Nicotine Patch Therapy for Smoking
Cessation Combined With Physician
Advice and Nurse Follow-up
One-Year Outcome and
Percentage of Nicotine Replacement
Richard D. Hurt, MD; Lowell C. Dale, MD; Paul A. Fredrickson, MD; Casey C. Caldwell, MD; Gary A. Lee, MD;
Kenneth P. Offord, MS; Gary G. Lauger, MS; Zrinka Mar\l=u%v\si\l=c'\,MS; Lewis W. Neese, MD; Thomas G. Lundberg, MD
Objective.\p=m-\Todetermine the efficacy of a 22-mg nicotine patch combined with
the National Cancer Institute program for physician advice and nurse follow-up in
providing withdrawal symptom relief, 1-year smoking cessation outcome, and percentage of nicotine replacement.
Design.\p=m-\Randomized,double-blind, placebo-controlled trial.
Subjects.\p=m-\Two-hundredforty healthy volunteers who were smoking at least 20
cigarettes per day.
Interventions.\p=m-\Basedon the National Cancer Institute program, subjects
received smoking cessation advice from a physician. Follow-up and relapse prevention were provided by a study nurse during individual counseling sessions.
Subjects were randomly assigned to 8 weeks of a 22-mg nicotine or placebo patch.
Main Outcome Measures.\p=m-\Abstinencefrom smoking was verified by expired
air carbon monoxide levels. Withdrawal symptoms were recorded during patch
therapy, and the percentage of nicotine replacement was calculated by dividing
serum nicotine and cotinine levels at week 8 of patch therapy by levels obtained
while smoking.
Results.\p=m-\Highersmoking cessation rates were observed in the active nicotine
patch group at 8 weeks (46.7% vs 20%) (P<.001) and at 1 year (27.5% vs 14.2%)
(P=.011). Higher smoking cessation rates were also observed in subjects assigned
to the active patch who had lower serum levels of nicotine and cotinine at baseline,
and withdrawal symptom relief was better in the active patch group compared with
placebo.
Conclusions.\p=m-\Clinicallysignificant smoking cessation can be achieved using
nicotine patch therapy combined with physician intervention, nurse counseling,
follow-up, and relapse prevention. Smokers with lower baseline nicotine and cotinine levels had better cessation rates, which provides indirect evidence that they
had more adequate nicotine replacement with this fixed dose of transdermal nicotine than those smokers with higher baseline levels.
(JAMA. 1994;271:595-600)
From the Nicotine Dependence Center (Drs Hurt,
Dale, and Lundberg), the Section of Biostatistics (Mr
Offord and Ms Mar\l=u%v\si\l=c'\),and the Division of Thoracic
Diseases and Internal Medicine (Mr Lauger and Dr
Neese), Mayo Clinic and Mayo Foundation, Rochester,
Minn; the Nicotine Dependence Center, Mayo Clinic
Jacksonville (Fla) (Drs Fredrickson and Lee); and the
Division of Community Internal Medicine, Mayo Clinic
Scottsdale (Ariz) (Dr Caldwell).
Reprint requests to Mayo Clinic, 200 First St SW,
Rochester, MN 55905 (Dr Hurt).
TRANSDERMAL nicotine has become
one of the most frequently prescribed
medications in the United States. Nico¬
tine patch therapy has been shown to be
effective in relieving withdrawal symp¬
toms and in achieving short-term suc¬
cessful smoking cessation, but to date
few studies have reported 1-year smok¬
ing cessation rates.1"4 To our knowledge,
study has combined nicotine patch
therapy with the National Cancer In¬
stitute (NCI) physician intervention pro¬
gram,5 an established physician approach
to smoking cessation adaptable to most
practice settings.
