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Efficacy of a Nicotine Lozenge for Smoking Cessation
Saul Shiffman, PhD;
Carolyn M. Dresler, MD;
Peter Hajek, PhD;
Simon J. A. Gilburt, PhD;
Darren A. Targett, MSc;
Kenneth R. Strahs, PhD
Arch Intern Med. 2002;162:1267-1276.
ABSTRACT
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Background Since nicotine gum was introduced in the 1980s, nicotine replacement
therapy has become the most widely used pharmacological smoking cessation
treatment. Some smokers prefer acute oral forms, but many smokers reject chewing
gum. We tested the safety and efficacy of a new nicotine polacrilex lozenge
for smoking cessation.
Methods Double-blind, placebo-controlled, randomized clinical trial with parallel
arms testing 2- and 4-mg nicotine lozenges. Smokers (n = 1818) were assigned
to a lozenge dose on the basis of nicotine dependence, assessed by time to
the first cigarette of the day. Low-dependence smokers were randomized to
receive the 2-mg nicotine (n = 459) or placebo (n = 458) lozenge; high-dependence
smokers, the 4-mg nicotine (n = 450) or placebo (n = 451) lozenge. We assessed
abstinence at 6, 12, 24, and 52 weeks and analyzed craving and withdrawal
symptoms.
Results Treatment with the nicotine lozenge resulted in significantly greater
28-day abstinence at 6 weeks, for the 2-mg (46.0% vs 29.7%; odds ratio [OR],
2.10; 95% confidence interval [CI], 1.59-2.79; P<.001)
and the 4-mg (48.7% vs 20.8%; OR, 3.69; 95% CI, 2.74-4.96; P<.001) lozenges, compared with placebo. Significant treatment effects
were maintained for a full year. Smokers who used more lozenges achieved significantly
better treatment effects. Use of the active lozenge also resulted in reduced
craving and withdrawal. Most adverse events were moderate and resembled those
seen with nicotine gum.
Conclusion The nicotine lozenge is a safe and effective new treatment for smoking
cessation in low- and high-dependence smokers.
INTRODUCTION
SMOKING IS the leading preventable cause of death and disease in the
Western world.1 Accordingly, clinical guidelines
call for physicians to provide counseling and treatment for all smokers.2-3 Nicotine replacement therapy (NRT)
is the most widely used pharmacological therapy for smoking cessation.4 The efficacy of NRT has been proven in many clinical
trials, approximately doubling the success rates for quitting compared with
placebo.5 Nevertheless, most smoking cessation
efforts are attempted without benefit of treatment,6-7
and only about 28% of US and 11% of European smokers have tried NRT7 (Katie Kemper, MBA, unpublished data, 1998; available
from GlaxoSmithKline, GSK House, 980 Great West Rd, Brentford, Middlesex TW8
9GS, England). Introducing new dosage forms and more effective therapy may
help bring more smokers into treatment, thus enhancing cessation rates and
improving public health.
Nicotine replacement therapy is available in several forms—patches,
nasal spray, inhalator, sublingual tablets, 1-mg lozenges, and chewing gum.
Nicotine patches provide a steady transdermal infusion of nicotine8 and are preferred by many smokers who are trying to
quit. However, acute administration of nicotine (orally or intranasally) has
potential advantages, notably in allowing the smoker to control the amount
and timing of dosing. This may allow smokers to self-titrate therapy to an
appropriate dosage and to use acute dosing as a rescue medication to combat
acute episodes of craving.9-10
Unfortunately, the current forms of NRT available for acute administration
also present significant barriers to patient acceptance and use.11
The nasal spray, available only by prescription in the United States, is initially
very irritating,12 and its use may carry some
stigma. The nicotine inhalator13 (which deposits
nicotine in the oropharynx) may raise similar concerns, as it is shaped like
a cigarette holder; it also delivers very modest doses of nicotine. Nicotine
gum is available without a prescription in many countries, but also presents
some barriers to acceptance and use. People with dentures or temporomandibular
joint pain may be unable to use gum. Some individuals and some cultures are
uncomfortable with chewing gum, whereas others may not view a gum as a serious
medication. A substantial minority of smokers dislike chewing gum (Colin Baker,
unpublished data, July 20, 2000). The dose of nicotine provided by nicotine
gum might not be adequate for some smokers, particularly given smokers' tendency
to underdose.2 These limitations may keep current
NRT medications from helping more smokers.
Two new oral forms of NRT have been recently introduced. A 2-mg nicotine
bitartrate dihydrate sublingual tablet is available in some countries (eg,
the United Kingdom, Sweden, and Denmark). The tablet delivers less nicotine
than nicotine gum, and falls short of dose proportionality when 2 tablets
are used simultaneously to mimic a 4-mg dose.14
It has been shown to be effective in highly dependent but not in less dependent
smokers.15 A 1-mg nicotine bitartrate salt
lozenge (Nicotinell) has also been introduced in the United Kingdom and Sweden,
but no pharmacokinetic or efficacy data have been published, so very little
is known about the product.
