Clinical and pharmacokinetic properties of a transdermal nicotine patch We examined the pharmacokinetics of a transdermal nicotine patch and evaluated the usefulness of such a patch in a pilot smoking-cessation program. Use of the patch was associated with plasma nicotine
concentrations that were comparable to smoking or to the use of other smoking-cessation devices. However, these plasma concentrations were maintained for 24 hours, and the patch appeared to be suitable
for use once a day. Its use in a 6-week placebo-controlled double-blind study resulted in a significant degree of smoking cessation or in reduction of smoking activity. The findings suggest that it may be valuable to extend investigations to a larger population and that transdermal nicotine may have a useful role in smoking-cessation therapy. (CLIN PHARmAcoL THER 1990;47:331-7.)
Seamus C. Mulligan, MSc, Joseph G. Masterson, MD, John G. Devane, PhD, and John G. Kelly, PhD Athlone, Ireland The association of nicotine with physical dependence
the pharmacokinetics of a once-daily transdermal patch
on cigarette smoking is well established.' Nicotine is self-administered by animals in appropriate test environments, corresponding to drug-seeking behavior.2-3 In human beings nicotine is self-administered in ways that are common to more conventionally recognized drugs of abuse.' Reduction of cigarette length' or of nicotine contene'2 result in proportionately more inten-
that contained 30 mg nicotine, and we examined the efficacy of a patch in a double-blind quit-rate study of
sive smoking.
area of 30 cm2. This was backed by a nicotineimpermeable material that in turn was backed by
Physical dependence on smoking results in a withdrawal syndrome when smoking is stopped. After cessation of smoking there is a well-known strong tendency
to relapse. The association of nicotine with physical dependence has led to suggestions that strategies involving replacement of tobacco-derived nicotine with nicotine from other sources may form a useful part of smoking-cessation programs. Such replacement therapy has taken many forms. The
earliest form was intravenous administration,' but replacement therapy has more practically involved oral administration,' transdermal administration in solution,' and oral administration in the form of chewing
gum." Of these, nicotine chewing gums have been available for some years and have been used as a part of smoking cessation therapies. Recently, the use of a transdermal nicotine patch, which delivers nicotine for a 24-hour period, has been described:2 In the studies reported here, we have investigated From the Elan Corporation and the Institute of Biopharmaceutics. Received for publication July 6, 1989; accepted Oct. 30, 1989. Reprint requests: John Kelly, PhD, Institute of Biopharmaceutics, Monlcsland, Athlone, Ireland. 13/1/17849
80 smokers.
METHODS
The transdermal nicotine patches contained 30 mg nicotine in a gel matrix with a circular surface a larger-diameter fleshtone adhesive tape. This was applied to the skin. The studies described here received the approval of the ethics committees of the participating institutions (Institute of Biopharmaceutics; Blackrock Hospital, Dublin; and Clane General Hospital, Dublin), and all participants gave informed consent. In the quit-rate study the rationale of the treatment was carefully explained to all of the participants.
Pharmaeokinetic investigations. This study was an in-patient, unblinded study. Observations were made of 24 healthy male smokers between the ages 18 and 43 years (mean age, 28.4 years) who weighed between 57.5 and 81 kg (mean weight, 69.1 kg). Each study participant smoked between 42 and 280 cigarettes per week (mean, 107 cigarettes). One subject did not fulfill prestudy laboratory inclusion criteria and did not participate in the study. After a supervised nicotine-free period of 60 hours, each subject had a nicotine patch applied to the volar aspect of his forearm daily for 24 hours over a 7-day period. The site of administration was varied each day. Carbon monoxide measurements in expired air were made periodically to check abstinence from smoking. Venous blood specimens (7 ml)
331
CLIN PHARMACOL THER MARCH 1990
332 Mulligan et al.
0
4
8
12
16
20
24
28
32
36
0
4
8
12
16
20
24
28
32
36
Fig. 1. Mean plasma concentrations of nicotine (open symbols) and cotinine (closed symbols) at day 1.
