Original Article
A Double-Blind Trial of a 16-Hour Transdermal Nicotine Patch in Smoking Cessation
N Engl J Med 1991; 325:311-315August 1, 1991
- Abstract
- Abstract
Background.
The use of nicotine chewing gum combined with psychological support improves the success rate in quitting smoking. We studied the safety and efficacy of a transdermal nicotine patch in smoking cessation.
Methods.
We conducted a double-blind randomized study comparing the effects of a 16-hour nicotine patch (15±3.5 mg of nicotine in 16 hours) with those of a placebo patch. Of the 289 smokers (207 women and 82 men) enrolled in the study, 145 were treated with nicotine patches and 144 with placebo patches for 16 weeks.
Results.
Rates of sustained abstinence were significantly better with active treatment than with placebo: 53, 41, 24, and 17 percent of those in the nicotine-patch group were abstinent after 6,12, 26, and 52 weeks, respectively, as compared with 17, 10, 5, and 4 percent of those in the placebo-patch group (P<0.0001). Only two subjects with the nicotine patch and one with the placebo patch had to withdraw from the study because of side effects.
Conclusions.
The nicotine skin patch proved to be safe and effective, as demonstrated by a higher rate of abstinence than with placebo. However, the absolute rate of abstinence after one year was only 17 percent, which is lower than the rate in studies that have combined the use of nicotine chewing gum with behavioral therapy. (N Engl J Med 1991;325:311–5.)
Media in This Article
Figure 1
Time to Relapse in 289 Smokers Using Nicotine Skin Patches or Placebo PatchesFigure 2
Mean (±SD) Daily Craving Score during the First Seven Days after Quitting Smoking in 289 Subjects Using Nicotine Skin Patches (N = 145) or Placebo Patches (N = 144)Article Activity
- Article
TO date, the use of nicotine chewing gum combined with psychological support during the initial months of quitting smoking is the only treatment that has been shown to increase long-term rates of quitting, as compared with placebo.1 , 2 Of six trials that have assessed the efficacy of a 24-hour transdermal nicotine patch, a significant increase in short-term cessation was found in five.3 4 5 6 7 8 There are a number of important differences between nicotine chewing gum and the nicotine patch. The gum is often used as the smoker wishes, and chewing may itself be of therapeutic value, even if it is associated with some adverse effects.9 , 10 In contrast, the patch delivers a fixed dose of nicotine, and it is not possible to set the dose oneself or use extra nicotine if desired. One of the principal advantages of the patch is that it may improve compliance, as compared with the gum.
The purpose of this double-blind clinical study was to examine the safety and efficacy of a 16-hour nicotine patch in smoking cessation when used for up to 16 weeks. A 16-hour patch was chosen to cover the period during which a smoker normally smokes.
Methods
Subjects and Randomization
Telephone Interview
Volunteers were recruited through advertisement in a local newspaper. Approximately 500 subjects contacted us, and their eligibility was prospectively screened by telephone. Smokers who were 20 years of age or older, had smoked at least 10 cigarettes a day for at least 3 years, and were motivated to stop smoking completely were eligible.
Exclusion criteria were the presence of severe or symptomatic cardiovascular disease, pregnancy or breast-feeding, regular use of psychotropic drugs, alcohol or drug abuse, use of smokeless tobacco, or chronic dermatologic disorders such as psoriasis, urticaria, or chronic dermatitis. The first 310 eligible subjects were accepted into the study, but only 289 (93 percent) attended the first session. A brochure containing advice on smoking cessation, a questionnaire on smoking habits, and measures of dependence on smoking were mailed to potential subjects. The Fagerstrom questionnaire11 and the Horn—Russell rating scale12 were used to measure the subjects' degree of dependence on nicotine. A medical history was also recorded.
Treatment Assignment
The subjects were sequentially and randomly assigned to either active treatment or placebo according to a computer-generated randomization code. Patches were packaged and labeled with consecutive numbers. One hundred forty-five subjects were assigned to receive the nicotine patch, and 144 to receive the placebo patch.
Treatment
Clinic Visits
The target date for smoking cessation was that of the first visit to the clinic. Seven visits were scheduled for the 52-week study period (at the outset and after weeks 1, 3, 6, 12, 26, and 52). Each visit lasted approximately 20 to 60 minutes, and each subject thus spent a total of 3 to 7 hours in the clinic during the year. The initial visit took place on August 14 to 18, 1989, when groups of approximately 15 subjects were seen hourly from 2 p.m. to 8 p.m. No group support was administered, except for a five-minute introductory presentation on smoking cessation given by the same physician at each session. The same two nurses conducted the assessments (recording weight, taking a saliva sample, and measuring carbon monoxide in end-expiratory air) and delivered the patches at each visit. During each visit each subject was seen by one of the investigators for 5 to 10 minutes. Most of the time was devoted to the collection of data, but a few minutes were used to give advice about smoking cessation and to explain how the patch worked and how it should be used. The first patch was then placed on the skin, and the subject was told to stop smoking immediately.