no
The NCI program stresses the im¬
portance of follow-up and gives detailed
instructions on arranging it. Smoking
cessation rates have been shown to be
positively influenced by the number of
visits to the physician.6 Telephone coun¬
seling and follow-up can be alternatives
to a visit7 and have been shown to be
effective in helping subjects who have
stopped smoking to maintain their ab¬
stinence.8 It is hypothesized that the
long-term effectiveness of smoking ces¬
sation efforts using nicotine patches may
be enhanced with these and other re¬
lapse prevention strategies.1·9·10
The level of nicotine replacement may
also affect the efficacy of nicotine
patches. Under controlled, smoke-free
conditions, we observed the steady-state
nadir
serum
nicotine and cotinine lev¬
els, using a 22-mg nicotine patch, to be
about half of the levels observed while
subjects were smoking.11 Under less con¬
trolled conditions, Daughton et al9
showed that salivary cotinine levels of
subjects while receiving nicotine patch
therapy were lower than while smok¬
ing.
We undertook this study to determine
the efficacy of nicotine patch therapy
when provided in conjunction with the
NCI-based physician intervention, in¬
dividual counseling by a nurse, and fol¬
low-up with a relapse prevention pro¬
gram. We also sought to determine the
level of nicotine replacement provided
Downloaded from jama.ama-assn.org at University of Utah on January 31, 2012
22-mg nicotine patch. The study
approved by the institutional re¬
view board of the Mayo Clinic and all
subjects gave informed consent.
by
a
was
SUBJECTS AND METHODS
We enrolled 240 cigarette smokers at
the three Mayo Clinic sites (Rochester,
Minn, Jacksonville, Fla, and Scottsdale,
Ariz). Volunteers were recruited by a
news release in the local media. Sub¬
jects who responded were randomly se¬
lected to be screened by telephone in¬
terview.
Qualified subjects were invited to an
informational meeting where study pro¬
cedures and requirements were dis¬
cussed. Laboratory tests performed in¬
cluded a chemistry profile, complete
blood cell count, baseline nicotine and
cotinine levels, cholesterol and triglyc¬
éride levels, urinalysis, and electrocar¬
diogram. A Fagerström Tolerance Ques¬
tionnaire,12 Fagerstròm Test for Nico¬
tine Dependence,13 Beck Depression
Inventory,14 Self-Administered Alcohol¬
ism Screening Test (SAAST),15 and a
daily diary of cigarette use combined
with the Hughes-Hatsukami withdrawal
questionnaire16 were collected. At the
second screening visit, the physician per¬
formed a physical examination and de¬
termined whether the subject met the
inclusion and exclusion criteria. Inclu¬
sion criteria included age of 20 to 65
years, a history of smoking 20 or more
cigarettes per day for the past year, an
expired carbon monoxide level of 10 ppm
or greater, the motivation to stop smok¬
ing, and good health. Exclusion criteria
included a recent (within 6 months) myocardial infarction, angina, serious car¬
diac arrhythmias, thromboangiitis oblit¬
erane, active chemical dependence on
alcohol or other non-nicotine drugs, cur¬
rent psychiatric
disorder, pregnancy
nursing, severe dermatitis, use of forms
or
of nicotine other than cigarettes, pre¬
vious nicotine patch study participant,
or current use of clonidine, buspirone
hydrochloride, doxepin hydrochloride, or
fluoxetine. Physician investigators
trained in the NCI program counseled
the subjects and assisted them in set¬
ting a stop date. The stop-smoking date
coincided with the third screening visit,
when the subjects were randomly as¬
signed to active or placebo patches. No
subjects were excluded after random
assignment.