Fig. 2. Mean plasma concentrations of nicotine (open symbols) and cotinine (closed symbols) at day 7.
were obtained from an antecubital vein on the arm opposite from the patch at the following times: day 1
ation (between assay) for plasma assays was 10.1% for
0, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 20 hours; days 2, 4, and 6-0 hours; days 3 and 5-0, 4, 6, and 8 hours;
and day 7-0, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 27, 30, 33, and 36 hours. Blood specimens were heparinized, and the plasma
nicotine at 7 ng/ ml, and it was 11.3% for cotinine at 70 ng/ ml (n = 27). The between-assay coefficient of variation for urine assays was 7.1% for nicotine at 35
ng/ml, and it was 8.8% for cotinine at 350 ng / ml (n = 14). Typical retention times were 2.9 minutes,
suitable aliquots of plasma (generally 1 ml) or urine
5.2 minutes, and 9.1 minutes for nicotine, anabasine, and cotinine, respectively. Clinical investigations. Eighty volunteer subjects participated in a 6-week double-blind placebocontrolled study to determine the effectiveness of the nicotine patches as an aid in cessation of smoking. Recruitment was done by newspaper advertising. Sub-
(generally 0.2 ml) were added anabasine internal
jects were white adults from 25 to 60 years of age (mean
standard and 0.25 ml 5 mol/L sodium hydroxide. These
age, 36.9 years) who weighed between 45 and 94 kg (mean weight, 65.8 kg). There were 38 men and 42
was separated and stored at
20° C until it was required
for assay for concentrations of nicotine and cotinine. Urine was collected for 24 hours on days 1 and 7. Plasma and urine concentrations of nicotine and cotinine were estimated by gas liquid chromatography. To
were extracted with 4 ml of a 9:1 vol/vol mixture of dichloromethane : ether and were shaken, centrifuged, and evaporated under vacuum at ambient temperature in tubes that contained 0.2 ml propan-2-ol. The residual alcohol was transferred to autosampler vials, and 4 ill
aliquots were chromatographed on a 10 m x 0.53 mm 50% phenylmethylsilicone capillary column (HP17, Hewlett-Packard, Brackwell, United Kingdom). The column flow rate was 12 to 14 ml per minute, with make-up gas at 25 ml per minute. The injector temperature was 240° C. The column was held at 120° to 125° C for 1 minute, raised by 20° C per minute to 145° C for 2 minutes, and raised by 12° C per minute to a final temperature of 210° C for 2 minutes. The detector was an alkali flame ionization detector (model FT9, Shimadzu Corporation, Kyoto, Japan). Recovery of nicotine was 54%, and recovery of cotinine was 72%.
The limits of detection for nicotine and cotinine were, respectively, 1 ng/ ml and 10 ng / ml in plasma and 10 ng/ ml and 50 ng / ml in urine. The coefficient of vari-
women, all of whom expressed a desire to quit smoking.
Subjects smoked an average of 25.1 cigarettes per day and had smoked for an average of 19 years. Dependence on smoking was quantified by use of the Fagerström tolerance questionnaire 13 Exclusion criteria were any
history of cardiovascular or psychiatric disease, inability to fulfill the study program with respect to visits, pregnancy, lactation, or a likelihood of pregnancy dur-
ing the study period, history of skin allergies, or evidence of dermatosis. Subjects were all found to be in good health during a medical evaluation that was performed before the study. No subject had any apparent significant chronic smoking-related illness. Subjects were equally and randomly assigned to active-patch or placebo-patch groups and were asked to quit smoking from the first day of patch use. There were no significant demographic differences between these two groups. The mean Fagerström scores were
7.40 -± 1.72 and 7.43 -± 1.71 for the placebo and
VOLUME 47 NUMBER 3
Transdermal nicotine patch 333
Table I. Plasma concentrations of nicotine and cotinine during daily patch application Nicotine
Cotinine
Day
Hourl day
Hour I study
(ng I ml)
(ng I ml)
2
o 0 4
104.06 -± 42.74 124.26 -± 35.78 130.76 41.54
3
6
3
8
4
o
5 5 5 5 6 7
0
24 48 52 54 56 72 96 100 102 104 120 144
5.92 -± 1.85
3 3
7 7 7
4
8
o
4 6 8
0 o 6 8
148 150 152 168
5.46 ± 1.79 10.34 ± 3.49 11.36 ± 4.05 13.69 ± 4.86 6.97 -± 3.29
5.48 ± 2.64 13.19 ± 5.06 13.86 ± 6.46 14.26 ± 5.39
122.17 ± 39.76 129.65 -± 40.79 136.08 -± 36.82 137.27 -± 34.06
6.35 ± 5.16
147.48 ± 41.93 149.04 ± 49.37 153.52 -± 49.84 147.61 ± 44.99 145.64 -± 38.96
14.15 ±- 5.98 13.84 -± 5.58 15.39 ±- 5.05
151.17 -± 49.05 146.91 ± 44.61 163.23 -± 48.44
6.90 ± 2.03
163.72 ± 50.65
6.25 ±_ 2.62
Data are mean values ± SD.
