoking and gum usage since the previous visit and were specifically asked about their current and recent smoking status to ascertain outcome. Participants who reported continuous abstinence (not even a puff) were subject to confirmation by two CO readings, with an average reading of ⱕ10 ppm verifying abstinence. (Participants who achieved initial abstinence but did not at first maintain 28 days of abstinence could schedule another 28-day follow-up visit if they again achieved another 24-hour period of abstinence—16.9% [85/ 504] of participants who achieved initial abstinence had more than one 28-day follow-up visit.)
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Participants with verified 28-day continuous abstinence were counted as successes on the primary outcome and scheduled for a follow-up visit 6 months from the beginning of treatment, at which time they reported on their smoking, gum use, and adverse events. Participants who reported continuous abstinence (not even a puff) since the 28-day abstinence evaluation were subject to confirmation by two CO readings, with an average reading of ⱕ10 ppm verifying abstinence. Participants who did not demonstrate 28-day abstinence were not scheduled for 6-month follow-up visits and were counted as treatment failures at 6 months. Throughout, participants who did not participate in follow-up visits were counted as treatment failures.
Treatment Consistent with use of an over-the-counter (OTC) medication, participants self-selected their study gum dosage (2 or 4 mg) after reviewing the labels for both doses, which told smokers of ⱖ25 CPD to select the 4-mg dose (per current U.S. Food and Drug Administration [FDA]–approved labeling). Using a 1:1 computer-generated randomization scheme, balanced across study sites and generated separately for the 2and 4-mg groups, participants were randomized on a doubleblind basis to receive active or placebo gum (Nicorette “Original” flavor) and were given 420 pieces of gum with which to initiate treatment. The study was run in a simulated OTC setting: Instructions on quitting and the use of nicotine gum were obtained from only a printed user’s guide and label. Absolutely no instruction, counseling, or intervention was provided by study personnel. The materials instructed smokers to start reducing by not smoking for the first hour of the day and instead using a single piece of gum during that hour. On each subsequent day, participants were to extend their abstinence by adding an additional hour of abstinence, using one additional piece of gum. Once smokers had quit completely (for 24 hours), they were to use the gum in a manner consistent with the current FDA-approved labeling for the following 12 weeks: one piece every 1–2 hours for the first 6 weeks of treatment; one piece every 2– 4 hours for the next 3 weeks; and then one piece every 4 – 8 hours for a final 3 weeks. Participants were then permitted to use the gum “as needed to stay smoke-free” for an additional 12 weeks.
Statistical Analysis The primary endpoint was 28-day continuous abstinence (which was the basis on which other NRT indications have been evaluated by the U.S. FDA28). Active and placebo treatment arms were compared, separately for 2- and 4-mg gum. Reduction in smoking, achievement of initial abstinence (24 hours), and abstinence at 6 months were also examined. Cochran–Mantel–Haenszel tests controlled for study site; analyses pooling 2- and 4-mg groups also controlled for dose (as fixed effects). Results are presented as ORs with 95% CIs. Analysis of variance was used in the analyses of reduction to examine change from baseline to Week 2 in average CPD and in CO concentration. (By a priori plan, the analysis focused on the first 2 weeks of treatment because, as the reduction phase went on, more and more participants achieved abstinence or withdrew from the study and were thus lost to analyses of reduction per se, potentially biasing the analyses.)
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Additionally, successful reduction— defined as a self-reported reduction of ⱖ50% in smoking level verified by a ⱖ25% reduction in CO levels (this measure was constructed to assess significant reduction in cigarette smoking because retrospectively reported smoking level is subject to error and CO is often used to validate self-reports of smoking)—was analyzed as an outcome of treatment and as a mediator of cessation. Finally, reductions in SCN among smokers in the 4-mg gum group were analyzed. Differences between active and placebo conditions in the proportions of subjects experiencing adverse events were tested, by dose. To identify effects of concomitant smoking and nicotine gum use on adverse events, the investigators identified as high-concomitant participants those who were in the upper two thirds for both smoking (CPD) and gum use (pieces per day). To test whether concomitant smoking and use of active gum increased the likelihood of adverse events, a Breslow–Day test was used to determine whether high-concomitant smoking had greater influence on the likelihood of experiencing an adverse event on active versus placebo gum users.