There were weekly visits with a study
during the patch phase where used
Table 1.—Baseline Characteristics*
Characteristics
Active
Placebo
P\
Female, %_517_55J3_NS
White, %_902_100.0_NS
46.7
NS
46.7
High school graduate or less, %
70.8
NS
71.7
Currently married, %
%_85 _73J3_.026
Employed,
Previous
89.2
91.7
31.7
19.2
29.2
1-4 wk
1-6
26.7
35.0
stop smoking attempts,
Longest time
off
<1 wk
cigarettes,
%
%
mo
7-12
mo
>1 y
Other smokers in household, %
Had felt depressed or down most of
the day nearly every day,
Previously treated for depression, %
NS
NS
22.5
12.5
3.3
10.0
10.0
43.3
35.8
NS
%_167_23J3_NS
8.3
of other
psychiatric disorders,
Mean±SD (range)
Age, y
Clgarettes/d (n=119/119)
History
%
0
42.8+11.1(20-65)
28.8 9.4(20-60)
+
13.3
NS
1.7
NS
43.6±10.6
30.6±9.4
(21-65)
(20-60)
20-29, %
30-39, %
52^9
4L2
30.3
35.3
a40, %
16.8
Years of
smoking (n=119/119)
Pack-years (n=118/118}+
Fagerstrom Tolerance Questionnaire
23.7±10.4
(4-47)
35.3±22 (4-120)
7±1.8(3-11)
]%
23.5
NS
39.7±20.9
.041
7.1
+
(5-50)
(5-103)
1.9(1-11)
6.7
5-6, %
26.7
34.2
a7, %
Fagerstrom
62.5
59.2
Test for Nicotine
6.3+2(0-10)
Dependence
NS
25.8±10.7
10.8
0-5, %
NS
6.8±2
(0-10)
30.0
2.0
30.8
38.3
NS
NS§
NS
NS«
SAAST
3.4±9.6
score
(0-99)
5.7± 15.6
7-9, %
2:10, %
Quetelet Index, kg/m2 (n=117/120)
Weight, kg
Female
Male
(n=61/67)
(n=56/53)
Carbon monoxide, ppm (n=120/119)#
Beck Depression Inventory score
Serum nicotine,
Serum cotinine,
ng/mL (n=118/111)
ng/mL (n=118/111)
Mean baseline withdrawal
score
(n=108/111)**
symptom
(0-99)
1.7
1.7
6.7
11.7
26.6±5.6
(16.4-44.5)
26.4±5.6
66.9±15.4
68.7± 15.4
86.7±17.2
83.3± 17.3
(41-121.2)
(51.7-147.8)
28.1 ±11.7 (7-64)
5.5±4.6 (0-22)
22.1 ±13.5 (4-68.3)
261.5±124.2 (24-655.9)
0.95±0.56
(0.02-2.73)
.041
86.7
91.7
29.7±11.8
6.8±5.3
23.1 ±12
294.6± 127.8
1.11 ±0.58
NSH
(18-59.2)
NS
(48-144)
(54.6-153.3)
(10-64)
(0-24)
(4-83.7)
(46.9-829.4)
NS
.051
(0.12-3.24)
.049
NS
NS
NS
NS
*For both groups n=120 unless otherwise indicated. NS indicates not significant; SAAST, Self-Administered
Alcoholism Screening Test.
tP value was obtained from 2 test or rank-sum test for the categorical and continuous variables, respectively.
^Cigarettes per day divided by 20, times years of smoking.
§Comparison Is 0 to 6 vs £7.
UComparison is 0 to 5 vs s6.
is 0 to 6 vs £7.
#Mean of two measurements minus background.
the
withdrawal
**For
symptom score, the following symptoms were considered: anger, irritability or frustration,
^Comparison
anxiety or nervousness, awakening at night, difficulty concentrating, depression, hunger. Impatience or restlessness,
and desire to smoke. Each symptom was scored on the scale: none (0), slight (1), mild (2), moderate (3), or severe
(4). The mean of all the symptoms was computed for each day for each subject and then was averaged over all days
prior to Initiating patch therapy.
nurse
patches were returned, a new supply
was provided, daily diaries of smoking
history and withdrawal symptoms were
collected, and vital signs and expired air
carbon monoxide levels were measured.
Smoking cessation was defined as self-
reported abstinence (not
even a
puff)
since the last visit and an expired air
carbon monoxide level of 8 ppm or less.
For the first 8 weeks, this represents
weekly point prevalence, and for 6, 9,
and 12 months, this represents 3-month
Blood samples were
obtained for nicotine and cotinine analy¬
sis at weeks 4 and 8 at the same time of
day as the baseline levels.
Brief individualized counseling using
the NCI booklet, "Clearing the Air,"
point prevalence.