active-treatment groups, respectively. Each participant
was given a total of 60 patches; of those, 42 were needed for daily application. Thus 18 patches should have been returned by each subject. Patches were active and contained 30 mg nicotine or were placebo and contained no nicotine. A new patch was applied every 24 hours and the old patch was removed. The location of
the patches on the forearm was alternated each day between the right and the left arms. Each subject recorded the number of cigarettes smoked each week. Carbon monoxide analysis in expired breath was used as an independent assessment of smoking behavior. Subjects were counseled throughout the study and adhered to a behavioral modification program-either the American Lung Association program, "A Lifetime of Freedom from Smoking" or the National Cancer Institute program, "Quitting for Good." RESULTS
Pharmacokinetics. Mean plasma concentrations of nicotine and cotinine (in 23 subjects) after application of the first and last patches are shown in Figs. 1 and 2, respectively. Fig. 1 shows that significant plasma
concentrations of nicotine appeared quite quickly, with an average of 5.45 ± 3.92 (SD) ng / ml present
at 3 hours. The highest mean concentration was 12.09 ± 4.2 ng / ml at 8 hours. The average peak con-
centration was 13.84 ± 4.02 ng / ml at 9.48 -± 2.64 hours. The apparent elimination half-life (t1/2) of nico-
tine was 11.71 ± 3.33 hours, but this most likely reflected continuing absorption. Plasma concentrations of cotinine increased steadily during the 24 hours after the
first patch application, to reach a mean value of
104.06 ± 42.74 ng/ ml at 24 hours. Plasma concentrations during the daily patch application period are shown in Table I. Nicotine concentrations appeared to reach stable values quite quickly. Concentrations of cotinine (before patch application) tended to increase over the study period, although the rate of increase was slow after day 4. Before application of the last patch (day 7), mean
plasma nicotine concentrations were 6.35 ± 5.16 ng /m1 and were very comparable 24 hours later, at 6.90 -± 2.03 ng/ml. The highest mean concentration was 15.39 ± 5.05 ng / ml, which was observed at 8 hours. The average peak concentration on day 7 was 17.02 ± 6.89 ng/ ml at 8.96 -± 4.82 hours. The apparent t1/2 of nicotine was 5.60 ± 2.55 hours, shorter than that estimated after the first patch. This was because of the longer (36 hours) sampling period, which decreased the contribution of continuing absorption. Plasma concentrations of cotinine demonstrated a remarkable flat profile over the 24-hour period after administration of the last patch. Residual patch contents and material remaining on the skin after removal of the patch were conserved and analyzed for nicotine content. Nicotine absorption was estimated as the difference between the original patch content (30 mg) and the sum of the residues in the patch and on the skin. From this, the absorption of nicotine from the patch was approximately 75% (Table II). Urinary recovery of nicotine was a little under 1 mg in 24 hours on day 1, and it was approximately 1.3 mg on day 7. Cotinine recovery was similar to nicotine on day 1 but exceeded it significantly on day 7. The findings indicate that, at steady state, approximately 11% of the
CLIN PHARMACOL THER MARCH 1990
334 Mulligan et al. Table II. Pharmacokinetic summary
Day 7
Day I
AUC(0-24) (ngi nil
hr)
(hr) Cmax (ng/ml) 13 (hr-1) (apparent) t1/2 (hr) (apparent) C,,a,/C245r (ng/ml)
Estimated absorption (mg) 24-hour urinary recovery (mg)
Nicotine
Cotinine*
Nicotine
212 r.F_- 62
1498 ± 709
276 ± 82 8.96 ± 4.82
9.48 -± 2.64 13.84 -± 4.02 0.064 ± 0.020 11.71 ± 3.33
17.02 -± 6.89
2.46 ± 0.94
1.03 ± 0.07
0.98 ± 0.49
0.83 ± 0.46
0.144 ± 0.051 5.60 -± 2.55 2.56 ± 1.03 22.41 ± 1.05 1.31 ± 0.73
Cotinine
3775 ± 1119 12.17
:_i_-
7.93
183.59 ± 52.73 0.043 -± 0.017 20.26 ± 13.86 1.14 ± 0.17
2.23 ± 0.81
Data are mean values ±- SD. ALIC(0-24), Area under the concentration-time curve; tma time to reach maximum concentration; Cma, peak concentration;n, elimination constant; 42, half-life; C24 hr, concentration at 24 hours.
5tmaa, Cam, and elimination rate for cotinine were not calculable for the day I patch.
applied dose of nicotine was recovered in the urine as nicotine or cotinine. This contrasts with the extent of absorption of approximately 75% and probably reflects extensive metabolism of nicotine to products other than cotinine and elimination by other routes. Table II summarizes the pharmacokinetic findings of this study.