Results Participant Characteristics and Disposition In total, 3297 participants were enrolled and randomized to treatment (Figure 1); 1636 participants selfselected the 2-mg gum, and 1661 self-selected the 4-mg gum. Self-selection conformed to label instructions 88.3% of the time. Accordingly, as expected, smokers in the 4-mg arm smoked more heavily and were more nicotine dependent than those using 2-mg gum (Table 1). Otherwise, the study arms were similar on baseline characteristics. The average participant was white, 44 years old, and had some college education. The majority of participants (57%) were women. Randomization within dose group resulted in well balanced groups. Treatment outcomes: initial abstinence and 28-day and 6-month continuous abstinence. Active treatment significantly increased the probability of achieving initial cessation: 26% of participants on active treatment achieved initial 24-hour abstinence, compared to 18.5% on placebo (OR⫽1.60, 95% CI⫽1.36, 1.90). This effect held for both the 2- and 4-mg dose groups (Figure 2). The rate at which participants first achieved abstinence was fairly constant over the 8 weeks of the reduction period. Among those who achieved abstinence, the median time to initial abstinence was 29 days, with no differences between the active and placebo groups (p⬎0.25). Active treatment increased both 28-day (10.3% vs 3.9%; OR⫽2.83, 95% CI⫽2.10, 3.81) and 6-month (5.9% vs 2.1%; OR⫽2.86, 95% CI⫽1.93, 4.24) continuous abstinence rates. The effects were strongest in the 4-mg group but significant for both doses (Figure 2). Once initial abstinence had been achieved, treatment with active gum improved the odds of participants remaining abstinent. Among participants who achieved initial abstinence, 28-day abstinence rates were significantly higher
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vs 11.2%; OR⫽1.81, 95% CI⫽1.49, 2.21). Regardless of treatment (active or placebo), the odds of achieving 28 days of continuous abstinence were approximately nine times higher among those who successfully reduced by this criterion, compared to those that did not (Figure 4).
3626 excluded 926 failed screening 509 refused 2191 did not enrolla
3297 enrolled
2 mg n=1636
Self-selected group
Randomly allocated
817 placebo
4 mg n=1661
819 active
24-hour abstinence
195 succeeded 622 failed
252 succeeded 567 failed
28-day abstinence
45 succeededb 150 failed 148 terminatedc 2 discontinuedd
86 succeeded 166 failed 159 terminated 7 discontinued
831 placebo
109 succeeded 722 failed 21 succeeded 88 failed 87 terminated 1 discontinued
830 active
184 succeeded 646 failed 88 succeeded 96 failed 92 terminated 4 discontinued
Gum Use
Gum use increased progressively during the first 40 completed 75 completed 18 completed 78 completed 6-month follow-up 4 weeks of the study in 5 did not completee 11 did not complete 3 did not complete 10 did not complete both treatment arms and Figure 1. Participant flow and disposition. Screening data presented are estimates generated both dose groups. Particifrom the records from 12 of the 27 study sites; the remaining sites did not adequately record pants in the 4-mg dose subject screening information. groups tended to use a Qualified for the study and did not explicitly decline, but did not schedule or did not keep an more gum than those in enrollment appointment b the 2-mg groups, but Includes two subjects who demonstrated 24-hour abstinence before 28 days postquit and five subjects who quit more than 9 weeks after the randomization date (includes a 1-week window there was little difference around the Week-8 visit). These seven subjects were considered failures in the primary efficacy between the active and analysis but were continued into the follow-up phase. placebo treatment arms c Terminated