Downloaded from jama.ama-assn.org at University of Utah on January 31, 2012
was provided by the nurse. For those
who abstained from smoking during the
patch phase, the nurses' counseling em¬
phasized means of maintaining absti¬
nence and preventing relapse. For those
subjects who continued to smoke, the
counseling addressed high-risk smoking
situations and encouragement to con¬
tinue to try to stop. Patch therapy was
completed at the end of the eighth week,
and the subjects were seen for a brief
exit examination by a physician. A re¬
turn visit within 3 days was scheduled
with the study nurse to collect ques¬
tionnaires, provide brief counseling, and
perform carbon monoxide testing. Be¬
tween that visit and a follow-up visit at
week 12, all subjects received weekly
phone calls for counseling from the study
nurse. Further follow-up visits for moni¬
toring and counseling were made with
the study nurse at 6, 9, and 12 months.
Univariate statistical methods in¬
cluded 2 analysis and Wilcoxon's rank
sum and signed-rank tests. Multivariate modeling of the smoking cessation
and relapse dichotomous outcome was
performed using logistic regression with
backward elimination of nonsignificant
variables. For analysis of smoking ces¬
sation and relapse rates, those subjects
with missing information or who dropped
out of the study for any reason were
considered to be smoking, ie, an intentto-treat analysis. With 120 subjects in
each of the two groups, we calculated a
statistical power of 90% of detecting
arithmetic differences in cessation rates
in either direction exceeding 16, 17, or
19 percentage points if the placebo ces¬
sation rates were 10%, 15%, or 20%,
respectively. All values correspond to
two-sided tests of significance with
P£.05 used to reflect differences not
attributable to chance.
RESULTS
Subject Demographics
Demographics and smoking history
data for the 240 subjects are shown in
Table 1. The active and placebo groups
were comparable except that the active
group had fewer pack-years of smoking
(mean of 35.3 vs 39.7 pack-years)
(P=.041), were employed outside the
home more often than the placebo group
(P=.026), and had a slightly lower mean
baseline withdrawal symptom score
(P=.049). Those subjects in the active
group had a lower mean SAAST score
(P=.041), but there was no difference in
the proportion with a score of 7 or
greater. There were no other differences
in demographics between the two
groups.
Of the 240 subjects enrolled and ran¬
domized into the study, 196 completed
Fig 1.—Smoking cessation rates. Cessation was defined as the subject reporting no smoking (not even a
puff) since the last visit and an expired carbon monoxide level of 8 ppm or less at the time of the visit. Sub¬
jects with missing information or who dropped out of the study for any reason were considered smokers.
8+ indicates the office visit 3 days after the patch phase. Numbers on top of bars are values.
the patch phase (first 8 weeks), while 44
dropped out (19 active, 25 placebo). Rea¬
sons for dropout included adverse skin
reactions from patches (six active, zero
placebo), other patch-related adverse
events (one active, three placebo), ad¬
verse events not related to the patch
(zero active,
two
placebo), noncompli-
with visit requirements (nine ac¬
tive, 13 placebo), and lost to follow-up
(two active, two placebo). One activepatch subject was dropped from the
study because she became pregnant dur¬
ing the patch phase (pregnancy and de¬
livery were normal). A placebo subject
was dropped for using nicotine gum.
ance
Smoking Cessation Outcome
and Related Factors
Figure 1 shows the smoking cessation
rates for the 8-week patch phase, at the
office visit 3 days after the patch phase
(noted on Fig 1 as 8+), and at 3,6,9, and
12 months from the stop-smoking date.
At week 8, abstinence rates were 46.7%
for the active group and were 20% for
the placebo group (P<.001). Cessation
rates remained significantly different be¬
tween the two patch groups throughout
the year of follow-up (P=.001, .008, and
.004 at 3,6, and 9 months, respectively).
One-year cessation rates were 27.5% for
the active group and were 14.2% for the
placebo group (P=.011).
Figure 2 displays the 8-week and
1-year cessation rates in relation to the
quartile baseline serum nicotine and co¬
tinine levels. In the active patch group,
those subjects with lower baseline lev¬
els of nicotine and cotinine had higher
8-week cessation rates (P=.019), a find¬
ing that was not observed in the placebo
group. There was a twofold to threefold
higher 8-week cessation rate for those
subjects in the lowest compared with
the highest quartile of nicotine and co¬
tinine levels.