Smoking cessation. The chief aim of this part of the study was to evaluate the efficacy and tolerability
of the transdermal nicotine patches in a controlled smoking-cessation program. The primary evaluation of efficacy was the rate of smoking cessation as claimed by the participants and as verified by measurement of carbon monoxide concentrations in expired air. Cigarettes smoked per week were also quantified after exclusion of those who claimed to have stopped smoking
and who claimed to not have smoked during a given week. Compliance with the treatment was judged by counting returned patches. The number returned should have been 18. Eight subjects in the placebo group and four in the active group returned more than 19 patches (no significant difference). Four subjects who received placebo patches did not complete the study because of reasons unrelated to the
study. Two subjects who received active patches did not complete the study. Statistical analyses were performed on an "intent-to-treat" basis. Fig. 3 shows the number of participants who claimed to have quit smoking, analyzed week by week. There was a time-related increase in these numbers for both nicotine-treated and placebo-treated participants. However, by the end of the study, 20 subjects (50%) in the nicotine group, compared with seven subjects (17.5%) in the placebo group, claimed to have stopped smoking (Table III). The nicotine group had a significantly higher proportion
of quitters at weeks 4, 5, and 6 (chi-square test). Carbon monoxide concentrations were consistent with
these findings (Table III). Smoking cessation was significantly higher in the nicotine patch group, based on findings at week 6 of a greater proportion of subjects
with carbon monoxide values that were less than or equal to 8.0 ppm (47.5% versus 15%) or 3.0 ppm (47.5% versus 12.5%). The great majority of subjects who quit smoking in a particular week (and who were verified as quitting) had not resumed smoking when they returned for subsequent study visits. Fig. 4 illustrates this (compare with Fig. 3). It is useful to consider smoking behavior in those
subjects who said that they were still smoking at a particular visit. Recording the total number of cigarettes
smoked in a given week by the individuals who said they had smoked during that week and averaging those figures over the 6-week study period produced an average number of cigarettes smoked of 53.99 ± 44.01 (SD) in the placebo group and 35.80 ± 34.12 in the nicotine group (p < 0.01; ANOVA).
Tolerability. As described earlier, four placebotreated subjects did not complete the protocol for reasons unrelated to the study. One subject who received active patches dropped out in the first week after reporting nausea and vomiting. This was believed to be the result of gastroenteritis unrelated to the study medication. Another subject dropped out in the second week after reporting nausea, sweating, tiredness, pains in the arms, and "pins and needles." These symptoms were
considered likely to be related to the medication. There were no additional study dropouts. A total of 15
placebo-treated subjects reported unwanted effects during any one week of the study, compared with 24 subjects who received the nicotine-containing patch. Ten subjects in each group reported nonspecific irrita-
tion caused by either the gel or the adhesive. Five placebo-treated and 11 nicotine-treated subjects reported erythema or a rash. These symptoms were
VOLUME 47 NUMBER 3
Transdermal nicotine patch
25
25
20
20
15
15
10
10
5
5
o
' WEEK 1 WEEK 3 WEEK 5 WEEK 2 WEEK 4 WEEK 6
Fig. 3. Number of subjects who claimed to quit smoking. Solid bars, Nicotine; hatched bars, placebo.
o
335
VISIT 4 VISIT 6 VISIT 3 VISIT 5 VISIT 7
VISTT 2
Fig. 4. Quit rate based on subjects who quit and remained abstinent for the remainder of the study. Solid bars, Nicotine; hatched bars, placebo.
transient and disappeared after the patch was removed
(0.1 > p > 0.05; chi-square test). Two placebotreated and 13 nicotine-treated subjects reported effects
Table III. Comparison of quit claims and carbon monoxide levels in expired air, week 6
that were not skin-related (p < 0.01). In the placebo group these were reported as edema in one subject and
as a "pins and needles" sensation in another. In the nicotine group, gastrointestinal discomfort was reported
by three subjects; sweating, difficulty sleeping, and a "pins and needles" sensation were reported by two subjects each. Headache, tiredness, "heavy arm," dizziness, paresthesia, pain at the patch site, and nightmares were reported by one subject each. One subject reported chest pain with no electrocardiographic features, and it
was not possible to give an opinion on whether or not this was related to the treatment. DISCUSSION Application of a single transdermal patch that con-
tained 30 mg nicotine resulted in plasma nicotine 1 hour after application (1.03 ± 1.53 ng /m1) and that increased steadily to
No. of subjects quitting (claimed) Supported by CO levels S8.0 ppm Supported by CO
levels s3.0 ppm
Placebo
Nicotine
7
20
Chi-square test 9.45
(p
concentrations that were comparable to smoking or to the use of other smoking-cessation devices. However, these plasma concentrations were maintained for 24 hours, and the patch appeared to be suitable
for use once a day. Its use in a 6-week placebo-controlled double-blind study resulted in a significant degree of smoking cessation or in reduction of smoking activity. The findings suggest that it may be valuable to extend investigations to a larger population and that transdermal nicotine may have a useful role in smoking-cessation therapy. (CLIN PHARmAcoL THER 1990;47:331-7.)