The Patch
The treatment consisted of daily use of a nicotine or placebo skin patch. The nicotine patch was 30 cm2 in size, with a nicotine content of 0.83 mg per square centimeter; it released a mean (±SD) of 15±3.5 mg of nicotine over a period of 16 hours. The patch was manufactured by Cygnus Research (Redwood City, Calif.) and supplied by Kabi Pharmacia Therapeutics (Helsingborg, Sweden). The maximal blood nicotine level of 14.2 ±3.9 ng per milliliter was attained after 5 to 10 hours. After 16 and 24 hours, the nicotine concentrations were 8.9±1.8 ng per milliliter and 2.5±0.8 ng per milliliter, respectively.
A new patch was applied in the morning to the medial region of the arm or the upper gluteal region and was removed at bedtime. To reduce local skin irritation, the patch was placed on the contralateral site the next day. At each session the subjects were supplied with sufficient patches to last until the next visit.
The placebo patches were identical to the active patches in appearance, packaging, and labeling, but contained no nicotine.
The subjects were told to use the patches for 12 weeks, and they were then offered 20 patches of 20 cm2 and 20 patches of 10 cm2 to reduce the dosage over a 4-week period, if they wished. Unused patches were then collected. Thereafter, no additional patches were available.
Assessments
Using a carbon monoxide analyzer (Bedfont Monitor, Sitting-bourne, United Kingdom), we measured carbon monoxide in end-expiratory air at each visit, after the subjects had held their breath for at least 10 seconds. Levels of carbon monoxide of 10 ppm or less were considered to indicate a nonsmoker.13 Subjects were weighed on the same scales at each visit.
A sample of at least 3 ml of unstimulated saliva was collected in a plastic cup at each afternoon visit and was frozen at — 20°C within one hour. The saliva samples were analyzed for cotinine by gas chromatography.14 Salivary cotinine levels were measured after 6 and 12 months to confirm abstinence; a concentration of more than 70 ng per milliliter (corresponding to a plasma level of 50 ng per milliliter) was considered to indicate that the subject was a smoker. During the first six weeks of the study, each subject was requested to record daily the number of cigarettes smoked, any adverse reactions, and any craving for cigarettes, along with eight other withdrawal symptoms,15 on a 100-mm visual-analogue scale. A base-line score was obtained at the first visit to the clinic. At each session the subjects were questioned about any skin irritation. The severity and duration of the skin symptoms were noted, and systemic side effects were also recorded.
Measures of Outcome
All 289 subjects who attended the first session were included in the assessment of outcome. Smoking less than 15 percent of one's previous consumption of cigarettes was allowed during the first week, although all subjects were advised to cease smoking completely from the start. Success was defined as a statement that smoking had ceased, verified by a concentration of carbon monoxide of 10 ppm or less in expired air at all sessions after the first week. Throughout the study, one lapse was allowed between every two visits. A lapse was defined as unlimited smoking for 24 hours, followed by up to five days of smoking less than 15 percent of the number of cigarettes smoked on entry. A more conservative definition of success was also used; this required a statement of complete abstinence at all visits, with no lapses. Subjects who did not return to the clinic or were lost to follow-up were assumed to be smokers.
A blinded interim analysis of the success rate was performed after 12 weeks. After the visit at the end of week 26 the code was broken.
The study was conducted in accordance with the Declaration of Helsinki. The protocol was approved by the ethics committee in Copenhagen, and informed consent was obtained from all subjects.
Statistical Analysis
We calculated the 95 percent confidence intervals for differences in outcome between the nicotine-patch and placebo-patch groups using normal approximations. Nonparametric tests (Pearson's chi-square test and the Mann—Whitney rank-sum test) were used in all comparisons. All P values are two-tailed. The generalized Wilcoxon test (Breslow test) was used in the life-table analysis.
Results
Population
The study population consisted of 289 subjects, 207 women and 82 men, 22 to 77 years old. The base-line characteristics of the subjects are shown in Table 1Table 1
Base-Line Characteristics of the 289 Study Subjects.. The values for all variables were very similar in the two groups. The 97 subjects who were not healthy had chronic obstructive lung disease (38), ischemic heart disease (2), hypertension (15), peripheral vascular disease (15), diabetes (2), or allergic disorders (44). Some of them had more than one disease.Subjects who failed to keep their appointments were contacted by telephone or letter. In most cases, the subjects had started to smoke again, and they were withdrawn from the study. Three subjects were completely lost to follow-up after 26 weeks. During the one-year study period 3 percent of the subjects who claimed that they did not smoke had a carbon monoxide level of more than 10 ppm, and they were therefore classified as smokers.