Thus, there is a need for an alternate oral form of NRT that delivers
more effective doses of nicotine and demonstrable efficacy across a broad
spectrum of smokers. Increasing the reach and appeal of NRT and enhancing
the use of smoking cessation treatment is a matter of public health urgency.
The current study presents clinical data on a new nicotine polacrilex lozenge
designed to meet these objectives. We tested 2-mg and 4-mg doses. Compared
with 2-mg or 4-mg nicotine gum, the nicotine lozenges deliver 25% to 27% more
nicotine (based on the area under the curve),16
because some nicotine is retained in the gum, whereas the lozenges dissolve
completely and deliver their full dose. The 2- and 4-mg lozenges were intended
for different groups of smokers. The higher dose was designed for more nicotine-dependent
smokers, who are thought to need a higher level of nicotine. Studies of nicotine
gum indicate that, for highly dependent smokers, the 4-mg dose achieves significantly
better success rates than does the 2-mg dose17-19;
indeed, for these smokers, the efficacy of 2-mg gum is roughly equivalent
to that of placebo.17-18 Conversely,
some evidence suggests that the 4-mg dose may actually be detrimental to smokers
who are not highly nicotine dependent.20 Thus,
it is important to select the right dose for different smokers.
At present, smokers who use nicotine gum are typically instructed to
self-select the higher dose based on their smoking rate. Although this method
has the advantage of simplicity, smoking rate is a poor marker of nicotine
dependence, especially as smoking restrictions force smokers to smoke fewer
cigarettes21-22 and as smoking
rates vary by cultural and ethnic groups.23
A better measure of nicotine dependence is needed to assist smokers in choosing
an effective nicotine dosage. The most widely used measure of nicotine dependence
is the Fagerström Tolerance Questionnaire (FTQ24-25).
The FTQ predicts the efficacy of NRT treatment26-27
and has been used in clinical trials to assign smokers to a 4-mg dose of gum
treatment.17-18 However, the FTQ
is scored from an 8-item written test, and thus is unsuitable for simple patient
selection or self-selection. Within the FTQ, the single best indicator of
nicotine dependence is the item that asks whether the smoker has the first
cigarette of the day within 30 minutes of waking.28
This is an important indicator, because all smokers wake up in a state of
nicotine deprivation, and the drive to self-administer nicotine is a good
marker of nicotine dependence. Moreover, this single item on time to first
cigarette (TTFC) correlates highly with the full Fagerström Test for
Nicotine Dependence test.29 Accordingly, in
this study, we allocated smokers to the following doses of nicotine lozenge
based on their TTFC: those who normally smoke their first cigarette within
30 minutes of waking were assigned to the 4-mg lozenge, and those who waited
longer were assigned to the 2-mg lozenge.
This study was an international, multicenter, placebo-controlled, double-blind,
randomized clinical trial of nicotine lozenges for smoking cessation. Parallel
arms were run with highly dependent and less dependent smokers assigned to
the 4- and 2-mg nicotine lozenge (or placebo), respectively. The primary end
point was 28-day continuous abstinence from smoking at 6 weeks. Participants
also underwent assessment after 12, 24, and 52 weeks. We also evaluated the
safety of the nicotine lozenge and its effects on nicotine craving and withdrawal.
SUBJECTS AND METHODS
PARTICIPANTS
One thousand eight hundred eighteen smokers were randomized to treatment,
965 at 4 sites in the United Kingdom and 853 at 11 sites in the United States.
Participants were solicited via advertisements and underwent initial screening
by telephone before screening at the research sites. To qualify for the study,
smokers had to be 18 years or older and interested in quitting smoking during
the next 30 days. Smokers were excluded if, during the past 30 days, they
had used other smoking cessation aids or forms of nicotine or tobacco other
than cigarettes, had smoked other substances, or had been in a clinical trial.
Other exclusion criteria included pregnancy, heart disease (within the previous
3 months), stomach ulcer, uncontrolled hypertension, insulin-dependent diabetes,
or difficulty metabolizing aspartame (for patients with phenylketonuria, aspartame
metabolizes to phenylalanine). Initially, 2168 volunteers underwent screening
and 75 were excluded; the most common reason for exclusion was smoking of
other substances (no other reason accounted for  10% of exclusions). Thus,
2093 participants entered baseline monitoring, 275 withdrew before randomization,
and 1818 were randomized (Figure 1).