includes adverse events, lack of efficacy, withdrawal of consent, and nonspecified within each dose group. factors contributing to failure of abstinence. d By the end of the first Subjects were discontinued for failing to follow the protocol. e Did not complete 6-month follow-up phase for reasons of adverse events, were lost to follow-up week of the study, participhase, or withdrew consent pants in the 2-mg group were using 3.8 (SD⫽3.8) pieces of gum per day, whereas those in the 4-mg group among those randomized to active gum treatment (38.8% were using 5.1 (SD⫽5.0) pieces per day. By the end of vs 21.1%; OR⫽2.29, 95% CI⫽1.62, 3.25), with both the the fourth week of the study, consumption of gum had 2-mg (33.3% vs 22.6%; OR⫽1.79, 95% CI⫽1.14, 2.79) risen to 5.7 (SD⫽4.9) and 7.5 (SD⫽5.9) pieces per day, and the 4-mg gum (46.2% vs 18.4%; OR⫽3.36, 95% respectively, for the 2- and 4-mg groups. CI⫽1.88, 5.99). Similarly, among this subset of participants, Smokers who used more pieces of gum achieved 6-month abstinence rates were significantly higher among substantially higher initial abstinence rates: Collapsed those on active gum treatment (overall: 22.3% vs 11.5%; across dose group, and controlling for both study site OR⫽2.07, 95% CI⫽1.36, 3.17; 2 mg: 18.3% vs 13.3%; and treatment group (active or placebo), those particOR⫽1.45, 95% CI⫽0.85, 2.49; 4 mg: 27.7% vs 8.3%; ipants who used more than the median amount of gum OR⫽3.58, 95% CI⫽1.71, 7.53). per week for the first 2 weeks were more than twice as likely to achieve 28-day continuous abstinence (13.8% Smoking Reduction vs 5.9%; OR ⫽2.66, 95% CI⫽1.96, 3.61). The interacAfter 2 weeks in the study, smokers on active treatment tion between treatment group and gum use was not reported greater reductions in number of cigarettes significant (p⫽0.471). smoked than those on placebo treatment (Figure 3); however, the difference between treatment groups was Adverse Events only significant in the 4-mg group. Participants randomized to active treatment (both doses) demonDuring the first 8 weeks of the study, 42.4% of particistrated significantly greater reductions in CO, indicatpants reported an adverse event (a total of 2515 ing reduced smoke intake. Finally, in the 4-mg group, events). Participants on active gum were more likely to active treatment resulted in significantly greater reducexperience an adverse event than participants taking tions in SCN. placebo gum (48.2% vs 36.6%; p⬍0.001). Among those Participants using active gum were significantly more on active gum, similar proportions of participants using likely to achieve successful reduction (ⱖ50% in smok2- or 4-mg gum reported adverse events (48.7% vs ing level and ⱖ25% in CO level) after 2 weeks (18.6% 47.7%). The most frequently reported adverse events February 2009
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Percent abstinent
were the mild adverse Table 1. Demographic and smoking history of sample, by treatment group (% unless events characteristic of otherwise indicated) nicotine gum use, such 2-mg group 4-mg group as nausea, hiccups, and Placebo Active Placebo Active heartburn. The most com(nⴝ817) (nⴝ819) (nⴝ831) (nⴝ830) monly affected body systems were the gastrointes- Gender Female 65.5 62.8 52.2 47.6 tinal (active: 26% of Age subjects, placebo: 14.5%; M 42.2 42.1 46.3 46.1 p⬍0.001) and respiratory SD 13.3 13.0 11.4 11.3 Race (active: 12%, placebo: Caucasian 83.2 84.5 91.0 90.8 8.6%; p⫽0.002) systems, Black 8.2 8.9 4.8 5.7 consistent with adverse Asian 1.7 1.0 0.5 0.7 events previously reported Hispanic 5.0 4.3 2.5 1.7 for nicotine gum. Adverse Other 1.8 1.3 1.2 1.1 Education events affecting other Some college or more 79.8 78.2 72.0 74.0 body systems occurred in Income ($) ⬍10% of participants in ⬍25,000 28.4 30.1 31.7 29.1 either