Outcome
The rates of sustained success (with lapses allowed) in the nicotine-patch and placebo-patch groups demonstrated a higher rate of abstinence with the active treatment (P<0.0001) (Fig. 1Figure 1
Time to Relapse in 289 Smokers Using Nicotine Skin Patches or Placebo Patches). The success rate after six weeks was 53 percent in the nicotine-patch group and 17 percent in the placebo-patch group (P<0.001). After 12 weeks the success rate was 41 percent in the nicotine group and 10 percent in the placebo group (P<0.001). After 52 weeks, 17 percent of the subjects in the nicotine group and 4 percent of those in the placebo group continued to abstain from smoking (P<0.001). The 95 percent confidence intervals for the differences in outcome after 6, 12, 26, and 52 weeks were 26 to 47 percent, 22 to 40 percent, 12 to 27 percent, and 6 to 19 percent, respectively.The more conservative outcome measure (i.e., total abstention for 12 and 52 weeks) gave success rates of 26 and 11 percent in the nicotine-patch group and 3 and 2 percent in the placebo-patch group (P<0.001).
Fifty-eight percent of the subjects with the placebo patch and 78 percent of those with the nicotine patch correctly guessed which treatment they had received. However, there was no significant difference in outcome between those who identified the treatment correctly and those who did not.
Compliance
The self-reported use of the patch every single day was very similar in the two groups through week 1 (80 percent in the nicotine group and 81 percent in the placebo group), but was lower in the placebo group at week 3 (66 vs. 36 percent) and week 6 (48 vs. 16 percent) (P<0.01). In the nicotine group daily use of the patch through week 12 with only one to seven missing days was reported by 40 percent of the subjects, as compared with 10 percent in the placebo group. During the first week, the patch was applied for 15±1.5 hours per day.
Side Effects
There were few systemic side effects. Only one subject using a nicotine patch (0.7 percent) had to stop treatment permanently after four days because of nausea. During the treatment period 31 of 145 subjects in the nicotine group (21 percent) reported one or more side effects, as compared with 21 of 144 subjects in the placebo group ( 15 percent) during the treatment period (P not significant). The most frequent symptoms with the nicotine as compared with the placebo patch were headache (4 vs. 4 percent), nausea (4 vs. 1 percent), and vertigo (4 vs. 0 percent). Except in the one subject already described, none of the reported effects were serious enough to warrant consideration as a health hazard or the withdrawal of treatment.
Transient mild itching under the patch lasting for 15 to 30 minutes after application was reported by 14 percent of the subjects in the nicotine group and 1 percent of those in the placebo group after the first week (P<0.001 ). At each visit, 4.5 to 7.3 percent of the remaining subjects in the nicotine group reported erythema, as compared with 2.3 to 6.7 percent of those in the placebo group (P not significant). Acute eczema persisting for several days in the area of the patch caused 1.4 percent of the subjects in the nicotine group and 0.7 percent of those in the placebo group to stop using the patch.
Changes in Weight
The median weight gain after 12 and 26 weeks was 2.7 kg (range, —3.0 to +11.8) and 3.8 kg (range, —3.0 to +10.0), respectively, in the nicotine group and 3.0 kg (range, —0.8 to +6.5) and 2.5 kg (range, —0.8 to + 6.5) in the placebo group (P not significant). The gain in weight was calculated only in subjects who abstained from smoking.
Withdrawal Symptoms
One hundred ninety-seven subjects returned diaries after one week. For the 142 who remained abstinent, the craving for tobacco was moderate in both study groups and tended to be lower in the nicotine group than in the placebo group (Fig. 2Figure 2
Mean (±SD) Daily Craving Score during the First Seven Days after Quitting Smoking in 289 Subjects Using Nicotine Skin Patches (N = 145) or Placebo Patches (N = 144)). The craving score then declined in both groups up to day 14. The score was then similar and remained stable in both groups up to week 6. The scores for the remaining eight withdrawal symptoms were very low, and the difference up to week 6 was not statistically significant. However, there was often inaccuracy in scoring when the scores for withdrawal symptoms were low — i.e., between 0 and 15 mm. Furthermore, because of dropouts during the first six weeks, the populations at weeks 1 and 6 were not comparable. Statistical analysis is therefore not valid.Nicotine Substitution
The degree of nicotine substitution attained with the patch was determined by measuring salivary cotinine, the main metabolite of nicotine, since this seems to be a reliable measure of nicotine intake.16 The mean degree of cotinine substitution was 56±27 percent (198±92 ng per milliliter) of the smoking level after one week in the 51 abstinent subjects who used the nicotine patch every day. In 29 subjects still using the patch, the degree of substitution was 45 percent after 6 weeks and 43 percent after 12 weeks.