In the active patch group, the
mean ± SD baseline nicotine levels were
18.5± 12.1 ng/mL for the 55 subjects who
were abstinent at week 8 compared with
25.2±14 ng/mL for the 63 subjects who
were smoking at week 8 (P=.004). Re¬
spective mean baseline serum cotinine
levels for the same subjects were
221.8±98.7 ng/mL and 296.1±134.1
ng/mL (P=.002). For the 21 placebo sub¬
jects who were not smoking at week 8,
mean baseline nicotine levels were
19.9±8.9 ng/mL compared with
23.9± 12.5 ng/mL for the 90 subjects who
smoking (not significant [NS]
[P>.05]). Respective mean baseline co¬
were
tinine levels were 295.6±115 and
294.4±131.2 ng/mL for these subjects
(P=NS). A lower baseline smoking rate,
however, was not found to be associated
with a higher cessation rate (data not
shown).
Table 2 shows the results of a logistic
regression analysis that was applied to
multivariate associations with
status at week 8. We consid¬
ered all variables in Table 1 as main
effects, and in a stepwise fashion we
eliminated those variables that did not
independently contribute to the predic¬
tion of the 8-week smoking status. Ac¬
tive patch assignment (P<.001), lower
baseline serum nicotine level (P=.002),
assess
smoking
Downloaded from jama.ama-assn.org at University of Utah on January 31, 2012
therapy
Active Placebo
O
Week 8 ·
70
1 Year
6050o
40-
E
CO
3020-
ICH
o
— —
<13.0
13.120.0
——
228.1
20.128.0
Baseline Serum Nicotine,
Active, No. 32
Placebo, No. 22
31
Fig 2.—Smoking status at week 8 and at 1
Table
2.—Summary
of Multivariate
36
20
28
32
nnine levels.
I
196.1258.0
year In relationship to
28
30
ng/mL
31
26
23
35
quartile baseline serum
Active
Nicotine, ng/mL
>362.1
nicotine and
co¬
Logistic Regression Findings*
Not
Baseline Serum
258.1362.0
Baseline Serum Cotinine,
ng/mL
27
30
27
I
<196.0
Placebo
at Week
Smoking
No. (%)
Not
8,
Smoking at Week 8,
No. (%)
No Other Smokers in Household
_
15.1-30
27
=30.1
_16(72.7)
_18
4
16(59.3)
6 (37.5)
39
8
15
1
13
2(15.4)
4 (33.3)
1 (7.7)
(22.2)
(20.5)
(6.7)
Other Smokers in Household
£15
17
=30.1
10
8(47.1)
7 (28.0)
1 (10.0)
13
'Observed 8-week cessation percentages resulted from cross-classification of
variables found significant in the stepwise multiple logistic regression model.
and absence of other smokers in the
household (P=.007) were found to be
simultaneously predictive of not smok¬
ing at week 8. Cessation rates ranged
from less than 10% to more than 70%
depending on these three variables. The
best results were for subjects receiving
active patch therapy with lower base¬
line serum nicotine levels and no other
smokers in the household.
The mean withdrawal scores for the
prepatch, patch, and postpatch periods
are displayed in Fig 3. Withdrawal symp¬
toms considered were based on the
Hughes-Hatsukami questionnaire (see
the footnotes to Table 1 for a listing of
withdrawal symptoms).16 Each symptom
was rated by the subject as none (0),
slight (1), mild (2), moderate (3), or se¬
vere (4). During the baseline period,
while the subjects were smoking, with¬
drawal symptom scores were higher for
subjects who were eventually random¬
ized to placebo. During the patch phase,
withdrawal scores (during the first 7
subjects according
to the three
days and weekly) for subjects receiving
active patch therapy were significantly
lower than for placebo (P ranged from
.05 to <.001).