study group. Ad25,000–49,999 40.4 40.9 39.2 38.8 verse events affecting the ⬎50,000 31.1 29.0 29.1 32.0 cardiovascular system were Cigarettes per day ⱖ25 9.8 9.0 85.4 84.3 very rare and were equally M 17.6 17.7 32.5 32.0 distributed across treatSD 6.1 6.0 10.0 9.6 ment arms: cardiovascular Years smoked disorders (active: 0.4%, plaM 24.3 24.1 29.5 29.2 SD 13.6 12.8 11.7 11.3 cebo: 0.4%); heart rate and Fagerstrom Test for Nicotine rhythm disorders (active: Dependence 0.4%, placebo: 0.4%). M 4.4 4.4 6.9 6.9 To examine the effects SD 2.1 2.1 1.7 1.7 of concomitant smoking Time to first cigarette ⱕ30 minutes 70.3 70.1 92.3 91.7 and nicotine gum use on adverse events, the first 4 Note: There were no significant differences between active and placebo treatments within group (2 mg or weeks of treatment were 4 mg) on any of these variables. focused on, as this is the period with greatest concompare the odds of an adverse event among high- versus comitant smoking and gum use. In each week, the low-concomitant users, while taking into account the use analysis compared the probability of experiencing an of active versus placebo gum (Figure 5). If concomitant adverse event among participants who engaged in high use increased the probability of adverse events, then levels of concomitant use versus those engaged in low among those on active gum, high-concomitant users or no concomitant use. The investigators classified as should be more likely to experience adverse events than high-concomitant users those who were in the 33rd low-concomitant users. However, significant differences percentile or higher on both smoking and gum use. This classified roughly 40% of participants as high40 6.0 1.8 2.0 4.7 1.4 1.9 concomitant users, but results were similar when the 35 (1.1, 2.9) (2.9, 12.2) (1.4, 2.9) (2.8, 7.7) (1.1, 1.8) (1.5, 2.5) top 20% of concomitant users were analyzed. In the 30 Placebo 25 2-mg arm, the high-concomitant group averaged 12.38 20 Active cigarettes (SD⫽5.47) and 6.78 pieces of gum 15 (SD⫽4.85) per day, and the low-concomitant group 10 averaged 8.49 cigarettes (SD⫽7.20) and 3.69 pieces of 5 gum (SD⫽4.54) per day. In the 4-mg arm, high0 2 mg 4 mg 2 mg 4 mg 2 mg 4 mg concomitant users averaged 22.26 cigarettes (SD⫽9.03) and 8.91 pieces of gum (SD⫽5.85) per day, and lowInitial abstinence 28-day abstinence 6-month abstinence concomitant users averaged 15.64 cigarettes Figure 2. Initial abstinence percentages and 28-day and (SD⫽11.46) and 5.17 pieces of gum (SD⫽5.79) per 6-month continuous smoking cessation percentages, by day. treatment and dose group. Figures above each set of bars To assess the effects of concomitant use on adverse events, represent the OR for active treatment versus placebo, and a Breslow–Day test for homogeneity of ORs was used to its 95% CI. 100
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Figure 3. Percentage reduction (and SE) in carbon monoxide (CO; n⫽2250), cigarettes per day (CPD; n⫽2260), and serum thiocyanate (SCN; 4 mg only; n⫽205) from baseline to week 2, by treatment and dose groups. Asterisks indicate a significant difference between treatment groups: *p⬍0.05; **p⬍0.01; ***p⬍0.001.
in the likelihood of adverse events between high- and low-concomitant users on active gum were not observed. (In fact, for high-concomitant users, there was a trend toward lower likelihood of reporting an adverse event.) Further, if concomitant use and the consequent increased nicotine intake caused adverse events, the differences between active and placebo gum should be more marked among high-concomitant users than among low-concomitant users. However, this interaction was not observed (p values ⬎0.10 for all weeks and both doses); the combination of chewing active gum and smoking did not increase the likelihood of adverse events.