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Figure 1. Disposition of subjects. Sample
sizes for the continuing samples represent the number of participants who
continued in the study after each study visit. At each visit, participants
who were smoking or who failed to appear were discontinued. High- and low-dependency
groups are described in the "Design" subsection of the "Subjects and Methods"
section.
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DESIGN
We conducted a randomized, double-blind, placebo-controlled parallel
clinical trial of nicotine lozenges for smoking cessation. The study procedures
were reviewed and approved by the appropriate ethics committees, and participants
provided written informed consent. Smokers were assigned to a lozenge dose
based on their reported TTFC of the day, ie, those who reported smoking within
30 minutes of waking were assigned to the 4-mg dose (n = 901), and the others
to the 2-mg dose (n = 917). (Recruiting low-dependency smokers for this cessation
trial proved more difficult, and the high-dependency arm was filled and closed
to new entries for a time while recruitment of low-dependency smokers was
completed. This resulted in some high-dependency volunteers being turned away
because that arm of the study was full.) Within these groups, smokers were
randomized to receive the active or the placebo lozenge. These sample sizes
were designed to be adequate to detect treatment effects independently for
each dose.
After enrolling, participants provided baseline assessment of craving
and withdrawal symptoms for 1 week. After a week of baseline monitoring, smokers
returned to the study site and were randomized to receive the active or the
placebo lozenges, dispensed a supply of medication, and directed to quit smoking.
Visits were scheduled at 2, 4, and 6 weeks (±3 days), 12 weeks (±7
days), 24 weeks (±7 days), and 52 weeks (±14 days) after randomization.
At each visit, participants who failed to maintain abstinence (assessed by
self-report or results of carbon monoxide verification) were discontinued
from the study; only abstainers were continued and followed up. At visits
up to week 4, methods for quitting smoking were discussed briefly. At visits
up to week 24, lozenges were distributed. At each visit, participants were
asked about any adverse events (AEs) they may have experienced; these were
coded in accordance with the World Health Organization Adverse Reaction Terms
system. Study personnel judged the seriousness of the AEs and their relationship
to the study medication (not related, unlikely to be related, possibly related,
probably related, or highly probably related).
OUTCOME MEASURES
Following a standard defined by the US Food and Drug Administration,30 the primary efficacy measure was complete, continuous
abstinence from smoking for at least 4 weeks before the 6-week visit. To count
as abstinent, participants had to report abstinence at the 2-week visit and
4 weeks of continuous abstinence at the 6-week visit. Participants' reports
of abstinence were subject to verification by an exhaled carbon monoxide level
of no greater than 10 ppm. Continuous smoking abstinence (no slips allowed)
was also assessed at 12, 24, and 52 weeks by self-report and confirmed by
results of exhaled carbon monoxide monitoring. At each visit after week 2,
participants who had smoked were discontinued; only continuous abstainers
were retained and followed up. Participants who did not appear for a visit
were counted as treatment failures.
ASSESSMENT OF WITHDRAWAL SYMPTOMS AND CRAVING
Weight was measured at each study visit. Data on subjective symptoms
were collected via daily ratings that participants made using an automated
telephone system (interactive voice response [IVR]). Starting 1 week before
being directed to quit (for baseline data) and continuing for 6 weeks after
the designated quit date, participants were instructed to call a toll-free
telephone number and respond to 9 questions about withdrawal symptoms by using
the telephone keypad. With the use of a 5-point scale (none, slight, mild,
moderate, or severe), ratings were captured for craving; urge; anger, irritability,
or frustration; anxiety; difficulty concentrating; restlessness; increased
appetite; insomnia or awakening at night; and depressed mood. The questions
on urge and craving were averaged to form a reliable craving index (Cronbach's  ,
0.96). All other items were averaged to form a reliable withdrawal index (Cronbach's ,
0.90). The analysis examined ratings during the first 2 weeks (before smokers
who failed to quit were systematically discontinued), with baseline ratings
used as a covariate. Compliance with the IVR system was poor, as less than
10% of eligible participants completed IVR ratings every day during baseline
and the first 2 weeks. For analysis, ratings were averaged by week, and individual
participants' data were included only when at least 3 daily ratings were available
for the relevant week. About half (47.5%) of all subjects had adequate data
for the first 3 weeks (baseline and weeks 1 and 2). Low-dependence smokers
were less likely than high-dependence smokers to meet this compliance criterion
(44.3% vs 50.7%; P<.01). As expected, because
early dropouts would be counted as failures and would also have failed to
complete IVR telephone calls, smokers who were counted as failures (at 6 weeks)
were more likely to have been noncompliant with IVR reporting (72.3% vs 33.3%; P<.001). However, within outcome groups, we found no
differences in compliance by treatment group (active vs placebo) or interactions
between lozenge treatment and IVR compliance. Treatment with the active lozenge
was comparably effective in IVR-compliant and non–IVR-compliant smokers.