Seamus C. Mulligan, MSc, Joseph G. Masterson, MD, John G. Devane, PhD, and John G. Kelly, PhD Athlone, Ireland The association of nicotine with physical dependence
the pharmacokinetics of a once-daily transdermal patch
on cigarette smoking is well established.' Nicotine is self-administered by animals in appropriate test environments, corresponding to drug-seeking behavior.2-3 In human beings nicotine is self-administered in ways that are common to more conventionally recognized drugs of abuse.' Reduction of cigarette length' or of nicotine contene'2 result in proportionately more inten-
that contained 30 mg nicotine, and we examined the efficacy of a patch in a double-blind quit-rate study of
sive smoking.
area of 30 cm2. This was backed by a nicotineimpermeable material that in turn was backed by
Physical dependence on smoking results in a withdrawal syndrome when smoking is stopped. After cessation of smoking there is a well-known strong tendency
to relapse. The association of nicotine with physical dependence has led to suggestions that strategies involving replacement of tobacco-derived nicotine with nicotine from other sources may form a useful part of smoking-cessation programs. Such replacement therapy has taken many forms. The
earliest form was intravenous administration,' but replacement therapy has more practically involved oral administration,' transdermal administration in solution,' and oral administration in the form of chewing
gum." Of these, nicotine chewing gums have been available for some years and have been used as a part of smoking cessation therapies. Recently, the use of a transdermal nicotine patch, which delivers nicotine for a 24-hour period, has been described:2 In the studies reported here, we have investigated From the Elan Corporation and the Institute of Biopharmaceutics. Received for publication July 6, 1989; accepted Oct. 30, 1989. Reprint requests: John Kelly, PhD, Institute of Biopharmaceutics, Monlcsland, Athlone, Ireland. 13/1/17849
80 smokers.
METHODS
The transdermal nicotine patches contained 30 mg nicotine in a gel matrix with a circular surface a larger-diameter fleshtone adhesive tape. This was applied to the skin. The studies described here received the approval of the ethics committees of the participating institutions (Institute of Biopharmaceutics; Blackrock Hospital, Dublin; and Clane General Hospital, Dublin), and all participants gave informed consent. In the quit-rate study the rationale of the treatment was carefully explained to all of the participants.
Pharmaeokinetic investigations. This study was an in-patient, unblinded study. Observations were made of 24 healthy male smokers between the ages 18 and 43 years (mean age, 28.4 years) who weighed between 57.5 and 81 kg (mean weight, 69.1 kg). Each study participant smoked between 42 and 280 cigarettes per week (mean, 107 cigarettes). One subject did not fulfill prestudy laboratory inclusion criteria and did not participate in the study. After a supervised nicotine-free period of 60 hours, each subject had a nicotine patch applied to the volar aspect of his forearm daily for 24 hours over a 7-day period. The site of administration was varied each day. Carbon monoxide measurements in expired air were made periodically to check abstinence from smoking. Venous blood specimens (7 ml)
331
CLIN PHARMACOL THER MARCH 1990
332 Mulligan et al.
0
4
8
12
16
20
24
28
32
36
0
4
8
12
16
20
24
28
32
36
Fig. 1. Mean plasma concentrations of nicotine (open symbols) and cotinine (closed symbols) at day 1.
Fig. 2. Mean plasma concentrations of nicotine (open symbols) and cotinine (closed symbols) at day 7.