Percentage of Nicotine Replacement
The percentage of replacement for se¬
rum nicotine and
cotinine was calculated
by dividing the level at week 8 by the
baseline level while subjects were smok¬
ing their usual number of cigarettes.
The median percentage of replacement
in nonsmokers receiving active patch
therapy was 69.9% for nicotine and 54%
for cotinine. Both were significantly less
than 100% replacement (P=.026 and
P=.002, respectively). For nonsmokers
receiving active patch therapy at week
8, 32.7% of subjects for nicotine and
25.5% for cotinine had values indicating
greater than 100% replacement. No clini¬
cal evidence of nicotine toxicity was
found in subjects with levels of nicotine
replacement greater than 100%.
In subjects receiving active patch
who were smoking at week 8,
the nicotine and cotinine levels reflect
nicotine from patch therapy and tobacco.
Thus, we have used the term "replace¬
ment" (in quotation marks) for smokers.
For this group, the median percentage of
"replacement" was 81% for nicotine and
82% for cotinine; neither was significantly
different from 100%. In the placebo group,
those who continued to smoke showed
evidence (P<.001) of reduced nicotine
and cotinine levels (median "replacement"
of 60.2% for nicotine and 78.7% for coti¬
nine, both less than 100% [P<.001]). The
percentage of replacement calculation
may be affected by other factors, eg,
falsely high percentage of replacement
would occur if subjects reduced their
smoking rate prior to the baseline blood
level measurement or if there was unreported use of other nicotine-contain¬
ing products (nicotine gum or smokeless
tobacco) during the patch phase.
Outcomes in Relation to Smoking
Status at Weeks 2 and 8
Table 3 shows the week-8 and 1-year
smoking status results in relation to
smoking status at weeks 2 and 8. At week
8 there were 56 nonsmokers receiving
active patch therapy and 24 receiving
placebo. Relapse rates beyond week 8
were comparable, with 53.6% (n=30) and
58.3% (n=14), respectively, not smoking
at 1 year. Among those who were smok¬
ing at week 8,4.7% (n=3) of the 64 activepatch subjects and 3.1% (n=3) of the 96
placebo-patch subjects were not smok¬
ing at 1 year (P=NS). Of the 78 subjects
who were not smoking at week 2, 74.4%
(n=58) were not smoking at week 8 (ac¬
tive patch therapy, 76.9% [n=40]; pla¬
cebo, 69.2% [n=18]; P=NS). For those
subjects who were smoking at week 2,
however, the 68 receiving active patch
therapy had a significantly higher
(P=.002) 8-week cessation rate (23.5%
[n=16]) than the 94 receiving placebo
(6.4% [n=6]), a difference that was not
present at 1 year.
Over all subjects a striking difference
was evident at the end of week 2. Among
the 78 subjects (active and placebo) who
were not smoking then, 46.2% (n=36)
were not smoking at 1 year. This com¬
pares with only 8.6% (n=14) not smok¬
ing at 1 year for the 162 subjects who
were smoking at week 2.
Adverse Events
Of active-patch
subjects, 87.5% re¬
ported one or more adverse events com¬
pared with 68.3% of the placebo sub¬
jects (P<.001). Skin reactions reported
by the subjects were examined and
graded by the study nurse (grade 1,
erythema only; grade 2, erythema and
edema; grade 3, presence of vesicles;
Downloaded from jama.ama-assn.org at University of Utah on January 31, 2012
grade 4, presence of bullae, ero¬
sions, or both). Grades 1 and 2 are con¬
sidered mild, 3 moderate, and 4 severe.
and
therapy and nurse follow-up can result
in clinically significant smoking cessa¬
tion rates. The 1-year cessation rate of
27.5% for those subjects receiving ac¬
tive patch therapy compares with ab¬
Analysis was based on the maximum
severity recorded for each subject. For
active-patch subjects, 40.8%, 15.8%,
4.2%, and 0.8% reported the respective
grade for their worst skin reaction, while
38.3% reported none. For placebo sub¬
jects, the percentages were 15.8%, 4.2%,
2.5%, 0%, and 77.5%, respectively
stinence rates of 22%, 11%, and 25% in
three other studies that used brief medicaladvice, intervention, and follow-up.1·2,4
Our higher success rate may reflect dif¬
ferences in study populations or differ¬
ences in the intervention package pro¬
vided, but all studies to date show a high
relapse rate between the end of patch
therapy and long-term follow-up.w In
our study, the nurses emphasized the
prevention of relapse as part of the brief
individual counseling at the weekly vis¬
its during patch therapy. Additional re¬
lapse prevention effort was provided by
a visit 3 days after patch therapy and
weekly telephone counseling for 1 month
after patch therapy.