Demographically, white smokers were more likely to be compliant (48.2% vs
36.9%; P<.05), as were smokers older than 40 years
(53.3% vs 40.2%; P<.001). Otherwise, IRV-compliant
and non–IRV-compliant smokers did not differ by sex or by smoking history
(smoking rate, Fagerström Test for Nicotine Dependence score, and age
at initiation), controlling for dosing group.
PHARMACOLOGICAL TREATMENT
Starting on the designated quit date, participants were provided with
nicotine or placebo lozenges, per randomization. The 4-mg lozenge was assigned
to those who smoked their first cigarette within 30 minutes of waking, and
the 2-mg lozenge was assigned to all others. The active lozenge delivers nicotine
into the mouth during a period of dissolution lasting approximately 30 minutes,
depending on subject use. These lozenges provide 25% to 27% more nicotine
than the corresponding nicotine gum doses.16
Participants were instructed to place the lozenge in their mouth and
allow it to dissolve, periodically to move the lozenge in the mouth, and to
avoid chewing or swallowing the lozenge. During the first 6 weeks of lozenge
use, the instructions recommended using a lozenge every 1 to 2 hours, with
a recommended minimum of 9 lozenges per day, and decreasing the dosage to
1 every 2 to 4 hours in weeks 7 to 9, and to 1 every 4 to 8 hours in weeks
10 to 12. From weeks 12 to 24, participants were instructed to keep the lozenges
available and to use them occasionally in situations when they might be tempted
to smoke. At each visit, participants were provided with sufficient lozenges
for the labeled maximum use of 20 per day. Lozenge use was to stop after 6
months. During the first 6 months, participants were to report the number
of lozenges used each day during daily telephone calls to the IVR system.
Compliance with IVR system was less than optimal and dropped over time. During
the first 2 weeks, participants called an average (±SD) of 4.4 (±2.6)
of 7 days. During the last 12 weeks of lozenge use, this had dropped to 3.1
(±2.7) calls per week. Lozenge use was estimated from the average of
completed IVR telephone calls and was not imputed for missing days.
BEHAVIORAL SUPPORT
Participants were provided with a written user's guide that included
behavioral guidance for smoking cessation and instructions on lozenge use.
At each of the first 4 visits (through week 4 after randomization), study
coordinators spent 5 to 10 minutes reviewing these behavioral tips and directing
participants' attention to the user's guide. No other behavioral intervention
was permitted.
STATISTICAL ANALYSIS
Analyses were performed separately for smokers assigned to the 2- and
the 4-mg lozenges. We analyzed abstinence rates using the  2
test, controlling for country (United States vs the United Kingdom). A logistic
regression model adjusted for site; we found no interaction between site and
treatment. The primary outcome variable was 28-day abstinence at the 6-week
visit. To assess the relation between outcome and use of lozenges, abstinence
rates were compared between participants who used less than or greater than
the median number of lozenges per day in the first 2 weeks of treatment (before
any participants were dropped as treatment failures) within dependence groups.
The effects of treatment on abstinence were analyzed at weeks 12, 24, and
52 and by survival analysis (which takes into account the duration of abstinence).
Participants who presented at the site and reported smoking were asked to
give a date of first smoking, which was used in the analysis. If no date was
given, the midpoint between the previous and the current visit was used. Those
participants unavailable for follow-up or those who remained smoke-free during
the entire study were considered censored as of the time of last observation.
We compared craving and withdrawal symptoms of the active-treatment
and placebo groups by analysis of covariance while adjusting for baseline
symptom scores. The analysis focused on symptoms in the first 2 weeks of treatment;
after this time, participants who smoked were discontinued for lack of efficacy,
biasing the remaining sample. (Because the withdrawal measure was not normally
distributed among the recipients of the 2-mg dose, a nonparametric analysis
of median differences was used for this group.) We examined weight gain by
analysis of variance at 6, 12, 24, and 52 weeks. We also compared the percentage
of participants in the active-treatment and placebo groups who reported any
AEs.
RESULTS
Figure 1 shows the treatment
assignment and disposition of all participants undergoing recruitment and
screening in the study. A total of 1818 smokers were randomized to treatment.
Of these, 901 were considered high-dependency smokers (TTFC,  30 minutes)
and were assigned to the 4-mg lozenge (450 to the active and 451 to the placebo
form). The remaining 917 were considered low-dependency smokers (TTFC, >30
minutes) and were assigned to the 2-mg lozenge (459 to the active and 458
to the placebo form). Table 1 shows the demographic profile and smoking history of the samples, which match
those typically seen in smoking cessation trials. Participants' average age
was 42 years, with more than 20 years of smoking. Most had previously tried
and failed to quit smoking, and most had previously used pharmacological treatment.