were obtained from an antecubital vein on the arm opposite from the patch at the following times: day 1
ation (between assay) for plasma assays was 10.1% for
0, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 20 hours; days 2, 4, and 6-0 hours; days 3 and 5-0, 4, 6, and 8 hours;
and day 7-0, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 27, 30, 33, and 36 hours. Blood specimens were heparinized, and the plasma
nicotine at 7 ng/ ml, and it was 11.3% for cotinine at 70 ng/ ml (n = 27). The between-assay coefficient of variation for urine assays was 7.1% for nicotine at 35
ng/ml, and it was 8.8% for cotinine at 350 ng / ml (n = 14). Typical retention times were 2.9 minutes,
suitable aliquots of plasma (generally 1 ml) or urine
5.2 minutes, and 9.1 minutes for nicotine, anabasine, and cotinine, respectively. Clinical investigations. Eighty volunteer subjects participated in a 6-week double-blind placebocontrolled study to determine the effectiveness of the nicotine patches as an aid in cessation of smoking. Recruitment was done by newspaper advertising. Sub-
(generally 0.2 ml) were added anabasine internal
jects were white adults from 25 to 60 years of age (mean
standard and 0.25 ml 5 mol/L sodium hydroxide. These
age, 36.9 years) who weighed between 45 and 94 kg (mean weight, 65.8 kg). There were 38 men and 42
was separated and stored at
20° C until it was required
for assay for concentrations of nicotine and cotinine. Urine was collected for 24 hours on days 1 and 7. Plasma and urine concentrations of nicotine and cotinine were estimated by gas liquid chromatography. To
were extracted with 4 ml of a 9:1 vol/vol mixture of dichloromethane : ether and were shaken, centrifuged, and evaporated under vacuum at ambient temperature in tubes that contained 0.2 ml propan-2-ol. The residual alcohol was transferred to autosampler vials, and 4 ill
aliquots were chromatographed on a 10 m x 0.53 mm 50% phenylmethylsilicone capillary column (HP17, Hewlett-Packard, Brackwell, United Kingdom). The column flow rate was 12 to 14 ml per minute, with make-up gas at 25 ml per minute. The injector temperature was 240° C. The column was held at 120° to 125° C for 1 minute, raised by 20° C per minute to 145° C for 2 minutes, and raised by 12° C per minute to a final temperature of 210° C for 2 minutes. The detector was an alkali flame ionization detector (model FT9, Shimadzu Corporation, Kyoto, Japan). Recovery of nicotine was 54%, and recovery of cotinine was 72%.
The limits of detection for nicotine and cotinine were, respectively, 1 ng/ ml and 10 ng / ml in plasma and 10 ng/ ml and 50 ng / ml in urine. The coefficient of vari-
women, all of whom expressed a desire to quit smoking.
Subjects smoked an average of 25.1 cigarettes per day and had smoked for an average of 19 years. Dependence on smoking was quantified by use of the Fagerström tolerance questionnaire 13 Exclusion criteria were any
history of cardiovascular or psychiatric disease, inability to fulfill the study program with respect to visits, pregnancy, lactation, or a likelihood of pregnancy dur-
ing the study period, history of skin allergies, or evidence of dermatosis. Subjects were all found to be in good health during a medical evaluation that was performed before the study. No subject had any apparent significant chronic smoking-related illness. Subjects were equally and randomly assigned to active-patch or placebo-patch groups and were asked to quit smoking from the first day of patch use. There were no significant demographic differences between these two groups. The mean Fagerström scores were
7.40 -± 1.72 and 7.43 -± 1.71 for the placebo and
VOLUME 47 NUMBER 3
Transdermal nicotine patch 333
Table I. Plasma concentrations of nicotine and cotinine during daily patch application Nicotine
Cotinine
Day
Hourl day
Hour I study
(ng I ml)
(ng I ml)
2
o 0 4
104.06 -± 42.74 124.26 -± 35.78 130.76 41.54
3
6
3
8
4
o
5 5 5 5 6 7
0
24 48 52 54 56 72 96 100 102 104 120 144
5.92 -± 1.85
3 3
7 7 7
4
8
o
4 6 8
0 o 6 8
148 150 152 168
5.46 ± 1.79 10.34 ± 3.49 11.36 ± 4.05 13.69 ± 4.86 6.97 -± 3.29
5.48 ± 2.64 13.19 ± 5.06 13.86 ± 6.46 14.26 ± 5.39
122.17 ± 39.76 129.65 -± 40.79 136.08 -± 36.82 137.27 -± 34.06
6.35 ± 5.16
147.48 ± 41.93 149.04 ± 49.37 153.52 -± 49.84 147.61 ± 44.99 145.64 -± 38.96
14.15 ±- 5.98 13.84 -± 5.58 15.39 ±- 5.05
151.17 -± 49.05 146.91 ± 44.61 163.23 -± 48.44
6.90 ± 2.03
163.72 ± 50.65
6.25 ±_ 2.62
Data are mean values ± SD.