Comments This study is the first to test the efficacy and safety of using nicotine gum to assist smoking cessation by gradual reduction. Treatment with nicotine gum en-
Figure 4. 28-day continuous smoking-cessation rates, by treatment group and successful smoking reduction. Figures above each set of bars represent the OR for those who successfully reduced (n⫽492) versus those who did not (n⫽2805), and its 95% CI. Successful reduction is defined as a ⱖ50% reduction in smoking rate combined with a ⱖ25% reduction in carbon monoxide (CO) between baseline and Week-2 values.
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hanced success levels at every step of the process: Smokers using active nicotine gum were more likely to substantially reduce their smoking, more likely to achieve initial abstinence, and more likely to maintain abstinence, both in the short run and for up to 6 months. Although the absolute quit rates achieved in this trial appear modest (with 10% of active gum users achieving 28-day abstinence and 6% maintaining abstinence at the 6-month follow-up visit), it must be recalled that this trial included no behavioral instruction or intervention whatsoever. The quit rates observed are comparable to those observed in abrupt quitting with nicotine gum under similar conditions (Shiffman et al.29 reported 6-month quit rates of 8%). In assessing the quit rates in this study, it is important to keep in mind that smokers who prefer quitting by gradual reduction differ from those who elect abrupt cessation. For example, smokers planning to quit by gradual reduction are less motivated to quit and are less than half as likely as abrupt quitters to even attempt quitting.11 Indeed, those saying they would quit gradually were no more likely to make a quit attempt than smokers who said they wanted to only reduce, not quit, smoking. Thus, smokers preferring to quit by gradual reduction are not comparable to those who want to quit abruptly, as in most cessation trials, and may be expected to have lower quit rates. Indeed, very low rates of quitting in the placebo group (4% at 28 days and 2% at 6 months) were observed. Against that background, treatment with active gum tripled the odds of quitting for 28 days, an advantage that was maintained at the 6-month follow-up visit. Indeed, the 6-month OR (2.86) is at the high end of those typically observed in trials of nicotine gum for abrupt smoking cessation (which average 1.667). The data suggest that for smokers quitting gradually, using nicotine gum can offer a very
Figure 5. Percentage (and 95% CI) of participants who reported adverse events (AEs) by concomitant use and treatment groups, during Weeks 1 (n⫽2265), 2 (n⫽2366), 3 (n⫽2027), and 4 (n⫽1841). High-concomitant smokers were those who were in the upper two thirds of the distribution on both daily cigarette consumption and daily gum use (see text). The “Low” group includes all other participants.
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substantial advantage. Interestingly, in a nonrandomized population study, Cheong et al.10 similarly found that using medication was associated with success in quitting by gradual reduction (OR⫽2.6), consistent with the findings from this RCT. The reduce-to-quit (RTQ) approach described here is not the only approach using an NRT-assisted reduction phase to promote cessation. The RTQ approach engages smokers who are ready to quit on a relatively time-limited program of structured reduction explicitly aimed at a quitting endpoint. A contrasting approach, described as “cut down to quit” (CDTQ),30 encourages smokers who are not currently interested in quitting to use NRT for reduction over a period of up to 12 months. Meta-analysis30 suggested that this approach was efficacious but less cost effective than abrupt cessation. In any case, the RTQ and CDTQ approaches address different populations with different propositions, making results difficult to compare. Treatment with active nicotine gum facilitated reductions in reported smoking and biochemical markers of smoke exposure. Although use of active 2-mg gum did not show significantly greater reductions in self-reports of cigarettes smoked, it did yield significantly greater drops in CO, demonstrating greater reductions in smoke intake. Smokers on placebo gum may have compensated for some of their reductions by smoking more intensely,31 whereas treatment with nicotine gum reduced the use of this compensation. Indeed, a measure of biochemically verified reduction, requiring a ⱖ50% reduction in cigarettes smoked and a ⱖ25% reduction in CO level, showed significant effects for