Women were slightly overrepresented. Differences between the 2- and the 4-mg
lozenge groups were consistent with their selection for low vs high nicotine
dependence. Within dependence groups, active-treatment and placebo groups
were well matched, with no significant differences between them. Most participants
(65.5%) reported having 1 or more preexisting medical conditions (not shown),
with respiratory, cardiovascular, digestive, and genitourinary conditions
accounting for almost two thirds of the stated conditions. Almost two thirds
of participants were taking concomitant medication, most often for gastrointestinal
tract or central nervous system conditions.
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Table 1. Demographic and Smoking Characteristics of Randomized Participants*
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ABSTINENCE RATES
Table 2 summarizes abstinence
rates and results of comparisons at 6, 12, 24, and 52 weeks. For the primary
efficacy measure at 6 weeks, the odds of being abstinent were 2.10 (for the
2-mg lozenge) or 3.69 (for the 4-mg lozenge) times greater for those receiving
the active lozenge vs placebo. Smokers receiving the active lozenge at either
dose continued to demonstrate significantly higher abstinence rates at 12,
24, and 52 weeks. Even after 1 year, the odds of being abstinent were more
than doubled by treatment with active lozenge.
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Table 2. Continuous Abstinence Rates*
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We also analyzed the abstinence data by using survival analysis and
contrasted active treatment and placebo within each dependence group by using
the log-rank test. Figure 2 shows
the resulting Kaplan-Meier survival curves. Among low-dependency smokers,
treatment with the active lozenge significantly improved abstinence (P<.01). Median abstinence duration (survival) while
receiving the active 2-mg lozenge was almost 3 times as long (266 days; 95%
confidence interval [CI], 141-304 days) as that for subjects receiving placebo
(95 days; 95% CI, 77-174 days). Similarly, for high-dependency smokers, treatment
with the active 4-mg lozenge significantly prolonged abstinence, resulting
in median survival times almost 6 times as long as those for placebo treatment
(median, 182 vs 32 days; 95% CI, 158-275 vs 27-52 days; P<.001). Figure 2 shows
that, whereas high-dependency smokers treated with placebo had poor outcomes
relative to those of low-dependency smokers treated with placebo, treatment
with active 4-mg lozenges allowed high-dependency smokers to achieve outcomes
comparable to those of the low-dependency smokers receiving 2-mg active lozenges,
thus eliminating the excess risk due to high dependence.
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Figure 2. Survival curves for the treatment
groups over time show the percentage of participants in each group who were
abstinent, accounting for censoring. The curves include all participants randomized
to treatment. When participants who had previously been abstinent failed to
appear for a visit, their data were censored as of the last visit. If a participant
was counted as smoking (based on self-report or results of carbon monoxide
monitoring), but a lapse day was not known, the lapse day was assigned halfway
between the present and the previous visit. Participants who did not appear
for the visit at 2 weeks were censored at 7 days after randomization (halfway
between randomization and the 2-week visit). Participants who remained abstinent
for the duration of the study were censored at their final visit.
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CRAVING, WITHDRAWAL, AND WEIGHT GAIN
As shown in Table 3, treatment
with the active lozenge significantly reduced baseline-adjusted craving in
groups receiving the 2- and the 4-mg lozenges in weeks 1 and 2. In a parallel
analysis of withdrawal symptoms, the active 4-mg lozenge yielded significantly
lower withdrawal symptom scores in weeks 1 and 2; for the 2-mg lozenge, using
nonparametric analysis, the reduction in symptoms was significant in week
1, but not in week 2. Similar outcomes were observed when we restricted the
analysis to those who were abstinent at week 2.
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Table 3. Withdrawal and Craving Scores in Weeks 1 and 2, by Treatment
and Dose*
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All groups gained weight after smoking cessation. As shown in Table 4, compared with placebo, treatment
with the active 4-mg lozenge significantly reduced weight gain by 45% (1.03
kg) at week 6 and by 21% (0.73 kg) at week 12. By 6 months, the differences
between active and placebo treatment were no longer significant. In the group
assigned to the 2-mg lozenge, treatment assignment had no reliable effect
on weight gain.
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Table 4. Analysis of Weight Gain*
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ADVERSE EVENTS
Table 5 shows that 61.8%
of participants reported 1 or more AEs during the 6 months when lozenges were
dispensed. Smokers assigned to the 2 (P<.001)
and the 4-mg (P<.001) active lozenges were more
likely than those assigned to placebo to report AEs.