In 16 subjects (11 percent) the salivary cotinine concentration was higher (mean, 38 percent; range, 2 to 95) after using the nicotine patch for one week than at the start. Thirteen of these subjects continued to smoke while using the patch. None of the 16 reported any symptoms consistent with an overdose of nicotine.
Discussion
In this study, the proportion of successful abstainers from smoking was higher for 12 months among the subjects who received daily treatment with a 16-hour nicotine patch for 12 to 16 weeks than among those who received placebo. The result after one year — 17 percent of the nicotine-patch group continued to abstain — may be regarded as poor if compared with the results of pharmacologic treatments of other medical diseases. However, if the result is compared with those of treatment of alcoholism and opiate addiction, the relapse rates and results are in the same range.17 18 19
In placebo-controlled studies combining the use of nicotine chewing gum with behavioral therapy, the long-term outcome has been better than in this study (i.e., 6- and 12-month rates of abstinence of 29 to 49 percent in the combined-treatment group).1 The rates of quitting associated with the use of nicotine gum in placebo-controlled trials performed in medical settings are lower and often differ insignificantly from the rates with placebo. These latter trials may be more comparable with ours.20 In seven studies, the one-year success rate of 3 to 25 percent (mean, 11) tends to be lower than the 17 percent in our study, but is in the same range. It should be noted, however, that our study was performed by an investigative team experienced in smoking-cessation studies and that assessments were carried out along with regular follow-up. Both factors might have favorably affected the outcome. Surprisingly high success rates were reported by Abelin et al. in their nicotine-patch study performed in general-practice settings with a minimum of support for the subjects and only four visits in three months.3 Comparing the results of the two studies is difficult, however, because of the many methodologic and demographic differences between them.
The present nicotine patch seemed to be acceptable to the majority of our study subjects. The local side effects were usually mild, with erythema in the patch area, and only 1.4 percent of the subjects stopped using the nicotine patch because of localized acute eczema.
Nicotine overdosing may have occurred in 11 percent of the subjects, who had higher salivary cotinine concentrations when using the patch than when smoking. Although no symptoms related to possible nicotine overdosing were reported in our study, harmful effects might occur in susceptible subjects — i.e., those with cardiovascular disease or cardiac arrhythmias.
The blinding of this study was imperfect, in that 67 percent correctly identified their treatment. Similarly, in the study by Abelin et al., 75 percent of the subjects guessed correctly which treatment they had received.3 This does not necessarily interfere with the validity of the results, however.21 The degree of nicotine substitution after the subjects had used the nicotine patch for one week was approximately 50 percent of the smoking level. Nicotine gum chewed as desired for 1 week9 and 12 weeks22 produced a degree of substitution of approximately one third (2-mg gum) and two thirds (4-mg gum) of the smoking level, respectively. The principal difference between the patch and the gum is the potential to set one's own intake of nicotine. Users of the patch cannot increase the nicotine concentration in the blood in order to decrease craving, and they cannot prevent overdosing. Smokers with low smoking concentrations of nicotine would have a higher degree of substitution with the patch than with the gum, whereas smokers with high smoking levels of nicotine would probably have a higher degree of compensation with the 4-mg gum.9 With the patch, however, subjects do not need to acquire any special skills, such as proper chewing technique. With respect to compliance, 40 to 55 percent of the subjects with a nicotine patch were still using it after 12 weeks, as compared with 54 percent of those receiving nicotine gum in a previous study.9 However, we had to devote much more time and effort to convincing the subjects to use the gum than to convincing them to use the patch.
Supported in part by a grant from Kabi Pharmacia Therapeutics.
Dr. Tønnesen has been a consultant for Kabi Pharmacia Therapeutics, developer of the nicotine patch, and has received grants from the company. Dr. Säwe is medical director of Kabi Pharmacia Therapeutics.
Source Information
From the Department of Pulmonary Medicine, Bispebjerg Hospital, Copenhagen, Denmark (P.T., J.N., K.S.), and Kabi Pharmacia Therapeutics, Helsingborg, Sweden (U.S.). Address reprint requests to Dr. Tønnesen at Rudolph Berghs Gade 20, DK-2100 Copenhagen ø, Denmark.
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