active treatment in both doses. Assays based on SCN, which has a longer half-life than CO, confirmed significant reductions in those using 4-mg gum. Many purely behavioral approaches to reducing smoking have been tested previously (e.g., keeping a strict schedule, elimination of least-favored cigarettes).32 It is not known which procedures are optimal for promoting reduction. In this study, smokers were instructed to progressively increase their gum use while simultaneously decreasing their smoking on an hour-by-hour basis.20 However, the pattern of gum use observed in the study, and the fact that smokers in the study did not necessarily achieve abstinence after 16 days (as would be expected if they followed the regimen and added a waking hour of abstinence each day), suggests that smokers did not strictly follow the hour-by-hour instruction. Further research is needed in order to determine whether alternate procedures more effectively promote reduction and cessation. However, it is clear that participants benefited from having 8 weeks to establish abstinence, as new participants continued to achieve initial abstinence each week throughout this 8-week period. This suggests that allowing a longer period for reduction might have led to higher quit rates. 102
Process analyses shed light on the ways in which active treatment helped smokers achieve abstinence. Nicotine gum was expected to help smokers reduce smoking effectively, and thus to promote achievement of initial abstinence. Indeed, the analysis showed that active treatment with nicotine gum promoted smoking reduction, which, in turn, promoted initial cessation. Once smokers achieved initial abstinence, active treatment with nicotine gum promoted maintenance of abstinence for 28 days– 6 months. Thus, active treatment provided a benefit at each step in the process of quitting by gradual reduction. As noted by Shiffman et al.,33 achievement of initial abstinence is an important but often ignored key step in successful quitting. In this study of quitting by gradual reduction, achieving initial cessation for 24 hours appeared to be the greatest hurdle—treatment with active gum helped increase the proportion who reached that milestone by 37%, from 19% (on placebo) to 26%. This demonstrates the contribution of active treatment during the reduction phase in bringing smokers to the point of quitting. After initial cessation was achieved, active treatment further demonstrated its well known ability to sustain abstinence, increasing 28-day abstinence by 40%, from 28% (placebo) to 39%. Further work is needed on behavioral and pharmacologic treatment regimens to increase achievement of initial quitting in the context of gradual reduction regimens. It is possible that a more structured approach to cessation, or selection of smokers who are more committed to complete cessation, would yield substantially higher initial quit rates. The data suggest that behavioral as well as pharmacologic processes are at work in determining success. Notably, whereas other studies have demonstrated a benefit of more NRT use in the active group only,34 in this study, smokers who used more gum early in the reduction phase were more likely to achieve 28-day abstinence, regardless of whether they used active or placebo gum. This could reflect nonspecific behavioral benefits of just chewing gum (chewing gum and candy is often recommended for quitting35), or it could be a marker distinguishing those smokers who were more motivated and prepared to make greater efforts to achieve and maintain abstinence. In either case, this suggests the importance of behavioral processes, even in the context of pharmacologic treatment. Nicotine gum has been used safely for cessation in clinical trials and in actual use for over 20 years.7 This study was unique in directing that smokers use nicotine gum while still smoking, for up to 8 weeks. The results were reassuring: Adverse events were generally mild and were consistent with those seen with nicotine gum used for abrupt quitting. Moreover, there was no evidence of increased risk among smokers who engaged in the most concomitant smoking and gum use. Even smokers who smoked an average of 18 CPD along with