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Table 5. Treatment-Emergent Adverse Events Occurring in at Least 5%
of Participants in Any Treatment Group (Intent-to-Treat Population)
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The pattern for AEs with some putative relation to study drug was similar
to that seen for all events, although the incidence was lower. Seventeen percent
of participants experienced an AE classified as severe. Among those who experienced
AEs, the risk for severe AEs did not differ for active vs placebo lozenge
(2-mg group, P = .11; 4-mg group, P = .57). A total of 7.1% of participants withdrew from the study because
of AEs. For participants receiving the 2-mg lozenge, withdrawal was more common
among those receiving the active form (P = .03, vs
placebo form), but this trend was reversed for the 4-mg lozenge (P = .08). Nonfatal, serious AEs were rare (1.6% of all participants)
and were not more common among those receiving active medication (2-mg group, P = .27; 4-mg group, P = .08).
Three deaths occurred during the study; all were among high-dependency smokers
assigned to the placebo lozenge.
Table 5 also shows the most
common events (those reported by 5% in any group) by body system. Gastrointestinal
and respiratory tract complaints were most frequent. Only heartburn, hiccup,
and nausea occurred significantly more often in the active-treatment than
in the placebo groups at both doses. Among respiratory tract events, upper
respiratory tract infections (9.5%), coughing (3.8%), and sore throat (3.6%)
were more often reported; only coughing showed any relationship to nicotine
dosing, and then only in the 4-mg group.
LOZENGE USE
Table 6 shows the reported
lozenge use at weeks 2, 6, 12, and 24 of the study, as reported by those who
were still in the study and providing reports via IVR reporting. At week 2,
almost all participants in all groups were using lozenges. By week 12, use
of lozenges had diminished and varied by group and treatment, with the greatest
use among high-dependence smokers receiving the active 4-mg lozenge. Finally,
at week 24, only a minority of the remaining participants (<15% of the
initial sample) reported using lozenges, and there were no differences between
active-treatment and placebo groups at either dose. The number of lozenges
used per day also dropped over time for active and placebo groups, as shown
in Table 6.
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Table 6. Lozenge Use by Week*
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It was hypothesized that the use of more lozenges might improve treatment
effects. To test this, groups with high- and low-level lozenge use were formed
by splitting participants at the median number of lozenges used per day during
the first 2 weeks. As Table 7
shows, the lozenge had significantly greater effect among those who used more
lozenges. Using more than the median number of lozenges more than doubled
the effect of lozenge treatment on abstinence. Finally, we assessed whether
participants who used more lozenges were more likely to experience AEs. The
character and pattern of AEs were similar among high- and low-level lozenge
users, but high-level lozenge users were slightly more likely to report AEs
(Table 5).
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Table 7. Smoking Cessation Rate at 6 Weeks Stratified by Lozenge Use*
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SEGMENTING SMOKERS BY NICOTINE DEPENDENCE AND SMOKING RATE
Although this trial allocated smokers to nicotine dose on the basis
of TTFC, an indicator of nicotine dependence, current indications for nicotine
gum allocate dose on the basis of smoking rate (divided at 25 cigarettes per
day in the United States and 20 in other jurisdictions). Allocating smokers
to dose by TTFC results in more smokers receiving the 4-mg dose. To test the
safety of this changed dose allocation, we examined AEs among light smokers
who were assigned to the 4-mg lozenge. Their AE reports were similar to those
of heavy smokers receiving the 4-mg lozenge. To assess the efficacy implications,
we examined treatment efficacy among heavy smokers assigned to the 2-mg lozenge
and among light smokers assigned to the 4-mg lozenge. The lozenge showed significant
efficacy in both groups.
COMMENT
This study demonstrated the efficacy and safety of 2- and 4-mg nicotine
lozenges for smoking cessation. The odds of being abstinent after 6 weeks
of treatment were 2.1 to 3.7 times greater among those receiving the active
lozenge (2- and 4-mg doses, respectively) than among those receiving placebo.
Increased abstinence was maintained even after 1 year since quitting and at
least 6 months without lozenges. These data demonstrate the efficacy of the
nicotine lozenges and thus add to the database demonstrating NRT efficacy.
The absolute success rates and the odds ratios achieved by use of the
nicotine lozenge were in the upper range of those observed in previous studies
of other forms of NRT,5 suggesting that this
NRT may be particularly effective. The present success rates were achieved
among smokers who had failed to quit smoking while receiving previous pharmacological
treatment (Table 1). Piece for
piece, the nicotine lozenge delivers approximately 25% more nicotine than
the comparable dose of nicotine gum,16 which
may help enhance efficacy. The nicotine lozenge achieved good efficacy even
among low-dependency smokers, which was not the case for the sublingual tablet.15 Definitive conclusions about comparative efficacy
require a randomized head-to-head comparison.