An important finding in this study is
that higher 8-week cessation rates were
observed in subjects receiving active
patch therapy who had lower nicotine
and cotinine levels while smoking their
usual number of cigarettes. This pro-
(P<.001).
Other adverse events were less com¬
General categories of events fre¬
quent enough to be considered were
mon.
headaches, nausea-vomiting, constipa¬
tion-diarrhea, and sleep problems. For
headaches, 11.7% of active vs 17.5% of
placebo subjects reported this finding;
for nausea-vomiting, 5% vs 2.5%; for con¬
stipation-diarrhea, 3.3% vs 5%; and for
sleep problems, 7.5% vs 4.2%. None of
these differences was significant.
COMMENT
In this report we show that a brief
physician intervention based on the NCI
program combined with nicotine patch
4 —
• Active Patch (n=120)
O Placebo Patch (n=120)
Day
Before Patch L
After Patch
Fig 3.—Mean ±1 SD scores for eight withdrawal symptoms according to the Hughes-Hatsukaml question¬
naire.'6 Symptoms were scored on a daily basis as none (0), slight (1), mild (2), moderate (3), and severe
(4). NS indicates not significant (P>.05); asterisk, P>.01 and £.05; dagger, P>.001 and £.01; double
dagger, Prs.001 ; and Avg, the average withdrawal syptoms score over the first 3 days after patch therapy.
values are from the Wilcoxon rank sum test.
Table 3.—Week-8 and 1-Year
Smoking Status
¡n Relation to
Smoking
Status at Weeks 2 and 8
Placebo
Active
No.
Week
Status
for This Week
Smoking
(%)
8 wk
Nonsmoker
40 (76.9)
Smoker
16(23.5)
Nonsmoker
Smoker
64
vides indirect evidence that subjects
with lower baseline levels had better
nicotine replacement with this fixed dose
of transdermal nicotine than those sub¬
jects with higher baseline levels. Other
researchers have observed that lower
cotinine levels at the time of smoking
cessation treatment are related to higher
cessation rates,17 but to our knowledge,
this is the first study in which this ob¬
servation has been made in subjects re¬
ceiving transdermal nicotine. For sub¬
jects receiving active patch therapy who
continued to smoke, nicotine and coti¬
nine levels at week 8 reflect both the
nicotine patch and smoking, confound¬
ing the replacement calculations. Thus,
with the current study, there was no
direct way to relate the percentage of
nicotine replacement with cessation. This
would require a study where all sub¬
jects are abstinent until they have
reached a steady state, at which time
blood levels could be used to determine
the percentage replacement.
There was no outcome predictive
value for subjects' baseline smoking rate.
The nicotine and cotinine levels were
also not related to this baseline smoking
rate. This is not surprising since smok¬
ers can maintain steady nicotine levels
while smoking fewer cigarettes by
changing their smoking behavior. It does
point out that cotinine levels are a more
precise measure of nicotine intake18 and
may be more useful than self-reported
smoking rates in determining the opti¬
mal dosing of nicotine patch therapy.
The relation between the 1-year ces¬
sation rates and the smoking status 2
weeks after initiating therapy suggests
that those individuals who do not achieve
abstinence by 2 weeks should be care¬
fully evaluated and offered other treat¬
ment options. Alternatives include a re¬
assessment of their motivation to stop,
more intensive intervention, or increas¬
ing the nicotine replacement dose. De¬
spite lower baseline levels, only 33% of
our abstinent subjects receiving active
patch therapy had complete nicotine re¬
placement (>100% replacement). This
finding is consistent with our previous
work11 and indicates the unlikelihood that
current maximum recommended doses
of nicotine replacement (21 or 22 mg/d)
will be adequate for all smokers. Higher
Not
No.