active-treatment groups, respectively. Each participant
was given a total of 60 patches; of those, 42 were needed for daily application. Thus 18 patches should have been returned by each subject. Patches were active and contained 30 mg nicotine or were placebo and contained no nicotine. A new patch was applied every 24 hours and the old patch was removed. The location of
the patches on the forearm was alternated each day between the right and the left arms. Each subject recorded the number of cigarettes smoked each week. Carbon monoxide analysis in expired breath was used as an independent assessment of smoking behavior. Subjects were counseled throughout the study and adhered to a behavioral modification program-either the American Lung Association program, "A Lifetime of Freedom from Smoking" or the National Cancer Institute program, "Quitting for Good." RESULTS
Pharmacokinetics. Mean plasma concentrations of nicotine and cotinine (in 23 subjects) after application of the first and last patches are shown in Figs. 1 and 2, respectively. Fig. 1 shows that significant plasma
concentrations of nicotine appeared quite quickly, with an average of 5.45 ± 3.92 (SD) ng / ml present
at 3 hours. The highest mean concentration was 12.09 ± 4.2 ng / ml at 8 hours. The average peak con-
centration was 13.84 ± 4.02 ng / ml at 9.48 -± 2.64 hours. The apparent elimination half-life (t1/2) of nico-
tine was 11.71 ± 3.33 hours, but this most likely reflected continuing absorption. Plasma concentrations of cotinine increased steadily during the 24 hours after the
first patch application, to reach a mean value of
104.06 ± 42.74 ng/ ml at 24 hours. Plasma concentrations during the daily patch application period are shown in Table I. Nicotine concentrations appeared to reach stable values quite quickly. Concentrations of cotinine (before patch application) tended to increase over the study period, although the rate of increase was slow after day 4. Before application of the last patch (day 7), mean
plasma nicotine concentrations were 6.35 ± 5.16 ng /m1 and were very comparable 24 hours later, at 6.90 -± 2.03 ng/ml. The highest mean concentration was 15.39 ± 5.05 ng / ml, which was observed at 8 hours. The average peak concentration on day 7 was 17.02 ± 6.89 ng/ ml at 8.96 -± 4.82 hours. The apparent t1/2 of nicotine was 5.60 ± 2.55 hours, shorter than that estimated after the first patch. This was because of the longer (36 hours) sampling period, which decreased the contribution of continuing absorption. Plasma concentrations of cotinine demonstrated a remarkable flat profile over the 24-hour period after administration of the last patch. Residual patch contents and material remaining on the skin after removal of the patch were conserved and analyzed for nicotine content. Nicotine absorption was estimated as the difference between the original patch content (30 mg) and the sum of the residues in the patch and on the skin. From this, the absorption of nicotine from the patch was approximately 75% (Table II). Urinary recovery of nicotine was a little under 1 mg in 24 hours on day 1, and it was approximately 1.3 mg on day 7. Cotinine recovery was similar to nicotine on day 1 but exceeded it significantly on day 7. The findings indicate that, at steady state, approximately 11% of the
CLIN PHARMACOL THER MARCH 1990
334 Mulligan et al. Table II. Pharmacokinetic summary
Day 7
Day I
AUC(0-24) (ngi nil
hr)
(hr) Cmax (ng/ml) 13 (hr-1) (apparent) t1/2 (hr) (apparent) C,,a,/C245r (ng/ml)
Estimated absorption (mg) 24-hour urinary recovery (mg)
Nicotine
Cotinine*
Nicotine
212 r.F_- 62
1498 ± 709
276 ± 82 8.96 ± 4.82
9.48 -± 2.64 13.84 -± 4.02 0.064 ± 0.020 11.71 ± 3.33
17.02 -± 6.89
2.46 ± 0.94
1.03 ± 0.07
0.98 ± 0.49
0.83 ± 0.46
0.144 ± 0.051 5.60 -± 2.55 2.56 ± 1.03 22.41 ± 1.05 1.31 ± 0.73
Cotinine
3775 ± 1119 12.17
:_i_-
7.93
183.59 ± 52.73 0.043 -± 0.017 20.26 ± 13.86 1.14 ± 0.17
2.23 ± 0.81
Data are mean values ±- SD. ALIC(0-24), Area under the concentration-time curve; tma time to reach maximum concentration; Cma, peak concentration;n, elimination constant; 42, half-life; C24 hr, concentration at 24 hours.
5tmaa, Cam, and elimination rate for cotinine were not calculable for the day I patch.
applied dose of nicotine was recovered in the urine as nicotine or cotinine. This contrasts with the extent of absorption of approximately 75% and probably reflects extensive metabolism of nicotine to products other than cotinine and elimination by other routes. Table II summarizes the pharmacokinetic findings of this study.