Many smokers in the trial used the number of lozenges recommended by
the product label. The average number of lozenges used peaked at an average
of 7 to 9 per day in the first few weeks and dropped over time. In this study,
lozenge use data were only obtained from the subset who provided IVR reports,
which may limit generalizability. Within this sample, those who used more
lozenges achieved significantly higher success rates and derived more benefit
from the active lozenge treatment. This finding is consistent with those on
compliance with NRT and with the expected dose-response function. It also
suggests that smokers should be encouraged to use at least 7 to 8 lozenges
per day. Use of more lozenges slightly increased AEs, but the increase was
not substantial and the events were not serious, and thus this increase does
not present a safety concern. Physicians and other health care professionals
should encourage patients to avoid underdosing, encourage use of sufficient
medication, and dispel patients' unwarranted concerns about the safety of
nicotine medications.
One could argue that the high absolute quit rates in this study may
also have been enhanced by contacts with the research sites. However, this
cannot account for the robust differences between the active-treatment and
placebo groups, since all participants received similar treatment at the sites.
In any case, smokers in this study were given very little face-to-face behavioral
support. The primary vehicle of behavioral advice and support was a written
user's guide that provided structure and techniques for quitting smoking.
The face-to-face contacts smokers had with research personnel (who were not
behavioral specialists) were focused on directing their attention to the user's
guide and reinforcing it, rather than delivering formal behavioral therapy
or introducing additional techniques. Thus, the results suggest that the nicotine
lozenge is suitable for use without adjunctive behavioral treatment. Although
the addition of behavioral treatment can boost quit rates, NRT efficacy is
independent of the degree of support provided.31
The use of a simple patient-reported measure of nicotine dependence—TTFC—to
allocate smokers to NRT dose may also have helped optimize the treatment.
Research has suggested that treating highly dependent smokers with 2 mg of
oral nicotine is ineffective,17-18
and one study found that giving low-dependency smokers the 4-mg gum may actually
lower their quit rates.20 In the present study,
light smokers who were allocated to the 4-mg dose by TTFC showed good quit
rates, strong lozenge efficacy, and no excess AEs, suggesting that they had
been appropriately assigned to that dose. Smokers who smoked heavily but appeared
less dependent based on TTFC and were thus assigned to receive the 2-mg lozenge
also showed good quit rates and differences between the active-treatment and
placebo groups, again implying appropriate dose allocation. The study did
not compare dose allocation based on TTFC with dose allocation based on smoking
rate, and thus cannot establish the relative strengths of one regimen over
another. Nevertheless, in the context of other studies of oral NRT dosing,17, 20 the data suggest that allocating
smokers to the nicotine lozenge dose on the basis of TTFC is an appropriate
regimen and may provide better dosing for some smokers.
Assigning smokers to lozenge dose on the basis of TTFC, rather than
smoking rate, is likely to result in more smokers being assigned to the 4-mg
dose. For example, for smokers in the United States, a recent survey found
that although only 29% smoke at least 25 cigarettes per day (qualifying for
the 4-mg dose under the current nicotine gum indication), 72% smoke their
first cigarette within 30 minutes of waking, thus qualifying for the 4-mg
lozenge.32 Similarly, in the United Kingdom,
25% of smokers smoke more than 20 cigarettes per day, but 67% smoke their
first cigarette within 30 minutes of waking (Katie Kemper, MBA, unpublished
data, 1998; available from GlaxoSmithKline). Thus, this new regimen will provide
higher doses of medication to a substantial subset of smokers who appear to
be nicotine dependent, although they are not heavy smokers. With the slightly
increased level of delivery of nicotine by the nicotine lozenge (vs nicotine
gum), this method may enhance treatment efficacy.
The nicotine lozenge also proved to be effective for relief of craving
and partially effective for relief of withdrawal. Among low- and high-dependency
smokers, treatment with the active lozenge resulted in lower craving within
the first 2 weeks of quitting, when craving is at its peak.33-34
This finding contrasts with that for the sublingual tablet, which affected
craving and withdrawal only among highly or moderately dependent smokers.15, 35 Among high-dependency smokers, the
4-mg lozenge also suppressed withdrawal symptoms in the second week of abstinence
and suppressed weight gain during a 12-week period. The latter result is consistent
with other findings that oral NRT suppresses weight gain while being used,
but does not have lasting effects.2 The withdrawal
results were less robust among low-dependency smokers treated with the 2-mg
nicotine lozenge, for whom withdrawal suppression did not reach significance
in week 2,15 and no suppression of weight gain
was observed. The fact that many participants did not comply with IVR reporting,
and thus did not provide data (or complete data) on craving and withdrawal,
may have biased the data and masked the effect of treatment. Among low-dependency
smokers, symptoms may be modest and thus difficult to further suppress. Less
dependent smokers, too, may benefit from higher doses of nicotine than 2 mg.