Smoking
iy
27(51.9)
6 (8.8)
30 (53.6)
3 (4.7)
(%)
8 wk
26
24
18(69.2)
6 (6.4)
Total
Not
Smoking
iy
(34.6)
8 (8.5)
14(58.3)
3(3.1)
9
No.
(%)
8 wk
78
162
160
Downloaded from jama.ama-assn.org at University of Utah on January 31, 2012
58
(74.4)
22(13.6)
Not
Smoking
iy
(46.2)
14(8.6)
44 (55.0)
6 (3.8)
36
replacement may be
in initiating abstinence in
some smokers. This highlights the need
for further research to determine if out¬
come can be improved with higher lev¬
els of nicotine replacement.18
For those who have not stopped smok¬
ing by week 8 of patch therapy, we ob¬
served little likelihood of their being ab¬
stinent at 1 year. However, there is a
need for flexibility and individualization
for those persons who continue to smoke
while receiving patch therapy. It may
be appropriate to continue patch therapy
for the person who has almost achieved
abstinence and who wants to continue
to try to stop smoking. Discontinuing
the patch and reassessing for a future
stop date or providing more intensive
intervention are the best alternatives
for those persons who are still smoking
at or near their baseline rate.
Concern has been expressed about po¬
tential harmful effects of nicotine on pa¬
tients who continue to smoke while re¬
ceiving nicotine patch therapy. Our study
demonstrates the relative safety of nico¬
tine patches since 10% to 20% of sub¬
jects had 200% or greater replacement
doses of nicotine
important
without the
events. While
stop smoking
of adverse
advise all patients to
at the start of patch
occurrence
we
we recognize that not all of
them will be able to do so. While re¬
ceiving nicotine patch therapy, smokers
decrease their smoking rate even if they
are unable to stop.2,10,19 Our study pro¬
vides biochemical support for this since
the average serum nicotine and cotinine
levels in subjects receiving active patch
therapy who continued to smoke did not
exceed 100% "replacement." Even for
those subjects receiving placebo who
were still smoking at week 8, there was
a significant (P<.001) reduction from
baseline in their nicotine and cotinine
levels.
Withdrawal symptom relief is an im¬
portant measure of the efficacy of nico¬
tine replacement therapy, and shortterm smoking cessation is, in part, re¬
lated to how well nicotine withdrawal
symptoms are relieved.20 With absti¬
nence from smoking, nicotine withdrawal
symptoms may rapidly appear and may
prevent even highly motivated smokers
from staying in counseling or stopping
smoking.21·22 In the baseline period be¬
fore the patch phase, we observed that
many smokers report daily withdrawal
symptoms even while smoking. This is
not surprising since one of the DSMIH-R criteria for psychoactive substance
dependence is the use of the substance
therapy,
to avoid withdrawal.23 There
was
sig¬
nificant withdrawal symptom relief in
the active-patch group even though sig¬
nificantly more in that group had stopped
smoking. Withdrawal symptoms contin¬
ued to exist at week 8 despite nicotine
patch therapy. This has clinical impor¬
tance and highlights the need for higher
dose and/or longer patch therapy in some
patients.
For those
nent at week
subjects
who
8, we found
absti¬
difference
were
no
by patch assignment in the relapse rate
duringthe 1-year follow-up period. Other
researchers have observed relapse rates
during down titration to be similar in
the active or placebo groups and have
judged that dose reduction steps during
tapering were in part responsible for
this effect.24 Though it is intuitive to
assume that a tapering dose schedule
might be desirable, its efficacy has not
been proven. Since the usual advice in
stopping smoking is abrupt cessation,
we chose not to have a tapering sched¬
ule for this study. The results suggest
that abrupt cessation of nicotine patch
therapy can be used without adversely
affecting cessation.
This study was supported by a grant from Led¬
erle Laboratories, Pearl River, NY.
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