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seven pieces of 4-mg nicotine gum (more than is used by the typical quitter36) did not experience an increased likelihood of adverse events. Nicotine regulation mechanisms37 likely limited exposure, causing smoking to decline as nicotine intake from the gum increased. The safety of concomitant smoking and NRT use seen in this study is consistent with analyses of long-time users of nicotine gum38 and with a study of myocardial perfusion during concomitant smoking and NRT use.39 Using nicotine gum while smoking carries little to no incremental risk. The study’s limitations include a lack of highly detailed data about how subjects used nicotine gum to quit and a lack of detailed information regarding subjects who were screened out of participation. The study also did not include some groups of smokers, such as those with cardiovascular disease, who may be at greater risk for adverse events; thus, the adverse event profile described in the study cannot be generalized to all smokers. The study’s strengths include a very large and diverse sample, studied under real-world conditions with no counseling or instruction; detailed data on cigarette and gum consumption; and biochemical measures of smoke exposure. This is the first study to demonstrate that smokers wanting to quit by gradual reduction can substantially increase their success by using nicotine gum to facilitate reduction and cessation. Nicotine gum helped smokers reduce smoking, achieve initial abstinence, and maintain abstinence. The advantage of active NRT treatment is particularly evident for heavy smokers treated with the 4-mg nicotine gum, for which treatment increased the odds of quitting for 6 months sixfold. This expands treatment options for the substantial proportion of smokers who prefer quitting gradually,8 who have relatively low chances of quitting, and who have heretofore been implicitly excluded from the use of NRT to help them quit. Offering this new way to use NRT may enhance the appeal and reach of a treatment that increases success, and thereby have positive public health impact. Given the ongoing extraordinary health toll from smoking, consideration should be given to novel approaches that increase success in quitting. This study was supported by SmithKline Beecham Consumer Healthcare, now GlaxoSmithKline Consumer Healthcare (GSKCH), which markets nicotine replacement medications for smoking cessation. Dr. Strahs is employed by GSKCH. Through their work at Pinney Associates, Drs. Shiffman and Ferguson serve as consultants to GSKCH on matters related to smoking control and/or nicotine replacement medications. Dr. Shiffman also has a financial interest in a venture to develop new nicotine replacement medications. The authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The authors wish to thank Mark Sembower and Gina Bittner for their assistance with analyzing the data and
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preparing the manuscript for publication. The authors owe a debt of gratitude to the 27 study-site Principal Investigators (listed in an online appendix at www.ajpm-online.net) who collected the data.
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Appendix Study-Site Principal Investigators Wanda D. Angueira, MD Sciman Biomedical Research San Antonio TX Robert Bettis, MD Edmonds Family Medicine Clinic Edmonds WA Stephen A. Braden, MD Sciman Biomedical Research Bryan TX David Brown, MD Community Clinical Research, Inc. Austin TX Michael Cassar, MD TKL Research, Inc. Paramus NJ Paul Cinciripini, PhD UT MD Anderson Cancer Center Houston TX Clinton N. Corder, PhD, MD COR Clinical Research Oklahoma City OK
Lawrence V. Larsen, PhD Intermountain Clinical Research Salt Lake City UT Samuel Lederman, MD Hill Top Research, Inc. West Palm Beach FL Robin Mermelstein, PhD University of Illinois at Chicago Chicago IL John S. Muchmore, MD Lynn Health Science Institute Oklahoma City OK Mitch Nides, PhD LA Smoking Research Center Los Angeles CA Stephen Rennard, MD University of Nebraska Medical Center Omaha NE Harvey Resnick, MD R/D Clinical Research, Inc. Lake Jackson TX Ernie Riffer, MD Central Phoenix Medical Clinic Phoenix AZ
Thomas Fiel, DO Tempe Primary Care Associates Tempe AZ
Nancy Rigotti, MD General Internal Medicine Unit Massachusetts General Hospital Boston MA
David Gonzales, PhD Oregon Health Sciences University Portland OR
Sid Rosenblatt, MD, FACP Irvine Clinical Research Center Irvine CA
Dorothy Hatsukami, PhD University of Minnesota Minneapolis MN
Joseph Salvatore, MD Vista Medical Research, Inc. Mesa AZ
F. Charles Hiller, MD University of Arkansas for Medical Sciences Little Rock AR
Teresa S. Sligh, MD Sciman Biomedical Research Euless TX
Larysa Hun, MD Research Testing Laboratories, Inc. Huntington NY
Kevin Tack, MD Research Testing Laboratories, Inc. Great Neck NY
Sharad Lakhanpal, MD Metroplex Clinical Research Dallas TX
Gerald Wolfley, MD Hill Top Research Scottsdale AZ
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