In any case, robust enhancement of cessation was seen in the 2-mg group, even
in the absence of documented lasting suppression of withdrawal, in contrast
to findings by Wallström et al.15 Additional
mechanisms beyond suppression of craving and withdrawal may underlie the efficacy
of NRT.
In general, the clinical outcomes seen with the 4-mg lozenge were particularly
robust, showing high quit rates, a favorable difference between active-treatment
and placebo groups, and suppression of craving, withdrawal, and weight gain.
The data show that although highly nicotine-dependent smokers were less successful
at abstaining when treated with placebo, treatment with the active lozenge
eliminated the excess failure due to dependence and helped high-dependency
smokers achieve outcomes comparable to those of low-dependency smokers27 (Figure 2
and Table 2). These data are consistent
with the notion that more dependent smokers particularly need nicotine replacement
and require higher doses. Only a modest increase in AEs associated with the
4-mg dose was found, despite the fact that participants assigned to the active
4-mg lozenge tended to use more lozenges. This finding suggests that future
studies should explore the possibility of using this dose with all but the
least nicotine-tolerant and -dependent smokers.
Our study demonstrated the safety of the nicotine lozenges tested in
this study. The AEs experienced by smokers using the lozenge were generally
moderate and transient and were similar in character and frequency to those
observed in trials of other oral NRT medications,36-37
most involving minor discomforts such as nausea, hiccups, and heartburn. We
found only a modest increase in AEs among smokers who used more lozenges.
Thus, the lozenge is safe when used as directed.
The study's most notable limitation was poor compliance with daily IVR
reports of craving and withdrawal symptoms. Non–IVR-compliant participants
differed from compliant ones on several factors. Thus, the data collected
by means of the telephone may be biased, and conclusions about those variables
may be limited to subjects who complied with reporting.
CONCLUSIONS
The new nicotine lozenge is an effective and safe treatment for smoking.
Physicians should counsel smokers to quit and suggest the nicotine lozenge
as an option for effective treatment. The nicotine lozenge provides smokers
and practitioners with an additional effective tool for smoking cessation.
AUTHOR INFORMATION
Accepted for publication October 15, 2001.
This study was supported by GlaxoSmithKline Consumer Healthcare, Parsippany,
NJ.
The principal investigators and site locations were as follows: Anthony
Lavelle, MD (Bristol, England); Peter Hajek, PhD (London, England); D. Mathis,
MB, ChB (Glasgow, Scotland); Jacqueline Jolleys, MB, ChB, MD, MRCGP, MBA,
MIHSM (Coventry, England); Dorothy Hatsukami, PhD (Minneapolis, Minn); Stephen
Braden, MD (Bryan, Tex); Teresa Sligh, MD (Euless, Tex); John Muchmore, MD,
PhD (Oklahoma City, Okla); Lawrence Larsen, MD, PhD (Salt Lake City, Utah);
Michael Casser, MD (Paramus, NJ); John Pappas, MD (Lexington, Ky); Larysa
Hun, MD (Huntington, NY); Kevin Tack, MD (Great Neck, NY); Wanda Angueira,
MD (San Antonio, Tex); and Wayne Harper, MD (Raleigh, NC).
We thank Martin Steiner, PhD, for overseeing the conduct of the study;
the investigators and staff at the study sites for their valiant efforts;
the staff at Quintiles, Inc, Atlanta, Ga, for their contributions to the study;
and Jonathan Foulds, PhD, and Karl Fagerström, PhD, for feedback on a
draft of this manuscript. We also thank Janine Pillitteri, PhD, and Gina Bittner
for their help in preparing the manuscript.
Corresponding author and reprints: Saul Shiffman, PhD, Pinney Associates,
201 N Craig St, Suite 320, Pittsburgh, PA 15213 (e-mail: shiffman{at}pinneyassociates.com).
From Pinney Associates and the Departments of Psychology, Psychiatry,
and Pharmaceutical Science, University of Pittsburgh, Pittsburgh, Pa (Dr Shiffman);
GlaxoSmithKline Consumer Healthcare, Parsippany, NJ (Drs Dresler and Strahs),
and Weybridge, England (Dr Gilburt and Mr Targett); and the Department of
Psychology, University of London, London, England (Dr Hajek). Dr Shiffman
provides consulting to GlaxoSmithKline Healthcare on matters relating to smoking
control, and was compensated for his work on this project. Dr Shiffman also
has an interest in a novel nicotine replacement product that is not addressed
by this article. Dr Hajek has provided consulting to and received research
funding from pharmaceutical companies, including GlaxoSmithKline Consumer
Healthcare and Pharmacia Consumer Healthcare, Peapack, NJ. Drs Dresler, Gilburt,
and Strahs and Mr Targett are employed by GlaxoSmithKline Consumer Healthcare.
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