Smoking cessation. The chief aim of this part of the study was to evaluate the efficacy and tolerability
of the transdermal nicotine patches in a controlled smoking-cessation program. The primary evaluation of efficacy was the rate of smoking cessation as claimed by the participants and as verified by measurement of carbon monoxide concentrations in expired air. Cigarettes smoked per week were also quantified after exclusion of those who claimed to have stopped smoking
and who claimed to not have smoked during a given week. Compliance with the treatment was judged by counting returned patches. The number returned should have been 18. Eight subjects in the placebo group and four in the active group returned more than 19 patches (no significant difference). Four subjects who received placebo patches did not complete the study because of reasons unrelated to the
study. Two subjects who received active patches did not complete the study. Statistical analyses were performed on an "intent-to-treat" basis. Fig. 3 shows the number of participants who claimed to have quit smoking, analyzed week by week. There was a time-related increase in these numbers for both nicotine-treated and placebo-treated participants. However, by the end of the study, 20 subjects (50%) in the nicotine group, compared with seven subjects (17.5%) in the placebo group, claimed to have stopped smoking (Table III). The nicotine group had a significantly higher proportion
of quitters at weeks 4, 5, and 6 (chi-square test). Carbon monoxide concentrations were consistent with
these findings (Table III). Smoking cessation was significantly higher in the nicotine patch group, based on findings at week 6 of a greater proportion of subjects
with carbon monoxide values that were less than or equal to 8.0 ppm (47.5% versus 15%) or 3.0 ppm (47.5% versus 12.5%). The great majority of subjects who quit smoking in a particular week (and who were verified as quitting) had not resumed smoking when they returned for subsequent study visits. Fig. 4 illustrates this (compare with Fig. 3). It is useful to consider smoking behavior in those
subjects who said that they were still smoking at a particular visit. Recording the total number of cigarettes
smoked in a given week by the individuals who said they had smoked during that week and averaging those figures over the 6-week study period produced an average number of cigarettes smoked of 53.99 ± 44.01 (SD) in the placebo group and 35.80 ± 34.12 in the nicotine group (p < 0.01; ANOVA).
Tolerability. As described earlier, four placebotreated subjects did not complete the protocol for reasons unrelated to the study. One subject who received active patches dropped out in the first week after reporting nausea and vomiting. This was believed to be the result of gastroenteritis unrelated to the study medication. Another subject dropped out in the second week after reporting nausea, sweating, tiredness, pains in the arms, and "pins and needles." These symptoms were
considered likely to be related to the medication. There were no additional study dropouts. A total of 15
placebo-treated subjects reported unwanted effects during any one week of the study, compared with 24 subjects who received the nicotine-containing patch. Ten subjects in each group reported nonspecific irrita-
tion caused by either the gel or the adhesive. Five placebo-treated and 11 nicotine-treated subjects reported erythema or a rash. These symptoms were
VOLUME 47 NUMBER 3
Transdermal nicotine patch
25
25
20
20
15
15
10
10
5
5
o
' WEEK 1 WEEK 3 WEEK 5 WEEK 2 WEEK 4 WEEK 6
Fig. 3. Number of subjects who claimed to quit smoking. Solid bars, Nicotine; hatched bars, placebo.
o
335
VISIT 4 VISIT 6 VISIT 3 VISIT 5 VISIT 7
VISTT 2
Fig. 4. Quit rate based on subjects who quit and remained abstinent for the remainder of the study. Solid bars, Nicotine; hatched bars, placebo.
transient and disappeared after the patch was removed
(0.1 > p > 0.05; chi-square test). Two placebotreated and 13 nicotine-treated subjects reported effects
Table III. Comparison of quit claims and carbon monoxide levels in expired air, week 6
that were not skin-related (p < 0.01). In the placebo group these were reported as edema in one subject and
as a "pins and needles" sensation in another. In the nicotine group, gastrointestinal discomfort was reported
by three subjects; sweating, difficulty sleeping, and a "pins and needles" sensation were reported by two subjects each. Headache, tiredness, "heavy arm," dizziness, paresthesia, pain at the patch site, and nightmares were reported by one subject each. One subject reported chest pain with no electrocardiographic features, and it
was not possible to give an opinion on whether or not this was related to the treatment. DISCUSSION Application of a single transdermal patch that con-
tained 30 mg nicotine resulted in plasma nicotine 1 hour after application (1.03 ± 1.53 ng /m1) and that increased steadily to
No. of subjects quitting (claimed) Supported by CO levels S8.0 ppm Supported by CO
levels s3.0 ppm
Placebo
Nicotine
7
20
Chi-square test 9.45
(p
